TW202038945A - Combination therapy - Google Patents

Abstract

Provided herein are methods of treating diseases, such as cancer, using a combination therapy. In certain embodiments, the methods comprise administering an effective amount of a phosphoinositide-3-kinase (PI3K) inhibitor and an effective amount of a bispecific antibody to a patient.

Description

Combination therapy

This article provides methods for treating diseases using combination therapies for the treatment of proliferative diseases, including cancer, autoimmune diseases, and inflammatory diseases. In certain embodiments, the methods include administering to the patient an effective amount of a phosphoinositide-3-kinase (PI3K) inhibitor and an effective amount of a T cell activating bispecific antigen binding molecule.

Phosphoinositide-3-kinase (PI3K) plays various roles in normal tissue physiology, among which p110α is in cancer growth, p110β is in thrombosis mediated by integrin α _Π β _3, and p110γ is in inflammation and rheumatoid arthritis. It has a specific role in other chronic inflammation states. PI3K inhibitors have therapeutic potential in the treatment of various proliferative diseases (including cancer).

Bispecific T cell adaptor proteins are a class of artificial bispecific monoclonal antibodies, which cause T cells to exert cytotoxic activity on tumor cells. These bispecific antibodies have therapeutic potential as anti-cancer drugs.

式(I)， 或其對映體、對映體之混合物、兩種或更多種非對映體之混合物或同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥； 其中： X、Y及Z各獨立地係N或CR^X ，條件為X、Y及Z中之至少兩者係氮原子；其中R^X 係氫或C_1-6 烷基； R¹ 及R² 各獨立地係(a)氫、氰基、鹵基或硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ；其中各R^1a 、R^1b 、R^1c 及R^1d 獨立地係(i)氫；(ii) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(iii) R^1b 及R^1c 與其等結合之N原子一起形成雜環基； R³ 及R⁴ 各獨立地係氫或C_1-6 烷基；或R³ 及R⁴ 連接在一起以形成鍵，C_1-6 伸烷基、C_1-6 伸雜烷基、C_2-6 伸烯基或C_2-6 伸雜烯基； R^5a 係(a)氫或鹵基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ； R^5b 係(a)鹵基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ； R^5c 係-(CR^5f R^5g )_n -(C_6-14 芳基)或-(CR^5f R^5g )_n -雜芳基； R^5d 及R^5e 各獨立地係(a)氫或鹵基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ； R^5f 及R^5g 各獨立地係(a)氫或鹵基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c ；或-S(O)₂ NR^1b R^1c ；或(d)當出現一次R^5f 及出現一次R^5g 係結合至相同碳原子時，則該R^5f 及R^5g 與其等結合之碳原子一起形成C_3-10 環烷基或雜環基； R⁶ 係氫、C_1-6 烷基、-S-C_1-6 烷基、-S(O)-C_1-6 烷基或-SO₂ -C_1-6 烷基； m係0或1；及 n係0、1、2、3或4； 其中R¹ 、R² 、R³ 、R⁴ 、R⁶ 、R^X 、R^1a 、R^1b 、R^1c 、R^1d 、R^5a 、R^5b 、R^5c 、R^5d 、R^5e 、R^5f 及R^5g 中之各烷基、伸烷基、伸雜烷基、烯基、伸烯基、伸雜烯基、炔基、環烷基、芳基、芳烷基、雜芳基及雜環基係視需要經一或多個，在一項實施例中，一、二、三、四或五個取代基Q取代，其中各取代基Q係獨立地選自(a)側氧基、氰基、鹵基及硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基及雜環基，其等中之各者係視需要進一步經一、二、三或四個取代基Q^a 取代；及(c) -C(O)R^a 、-C(O)OR^a 、-C(O)NR^b R^c 、-C(NR^a )NR^b R^c 、-OR^a 、-OC(O)R^a 、-OC(O)OR^a 、-OC(O)NR^b R^c 、-OC(=NR^a )NR^b R^c 、-OS(O)R^a 、-OS(O)₂ R^a 、-OS(O)NR^b R^c 、-OS(O)₂ NR^b R^c 、-NR^b R^c 、-NR^a C(O)R^d 、-NR^a C(O)OR^d 、-NR^a C(O)NR^b R^c 、-NR^a C(=NR^d )NR^b R^c 、-NR^a S(O)R^d 、-NR^a S(O)₂ R^d 、-NR^a S(O)NR^b R^c 、-NR^a S(O)₂ NR^b R^c 、-SR^a 、-S(O)R^a 、-S(O)₂ R^a 、-S(O)NR^b R^c 及-S(O)₂ NR^b R^c ，其中各R^a 、R^b 、R^c 及R^d 獨立地係(i)氫；(ii) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基，其等中之各者係視需要進一步經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代；或(iii) R^b 及R^c 與其等結合之N原子一起形成雜環基，其係視需要進一步經一、二、三或四個取代基Q^a 取代； 其中各Q^a 係獨立地選自由以下組成之群：(a)側氧基、氰基、鹵基及硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基及雜環基；及(c) -C(O)R^e 、-C(O)OR^e 、-C(O)NR^f R^g 、-C(NR^e )NR^f R^g 、-OR^e 、-OC(O)R^e 、-OC(O)OR^e 、-OC(O)NR^f R^g 、-OC(=NR^e )NR^f R^g 、-OS(O)R^e 、-OS(O)₂ R^e 、-OS(O)NR^f R^g 、-OS(O)₂ NR^f R^g 、-NR^f R^g 、-NR^e C(O)R^h 、-NR^e C(O)OR^h 、-NR^e C(O)NR^f R^g 、-NR^e C(=NR^h )NR^f R^g 、-NR^e S(O)R^h 、-NR^e S(O)₂ R^h 、-NR^e S(O)NR^f R^g 、-NR^e S(O)₂ NR^f R^g 、-SR^e 、-S(O)R^e 、-S(O)₂ R^e 、-S(O)NR^f R^g 及-S(O)₂ NR^f R^g ；其中各R^e 、R^f 、R^g 及R^h 獨立地係(i)氫；(ii) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(iii) R^f 及R^g 與其等結合之N原子一起形成雜環基； 其中彼此相鄰之兩個取代基Q視需要形成C_3-10 環烯基、C_6-14 芳基、雜芳基或雜環基，其等各視需要經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代；及 b)     T細胞活化性雙特異性抗原結合分子。A method for treating or preventing cancer is disclosed herein, which includes administering an effective amount of the following to an individual in need: a) A compound of formula (I):

Formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrugs; wherein: X, Y, and Z are each independently N or CR ^X , provided that at least two of X, Y, and Z are nitrogen atoms; wherein R ^X is hydrogen or C _1-6 alkyl; R ¹ And R ^{2 are} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O )NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC( =NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c ,- NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a ,- S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; each of R ^1a , R ^1b , R ^1c and R ^1d Independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _{7- 15} Aralkyl, heteroaryl or heterocyclic group; or (iii) R ^1b and R ^1c together with the N atom to which they are bonded form a heterocyclic group; R ³ and R ^{4 are} each independently hydrogen or C _1-6 alkane Group; or R ³ and R ^{4 are} connected together to form a bond, C _1-6 alkylene, C _1-6 heteroalkylene, C _2-6 alkenylene or C _2-6 heteroalkenylene; R ^5a is (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 Aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O) NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(= NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5b is (a) halo; (b) C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; Or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O) R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O )NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5c series -(CR ^5f R ^5g ) _n -(C _{6-1 4} aryl) or -(CR ^5f R ^5g ) _n -heteroaryl; R ^5d and R ^{5e are} each independently (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkene Group, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c ,- NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S (O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5f and R ^{5g are} each independently (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S (O)R ^1d 、-NR ^1a S( O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c ; or -S(O) ₂ NR ^1b R ^1c ; or (d) when R ^5f occurs once and R ^5g is bonded to the same carbon atom once, then the R ^5f And R ^5g together with the carbon atom to which it is bound to form a C _3-10 cycloalkyl or heterocyclic group; R ⁶ is hydrogen, C _1-6 alkyl, -SC _1-6 alkyl, -S(O)-C _1-6 alkyl or -SO ₂ -C _1-6 alkyl; m is 0 or 1; and n is 0, ¹ , ² , 3 or 4; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^X , R ^1a , R ^1b , R ^1c , R ^1d , R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f and R ^5g each of the alkyl, alkylene, and heteroalkane Group, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic group may be optionally selected by one or more groups. In one embodiment , One, two, three, four or five substituents Q substituted, wherein each substituent Q is independently selected from (a) pendant oxy, cyano, halo and nitro; (b) C _1-6 alkane Group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-15 aralkyl group, heteroaryl group and heterocyclic group, among others Each of them is further substituted with one, two, three or four substituents Q ^a as necessary; and (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(=NR ^a ) NR ^b R ^c , -OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c ,- NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S( O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O) R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c and -S(O) ₂ NR ^b R ^c , where each R ^a , R ^b , R ^c and R ^{d are} independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _{6 -14} aryl group, C _7-15 aralkyl group, heteroaryl group or heterocyclic group, each of which is further subjected to one or more as necessary. In one embodiment, one, two, three or Four substituents Q ^{a are} substituted; or (iii) R ^b and R ^c together with the N atoms to which they are bonded form a heterocyclic group, which is further substituted with one, two, three or four substituents Q ^a as necessary; Each Q ^a is independently selected from the group consisting of (a) pendant oxy, cyano, halo and nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl and heterocyclic group; and (c) -C(O)R ^e , -C(O )OR ^e , -C(O)NR ^f R ^g , -C(NR ^e )NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O) NR ^f R ^g , -OC(=NR ^e )NR ^f R ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^h , -NR ^e C(O)NR ^f R ^g , -NR ^e C(=NR ^h )NR ^f R ^g , -NR ^e S(O)R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^{f R g, -SR e, -S (} O) R e, -S (O) 2 R e, -S (O) NR f R g , and ^{_{-S (O) 2 NR f R}} g; wherein each R ^e, R ^f , R ^g and R ^{h are} independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _{6 -14} aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (iii) R ^f and R ^g together with the N atom to which they are bonded to form a heterocyclic group; wherein two adjacent to each other are substituted The group Q optionally forms a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a heteroaryl group or a heterocyclic group, each of which is optionally combined with one or more groups. In one embodiment, one, two, Three or four substituents Q ^a substitution; and b) T cell activating bispecific antigen binding molecule.

Disclosed herein is a method for treating or preventing cancer, which includes administering an effective amount of a compound of formula (I), or its enantiomer, a mixture of enantiomers, or two or more non-pairs to an individual in need Mixtures of enantiomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof; and bispecific antibodies or bispecific antigen binding molecules.

In some embodiments, R ^5b is (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _{6- 14} aryl, C _7-15 aralkyl or heteroaryl; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c ,- OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -S(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O) R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d ,- NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S( O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c .

In some embodiments, R ^5a and R ^{5b are} each independently (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O )NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC( =NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c ,- NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a ,- S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c .

In some embodiments, each of R ^5a and R ^{5b is a} methyl group, which is optionally substituted with one, two, or three halo groups. In some embodiments, n is 1. In some embodiments, R ^5f and R ^{5g are} each hydrogen. In some embodiments, n is zero. In some embodiments, m is zero.

式(XI)， 或其對映體、對映體之混合物、兩種或更多種非對映體之混合物或同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥； 其中： R^7a 、R^7b 、R^7c 、R^7d 及R^7e 各獨立地係(a)氫、氰基、鹵基或硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基，其等中之各者係視需要經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代；或(c) -C(O)R^a 、-C(O)OR^a 、-C(O)NR^b R^c 、-C(NR^a )NR^b R^c 、-OR^a 、-OC(O)R^a 、-OC(O)OR^a 、-OC(O)NR^b R^c 、-OC(=NR^a )NR^b R^c 、-OS(O)R^a 、-OS(O)₂ R^a 、-OS(O)NR^b R^c 、-OS(O)₂ NR^b R^c 、-NR^b R^c 、-NR^a C(O)R^d 、-NR^a C(O)OR^d 、-NR^a C(O)NR^b R^c 、-NR^a C(=NR^d )NR^b R^c 、-NR^a S(O)R^d 、-NR^a S(O)₂ R^d 、-NR^a S(O)NR^b R^c 、-NR^a S(O)₂ NR^b R^c 、-SR^a 、-S(O)R^a 、-S(O)₂ R^a 、-S(O)NR^b R^c 或-S(O)₂ NR^b R^c ；或彼此相鄰之R^7a 、R^7b 、R^7c 、R^7d 及R^7e 中之兩者形成C_3-10 環烯基、C_6-14 芳基、雜芳基或雜環基，其等各視需要經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代。In some embodiments, the compound of formula (I) is a compound of formula (XI):

Formula (XI), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrugs; wherein: R ^7a , R ^7b , R ^7c , R ^7d and R ^{7e are} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group, each of which is based on Need to be substituted by one or more, in one embodiment, one, two, three or four substituents Q ^a ; or (c) -C(O)R ^a , -C(O)OR ^a , -C (O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c ,- OC(=NR ^a )NR ^b R ^c , -OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c ,- NR ^b R ^c , -NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c or -S(O) ₂ NR ^b R ^c ; or adjacent to each other R ^7a , R ^7b , ^{Two of} R ^7c , R ^7d and R ^7e form a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a heteroaryl group, or a heterocyclic group, each of which is optionally combined with one or more groups. In the embodiments, one, two, three or four substituents Q ^{a are} substituted.

化合物A35， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A35:

Compound A35, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

化合物A36， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A36:

Compound A36, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

化合物A68， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A68:

Compound A68, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

化合物A70， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A70:

Compound A70, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

化合物A37， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A37:

Compound A37, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

化合物A38， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A38:

Compound A38, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

化合物A41， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A41:

Compound A41, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

化合物A42， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A42:

Compound A42, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

化合物A43， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A43:

Compound A43, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

化合物A44， 或其同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。In some embodiments, the compound of formula (I) is compound A44:

Compound A44, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In some embodiments, the T cell activating bispecific antigen binding molecule comprises: The first Fab molecule that specifically binds to the first antigen; and A second Fab molecule that specifically binds to a second antigen, wherein the first antigen is an activating T cell antigen and the second antigen is a target cell antigen.

In some embodiments, the T cell antigen is CD3. In some embodiments, the T cell activating bispecific antigen binding molecule comprises a complete Fc region that can bind to cell surface receptors (Fc receptors).

In some embodiments, the target cell antigen is CD19, CD20, CD13, CD30, CD33, or CD40.

In some embodiments, the T cell activating bispecific antigen-binding molecule is obinutuzumab, mosunetuzumab, selicrelumab, brinner Blinatumomab, AMV564, AFM13, REGN-1979, GEN-3013 or pasotuxizumab.

In some embodiments, the cancer under treatment is a hematological malignancy. In some embodiments, the cancer under treatment is a B cell malignancy. In some embodiments, the cancer being treated is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia ( CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL) (including relapsed/refractory FL) , Diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B cells Lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B cell lymphoma (PMBL), immunoblast large cell Lymphoma, precursor B lymphoblastic lymphoma, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasma cell tumor, mediastinal (thymic) large B cell lymphoma Tumor, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphoma-like granulomatous disease. In some embodiments, the cancer under treatment is chronic lymphocytic leukemia or non-Hodgkin's lymphoma. In some embodiments, the cancer under treatment is non-Hodgkin's lymphoma and the non-Hodgkin's lymphoma is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer under treatment is relapsed and refractory diffuse large B-cell lymphoma (r/r DLBCL). In some embodiments, the diffuse large B cell lymphoma is activated B cell diffuse large B cell lymphoma (ABC-DLBCL) or germinal center B cell diffuse large B cell lymphoma (GCB-DLBCL) . In some embodiments, the cancer is follicular lymphoma (FL).

In some embodiments, the compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof, and T cell activating bispecific antigens The binding molecules are administered simultaneously, approximately simultaneously, or sequentially in any order.

In some embodiments, the compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof, and T cell activating bispecific antigens The binding molecules are administered simultaneously or approximately simultaneously.

In some embodiments, the compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof, and T cell activating bispecific antigens The binding molecules are administered sequentially.

In some embodiments, the compound of formula (I), or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or its isotope variant system is used for administering T cell activation bispecific The sex antigen-binding molecule was previously administered.

In some embodiments, the compound of formula (I), or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or its isotope variant system is used for administering T cell activation bispecific The sex antigen-binding molecule is then administered.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof , Solvates, hydrates or prodrugs are formulated for oral administration.

In some embodiments, about 30 mg, about 60 mg, about 120 mg, or about 180 mg of the compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more of them are administered to the individual Mixtures of diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof , Solvates, hydrates or prodrugs are formulated into tablets or capsules.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof , Solvates, hydrates or prodrugs are formulated together with T cell activating bispecific antigen binding molecules.

In some embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to an individual; or a pharmaceutically Acceptable salts, solvates, hydrates or prodrugs for at least a 28-day cycle.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to an individual; or a pharmaceutically Two 28-day cycles of acceptable salts, solvates, hydrates or prodrugs.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to the individual daily on a continuous schedule ; Or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs, until disease progression or intolerable toxicity appears.

In some embodiments, the cycle is a 28-day cycle.

In some embodiments, the method includes at least three cycles, among them: (i) The first two cycles include a continuous daily dosing schedule (CS), which includes administering the compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more to the individual once a day A mixture of diastereomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for two cycles; and (ii) Subsequent cycles include an intermittent dosing schedule (IS), which includes the administration of a compound of formula (I), or its enantiomers, mixtures of enantiomers, two or Mixtures of more diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof only for the previous 7 days.

In some embodiments, the CS and IS cycles are each a 28-day cycle.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or its isotope variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs, until disease progression appears or the incidence of at least one toxicity is reduced.

In some embodiments, after disease progression occurs according to the intermittent dosing schedule (IS), the compound of formula (I), or its enantiomers, pairs are administered to the individual daily according to the continuous dosing schedule (CS) Mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to an individual daily; or a medicine thereof The acceptable salt, solvate, hydrate or prodrug.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or a mixture of two or more diastereomers is administered to the individual once a day, twice a day, or three times a day Its isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to the individual once a day; or A pharmaceutically acceptable salt, solvate, hydrate or prodrug.

In some embodiments, about 60 mg/day of a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variation thereof is administered to an individual. Body; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In some embodiments, the T cell activating bispecific antigen-binding molecule is obineutuzumab. In some embodiments, obineutuzumab is administered by intravenous infusion. In some embodiments, about 100 mg to about 1,000 mg of obinostatuzumab is administered. In some embodiments, a loading dose of Obinutuzumab is administered. In some embodiments, Obinutuzumab is administered for at least six 28-day cycles. In some embodiments, 100 mg of obinostat is administered on Day 1 of Cycle 1 and 900 mg of Obinutuzumab is administered on Day 2. In some embodiments, 1,000 mg of Obinutuzumab is administered on Day 8 and Day 15 of Cycle 1. In some embodiments, 1,000 mg of Obinutuzumab is administered on Day 1 of Cycles 2-6. In some embodiments, 1,000 mg of Obinutuzumab is administered on Days 1, 8 and 15 of Cycle 1. In some embodiments, 1,000 mg of Obinutuzumab is administered on Day 1 of Cycles 2-6.

In some embodiments, Obinutuzumab is administered every 2 months when cycles ≥7.

In one aspect, provided herein is a pharmaceutical composition comprising: (i) The compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants thereof; or pharmaceutically acceptable salts or solvates thereof Substance, hydrate or prodrug; (ii) T cell activating bispecific antigen binding molecules; and (iii) At least one pharmaceutically acceptable excipient.

In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is a compound of formula (XI), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or Isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A35. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A36. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A68. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A70. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A37. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A38. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A41. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A42. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A43. In some embodiments of the pharmaceutical compositions provided herein, the compound of formula (I) is compound A44.

In some embodiments of the pharmaceutical compositions provided herein, the T cell activating bispecific antigen binding molecule comprises: The first Fab molecule that specifically binds to the first antigen; and A second Fab molecule that specifically binds to a second antigen, wherein the first antigen is an activating T cell antigen and the second antigen is a target cell antigen.

In some embodiments of the pharmaceutical compositions provided herein, the T cell antigen is CD3. In some embodiments of the pharmaceutical compositions provided herein, the target cell antigen is CD19, CD20, CD13, CD30, CD33, BCMA, ROR1 or CD40. In some embodiments of the pharmaceutical compositions provided herein, the T cell activating bispecific antigen binding molecule comprises a complete Fc region that can bind to a cell surface receptor (Fc receptor). In some embodiments of the pharmaceutical compositions provided herein, the T cell activating bispecific antigen-binding molecule is obin eutuzumab, mosutuzumab, celecruzumab, blenate Mab, AMV564, AFM13, REGN-1979, GEN-3013 or Pasotuximab.

In one aspect, this article provides a method for treating or preventing cancer, which includes administering an effective amount of the following to an individual in need: (i) The compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants thereof; or pharmaceutically acceptable salts or solvates thereof Substance, hydrate or prodrug; (ii) T cell activating bispecific antigen binding molecules; and (iii) At least one pharmaceutically acceptable excipient.

Cross-reference of related applications

This application claims the rights of U.S. Provisional Application No. 62/783,910 filed on December 21, 2018, which is incorporated into the disclosure of this application by reference. Incorporated for reference

All publications, patents and patent applications mentioned in this specification are incorporated herein by reference, and the degree of such citation is as clear as the individual publications, patents or patent applications by reference And individually incorporated into this article.

Some examples provided herein describe pharmaceutical compositions containing PI3K delta inhibitors and methods of using PI3K inhibitors to treat patients with B-cell malignancies. In some embodiments, the dosing regimen and schedule described herein reduce the toxicity associated with PI3K delta inhibitors.

Class I phosphoinositide 3-kinase (PI3K) regulates many cellular functions. PI3K includes regulation (p85) and catalysis (p110) subunits, and the catalytic unit is composed of 4 different isoforms designated as α, β, γ and δ. PI3Kδ is mainly expressed in lymphocytes, and the PI3Kδ plays a key role in normal lymphocyte biology (including proliferation, homing and survival). PI3Kδ is frequently active in B-cell malignant tumors and is the center of multiple B-cell receptor (BCR) signaling pathways. These B-cell receptor signaling pathways drive the proliferation, survival, and survival of malignant B cells in lymphoid tissues and bone marrow. Homing and staying.

Small molecule PI3Kδ (or PI3Kδ) inhibitors can effectively treat B-cell malignancies, including chronic lymphocytic leukemia (CLL), follicular lymphoma and other B-cell lymphomas. However, in some instances, the toxicity associated with the PI3Kδ is severe and has been fatal in some patients. With PI3Kδ inhibitors (e.g., idelalisib, parsaclisib (INCB050465), copanlisib, duvelisib, duvelisib, umbralisib ), etc.) reported toxicity includes (but is not limited to) enterocolitis (shown as diarrhea/colitis), skin toxicity (for example, skin rash), liver toxicity (shown as an increase in transaminases), pulmonary toxicity (shown as Non-infectious pneumonia) and infection. Such toxicity can be severe and has been fatal in some patients. The frequency, severity and time of these adverse events (AE) onset vary among PI3Kδ inhibitors. Enterocolitis, skin rash, and transaminitis have been reported in certain clinical studies of PI3Kδ in patients with B-cell malignancies. In some instances, lymphocyte infiltrates have been reported in biopsies obtained from individuals with colitis and/or severe skin rashes and corticosteroid therapy is an effective treatment for patients who develop diarrhea and rashes.

A better understanding of the pathogenesis of these toxicities can help to develop methods to mitigate their risks. Several studies have shown that some of these toxicities are related to dysfunction in immune homeostasis. Based on observations, the immune mechanism against PI3Kδ-related enterocolitis has been postulated. These observations include the development of autoimmune colitis in mice with gene inactivation of p110δ; from diarrhea/colon associated with PI3Kδ inhibitors Histopathological data of patients with inflammation showed increased intraepithelial lymphocytes, indicating an immune response; and some patients with delayed PI3Kδ inhibitor-related diarrhea/colitis did not respond to antidiarrheal drugs or empirical antibacterial therapy but could It responds to treatments with corticosteroids, which supports the immune mechanism against diarrhea.

There is also evidence pointing to the role of the PI3K pathway in T lymphocytes, which may explain these immune disorders. For example, in mice, gene inactivation of p110δ leads to a decrease in the function of regulatory T cells (TREG), a subpopulation of T cells. TREG has been shown to play an important role in controlling autoimmunity. In mice, p110δ has been shown to be necessary for viral and bacterial infections and effective T cell response. In some instances, PI3Kδ inhibition leads to various immune-mediated toxicities, such as enterocolitis and skin toxicity due to TREG inhibition, and infections due to the inhibition of B cells and effector T cells. In some examples, a treatment regimen using small molecule PI3Kδδ (or PI3Kδ) inhibitors according to an intermittent dosing schedule (IS) is used. However, in some instances, the progression of the disease is directed against B-cell malignancies, including chronic lymphocytic leukemia (CLL), and the use of small molecule PI3Kδ inhibitors (e.g., parsaclisib) according to the IS dosing schedule (INCB050465)) is observed in individuals undergoing treatment for lymphoma. It has been proven that once a week administration of Pasaklis results in plasma concentration> IC ₉₀ for 1.5/7 days (ie, 32%). As far as Pasaklis is concerned, in most patients, plasma approximate tissue concentration and off-target within 7 days ~ 5 days are not enough to maintain response to treatment. In some embodiments, the treatment methods and dosing schedules and schedules described herein provide effective and tolerable treatment of cancer. In some embodiments, the treatment methods and dosing regimens and schedules described herein improve the frequency, severity, and timing of the onset of adverse events (AE) related to PI3K delta inhibitors. In some embodiments, the treatment methods and dosing schedules and schedules described herein (including IS dosing schedules) result in partial or complete remission. In some embodiments, the treatment methods and dosing schedules and schedules described herein (including IS dosing schedules (eg, one week dosing/three weeks dosing)) result in plasma concentrations of the compounds described herein> IC ₉₀ continuous 9/28 days (ie, 32%). For the compounds described herein (e.g., compound A35), plasma concentrations underestimate tissue concentrations, and compared with plasma, the compounds described herein are predicted to have higher concentrations in tumors.

This document describes a pharmaceutical composition comprising: i) PI3K inhibitor; and ii) T cell activating bispecific antigen binding molecule. In some examples, the pharmaceutical compositions described herein can be used to treat diseases or disorders, such as cancer. Also described herein are methods of using a combination of i) PI3K inhibitors and ii) T cell activating bispecific antigen binding molecules to treat diseases and disorders (such as cancer).

In order to help understand the disclosures set forth in this article, many terms are defined below.

Generally speaking, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry and pharmacology described herein are familiar to those who are familiar with this technology and are commonly used in this technology. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. definition

The term "individual" refers to animals, including but not limited to primates (e.g., humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "individual" and "patient" are used interchangeably herein to refer to, for example, mammalian individuals, such as human individuals, and in one embodiment, humans.

The term "treat (treat, treating and treatment)" means to reduce or eliminate one or more of the disorder, disease or condition, or symptoms related to the disorder, disease or condition; or to reduce or eradicate the disorder , The cause of the disease or disease itself.

The term "prevent, preventing, and prevention" means to include delaying and/or preventing the onset of a disorder, disease or condition, and/or its accompanying symptoms; preventing an individual from suffering from a disorder, disease or condition; or reducing an individual from suffering from a disorder The risk of disease, disease or illness.

The terms "therapeutically effective amount" and "effective amount" mean that when administered, it is sufficient to prevent the development of one or more of the symptoms of disorders, diseases, or disorders under treatment, or to treat disorders, diseases Or the amount of the compound that reduces one or more of the symptoms of the disease to a certain degree. The term "therapeutically effective amount" or "effective amount" also refers to biomolecules (for example, proteins, enzymes, RNA or DNA), cells, tissues, systems, animals or animals that researchers, veterinarians, doctors or clinicians are seeking The amount of the compound of the human biological or medical reaction.

The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" and "physiologically acceptable excipient" refer to pharmaceutically acceptable materials , Composition or vehicle, such as liquid or solid fillers, diluents, solvents or encapsulating materials. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with other ingredients of the pharmaceutical formulation, and is suitable for contact with human and animal tissues or organs without excessive toxicity or irritation , Allergic reactions, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams and Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th edition, Rowe et al. Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; And Handbook of Pharmaceutical Additives, 3rd edition, Ash and Ash eds, Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition, Gibson ed., CRC Press LLC: Boca Raton, FL, 2009.

The terms "approximately" and "approximately" mean the acceptable error of a specific value as determined by ordinary technicians, and part of it depends on the measurement or measurement method of the value. In some embodiments, the terms "about" and "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, of a given value or a given range. Within 5%, 4%, 3%, 2%, 1%, 0.5% or 0.05%.

The terms "active ingredient" and "active substance" refer to compounds that are administered to an individual alone or in combination with one or more pharmaceutically acceptable excipients to treat, prevent, or alleviate one or more symptoms of disorders, diseases, or disorders. As used herein, "active ingredient" and "active substance" may be optically active isomers of the compounds described herein.

The terms "drug", "therapeutic agent" and "chemotherapeutic agent" refer to a compound or pharmaceutical composition thereof that is administered to an individual to treat, prevent, or alleviate one or more symptoms of a disorder, disease or condition.

When used in conjunction with biological materials (such as nucleic acid molecules, polypeptides, host cells, and the like), the terms "naturally occurring" and "natural" refer to materials that are found in nature and not manipulated by humans. Similarly, "non-naturally occurring" or "non-natural" refers to materials that are not found in nature and have been structurally modified or synthesized by humans.

The term "PI3K" refers to phosphoinositide 3-kinase or variants thereof, which can phosphorylate the inositol ring of PI in the D-3 position. The term "PI3K variant" is intended to include proteins that are substantially homologous to natural PI3K, that is, as compared to the amino acid sequence of natural PI3K, having one or more natural or non-naturally occurring amino acid deletions, insertions, or Substituted proteins (for example, PI3K derivatives, homologs, and fragments). The amino acid sequence of PI3K variants has at least about 80% identity, at least about 90% identity, or at least about 95% identity with native PI3K. Examples of PI3K include (but are not limited to) p110α, p110β, p110δ, p110γ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta 1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res. 1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. Categorize PI3K into at least four categories. Class I includes p110α, p110β, p110δ and p110γ. Class II includes PI3K-C2α, PI3K-C2β and PI3K-C2γ. Class III includes Vps34. Class IV includes mTOR, ATM, ATR and DNA-PK. In certain embodiments, the PI3K is a type I kinase. In certain embodiments, the PI3K is p110α, p110β, p110δ, or p110γ. In certain embodiments, the PI3K is a variant of class I kinase. In certain embodiments, the PI3K is a p110α mutant. Examples of p110α mutants include (but are not limited to) R38H, G106V, K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M10431, M1043V, H1047L , H1047R and H1047Y (Ikenoue et al., Cancer Res. 2005, 65, 4562-4567; Gymnopoulos et al., Proc. Natl. Acad Sci., 2007, 104, 5569-5574). In certain embodiments, the PI3K is a type II kinase. In certain embodiments, the PI3K is PI3K-C2α, PI3K-C2β, or PI3K-C2γ. In certain embodiments, the PI3K is a class III kinase. In some embodiments, the PI3K is Vps34. In certain embodiments, the PI3K is a type IV kinase. In certain embodiments, the PI3K is mTOR, ATM, ATR or DNA-PK.

As used herein, the terms "bispecific antibody (BsAb)", "bispecific monoclonal antibody (BsMAb)", "T cell activating bispecific antigen binding molecule" and "bispecific T cell adaptor protein (BiTE )" is used interchangeably and refers to antibodies or monoclonal antibodies having binding sites for two different antigens (for example, a first Fab molecule that specifically binds to a first antigen and a second Fab molecule that specifically binds to a second antigen. Fab molecule). In some embodiments, the T cell activating bispecific antigen binding molecules described herein comprise a first antigen and a second antigen, wherein the first antigen line is an activating T cell antigen and the second antigen line is a target cell antigen. It should be understood that the first antigen line activating T cell antigen and the second antigen line target cell antigen or the second antigen line activating T cell antigen and the first antigen line target cell antigen. In some embodiments, the terms (for example) anti-CD20 x anti-CD3 antibody or CD20 x CD3 antibody and the like are synonymous and refer to bispecific antibodies that bind to the antigens CD3 and CD20.

As used herein, the terms "synergistic", "synergistic" and "synergistic" refer to the combination of therapies (for example, the PI3K inhibitor of formula (I) and the T cell activating bispecific antigen binding molecule), which is more The expected additive effect of any two or more monotherapy is more effective. For example, the synergistic effect of the combination of therapies allows the use of lower doses of one or more of the therapies and/or the lower frequency administration of the therapies to the individual. The ability to use lower dose therapies and/or lower frequency to administer the therapies reduces the toxicity associated with the administration of the therapies to the individual without reducing the therapies in a given disease such as autoimmune diseases, inflammatory diseases Or cancer (including but not limited to chronic lymphocytic leukemia or non-Hodgkin's lymphoma) in the prevention, control, treatment or improvement of efficacy. In addition, the synergistic effect can lead to the prevention, control, treatment or improvement of therapies in a given disease such as autoimmune disease, inflammatory disease or cancer (including but not limited to chronic lymphocytic leukemia or non-Hodgkin’s lymphoma) The improved effect of Nakajima. Finally, the synergistic effect of the combination of therapies can avoid or reduce the adverse or undesirable side effects associated with the use of any monotherapy. The "synergistic," "synergistic," or "synergistic" effect of a combination can be determined by the method of Chou et al. and/or Clarke et al. See Ting-Chao Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol Rev 58:621-681 (2006), and Clarke et al., Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models, Breast Cancer Research and Treatment 46:255-278 (1997), which are incorporated herein by reference to determine the “synergy” and “synergism” of the combination "Or "synergistic" effects.

The term "isotopic variant" refers to a compound that contains an unnatural proportion of isotopes at one or more of the atoms constituting the compound. In certain embodiments, the "isotopic variants" of the compound contain one or more isotopes in unnatural proportions, including (but not limited to) hydrogen ( ¹ H), deuterium ( ² H), tritium ( ³ H), carbon- 11 ( ¹¹ C), carbon-12 ( ¹² C), carbon-13 ( ¹³ C), carbon-14 ( ¹⁴ C), nitrogen-13 ( ¹³ N), nitrogen-14 ( ¹⁴ N), nitrogen-15 ( ¹⁵ N), oxygen-14 ( ¹⁴ O), oxygen-15 ( ¹⁵ O), oxygen-16 ( ¹⁶ O), oxygen-17 ( ¹⁷ O), oxygen-18 ( ¹⁸ O), fluorine-17 ( ¹⁷ F ), fluorine-18 ( ¹⁸ F), phosphorus-31 ( ³¹ P), phosphorus-32 ( ³² P), phosphorus-33 ( ³³ P), sulfur-32 ( ³² S), sulfur-33 ( ³³ S), Sulfur-34 ( ³⁴ S), Sulfur-35 ( ³⁵ S), Sulfur-36 ( ³⁶ S), Chlorine-35 ( ³⁵ Cl), Chlorine-36 ( ³⁶ Cl), Chlorine-37 ( ³⁷ Cl), Bromine- 79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br), iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), iodine-127 ( ¹²⁷ I), iodine-129 ( ¹²⁹ I) and iodine-131 ( ¹³¹ I). In certain embodiments, the "isotopic variant" of the compound is in a stable form, that is, non-radioactive. In certain embodiments, the "isotopic variants" of the compound contain one or more isotopes in unnatural proportions, including (but not limited to) hydrogen ( ¹ H), deuterium ( ² H), carbon-12 ( ¹² C), Carbon-13 ( ¹³ C), Nitrogen-14 ( ¹⁴ N), Nitrogen-15 ( ¹⁵ N), Oxygen-16 ( ¹⁶ O), Oxygen-17 ( ¹⁷ O), Oxygen-18 ( ¹⁸ O), Fluorine- 17 ( ¹⁷ F), phosphorus-31 ( ³¹ P), sulfur-32 ( ³² S), sulfur-33 ( ³³ S), sulfur-34 ( ³⁴ S), sulfur-36 ( ³⁶ S), chlorine-35 ( ³⁵ Cl), chlorine-37 ( ³⁷ Cl), bromine-79 ( ⁷⁹ Br), bromine-81 ( ⁸¹ Br) and iodine-127 ( ¹²⁷ I). In certain embodiments, the "isotopic variant" of the compound is in an unstable form, that is, radioactive. In certain embodiments, the "isotopic variants" of the compound contain one or more isotopes in unnatural proportions, including (but not limited to) tritium ( ³ H), carbon-11 ( ¹¹ C), carbon-14 ( ¹⁴ C ), nitrogen-13 ( ¹³ N), oxygen-14 ( ¹⁴ O), oxygen-15 ( ¹⁵ O), fluorine-18 ( ¹⁸ F), phosphorus-32 ( ³² P), phosphorus-33 ( ³³ P), Sulfur-35 ( ³⁵ S), chlorine-36 ( ³⁶ Cl), iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), iodine-129 ( ¹²⁹ I) and iodine-131 ( ¹³¹ I). It should be understood that in the compounds as provided herein, any hydrogen can be, for example, ² H, or any carbon can be, for example, ¹³ C, or any nitrogen can be, for example, ¹⁵ N, if feasible according to the judgment of those skilled in the art. , Or any oxygen can be ¹⁸ O, for example. In certain embodiments, the "isotopic variant" of the compound contains unnatural proportions of deuterium (D).

The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon group, wherein the alkylene group may optionally be substituted with one or more substituents Q as described herein. Unless otherwise specified, the term "alkyl" also includes both straight chain and branched chain alkyl. In certain embodiments, the alkyl group has 1 to 20 (C _1-20 ), 1 to 15 (C _1-15 ), 1 to 10 (C _1-10 ), or 1 to 6 (C _1-6 ) Straight-chain saturated monovalent hydrocarbon group of carbon atoms, or 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ) or 3 to 6 (C _{3- 6} ) A branched chain saturated monovalent hydrocarbon group of carbon atoms. As used herein, linear C _1-6 and branched C _3-6 alkyl groups are also referred to as "lower carbon number alkyl groups." Examples of alkyl groups include (but are not limited to) methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl Group, second butyl, tertiary butyl, pentyl (including all isomeric forms) and hexyl (including all isomeric forms). For example, C _1-6 alkyl refers to a straight chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms.

The term "alkylene" refers to a straight or branched chain saturated divalent hydrocarbon group, wherein the alkylene group can optionally be substituted with one or more substituents Q as described herein. Unless otherwise specified, the term "alkylene" includes both linear and branched alkylene. In certain embodiments, the alkylene has 1 to 20 (C _1-20 ), 1 to 15 (C _1-15 ), 1 to 10 (C _1-10 ), or 1 to 6 (C _{1- 6} ) A straight-chain saturated divalent hydrocarbon group of carbon atoms, or 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ), or 3 to 6 (C _3-6 ) A branched saturated divalent hydrocarbon group of carbon atoms. As used herein, straight chain C _1-6 and branched C _3-6 alkylene groups are also referred to as "lower carbon number alkylene groups." Examples of alkylene include (but are not limited to) methylene, ethylene, propylene (including all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), N-butylene, isobutylene, tertiary butylene, pentylene (including all isomeric forms) and hexylene (including all isomeric forms). For example, C _1-6 alkylene refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group having 3 to 6 carbon atoms.

The term "heteroalkylene" refers to a linear or branched saturated divalent hydrocarbon group containing one or more heteroatoms each independently selected from O, S and N in the hydrocarbon chain. For example, C _1-6 heteroalkylene refers to a straight chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene has 1 to 20 (C _1-20 ), 1 to 15 (C _1-15 ), 1 to 10 (C _1-10 ), or 1 to 6 (C _{1 -6} ) A straight-chain saturated divalent hydrocarbon group of carbon atoms, or 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ), or 3 to 6 ( C _3-6 ) A branched saturated divalent hydrocarbon group of carbon atoms. As used herein, straight chain C _1-6 and branched C _3-6 heteroalkylenes are also referred to as "low carbon number heteroalkylenes". Examples of heteroalkylenes include (but are not limited to) -CH ₂ O-, -CH ₂ OCH ₂ -, -CH ₂ CH ₂ O-, -CH ₂ NH-, -CH ₂ NHCH ₂ -, -CH ₂ CH ₂ NH-, -CH ₂ S-, -CH ₂ SCH ₂ -and -CH ₂ CH ₂ S-. In certain embodiments, the heteroalkylene group may optionally be substituted with one or more substituents Q as described herein.

The term "alkenyl" refers to a straight or branched chain containing one or more, in one embodiment, one, two, three, four, or five, and in another embodiment, a carbon-carbon double bond Monovalent hydrocarbon group. The alkenyl group may optionally be substituted with one or more substituents Q as described herein. As those skilled in the art know, the term "alkenyl" also includes groups having "cis" and "trans" configurations, or "Z" and "E" configurations. Unless otherwise specified, as used herein, the term "alkenyl" includes both linear and branched alkenyl. For example, a C _2-6 alkenyl group refers to a straight chain unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, the alkenyl group has 2 to 20 (C _2-20 ), 2 to 15 (C _2-15 ), 2 to 10 (C _2-10 ), or 2 to 6 (C _2-6 ) Straight-chain monovalent hydrocarbon group of carbon atoms, or having 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ) or 3 to 6 (C _3-6 ) A branched chain monovalent hydrocarbon group of carbon atoms. Examples of alkenyl include, but are not limited to, vinyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

The term "alkenylene" refers to a straight chain or branch containing one or more, in one embodiment, one, two, three, four or five, and in another embodiment, a carbon-carbon double bond Chain divalent hydrocarbon group. The alkenylene group may optionally be substituted with one or more substituents Q as described herein. Similarly, the term "alkenylene" also includes groups having "cis" and "trans" configurations, or "E" and "Z" configurations. As used herein, unless otherwise specified, the term "alkenylene" includes straight chain and branched chain alkenylene. For example, a C _2-6 alkenylene group refers to a straight chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain unsaturated divalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, the alkenylene group has 2 to 20 (C _2-20 ), 2 to 15 (C _2-15 ), 2 to 10 (C _2-10 ), or 2 to 6 (C _{2- 6} ) A straight-chain divalent hydrocarbon group of carbon atoms, or 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ), or 3 to 6 (C _{3 -6} ) A branched chain divalent hydrocarbon group of carbon atoms. Examples of alkenylene groups include, but are not limited to, vinylene, allyl, propenylene, butenylene, and 4-methylbutenyl.

The term "heteroalkenyl" refers to containing one or more, in one embodiment, one, two, three, four or five, in another embodiment, a carbon-carbon double bond, and a hydrocarbon chain A straight or branched divalent hydrocarbon group containing one or more heteroatoms each independently selected from O, S and N. The heteroalkenylene group may optionally be substituted with one or more substituents Q as described herein. As those familiar with the art know, the term "heteroalkenyl" includes groups having a "cis" or "trans" configuration or a mixture thereof, or a "Z" or "E" configuration or a mixture thereof group. For example, a C _2-6 heteroalkenylene group refers to a straight chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain unsaturated divalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, the heteroalkenylene group has 2 to 20 (C _2-20 ), 2 to 15 (C _2-15 ), 2 to 10 (C _2-10 ), or 2 to 6 (C _{2 -6} ) A straight-chain divalent hydrocarbon group with carbon atoms, or 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ), or 3 to 6 (C _3-6 ) A branched chain divalent hydrocarbon group of carbon atoms. Examples of heteroalkenylene groups include (but are not limited to) -CH=CHO-, -CH=CHOCH ₂ -, -CH=CHCH ₂ O-, -CH=CHS-, -CH=CHSCH ₂ -, -CH=CHCH ₂ S- or -CH=CHCH ₂ NH-.

The term "alkynyl" refers to a straight chain or branched chain containing one or more, in one embodiment, one, two, three, four or five, and in another embodiment, a carbon-carbon triple bond Monovalent hydrocarbon group. The alkynyl group may optionally be substituted with one or more substituents Q as described herein. Unless otherwise specified, the term "alkynyl" also includes both linear and branched alkynyl groups. In certain embodiments, the alkynyl group has 2 to 20 (C _2-20 ), 2 to 15 (C _2-15 ), 2 to 10 (C _2-10 ), or 2 to 6 (C _2-6 ) Straight-chain monovalent hydrocarbon group of carbon atoms, or having 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ) or 3 to 6 (C _3-6 ) A branched chain monovalent hydrocarbon group of carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH ₂ C≡CH). For example, the C _2-6 alkynyl group refers to a straight chain unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms.

The term "cycloalkyl" refers to a cyclic saturated bridged and/or unbridged monovalent hydrocarbon group optionally substituted with one or more substituents Q as described herein. In certain embodiments, the cycloalkyl has 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ), or 3 to 7 (C _3-7 ) Carbon atoms. Examples of cycloalkyl groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalin And adamantyl groups.

The term "cycloalkenyl" refers to a cyclic unsaturated, non-aromatic bridged and/or non-bridged monovalent hydrocarbon group, which may optionally be substituted with one or more substituents Q as described herein. In certain embodiments, the cycloalkenyl has 3 to 20 (C _3-20 ), 3 to 15 (C _3-15 ), 3 to 10 (C _3-10 ), or 3 to 7 (C _3-7 ) Carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl.

The term "aryl" refers to a monocyclic aromatic group and/or a polycyclic monovalent aromatic group containing at least one aromatic hydrocarbon ring. In certain embodiments, the aryl group has 6 to 20 (C _6-20 ), 6 to 15 (C _6-15 ), or 6 to 10 (C _6-10 ) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, stilbyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a bicyclic or tricyclic carbocyclic ring, wherein one of the rings is aromatic and the other of the rings may be saturated, partially unsaturated or aromatic, for example, dihydronaphthyl, Indenyl, dihydroindenyl or tetrahydronaphthyl (tetrahydronaphthyl). In certain embodiments, the aryl group may optionally be substituted with one or more substituents Q as described herein.

The terms "aralkyl" and "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl group has 7 to 30 (C _7-30 ), 7 to 20 (C _7-20 ), or 7 to 16 (C _7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments, the aralkyl groups are optionally substituted with one or more substituents Q as described herein.

The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more independently selected from O, Heteroatoms of S, N and P. The heteroaryl group is bonded to the rest of the molecule through its aromatic ring. Each ring of the heteroaryl group may contain one or two O atoms, one or two S atoms, one to four N atoms and/or one or two P atoms, provided that the total number of heteroatoms in each ring is four Or below and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, Pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. Examples of bicyclic heteroaryl groups include (but are not limited to) benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophene Group, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridyl, imidazothiazolyl, indolazinyl, indolyl, indazolyl, isobenzofuranyl, isobenzene Othienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridyl, phthalazinyl, pterridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinoline Linyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, oxazolyl, dibenzofuranyl, piperidinyl, phenanthryl, phenanthridinyl, phenanthryl Azinyl, phenazinyl, phenothiazinyl, benzoxazinyl and xanthene groups In certain embodiments, these heteroaryl groups may optionally be substituted with one or more substituents Q as described herein.

The terms "heterocyclic group" and "heterocyclic ring" refer to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are independent Heteroatoms selected from O, S, N and P; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. The heterocyclic group is bonded to the remainder of the molecule through its non-aromatic ring. In certain embodiments, the heterocyclic group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may be spirocyclic, fused or bridged, and wherein the nitrogen or sulfur atom may be oxidized if necessary, and the nitrogen atom It may be quaternized if necessary, and some of the rings may be partially or fully saturated or aromatic. The heterocyclic group can be bonded to the main structure at any heteroatom or carbon atom, which results in the production of stable compounds. Examples of such heterocyclic groups include (but are not limited to) azepinyl, benzodioxanyl, benzodioxazolyl, benzofuranone, benzopiperanone, benzene Piperanyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-dihydropyranyl, chromanyl, chromanyl, cinnoline , Coumarin, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropiperanyl, two Hydropyrazolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolyl, 1,4-dithienyl, furanone, imidazolidinyl, imidazole Linyl, indolyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarin, isoindolyl, isothiazolidinyl, isoxazolidinyl , Morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinone, oxazolidinyl, oxirane, piperazinyl, piperidinyl, 4-piperidinone, Pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropiperanyl, tetrahydrothienyl, thiamorpholinyl, thiazole Ridinyl, tetrahydroquinolinyl and 1,3,5-trithienyl. In certain embodiments, the heterocyclic group may optionally be substituted with one or more substituents Q as described herein.

The terms "halogen", "halide" and "halo" refer to fluorine, chlorine, bromine and/or iodine.

The term "optionally substituted" is intended to mean groups or substituents such as alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkenyl , Aryl, aralkyl, heteroaryl, heteroaryl-C _1-6 alkyl and heterocyclyl may be substituted by one or more substituents Q, each of which is independently selected from, for example ( a) Pendant oxy (=O), halo, cyano (-CN) and nitro (-NO ₂ ); (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne Group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-15 aralkyl group, heteroaryl group and heterocyclic group, each of which may be further subjected to one or more as necessary, in In one embodiment, one, two, three, four or five substituents Q ^{a are} substituted; and (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(=NR ^a ) NR ^b R ^c , -OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c ,- NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S( O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -P(O)R ^a R ^d , -P(O)(OR ^a )R ^d , -P(O)(OR ^a )(OR ^d ), -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S (O) NR ^b R ^c and -S(O) ₂ NR ^b R ^c , wherein each of R ^a , R ^b , R ^c and ^{Rd is} independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group, each of them Those are optionally substituted by one or more, in one embodiment, one, two, three or four substituents Q ^a ; or (iii) R ^b and R ^c together with the N atoms to which they are bound to form a heteroaryl The group or heterocyclic group is optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q ^a . As used herein, unless otherwise specified, all groups that can be substituted are "optionally substituted."

In one embodiment, each substituent Q ^a is independently selected from the group consisting of: (a) pendant oxy, cyano, halo and nitro; and (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl and heterocyclic group; and (c) -C (O)R ^e , -C(O)OR ^e , -C(O)NR ^f R ^g , -C(NR ^e )NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC( O)OR ^e , -OC(O)NR ^f R ^g , -OC(=NR ^e )NR ^f R ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^h , -NR ^e C(O)NR ^f R ^g , -NR ^e C(=NR ^h )NR ^f R ^g , -NR ^e S(O)R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^f R ^g , -P(O)R ^e R ^h , -P(O)(OR ^e )R ^h , -P(O)(OR ^e )(OR ^h ),- ^{SR e, -S (O) R} e, -S (O) 2 R e, -S (O) NR f R g , and ^{_{-S (O) 2 NR f R}} g; wherein each of R ^e, R ^f, R ^g and R ^{h are} independently (i) hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _{7 -15} Aralkyl, heteroaryl or heterocyclic group; or (ii) R ^f and R ^g together with the N atom to which they are bonded form a heteroaryl or heterocyclic group.

In certain embodiments, "optical activity" and "enantiomeric activity" refer to a collection of molecules that have not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, Not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than An enantiomeric excess of about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound contains about 95% or more of the desired enantiomer and about 5% or less of the non-preferred enantiomer based on the total weight of the racemate.

In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule with respect to its opposing center. (+) and (-) are used to indicate the optical rotation of the compound, that is, the direction in which the plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is left-handed, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) of the optical rotation are not related to the absolute configuration (R and S) of the molecule.

The phrase "enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof" With the phrase "enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants of the referenced compound; or the pharmaceutically acceptable salt of the referenced compound , Solvates, hydrates or prodrugs; or the enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or pharmaceutically acceptable isotopic variants of the reference compound "Salt, solvate, hydrate or prodrug" has the same meaning.

The term "solvate" refers to a complex or aggregate formed by one or more solute molecules (eg, compounds provided herein) and one or more solvent molecules present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate system is in crystalline form. In another embodiment, the complex or aggregate system is in an amorphous form. In the case of the solvent-based water, the solvate-based hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

The terms "resistant", "relapsed" or "refractory" refer to cancers that are less responsive to treatment, for example, the degree to which the cancer does not respond to the attempted form of treatment. The cancer may be resistant at the beginning of treatment or it may become resistant during treatment. The term "refractory" may refer to cancers in which treatments (eg, chemotherapy drugs, biopharmaceuticals, and/or radiotherapy) have proven ineffective. Refractory cancer tumors can shrink, but it is impossible to determine the degree of effectiveness of the treatment. However, usually, the tumor remains the same size as before treatment (stable disease), or it grows (progressive disease).

The term "intermittent dosing schedule" or "IS" refers to a drug (for example, a compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or Its isotope variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs) are administered or administered less than once a day. In some embodiments herein, IS refers to the administration or administration of drugs (for example, a compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more A mixture of multiple diastereomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof) for about 7 days. In other embodiments herein, IS refers to daily administration or administration of a drug (for example, a compound of formula (I), or its enantiomer, a mixture of enantiomers, or a combination of two or more diastereomers Mixtures or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof) for up to three 28-day cycles (for example, two 28-day cycles), and in the third cycle and subsequent cycles In this, the individual is administered once a day or the drug is administered for about 7 days in a 28-day cycle. In some embodiments, IS is continued until progression of the disease appears/observed or until the incidence of at least one toxicity decreases.

The term "continuous administration schedule" or "CS" refers to once a day administration or administration of drugs (for example, a compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more Mixtures of diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof). In some embodiments herein, CS refers to the daily administration or administration of drugs (for example, a compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more A mixture of diastereomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof). In other embodiments herein, CS refers to daily administration or administration of drugs (for example, a compound of formula (I), or its enantiomer, a mixture of enantiomers, or a combination of two or more diastereomers Mixtures or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof)> three 28-day cycles, and one or more subsequent cycles, to the individual every day during the 28-day cycle The drug is administered at one time or administered for about 7 days (ie, converted to IS later). In some embodiments, individuals who follow CS never convert to IS. In some embodiments, a system that follows CS is converted to IS after> three 28-day periods (ie, converted to IS later). In some embodiments, CS is continued until intolerable toxicity appears/observed.

As used herein, "responsiveness" to treatment or "responsiveness" to treatment and other forms of this term refer to the individual's use of a therapeutic agent (e.g., PI3K inhibitor) alone or in combination with (e.g.) monotherapy or combination therapy ) Of the treatment response. The responsiveness to therapies (for example, treatments using PI3K inhibitors alone or in combination) can be assessed by comparing individual responses to therapies using one or more clinical criteria, such as those described (for example) in Hallek, M., etc. Human, (2008) Blood 111 (12): 5446-5456 in IWCLL 2008 (for CLL); described, for example, in Cheson, BD et al., Journal of Clinical Oncology, 32(27): 3059-3067 Gano classification; and analogues. This article provides additional classifications of reactivity. These standards provide a set of published rules that define when a cancer patient improves ("response"), stay the same ("stable") or worsen ("progress") during treatment.

For example, individuals with CLL can be judged as complete remission (CR) or partial remission (PR). For example, according to IWCLL 2008, an individual is considered to be in CR if the assessment meets at least all of the following criteria after the completion of the treatment: (i) Peripheral blood lymphocytes (evaluated by blood and different counts) are less than 4 x 10 ⁹ /L (4000 μί); (ii) no hepatomegaly or splenomegaly by physical examination; (iii) no physical symptoms; and (iv) blood cell count (eg, neutrophils, platelets, hemoglobin) higher than Hallek, The value stated in M. et al. Partial remission (PR) for CLL is defined by IWCLL 2008 as including one of the following: (i) the number of blood lymphocytes is reduced by 50% or more than the value before treatment; (ii) such as by CT scan or touch Diagnosis, lymphadenopathy is reduced; or (iii) if detected by CT scan or palpation, the enlargement of the spleen or liver before treatment is reduced by 50% or more; and according to the value stated in Hallek, M. et al., blood cells Count (eg, neutrophils, platelets, hemoglobin). In other embodiments, a system with CLL is determined to have progressive disease (PD) or stable disease (SD). For example, according to IWCLL 2008, if at least one of the following criteria is met, a system is considered to be in PD during or after treatment: (i) progression of lymphadenopathy; (ii) expansion of the spleen or liver before treatment by 50 % Or more, or reappearance of hepatomegaly or splenomegaly; (iii) the number of blood lymphocytes increased by 50% or more and at least 5000 B lymphocytes per microliter; (iv) transformed into more aggressive tissues (E.g., Richter syndrome); or (v) the appearance of cytopenia (neutropenia, anemia, or thrombocytopenia) due to CLL. Stable disease (SD) for CLL is defined by IWCLL 2008 as patients who have not achieved CR or PR and have not shown progressive disease.

For example, in some embodiments, if at least one of the criteria for disease progression according to IWCLL is to slow down or reduce (for example) about 10%, 20%, 30%, 40%, 50%, 60%, 70% , 80%, 90% or more, individuals with CLL respond to treatment with PI3K inhibitors alone or in combination. In another example, if the individual experiences an increase in life expectancy, for example, an increase of about 5%, 10%, 20%, 30%, 40%, 50% or more than the expected life expectancy in the absence of treatment, Then the individual responds to treatment with PI3K inhibitors alone or in combination. In another example, if an individual has one or more of the following, the individual responds to treatment with PI3K inhibitors alone or in combination: increased progression-free survival, overall survival, or increased time to progression (TTP) , For example, as described in Hallek, M. et al. PI3K inhibitor

Some examples provided herein describe pharmaceutical compositions or methods of using the pharmaceutical compositions, the pharmaceutical compositions comprising a combination of the PI3K inhibitor described herein and a T cell activating bispecific antigen binding molecule. In some embodiments, the PI3K inhibitor is a PI3Kδ inhibitor.

(I)， 或其對映體、對映體之混合物、兩種或更多種非對映體之混合物或同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥； 其中： X、Y及Z各獨立地係N或CR^X ，條件為X、Y及Z中之至少兩者係氮原子；其中R^X 係氫或C_1-6 烷基； R¹ 及R² 各獨立地係(a)氫、氰基、鹵基或硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ；其中各R^1a 、R^1b 、R^1c 及R^1d 獨立地係(i)氫；(ii) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(iii) R^1b 及R^1c 與其等結合之N原子一起形成雜環基； R³ 及R⁴ 各獨立地係氫或C_1-6 烷基；或R³ 及R⁴ 連接在一起以形成鍵，C_1-6 伸烷基、C_1-6 伸雜烷基、C_2-6 伸烯基或C_2-6 伸雜烯基； R^5a 係(a)氫或鹵基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ； R^5b 係(a)鹵基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ； R^5c 係-(CR^5f R^5g )_n -(C_6-14 芳基)或-(CR^5f R^5g )_n -雜芳基； R^5d 及R^5e 各獨立地係(a)氫或鹵基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ； R^5f 及R^5g 各獨立地係(a)氫或鹵基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ；或(d)當出現一次R^5f 及出現一次R^5g 係結合至相同之碳原子時，則該R^5f 及R^5g 與其等結合之碳原子一起形成C_3-10 環烷基或雜環基； R⁶ 係氫、C_1-6 烷基、-S-C_1-6 烷基、-S(O)-C_1-6 烷基或-SO₂ -C_1-6 烷基； m係0或1；及 n係0、1、2、3或4； 其中R¹ 、R² 、R³ 、R⁴ 、R⁶ 、R^X 、R^1a 、R^1b 、R^1c 、R^1d 、R^5a 、R^5b 、R^5c 、R^5d 、R^5e 、R^5f 及R^5g 中之各烷基、伸烷基、伸雜烷基、烯基、伸烯基、伸雜烯基、炔基、環烷基、芳基、芳烷基、雜芳基及雜環基係視需要經一或多個，在一項實施例中，一、二、三、四或五個取代基Q取代，其中各取代基Q係獨立地選自(a)側氧基、氰基、鹵基及硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基及雜環基，其等中之各者係視需要進一步經一、二、三或四個取代基Q^a 取代；及(c) -C(O)R^a 、-C(O)OR^a 、-C(O)NR^b R^c 、-C(NR^a )NR^b R^c 、-OR^a 、-OC(O)R^a 、-OC(O)OR^a 、-OC(O)NR^b R^c 、-OC(=NR^a )NR^b R^c 、-OS(O)R^a 、-OS(O)₂ R^a 、-OS(O)NR^b R^c 、-OS(O)₂ NR^b R^c 、-NR^b R^c 、-NR^a C(O)R^d 、-NR^a C(O)OR^d 、-NR^a C(O)NR^b R^c 、-NR^a C(=NR^d )NR^b R^c 、-NR^a S(O)R^d 、-NR^a S(O)₂ R^d 、-NR^a S(O)NR^b R^c 、-NR^a S(O)₂ NR^b R^c 、-SR^a 、-S(O)R^a 、-S(O)₂ R^a 、-S(O)NR^b R^c 及-S(O)₂ NR^b R^c ，其中各R^a 、R^b 、R^c 及R^d 獨立地係(i)氫；(ii) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基，其等中之各者係視需要進一步經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代；或(iii) R^b 及R^c 與其等結合之N原子一起形成雜環基，其係視需要進一步經一、二、三或四個取代基Q^a 取代； 其中各Q^a 係獨立地選自由以下組成之群：(a)側氧基、氰基、鹵基及硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基及雜環基；及(c) -C(O)R^e 、-C(O)OR^e 、-C(O)NR^f R^g 、-C(NR^e )NR^f R^g 、-OR^e 、-OC(O)R^e 、-OC(O)OR^e 、-OC(O)NR^f R^g 、-OC(=NR^e )NR^f R^g 、-OS(O)R^e 、-OS(O)₂ R^e 、-OS(O)NR^f R^g 、-OS(O)₂ NR^f R^g 、-NR^f R^g 、-NR^e C(O)R^h 、-NR^e C(O)OR^h 、-NR^e C(O)NR^f R^g 、-NR^e C(=NR^h )NR^f R^g 、-NR^e S(O)R^h 、-NR^e S(O)₂ R^h 、-NR^e S(O)NR^f R^g 、-NR^e S(O)₂ NR^f R^g 、-SR^e 、-S(O)R^e 、-S(O)₂ R^e 、-S(O)NR^f R^g 及-S(O)₂ NR^f R^g ；其中各R^e 、R^f 、R^g 及R^h 獨立地係(i)氫；(ii) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基；或(iii) R^f 及R^g 與其等結合之N原子一起形成雜環基； 其中彼此相鄰之兩個取代基Q視需要形成C_3-10 環烯基、C_6-14 芳基、雜芳基或雜環基，其等各視需要經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代。In some embodiments, the PI3K inhibitor has structural formula (I):

(I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates or pro- Medicine; Wherein: X, Y and Z are each independently N or CR ^X , provided that at least two of X, Y and Z are nitrogen atoms; wherein R ^X is hydrogen or C _1-6 alkyl; R ¹ and R ^{2 is} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane Group, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O) NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(= NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; where each R ^1a , R ^1b , R ^1c and R ^{1d are} independent Ground system (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 Aralkyl, heteroaryl or heterocyclic group; or (iii) R ^1b and R ^1c together with the N atom to which they are bonded form a heterocyclic group; R ³ and R ^{4 are} each independently hydrogen or C _1-6 alkyl ; Or R ³ and R ^{4 are} joined together to form a bond, C _1-6 alkylene, C _1-6 heteroalkylene, C _2-6 alkenylene or C _2-6 heteroalkenylene; R ^5a System (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _{7 -15} Aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)N R ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(= NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5b is (a) halo; (b) C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; Or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O) R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O )NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5c series -(CR ^5f R ^5g ) _n -(C _6-14 Aryl) or -(CR ^5f R ^5g ) _n -heteroaryl; R ^5d and R ^{5e are} each independently (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c ,- OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S( O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5f and R ^{5g are} each independently (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a ) NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c ,- NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S( O)R ^1d 、-NR ^1a S(O ) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; or (d) when R ^5f occurs once and R ^5g is bonded to the same carbon atom once, then the R ^5f and R ^5g and the carbon atom to which it is bound together form a C _3-10 cycloalkyl or heterocyclic group; R ⁶ is hydrogen, C _1-6 alkyl, -SC _1-6 alkyl, -S(O)-C _{1 -6} alkyl or -SO ₂ -C _1-6 alkyl; m is 0 or 1; and n is 0, ¹ , ² , 3 or 4; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^X , R ^1a , R ^1b , R ^1c , R ^1d , R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f and R ^5g each of the alkyl, alkylene and heteroalkylene groups , Alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl groups are optionally included in one or more groups. In one embodiment, One, two, three, four or five substituents Q substituted, wherein each substituent Q is independently selected from (a) pendant oxy, cyano, halo and nitro; (b) C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl and heterocyclyl, among them Each is further substituted with one, two, three or four substituents Q ^a as necessary; and (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(=NR ^a )NR ^b R ^c , -OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(O )R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c and -S(O) ₂ NR ^b R ^c , where each R ^a , R ^b , R ^c and R ^{d are} independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _{6- 14} aryl group, C _7-15 aralkyl group, heteroaryl group or heterocyclic group, each of which is further subjected to one or more as necessary. In one embodiment, one, two, three or four One substituent Q ^{a is} substituted; or (iii) R ^b and R ^c together with the N atom to which they are bonded form a heterocyclic group, which is further substituted with one, two, three or four substituents Q ^a as necessary; wherein each Q ^a is independently selected from the group consisting of: (a) pendant oxy, cyano, halo and nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne Group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-15 aralkyl group, heteroaryl group and heterocyclic group; and (c) -C(O)R ^e , -C(O) OR ^e , -C(O)NR ^f R ^g , -C(NR ^e )NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O)NR ^f R ^g , -OC(=NR ^e )NR ^f R ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^h , -NR ^e C(O)NR ^f R ^g , -NR ^e C(=NR ^h )NR ^f R ^g , -NR ^e S(O)R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^f R ^{g, -SR e, -S (O} ) R e, -S (O) 2 R e, -S (O) NR f R g , and ^{_{-S (O) 2 NR f R}} g; wherein each of R ^e, R ^f , R ^g and R ^{h are} independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _{6- 14} aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (iii) R ^f and R ^g together with the N atom to which they are bonded to form a heterocyclic group; wherein two substituents adjacent to each other Q optionally forms a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a heteroaryl group or a heterocyclic group, each of which is optionally combined with one or more groups. In one embodiment, one, two, three Or four substituents Q ^a substituted.

In some embodiments, the compound of structural formula (I) is not 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholinyl-N-(2 -Phenyl-2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2-amine or 6-(2-(difluoromethyl)-1H-benzo[d] (Imidazol-1-yl)-N-(1-(4-((R)-3-(Methoxymethyl)morpholino)phenyl)ethyl)-2-morpholinopyrimidin-4-amine .

In some embodiments of compounds of formula (I), X, Y, and Z are each independently N or CR ^X , provided that at least two of X, Y, and Z are nitrogen atoms; wherein R ^X is hydrogen or C _{1 -6} alkyl _. In another embodiment of the compound of formula (I), X, Y and Z are N. In some embodiments, R ^5b is (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _{6- 14} aryl, C _7-15 aralkyl or heteroaryl; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c ,- OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -S(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O) R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d ,- NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S( O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c .

In some embodiments, R ^5a and R ^{5b are} each independently (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O )NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC( =NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c ,- NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a ,- S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c .

In some embodiments, each of R ^5a and R ^{5b is a} methyl group, which is optionally substituted with one or more halo groups.

In some embodiments, R ^5f and R ^{5g are} each hydrogen.

In some embodiments of the compound of structural formula (I): X, Y, and Z are each N; R ¹ and R ^{2 are} each hydrogen; R ³ and R ^{4 are} each hydrogen; R ^5a is C _1-6 alkyl; R ^5b is a C _1-6 alkyl group; R ^5c is -(CH ₂ )-phenyl, wherein R ^5c is substituted with one, two, three or four substituents Q as necessary; R ^5d and R ^{5e are} each hydrogen ; R ⁶ is CHF ₂ ; and m is 0; wherein each alkyl group is optionally substituted by one, two, three or four substituents Q, wherein each substituent Q is independently selected from C _6-14 aryl, Heteroaryl and heterocyclyl, each of which is further substituted with one, two, three or four substituents Q ^a as necessary, wherein the heteroaryl has 5 to 10 ring atoms and one or more Heteroatoms independently selected from O, S and N, and the heterocyclic group has 3 to 15 ring atoms and one or more heteroatoms independently selected from O, S and N; wherein each Q ^a is independently It is selected from the group consisting of halo, C _1-6 alkyl, C _1-6 alkylsulfonyl and -OR ^e , wherein R ^e is hydrogen or C _1-6 alkyl.

In some embodiments of the compound of structural formula (I): X, Y, and Z are each N; R ¹ and R ^{2 are} each hydrogen; R ³ and R ^{4 are} each hydrogen; R ^5a and R ^{5b are} each methyl, It is optionally substituted by one or more halo groups; R ^5c is -(CH ₂ )-phenyl, wherein R ^5c is optionally substituted by one, two, three or four substituents Q; R ^5d and R ^{5e are} each R ⁶ is CHF ₂ ; and m is 0; wherein each alkyl group is optionally substituted with one, two, three or four substituents Q, wherein each substituent Q is independently selected from C _6-14 aromatic Group, heteroaryl group and heterocyclic group, each of them is further substituted with one, two, three or four substituents Q ^a as necessary, wherein the heteroaryl group has 5 to 10 ring atoms and one or A plurality of heteroatoms independently selected from O, S, and N, and the heterocyclic group has 3 to 15 ring atoms and one or more heteroatoms independently selected from O, S, and N; wherein each Q ^a is Independently selected from the group consisting of halo, C _1-6 alkyl, C _1-6 alkylsulfonyl and -OR ^e , wherein R ^e is hydrogen or C _1-6 alkyl.

(II)， 或其對映體、對映體之混合物、兩種或更多種非對映體之混合物或同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。在一些實施例中，R^5c 係C_6-14 芳基，其視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係苯基，其視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係萘基，其視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係-(CR^5f R^5g )_n -(C_6-14 芳基)，其中該芳基係視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係-(CH₂ )-苯基，其中該苯基係視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係-(CH₂ )-萘基，其中該萘基係視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係雜芳基，其視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係單環雜芳基，其視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係5或6員雜芳基，其視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係雙環雜芳基，其視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係-(CR^5f R^5g )_n -雜芳基，其中該雜芳基係視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係-(CR^5f R^5g )_n -(單環雜芳基)，其中該雜芳基係視需要經一或多個取代基Q取代。R^5c 係-(CR^5f R^5g )_n -(5或6員雜芳基)，其中該雜芳基係視需要經一或多個取代基Q取代。在一些實施例中，R^5c 係-(CR^5f R^5g )_n -(雙環雜芳基)，其中該雜芳基係視需要經一或多個取代基Q取代。This article provides compounds of formula (II):

(II), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates or pro- medicine. In some embodiments, R ^5c is a C _6-14 aryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is a phenyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is naphthyl, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is -(CR ^5f R ^5g ) _n -(C _6-14 aryl), wherein the aryl group is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is -(CH ₂ )-phenyl, wherein the phenyl is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is -(CH ₂ )-naphthyl, wherein the naphthyl is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is a heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is a 5- or 6-membered heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is a bicyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is -(CR ^5f R ^5g ) _n -heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is -(CR ^5f R ^5g ) _n- (monocyclic heteroaryl), wherein the heteroaryl group is optionally substituted with one or more substituents Q. R ^5c is -(CR ^5f R ^5g ) _n- (5- or 6-membered heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q. In some embodiments, R ^5c is -(CR ^5f R ^5g ) _n -(bicyclic heteroaryl), wherein the heteroaryl group is optionally substituted with one or more substituents Q.

(VII)， 或其對映體、對映體之混合物、兩種或更多種非對映體之混合物或同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥， 其中： R^7a 、R^7b 、R^7c 、R^7d 及R^7e 各獨立地係(a)氫、氰基、鹵基或硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基，其等中之各者係視需要經一或多個，在一項實施例中，一、二、三、四或五個取代基Q取代；或(c) -C(O)R^1a 、-C(O)OR^1a 、-C(O)NR^1b R^1c 、-C(NR^1a )NR^1b R^1c 、-OR^1a 、-OC(O)R^1a 、-OC(O)OR^1a 、-OC(O)NR^1b R^1c 、-OC(=NR^1a )NR^1b R^1c 、-OS(O)R^1a 、-OS(O)₂ R^1a 、-OS(O)NR^1b R^1c 、-OS(O)₂ NR^1b R^1c 、-NR^1b R^1c 、-NR^1a C(O)R^1d 、-NR^1a C(O)OR^1d 、-NR^1a C(O)NR^1b R^1c 、-NR^1a C(=NR^1d )NR^1b R^1c 、-NR^1a S(O)R^1d 、-NR^1a S(O)₂ R^1d 、-NR^1a S(O)NR^1b R^1c 、-NR^1a S(O)₂ NR^1b R^1c 、-SR^1a 、-S(O)R^1a 、-S(O)₂ R^1a 、-S(O)NR^1b R^1c 或-S(O)₂ NR^1b R^1c ；或彼此相鄰之R^7a 、R^7b 、R^7c 、R^7d 及R^7e 中之兩者形成C_3-10 環烯基、C_6-14 芳基、雜芳基或雜環基，其等各視需要經一或多個，在一項實施例中，一、二、三、四或五個取代基Q取代。This article also provides compounds of formula (VII):

(VII), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or pro Medicine, wherein: R ^7a , R ^7b , R ^7c , R ^7d and R ^{7e are} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group, each of which is optional With one or more, in one embodiment, one, two, three, four or five substituents Q substituted; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C (O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c ,- OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c ,- NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; or adjacent to each other R ^7a , R ^7b , ^{Two of} R ^7c , R ^7d and R ^7e form a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a heteroaryl group or a heterocyclic group, each of which is optionally combined with one or more, in one In the embodiments, one, two, three, four or five substituents Q are substituted.

式(IX)， 或其對映體、對映體之混合物、兩種或更多種非對映體之混合物或同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥，其中：  R^7a 、R^7b 、R^7c 、R^7d 及R^7e 各獨立地係(a)氫、氰基、鹵基或硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基，其等中之各者係視需要經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代；或(c) -C(O)R^a 、-C(O)OR^a 、-C(O)NR^b R^c 、-C(NR^a )NR^b R^c 、-OR^a 、-OC(O)R^a 、-OC(O)OR^a 、-OC(O)NR^b R^c 、-OC(=NR^a )NR^b R^c 、-OS(O)R^a 、-OS(O)₂ R^a 、-OS(O)NR^b R^c 、-OS(O)₂ NR^b R^c 、-NR^b R^c 、-NR^a C(O)R^d 、-NR^a C(O)OR^d 、-NR^a C(O)NR^b R^c 、-NR^a C(=NR^d )NR^b R^c 、-NR^a S(O)R^d 、-NR^a S(O)₂ R^d 、-NR^a S(O)NR^b R^c 、-NR^a S(O)₂ NR^b R^c 、-SR^a 、-S(O)R^a 、-S(O)₂ R^a 、-S(O)NR^b R^c 或-S(O)₂ NR^b R^c ；或彼此相鄰之R^7a 、R^7b 、R^7c 、R^7d 及R^7e 中之兩者形成C_3-10 環烯基、C_6-14 芳基、雜芳基或雜環基，其等各視需要經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代。This article also provides compounds of formula (IX):

Formula (IX), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrugs, wherein: R ^7a , R ^7b , R ^7c , R ^7d and R ^{7e are} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group, each of which is based on Need to be substituted by one or more, in one embodiment, one, two, three or four substituents Q ^a ; or (c) -C(O)R ^a , -C(O)OR ^a , -C (O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c ,- OC(=NR ^a )NR ^b R ^c , -OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c ,- NR ^b R ^c , -NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c or -S(O) ₂ NR ^b R ^c ; or adjacent to each other R ^7a , R ^7b , ^{Two of} R ^7c , R ^7d and R ^7e form a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a heteroaryl group or a heterocyclic group. In the embodiments, one, two, three or four substituents Q ^{a are} substituted.

In some embodiments, R ^7a is hydrogen, halo, optionally C _1-6 alkyl substituted with one or more substituents Q, or -OR ^1a .

In some embodiments, R ^7a is hydrogen. In some embodiments, R ^7a is (a) cyano, halo or nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring An alkyl group, a C _6-14 aryl group, a C _7-15 aralkyl group, a heteroaryl group, or a heterocyclic group, each of which is optionally selected by one or more groups, in one embodiment, one, Two, three, four or five substituents Q substitution; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O )R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S (O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c . In some embodiments, R ^7a is (i) halo; (ii) C _1-6 alkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group, etc. Each of them is optionally substituted with one or more, in one embodiment, one, two, three, four or five substituents Q; or (iii) -OR ^1a or -NR ^1b R ^1c .

In some embodiments, R ^7b is hydrogen, halo, optionally C _1-6 alkyl substituted with one or more substituents Q, or -OR ^1a . In some embodiments, R ^7b is hydrogen.

In some embodiments, R ^7c is hydrogen, halo, C _1-6 alkyl optionally substituted with one or more substituents Q, or -OR ^1a . In some embodiments, R ^7c is hydrogen, halo, or -OR ^1a . In some embodiments, R ^7c is chlorine. In some embodiments, R ^7c is -OC _1-6 alkyl, which is optionally substituted with one or more substituents Q.

In some embodiments, R ^7d is hydrogen, halo, optionally C _1-6 alkyl substituted with one or more substituents Q, or -OR ^1a . In some embodiments, R ^7d is hydrogen.

In some embodiments, R ^7e is hydrogen, halo, optionally C _1-6 alkyl substituted with one or more substituents Q, or -OR ^1a . In some embodiments, R ^7e is hydrogen. In some embodiments, two of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e adjacent to each other form a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a heteroaryl group or a heterocyclic ring The group, each of which is optionally substituted with one or more, in one embodiment, one, two, three, four or five substituents Q. In some embodiments, R ^7a and R ^7b together with the carbon atoms to which they are bonded form a C _6-14 aryl group, which is optionally substituted with one or more substituents Q.

In some embodiments, R ^5a is hydrogen. In some embodiments, R ^5a is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5a is hydrogen, methyl, or ethyl.

In some embodiments, R ^5b is a C _1-6 alkyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5b is methyl, ethyl or propyl. In some embodiments, R ^5b is -C(O)OR ^1a . In some embodiments, R ^5b is -C(O)OC _1-6 alkyl. In some embodiments, R ^5b is -C(O)OCH ₃ .

式(X)， 或其對映體、對映體之混合物、兩種或更多種非對映體之混合物或同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。This article also provides compounds of formula (X):

Formula (X), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrug.

式(XI)， 或其對映體、對映體之混合物、兩種或更多種非對映體之混合物或同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥，其中：  R^7a 、R^7b 、R^7c 、R^7d 及R^7e 各獨立地係(a)氫、氰基、鹵基或硝基；(b) C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_6-14 芳基、C_7-15 芳烷基、雜芳基或雜環基，其等中之各者係視需要經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代；或(c) -C(O)R^a 、-C(O)OR^a 、-C(O)NR^b R^c 、-C(NR^a )NR^b R^c 、-OR^a 、-OC(O)R^a 、-OC(O)OR^a 、-OC(O)NR^b R^c 、-OC(=NR^a )NR^b R^c 、-OS(O)R^a 、-OS(O)₂ R^a 、-OS(O)NR^b R^c 、-OS(O)₂ NR^b R^c 、-NR^b R^c 、-NR^a C(O)R^d 、-NR^a C(O)OR^d 、-NR^a C(O)NR^b R^c 、-NR^a C(=NR^d )NR^b R^c 、-NR^a S(O)R^d 、-NR^a S(O)₂ R^d 、-NR^a S(O)NR^b R^c 、-NR^a S(O)₂ NR^b R^c 、-SR^a 、-S(O)R^a 、-S(O)₂ R^a 、-S(O)NR^b R^c 或-S(O)₂ NR^b R^c ；或彼此相鄰之R^7a 、R^7b 、R^7c 、R^7d 及R^7e 中之兩者形成C_3-10 環烯基、C_6-14 芳基、雜芳基或雜環基，其等各視需要經一或多個，在一項實施例中，一、二、三或四個取代基Q^a 取代。This article provides compounds of formula (XI):

Formula (XI), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrugs, wherein: R ^7a , R ^7b , R ^7c , R ^7d and R ^{7e are} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group, each of which is based on Need to be substituted by one or more, in one embodiment, one, two, three or four substituents Q ^a ; or (c) -C(O)R ^a , -C(O)OR ^a , -C (O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c ,- OC(=NR ^a )NR ^b R ^c , -OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c ,- NR ^b R ^c , -NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c or -S(O) ₂ NR ^b R ^c ; or adjacent to each other R ^7a , R ^7b , ^{Two of} R ^7c , R ^7d and R ^7e form a C _3-10 cycloalkenyl group, a C _6-14 aryl group, a heteroaryl group, or a heterocyclic group, each of which is optionally combined with one or more groups. In the embodiments, one, two, three or four substituents Q ^{a are} substituted.

In certain embodiments, R ^5a and R ^{5b are} each independently (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 Cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C( O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC (=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c . In certain embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is a C _6-14 aryl, heteroaryl, or heterocyclic group, each of which is optional With one or more, in one embodiment, one, two, three or four substituents Q ^a substituted; in certain embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e One is a C _6-14 aryl group, for example, a phenyl group, which is optionally substituted with one, two, three or four substituents Q ^a ; in certain embodiments, R ^7a , R ^7b , R ^7c , R ^{One of 7d} and R ^7e is a heteroaryl group, for example, a 5-membered or 6-membered heteroaryl group, which is optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments, R ^{One of 7a} , R ^7b , R ^7c , R ^7d, and R ^7e is a heterocyclic group, for example, a 5-membered or 6-membered heterocyclic group, which is optionally substituted by one, two, three or four substituents Q ^a In some embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, etc. Each is optionally substituted with one, two, three or four substituents Q ^a ; in certain embodiments, one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is phenyl, imidazolyl, Pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted with one or more substituents Q ^a ; in certain embodiments, R ^7a and R ^7b , R ^7c , R ^7d and R ^7e are phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazole-1- Group, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl or 4-methylpiperazin-1-yl; and in certain embodiments , R ^7a , R ^7b , R ^7c , R ^7d and R ^7e are phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-Dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4 -Fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methyl Oxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl -Pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2- Fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidine- 5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl , 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In certain embodiments, R ^7a is C _6-14 aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q ^a (in one embodiment In certain embodiments, R ^7a is a C _6-14 aryl group (for example, phenyl), which is substituted by one, two, three or four Substituent Q ^{a is} substituted; in certain embodiments, R ^7a is a heteroaryl group (for example, a 5-membered or 6-membered heteroaryl group), which is optionally substituted with one, two, three or four substituents Q ^a ; In certain embodiments, R ^7a is a heterocyclic group (for example, a 5-membered or 6-membered heterocyclic group), which is optionally substituted with one, two, three, or four substituents Q ^a ; in certain embodiments , R ^7a is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted with one, two, three or four substituents Q ^a ; in certain embodiments ^{Among them} , R ^7a is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted with one, two, three or four substituents Q ^a substitution; in certain embodiments, R ^7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3 -Fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl , Pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2 -Methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl or 4-methylpiperazin-1-yl; and in certain embodiments, R ^7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methyl Oxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl Phenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazole-3 -Yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazine- 1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidine-4-yl Group, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1- Methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In certain embodiments: R ¹ is hydrogen or -OR ^1a , wherein R ^1a is C _1-6 alkyl, which is optionally substituted with one, two, three, four or five substituents Q; R ² is hydrogen ; R ³ and R ⁴ are hydrogen; R ⁶ is a C _1-6 alkyl group, which may be substituted with one, two, three, four or five substituents Q as necessary; R ^5a and R ^{5b are} each independently C _{1- 6} Alkyl group, which is optionally substituted by one, two, three, four or five substituents Q; R ^5f and R ^{5g are} each independently hydrogen, halogen, and optionally one, two, three, four or five The C _1-6 alkyl substituted by the substituent Q; or R ^5f and R ^5g together with the carbon atoms to which they are bound to form a C _1-10 cycloalkyl or heterocyclic group, each of which is optionally controlled by one, Two, three, four or five substituents Q substituted; R ^7a is a C _6-14 aryl, heteroaryl or heterocyclic group, each of which is substituted by one, two, three or four as necessary The group Q ^{a is} substituted; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z are each independently N or CR ^x , provided that at least two of X, Y and Z are N; wherein R ^x is hydrogen or ^a C _1-6 alkyl group substituted with one, two, three or four substituents Q ^a as necessary.

In certain embodiments: R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is C _1-6 alkyl, which is optionally substituted with one or more halo groups ; R ^5a and R ^{5b are} each independently a C _1-6 alkyl group; R ^5f and R ^{5g are} each independently a hydrogen or a C _1-6 alkyl group; or R ^5f and R ^5g and the carbon atoms to which they are bonded together form C _1-10 cycloalkyl; R ^7a is a C _6-14 aryl, heteroaryl or heterocyclic group, each of which is optionally substituted with one, two, three or four substituents Q ^a ; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z are each independently N or CH.

In certain embodiments: R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is difluoromethyl; R ^5a and R ^5b are methyl; R ^5f and R ^5g is hydrogen; or R ^5f and R ^5g together with the carbon atoms to which they are bonded form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R ^7a is C _6-14 aryl, monocyclic heteroaryl or monocyclic Cyclic heterocyclic groups, each of which is optionally substituted with one, two, three or four substituents Q ^a ; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z each Line N or CH independently.

In certain embodiments: R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is difluoromethyl; R ^5a and R ^5b are methyl; R ^5f and R ^5g is hydrogen; or R ^5f and R ^5g together with the carbon atoms to which they are bonded form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R ^7a is phenyl, 5- or 6-membered heteroaryl or 5 or 6 A heterocyclic group, each of which is optionally substituted with one, two, three or four substituents Q ^a ; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z each Line N or CH independently.

In certain embodiments: R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is difluoromethyl; R ^5a and R ^5b are methyl; R ^5f and R ^5g is hydrogen; or R ^5f and R ^5g are combined with the carbon atoms to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R ^7a is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidine R ^7b , R ^7c , R ^7d and R ^7e are substituted with one, two, three or four substituents Q ^a as necessary, each of them is substituted by one, two, three or four substituents Q ^a ; Hydrogen; and X, Y, and Z are each independently N or CH.

In certain embodiments, R ^7a is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one, two, three or four The group Q ^{a is} substituted.

式(XVI)， 或其對映體、對映體之混合物、兩種或更多種非對映體之混合物或同位素變體；或其醫藥上可接受之鹽、溶劑合物、水合物或前藥。This article provides compounds of formula (XVI):

Formula (XVI), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrug.

In some embodiments, R ^5a is C _1-6 alkyl, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5a is methyl.

In some embodiments, R ^5b is a C _1-6 alkyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^5b is methyl.

In some embodiments, R ^5a and R ^5b are methyl groups.

In some embodiments, R ^7a is hydrogen, halo, C _1-6 alkyl, C _6-14 aryl, heteroaryl or heterocyclyl, wherein these alkyl, aryl, heteroaryl and hetero The cyclic groups are each optionally substituted by one or more, in one embodiment, one, two, three, four or five substituents Q. In some embodiments, R ^7a is a C _6-14 aryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is a phenyl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl) Phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxybenzene Group, 4-methoxyphenyl or 3-morpholin-4-ylmethylphenyl. In some embodiments, R ^7a is a heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is a monocyclic heteroaryl group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is a 5- or 6-membered heteroaryl group, each of which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is imidazolyl, pyrazolyl, pyridyl, or pyrimidinyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl , Pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridine-4- Group, 2-methoxypyridin-4-yl, pyrimidin-5-yl. In some embodiments, R ^7a is a heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is a monocyclic heterocyclic group, which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is a 5- or 6-membered heterocyclic group, each of which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or more substituents Q. In some embodiments, R ^7a is pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidine Pyridin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazine -1-base.

In some embodiments, R ^7b is hydrogen, halo, or C _1-6 alkyl substituted with one or more substituents Q as needed. In some embodiments, R ^7b is hydrogen.

In some embodiments, R ^7c is hydrogen, halo, or C _1-6 alkyl substituted with one or more substituents Q as needed. In some embodiments, R ^7c is hydrogen.

In some embodiments, R ^7d is hydrogen, halo, or C _1-6 alkyl substituted with one or more substituents Q as needed. In some embodiments, R ^7d is hydrogen.

In some embodiments, R ^7e is hydrogen, halo or C _1-6 alkyl substituted with one or more substituents Q as needed. In some embodiments, R ^7e is hydrogen.

In some embodiments, R ^7a is a C _6-14 aryl, heteroaryl, or heterocyclic group, each of which is optionally combined with one or more. In one embodiment, one, two, three, four or Five substituents Q are substituted; and R ^7b , R ^7c R ^7d and R ^7e are hydrogen.

In an embodiment of the compound of formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is a C _6-14 aryl, heteroaryl or heterocyclic group, among them Each of them is optionally substituted with one, two, three or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7a , R ^7b , R The remaining parts of ^7c , R ^7d and R ^7e , X, Y and Z are each as defined herein.

In another embodiment of the compound of formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is a C _6-14 aryl group, which is optionally subjected to one, two, three or Four substituents Q ^a substituted; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7a , R ^7b , R ^7c , R ^7d and the remaining part of R ^7e , X, Each of Y and Z is as defined herein.

In yet another embodiment of the compound of formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is a heteroaryl group, which may be through one, two, three or four Substituent Q ^{a is} substituted; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7a , R ^7b , R ^7c , R ^7d and R ^7e remainder, X, Y and The Z series are as defined herein.

In yet another embodiment of the compound of formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is a heterocyclic group, which may be through one, two, three or four Substituent Q ^{a is} substituted; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7a , R ^7b , R ^7c , R ^7d and R ^7e remainder, X, Y and The Z series are as defined herein.

In yet another embodiment of the compound of formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is a 5-membered or 6-membered heterocyclic group, which may be controlled by one or two , Three or four substituents Q ^a substituted; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7a , R ^7b , R ^7c , R ^7d and the remainder of R ^7e , X, Y and Z are as defined herein.

In yet another embodiment of the compound of formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrole Ridinyl, piperidinyl or piperazinyl, each of which is optionally substituted with one, two, three or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , The remaining parts of R ^5b , R ^7a , R ^7b , R ^7c , R ^7d and R ^7e , X, Y and Z are each as defined herein.

In yet another embodiment of the compound of formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2- Bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methyl Phenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6 -Difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazole-1 -Yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl , 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl , Pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidine- 4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazine-1 -base.

In yet another embodiment of the compound of formula (XVI), one of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2- Bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl , 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl , Pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl Or 4-methylpiperazin-1-yl; and the remainder of R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7a , R ^7b , R ^7c , R ^7d and R ^7e Part, X, Y and Z are as defined herein.

In an embodiment of the compound of formula (XVI), R ^7a is a C _6-14 aryl, heteroaryl or heterocyclic group, each of which is substituted with one, two, three or four as necessary The group Q ^{a is} substituted; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y and Z are each as defined herein.

In yet another embodiment of the compound of formula (XVI), R ^7a is a heterocyclic group, which is optionally substituted with one, two, three or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

In yet another embodiment of the compound of formula (XVI), R ^7a is a 5-membered or 6-membered heterocyclic group, which is optionally substituted with one, two, three or four substituents Q ^a ; and R ¹ , R ^2. Each of R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y and Z is as defined herein.

In yet another embodiment of the compound of formula (XVI), R ^7a is phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optional Substituted by one, two, three or four substituents Q ^a ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X , Y and Z are as defined herein.

In yet another embodiment of the compound of formula (XVI), R ^7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3- Dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorobenzene Group, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxybenzene Group, 3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyridine Azol-4-yl, 2-methylpyrazole-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridine 4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1- Methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-Acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In yet another embodiment of the compound of formula (XVI), R ^7a is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxy Phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazole -1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridine-4 -Yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl or 4-methylpiperazin-1-yl; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^7b , R ^7c , R ^7d , R ^7e , X, Y, and Z are each as defined herein.

In an embodiment of the compound of formula (XVI), R ¹ is hydrogen or -OR ^1a , wherein R ^1a is C _1-6 alkyl, which is optionally substituted by one, two, three, four or five substituents Q Substitution; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is C _1-6 alkyl, which is substituted by one, two, three, four or five substituents Q as necessary; R ^5a and R ^5b each Independently is a C _1-6 alkyl group, which is optionally substituted with one, two, three, four or five substituents Q; R ^7a is a C _6-14 aryl, heteroaryl or heterocyclic group, among others Each of them is optionally substituted with one or more substituents Q ^a ; and R ^7b , R ^7c , R ^7d and R ^7e are hydrogen.

In one embodiment of the compound of formula (XVI): R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is a C _1-6 alkyl group, which is optionally controlled by one Or more halo groups; R ^5a and R ^{5b are} each independently a C _1-6 alkyl group; R ^7a is a C _6-14 aryl group, heteroaryl group or heterocyclic group, each of which is optional Substituted by one, two, three or four substituents Q ^a ; and R ^7b , R ^7c , R ^7d and R ^7e are hydrogen.

In one embodiment of the compound of formula (XVI): R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is difluoromethyl; R ^5a and R ^5b are methyl R ^7a is a phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl group, each of which is selected by one, two, three, Or substituted by five substituents Q; and R ^7b , R ^7c , R ^7d and R ^7e are hydrogen.

In one embodiment of the compound of formula (XVI), R ^5a and R ^{5b are} each independently (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne Group, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclyl; or (c) -C(O)R ^1a , -C(O) OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , R ^1a , R ^1b , R ^1c and R ^1d are defined elsewhere herein.

In an embodiment of any one of the formulae provided herein: R ¹ is hydrogen or -OR ^1a , wherein R ^1a is a C _1-6 alkyl group, which is subject to one, two, three, four or five Substituent Q is substituted; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is C _1-6 alkyl, which is substituted by one, two, three, four or five substituents Q as necessary; R ^5a and R ^{5b is} each independently hydrogen or C _1-6 alkyl substituted with one, two, three, four or five substituents Q as necessary; R ^7a is C _6-14 aryl, heteroaryl or heterocyclic group , Each of them is substituted by one, two, three or four substituents Q ^a as necessary; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z are each independently N Or CR ^x , provided that at least two of X, Y, and Z are N; wherein R ^x is hydrogen or ^a C _1-6 alkyl group substituted with one, two, three or four substituents Q ^a as necessary.

In one embodiment of any one of the formulae provided herein: R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is C _1-6 alkyl, which depends on Need to be substituted by one or more halo groups; R ^5a and R ^{5b are} each independently hydrogen or C _1-6 alkyl; R ^7a is C _6-14 aryl, heteroaryl or heterocyclic group, among them Each is substituted with one, two, three or four substituents Q ^a as necessary; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein: R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is difluoromethyl; R ^5a and R ^{5b is} each independently hydrogen or C _1-6 alkyl; R ^7a is C _6-14 aryl, monocyclic heteroaryl, or monocyclic heterocyclic group, each of which is optionally controlled by one, two, Three or four substituents Q ^{a are} substituted; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein: R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is difluoromethyl; R ^5a and R ^{5b is} each independently hydrogen or C _1-6 alkyl; R ^7a is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclic group, each of which is optionally controlled by one, two, Three or four substituents Q ^{a are} substituted; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein: R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is difluoromethyl; R ^5a and R ^{5b is} each independently hydrogen or C _1-6 alkyl; R ^7a is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of them Those are optionally substituted with one, two, three or four substituents Q ^a ; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein: R ¹ is hydrogen or methoxy; R ² is hydrogen; R ³ and R ⁴ are hydrogen; R ⁶ is difluoromethyl; R ^5a and R ^{5b is} each independently hydrogen or C _1-6 alkyl; R ^7a is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl, or piperazinyl, each of which is optionally tested Two, three or four substituents Q ^{a are} substituted; R ^7b , R ^7c , R ^7d and R ^7e are hydrogen; and X, Y and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein, R ¹ is hydrogen. In one embodiment of any of the formulae provided herein, R ¹ is -OR ^1a . In one embodiment of any of the formulae provided herein, R ¹ is -OC _1-6 alkyl. In one embodiment of any of the formulae provided herein, R ¹ is methoxy.

In one embodiment of any of the formulae provided herein, R ² is hydrogen. In one embodiment of any of the formulae provided herein, R ² is -NR ^1b R ^1c . In one embodiment of any of the formulae provided herein, R ² is an amino group.

In one embodiment of any of the formulae provided herein, R ³ is hydrogen.

In one embodiment of any of the formulae provided herein, R ⁴ is hydrogen.

In one embodiment of any of the formulae provided herein, R ⁶ is a C _1-6 alkyl group, which is optionally substituted with one or more substituents Q.

In one embodiment of any of the formulae provided herein, R ⁶ is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. In one embodiment of any of the formulae provided herein, R ⁶ is difluoromethyl.

The groups or variables R ¹ , R ² , R ^{3 in} the formulas provided herein (for example, formulas (I), (II), (VII), (IX), (X), (XI), (XVI)) , R ⁴ , R ⁶ , R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g , R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , m, n, X, Y And Z is further defined in the examples described herein. All combinations of the embodiments provided herein for these groups and/or variables are within the scope of the present invention.

In some embodiments, m is 0. In some embodiments, m is 1.

In some embodiments, n is zero. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2.

In some embodiments, m is 0, and n is 0, 1, 2, or 3. In some embodiments, m is 0 and n is 0, 1, or 2. In some embodiments, m is 0 and n is 0 or 1. In some embodiments, m is 0 and n is 0. In some embodiments, m is 0 and n is 1. In some embodiments, m is 1, and n is 0, 1, 2, or 3. In some embodiments, m is 1, and n is 0, 1, or 2. In some embodiments, m is 1, and n is 0 or 1. In some embodiments, m is 1 and n is 0. In some embodiments, m is 1 and n is 1.

In a specific embodiment, m is 0, n is 1 and R ^5a and R ^{5b are} each methyl.

In certain embodiments, X is N. In certain embodiments, X is CR ^x , wherein R ^x is as defined herein. In certain embodiments, X is CH.

In certain embodiments, Y is N. In certain embodiments, Y is CR ^x , where R ^x is as defined herein. In certain embodiments, Y is CH.

In certain embodiments, Z is N. In certain embodiments, Z is CR ^x , where R ^x is as defined herein. In certain embodiments, Z is CH.

In certain embodiments, X, Y, and Z are N. In certain embodiments, X and Y are N, and Z is CH. In certain embodiments, X and Z are N, and Y is CH. In certain embodiments, Y and Z are N, and X is CH.

In certain embodiments, the compound provided herein is not 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholinyl-N-(2- Phenyl-2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazine-2-amine. In certain embodiments, the compound provided herein is not 6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-((R )-3-(Methoxymethyl)morpholinyl)phenyl)ethyl)-2-morpholinylpyrimidin-4-amine.

In certain embodiments, when X, Y, and Z are N and R ^5a is hydrogen, R ^{5b is} not a heterocyclic group. In certain embodiments, when X, Y, and Z are N and R ^5a is hydrogen, R ^{5b is} not a 5-membered heterocyclic group. In certain embodiments, when X, Y, and Z are N and R ^5a is hydrogen, R ^{5b is} not pyrrolidinyl. In certain embodiments, when X, Y, and Z are N and R ^5a is hydrogen, R ^{5b is} not pyrrolidin-1-yl.

In certain embodiments, when X and Z are N, Y is CH and R ^5a is hydrogen, R ^5b is a phenyl substituted with a morpholino group. In certain embodiments, when X and Z are N, Y is CH and R ^5a is hydrogen, R ^{5b is} not 4-((R)-3-(methoxymethyl)morpholinyl)phenyl .

、 A11

、 A12      

、 A13

、 A14      

、 A15

、 A16      

、 A17

、 A18      

、 A19

、 A20      

、 A21

、 A22      

、 A23

、 A24      

、 A25

、 A26      

、 A27

、 A28      

、 A29

、 A30      

、 A31

、 A32      

、 A33

、 A34      

、 A35

、 A36      

、 A37

、 A38      

、 A39

、 A40      

、 A41

、 A42      

、 A43

、 A44      

、 A45

、 A46      

、 A47

、 A49      

、 A50

、 A51      

、 A52

、 A59      

、 A60

、 A61      

、 A62

、 A63      

、 A64

、 A65      

、 A66

、 A67      

、 A68

、 A70      

、 A73

、 A74      

A75                             及

； A76 或其同位素變體、醫藥上可接受之鹽、溶劑合物、水合物或前藥。In one embodiment, provided herein is a compound selected from:

, A11

, A12

, A13

, A14

, A15

, A16

, A17

, A18

, A19

, A20

, A21

, A22

, A23

, A24

, A25

, A26

, A27

, A28

, A29

, A30

, A31

, A32

, A33

, A34

, A35

, A36

, A37

, A38

, A39

, A40

, A41

, A42

, A43

, A44

, A45

, A46

, A47

, A49

, A50

, A51

, A52

, A59

, A60

, A61

, A62

, A63

, A64

, A65

, A66

, A67

, A68

, A70

, A73

, A74

A75 and

; A76 Or its isotope variants, pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

In one embodiment, the PI3K inhibitor is compound A35, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A36, or an isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A68, or an isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A70, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A37, or an isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A38, or an isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A41, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A42, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A43, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A44, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A62, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A63, or an isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A64, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A65, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A66, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In one embodiment, the PI3K inhibitor is compound A67, or an isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

The synthesis of the compound of any one of the formulae (for example, formula (I), (II), (VII), (IX), (X), (XI), (XVI)) provided herein is described in the US patent case No. 9,056,852 B2, which is incorporated into the present invention by reference. Bispecific antigen binding molecule

Some examples provided herein describe pharmaceutical compositions or methods of using such pharmaceutical compositions, the pharmaceutical compositions comprising a combination of a PI3K inhibitor described herein and a bispecific antibody or bispecific antigen binding molecule.

Some examples provided herein describe pharmaceutical compositions or methods of using the pharmaceutical compositions, the pharmaceutical compositions comprising a combination of the PI3K inhibitor described herein and a T cell activating bispecific antigen binding molecule.

Some examples provided herein describe pharmaceutical compositions or methods of using the pharmaceutical compositions, the pharmaceutical compositions comprising a combination of the PI3K inhibitor described herein and a bispecific antigen-binding molecule or bispecific antibody, the bispecific Sexual antigen binding molecules or bispecific antibodies include, but are not limited to, bispecific antigen binding molecules or bispecific antibodies that are bispecific T cell adaptor proteins or bispecific antibodies that disrupt tumor cell proliferation. In some embodiments, the bispecific antibodies disclosed herein destroy tumor cell proliferation through bispecific antibody-dependent T cell-mediated lysis, cell-mediated cytotoxicity, and/or phagocytosis of tumor cells. In some embodiments, the bispecific antibodies disclosed herein destroy tumor cell proliferation by, for example, selectively blocking CD47 on tumor cells.

Any suitable T cell activating bispecific antigen binding molecule or other bispecific antigen binding molecule (eg, anti-CD47/anti-CD19 antibody) can be used in combination with the PI3K inhibitors described herein. In some embodiments, the T cell activating bispecific antigen-binding molecule is obineutuzumab or a pharmaceutically acceptable salt thereof.

In some embodiments, the T-cell activating bispecific antigen-binding molecule is obiniutuzumab, mosutuzumab, celecruzumab, brenastuzumab, AMV564, AFM13, REGN -1979, Mosutuzumab, GEN-3013 or Pasotuximab. In some embodiments, the T cell antigen is CD3.

In some embodiments, the T-cell activating bispecific antigen-binding molecule is obiniutuzumab, mosutuzumab, celecruzumab, brenastuzumab, AMV564, AFM13, REGN -1979, Mosutuzumab, GEN-3013, Pasotuximab, Catumaxomab, Cemiplimab, RG-7802, MCLA-128, MGD- 007, MGD-007, MCLA-117, REGN-4018, AMG-330, XmAb-14045, ABL-001, MGD-013, XmAb-18087, ABBV-428, RO-7121661, JNJ-9178, GBR-1302, PF-06863135, CC-93269, MEDI-5752, AMG-757, AMG-427, GEM-333, MBS-301, PF-06671008, orlotamab, KN-046, ERY-974, JNJ -7957, navicixizumab, ZW-25, JNJ-6372, flotetuzumab, BI-836880, RO-7082859, XmAb-20717, AMG-424, AMG-701, AMG -596, AK-104, AMG-673, RG-7992, RG-7992, GBR-1342, AMG-570, FS-118, BTRC-4017A, JNJ-7564, XmAb-13676, AMG-420, MCLA-158 , A-337, KN-026, vanucizumab, AMG-562, UCB-0159, M-701, APVO-436, ATOR-1015, AK-112, MGD-019, A-319, EMB -01, M-802, XmAb-23104, MPE-831959, TB-535H, VB-601, XmAb-14484, XmAb-19722, ND-007, E1-3s, IMM-0306, IMM-03, AP-505 , SIB-003, HMBD-004A, HMBD-003, ABP-100, ABP-120, BH-2941, CB-307, FIT-012, BA-002, ABL-503, KY-1055, NIBX-2101, BH -2950, GBR-1372, COVA-4231, MT-6194, JNJ-0819, BH-2922, ABP-200, ABP-110, ABL-501, IBI-318, IBI-322, A LLI-0143, SBT-200, GNR-022, AFM-24I, FIT-1, GO-2, SMET-1, KY-1049, EM-801, TRIO-201, JS-003, AFM-24T, ABL- 301, AMG-160, GMA-104, AGEN-1423, AP-201, IBI-323, INBRX-105, BA-003, MPEV-201959, ALG.APV-527, TG-1801, PMC-201, CKD- 702, JNJ-9383, PMC-001, BS-027125, KN-052, VIS-FNG, PMC-002, IPH-61, Fsn-1006, XmAb-22841, AFM-26, KN-043, NI-1801, REGN-5458, BH-2954, A-329, SIB-001, KY-1043, VIS-RSV, TF-12, TMB-365, AMG-910, AGEN-1223, SMET-2, ATOR-1144, BMX- 002, BMX-101, SL-634, TSR-075, ALX-0141, IMM-02, APVO-437, TNB-383B, GO-6, FS-120, FS-222, TACSYN, MCLA-145, Novotarg, IBI-319, IBI-322, PC-101, PT-217, RG6026, DSP-107 (KAHR-107) or ABP-201.

In some embodiments, the T cell activating bispecific antigen binding molecule comprises a first Fab molecule that specifically binds to a first antigen; and a second Fab molecule that specifically binds to a second antigen, wherein the first antigen is Activated T cell antigen and target cell antigen of the second antigen line, wherein the target line is selected from one or more of the following: CD37, CD123, PDL1, PD1, VEGFR1, CD98hc, HER-2, HER-3, FLT3, CD19, CD20, 5T4, CD27, CD279, cd73, CD47, CD276, CD340, CD4, GD2, TfR, CD40, 4-1BB, BCMA, ROR1, PSMA, CD137, LAG3, EGFR, HLA-DR, CD5, CD16, HBsAg, HBV, CD3E, CD133, IL13RA2, IL-8, CD274, TNFRSF9, CLL-1, Gp120, TNF, TAFI, PAI-1, CD33, CEACAM6, TNFRSF9, Ang2, EphA2, EpCAM, EGFRvIII, MUC- 1. RG6026, 41BBL, mesothelin and CXCL-12. In some embodiments comprising a first Fab molecule that specifically binds to a first antigen; and a T cell activating bispecific antigen-binding molecule of a second Fab molecule, the second Fab molecule can bind to a target selected from There is more than one target antigen on the target: CD37, CD123, PDL1, VEGFR1, CD98hc, HER-2, HER-3, FLT3, CD19, CD20, 5T4, CD27, CD47, CD276, CD340, CD4, GD2, TfR, CD40 , 4-1BB, BCMA, ROR1, PSMA, CD137, LAG3, EGFR, HLA-DR, CD5, CD16, HBsAg, HBV, CD3E, CD133, IL13RA2, IL-8, CD274, TNFRSF9, CLL-1, Gp120, TNF , TAFI, PAI-1, CD33, CEACAM6, TNFRSF9, Ang2, EphA2, EpCAM, EGFRvIII, MUC-1, RG6026, 41BBL, Mesothelin and CXCL-12.

Provided herein are monovalent antibodies and/or bispecific antibodies that include at least one first arm specific for CD47. Provided herein are bispecific antibodies that recognize CD47 and a second target. In some embodiments, provided herein are bispecific antibodies in which one binding site is specific for CD47 and the second binding site is specific for another target, such as a tumor-associated antigen (TAA). In some embodiments, the TAA is an antigen expressed on the cell surface of cancer cells. In some embodiments, the TAA is CD19. In some embodiments, the TAA is 41BBL. In some embodiments, the TAA is CD33.

In one aspect, this article provides bispecific antibodies that selectively block targets on tumor cells and elicit anti-tumor immune responses. In some embodiments of the bispecific antibodies provided herein, the antibody comprises three arms. In some embodiments of the bispecific antibodies provided herein, the antibody comprises a targeting arm, an effector arm, and an Fc arm. In some embodiments of the bispecific antibodies provided herein, the antibody comprises a targeting arm, an effector arm, and an Fc arm that bind to CD19 on tumor cells. In some embodiments of the bispecific antibodies provided herein, the antibody comprises a targeting arm that binds to CD19 on tumor cells, an effector arm with CD47 blocking activity, and an Fc arm. In some embodiments of the bispecific antibodies provided herein, the antibody comprises a targeting arm that binds to CD19 on tumor cells, an effector arm with selective tumor cell CD47 blocking activity, and acts as a barrier to macrophages and other innate Sexual immune killer cells complement the Fc arm of the tumor cell bridge.

In one aspect, provided herein is a trifunctional antibody (triAb) that can bind to three different cell types. In some embodiments, the trifunctional antibody system of the present invention can bind to T cell activating bispecific antibodies of tumor cells, T cells and helper cells. In some embodiments, the T cell activating bispecific antigen-binding molecule is a trifunctional antibody, which comprises a first Fab molecule that specifically binds to a first antigen; a second Fab molecule that specifically binds to a second antigen, Wherein the first antigen line activating T cell antigen and the second antigen line target cell antigen; and the complete Fc region of cell surface receptors (Fc receptors) that can bind to helper cells or other Fc receptor expressing cells. In some embodiments, helper cells include (but are not limited to) monocytes/macrophages, natural killer cells, and dendritic cells. Examples of trifunctional antibodies include (but are not limited to) catumaxomab, ertuxomab, FBTA05 (lymphomun) and TRBS07 (ektomab). In some embodiments of the T cell activating bispecific antigen binding molecule of the present invention, the first Fab molecule of the T cell activating bispecific antigen binding molecule binds to the first antigen, wherein the first antigen system is activating T cell antigen. In some embodiments, the activating T cell antigen is CD3. In some embodiments, the trifunctional antibody of the present invention causes an immune response or a cytotoxic T cell response of CD4 T cells and/or CD8 T cells. Instructions

In certain embodiments, methods for treating or preventing diseases are provided herein, which include administering an effective amount of a compound of formula (I), or an isotopic variant or a pharmaceutically acceptable salt, solvate, hydrate And an effective amount of T cell activating bispecific antigen-binding molecule.

Some examples provided herein describe methods for treating patients suffering from B-cell malignancies, the method comprising administering an effective amount of a compound of formula (I), or an isotopic variant or a pharmaceutically acceptable salt or solvent thereof Hydrate, hydrate or prodrug and effective amount of T cell activating bispecific antigen binding molecule. In some embodiments, the T cell activating bispecific antigen binding molecule is obinouxtuzumab.

In some embodiments, the methods described herein avoid and/or reduce the adverse or undesirable side effects associated with the use of PI3K inhibitors and/or T cell activating bispecific antigen binding molecules. In some embodiments, the methods described herein avoid, reduce or minimize the risk of death due to infections associated with PI3K inhibitors and/or T cell activating bispecific antigen binding molecules. In some embodiments, the methods described herein avoid, reduce or minimize infections, neutropenia, diarrhea/colitis, high liver transaminase (alanine aminotransferase) in patients receiving the treatments described herein. Transferase/aspartate aminotransferase> 5x upper limit of normal), pneumonia, rash, liver insufficiency, renal insufficiency, fever or increased triglycerides, or a combination thereof. In certain embodiments, the methods described herein avoid, reduce or minimize the incidence of infection. In certain embodiments, the methods described herein avoid, reduce or minimize the incidence of neutropenia. In certain embodiments, the methods described herein avoid, reduce or minimize the incidence of diarrhea/colitis. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of high liver transaminases. In certain embodiments, the methods described herein avoid, reduce or minimize the incidence of pneumonia. In certain embodiments, the methods described herein avoid, reduce or minimize the incidence of skin rashes. In certain embodiments, the methods described herein avoid, reduce, or minimize the incidence of liver or renal insufficiency. In certain embodiments, the methods described herein avoid, reduce or minimize the incidence of fever. In certain embodiments, the methods described herein avoid, reduce or minimize the incidence of increased triglycerides. In certain embodiments, the methods described herein avoid, reduce or minimize enterocolitis (shown as diarrhea), skin toxicity, liver toxicity (shown as an increase in transaminases), pulmonary toxicity (shown as non-infectious Pneumonia), infection, or a combination thereof.

In some embodiments, the methods described herein provide a high objective response rate (ORR), as determined by tumor assessment from radiological testing and/or physical examination. In some embodiments, the methods described herein provide a durable response (DR) and/or an increased durable response rate (DRR) in an individual or patient; a sustained response that begins within 12 months of treatment and lasts for ≥6 months [Full or partial objective response]). In some embodiments, the methods described herein provide complete relief. In some embodiments, the methods described herein provide a better response than monotherapy treatment with compounds of formula (I) and/or T cell activating bispecific antigen binding molecules. In some embodiments, the methods described herein provide complete remission starting within 12 months of treatment and lasting for ≥ 6 months. In some embodiments, the methods described herein provide a complete response (CR) and/or no evidence of disease (NED) starting within 12 months of treatment and lasting ≥ 6 months.

In some embodiments of the method of treating follicular lymphoma (FL) including relapsed or refractory FL, the discontinuation rate due to adverse events is less than 25%, less than 20%, less than 15%, less than 10%, Less than 8%, less than 5%. In some embodiments of the method of treating T cell malignancies including relapsed or refractory T cell malignancies, the discontinuation rate due to adverse events is less than 25%, less than 20%, less than 15%, less than 10%, less than 8%, less than 5%. In some embodiments of the method of treating B-cell malignancies including recurrent or refractory B-cell malignancies, the discontinuation rate due to adverse events is less than 25%, less than 20%, less than 15%, less than 10%, less than 8%, less than 5%.

"Discontinuation rate" is defined as the number of individuals who discontinued the study drug before the completion of the study divided by the number of individuals treated.

In some embodiments, the discontinuation rate due to adverse events is less than 25%, less than 20%, less than 15%, less than 10%, less than 8%, and less than 5%. In some embodiments, the abort rate due to adverse events is less than 25%. In some embodiments, the abort rate due to adverse events is less than 20%. In some embodiments, the abort rate due to adverse events is less than 15%. In some embodiments, the abort rate due to adverse events is less than 10%. In some embodiments, the abort rate due to adverse events is less than 8%. In some embodiments, the discontinuation rate due to adverse events is about 4%.

In some embodiments, when an individual is administered a compound of formula (I), or an isotopic variant or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, the discontinuation rate due to adverse events is less The intermittent dosing schedule (IS) for individuals is less than the observed interruption rate for individuals based on the continuous dosing schedule (CS).

In certain embodiments, methods for treating or preventing diseases are provided herein, which include administering to an individual in need an effective amount of the following: a compound of formula (I), or an isotopic variant thereof; or a pharmaceutical Acceptable salts, solvates, hydrates or prodrugs and T cell activating bispecific antigen binding molecules. In some embodiments, the compound of formula (I) is compound A35 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A36 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A68 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A70 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A37 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A38 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A41 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A42 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A43 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A44 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A62 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A63 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A64 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A65 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A66 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A67 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (II) is compound XVII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In one embodiment, methods for treating or preventing proliferative diseases are provided herein, which include administering a compound of formula (I), or an isotope variant thereof, to an individual in need thereof; or a pharmaceutically acceptable Salt, solvate, hydrate or prodrug and effective amount of T cell activating bispecific antigen binding molecule. In one embodiment, the T cell activating bispecific antigen-binding molecule is obineutuzumab.

In certain embodiments, methods for the treatment or prevention of proliferative diseases are provided herein, which include administering to an individual in need an effective amount of the following: a compound of formula (I), or an isotopic variant thereof; or Pharmaceutically acceptable salts, solvates, hydrates or prodrugs and T cell activating bispecific antigen binding molecules. In some embodiments, the compound of formula (I) is compound A35 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A36 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A68 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A70 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A37 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A38 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A41 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A42 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A43 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A44 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A62 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A63 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A64 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A65 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A66 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A67 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (II) is compound XVII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In one embodiment, provided herein is a method for treating or preventing cancer, which includes administering a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, to an individual in need thereof, Solvate, hydrate or prodrug and effective amount of T cell activating bispecific antigen binding molecule. In one embodiment, the T cell activating bispecific antigen-binding molecule is obineutuzumab.

In one embodiment, methods for the treatment or prevention of cancer are provided herein, which include administering to an individual in need an effective amount of the following: a compound of formula (I), or an isotopic variant thereof; or a pharmaceutical Acceptable salts, solvates, hydrates or prodrugs and T cell activating bispecific antigen binding molecules. In some embodiments, the compound of formula (I) is compound A35. In some embodiments, the compound of formula (I) is compound A36. In some embodiments, the compound of formula (I) is compound A68. In some embodiments, the compound of formula (I) is compound A70. In some embodiments, the compound of formula (I) is compound A37. In some embodiments, the compound of formula (I) is compound A38. In some embodiments, the compound of formula (I) is compound A41. In some embodiments, the compound of formula (I) is compound A42. In some embodiments, the compound of formula (I) is compound A43. In some embodiments, the compound of formula (I) is compound A44. In some embodiments, the compound of formula (I) is compound A62. In some embodiments, the compound of formula (I) is compound A63. In some embodiments, the compound of formula (I) is compound A64. In some embodiments, the compound of formula (I) is compound A65. In some embodiments, the compound of formula (I) is compound A66. In some embodiments, the compound of formula (I) is compound A67.

In some embodiments, the proliferative disease or cancer is hematological cancer or malignant tumor.

In certain embodiments, the proliferative disease or cancer is breast cancer, skin cancer, prostate cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, lung cancer, liver cancer, laryngeal cancer, oral cancer, colon cancer, and Gastrointestinal cancer (eg, esophageal cancer, stomach cancer, pancreatic cancer), brain cancer, thyroid cancer, blood cancer, and lymphatic system cancer.

In certain embodiments, cancers that can be treated with the methods provided herein include (but are not limited to) (1) Leukemia, including (but not limited to) acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (such as granulocytes, early Myelocytes, myelomonocytic cells, monocytes, erythroleukemia leukemia) and myelodysplastic syndromes or their symptoms (such as anemia, thrombocytopenia, neutropenia, double cytopenia, or pancytopenia) ), refractory anemia (RA), RA with ring sideroblasts (RARS), RA with excessive blasts (RAEB), RAEB in transformation (RAEB-T), pre-leukemia, and chronic myelomonocytic leukemia ( CMML), (2) chronic leukemia, including (but not limited to) chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphoma, Including (but not limited to) follicular lymphoma (FL), Hodgkin's disease (Hodgkin's disease) and non-Hodgkin's disease; (5) multiple myeloma, including (but not limited to) slowly progressing multiple Myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) Unidentified single Strain gamma globulin disease; (8) benign single gamma globulin disease; (9) heavy chain disease; (10) bone and connective tissue sarcoma, including (but not limited to) osteosarcoma, osteosarcoma, chondrosarcoma, especially Ewing's sarcoma (Ewing's sarcoma), malignant giant cell tumor, osteofibrosarcoma, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (hemangiendothelioma), fibrosarcoma, Kaposi's sarcoma (Kaposi's sarcoma), leiomyosarcoma, Liposarcoma, lymphangiosarcoma, metastatic cancer, neuroma, rhabdomyosarcoma and synovial sarcoma; (11) Brain tumors, including (but not limited to) glioma, astrocytoma, brain stem glioma, ependymoma , Anaplastic oligodendrogliorna (aligodendrogliorna), non-glioma, acoustic neuroma, craniopharyngioma, medulloblastoma, meningioma, pineal cell tumor, pineal blastoma and primary brain lymph Tumor; (12) Breast cancer, including (but not limited to) adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mutant breast cancer, tubular breast cancer, papillary breast cancer, primary cancer, Paget Paget's disease and inflammatory breast cancer; (13) Adrenal gland cancer, including (but not limited to) pheochromocytoma and adrenocortical carcinoma; (14) Thyroid cancer, including (but not limited to) papillary or follicular Thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; (15) Pancreatic cancer, including (but not limited to) insulinoma, gastrinoma, glucagon tumor, virus tumor, somatostatin secreting tumor and carcinoid Or islet cell tumor; (16) Pituitary cancer, including but not limited to bank Cushing's disease, prolactin-secreting tumors, acromegaly and diabetes insipidus; (17) eye cancer, including (but not limited to) ocular melanoma, such as iris melanoma, choroidal melanoma and ciliary body Melanoma, and retinoblastoma; (18) vaginal cancer, including (but not limited to) squamous cell carcinoma, adenocarcinoma and melanoma; (19) vulvar cancer, including (but not limited to) squamous cell carcinoma, melanoma Tumor, adenocarcinoma, basal cell carcinoma, sarcoma and Paget’s disease; (20) cervical cancer, including (but not limited to) squamous cell carcinoma and adenocarcinoma; (21) uterine cancer, including (but not limited to) uterus Endometrial cancer and uterine sarcoma; (22) Ovarian cancer, including (but not limited to) ovarian epithelial cancer, borderline tumor, germ cell tumor and stromal tumor; (23) Esophageal cancer, including (but not limited to) squamous carcinoma, Adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma and oat cell (small cell) carcinoma; (24) Gastric cancer, including (but not limited to) Adenocarcinoma, fungal growth (polypoid), ulcers, superficial spread, extensive spread, malignant lymphoma, liposarcoma, fibrosarcoma and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, Including (but not limited to) hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer, including (but not limited to) adenocarcinoma; (29) cholangiocarcinoma, including (but not limited to) papillary, nodular, and diffuse (30) Lung cancer, including (but not limited to) non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma and small cell lung cancer; (31) Testicular cancer, including (but not limited to) Germinal tumor, seminoma, anaplastic, classic (typical), sperm cell, non-neuroma, embryonic carcinoma, teratoma and choriocarcinoma (yolk sac tumor); (32) prostate cancer, including (but not limited to) ) Adenocarcinoma, leiomyosarcoma and rhabdomyosarcoma; (33) Penile cancer; (34) Oral cancer, including (but not limited to) squamous cell carcinoma; (35) Basal carcinoma; (36) Salivary gland cancer, including (but not limited to) ) Adenocarcinoma, mucoepidermoid carcinoma and adenoid cystic carcinoma; (37) Pharyngeal carcinoma, including (but not limited to) squamous cell carcinoma and verrucous; (38) Skin cancer, including (but not limited to) basal cell carcinoma , Squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, tonsil malignant melanoma and acute acral melanoma; (39) Renal cancer, including (but not limited to) renal cell carcinoma, adenocarcinoma, Adrenoid tumor, fibrosarcoma and transitional cell carcinoma (renal pelvis and/or ureter); (40) Wilms' tumor; (41) bladder cancer, including (but not limited to) transitional cell carcinoma, squamous cell carcinoma Adenocarcinoma, adenocarcinoma, and carcinosarcoma; and other cancers, including but not limited to myxosarcoma, osteosarcoma, endothelial sarcoma, lymphatic-endothelial sarcoma, mesothelioma, synovial tumor, hemangioblastoma, epithelial Carcinoma, bladder adenocarcinoma, bronchial carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinoma (see Fishman Et al., 1985, Medicine, 2nd edition, JB Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books USA, Inc., USA ).

In certain embodiments, provided herein is an effective amount of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and an effective amount thereof for use in a patient A method for the treatment of hematological malignancies with a combination of T cell activating bispecific antigen binding molecules. In one embodiment, the T cell activating bispecific antigen-binding molecule is obineutuzumab.

In certain embodiments, provided herein is an effective amount of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and A method for the treatment of hematological malignancies with a combination of T cell activating bispecific antigen binding molecules In certain embodiments, the hematological malignancy is leukemia, lymphoma, myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, T cell malignancy or B cell malignancy. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia or non-Hodgkin's lymphoma. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia. In other embodiments, the hematological malignancy is non-Hodgkin's lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma. In other embodiments, the hematological malignancy is diffuse large B-cell lymphoma. In some embodiments, the compound of formula (I) is compound A35 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A36 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A68 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A70 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A37 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A38 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A41 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A42 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A43 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A44 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A62 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A63 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A64 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A65 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A66 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A67 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In certain embodiments, hematological malignancies are T cell malignancies. In certain embodiments, T cell malignancies include peripheral T cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, hemangioimmunoblastic lymphoma, skin T cell lymphoma, adult T cell Leukemia/lymphoma (ATLL), blastic NK cell lymphoma, enteropathic T cell lymphoma, liver and spleen γ-δ T cell lymphoma, lymphoblastic lymphoma, nasal NK/T cell lymphoma or treatment related T-cell lymphoma.

In certain embodiments, the hematological malignancy is a B cell malignancy. In certain embodiments, B-cell malignancies include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia ( CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma ( DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burch's lymphoma, non-Burch's High-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblast large-cell lymphoma, precursor B-cell lymphoblastic lymphoma, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma, Splenic marginal zone lymphoma, plasma cell myeloma, plasma cell tumor, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary exudative lymphoma, or lymphoma-like granulomatous disease. In certain embodiments, the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the DLBCL is activated B cell DLBCL (ABC-DLBCL), germinal center B cell-like DLBCL (GBC-DLBCL), double-hit DLBCL (DH-DLBCL) or triple-hit DLBCL (TH-DLBCL) . In certain embodiments, the hematological malignancy is relapsed and refractory diffuse large B-cell lymphoma (r/r DLBCL). In some embodiments, the B-cell malignancy is B-cell non-Hodgkin's lymphoma (NHL). In certain embodiments, the B-cell malignant tumor line is selected from chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and marginal zone B-cell lymphoma (MZL) , Diffuse large B-cell lymphoma (DLBCL) and high-grade non-Hodgkin's lymphoma. In certain embodiments, the B-cell malignant tumor line is selected from chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone B-cell lymphoma (MZL), or diffuse large B-cell lymphoma ( DLBCL). In certain embodiments, the B cell malignancy is a relapsed or refractory B cell malignancy. In certain embodiments of the methods provided herein, the FL is relapsed or refractory FL (R/R FL).

In certain embodiments, hematological malignancies are recurrent or refractory hematological malignancies. In certain embodiments, the relapsed or refractory hematological malignancy is a relapsed or refractory T cell malignancy. In certain embodiments, the relapsed or refractory hematological malignancy is a relapsed or refractory B cell malignancy.

Some examples provided herein describe methods for treating or preventing proliferative diseases or disorders, which include administering a combination of a PI3K inhibitor and a T cell activating bispecific antigen binding molecule. In some embodiments, the combination therapy of PI3K inhibitors (e.g., compounds of formula (I)) and T cell activating bispecific antigen-binding molecules (e.g., obinostatuzumab) described herein provides a synergistic effect. In some embodiments, the combination therapy of PI3K inhibitors (e.g., compounds of formula (I)) and T cell activating bispecific antigen-binding molecules (e.g., obinostatuzumab) described herein provides synergistic anti-tumor Or anti-cancer activity. In certain embodiments, the combination therapies described herein allow the use of lower doses of PI3K inhibitors and/or T cell activating bispecific antigen binding molecules. In some embodiments, the combination therapies described herein allow for lower frequency administration of PI3K inhibitors and/or T cell activating bispecific antigen binding molecules to individuals. In some embodiments, the combination therapies described herein reduce the toxicity associated with the administration of PI3K inhibitors and/or T cell activating bispecific antigen-binding molecules to an individual without reducing cancer (such as chronic lymphocytic leukemia) The effectiveness of prevention, control, treatment or improvement. In some embodiments, the synergistic effects observed with the combination therapies described herein result in improved efficacy of the therapy in the prevention, control, treatment, or amelioration of cancer (such as chronic lymphocytic leukemia).

In some embodiments, the combination therapies described herein avoid or reduce the adverse or undesirable side effects associated with the use of PI3K inhibitors and/or T cell activating bispecific antigen binding molecules. In some embodiments, the combination therapy described herein avoids, reduces, or minimizes infection, neutropenia, diarrhea, pneumonia, anemia, thrombocytopenia, nausea, vomiting, and extremities in patients receiving the combination therapy. Swelling, or a combination thereof. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of infection. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of neutropenia. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of diarrhea. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of pneumonia. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of anemia. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of thrombocytopenia. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of nausea. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of vomiting. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of swelling of the limbs.

Depending on the disorder, disease or condition to be treated and the condition of the individual, the compounds or pharmaceutical compositions provided herein can be administered orally or parenterally (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracranial injection) Or infusion, subcutaneous injection or transplantation), inhalation, nasal, vaginal, rectal, sublingual or topical (e.g., transdermal or topical) administration route, and can be administered in suitable dosage units and suitable for those described elsewhere herein The pharmaceutically acceptable excipients, carriers, adjuvants and vehicles for each administration route are formulated separately or together. Dosage and dosing schedule

Depending on the disorder, disease or condition to be treated and the condition of the individual, the compounds or pharmaceutical compositions provided herein can be administered orally or parenterally (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracranial injection) Or infusion, subcutaneous injection or transplantation), inhalation, nasal, vaginal, rectal, sublingual or topical (e.g., transdermal or topical) administration route, and can be administered in suitable dosage units and suitable for those described elsewhere herein The pharmaceutically acceptable excipients, carriers, adjuvants and vehicles for each administration route are formulated separately or together.

In certain embodiments, the methods provided herein include administering a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt thereof, to the patient simultaneously or sequentially through the same or different routes of administration , Solvates, hydrates or prodrugs and T cell activating bispecific antigen binding molecules.

The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (for example, whether it can be administered orally without decomposition before entering the bloodstream) and the disease under treatment.

In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and a T cell activating bispecific antigen binding molecule are simultaneously , Substantially simultaneously or sequentially. If the administration occurs sequentially, the T cell activating bispecific antigen-binding molecule can be administered to the compound of formula (I), or an isotope variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof Or administered before or after the prodrug. In some embodiments, the T cell activating bispecific antigen-binding molecule is administered before administration of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or pre Administer before medicine. In some embodiments, the T cell activating bispecific antigen-binding molecule is administered to a compound of formula (I), an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof At the same time. In some embodiments, the T cell activating bispecific antigen-binding molecule is administered to a compound of formula (I), an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof Then vote.

The compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and a T cell activating bispecific antigen binding molecule need not be administered with the same vehicle. In some embodiments, the T cell activating bispecific antigen-binding molecule and the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof Cast in different vehicles. The T cell activating bispecific antigen-binding molecule can be administered one or more times, and the dosage of each component of the combination can be the same or different. In addition, the compound of formula (I), or its isotope variant, or its pharmaceutically acceptable salt, solvate, hydrate or prodrug and the T cell activating bispecific antigen binding molecule need not be administered at the same site versus.

In some examples, the methods described herein further include administering PI3K inhibitors and T cell activating bispecificity to individuals or patients in need in multiple cycles repeated on a regular schedule with resting time between cycles Combination of sex antigen binding molecules. For example, in some instances, treatment is given for one week, followed by three weeks of rest, which is one treatment cycle.

In some examples, one cycle includes the administration of a PI3K inhibitor concurrently with the administration of the T cell activating bispecific antigen binding molecule. In some examples, the PI3K inhibitor and the T cell activating bispecific antigen-binding molecule are administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days. Days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, About 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days.

In some examples, one cycle includes the first administration of the PI3K inhibitor, followed by the second administration of the T cell activating bispecific antigen binding molecule. In some examples, the PI3K inhibitor is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days. Day, about 11 days, about 12 days, about 13 days, or about 14 days, followed by administration of the T cell activating bispecific antigen-binding molecule for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days Days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

In some examples, one cycle includes the first administration of the PI3K inhibitor, followed by simultaneous administration of the T cell activating bispecific antigen binding molecule. In some examples, the PI3K inhibitor is first administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days, followed by simultaneous administration of the T cell activating bispecific antigen-binding molecule for about 1 day, about 2 days, about 3 days, about 4 days, About 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some examples, the PI3K inhibitor is first administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days, followed by simultaneous administration of the T cell activation The bispecific antigen-binding molecule is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, About 12 days, about 13 days, or about 14 days. In some examples, the PI3K inhibitor is first administered for about 7 days, and then the T cell activating bispecific antigen-binding molecule is administered simultaneously for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days. Days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some examples, the PI3K inhibitor is first administered for about 7 days, followed by simultaneous administration of the T cell activating bispecific antigen-binding molecule for about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. day.

In some instances, one cycle includes the administration of PI3K inhibitors only. In some examples, the PI3K inhibitor is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days. Days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, About 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days.

In some examples, one cycle includes the administration of only T cell activating bispecific antigen binding molecules. In some examples, the T cell activating bispecific antigen-binding molecule is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days , About 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days.

In some examples, methods for multiple cycles of chemotherapy include administering a second cycle within about 60 days or about 3 months. In some examples, the method for multiple cycles of chemotherapy includes administering a second cycle within 50 days. In another example, the second period is 45, 40, 35, 30, 28, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, Administer within 3, 2 or 1 days. In some embodiments, the administration of any additional cycles is within 50 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 10 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 9 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 8 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 7 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 6 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 5 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 4 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 3 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 2 days of the previous cycle. In some embodiments, the administration of any additional cycles is within 1 day of the previous cycle. In another embodiment, the additional period is 45, 40, 35, 30, 28, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, Administer within 3, 2 or 1 days.

The length of the treatment cycle depends on the treatment being given. In some embodiments, the length of the treatment cycle is in the range of two to six weeks. In some embodiments, the length of the treatment cycle is in the range of four to six weeks. In some embodiments, the length of the treatment period is 28 days. In some embodiments, the length of the treatment period is 56 days. In some embodiments, the treatment cycle lasts for one, two, three, or four weeks. In some embodiments, the treatment cycle lasts four weeks. The number of therapeutic doses scheduled in each cycle also depends on the changes in the drug being administered.

In certain examples, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to an individual on a 28-day cycle. In some embodiments, a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to an individual for at least a 28-day cycle. In some embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to an individual; or a pharmaceutically Acceptable salts, solvates, hydrates or prodrugs for at least two 28-day cycles.

In certain embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to an individual; or a medicine thereof The acceptable salt, solvate, hydrate or prodrug is up to about 7 days. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof , Solvates, hydrates or prodrugs are intermittent. In some embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to an individual within a 28-day period; Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for about 7 consecutive days.

In some embodiments, the method includes an intermittent dosing schedule (IS), which includes administering a compound of formula (I), or its enantiomers, mixtures of enantiomers, two Mixtures of or more diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof for 7 consecutive days, followed by 21 days without treatment. In some embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to an individual; or a pharmaceutically Acceptable salts, solvates, hydrates or prodrugs for at least a 28-day cycle. In some embodiments, the IS avoids or reduces adverse or undesirable side effects associated with the use of PI3K inhibitors, such as enterocolitis (shown as diarrhea), skin toxicity, and liver toxicity (shown as an increase in transaminases) ), pulmonary toxicity (shown as non-infectious pneumonia) and infection. In some embodiments, the IS avoids or reduces enterocolitis, skin rash, transaminitis, or a combination thereof.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variation thereof is administered to the individual once a day during a 28-day period. Body; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for 28 consecutive days. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to the individual according to a continuous dosing schedule (CS) Or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the continuous dosing schedule (CS) includes administering the compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more to the individual once a day during a 28-day cycle A mixture of diastereomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for 28 consecutive days. In some embodiments, the continuous dosing schedule (CS) includes administering the compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more to the individual once a day during a 28-day cycle A mixture of two diastereomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for 28 consecutive days until disease progression or intolerable toxicity appears. In some instances, cases of enterocolitis and skin rashes reported delayed onset by CS patients.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variation thereof is administered to the individual once a day during a 28-day period. Body; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for up to about 7 days. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variation thereof is administered to the individual once a day during a 28-day period. Body; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof with an interval of about 7 days. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variation thereof is administered to the individual once a day during a 28-day period. Body; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for up to about 7 consecutive days. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variation thereof is administered to the individual once a day during a 28-day period. Body; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for up to about 7 consecutive days. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variation thereof is administered to the individual once a day during a 28-day period. Body; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for 7 consecutive days. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the intermittent dosing schedule (IS) includes administering the compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more of them once a day in a 28-day cycle Mixtures of diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof to the individual for 7 consecutive days, followed by 21 days without treatment.

In some embodiments of the methods provided herein, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to an individual ; Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug of at least three 28-day cycles, wherein: the first two 28-day cycles include a continuous daily dosing schedule (CS), which includes the subject Administer the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, once a day; or a pharmaceutically acceptable salt thereof, Two 28-day cycles of solvates, hydrates or prodrugs; and the third 28-day cycle includes an intermittent dosing schedule (IS), which includes administering the compound of formula (I) to the individual once a day, or Enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof The 28-day period The first 7 consecutive days. In some embodiments of the methods provided herein, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic change thereof is administered to an individual Body; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for at least three cycles, wherein: the first two cycles include a continuous daily dosing schedule (CS), which includes once a day to the individual With the compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts or solvates thereof , Hydrate or prodrug; and the subsequent cycles include an intermittent dosing schedule (IS), which includes the administration of the compound of formula (I), or its enantiomer, to the individual once a day in each subsequent cycle Mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof only for the previous 7 days. In some embodiments of the methods provided herein, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic change thereof is administered to an individual Body; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs four or more 28-day cycles, wherein: the first two or three 28-day cycles include continuous daily dosing schedule ( CS), which includes administering the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, to an individual once a day; or Three or more 28-day cycles of pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; and the subsequent 28-day cycle includes an intermittent dosing schedule (IS), which includes administration to the individual once a day The compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, The hydrate or prodrug is the first 7 consecutive days of the 28-day cycle.

In some instances, CS refers to the administration of the compound of formula (I), or its enantiomers, mixtures of enantiomers, or two or more diastereomers to an individual once a day on a 28-day schedule. The mixture or its isotope variant; or its pharmaceutically acceptable salt, solvate, hydrate or prodrug without conversion to IS. In some instances, CS refers to the administration of the compound of formula (I), or its enantiomers, mixtures of enantiomers, or two or more diastereomers to an individual once a day on a 28-day schedule. Four or more cycles of a mixture of, or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and then converted to IS (ie, converted to IS later). In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or its isotope variant; or its pharmaceutically acceptable salt, solvate, hydrate or prodrug until disease progression. In some embodiments, if the disease progresses, the individual recovers the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof ; Or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs for continuous daily administration (CS).

It includes administration of a compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants thereof; or pharmaceutically acceptable salts and solvents thereof In some examples of a treatment regimen of only the first seven days of the hydrate, hydrate or prodrug administered daily (CS) for two consecutive cycles, followed by daily administration for each subsequent cycle, the CS and IS cycles are 28-day cycles . In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or its isotope variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs to reduce or alleviate the adverse side effects associated with PI3Kδ inhibitors (for example, enterocolitis, skin rash, and/or transamine Enzyme elevation). In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or isotope variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, which result in the reduction or reduction of the incidence of immune-mediated toxicity by allowing the restoration of TREG during non-treatment intervals.

In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or its isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs, leading to stable disease. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or its isotope variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs, leading to regression of the disease. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or its isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs, causing objective reactions. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or its isotope variant; or its pharmaceutically acceptable salt, solvate, hydrate or prodrug, until stable disease is no longer observed. In some embodiments, the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to an individual on an intermittent dosing schedule (IS) Or its isotope variant; or its pharmaceutically acceptable salt, solvate, hydrate or prodrug, until disease progression is observed.

It includes administration of a compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants thereof; or pharmaceutically acceptable salts and solvents thereof In some examples of treatment regimens where the hydrate, hydrate or prodrug is continuously administered daily (CS) for two cycles, followed by daily administration of each subsequent (IS) cycle for only the first seven days of the treatment regimen, these CS and IS cycles are A 28-day cycle, in which the IS cycle is repeated until no more disease regression is observed. In some or additional embodiments, if disease progression is observed in an individual, the individual resumes a 28-day cycle of continuous daily administration (CS) until regression or stabilization of the disease is observed.

It includes administration of a compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants thereof; or pharmaceutically acceptable salts and solvents thereof Two 28-day cycles of continuous daily administration (CS) of hydrates, hydrates or prodrugs, followed by daily administration for only the first seven days of each subsequent (IS) 28-day cycle; where intermittent dosing schedule (IS) Cycles In certain instances of treatment regimens in which regression or stabilization of the disease is no longer observed in the individual, the individual resumes a 28-day cycle of continuous daily administration (CS) until regression or stabilization of the disease is observed.

In some embodiments, about 60 mg of the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to the individual once a day over a 28-day period Or its isotope variant; or its pharmaceutically acceptable salt, solvate, hydrate or prodrug for 7 consecutive days, followed by 21 days without treatment, with repeated cycles every 28 days.

In some embodiments, about 60 mg of the compound of formula (I), or its enantiomers, mixtures of enantiomers, or two or more non-pairs are administered once a day to individuals in need within a 28-day cycle A mixture of enantiomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof for 7 consecutive days, followed by 21 days without treatment, results in sufficient inhibition in targeted malignant B cells Steady-state plasma concentration of PI3Kδ. In other or additional embodiments, no treatment for the next 21 days is sufficient to refill TREG (ie, 7 days to clear the compound of formula (I) from plasma (~7 half-life) and after clearing the compound of formula (I) from plasma, the TREG rehydrated for 14 days.

In certain instances, the method includes a daily dosing schedule (CS) of at least two CS 28-day cycles, followed by an intermittent dosing schedule (IS), which includes at least two CS 28-day cycles in a 28-day cycle Thereafter, the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to the individual once a day; or pharmaceutically acceptable The salt, solvate, hydrate, or prodrug of the drug is 7 consecutive days, followed by 21 days without treatment. In some embodiments, the dosing schedule avoids or reduces adverse or undesirable side effects associated with the use of PI3K inhibitors, such as enterocolitis (shown as diarrhea), skin toxicity, and liver toxicity (shown as transaminase) The increase), pulmonary toxicity (shown as non-infectious pneumonia) and infection. In some embodiments, the dosing schedule avoids or reduces enterocolitis, skin rash, elevated transaminases, or a combination thereof.

In some examples, methods for administering multiple compounds include administering the compounds within 48 hours or less of each other. In some embodiments, the administration occurs within 24 hours, 12 hours, 6 hours, 3 hours, 1 hour, or 15 minutes. In some instances, the compounds are administered simultaneously. An example of simultaneous administration is the injection of one compound immediately before, after or during the oral administration of the second compound, and immediate refers to a period of less than about 5 minutes.

In some examples, the methods for administering multiple compounds occur sequentially, where the PI3K inhibitor is administered before the T cell activating bispecific antigen binding molecule. In another example, the T cell activating bispecific antigen binding molecule is administered before the PI3K inhibitor.

In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and T cell activating bispecific are administered to the patient periodically Sex antigen binding molecules. As discussed above, cyclic therapy involves the administration of active agents or combinations of active agents for a period of time, followed by a period of rest, and repeating this sequential administration. In some embodiments, periodic therapy reduces the development of resistance to one or more of the therapies, avoids or reduces the side effects of one of the therapies, and/or improves the efficacy of the therapy.

In some embodiments, the compound of formula (I) is daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly, once every two weeks, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, every Administer once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. In some embodiments, the compound of formula (I) is administered daily. In some embodiments, the compound of formula (I) is administered daily for up to about 28 days. In some embodiments, the compound of formula (I) is administered daily for up to about 7 days.

In some embodiments, the T cell activating bispecific antigen-binding molecule is daily, every other day, every other day 3 times a week, every 3 days, every 4 days, every 5 days, every 6 days, every week, every 8 days, every 9 days, every 10 days, every 11 days, every 12 days, every 13 days, every 2 weeks, every 15 days, every 3 weeks, every 4 weeks, every 5 weeks, every two weeks, every week 3 times, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, Dosing every 5 months or every 6 months.

In some embodiments, T cell activating bispecific antigen binding molecules are administered periodically. In some embodiments, the T cell activating bispecific antigen binding molecule is administered within a 28-day cycle. In some embodiments, the loading dose of the T cell activating bispecific antigen binding molecule is administered for one cycle (e.g., on day 1, day 8, and day 15, or on day 1, day 2 , Day 8 and Day 15), and then administer the T cell activating bispecific antigen-binding molecule once a month for 2 to 6 or 2 to 8 cycles (for example, on day 1). In some embodiments, the treatment with the T cell activating bispecific antigen binding molecule continues every two months for up to two years after 2 to 6 or 2 to 8 cycles. In some embodiments, the loading dose of the T cell activating bispecific antigen binding molecule is 1,000 mg. In other embodiments, the loading dose of the T cell activating bispecific antigen binding molecule is 900 mg. In other embodiments, the loading dose of the T cell activating bispecific antigen binding molecule is 100 mg. In some embodiments, the loading dose of the T cell activating bispecific antigen binding molecule is 900 mg on day 1, 100 mg on day 2, and 1,000 mg on day 15. In some embodiments, the loading dose of the T cell activating bispecific antigen-binding molecule is 900 mg on day 1 of cycle 1, 100 mg on day 2, and 1,000 mg on day 15, and then on day 1. 1,000 mg is administered daily for cycles 2 to 6. In some embodiments, in the combination therapy using the T-cell activating bispecific antigen-binding molecule (for example, obinostatuzumab), the subject is administered to the individual on days 1 and 15 of cycles 1 to 6. Orally administer the compound of formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts or solvates thereof Substance, hydrate or prodrug.

In some examples, the compound of formula (I) or T cell activating bispecific antigen-binding molecule is continuously administered as needed; or, the dose of the drug being administered is temporarily reduced or temporarily suspended for a certain length of time (ie, "rest Drug period"). In some embodiments, the length of the drug holiday varies from 2 days to 1 year, including 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, as illustrated by examples only, 10 days, 12 days, 14 days, 15 days, 20 days, 21 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days , 300 days, 320 days, 350 days or 365 days. The dose reduction during the drug withdrawal period includes 10% to 100%, including, for example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

In certain embodiments, the methods provided herein include simultaneous or sequential administration of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, to the patient through the same or different routes of administration , Solvates, hydrates or prodrugs, and T cell activating bispecific antigen binding molecules (for example, obinostatuzumab). In certain embodiments, the methods provided herein include simultaneous or sequential administration of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, to the patient through the same or different routes of administration , Solvates, hydrates or prodrugs and T cell activating bispecific antigen binding molecules) (e.g., obinostatuzumab). In some embodiments, the compound of formula (I) is compound A35 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A36 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A68 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A70 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A37 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A38 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A41 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A42 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A43 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A44 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A62 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A63 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A64 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A65 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A66 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound A67 or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (for example, whether it can be administered orally without decomposition before entering the bloodstream) and the disease under treatment. The suggested route of administration for the second active agent is known to those skilled in the art. See, for example, Physicians' Desk Reference, 1755-1760 (56th edition, 2002).

In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and a T cell activating bispecific antigen binding molecule (e.g., , Obin (Utuzumab) is administered simultaneously, substantially simultaneously or sequentially. In some embodiments, the administration occurs sequentially and the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered to the compound of formula (I), or an isotopic variant thereof; Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof before or after administration. In some embodiments, the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) is administered to a compound of formula (I), or an isotope variant thereof; or a pharmaceutically acceptable Before administration of the salt, solvate, hydrate or prodrug of it. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered to the compound of formula (I), its isotope variant; or its pharmaceutically acceptable Simultaneous administration of salts, solvates, hydrates or prodrugs. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered to the compound of formula (I), its isotope variant; or its pharmaceutically acceptable The salt, solvate, hydrate or prodrug is administered afterwards. In some embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and a T cell activating bispecific antigen binding molecule (e.g., Obin (Utuzumab) does not need to be administered with the same vehicle. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) and the compound of formula (I), or an isotope variant thereof; or a pharmaceutically acceptable salt thereof, Solvates, hydrates or prodrugs are administered in different vehicles. The T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) can be administered one or more times, and the number of administrations of each component of the combination can be the same or different. In addition, the compound of formula (I), or its isotope variant, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and the T cell activating bispecific antigen binding molecule (for example, Opinio Tocilizumab) does not need to be administered at the same site.

In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and a T cell activating double Specific antigen binding molecules (e.g., Obine Tuzumab). Cyclic therapy involves administering an active agent or a combination of active agents for a period of time, followed by a period of rest, and repeating this sequential administration. Cyclic therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment. In some embodiments, the periods are 28 days.

In certain embodiments, in the treatment, prevention or alleviation of one or more of the symptoms of the disorder, disease or condition described herein, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof The appropriate dose concentration of solvate, hydrate or prodrug is usually between about 1 to 1,000 mg, about 1 to about 500 mg, about 5 to about 500 mg, about 5 to about 200 mg, about 5 to about It can be administered in single or multiple doses of 250 mg or within the range of about 10 to about 150 mg. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is in the range of about 1, 5, 10, 15, 20 , 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 , 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, or 1,000 mg. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is in the amount of about 60 mg, about 120 mg, or about 150 mg. mg or about 180 mg. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered in an amount of about 60 mg.

In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is at about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500 or 1,000 mg/day .

In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered in an amount of about 45 mg/day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered in an amount of about 60 mg/day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered in an amount of about 90 mg/day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered in an amount of about 120 mg/day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered in an amount of about 150 mg/day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered in an amount of about 180 mg/day.

For oral administration, the pharmaceutical composition provided herein can be formulated to contain about 1.0 to about 1,000 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, A hydrate or prodrug in the form of a tablet or capsule, in one embodiment, contains about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45 , About 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 225, about 250, About 275, about 300, about 325, about 350, about 375, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950 Or about 1,000 mg of the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, for symptomatically adjusting the dose for the patient to be treated. These pharmaceutical compositions can be administered in a regimen of one (1) to four (4) times a day, including once, twice, three and four times a day. In some embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered once a day. In some embodiments, about 30 mg, about 45 mg, or about 60 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof One vote.

In some embodiments, the pharmaceutical composition provided herein can be formulated to contain about 45 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof The form of lozenge. These pharmaceutical compositions can be administered in a regimen of 1 to 4 times a day, including once, twice, three times and four times a day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is in need of such a compound in an amount of about 45 mg per day The patient was administered for 28 days or 56 days. In certain specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is required to be in an amount of about 45 mg per day The patient was administered for 28 days. In other specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is needed in an amount of about 45 mg per day The patient was administered for 56 days.

In some embodiments, the pharmaceutical composition provided herein can be formulated to contain about 60 mg of the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof The form of lozenge. These pharmaceutical compositions can be administered in a regimen of 1 to 4 times a day, including once, twice, three times and four times a day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is in need of such a compound in an amount of about 60 mg per day The patient was administered for 28 days or 56 days. In certain specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is required to be in an amount of about 60 mg per day The patient was administered for 28 days. In other specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is in need of such a compound in an amount of about 60 mg per day The patient was administered for 56 days.

In some embodiments, the pharmaceutical composition provided herein can be formulated to contain about 90 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof The form of lozenge. These pharmaceutical compositions can be administered in a regimen of 1 to 4 times a day, including once, twice, three times and four times a day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is required for this in an amount of about 90 mg per day The patient was administered for 28 days or 56 days. In certain specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is required to be in an amount of about 90 mg per day The patient was administered for 28 days. In other specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is required for this in an amount of about 90 mg per day The patient was administered for 56 days.

In some embodiments, the pharmaceutical composition provided herein can be formulated to contain about 120 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof The form of lozenge. These pharmaceutical compositions can be administered in a regimen of 1 to 4 times a day, including once, twice, three times and four times a day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is required for this in an amount of about 120 mg per day The patient was administered for 28 days or 56 days. In certain specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is required to be in an amount of about 120 mg per day The patient was administered for 28 days. In other specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is required for this purpose in an amount of about 120 mg per day The patient was administered for 56 days.

In some embodiments, the pharmaceutical composition provided herein can be formulated to contain about 150 mg of the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof The form of lozenge. These pharmaceutical compositions can be administered in a regimen of 1 to 4 times a day, including once, twice, three times and four times a day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is required for this in an amount of about 150 mg per day The patient was administered for 28 days or 56 days. In certain specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is required to be in an amount of about 150 mg per day The patient was administered for 28 days. In other specific embodiments, the compound of formula (I), or isotope variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is required for such a need in an amount of about 150 mg per day The patient was administered for 56 days.

In some embodiments, the pharmaceutical composition provided herein can be formulated to contain about 180 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof Formulated in the form of tablets. These pharmaceutical compositions can be administered in a regimen of 1 to 4 times a day, including once, twice, three times and four times a day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is required for this in an amount of about 180 mg per day The patient was administered for 28 days or 56 days. In certain specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is required to be in an amount of about 180 mg per day The patient was administered for 28 days. In other specific embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is required for such a need in an amount of about 180 mg per day The patient was administered for 56 days.

In the method of treating, preventing or alleviating one or more of the symptoms of the disorders, diseases or conditions described herein, the appropriate dosage concentration of the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) Generally, it is in the range of about 0.1 to 2,000 mg per day, week, month or every two months. For example, 100, 900, or 1,000 mg once or more times a month can be effective in obtaining the desired results.

In certain embodiments, the T cell activating bispecific antigen-binding molecule is obine eutuzumab and the amount administered to it is approximately 10 mg/day up to, and includes, 2,000 mg/day. In certain embodiments, the amount of Obin Utuzumab administered is about 10 mg/day to 1,000 mg/day. In certain embodiments, the amount of Obin Utuzumab administered is about 100 mg/day to 1,000 mg/day. In certain embodiments, in the treatment, prevention, or alleviation of one or more of the disorders, diseases, or conditions described herein, a T cell activating bispecific antigen binding molecule (e.g., obin utuzumab ) Is generally between about 100 to 1,000 mg, about 250 to about 1,000 mg, about 500 to about 1,000 mg, about 750 to about 1,000 mg, about 900 to about 1,000 mg, or about 10 to about 150 mg. Within the scope, it can be administered in single or multiple doses. In certain embodiments, the T cell activating bispecific antigen-binding molecule (e.g., obinostatuzumab) is at about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 1,000, or 2,000 mg are administered. In certain embodiments, the T cell activating bispecific antigen binding molecule (e.g., obin utuzumab) is at about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 1,000, or 2,000 mg/day.

In the method of treating, preventing or alleviating one or more of the symptoms of the disorders, diseases or conditions described herein, the appropriate dosage concentration of the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) Generally, it is in the range of about 1 to 2,000 mg per day, weekly, monthly or every two months. For example, 100, 900, or 1,000 mg once or more times a month can be effective in obtaining the desired results.

For oral administration, the pharmaceutical compositions provided herein can be formulated into the form of tablets or capsules containing about 1 to about 2,000 mg. For administration by infusion, the pharmaceutical composition provided herein can be formulated to 1,000 mg/40 mL (25 mg/mL) T cell activating bispecific antigen-binding molecule (e.g., obin utuzumab ) Of the solution. These pharmaceutical compositions can be administered on a schedule of one (1) to four (4) times a month, including once, twice, three and four times a month. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered once a month. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered twice a month. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered three times a month. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered four times a month. In some embodiments, the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) is administered once every other month. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obin utuzumab) is administered twice a day. In some embodiments, about 100 mg of the T cell activating bispecific antigen-binding molecule (for example, obineutuzumab) is administered by infusion. In some embodiments, about 900 mg of the T cell activating bispecific antigen binding molecule (for example, obinetuzumab) is administered by infusion. In some embodiments, about 1,000 mg of the T cell activating bispecific antigen binding molecule (for example, obinetuzumab) is administered by infusion. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered by infusion for up to six 28-day cycles. In some embodiments, the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) is administered by infusion for at least six 28-day cycles. In some embodiments, about 100 mg of the T cell activating bispecific antigen binding molecule (for example, obinetuzumab) is administered by infusion on the first day of the 28-day cycle. In some embodiments, about 900 mg of the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) is administered by infusion on the second day of the 28-day cycle. In some embodiments, about 1,000 mg of the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) is administered by infusion on days 8 and 15 of the 28-day cycle. In some embodiments, about 100 mg is administered by infusion on the first day of cycle 1 of a 28-day cycle, 900 mg is administered on the second day of cycle 1, and 1,000 is administered on days 8 and 15 of cycle 1. mg and 1,000 mg of T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) administered on the first day of cycle 2 to 6. In some embodiments, about 100 mg is administered by infusion administration on days 1, 8 and 15 of cycle 1 of a 28-day cycle, and 1,000 mg of T cell activation is administered on the first day of cycles 2 to 6 Sexual bispecific antigen-binding molecules (e.g., Obinetuzumab). In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered by infusion at 25 mg/hr for 4 hours. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered by infusion at 50 mg/hr. In some embodiments, the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) is administered by infusion at 100 mg/hr. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered by infusion at 150 mg/hr. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered by infusion at 200 mg/hr. In some embodiments, the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) is administered by infusion at 250 mg/hr. In some embodiments, the T cell activating bispecific antigen binding molecule (for example, obinouximab) is administered by infusion at 300 mg/hr. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered by infusion at 350 mg/hr. In some embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is administered by infusion at 400 mg/hr.

In certain embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is combined with a compound of formula (I), or an isotope variant thereof; or a pharmaceutically acceptable salt thereof , Solvates, hydrates, or prodrugs are co-administered once a day (e.g., in a single dosage form). In certain embodiments, the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) is combined with a compound of formula (I), or an isotope variant thereof; or a pharmaceutically acceptable The salt, solvate, hydrate, or prodrug is co-administered twice daily (e.g., in a single dosage form).

However, it should be understood that the specific dosage and dosage frequency for any particular patient can vary and will depend on various factors, including the activity of the particular compound used, the metabolic stability and length of action of the compound, age, weight, general health, Gender, diet, mode of administration and time of administration, excretion rate, drug combination, severity of specific disease and host of formal therapy. Additional combination therapy

In certain embodiments, it includes a compound of formula (I), an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and a T cell activating bispecific antigen binding molecule (e.g. The method of combination therapy of obinouxtuzumab can also be combined or used in combination with a third agent or therapy suitable for treating, preventing or alleviating one or more symptoms of proliferative disorders, diseases or disorders.

Suitable third agents for treatment include (but are not limited to) (1) α-adrenergic agents; (2) anti-arrhythmic agents; (3) anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics , Such as anthracyclines, bleomycin, mitomycin, actinomycin and pracamycin; (5) anticancer agents and cytotoxic agents, for example, alkylating agents, such as nitrogen mustard, alkyl sulfonate Acid salts, nitrosoureas, acetylene imines and triazenes; (6) Anticoagulants, such as acetocoumarol, argatroban, bivalirudin, and lepirudine (lepirudin), fondaparinux, heparin, fenbutanone, warfarin and xirnelagatran, (7) anti-diabetic agents, such as biguanides (for example, metformin), glucosidase Inhibitors (e.g., acarbose), insulin, mecobalamin (e.g., repaglinide), sulfonylurea (e.g., glimepiride, glibenclamide) (glyburide and glipizide), thiazolidinediones (for example, troglitazone, rosiglitazone and pioglitazone) and PPAR-γ agonists; (8) Antifungal agents, such as amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, carbopol Caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, iso Conazole (isoconazole), itraconazole (itraconazole), ketoconazole (ketoconazole), micafungin (micafungin), miconazole (miconazole), naftifine (naftifine), natamycin (natamycin) , Nystatin (nystatin), oxyconazole (oxyconazole), ravuconazole (ravuconazole), posaconazole (posaconazole), rimocidin (rimocidin), sertaconazole (sertaconazole), Sulconazole (sulconazole), terbinafine (terbinafine), terconazole (terconazole), sulconazole ( tioconazole and voriconazole; (9) anti-inflammatory drugs, for example, non-steroidal anti-inflammatory drugs, such as aceclofenac, acemetacin, amoxiprin, aspirin (aspirin), azapropazone, benolate, bromfenac, carprofen, celecoxib, choline magnesium salicylate ), diclofenac (diclofenac), diflunisal (diflunisal), etodolac, etoricoxib, faislamine, fenbufen, fenoprofen , Flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen (loxoprofen), lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate Ester, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, butazone ( phenylbutazone, piroxicam, salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, thiol Tiaprofenic acid and tolmetin; (10) antimetabolites, such as folate antagonists, purine analogs, and pyrimidine analogs; (11) antiplatelet agents, such as GPIIb/IlIa blockers (For example, abciximab (abciximab), eptifibatide (eptifibatide) and tirofiban (tirofiban)), P2Y (AC) antagonists (for example, clopidogrel (clopidogrel), ticlopidine) ) And CS-747), cilostazol, dipyridamole (dip yridamole) and aspirin; (12) antiproliferative agents, such as methotrexate, FK506 (tacrolimus) and mycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptors, such as etanercept Etanercept, rapamycin and leflunimide; (14) aP2 inhibitors; (15) β-adrenergic agents, such as carvedilol and metoprolol (metoprolol); (16) bile acid sequestrants, such as questran; (17) calcium channel blockers, such as amlodipine besylate; (18) chemotherapeutics; (19) ) Cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; (20) cyclosporin; (21) cytotoxic drugs, such as azathioprine ) And cyclophosphamide (cyclophosphamide); (22) Diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, benzfluorothiazide ( bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlorthalidone ( chlorthalidone, furosenide, muzolimine, bumetanide, triamterene, amiloride and spironolactone; (23) endothelium ECE inhibitors, such as phosphoramidon; (24) enzymes, such as L-aspartase; (25) factor VIIa inhibitors and factor Xa inhibitors; (26) Fame Famesyl-protein transferase inhibitors; (27) fibric acids; (28) growth factor inhibitors, such as modulators of PDGF activity; (29) growth hormone secretagogues; (30) HMG CoA reductase inhibitors , Such as pravastatin (pravastatin), lovastatin (lovastatin), atorvastatin (atorvastatin), simvastatin (simvastatin), NK-104 ( Also known as itavastatin, nisvastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin, atavastatin or fes (Visastatin); neutral endopeptidase (NEP) inhibitor; (31) hormonal agents, such as glucocorticoids (for example, cortisone), estrogen/antiestrogens (antiestrogen) ), androgen/antiandrogen, progestin, and luteinizing hormone releasing hormone antagonist, and octreotide acetate; (32) immunosuppressant; (33) mineralocorticoid Hormone receptor antagonists, such as spironolactone and eplerenone; (34) microtubule disruptors, such as ecteinascidin; (35) microtubule stabilizers, such as paclitaxel (pacitaxel), docetaxel Docetaxel and epothilone AF; (36) MTP inhibitors; (37) nicotinic acid; (38) phosphodiesterase inhibitors, such as PDE III inhibitors (for example, cilostazin Azole) and PDE V inhibitors (for example, sildenafil, tadalafil, and vardenafil); (39) products derived from plants, such as vinca alkaloids ( vinca alkaloid), epipodophyllotoxin and taxane; (40) platelet activating factor (PAF) antagonist; (41) platinum complexes, such as cisplatin, saplatin ( satraplatin) and carboplatin; (42) potassium channel opener; (43) isopentenyl-protein transferase inhibitor; (44) protein tyrosine kinase inhibitor; (45) renin inhibitor; (46) Squalene synthase inhibitors; (47) Steroids such as aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrogen Cortisone (hydrocortis) one (cortisol), prednisolone, prednisone, methylprednisolone ), dexamethasone and triamcinolone; (48) TNF-α inhibitors, such as tenidap; (49) thrombin inhibitors, such as hirudin; ( 50) Thrombolytic agents, such as anistreplase, reteplase, tenecteplase, tissue plasminogen activator (tPA), recombinant tPA, streptokinase , Urokinase, prourokinase, and streptokinase activator complex (APSAC); (51) thromboxane receptor antagonists, such as ifetroban ( ifetroban); (52) topoisomerase inhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat , And (54) other various agents, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine and gold compounds.

In certain embodiments, third therapies that can be used in combination with the methods provided herein include (but are not limited to) surgery, endocrine therapy, biological response modifiers (e.g., interferon, interleukin, and tumor necrosis factor (TNF) )), overheating and cryotherapy, and medications to reduce any side effects (for example, antiemetics).

In certain embodiments, third therapeutic agents that can be used in combination with the compounds provided herein include, but are not limited to, alkylating drugs (methyl diamine, chlorambucil, cyclophosphamide, melphalan ( melphalan) and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C), and methotrexate), purine antagonists and pyrimidine antagonists (6-mercapto Purine, 5-fluorouracil, cytarabine and gemcitabine), spindle toxins (vinblastine, vincristine and vinorelbine), podophyllotoxin (etoposide ( etoposide), irinotecan and topotecan), antibiotics (daunorubicin, doxorubicin, bleomycin and mitomycin) , Nitrosoureas (carmustine and lomustine), enzymes (asparaginasc), and hormones (tamoxifen, leuprolide (leuprolide), flutamide and megestrol), imatinib, adriamycin, dexamethasone and cyclophosphamide. For a broader discussion of the latest cancer therapies; see, the World Wide Web under nci.nih.gov/, the list of FDA-approved oncology drugs under the World Wide Web fda.gov/cder/cancer/dniglistframe.htm , And The Merck Manual, Seventeenth ed., 1999, the entire contents of which are incorporated herein by reference to this disclosure.

In another embodiment, the method provided herein comprises administering a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and a T cell activating double Specific antigen binding molecules (e.g., obinostatuzumab) are administered together with one or more chemotherapeutic agents and/or therapies selected from the following: alkylating agents (e.g., cisplatin, carboplatin; antimetabolites) (For example, methotrexate and 5-FU); antitumor antibiotics (for example, adriamymycin and bleomycin); antitumor vegetable alkaloids (for example, taxol and etoposide) ; Anti-tumor hormones (for example, dexamethasone and tamoxifen); anti-tumor immune agents (for example, interferon alpha, beta, and gamma); radiotherapy; and surgery. In certain embodiments, these one Or multiple chemotherapeutic agents and/or therapies are administering the compound of formula (I), or its isotope variant, or its pharmaceutically acceptable salt, solvate, hydrate or prodrug and T cell activating bispecific The antigen binding molecule (e.g., obinostatuzumab) is administered to the individual before, during, or after.

These other medicaments or drugs can be combined with the compound of formula (I), or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs and T cell activating bispecific antigen binding molecules ( For example, obin utuzumab) is administered simultaneously or sequentially by a certain route and a certain amount commonly used for this purpose. When using the compound of formula (I) and T cell activating bispecific antigen-binding molecule (for example, obin utuzumab) together with one or more other drugs, the compound of formula (I) or its isotopes can be used Variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs and T cell activating bispecific antigen-binding molecules (for example, obin utuzumab), and also contain these other Pharmaceutical composition of medicine, but not essential. Therefore, the pharmaceutical compositions provided herein include those that, in addition to the compound of formula (I), also contain one or more other active ingredients or therapeutic agents. Pharmaceutical composition and route of administration

Provided herein are the compounds provided herein, compounds of formula (I), and/or T cell activating bispecific antigen-binding molecules (for example, obinostatuzumab) and pharmaceutically acceptable excipients and adjuvants , Carrier, buffer or stabilizer of the pharmaceutical composition. In some embodiments, the compound of formula (I) and the T cell activating bispecific antigen binding molecule (for example, obinostatuzumab) are present in the same pharmaceutical composition. In some embodiments, the compound of formula (I) and the T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab) are in different pharmaceutical compositions.

In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration. The pharmaceutical composition includes the compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical composition provided herein may be in the form of a lozenge, capsule, powder or liquid formulated for oral administration. In some embodiments, the lozenge contains a solid carrier or adjuvant. Liquid pharmaceutical compositions generally contain a liquid carrier such as water, petroleum, animal or vegetable oil, mineral oil, or synthetic oil. It may include physiological saline solution, glucose or other sugar solutions, or glycols, such as ethylene glycol, propylene glycol, or polyethylene glycol. In some embodiments, the capsule contains a solid carrier, such as gelatin.

In another embodiment, the pharmaceutical composition is provided in a dosage form for parenteral administration. The pharmaceutical composition includes the compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. In the case that the pharmaceutical composition can be formulated for intravenous, skin or subcutaneous injection, the active ingredient will be in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has suitable pH, isotonicity and stability Sex. Those who are familiar with the related art can use, for example, isotonic vehicles (such as sodium chloride injection, Ringer's injection or lactated Ringer's injection) to prepare a suitable solution. In some embodiments, preservatives, stabilizers, buffers, antioxidants, and/or other additives are included as needed.

In yet another embodiment, the pharmaceutical composition is provided in a dosage form for topical administration. The pharmaceutical composition includes the compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.

The pharmaceutical composition can also be formulated into modified release dosage forms, including delayed release, extended release, extended release, sustained release, pulsed release, controlled release, accelerated release, rapid release, targeted release and programmed release, and gastric retention Dosage form. These dosage forms can be prepared according to known methods and techniques known to those who are familiar with the art (see Remington: The Science and Practice of Pharmacy, ibid; Modified-Release Drug Delivery Technology, 2nd edition, edited by Rathbone et al., Marcel Dekker, Inc.: New York, NY, 2008).

The pharmaceutical compositions provided herein can be provided in unit dosage form or in multiple dosage forms. As used herein, the unit dosage form refers to physically discrete units suitable for administration to humans and animal individuals, and individually packaged as known in the art. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, and the required pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. Unit dosage forms can be administered in fractions or multiples thereof. A multi-dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of multi-dose forms include vials, lozenges or capsule bottles, or pint or gallon bottles.

The pharmaceutical compositions provided herein can be administered at one time or multiple times at certain time intervals. It should be understood that the precise dose and duration of treatment can vary with the age, weight, and condition of the patient being treated, and can be determined empirically using known test protocols or by extrapolating from in vivo or in vitro tests or diagnostic data. It should be further understood that for any specific individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person who administers or supervises the administration of the formulation.

In certain embodiments, the pharmaceutical compositions provided herein further comprise one or more chemotherapeutic agents as defined herein. A. Oral investment

For oral administration The pharmaceutical compositions provided herein can be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, translingual, and sublingual administration. Suitable oral dosage forms include (but are not limited to) lozenges, instant powders, chewable lozenges, capsules, pills, patches, tablets, lozenges, pastilles, cachets, pellets, medicinal chewing gum, and bulk Powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, flakes, spray medicines, elixirs and syrups. In addition to the active ingredients, these pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, which include (but are not limited to) binders, fillers, diluents, disintegrants, wetting agents, etc. Sources of agents, lubricants, glidants, colorants, dye migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide.

The binder or granulation agent imparts cohesiveness to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches, such as corn starch, potato starch, and pregelatinized starch (for example, starch 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose ; Natural gums and synthetic gums, such as gum arabic, alginic acid, alginate, Irish moss extract, Panwar gum, Gandhi gum, mucilage of Isaboo husk, carboxymethyl cellulose, methyl cellulose, poly Vinylpyrrolidone (PVP), magnesium aluminum silicate, larch arabinogalactan, powdered tragacanth and guar gum; cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, Sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose, such as AVICEL-PH -101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include (but are not limited to) talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextran, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and Its mixture. The amount of binder or filler in the pharmaceutical composition provided herein varies depending on the type of formulation, and is easily distinguishable by those skilled in the art. The binder or filler may be present in the pharmaceutical composition provided herein at about 50 to about 99% by weight.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, anhydrous starch and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart properties to some compressed lozenges that allow disintegration in the oral cavity by chewing. These compressed lozenges can be used as chewable lozenges. The amount of diluent in the pharmaceutical composition provided herein varies depending on the type of formulation and can be easily distinguished by those skilled in the art.

Suitable disintegrants include (but are not limited to) agar; bentonite; cellulose, such as methyl cellulose and carboxymethyl cellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums, such as guar gum and silicon Magnesium aluminum HV; citrus pulp; cross-linked cellulose, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as starch ethanol Sodium; Pollacrine potassium; Starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starches; clay; lignins; and mixtures thereof. The amount of disintegrant in the pharmaceutical composition provided herein varies depending on the type of formulation and is easily distinguishable by those skilled in the art. The amount of disintegrant in the pharmaceutical composition provided herein varies depending on the type of formulation and is easily distinguishable by those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% by weight or about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include (but are not limited to) calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol Alcohol (PEG); Stearic acid; Sodium lauryl sulfate; Talc; Hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; Zinc stearate; Ethyl oleate; Laurel Ethyl acid; Agar; Starch; Lycopodium pine nuts; Silica or silicone, such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL® (Boston Cabot, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of lubricant.

Suitable glidants include (but are not limited to) colloidal silica, CAB-O-SIL® (Boston Cabot, MA) and non-asbestos talc. Suitable coloring agents include, but are not limited to, approved water-soluble FD&C dyes, water-insoluble FD&C dyes suspended on hydrated alumina, and lakes and their mixtures. Lakes cause a combination of insoluble forms of dyes by adsorbing water-soluble dyes to hydrated oxides of heavy metals. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants (such as fruits), and synthetic blends of compounds that produce pleasant taste, such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, tragacanth, bentonite and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan mono oil Ester 80 (TWEEN® 80) and triethanolamine oleate. Suitable suspending and dispersing agents include (but are not limited to) sodium carboxymethyl cellulose, pectin, tragacanth, magnesium aluminum silicate, acacia, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and Polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propyl paraben, benzoic acid, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethanol, and syrup. Suitable non-aqueous liquids used in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include (but are not limited to) sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients can perform several functions, even in the same formulation.

For oral administration, the pharmaceutical compositions provided herein can be used as compressed lozenges, lozenges mills, chewable lozenges, fast-dissolving lozenges, multiple compressed lozenges, or enteric-coated lozenges, sugar packets Coated or film-coated tablets are provided. Enteric-coated tablets are compressed tablets coated with substances that resist the action of gastric acid but dissolve or disintegrate in the intestine, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated lozenges are compressed lozenges surrounded by a sugar coating. The sugar coating can help mask unpleasant taste or odor and protect the lozenges from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

The lozenge dosage form can be in powder, crystal or granular form, alone or with one or more of the carriers or excipients described herein (including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants). ) Combinations, prepared from active ingredients. Flavoring and sweetening agents are especially suitable for formulating chewing tablets and lozenges.

For oral administration, the pharmaceutical compositions provided herein can be provided as soft or hard capsules, which can be manufactured from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules (also known as dry-filled capsules (DFC)) consist of two parts, one part is stroked across the other, so the active ingredient is completely enclosed. Soft elastic capsules (SEC) are soft spherical shells, such as gelatin shells, which are plasticized by adding glycerin, sorbitol or similar polyols. The soft gelatin shell may contain preservatives to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing these solutions can be prepared as described in US Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules can also be coated to modify or maintain the dissolution of the active ingredients as known by those skilled in the art.

Coloring and flavoring agents can be used in all the above dosage forms.

For oral administration, the pharmaceutical compositions provided herein can be formulated into immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release forms. B. Intestinal administration

The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or transplantation, for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrasaccular, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

For parenteral administration The pharmaceutical composition provided herein can be suitable for parenteral administration with any dosage form formulation, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and suitable for A solid form dissolved or suspended in a liquid before injection. These dosage forms can be prepared according to the well-known methods known to those skilled in medical science (see, Remington: The Science and Practice of Pharmacy, ibid.).

The pharmaceutical composition intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, which include (but are not limited to) aqueous vehicles, water-miscible vehicles, and non-aqueous vehicles. Agents, antibacterial agents or preservatives to resist the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting agents or emulsifiers, complexing agents, masking Agents or chelating agents, cryoprotectants, freeze-dried protective agents, thickeners, pH regulators and inert gases.

Suitable aqueous vehicles include (but are not limited to) water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose And lactated Ringer's injection. Suitable non-aqueous vehicles include (but are not limited to) fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and Coconut oil medium chain triglycerides and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- Methyl-2-pyrrolidone, N,N-dimethylacetamide and dimethyl sulfoxide.

Suitable antibacterial or preservatives include (but are not limited to) phenol, cresol, amalgam, benzyl alcohol, chlorobutanol, methyl paraben and propyl paraben, thimerosal, benzene Ammonium chloride (for example, phenyl vinyl chloride), methyl and propyl p-hydroxybenzoate and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable emulsifiers are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable masking or chelating agents include (but are not limited to) EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include (but are not limited to) cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin and sulfonbutane Base ether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

When the pharmaceutical composition provided herein is formulated for multi-dose administration, the multi-dose parenteral formulation must contain a bacteriostatic or fungal antibacterial agent at a static concentration. As known and practiced in this technology, all parenteral formulations must be sterile.

In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical compositions are provided as sterile anhydrous soluble products (including freeze-dried powders and subcutaneous lozenges) to be reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical compositions are provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical compositions are provided as sterile, anhydrous and insoluble products to be reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.

For parenteral administration, the pharmaceutical compositions provided herein can be formulated into immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms.

For parenteral administration The pharmaceutical composition provided herein can be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implantable storage. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner substrate surrounded by an outer polymeric film that is insoluble in body fluids but allows the active ingredients in the pharmaceutical compositions to diffuse completely.

Suitable internal substrates include (but are not limited to) polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate , Natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymer (Such as acrylate and methacrylate hydrogels), collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate.

Suitable external polymer films include (but are not limited to) polyethylene, polypropylene, ethylene/propylene copolymer, ethylene/polypropylene ethyl copolymer, ethylene/vinyl acetate copolymer, silicone rubber, polydimethylsiloxane , Neoprene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber sheet Chlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/ethyleneoxyethanol copolymer. C. Modified release

The pharmaceutical compositions provided herein can be formulated into modified release dosage forms. As used herein, the term "modified release" refers to a dosage form in which when administered by the same route, the release rate or location of the active ingredient is different from the immediate release dosage form. Modified release dosage forms include (but are not limited to) delayed release, extended release, extended release, sustained release, pulsed release, controlled release, accelerated release and rapid release, targeted release, programmed release, and gastric retention dosage forms. The pharmaceutical composition in a modified release dosage form can be prepared using various modified release devices and methods known to those skilled in the art, including (but not limited to) substrate-controlled release devices, permeability control The release device, multi-particle controlled release device, ion exchange resin, enteric coating, multilayer coating, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by changing the particle size and polymorphism of the active ingredient.

Examples of modified releases include (but are not limited to) they are described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,476; ; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,613,358; and 6,699,358;

This document also provides kits which, when used by the physician, can simplify the administration of an appropriate amount of active ingredients to the individual. In certain embodiments, the kits provided herein include one or more containers and a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and Dosage form of T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab).

In certain embodiments, the kits provided herein include one or more containers and a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and Dosage form of T cell activating bispecific antigen-binding molecule (for example, obinostatuzumab). The kits provided herein may further include devices for administering active ingredients. Examples of such devices include, but are not limited to, syringes and needleless syringe drip bags.

The kits provided herein may further include a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may contain a sealed container of a suitable vehicle, in which the active ingredient can be dissolved to form a solid form suitable for parenteral administration. It is a sterile solution without particles. Examples of pharmaceutically acceptable vehicles include (but are not limited to): aqueous vehicles, including (but not limited to) water for injection USP, sodium chloride injection, Ringer's injection, glucose injection, glucose and chloride Sodium injection and lactated Ringer's injection; water-miscible vehicles, including (but not limited to) ethanol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles, including (but not limited to) corn oil, cottonseed oil , Peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

The present invention will be further understood by the following non-limiting examples. Instance

As used herein, the symbols and conventions used in these methods, schemes, and examples, regardless of whether specific abbreviations are specifically defined, are consistent with their users in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. To be specific, but not limited, the following abbreviations can be used in the examples and throughout the specification: g (grams); mg (mg); mL (milliliters); µL (microliters); M (moles); mM (millimoles) Ear); µM (micromole); eq. (equivalent); mmol (millimoles); Hz (hertz); MHz (megahertz); hr or hrs (hours); min (minutes); and MS (mass spectrometry ).

For all the following examples, standard post-processing and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in °C (Celsius). Unless otherwise stated, all reactions were carried out at room temperature. The synthetic methods described herein are intended to illustrate applicable chemistry by using specific examples and are not indicative of the scope of the present invention.

The synthesis of compound A35 is described in US Patent No. 9,056,852 B2, which is incorporated into the present invention by reference. Example 1 : 4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(1-methylpiperidine- 4-yl)phenyl)propan-2-yl)-6-morpholinyl-1,3,5-triazin-2-amine, synthesis of compound A35

Add 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(piperidin-4- (Yl)phenyl)propan-2-yl)-6-morpholinyl-1,3,5-triazine-2-amine (80 mg, 0.14 mmol), aqueous formaldehyde solution (37%, 23 mg) and cyano A mixture of sodium borohydride (11 mg, 0.17 mmol) in methanol (2 mL) was stirred for 1 hr. The crude product was purified by preparative HPLC to give compound A35 as a white solid (11 mg, 13% yield): 99% purity (HPLC); MS m/z: 577.3 (M+1); ¹ H NMR ( CDCl ₃ , 500 MHz) δ 8.37 (d, 1H), 7.90 (d, 1H), 7.64 (t, 1H), 7.42 (m, 2H), 7.32 (d, 1H), 7.24 (1, 1H), 7.13 (t, 1H), 7.07 (d, 1H), 5.15 (s, 1H), 4.00-3.70 (m, 8H), 3.28 (s, 2H), 2.94 (m, 2H), 2.78 (m, 2H), 2.28 (s, 3H), 1.89-1.60 (m, 6H), 1.53 (s, 6H) ppm. Example 2 : The study of the combination of PI3K inhibitor and Obinutuzumab in patients with chronic lymphocytic leukemia (CLL)

The purpose of this study is to evaluate the safety and efficacy of compounds A35, A36, A68 or A70 and Obineutuzumab in patients with CLL.

Main outcome measurement: To determine acceptable adverse events related to treatment [time range: 6 months of treatment]. To determine the incidence of adverse events, any potential abnormal laboratory results and any dose-limiting toxicity.

Secondary outcome measurement: overall response rate [time frame: up to one year]. The overall response rate (ORR) in patients with CLL treated with a combination of compound A35, A36, A68 or A70 and obinouxtuzumab. arm Designated intervention Experiment: Obinostatuzumab + compound A35, A36, A68 or A70 Obinostatuzumab dose: 10 to 1000 mg Compound A35, A36, A68 or A70 oral daily dose: 30 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day orally orally once a day or utuzumab injection for intravenous infusion Experiment: Obinostatuzumab + compound A35, A36, A68 or A70 Obinostatuzumab dose: 10 to 1000 mg Compound A35, A36, A68 or A70 oral daily dose: 45 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day (oral medication) Obineutuzumab injection for intravenous infusion Experiment: Obinetuzumab + compound A35, A36, A68 or A70 Obinetuzumab oral daily dose: 10 to 500 mg Compound A35, A36, A68 or A70 oral daily dose: 60 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day orally orally once a day or utuzumab injection for intravenous infusion Experiment: Obinostatuzumab + compound A35, A36, A68 or A70 Obinostatuzumab dosage: 10 to 1000 mg Compound A35, A36, A68 or A70 oral daily dosage: 120 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day orally orally once a day or utuzumab injection for intravenous infusion Experiment: Obinostatuzumab + compound A35, A36, A68 or A70 Obinostatuzumab dose: 10 to 1000 mg Compound A35, A36, A68 or A70 oral daily dose: 150 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day orally orally once a day or utuzumab injection for intravenous infusion

Patients should not have been exposed to the compound before entering the study. Patients must have not received treatment for their cancer within 2 weeks of starting the trial. Treatment includes the use of chemotherapy, hematopoietic growth factors, and biological therapies (such as monoclonal antibodies). The patient must have recovered from all toxicities related to the previous treatment (to grade 0 or 1). All blood collections for safety assessment and pharmacokinetic analysis of all systems are collected on a schedule. All studies were conducted with the approval of the institutional ethics committee and patient consent.

Based on the assessment as outlined below, the dose of the compound can be maintained or modified for toxicity. In the absence of unacceptable toxicity, treatment is repeated every 28 days. Dose-limiting toxicity was determined according to the definition and standards set by the National Cancer Institute (NCI) Common Adverse Events (CTCAE) version 3.0 (August 9, 2006).

Blood sampling series Blood is sampled by direct venipuncture before and after compound administration. The venous blood sample (5 mL) used to determine the serum concentration was obtained approximately 10 minutes before administration and approximately at the following time after administration: Days 1, 8 and 15. Divide each serum sample into two equal parts. All serum samples are stored at -20°C. The serum samples are shipped on dry ice.

Pharmacokinetics: Before starting treatment and on days 1, 8, and 15, patients undergo plasma/serum sample collection for pharmacokinetic evaluation. The pharmacokinetic parameters were calculated on the computer system of the digital equipment company VAX 8600 using the latest version of BIOAVL software by the model-independent method. Determine the following pharmacokinetic parameters: peak serum concentration (C _max ); time to reach peak serum concentration (t _max ); concentration-time from time zero to the last blood sampling time (AUC _0-72 ) calculated using the linear trapezoidal rule Area under the curve (AUC); and terminal elimination half-life (t _1/2 ), calculate the self-elimination rate constant. The elimination rate constant is evaluated by linear regression of continuous data points in the terminal linear region of the log-linear concentration-time graph. Calculate the average value, standard deviation (SD) and coefficient of variation (CV) of the pharmacokinetic parameters for each treatment. Calculate the parameter-average ratio (preserved formulation/non-preserved formulation).

Patient response to combination therapy: Patient response is assessed by X-ray, CT scan, and MRI imaging, and imaging is performed before the start of the study and at the end of the first cycle, and additional imaging every four weeks or in subsequent cycles Carried out at the end. The imaging format is selected based on the cancer type and feasibility/availability, and the same imaging format is used for similar cancer types and throughout the research process of each patient. Patient response is also assessed by complete blood count and/or bone marrow biopsy. The reaction rate was measured using RECIST standards. (Therasse et al., J. Natl. Cancer Inst. 2000 Feb 2; 92(3):205-16; https://ctep.cancer.gov/forms/TherasseRECISTJNCI.pdf). After completing the study treatment, the patients were followed up regularly for 4 weeks. Example 3 : The study of the combination of PI3K inhibitor and obinoiutuzumab in patients with follicular lymphoma (FL)

The purpose of this study is to evaluate the safety and efficacy of compounds A35, A36, A68 or A70 and obinoeutuzumab in patients with FL.

Main outcome measurement: To determine acceptable adverse events related to treatment [time range: 6 months of treatment]. To determine the incidence of adverse events, any potential abnormal laboratory results and any dose-limiting toxicity.

Secondary outcome measurement: overall response rate [time frame: up to one year]. The overall response rate (ORR) in patients with FL treated with a combination of compound A35, A36, A68 or A70 and obinoeutuzumab. arm Designated intervention Experiment: Obinostatuzumab + compound A35, A36, A68 or A70 Obinostatuzumab dose: 10 to 1000 mg Compound A35, A36, A68 or A70 oral daily dose: 30 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day orally orally once a day or utuzumab injection for intravenous infusion Experiment: Obinostatuzumab + compound A35, A36, A68 or A70 Obinostatuzumab dose: 10 to 1000 mg Compound A35, A36, A68 or A70 oral daily dose: 45 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day orally orally once a day or utuzumab injection for intravenous infusion Experiment: Obinetuzumab + compound A35, A36, A68 or A70 Obinetuzumab oral daily dose: 10 to 500 mg Compound A35, A36, A68 or A70 oral daily dose: 60 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day orally orally once a day or utuzumab injection for intravenous infusion Experiment: Obinostatuzumab + compound A35, A36, A68 or A70 Obinostatuzumab dosage: 10 to 1000 mg Compound A35, A36, A68 or A70 oral daily dosage: 120 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day orally orally once a day or utuzumab injection for intravenous infusion Experiment: Obinostatuzumab + compound A35, A36, A68 or A70 Obinostatuzumab dose: 10 to 1000 mg Compound A35, A36, A68 or A70 oral daily dose: 150 mg PI3K inhibitors: compound A35, A36, A68 or A70 once a day orally orally once a day or utuzumab injection for intravenous infusion

Patients should not have been exposed to the compound before entering the study. Patients must have not received treatment for their cancer within 2 weeks of starting the trial. Treatment includes the use of chemotherapy, hematopoietic growth factors, and biological therapies (such as monoclonal antibodies). The patient must have recovered from all toxicities related to the previous treatment (to grade 0 or 1). All blood collections for safety assessment and pharmacokinetic analysis of all systems are collected on a schedule. All studies were conducted with the approval of the institutional ethics committee and patient consent.

Based on the assessment as outlined below, the dose of the compound can be maintained or modified for toxicity. In the absence of unacceptable toxicity, treatment is repeated every 28 days. Dose-limiting toxicity was determined according to the definition and standards set by the National Cancer Institute (NCI) Common Adverse Events (CTCAE) version 3.0 (August 9, 2006).

Blood sampling series Blood is sampled by direct venipuncture before and after compound administration. The venous blood sample (5 mL) used to determine the serum concentration was obtained approximately 10 minutes before administration and approximately at the following time after administration: Days 1, 8 and 15. Divide each serum sample into two equal parts. All serum samples are stored at -20°C. The serum samples are shipped on dry ice.

Pharmacokinetics: Before starting treatment and on days 1, 8, and 15, patients undergo plasma/serum sample collection for pharmacokinetic evaluation. The pharmacokinetic parameters are calculated on the computer system of the digital equipment company VAX 8600 using the latest version of BIOAVL software by the model-independent method. The following pharmacokinetic parameters were determined: peak serum concentration (C _max ); time to reach peak serum concentration (t _max ); concentration-time from zero to the last blood sampling time (AUC _0-72 ) calculated using the linear trapezoidal rule Area under the curve (AUC); and terminal elimination half-life (t _1/2 ), calculate the self-elimination rate constant. The elimination rate constant is evaluated by linear regression of continuous data points in the terminal linear region of the log-linear concentration-time graph. Calculate the average value, standard deviation (SD) and coefficient of variation (CV) of the pharmacokinetic parameters for each treatment. Calculate the parameter-average ratio (preserved formulation/non-preserved formulation).

Patient response to combination therapy: Patient response is assessed by X-ray, CT scan, and MRI imaging, and imaging is performed before the start of the study and at the end of the first cycle, and additional imaging every four weeks or in subsequent cycles Carried out at the end. The imaging format is selected based on the cancer type and feasibility/availability, and the same imaging format is used for similar cancer types and throughout the research process of each patient. The patient's response is also assessed by a complete blood count and/or bone marrow biopsy. The reaction rate was determined using RECIST standards. (Therasse et al., J. Natl. Cancer Inst. 2000 Feb 2; 92(3):205-16; https://ctep.cancer.gov/forms/TherasseRECISTJNCI.pdf). After completing the study treatment, the patients were followed up regularly for 4 weeks.

The examples set forth above are provided to give them the full disclosure and description of the methods of making and using the embodiments claimed by the present invention and are not intended to limit the scope of the content disclosed herein. The modifications obvious to those familiar with the technology are intended to be within the scope of the following patent applications.

Claims (101)

A method for the treatment or prevention of cancer, which comprises administering an effective amount of: a) a compound of formula (I):

Formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrug; wherein: X, Y and Z are each independently N or CR ^X , provided that at least two of X, Y and Z are nitrogen atoms; wherein R ^X is hydrogen or C _1-6 alkyl; R ¹ And R ^{2 are} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O )NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC( =NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c ,- NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a ,- S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; each of R ^1a , R ^1b , R ^1c and R ^1d Independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _{7- 15} Aralkyl, heteroaryl or heterocyclic group; or (iii) R ^1b and R ^1c together with the N atom to which they are bonded form a heterocyclic group; R ³ and R ^{4 are} each independently hydrogen or C _1-6 alkane Group; or R ³ and R ^{4 are} joined together to form a bond, C _1-6 alkylene, C _1-6 heteroalkylene, C _2-6 alkenylene or C _2-6 heteroalkenylene; R ^5a is (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 Aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)N R ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(= NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5b is (a) halo; (b) C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; Or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O) R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O )NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5c series -(CR ^5f R ^5g ) _n -(C _6-14 Aryl) or -(CR ^5f R ^5g ) _n -heteroaryl; R ^5d and R ^{5e are} each independently (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c ,- OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S( O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5f and R ^{5g are} each independently (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a ) NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c ,- NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S( O)R ^1d 、-NR ^1a S(O ) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c ; or -S(O) ₂ NR ^1b R ^1c ; or (d) when R ^5f occurs once and R ^5g is bonded to the same carbon atom once, then the R ^5f And R ^5g together with the carbon atom to which it is bound to form a C _3-10 cycloalkyl or heterocyclic group; R ⁶ is hydrogen, C _1-6 alkyl, -SC _1-6 alkyl, -S(O)-C _1-6 alkyl or -SO ₂ -C _1-6 alkyl; m is 0 or 1; and n is 0, ¹ , ² , 3 or 4; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^X , R ^1a , R ^1b , R ^1c , R ^1d , R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f and R ^5g each of the alkyl, alkylene, and heteroalkane Alkenyl, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are optionally substituted with one, two, three, four or five Group Q is substituted, wherein each substituent Q is independently selected from (a) pendant oxy, cyano, halo and nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl and heterocyclic group, each of which may be further subjected to one, two, Three or four substituents Q ^a substituted; and (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(=NR ^a )NR ^b R ^c , -OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(O)R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c and -S(O) ₂ NR ^b R ^c , where each of R ^a , R ^b , R ^c and R ^d Independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _{7- 15} Aralkyl, heteroaryl or heterocyclyl, each of them is further substituted with one, two, three or four substituents Q ^a as necessary; or (iii) R ^b and R ^c are combined with them The N atoms together form a heterocyclic group, which is further substituted by one, two, three or four substituents Q ^a as necessary; wherein each Q ^a is independently selected from the group consisting of: (a) pendant oxy, Cyano, halo and nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _{7 -15} Aralkyl, heteroaryl and heterocyclyl; and (c) -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^f R ^g , -C(NR ^e ) NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O)NR ^f R ^g , -OC(=NR ^e )NR ^f R ^g , -OS( O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^h , -NR ^e C(O)NR ^f R ^g , -NR ^e C(=NR ^h )NR ^f R ^g , -NR ^e S(O)R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^f R ^g , -SR ^e , -S(O)R ^e , -S(O) ^{_{2 R e, -S (O)}} NR f R g , and ^{_{-S (O) 2 NR f R}} g; wherein each of R ^e, R ^f, R ^g and R ^h are independently lines (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group Or (iii) R ^f and R ^g together with the N atoms to which they are bound to form a heterocyclic group; wherein the two adjacent substituents Q form a C _3-10 cycloalkenyl group, a C _6-14 aryl group, Heteroaryl or heterocyclic group, each optionally substituted with one, two, three or four substituents Q ^a ; and b) T cell activating bispecific antigen binding molecule. As the method of claim 1, wherein R ^5b is (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl or heteroaryl; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C (NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -S(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C( O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a ,- S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c . As in the method of claim 1, wherein R ^5a and R ^{5b are} each independently (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 10} cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C (O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c ,- OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c ,- NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c . Such as the method of claim 3, wherein each of R ^5a and R ^{5b is a} methyl group, which is substituted with one, two or three halo groups as necessary. Such as the method of any one of claims 1 to 4, where n is 1. The method according to any one of claims 1 to 5, wherein R ^5f and R ^{5g are} each hydrogen. Such as the method of any one of claims 1 to 4, where n is 0. Such as the method of any one of claims 1 to 7, wherein m is 0. The method according to any one of claims 1 to 6, wherein the compound of formula (I) is a compound of formula (XI):

Formula (XI), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrugs; wherein: R ^7a , R ^7b , R ^7c , R ^7d and R ^{7e are} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group, each of which is based on Need to be substituted by one, two, three or four substituents Q ^a ; or (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(=NR ^a )NR ^b R ^c ,- OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O) R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(O)R ^d ,- NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S( O) ₂ R ^a , -S(O)NR ^b R ^c or -S(O) ₂ NR ^b R ^c ; or two of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e adjacent to each other A C _3-10 cycloalkenyl group, a C _6-14 aryl group, a heteroaryl group or a heterocyclic group is formed, each of which is optionally substituted with one, two, three, or four substituents Q ^a . The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A35:

Compound A35, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A36:

Compound A36, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A68:

Compound A68, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A70:

Compound A70, or its isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A37:

Compound A37, or its isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A38:

Compound A38, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A41:

Compound A41, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A42:

Compound A42, or its isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A43:

Compound A43, or its isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is compound A44:

Compound A44, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method according to any one of claims 1 to 19, wherein the T cell activating bispecific antigen binding molecule comprises: The first Fab molecule that specifically binds to the first antigen; and A second Fab molecule that specifically binds to a second antigen, wherein the first antigen is an activating T cell antigen and the second antigen is a target cell antigen. The method of claim 20, wherein the T cell antigen is CD3. The method of claim 20 or 21, wherein the target cell antigen system is CD3, CD19, CD20, CD13, CD30, CD33, CD123, HER1, HER2, CEA, disialylganglioside GD2, PSMA, gpA33, BCMA, ROR1 or CD40. The method according to any one of claims 1 to 22, wherein the T cell activating bispecific antigen binding molecule comprises a complete Fc region that can bind to a cell surface receptor (Fc receptor). The method according to any one of claims 1 to 19, wherein the T cell activating bispecific antigen-binding molecule is obinutuzumab, mosunetuzumab, celecru Monoclonal antibody (selicrelumab), blinatumomab (blinatumomab), ertumaxomab (ertumaxomab), maxomab (maxomab), AMV564, AFM13, REGN-1979, GEN-3013 or Pasotuximab (pasotuxizumab). The method according to any one of the preceding claims, wherein the cancer is a hematological malignancy. The method according to any one of the preceding claims, wherein the cancer is a B-cell malignancy. The method according to any one of the preceding claims, wherein the cancer is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia Cellular leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B cell Lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Birch's Lymphoma (Burkitt's lymphoma), non-Burkitt's high-grade B-cell lymphoma (non-Burkitt's high-grade B-cell lymphoma), primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursors B lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasma cell tumor, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphoma-like granulomatous disease. The method according to any one of the preceding claims, wherein the cancer is chronic lymphocytic leukemia or non-Hodgkin's lymphoma (non-Hodgkin's lymphoma). The method according to any one of the preceding claims, wherein the cancer is non-Hodgkin's lymphoma diffuse large B-cell lymphoma (DLBCL). The method according to any one of the preceding claims, wherein the cancer is relapsed and refractory diffuse large B-cell lymphoma (r/r DLBCL). The method of claim 29 or 30, wherein the diffuse large B cell lymphoma is activated B cell diffuse large B cell lymphoma (ABC DLBCL) or germinal center B cell diffuse large B cell lymphoma (GCB DLBCL). The method according to any one of claims 1 to 27, wherein the cancer is follicular lymphoma (FL). The method according to any one of the preceding claims, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or the isotopic variant and T The cell-activating bispecific antigen-binding molecules are administered simultaneously, approximately simultaneously, or sequentially in any order. The method according to any one of claims 1 to 33, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof And the T cell activating bispecific antigen binding molecule is administered simultaneously or approximately simultaneously. The method according to any one of claims 1 to 33, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof And the T cell activating bispecific antigen binding molecules are administered sequentially. The method of claim 35, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to the T cell The activating bispecific antigen-binding molecule was previously administered. The method of claim 35, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof is administered to the T cell The activating bispecific antigen binding molecule is then administered. The method according to any one of claims 1 to 37, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof ; Or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs are formulated for oral administration. The method of claim 38, wherein the compound of formula (I), or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers or an isotopic variant thereof; or its pharmaceutically acceptable The accepted salts, solvates, hydrates or prodrugs are formulated into tablets or capsules. The method according to any one of claims 1 to 39, wherein about 30 mg, about 60 mg, about 120 mg or about 180 mg of the compound of formula (I), or its enantiomers, enantiomers are administered to the individual A mixture of two or more diastereomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method according to any one of claims 1 to 40, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to the individual Or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof for at least a 28-day cycle. The method according to any one of claims 1 to 40, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to the individual Or its isotope variant; or its pharmaceutically acceptable salt, solvate, hydrate or prodrug for two 28-day cycles. The method according to any one of claims 1 to 43, wherein the compound of formula (I), or its enantiomers, mixtures of enantiomers, or two or more nonionic compounds are administered to the individual daily on a continuous schedule A mixture of enantiomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof until disease progression or intolerable toxicity appears. Such as the method of any one of claims 1 to 43, wherein the method includes at least three cycles, among them: (i) The first two cycles include a continuous daily dosing schedule (CS), which includes the administration of the compound of formula (I), or its enantiomers, mixtures of enantiomers, two or Mixtures of more diastereomers or isotopic variants thereof; or two cycles of pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof; and (ii) Subsequent cycles include an intermittent dosing schedule (IS), which includes administering the compound of formula (I), or its enantiomers, mixtures of enantiomers, or both to the individual once a day in each subsequent cycle A mixture of one or more diastereomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof only for the first 7 consecutive days. Such as the method of claim 44, wherein each of the CS and IS cycles is a 28-day cycle. The method of claim 44 or 45, wherein the compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more of them are administered to the individual according to an intermittent administration schedule (IS) Mixtures of diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof until disease progression occurs or the incidence of at least one toxicity is reduced. The method of claim 46, wherein after disease progression occurs according to the intermittent dosing schedule (IS), the individual is administered the compound of formula (I) daily according to the continuous dosing schedule (CS), or its pair Enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof. The method of claim 1 or 2, wherein the compound of formula (I), or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or its isotopes is administered to the individual daily Variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method of any one of the preceding claims, wherein the compound of formula (I), or its enantiomers, mixtures of enantiomers, two or more are administered to the individual once a day, twice a day or three times a day A mixture of diastereomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method of any one of the preceding claims, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers is administered to the individual once a day Or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method of any one of the preceding claims, wherein about 60 mg/day of the compound of formula (I), or its enantiomers, mixtures of enantiomers, or two or more non-pairs are administered to the individual A mixture of enantiomers or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The method according to any one of claims 1 to 37, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof ; Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug of the T cell activating bispecific antigen-binding molecule. The method according to any one of claims 1 to 52, wherein the T cell activating bispecific antigen-binding molecule is obineutuzumab. Such as the method of claim 53, wherein the obineutuzumab is administered by intravenous infusion. The method of claim 53 or 54, wherein about 100 mg to about 1,000 mg of obinostatuzumab is administered. The method according to any one of claims 53 to 55, wherein a loading dose of obinostatuzumab is administered. The method according to any one of claims 53 to 56, wherein the administration of Obin Utuzumab is at least six cycles of 28 days. The method according to any one of claims 53 to 57, wherein 100 mg of obinostatuzumab is administered on day 1 of cycle 1 and 900 mg of obinostatuzumab is administered on day 2. Such as the method of claim 58, wherein 1,000 mg of obinostatuzumab is administered on the 8th and 15th days of cycle 1. The method of claim 59, wherein 1,000 mg of Obinutuzumab is administered on the first day of cycles 2 to 6. The method according to any one of claims 53 to 57, wherein 1,000 mg of obinostatuzumab is administered on days 1, 8 and 15 of cycle 1. The method according to claim 61, wherein 1,000 mg of obineutuzumab is administered on the first day of cycles 2 to 6. Such as the method of claim 62, wherein when the cycle is ≥7, eutuzumab is administered every 2 months. A pharmaceutical composition comprising: a) a compound of formula (I):

Formula (I), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrug; wherein: X, Y and Z are each independently N or CR ^X , provided that at least two of X, Y and Z are nitrogen atoms; wherein R ^X is hydrogen or C _1-6 alkyl; R ¹ And R ^{2 are} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O )NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC( =NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c ,- NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a ,- S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; each of R ^1a , R ^1b , R ^1c and R ^1d Independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _{7- 15} Aralkyl, heteroaryl or heterocyclic group; or (iii) R ^1b and R ^1c together with the N atom to which they are bonded form a heterocyclic group; R ³ and R ^{4 are} each independently hydrogen or C _1-6 alkane Group; or R ³ and R ^{4 are} joined together to form a bond, C _1-6 alkylene, C _1-6 heteroalkylene, C _2-6 alkenylene or C _2-6 heteroalkenylene; R ^5a is (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 Aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)N R ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(= NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S (O) R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5b is (a) halo; (b) C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; Or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O) R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O )NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5c series -(CR ^5f R ^5g ) _n -(C _6-14 Aryl) or -(CR ^5f R ^5g ) _n -heteroaryl; R ^5d and R ^{5e are} each independently (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c ,- OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S( O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c ; R ^5f and R ^{5g are} each independently (a) hydrogen or halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a ) NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c ,- NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S( O)R ^1d 、-NR ^1a S(O ) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c ; or -S(O) ₂ NR ^1b R ^1c ; or (d) when R ^5f occurs once and R ^5g is bonded to the same carbon atom once, the R ^5f and R ^5g together with the carbon atoms to which it is bound to form a C _3-10 cycloalkyl or heterocyclic group; R ⁶ is hydrogen, C _1-6 alkyl, -SC _1-6 alkyl, -S(O)-C _{1- 6} alkyl or -SO ₂ -C _1-6 alkyl; m is 0 or 1; and n is 0, ¹ , ² , 3 or 4; wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^X , R ^1a , R ^1b , R ^1c , R ^1d , R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f and R ^5g each of the alkyl, alkylene, heteroalkylene, Alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl groups may optionally contain one or more groups. In one embodiment, one , Two, three, four or five substituents Q, wherein each substituent Q is independently selected from (a) pendant oxy, cyano, halo and nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl and heterocyclic group, each of them Those are further substituted with one, two, three or four substituents Q ^a as necessary; and (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(=NR ^a )NR ^b R ^c , -OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O)R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(O) R ^d , -NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^b R ^c and -S(O) ₂ NR ^b R ^c , where each R ^a , R ^b , R ^c and R ^{d are} independently (i) hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _{6- 14} aryl group, C _7-15 aralkyl group, heteroaryl group or heterocyclic group, each of which is further substituted with one, two, three or four substituents Q ^a as necessary; or (iii) R ^b and R ^c form a heterocyclic group together with the N atoms to which they are bonded, which are further substituted with one, two, three or four substituents Q ^a as necessary; wherein each Q ^a is independently selected from the group consisting of: (a) Pendant oxy, cyano, halo and nitro; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _{6 -14} aryl, C _7-15 aralkyl, heteroaryl and heterocyclic group; and (c) -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^f R ^g , -C(NR ^e )NR ^f R ^g , -OR ^e , -OC(O)R ^e , -OC(O)OR ^e , -OC(O)NR ^f R ^g , -OC(=NR ^e )NR ^f R ^g , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^f R ^g , -OS(O) ₂ NR ^f R ^g , -NR ^f R ^g , -NR ^e C(O)R ^h , -NR ^e C(O)OR ^h , -NR ^e C(O)NR ^f R ^g , -NR ^e C(=NR ^h )NR ^f R ^g , -NR ^e S(O )R ^h , -NR ^e S(O) ₂ R ^h , -NR ^e S(O)NR ^f R ^g , -NR ^e S(O) ₂ NR ^f R ^g , -SR ^e , -S(O)R _{^{e, -S (O) 2 R}} e, -S (O) NR f R g , and ^{_{-S (O) 2 NR f R}} g; wherein each of R ^e, R ^f, R ^g and R ^h are independently lines (i ) Hydrogen; (ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, Heteroaryl or heterocyclic group; or (iii) R ^f and R ^g together with the N atom to which they are bound to form a heterocyclic group; wherein two adjacent substituents Q form a C _3-10 cycloalkenyl group, C _6-14 aryl, heteroaryl or heterocyclic group, each of which is optionally substituted with one, two, three or four substituents Q ^a ; and b) T cell activating bispecific antigen-binding molecule; and c) At least one pharmaceutically acceptable excipient. The pharmaceutical composition of claim 64, wherein R ^5b is (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl , C _6-14 aryl, C _7-15 aralkyl or heteroaryl; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -S(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O) R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c , -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c . The pharmaceutical composition of claim 64, wherein R ^5a and R ^{5b are} each independently (a) halo; (b) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group; or (c) -C(O)R ^1a , -C(O)OR ^1a , -C(O)NR ^1b R ^1c , -C(NR ^1a )NR ^1b R ^1c , -OR ^1a , -OC(O)R ^1a , -OC(O)OR ^1a , -OC(O)NR ^1b R ^1c , -OC(=NR ^1a )NR ^1b R ^1c , -OS(O)R ^1a , -OS(O) ₂ R ^1a , -OS(O)NR ^1b R ^1c , -OS(O) ₂ NR ^1b R ^1c , -NR ^1b R ^1c , -NR ^1a C(O)R ^1d , -NR ^1a C(O)OR ^1d , -NR ^1a C(O)NR ^1b R ^1c , -NR ^1a C(=NR ^1d )NR ^1b R ^1c , -NR ^1a S(O)R ^1d , -NR ^1a S(O) ₂ R ^1d , -NR ^1a S(O)NR ^1b R ^1c , -NR ^1a S(O) ₂ NR ^1b R ^1c ,- SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -S(O)NR ^1b R ^1c or -S(O) ₂ NR ^1b R ^1c . The pharmaceutical composition of claim 66, wherein each of R ^5a and R ^{5b is a} methyl group, which is substituted with one, two or three halo groups as necessary. The pharmaceutical composition according to any one of claims 64 to 67, wherein n is 1. The pharmaceutical composition according to any one of claims 64 to 68, wherein R ^5f and R ^{5g are} each hydrogen. The pharmaceutical composition according to any one of claims 64 to 67, wherein n is 0. The pharmaceutical composition according to any one of claims 64 to 70, wherein m is 0. The pharmaceutical composition according to any one of claims 64 to 69, wherein the compound of formula (I) is a compound of formula (XI):

Formula (XI), or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or Prodrugs; wherein: R ^7a , R ^7b , R ^7c , R ^7d and R ^{7e are} each independently (a) hydrogen, cyano, halo or nitro; (b) C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl or heterocyclic group, each of which is based on Need to be substituted by one, two, three or four substituents Q ^a ; or (c) -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -C(NR ^a )NR ^b R ^c , -OR ^a , -OC(O)R ^a , -OC(O)OR ^a , -OC(O)NR ^b R ^c , -OC(=NR ^a )NR ^b R ^c ,- OS(O)R ^a , -OS(O) ₂ R ^a , -OS(O)NR ^b R ^c , -OS(O) ₂ NR ^b R ^c , -NR ^b R ^c , -NR ^a C(O) R ^d , -NR ^a C(O)OR ^d , -NR ^a C(O)NR ^b R ^c , -NR ^a C(=NR ^d )NR ^b R ^c , -NR ^a S(O)R ^d ,- NR ^a S(O) ₂ R ^d , -NR ^a S(O)NR ^b R ^c , -NR ^a S(O) ₂ NR ^b R ^c , -SR ^a , -S(O)R ^a , -S( O) ₂ R ^a , -S(O)NR ^b R ^c or -S(O) ₂ NR ^b R ^c ; or two of R ^7a , R ^7b , R ^7c , R ^7d and R ^7e adjacent to each other A C _3-10 cycloalkenyl group, a C _6-14 aryl group, a heteroaryl group or a heterocyclic group is formed, each of which is optionally substituted with one, two, three, or four substituents Q ^a . The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A35:

Compound A35, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A36:

Compound A36, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A68:

Compound A68, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A70:

Compound A70, or its isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug. The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A37:

Compound A37, or its isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug. The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A38:

Compound A38, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A41:

Compound A41, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A42:

Compound A42, or its isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug. The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A43:

Compound A43, or its isotope variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug. The pharmaceutical composition according to any one of claims 64 to 67, wherein the compound of formula (I) is compound A44:

Compound A44, or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The pharmaceutical composition according to any one of claims 64 to 82, wherein the T cell activating bispecific antigen binding molecule comprises: The first Fab molecule that specifically binds to the first antigen; and A second Fab molecule that specifically binds to a second antigen, wherein the first antigen is an activating T cell antigen and the second antigen is a target cell antigen. The pharmaceutical composition of claim 83, wherein the T cell antigen is CD3. The pharmaceutical composition of claim 83 or 84, wherein the target cell antigen is CD19, CD20, CD13, CD30, CD33, BCMA, ROR1 or CD40. The pharmaceutical composition according to any one of claims 64 to 85, wherein the T cell activating bispecific antigen binding molecule comprises a complete Fc region that can bind to a cell surface receptor (Fc receptor). The pharmaceutical composition according to any one of claims 64 to 82, wherein the T cell activating bispecific antigen-binding molecule is obin eutuzumab, mosutuzumab, celecruzumab, and Lenatuzumab, AMV564, AFM13, REGN-1979, GEN-3013 or Pasotuximab. A method for treating or preventing cancer, which comprises administering an effective amount of the pharmaceutical composition according to any one of claims 64 to 87 to an individual in need thereof. The method of claim 88, wherein the T cell activating bispecific antigen binding molecule comprises: The first Fab molecule that specifically binds to the first antigen; and A second Fab molecule that specifically binds to a second antigen, wherein the first antigen is an activating T cell antigen and the second antigen is a target cell antigen. The method of claim 89, wherein the T cell antigen is CD3. The method of claim 88 or 89, wherein the target cell antigen is CD19, CD20, CD13, CD30, CD33, BCMA, ROR1 or CD40. The method according to any one of claims 88 to 91, wherein the T cell activating bispecific antigen binding molecule comprises a complete Fc region that can bind to a cell surface receptor (Fc receptor). The method according to any one of claims 88 to 92, wherein the T cell activating bispecific antigen-binding molecule is obin eutuzumab, mosutuzumab, celecruzumab, brinner Tumumab, AMV564, AFM13, REGN-1979, GEN-3013 or Pasotuximab. The method according to any one of the preceding claims, wherein the cancer is a hematological malignancy. The method according to any one of the preceding claims, wherein the cancer is a B-cell malignancy. The method according to any one of the preceding claims, wherein the cancer is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia Cellular leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B cell Lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burch's lymphoma, non Burch's high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblast large cell lymphoma, precursor B lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma Tumor, splenic marginal zone lymphoma, plasma cell myeloma, plasma cell tumor, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary exudative lymphoma, or lymphoma-like granuloma disease. The method according to any one of the preceding claims, wherein the cancer is chronic lymphocytic leukemia or non-Hodgkin's lymphoma. The method according to any one of the preceding claims, wherein the cancer is non-Hodgkin's lymphoma diffuse large B-cell lymphoma (DLBCL). The method according to any one of the preceding claims, wherein the cancer is relapsed and refractory diffuse large B-cell lymphoma (r/r DLBCL). The method of claim 98 or 99, wherein the diffuse large B cell lymphoma is activated B cell diffuse large B cell lymphoma (ABC DLBCL) or germinal center B cell diffuse large B cell lymphoma (GCB DLBCL). The method according to any one of claims 88 to 96, wherein the cancer is follicular lymphoma (FL).