CN117222654A

CN117222654A - KRAS G12C inhibitors and uses thereof

Info

Publication number: CN117222654A
Application number: CN202280008285.6A
Authority: CN
Inventors: 王铮; 周鼎; 程子强
Original assignee: Suzhou Zanrong Medical Technology Co ltd
Current assignee: Suzhou Zanrong Medical Technology Co ltd
Priority date: 2021-09-06
Filing date: 2022-09-05
Publication date: 2023-12-12
Also published as: WO2023030517A1

Abstract

Novel compounds useful as KRAS G12C inhibitors, pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions are provided.

Description

KRAS G12C inhibitors and uses thereof

Technical Field

The present disclosure relates generally to novel compounds useful as KRAS G12C inhibitors, pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

Background

RAS is one of the most well known proto-oncogenes. Its gain of function mutation occurs in about 30% of human cancers. KRAS (Kirsten rat sarcoma virus oncogene homolog), the most common mutant RAS isoform, has been extensively studied over the past few years. KRAS and highly related NRAS and HRAS gtpases hydrolyze Guanosine Triphosphate (GTP) to Guanosine Diphosphate (GDP). It controls a variety of cellular functions by cycling between an active GTP-binding conformation and an inactive GDP-binding conformation (Hobbs, G.A. et al, J.Cell Sci.) "129, 1287-1292, (2016)).

KRAS is an important Oncogene that has been shown to drive tumorigenesis (G G Jinesh et al, oncogene, volume 37, pages 839-846 (2018)). K-RAS also regulates many genetic regulatory mechanisms and forms a large tumorigenic network. The KRAS gene encodes a 21kDa protein, referred to as KRAS, which is part of the RAS/MAPK pathway. KRAS protein is a GTPase enzyme, meaning that it binds with high affinity to the guanosine nucleotides GDP and guanosine-triphosphate (GTP) and hydrolyzes GTP to GDP (Dhirendra K.Simanshu et al, cell (Cell) 29, 2017, 6, 170 (1): 17-33). The GDP/GTP cycle is tightly regulated by a variety of families of multi-domain proteins: guanosine nucleotide exchange factors (GEFs) and Gtpase Activating Proteins (GAPs). GEF stimulates dissociation and subsequent GTP association of GDP, thereby activating KRAS protein, whereas GAP accelerates intrinsic GTP hydrolysis, thereby converting KRAS into its inactive state (Dhirendra k.simansu et al, cell 2017, month 6, 29; 170 (1): 17-33). The GTP-bound form of KRAS is considered to be the active form and downstream signal effectors bind specifically to the GTP-bound form of KRAS. When KRAS protein binds to GDP, the KRAS protein is turned off (inactivated) and does not relay signals to the nucleus.

KRAS mutations are present in up to 25% of cancers, with oncogenic variants having different prevalence in different cancers. As one of the most common KRAS mutations, the G12C mutation is present in an estimated about 14% of lung adenocarcinomas and 3% of colon adenocarcinomas. According to the american cancer society (American Cancer Society) data, about 200,000 patients are diagnosed with lung adenocarcinoma each year. This has resulted in 14,000-28,000 patients in the KRAS-G12C population annually in the united states. In the case of KRAS-G12C positive colorectal cancer (CRC), nearly 3,000 patients are diagnosed each year. KRAS-G12C accounts for more than 40% of all KRAS mutations, and thus has been a key target for cancer drug developers. G12C is a single point mutation with a glycine to cysteine substitution at codon 12. The presence of cysteine at position 12 in KRAS-G12C protects the bound GTP from rapid regulatory hydrolysis catalyzed by GTPase Activating Protein (GAP) family proteins, resulting in overall pathway activation (Victoria Dunnett-Kane et al Cancer (Cancer) Basel 2021 month 1; 13 (1): 151).

Brain is a common site of metastasis in NSCLC patients, 25% -30% of which appear at diagnosis, and most (40-50%) of which develop brain metastasis during their course (Timothy G et al, study of transformed lung cancer (Transl Lung Cancer Res) 2013;2 (4): 273-283). Patients with KRAS-G12C NSCLC have a high prevalence of Brain Metastases (BM); 28% of patients have BM at diagnosis and 40% of patients have BM during follow-up (W.Cui et al, lung Cancer 146 (2020) 310-317). The incidence of BM in CRC is in the range of 0.6% to 3.2%. In many patients, metastatic spread of CRC is thought to progress sequentially, from liver to lung, and then to bone and brain as late affected sites. Remarkably, nearly two-thirds of brain metastases were identified to occur in RAS mutant mCRC, and the total survival (OS) of patients with KRAS-G12C mutant mCRC was shorter than that of patients with other KRAS mutant cancers (Sophie muller et al, cancer 2021,13,900).

The incidence of brain metastases is increasing due to improvements in diagnostic techniques and increased survival in cancer patients through advanced systemic treatment. It is estimated that the brain metastasis rate of extracranial solid tumors is now about 10 times that of primary malignant brain tumors (Kromer, c. Et al, journal of neurooncology (j. Neuroncol.)) 134,55-64 (2017)).

Treatment options for lung cancer or colon adenocarcinoma brain metastases are limited and include topical treatments (surgical excision, whole Brain Radiation Therapy (WBRT), stereotactic Radiosurgery (SRS) and systemic treatments (chemotherapy and targeted therapies), which are intended to alleviate symptoms (palliative), but can cause serious side effects (nerve damage, "tumor leakage", cognitive deterioration.) the big problem of systemic treatment of brain metastases is that systemic drugs cannot penetrate the blood-brain barrier (BBB). Furthermore, many small targeted drugs are substrates of active efflux pumps in the BBB, such as P-glycoprotein (P-gp) and breast cancer drug resistance protein (BCRP), which prevent these agents from entering the brain interstitial space (Riccardo Soffietti et al, natural review neurology (Nature Reviews Neurology), volume 16, pages 557-574 (2020)).

The research community has made great efforts in developing drugs that target KRAS mutations, but until recently, has not been successful enough, resulting in KRAS being considered "drug-free". Two main reasons are proposed: first, RAS has picomolar affinity for guanine nucleotides, whereas cell concentrations of guanine nucleotides are in the millimolar range, which is detrimental to the binding of nucleotide analogs; second, outside the nucleotide binding pocket, RAS appears to lack a deep pocket suitable for small molecule binding. Attempts to directly target KRAS have been hampered by their structure: KRAS presents a smooth surface without deep hydrophobic pockets that can tightly bind. Thus, past efforts have shifted emphasis to other targets. Recently, development of several small molecule inhibitors of KRAS-G12C has achieved greater success. ARS-1620 was the first G12C-specific inhibitor to demonstrate efficacy in vivo, and since then several other related compounds with enhanced biological activity have been produced, of which Adraganib (MRTX 849) and Sotorasib (AMG-510) (Janes, M.R. et al, cells (Cell), 172,578-589.e17 (2018), canon, J. Et al, nature, 575,217-223 (2019), hallin, J. Et al, cancer discovery (Cancer discover), 10,54-71 (2020)), were the earliest to enter the clinic. These compounds rely on mutant cysteines to bind, disrupt switch-I// II, and convert KRAS preference from GTP to GDP, thus placing KRAS in an inactive GDP-binding state (Ostrem, j.m. et al, nature cell biology (Nature cell biol.)) 503,548-551 (2013). Indeed, KRAS G12C appears to retain near wild-type gtpase activity levels and undergo nucleotide cycling in cells. The role of the G12C inhibitor is to prevent further nucleotide exchange, thus "trapping" the protein in an inactive state (Janes, M.R. et al, cell 172,578-589.E17 (2018)). The inherent gtpase activity of KRAS-G12C not only demonstrates the efficacy of direct inactive status inhibitors, but also broadens the possibility of effective upstream targeting in G12C mutant cancers. Brain metastases of extracranial solid tumors show increased related unmet needs, as their incidence is greatly rising. The fields of targeted therapies and immunotherapy for brain metastasis are rapidly expanding.

In summary, KRAS-G12C variants are most commonly found in non-small cell lung cancer and colorectal cancer (CRC). NSCLC is the most common cause of BM and the development of BM in CRC is associated with KRAS-G12C mutations. KRAS-G12C is one of the most common driving oncoproteins and relies on nucleotide exchange for activation and is sensitive to drugs that block this process. The inactive state selective inhibitor disrupts the circulation and traps KRAS-G12C in its GDP-binding state to inhibit tumor growth in cancer patients.

Therefore, there is a need to develop new KRAS-G12C selective inhibitors that demonstrate sufficient efficacy for targeting KRAS-G12C, in particular new KRAS-G12C selective inhibitors with BBB penetration, and thus are promising for the treatment of KRAS-G12C lung cancer and colorectal cancer patients, especially brain metastasis patients.

Disclosure of Invention

Disclosed herein are novel compounds capable of inhibiting KRAS G12C protein. Thus, the compounds of the present disclosure are useful for treating KRAS G12C-related diseases, such as cancer.

In one aspect, the present disclosure provides a compound having formula (I) or formula (II):

or a pharmaceutically acceptable salt thereof,

wherein the method comprises the steps of

Is a single bond or a double bond;

g is C (R) ^a ) Or N;

z is-N-C (O) -C (R) ^a )C(R ^b ) _r or-N-SO ₂ C(R ^a )C(R ^b ) _r or-N-C (R) ^a )C(R ^b ) _r ；

R ^a Is absent, hydrogen, deuterium, cyano, halogen, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or-C (O) N (R ^c ) ₂ ；

Each R ^b Independently is hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, cycloalkyl, or heteroaryl, wherein the alkyl, the heteroalkyl, the cycloalkyl, and the heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, -NR ^c R ^d And heterocyclyl optionally substituted with one or more groups selected from hydroxy, halogen, cyano and amino;

each R ^c Independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl;

R ^d selected from the group consisting of: optionally heteroaryl or-N (R) ^c ) ₂ Substituted alkyl, haloalkyl, -C (O) N (R) ^c ) ₂ 、-(CH ₂ ) _n NHC (O) -alkyl, heterocyclyl, and heteroaryl, wherein the heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from: halo, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, hydroxyalkyl, -O-haloalkyl, and-S-haloalkyl;

w is CR ^e Or N;

R ^e selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, -OR ^c Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, cyano, -OR ^c and-N (R) ^c ) ₂ ；

Q is CR ^f Or N;

R ^f is-Y- (CH) ₂ ) _m -T-R ^g Wherein- (CH) ₂ ) _m -optionally substituted with hydroxy, halogen, cyano or amino;

y is selected from the group consisting of bond, -O-, -S-, -N (R) ^c ) -or alkynyl;

t is selected from bond, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl are optionally substituted with one or more groups independently selected from: oxo, hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl;

R ^g selected from the group consisting of: hydrogen, hydroxy, halogen, -OR ^c 、-N(R ^c ) ₂ 、-N(R ^c )SO ₂ -alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH ₂ OC (O) -heterocyclyl, -NHC (=nh) NH ₂ 、-C(O)N(R ^c ) ₂ 、-(CH ₂ OR ^c )(CH ₂ ) _p OR ^c and-N (R) ^c ) C (O) -aryl, wherein said cycloalkyl, said heterocyclyl, said aryl and said heteroaryl are optionally substituted with oneOr a plurality of R' substitutions, and-N (R ^c ) Aryl moiety in C (O) -aryl and-CH ₂ The heterocyclyl moiety in the OC (O) -heterocyclyl is optionally substituted with one or more R ";

each R' is independently selected from hydroxy, halogen, -C (O) H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, or-N (R ^c ) ₂ ；

Each R' is independently selected from oxo, hydroxy, halogen, alkyl, heteroalkyl, hydroxyalkyl, haloalkyl, alkoxy, -E-phenyl, -E-phenylSO ₂ F、-N(R ^c ) ₂ 、-SO ₂ F. -C (O) (alkyl) or-C (O) (haloalkyl), wherein said alkyl, said heteroalkyl, said hydroxyalkyl, said haloalkyl and said alkoxy are optionally substituted with one or more groups independently selected from aryl, heteroaryl or t-butyldimethylsilyloxy;

e is a bond, -O-or-NHC (O) -;

R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b and R is ⁴ Each of which is independently absent OR selected from hydrogen, oxo, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^c 、-C(O)N(R ^c ) ₂ 、-N(R ^c ) ₂ Or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: cyano, hydroxy, halogen, -OR ^c or-N (R) ^c ) ₂ or-SO ₂ (R ^c ) The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively

R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Together with the carbon atoms to which they are attached, form an alkyl, alkenyl, cycloalkyl or heterocyclyl group, said alkyl, said cycloalkyl or said heterocyclyl group being optionally substituted with one or more groups independently selected from: cyano, halogen, hydroxy, amino, alkoxy, alkyl, alkenyl or alkynyl;

L ¹ Is a bond, - [ C (R) ^h ) ₂ ] _u -*、-[C(R ^h ) ₂ ] _u -C (O) -, or-N (R) ^c ) C (O) -, wherein x represents L ¹ And L is equal to ² A point of connection;

L ² is a bond, -O-, -N (R) ⁱ ) -or-S (O) _v -；

Each R ^h Independently selected from the group consisting of: hydrogen, hydroxy, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; or alternatively

R ⁱ Absent or selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, or-C (O) -heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, and cycloalkyl are optionally substituted with one or more R' "and the heterocyclyl moiety in the-C (O) -heterocyclyl is optionally substituted with one or more groups independently selected from: halogen, hydroxy, cyano, alkyl and-N (R) ^c ) ₂ ；

Or R is ^h And R is ⁱ Together with the carbon and nitrogen atoms to which they are attached, respectively, form a heterocyclic group or heteroaryl group, which is optionally substituted with one or more groups independently selected from: cyano, halogen, hydroxy, amino, nitro, alkoxy, haloalkyl, hydroxyalkyl, alkyl or-alkyl-N (R) ^c ) ₂ ；

Each R' "is independently selected from the group consisting of-N (R ^c ) ₂ Heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano or alkyl;

L ³ is a bond, -C (O) -or alkyl;

R ⁵ is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkylThe heterocyclyl, the aryl and the heteroaryl are optionally substituted with one or more R ^j Substitution;

each R ^j Independently selected from the group consisting of: hydrogen, oxo, hydroxy, halogen, cyano, amino, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: deuterium, hydroxy, halogen, cyano, amino, nitro, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

n is 0, 1 or 2;

m is an integer from 0 to 4;

p is an integer from 0 to 2;

r is 1 or 2;

u is an integer from 0 to 4;

v is an integer from 0 to 2;

provided that it is

When (when)When one of them is a double bond, then the other +.>Is a single bond;

when (when)When it is a triple bond, then R ^a Absent, R ^b Exists and r is 1;

or whenWhen it is a double bond, then R ^a In presence of R ^b Exists and R is 2, or R ^a And R is ^b And the carbon atoms to which they are attached form a chain optionally substituted with one or more R ^e Substituted cycloalkyl groups.

In another aspect, the present disclosure provides a compound having formula (Ia) or formula (Ic):

or a pharmaceutically acceptable salt thereof,

wherein ring a is a heterocyclyl or heteroaryl, said heterocyclyl or said heteroaryl being optionally substituted with one or more groups independently selected from the group consisting of: cyano, halogen, hydroxy, amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl or-alkyl-N (R) ^c ) ₂ 。

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In a further aspect, the present disclosure provides a method of inhibiting KRas G12C activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

In a further aspect, the present disclosure provides a method of treating KRas G12C-related cancer, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

In a further aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising:

(a) Knowing that the cancer is associated with a KRas G12C mutation; and

(b) Administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer.

In another aspect, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in treating cancer.

Detailed Description

Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the disclosure will be described in conjunction with the enumerated embodiments, it will be understood that the embodiments are not intended to limit the disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present disclosure as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event of a departure or conflict between one or more of the incorporated references and similar materials (including but not limited to the defined terms, term usage, described techniques, etc.) and the present application, the present disclosure controls. All references, patents, patent applications cited in this disclosure are hereby incorporated by reference in their entirety.

It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

Definition of the definition

The definition of specific functional groups and chemical terms is described in more detail below. For purposes of this disclosure, chemical elements are identified according to the periodic Table of elements (Periodic Table of the Elements), CAS version, handbook of physics and chemistry (Handbook of Chemistry and Physics), 75 th edition, inner cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry and specific functional moieties and reactivities are described in the following documents: organic chemistry (Organic Chemistry), thomas Sorrell, 2 nd edition, sossary science book Press (University Science Books, sausalito), 2006; smith and March, march higher organic chemistry (March's Advanced Organic Chemistry), 6 th edition, john Wiley father-child publishing company (John Wiley & Sons, inc., new York), 2007; larock, complex organic transformations (Comprehensive Organic Transformations), 3 rd edition, VCH Press, inc. (VCH Publishers, inc., new York), 2018; carruther, some modern methods of organic synthesis (Some Modern Methods of Organic Synthesis), 4 th edition, cambridge university Press, cambridge (Cambridge University Press, cambridge), 2004; each of these documents is incorporated by reference in its entirety.

Throughout this disclosure, linking substituents are described. It is particularly desirable that each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR (CR ' R ") -includes both-NR (CR ' R") -and- (CR ' R ") NR-. In the case where a linking group is explicitly required for a structure, the Markush variable (Markush variable) listed for the group is understood to be the linking group. For example, if the structure requires a linking group and the markush group definition of the variables lists "alkyl", it is understood that "alkyl" means a linking alkylene.

Where a bond to a substituent is shown intersecting a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. Where substituents are listed, but it is not specified through which atom such substituent is bonded to the remainder of a given formula compound, such substituent may be bonded through any atom in this formula. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, for convenience, a dash "-" is used in front of or at the end of a chemical group to indicate the point of attachment of a substituent. For example, -OH is attached through a carbon atom; chemical groups may be delineated by one or more dashes or without losing their ordinary meaning. Wavy lines drawn through lines in the structure indicate the point of attachment of the group. The order in which chemical groups are written or named does not indicate or imply a direction unless chemical or structural requirements. As used herein, the solid line from the center of the ring indicates that the point of attachment of the substituent on the ring can be at any ring atom. Where substituents are listed, but it is not specified through which atom such substituent is bonded to the remainder of a given formula compound, such substituent may be bonded through any atom in this formula. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

In any variable (e.g., R ⁱ ) When a compound occurs more than one time in any component or formula, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if the display group is 0 to 2R ⁱ Partially substituted, then the radicals may optionally be substituted by up to two R ⁱ Partially substituted, and R ⁱ Each at each occurrence is independently selected from R ⁱ Is defined in (a). Moreover, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, the term "compound provided herein," or "compound disclosed herein," or "compound of the present disclosure," refers to a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), and specific compounds disclosed herein.

As used herein, the term "C _i-j "indicates a range of the number of carbon atoms, where i and j are integers, and the range of the number of carbon atoms includes the endpoints (i.e., i and j) and each integer point therebetween, and where j is greater than i. For example, C _1-6 Indicating a range of one to six carbon atomsIncluding one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C _1-12 "indicates 1 to 12 carbon atoms, in particular 1 to 10 carbon atoms, in particular 1 to 8 carbon atoms, in particular 1 to 6 carbon atoms, in particular 1 to 5 carbon atoms, in particular 1 to 4 carbon atoms, in particular 1 to 3 carbon atoms or in particular 1 to 2 carbon atoms.

As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated straight or branched chain hydrocarbon group that may optionally be independently substituted with one or more substituents described below. The term "C _i-j Alkyl "refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group comprises 1 to 10 carbon atoms. In some embodiments, the alkyl group comprises 1 to 9 carbon atoms. In some embodiments, the alkyl group comprises 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C _1-10 Examples of alkyl "include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "C _1-6 Examples of alkyl "are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl and the like.

As used herein, the term "alkenyl", whether used as part of another term or independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond that may be optionally independently substituted with one or more substituents described herein and includes groups having a "cis" orientation and a "trans" orientation or alternatively an "E" orientation and a "Z" orientation. In some embodiments, alkenyl groups include 2 to 12 carbon atoms. In some embodiments, alkenyl groups include 2 to 11 carbon atoms. In some embodiments, alkenyl groups include 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups include 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (ethylene or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, and the like.

As used herein, the term "alkynyl", whether used as part of another term or independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond that may be optionally independently substituted with one or more substituents described herein. In some embodiments, alkenyl groups include 2 to 12 carbon atoms. In some embodiments, alkynyl groups include 2 to 11 carbon atoms. In some embodiments, alkynyl groups include 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups include 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

As used herein, the term "alkoxy", whether used as part of another term or independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. The term "C _i-j Alkoxy "means that the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, the alkoxy group comprises 1 to 10 carbon atoms. In some embodiments, the alkoxy group comprises 1 to 9 carbon atoms. In some embodiments, the alkoxy group comprises 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C _1-6 Examples of alkoxy "include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, neopentaneOxy, n-hexyloxy, and the like.

As used herein, the term "amino" refers to-NH ₂ A group. The amino group may also be substituted with one or more groups such as alkyl, aryl, carbonyl, or other amino groups.

As used herein, the term "aryl", whether used as part of another term or independently, refers to mono-and polycyclic ring systems having a total of from 5 to 20 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system comprises from 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents. As used herein, the term "aryl" also includes groups in which an aromatic ring is fused to one or more additional rings. In the case of a polycyclic system, only one ring need be aromatic (e.g., 2, 3-indoline), but all rings may be aromatic (e.g., quinoline). The second ring may also be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthalimidyl, phenanthridinyl, tetrahydronaphthyl, and the like. Aryl groups may be substituted at one or more ring positions with substituents as described above.

As used herein, the term "cyano" refers to-CN.

As used herein, the term "cyanoalkyl" refers to an alkyl group as defined above substituted with one or more cyano groups as defined above.

As used herein, the term "cycloalkyl", whether used as part of another term or independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic systems wherein all ring atoms are carbon and the system includes at least three ring-forming carbon atoms. In some embodiments, cycloalkyl groups may include 3 to 12 ring carbon atoms, 3 to 10 ring carbon atoms, 3 to 9 ring carbon atoms, 3 to 8 ring carbon atoms, 3 to 7 ring carbon atoms, 3 to 6 ring carbon atoms, 3 to 5 ring carbon atoms, 4 to 12 ring carbon atoms, 4 to 10 ring carbon atoms, 4 to 9 ring carbon atoms, 4 to 8 ring carbon atoms, 4 to 7 ring carbon atoms, 4 to 6 ring carbon atoms, 4 to 5 ring carbon atoms. Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, cycloalkyl groups may be saturated cyclic alkyl groups. In some embodiments, cycloalkyl groups may be partially unsaturated cyclic alkyl groups that include at least one double or triple bond in their ring system. In some embodiments, cycloalkyl groups may be monocyclic or polycyclic. Fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decyl, bicyclo [1, 1] pentenyl, bicyclo [2, 1] heptenyl, and the like.

As used herein, the term "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromoo), and iodine (or iodoo).

As used herein, the term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens as defined above. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl and the like.

As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur as well as any quaternized form of basic nitrogen (including N-oxides).

As used herein, the term "heteroalkyl" refers to an alkyl group having at least one of its carbon atoms replaced with a heteroatom selected from N, O or S. Heteroalkyl groups may be carbon or heteroatom radicals (i.e., heteroatoms may be present in the middle or at the ends of the group) and may optionally be independently substituted with one or more substituents described herein. The term "heteroalkyl" encompasses both alkoxy and heteroalkoxy.

As used herein, the term "heteroalkenyl" refers to an alkenyl group having at least one of its carbon atoms replaced with a heteroatom selected from N, O or S. The heteroalkenyl group may be a carbon radical or a heteroatom radical (i.e., a heteroatom may occur in the middle or at the end of the group) and may optionally be independently substituted with one or more substituents described herein.

As used herein, the term "heteroalkynyl" refers to an alkynyl group having at least one of its carbon atoms replaced with a heteroatom selected from N, O or S. Heteroalkynyl groups may be carbon radicals or heteroatom radicals (i.e., a heteroatom may occur in the middle or at the ends of a group) and may optionally be independently substituted with one or more substituents described herein.

As used herein, the term "heteroaryl", whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. Heteroaryl groups may be monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl also includes polycyclic groups in which the heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, wherein the linking group or point of attachment is on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo [1,3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclic group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally independently substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, a heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl may include any oxidized form of carbon, nitrogen or sulfur and any quaternized form of basic nitrogen. "heterocyclyl" also includes groups in which the heterocyclyl is fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. The heterocyclic group may be carbon-linked or nitrogen-linked, where possible. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, the groups derived from pyrrole may be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). Further, the group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked).

In some embodiments, the term "3-to 12-membered heterocyclyl" refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, 1-dioxothietanylpyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidinonyl, pyrazinonyl, pyrimidinonyl, pyridazinonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclic groups include, but are not limited to, phenyl condensed rings or pyridyl condensed rings, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chroenyl, isochroenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, hexahydro-1H-pyrrolizinyl, imidazo [1,2-a ] pyridinyl, [1,2,4] triazolo [4,3-a ] pyridinyl, [1,2,3] triazolo [4,3-a ] pyridinyl, and the like. Examples of spiroheterocyclyl groups include, but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of bridged heterocyclyl groups include, but are not limited to, morphinan, hexamethylenetetramine, 3-aza-bicyclo [3.1.0] hexane, 8-aza-bicyclo [3.2.1] octane, 1-aza-bicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane (DABCO), and the like.

As used herein, the term "hydroxyl" refers to-OH.

As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxyl groups.

As used herein, the term "oxo" refers to an =o substituent.

As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

As used herein, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It is to be understood that "substitution" or "substitution by … …" includes implicit preconditions that such substitution is consistent with the permissible valence of the substituted atom, and that the substitution results in a stable or chemically feasible compound, e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, and the like. Unless otherwise indicated, an "optionally substituted" group may have the appropriate substituent at each substitutable position of the group, and where more than one position in any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at each position. It will be appreciated by those skilled in the art that the substituents themselves may be substituted, if appropriate. Unless specifically stated as "unsubstituted", references to chemical moieties herein are to be understood as including substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

Compounds of formula (I)

In one aspect, the present disclosure provides a compound having formula (I):

or a pharmaceutically acceptable salt thereof,

wherein the method comprises the steps of

Is a single bond or a double bond;

g is C (R) ^a ) Or N;

z is-N-C (O) -C (R) ^a )C(R ^b ) _r 、-N-SO ₂ C(R ^a )C(R ^b ) _r or-N-C (R) ^a )C(R ^b ) _r ；

each R ^c Independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl;

W is CR ^e Or N;

Q is CR ^f Or N;

R ^g selected from the group consisting of: hydrogen, hydroxy, halogen, -OR ^c 、-N(R ^c ) ₂ 、-N(R ^c )SO ₂ -alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOH, -CH ₂ OC (O) -heterocyclyl, -NHC (=nh) NH ₂ 、-C(O)N(R ^c ) ₂ 、-(CH ₂ OR ^c )(CH ₂ ) _p OR ^c and-N (R) ^c ) C (O) -aryl, wherein the cycloalkyl, the heterocyclyl, the aryl and the heteroaryl are optionally substituted with one or more R', and-N (R ^c ) Aryl moiety in C (O) -aryl and-CH ₂ The heterocyclyl moiety in the OC (O) -heterocyclyl is optionally substituted with one or more R ";

e is a bond, -O-or-NHC (O) -;

R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b and R is ⁴ Each of which is independently absent OR selected from hydrogen, oxo, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^c 、-C(O)N(R ^c ) ₂ 、-N(R ^c ) ₂ Or heteroaryl, wherein said alkyl, saidAlkenyl, the alkynyl, and the heteroaryl are optionally substituted with one or more groups independently selected from: cyano, hydroxy, halogen, -OR ^c 、-N(R ^c ) ₂ or-SO ₂ (R ^c ) The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively

L ² is a bond, -O-, -N (R) ⁱ ) -or-S (O) _v -；

L ³ is a bond, -C (O) -or alkyl;

R ⁵ is hydrogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, said heterocyclyl, said aryl and said heteroaryl are optionally substituted with one or more R ^j Substitution;

n is 0, 1 or 2;

m is an integer from 0 to 4;

p is an integer from 0 to 2;

r is 1 or 2;

u is an integer from 0 to 4;

v is an integer from 0 to 2;

provided that it is

when (when)When it is a triple bond, then R ^a Absent, R ^b Exists and r is 1;

In some embodiments, twoAre all single bonds, G is C (R ^a ) And R is ^a Is hydrogen.

In some embodiments, oneIs a single bond, another->Is a double bond, G is C (R ^a ) And R is ^a Is not present.

In some embodiments, twoAre all single bonds and G is N.

In some embodiments, Z is-N-C (O) -C (R) ^a )＝C(R ^b ) _r 。

In some embodiments, Z is-N-SO ₂ C(R ^a )＝C(R ^b ) _r 。

In certain embodiments, R ^a Is hydrogen, deuterium, cyano, halogen or alkyl.

In certain embodiments, R ^a Is hydrogen, an R ^b Is hydrogen, another R ^b Selected from the group consisting of: hydrogen, alkyl, heteroalkyl, haloalkyl, heteroaryl, -alkyl-NR ^c R ^d Cycloalkyl and-alkyl-heterocyclyl, wherein the heterocyclyl in the-alkyl-heterocyclyl is optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano or amino.

In certain embodiments, R ^a And two R ^b Is deuterium.

In certain embodiments, R ^a Is halogen, and two R ^b Is hydrogen.

In some embodiments, Z is-N-C (O) -CC(R ^b ) _r 。

In some embodiments, Z is-N-SO ₂ CC(R ^b ) _r 。

In certain embodiments, R ^b Is hydrogen or-alkyl-NR ^c R ^d 。

In some embodiments, Z is-N-C (R ^a )C(R ^b ) _r 。/>

In certain embodiments, R ^a Is hydrogen, and R ^b Is hydrogen.

In some embodiments, W is N.

In some embodiments, W is CR ^e 。

In certain embodiments, R ^e Selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, -OR ^c Alkyl, alkenyl, and alkynyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, cyano, -OR ^c and-N (R) ^c ) ₂ 。

In certain embodiments, R ^e Selected from the group consisting of: halogen, hydrogen, halogen, hydroxy, cyano, methoxy or ethynyl.

In some embodiments, Q is N.

In some embodiments, Q is CR ^f And R is ^f is-Y- (CH) ₂ ) _m -T-R ^g 。

In some embodiments, Y is a bond, -O-, or-S-.

In some embodiments, Y is-N (R ^c )-。

In some embodiments, Y is alkynyl. In certain embodiments, Y is C _2-6 Alkynyl, C _2-5 Alkynyl, C _2-4 Alkynyl or C _2-3 Alkynyl groups. In certain embodiments, Y is ethynyl.

In some embodiments, m is 0.

In some embodiments, m is 1, 2, or 3.

In some embodiments, T is a bond.

In some embodiments, T is heterocyclyl optionally substituted with one or more groups independently selected from: oxo, hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In certain embodiments, T is heterocyclyl selected from the group consisting of:

each of which is optionally substituted with one or more groups independently selected from the group consisting of: oxo, hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In some embodiments, Y is a bond and T is a bond. In certain embodiments, Y is a bond, m is 0, and T is a bond.

In some embodiments, Y is a bond, and T is heterocyclyl optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl. In certain embodiments, Y is a bond, m is 0, and T is heterocyclyl optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In some embodiments, Y is-O-or-S-, and T is a bond or a heterocyclyl optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl. In certain embodiments, Y is-O-or-S-, m is 1, 2, or 3, and T is a bond or a heterocyclyl optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In some embodiments, Y is-N (R ^c ) And T is a bond. In certain embodiments, Y is-N (R ^c ) -, m is 1 or 2, and T is a bond.

In some embodiments, Y is alkynyl and T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl. In certain embodiments, Y is alkynyl, m is 0 or 1, and T is a bond or heterocyclyl optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

In some embodiments, R ^g Selected from the group consisting of: hydrogen, hydroxy, halogen, alkyl, -N (R) ^c ) ₂ OR-OR ^c 。

In certain embodiments, R ^g Is hydrogen, hydroxy or halogen.

In certain embodiments, R ^g Is an alkyl group. In certain embodiments, R ^g Is C _1-6 Alkyl, C _1-5 Alkyl, C _1-4 Alkyl or C _1-3 An alkyl group. In certain embodiments, R ^g Is alkyl, ethyl or isopropyl.

In certain embodiments, R ^g is-N (R) ^c ) ₂ Wherein each R is ^c Independently C _1-6 Alkyl, C _1-5 Alkyl, C _1-4 Alkyl or C _1-3 An alkyl group. In certain embodiments, each R ^c Is methyl.

In certain embodiments, R ^g is-OR ^c Wherein R is ^c Is C _1-6 Alkyl, C _1-5 Alkyl, C _1-4 Alkyl or C _1-3 An alkyl group. In certain embodiments, R ^c Is methyl.

In some embodiments, Y is a bond, -O-, -S-or alkynyl, T is heterocyclyl optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl, and R ^g Is hydrogen, halogen, alkyl, -N (R) ^c ) ₂ OR-OR ^c 。

In some embodiments, Y is a bond, -O-, -S-, -N (R) ^c ) Or alkynyl, T is a bond, and R ^g is-N (R) ^c ) ₂ 。

In some embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Independently selected from hydrogen, alkyl, or heteroalkyl, wherein the alkyl and the heteroaryl are optionally substituted with one or more groups independently selected from: cyano, hydroxy, halogen, -OR ^c 、-N(R ^c ) ₂ or-SO ₂ (R ^c )。

In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Independently selected from hydrogen.

In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of them is C _1-6 Alkyl, C _1-5 Alkyl, C _1-4 Alkyl or C _1-3 Alkyl, and others are hydrogen. In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of which is methyl and the other is hydrogen.

In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of them is C _1-6 Cyanoalkyl, C _1-5 Cyanoalkyl, C _1-4 Cyanoalkyl or C _1-3 Cyanoalkyl, and others are hydrogen. In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of them is-CH ₂ CN, and the others are hydrogen.

In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of them is C _1-6 Haloalkyl, C _1-5 Haloalkyl, C _1-4 Haloalkyl or C _1-3 Haloalkyl, and others are hydrogen. In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of them is-CH ₂ F, and the others are hydrogen.

In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of them is C _2-6 Heteroalkyl, C _2-5 Heteroalkyl, C _2-4 Heteroalkyl or C _2-3 Heteroalkyl, and others are hydrogen. In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of them is-CH ₂ OCH ₃ And others are hydrogen.

In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of them is-C _1-6 alkyl-SO ₂ CH ₃ 、-C _1-5 alkyl-SO ₂ CH ₃ 、-C _1-4 alkyl-SO ₂ CH ₃ 、-C _1-3 alkyl-SO ₂ CH ₃ or-C _1-2 alkyl-SO ₂ CH ₃ And others are hydrogen. In certain embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ One of them is-CH ₂ SO ₂ CH ₃ And others are hydrogen.

In some embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Together with the carbon atoms to which they are attached, form an alkyl group.

In certain embodiments, R ^1a And R is ^3a Together with the carbon atoms to which they are attached, form propyl or butyl.

In certain embodiments, R ^1a And R is ⁴ Together with the carbon atoms to which they are attached, form propyl or butyl.

In certain embodiments, R ^2a And R is ^3a Together with the carbon atoms to which they are attached, form propyl or butyl.

In some embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Together with the carbon atoms to which they are attached, form an alkenyl group.

In certain embodiments, R ^1a And R is ^3a Forms a butenyl group together with the carbon atoms to which they are attached.

In certain embodiments, R ^1a And R is ⁴ Forms a butenyl group together with the carbon atoms to which they are attached.

In certain embodiments, R ^2a And R is ^3a Forms a butenyl group together with the carbon atoms to which they are attached.

In some embodiments, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl group.

In certain embodiments, R ^1a And R is ^1b Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

In certain embodiments, R ^2a And R is ^2b Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

In certain embodiments, R ^3a And R is ^3b Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

In certain embodiments, R ^1a And R is ^2a Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

In certain embodiments, R ^3a And R is ⁴ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

In some embodiments, L ¹ Is a key.

In some embodiments, L ¹ Is- [ C (R) ^h ) ₂ ] _u - *. In certain embodiments, L ¹ Is- [ C (R) ^h ) ₂ ] _u -*，R ^h Is hydrogen and u is 0, 1, 2 or 3.

In some embodiments, L ¹ Is- [ C (R) ^h ) ₂ ] _u -C (O) -. In certain embodiments, L ¹ Is- [ C (R) ^h ) ₂ ] _u -C(O)-*，R ^h Is hydrogen and u is 0, 1, 2 or 3.

In some embodiments, L ¹ is-N (R) ^c ) C (O) -. In certain embodiments, L ¹ is-N (R) ^c ) C (O) -, and R ^c Is hydrogen.

In some embodimentsIn the mode, L ¹ is-S (O) _v -。

In some embodiments, L ² Is a key.

In some embodiments, L ² is-O-.

In some embodiments, L ² is-N (R) ⁱ ) -. In certain embodiments, L ² is-N (R) ⁱ )-，R ⁱ Is hydrogen, alkyl or-C (O) -heterocyclyl, wherein the alkyl is optionally substituted with one or more R' ", and the heterocyclyl moiety in the-C (O) -heterocyclyl is optionally substituted with one or more groups independently selected from alkyl or-N (R ^c ) ₂ Is substituted with a group of (a).

In certain embodiments, L ¹ Is- [ C (R) ^h ) ₂ ] _u -*，L ² is-N (R) ⁱ ) -, u is 1, and R ^h And R is ⁱ Together with the carbon and nitrogen atoms to which they are attached, respectively, form a heteroaryl group, which heteroaryl group is optionally substituted with one or more groups independently selected from: cyano, halogen, hydroxy, haloalkyl, hydroxyalkyl, alkyl or-alkyl-N (R) ^c ) ₂ 。

In certain embodiments, L ¹ Is- [ C (R) ^h ) ₂ ] _u -*，L ² is-N (R) ⁱ ) -, u is 1, and R ^h And R is ⁱ Together with the carbon and nitrogen atoms to which they are attached, respectively, form a triazolyl or imidazolyl group, each optionally substituted with one or more groups independently selected from the group consisting of: cyano, halogen, hydroxy, haloalkyl, hydroxyalkyl, alkyl or-alkyl-N (R) ^c ) ₂ 。

In some embodiments, L ¹ Is- [ C (R) ^h ) ₂ ] _u -C(O)-*，L ² is-N (R) ⁱ ) -, and u is 0.

In some embodiments, L ³ Is a key.

In some embodiments, L ³ is-C (O) -.

In some embodiments, L ³ Is an alkyl group. In some embodiments，L ³ Is C _1-6 Alkyl, C _1-5 Alkyl, C _1-4 Alkyl or C _1-3 An alkyl group.

In some embodiments, R ⁵ Is optionally substituted with one or more R ^j Substituted aryl. In certain embodiments, R ⁵ Is C _5-12 Aryl, C _5-11 Aryl, C _5-10 Aryl, C _5-9 Aryl, C _5-8 Aryl or C _5-7 Aryl groups, each of which is optionally substituted with one or more R ^j And (3) substitution. In certain embodiments, R ⁵ Is phenyl, naphthyl or 2, 3-dihydro-1H-indenyl, each of which is optionally substituted with one or more R ^j And (3) substitution. In certain embodiments, R ^j Is hydroxy, halogen, amino, alkyl, alkynyl, haloalkyl or cycloalkyl.

In some embodiments, R ⁵ Is optionally substituted with one or more R ^j Substituted heteroaryl groups. In certain embodiments, R ⁵ Is C _5-12 Heteroaryl, C _5-11 Heteroaryl, C _5-10 Heteroaryl, C _5-9 Heteroaryl, C _5-8 Heteroaryl or C _5-7 Heteroaryl, each of which is optionally substituted with one or more R ^j And (3) substitution. In certain embodiments, R ⁵ Is pyridinyl, quinolinyl, isoquinolinyl, indazolyl or benzo [ b ]]Thienyl, each of which is optionally substituted with one or more R ^j And (3) substitution. In certain embodiments, R ^j Is hydroxy, halogen, amino, alkyl or alkynyl.

In a further aspect, the present disclosure provides a compound having formula (Ia), formula (Ib) or formula (Ic):

or a pharmaceutically acceptable salt thereof,

wherein the method comprises the steps of

Wherein ring A is a heterocyclyl or heteroaryl, said heterocyclyl or said heteroaryl optionally being selected independently from one or more of Is substituted by a group of: cyano, halogen, hydroxy, amino, alkyl, alkoxy, haloalkyl, hydroxyalkyl or-alkyl-N (R) ^c ) ₂ 。

In certain embodiments, twoAre all single bonds.

In certain embodiments, Q is CR ^f 。

In certain embodiments, Q is N.

In certain embodiments, L ³ Is a key.

In certain embodiments, R ⁵ Is aryl or heteroaryl, each of which is optionally substituted with one or more R ^j And (3) substitution.

In certain embodiments, R ⁵ Selected from the group consisting of: phenyl, naphthyl, 2, 3-dihydro-1H-indenyl, pyridyl, quinolyl, isoquinolyl, indazolyl and benzo [ b ]]Thienyl, each of which is optionally substituted with one or more R ^j And (3) substitution.

In certain embodiments, u is 0 or 1.

In some embodiments, the present disclosure provides a compound having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

The compounds provided herein are described with reference to both general and specific compounds. In addition, the compounds of the present disclosure may exist in a variety of different forms or derivatives, including but not limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites), and pharmaceutically acceptable salts thereof, all of which are within the scope of the present disclosure.

As used herein, the term "prodrug" refers to a compound or a pharmaceutically acceptable salt thereof that upon metabolism under physiological conditions or conversion by solvolysis yields the desired active compound. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureides, solvates or hydrates of the active compounds. Typically, prodrugs are inactive or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolism, the ester groups are cleaved to yield the active drug. In addition, some prodrugs are enzymatically activated to produce the active compound or compounds that produce the active compound upon further chemical reaction. The prodrug may be developed from a prodrug form to an active form in a single step, or may have one or more intermediate forms that may or may not be active themselves. The preparation and use of prodrugs is discussed in the following references: higuchi and v.stilla, "Pro-drug as novel delivery system (Pro-drugs as Novel Delivery Systems)", volume 14 of the a.c.s. seminar Series (a.c. symposium Series), bioreversible carrier in drug design (Bioreversible Carriers in Drug Design), editors Edward b.roche, american pharmaceutical society (American Pharmaceutical Association) and pegamon Press, 1987. Prodrug: challenge and return (Prodrugs: challenges and Rewards), editorial V.Stella, R.Borchardt, M.Hageman, R.Oliyai, H.Maag, J.Tilley, new York Springs Press (Springer Verlag New York), 2007, all of which are hereby incorporated by reference in their entirety.

As used herein, the term "soft drug" refers to a compound that exerts a pharmacological effect but breaks down into inactive metabolite degradants such that the activity time is limited. See, for example, "soft drugs: principles and methods of safe drug design (Soft drugs: principles and methods for the design of safe drugs) ", nicholas Bodor, drug research review (Medicinal Research Reviews), volume 4, stage 4, 449-469,1984, which references are hereby incorporated by reference in their entirety.

As used herein, the term "metabolite", e.g., an active metabolite, overlaps with the prodrug as described above. Such metabolites are therefore pharmacologically active compounds, or compounds that are further metabolized to pharmacologically active compounds, which are derivatives produced by metabolic processes in the subject. For example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Wherein the active metabolite is such a pharmacologically active derivative compound. For prodrugs, the prodrug compounds are generally inactive or less active than the metabolite. For active metabolites, the parent compound may be an active compound or may be an inactive prodrug.

Prodrugs and active metabolites may be identified using conventional techniques known in the art. See, for example, bertolini et al, 1997, journal of pharmaceutical chemistry (J Med Chem) 40:2011-2016; shan et al, J.Pharm.Sci.86:756-757; bagshawe,1995, drug development study (drug Dev Res) 34:220-230; wermuth, supra.

As used herein, the term "pharmaceutically acceptable" means that the substance or composition is chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the subject being treated.

As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the indicated compounds and are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono-, di-, tri-, tetra-salts, and the like. The pharmaceutically acceptable salts are non-toxic in the amount and concentration in which they are administered. The preparation of such salts may facilitate pharmacological use by altering the physical properties of the compound without impeding its performance in terms of its physiology. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administration of higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts, such as acid addition salts including: sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinic acid salts. Pharmaceutically acceptable salts can be obtained from acids such as: hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid and quinic acid.

When an acidic functional group such as carboxylic acid or phenol is present, pharmaceutically acceptable salts also include base addition salts, such as base addition salts including: benzathine (benzathine), chloroprocaine (chloroprocaine), choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine (procaine), aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines and zinc. See, for example, remington's Pharmaceutical Sciences, 19 th edition, mark publication company, mack Publishing co., easton, PA, volume 2, page 1457, 1995; manual of pharmaceutical salts: properties, selection and Use (Handbook of Pharmaceutical Salts: properties, selection, and Use), stahl and Wermuth, wiley-VCH Press of Wei Yinhai M, germany (Wiley-VCH, weinheim, germany), 2002. Such salts may be prepared using the appropriate corresponding base.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound may be dissolved in a suitable solvent (e.g., an aqueous or water-alcohol solution including a suitable acid) and then isolated by evaporation of the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treating the free base with the following acid: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and the like; pyranosyl acids such as glucuronic acid or galacturonic acid; alpha-hydroxy acids such as citric acid or tartaric acid; amino acids such as aspartic acid or glutamic acid; aromatic acids such as benzoic acid or cinnamic acid; sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid; etc.

Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include amino acids derived from, for example, L-glycine, L-lysine and L-arginine; ammonia, primary, secondary and tertiary amines; organic salts of cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

It is also to be understood that the compounds of the present disclosure may exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polycrystalline forms), and that the present disclosure is intended to cover all such forms.

As used herein, the term "solvate" or "solvated form" refers to a solvent addition form that includes a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and if the solvent is an alcohol, the solvate formed is an alkoxide (alcoholate). The hydrate is produced by maintaining one or more water molecules with water as H ₂ One molecule of the substance in the molecular state of O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

As used herein, the terms "crystalline form," "polymorphic form," and "polymorph" are used interchangeably and refer to a crystalline structure of a compound (or a salt or solvate thereof) that can crystallize in a different crystal packing arrangement, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may dominate one crystal form. Polymorphs of a compound can be prepared by crystallization under different conditions.

The present disclosure is also intended to include all isotopes of atoms in the compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise indicated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in a compound of the present disclosure is meant to also include isotopes thereof, such as, but not limited to ¹ H、 ² H、 ³ H、 ¹¹ C、 ¹² C、 ¹³ C、 ¹⁴ C、 ¹⁴ N、 ¹⁵ N、 ¹⁶ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³² S、 ³³ S、 ³⁴ S、 ³⁶ S、 ¹⁷ F、 ¹⁸ F、 ¹⁹ F、 ³⁵ Cl、 ³⁷ Cl、 ⁷⁹ Br、 ⁸¹ Br、 ¹²⁴ I、 ¹²⁷ I and ¹³¹ I. in some embodiments, the hydrogen comprises protium, deuterium, and tritium. In some embodiments, the carbon comprises ¹² C and C ¹³ C。

Those skilled in the art will appreciate that the compounds of the present disclosure may exist in different tautomeric forms, and that all such forms are contemplated as falling within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be converted to each other by a low energy barrier. The existence and concentration of the isomeric forms will depend on the environment in which the compound is located and may vary depending, for example, on whether the compound is solid or in an organic or aqueous solution. For example, proton tautomers (also known as proton-metamorphosing tautomers) include interconversions by proton transfer, such as keto-enol, amide-imide, lactam-lactam, imine-enamine isomerisation, and cyclic forms where a proton may occupy two or more positions of a heterocyclic ring system. Valence tautomers include interconversions by recombination of some of the bond-forming electrons. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution. Unless otherwise indicated, compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms.

Synthesis of Compounds

The compounds provided herein may be prepared using any known organic synthesis technique and may be synthesized according to any of a number of possible synthetic routes.

The reactions for preparing the compounds of the present disclosure may be carried out in suitable solvents that may be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, for example, a temperature which may range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, the appropriate solvent for the particular reaction step may be selected by one skilled in the art.

The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one of skill in the art. The chemistry of protecting groups can be found, for example, in the following references: T.W.Greene and P.G.M.Wuts protecting group in organic Synthesis (Protective Groups in Organic Synthesis), 3 rd edition, john wili's father-son publishing company, N.Y. (1999); kocienski, protecting group (Protecting Groups), qiao Zhitai m press (Georg Thieme Verlag), 2003; and Peter g.m.wuts, greene's Protective Groups in Organic Synthesis, 5 th edition, wili publishing (Wiley), 2014, incorporated herein by reference in its entirety.

The reaction may be monitored according to any suitable method known in the art. For example, the radiation may be detected by, for example, nuclear magnetic resonance spectroscopy (e.g., ¹ h or ¹³ C) Spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by techniques such as High Performance Liquid Chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or Thin Layer Chromatography (TLC)Chromatographic methods monitor product formation. The compounds can be purified by a variety of methods including High Performance Liquid Chromatography (HPLC) ("Preparative LC-MS Purification: improved Compound Specific Method Optimization) improved compound specific method optimization" Karl F.Blom, brian Glass, richard Sparks, andrew P.combos J.Combined chemistry (J.combi.chem.)) "2004,6 (6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica gel chromatography.

Use of compounds

In one aspect, the present disclosure provides compounds capable of inhibiting KRAS proteins, particularly KRAS G12C proteins.

As used herein, the term "therapy" is intended to have its normal meaning, i.e., treating a disease so as to completely or partially alleviate one, some or all of its symptoms, or correct or compensate for an underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization of disease state (i.e., not worsening), delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "therapy" may also mean an increase in survival compared to the expected survival in the absence of receiving therapy. The condition requiring therapy includes a condition that has suffered from a condition or disorder, a condition that is susceptible to suffering from a condition or disorder, or a condition that is to be prevented from a condition or disorder. The term "therapy" also encompasses prophylaxis unless there is a specific indication to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

As used herein, the term "prevention" is intended to have its normal meaning and includes primary prevention for preventing the development of a disease and secondary prevention in which the disease has progressed and the patient is temporarily or permanently protected from exacerbation or worsening of the disease or suffering from new symptoms associated with the disease.

The term "treatment" is used synonymously with "therapy". Similarly, the term "treatment" may be regarded as "application of therapy", wherein "therapy" is as defined herein.

In a further aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for therapy, e.g., for therapy related to KRAS proteins, in particular KRAS G12C proteins.

In a further aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for the treatment of cancer.

In some embodiments, the cancer is mediated by KRAS proteins. In some embodiments, the cancer is mediated by KRAS G12C protein.

Pharmaceutical composition

In a further aspect, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.

In another aspect, a pharmaceutical composition is provided comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

As used herein, the term "pharmaceutical composition" refers to a formulation of the present disclosure including a molecule or compound in a form suitable for administration to a subject.

As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically and otherwise desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used herein, "pharmaceutically acceptable excipients" includes one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent".

The particular excipients used will depend on the means and purpose for which the compounds of the present disclosure are applied. The solvent is generally selected based on solvents deemed safe by those skilled in the art to be administered to mammals, including humans. Generally, the safe solvent is a non-toxic aqueous solvent such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), and the like, and mixtures thereof.

In some embodiments, suitable excipients may include buffers, such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride, hexamethylammonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol or benzyl alcohol, alkyl parabens such as methyl or propyl parabens, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); a low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zn protein complexes); and/or nonionic surfactants, e.g. TWEEN ^TM 、PLURONICS ^TM Or polyethylene glycol (PEG).

In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide an optimal presentation of a drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a drug). The active pharmaceutical ingredient may also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions, respectively, hydroxymethyl cellulose or gelatin microcapsules and poly- (methyl methacrylate) microcapsules. Such techniques are disclosed in the Remington's pharmaceutical sciences 16 th edition, osol, A. Edition (1980). A "liposome" is a vesicle comprising various types of lipids, phospholipids, and/or surfactants that can be used to deliver a drug (such as a compound disclosed herein and optionally a chemotherapeutic agent) to a mammal, including a human. The components of liposomes are typically arranged in bilayer form, similar to the lipid arrangement of biological membranes.

The pharmaceutical compositions provided herein may be in any form that allows for administration of the composition to a subject, including but not limited to humans, and allows for formulation of the composition to be compatible with the intended route of administration.

Various routes are contemplated for the pharmaceutical compositions provided herein, and thus the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage forms depending on the intended route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules, and caplets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms. For injectable administration, emulsions and suspensions may be acceptable as liquid dosage forms, and powders suitable for reconstitution with a suitable solution may be acceptable as solid dosage forms. For inhaled administration, solutions, sprays, dry powders and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches may be in acceptable dosage forms. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams, and sprays can be in acceptable dosage forms.

The amount of active ingredient in a unit dosage form of the composition is a therapeutically effective amount and will vary depending upon the particular treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents the identified disease or condition or exhibits a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. The precise effective amount of the subject will depend on the weight, size and health of the subject; the nature and extent of the pathology; the rate of application; selecting a treatment or combination of treatments for administration; judgment of prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oral administration formulations.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a tablet formulation. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch; lubricants, such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl parahydroxybenzoate; and antioxidants such as ascorbic acid. The tablet formulation may be uncoated or coated to regulate its disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil, for example peanut oil, liquid paraffin or olive oil.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which generally comprises the active ingredient in the form of a fine powder, and one or more suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and gum acacia; dispersants or wetting agents, such as lecithin or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate); or condensation products of ethylene oxide with long chain fatty alcohols, such as heptadecaethyleneoxy cetyl alcohol; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspension may also include one or more preservatives (e.g., ethyl or propyl parahydroxybenzoate), antioxidants (e.g., ascorbic acid), colorants, flavors, and/or sweeteners (e.g., sucrose, saccharin, or aspartame).

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oily suspension, typically comprising the suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). Oily suspensions may also contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners (e.g., as set forth above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil; or mineral oils such as liquid paraffin; or a mixture of any of these oils. Suitable emulsifying agents may be, for example, naturally-occurring gums, such as acacia or tragacanth; naturally occurring phospholipids, such as soybean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also include sweeteners, flavoring agents and preservatives.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may include sweetening agents, such as glycerol, propylene glycol, sorbitol, aspartame, or sucrose; a demulcent; a preservative; flavoring and/or coloring agents.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for injection administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1, 3-butanediol or as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for inhalation administration.

In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols comprising any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers, and combinations thereof. The carrier and stabilizer will vary depending on the requirements of the particular compound, but typically includes nonionic surfactants (Tween, pluronic (Pluronic) or polyethylene glycol), innocuous proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for topical or transdermal administration.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which may be formulated, typically with conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal patches well known to those of ordinary skill in the art.

Pharmaceutically acceptable excipients and carriers, in addition to those representative dosage forms described above, are generally known to those skilled in the art and are therefore included in the present disclosure. Such excipients and carriers are described, for example, in the following references: ramington's pharmaceutical science (Remingtons Pharmaceutical Sciences), mark publishing company (Mack Pub.Co., new Jersey) (1991); leimngton: pharmaceutical science and practice (Remington: the Science and Practice of Pharmacy), editorial, university of philadelphia science (University of the Sciences in Philadelphia), 21 st edition, LWW (2005), which is incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated into a single dosage form. The amount of a compound provided herein in a single dosage form will vary depending upon the subject being treated and the particular mode of administration.

In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated such that 0.001mg/kg body weight/day to 1000mg/kg body weight/day may be administered, for example, 0.01mg/kg body weight/day to 800mg/kg body weight/day, 0.01mg/kg body weight/day to 700mg/kg body weight/day, 0.01mg/kg body weight/day to 600mg/kg body weight/day, 0.01mg/kg body weight/day to 500mg/kg body weight/day, 0.01mg/kg body weight/day to 400mg/kg body weight/day, 0.01mg/kg body weight/day to 300mg/kg body weight/day, 0.1mg/kg body weight/day to 200mg/kg body weight/day, 0.1mg/kg body weight/day to 150mg/kg body weight/day, 0.1mg/kg body weight/day to 100mg/kg body weight/day 0.5mg/kg body weight/day to 100mg/kg body weight/day, 0.5mg/kg body weight/day to 80mg/kg body weight/day, 0.5mg/kg body weight/day to 60mg/kg body weight/day, 0.5mg/kg body weight/day to 50mg/kg body weight/day, 1mg/kg body weight/day to 45mg/kg body weight/day, 1mg/kg body weight/day to 40mg/kg body weight/day, 1mg/kg body weight/day to 35mg/kg body weight/day, 1mg/kg body weight/day to 30mg/kg body weight/day, A compound provided herein, or a pharmaceutically acceptable salt thereof, at a dose of 1mg/kg body weight/day to 25mg/kg body weight/day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases larger doses may be employed without causing any adverse side effects, provided that such larger doses are first divided into several small doses for administration throughout the day. For additional information on route of administration and dosage regimen, see, comprehensive pharmaceutical chemistry (Comprehensive Medicinal Chemistry), volume 5, chapter 25.3 (Corwin Hansch; editorial Committee chairman 1990), which is expressly incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated for short-acting, rapid-release, long-acting, and sustained-release. Thus, the pharmaceutical formulations of the present disclosure may also be formulated for controlled or slow release.

In a further aspect, there is also provided a veterinary composition comprising one or more molecules or compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

The pharmaceutical or veterinary composition may be packaged in various ways depending on the method used to administer the drug. For example, the article for dispensing may comprise a container containing the composition in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cans and the like. The container may also include a tamper evident assembly to prevent easy access to the contents of the package. In addition, the container has a label placed thereon describing the contents of the container. The tag may also include an appropriate warning. The compositions may also be packaged in unit-dose or multi-dose containers, such as sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

In a further aspect, there is also provided a pharmaceutical composition comprising as a first active ingredient one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a second active ingredient.

In some embodiments, the second active ingredient has activity complementary to the compounds provided herein such that it does not adversely affect each other. Such ingredients are suitably present in combination in amounts effective for the intended purpose.

Methods of treating diseases

In a further aspect, the present disclosure provides a method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof and the compositions provided herein may be used to treat KRAS G12C-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof.

In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts and compositions thereof, can be used to treat a variety of cancers, including tumors, such as lung, prostate, breast, brain, skin, cervical, testicular cancer. More specifically, cancers that may be treated by the compounds provided herein or pharmaceutically acceptable salts and compositions thereof include, but are not limited to, tumor types such as astrocyte, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid cancers, sarcomas, and the like. More specifically, the compounds provided herein, or pharmaceutically acceptable salts and compositions thereof, may be used for the treatment of:

(i) Heart cancer: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

(ii) Lung cancer: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, hamartoma, mesothelioma;

(iii) Gastrointestinal cancer: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, schuvascular intestinal peptide tumor), small intestinal cancer (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, smooth myoma, hemangioma, lipoma, neurofibroma, fibroma), large intestinal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth myoma);

(iv) Genitourinary tract cancer: kidney cancer (adenocarcinoma, wilm's tumor (Wilm's tumor), lymphoma, leukemia), bladder and urinary tract cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

(v) Liver cancer: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

(vi) Biliary tract cancer: gall bladder cancer, ampulla cancer, bile duct cancer; bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor (bone exochondral osteowart), benign chondrioma, chondroblastoma, cartilage myxoid fibroma, osteoid osteoma and giant cell tumor;

(vii) Nervous system cancer: head bone cancer (osteoma, hemangioma, granuloma, xanthoma, malformed osteoma), meningioma (meningioma, glioblastoma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);

(viii) Gynecological cancer: uterine cancer (endometrial cancer (serous cyst adenocarcinoma, mucinous cyst adenocarcinoma, unclassified cancer), granulosa cell tumors, sertoli-Leydig cell tumor, asexual cell tumors, malignant teratomas), vulval cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer (carcinoma);

(ix) Blood cancer: hematological cancers (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

(x) Skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, cutaneous fibroma, keloids, psoriasis; and

(xi) Adrenal cancer: neuroblastoma.

In certain embodiments, the cancer that can be treated with the compounds provided herein or pharmaceutically acceptable salts and compositions thereof is non-small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

In certain embodiments, the cancers that may be treated with the compounds provided herein or pharmaceutically acceptable salts and compositions thereof are non-small cell lung cancer or colorectal cancer, particularly non-small cell lung cancer or colorectal cancer with brain metastases.

The concentration of administration and the route of administration of the subject will vary depending on the cancer to be treated. In certain embodiments, the administering is by a route selected from the group consisting of: parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, cerebrospinal, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous and topical administration.

The compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts may also be co-administered with other anti-neoplastic compounds, such as chemotherapy, or in combination with other therapies, such as radiation or surgical intervention, as a pre-or post-operative aid.

In some embodiments, the compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts may be administered simultaneously, separately, or sequentially with one or more additional therapeutic agents. In certain embodiments, the additional therapeutic agent is selected from an anti-PD-1 or PD-L1 antagonist, a MEK inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an SHP2 inhibitor, a SOS1 inhibitor, an mTOR inhibitor, a VEGFR inhibitor, an EGFR antibody, a platinum agent, or pemetrexed. In certain embodiments, the anti-PD-1 antagonist is selected from nivolumab (nivolumab), pembrolizumab (pembrolizumab), or AMB 404. In certain embodiments, the MEK inhibitor is Trametinib (Trametinib). In certain embodiments, the SHP2 inhibitor is RMC-4630.

In another aspect, the present disclosure also provides a method of treating cancer in a subject in need thereof, the method comprising:

(a) Knowing that the cancer is associated with a KRAS G12C mutation; and

(b) Administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In another aspect, the present disclosure provides a method of inhibiting KRAS G12C activity in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

Examples

The following examples are included for illustrative purposes. However, it should be understood that these examples are not limiting of the present disclosure and are intended only to demonstrate methods of practicing the present disclosure.

General synthetic route

Step 1:

the starting materials of formula (Ia' _1) are commercially available. The compounds of formula (Ia '_2) can be prepared by a Ke Disi rearrangement reaction (Curtius rearrangement reaction) with the compounds of formula (Ia' _1) under standard conditions in the presence of diphenyl azide phosphate (DPPA).

Step 2:

compounds of formula (Ia '_3) can be prepared by removing the Boc protecting group of a compound of formula (Ia' _2) with an acid (e.g., TFA) under standard conditions.

Step 3:

the compounds of formula (Ia ' _5) may be prepared by cyclizing a compound of formula (Ia ' _3) with a compound of formula (Ia ' _4) under standard conditions.

Step 4:

the compounds of formula (Ia '_6) may be prepared by nitration of compounds of formula (Ia' _5) with nitric acid under standard conditions.

Step 5:

the compound of formula (Ia '_7) can be prepared by reacting a compound of formula (Ia' _6) with a chloride reagent (e.g., POCl) in the presence of a base (e.g., DIPEA) ₃ ) The chlorination reaction is carried out under standard conditions.

Step 6:

the compounds of formula (Ia '_9) may be prepared by reacting a compound of formula (Ia' _9) in the presence of a base (e.g., DIPEA, naHCO ₃ ) Is prepared by substitution reaction with a compound of formula (Ia '_7) and a compound of formula (Ia' _8) under standard conditions.

Step 7:

the compound of formula (Ia '_10) may be prepared by reduction of the compound of formula (Ia' _9) followed by standard reduction conditions (e.g., fe/NH ₄ Cl) is subjected to intramolecular cyclization.

Step 8:

compounds of formula (Ia '_11) can be prepared by subjecting a compound of formula (Ia' _10) to a methylation reaction with a methylation reagent (e.g., meI) under standard conditions.

Step 9:

the compound of formula (Ia') may be in the presence of a palladium catalyst (e.g., pddppfCl ₂ ) And a base (e.g., na ₂ CO ₃ ) Is prepared by subjecting a compound of formula (Ia '_11) to suzuki coupling reaction (Suzuki coupling reaction) with a compound of formula (Ia' _12) under standard conditions.

Example 1:

2- (10-propenoyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1:5- (2- (tert-butoxy) -1-cyano-2-oxoethyl) pyrazine-2-carboxylic acid methyl ester

A solution of tert-butyl 2-cyanoacetate (25 g,177.09 mmol) and t-BuOK (19.87 g,177.09 mmol) in THF (800 mL) was stirred at room temperature for 0.5 hours, then methyl 5-chloropyrazine-2-carboxylate (20.37 g,118.06 mmol) was added. The reaction mixture was refluxed overnight. However, the method is thatThe reaction mixture was then cooled to room temperature and filtered to give the desired product (25 g, 76.36%). LC/MS (ESI) M/z 278 (M+H) ⁺ 。

Step 2:5- (cyanomethyl) pyrazine-2-carboxylic acid methyl ester

A solution of methyl 5- (2- (tert-butoxy) -1-cyano-2-oxoethyl) pyrazine-2-carboxylate (24 g,86.55 mmol) and PTSA (14.9 g,86.55 mmol) in toluene (800 mL) was heated at 110℃for 3 h. The reaction mixture was then concentrated and the residue was dissolved in H ₂ O (200 mL). The resulting solution was extracted twice with EA. The combined organic layers were washed with saturated NaHCO ₃ Washing with Na ₂ SO ₄ Drying and concentrating. The residue was purified by column chromatography (eluting with PE/ea=5/1) to give the desired product (9.5 g, 61.95%). LC/MS (ESI) M/z 178 (M+H) ⁺ 。

Step 3:5- (cyanomethyl) -5, 6-dihydropyrazine-1, 2 (4H) -dicarboxylic acid 1- (tert-butyl) 2-methyl ester

To 5- (cyanomethyl) pyrazine-2-carboxylic acid methyl ester (9.5 g,53.62 mmol) and Boc ₂ To a solution of O (17.2 mL,80.44 mmol) in ethyl acetate (500 mL) was added Pd/C (4 g,10% Pd carbon) and H at atmospheric pressure ₂ The reaction was stirred overnight at 50 ℃ under an atmosphere. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (12 g, 79.55%). LC/MS (ESI) M/z 282 (M+H) ⁺ 。

Step 4:5- (cyanomethyl) piperazine-1, 2-dicarboxylic acid 1- (tert-butyl) 2-methyl ester

To a solution of 1- (tert-butyl) 2-methyl 5- (cyanomethyl) -5, 6-dihydropyrazine-1, 2 (4H) -dicarboxylic acid 1- (tert-butyl) 2-methyl ester (10 g,35.55 mmol) in MeOH (100 mL) was added AcOH (20 mL) and NaBH ₃ CN (4.47 g,71.09 mmol) and the reaction mixture was stirred overnight at 30 ℃. The reaction mixture was taken up with saturated NaHCO ₃ Quench and extract twice with EA. The combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (8 g, 79.43%). LC/MS (ESI) M/z 284 (M+H) ⁺ 。

Step 5:5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-1, 2-dicarboxylic acid 1- (tert-butyl) 2-methyl ester

To a solution of 1- (tert-butyl) 2-methyl 5- (cyanomethyl) piperazine-1, 2-dicarboxylate (67 g,211.12 mmol) and 4-methoxybenzaldehyde (56.4 mL,464.47 mmol) in DCM (1200 mL) and AcOH (12.09 mL,211.12 mol) at 0deg.C was added NaBH ₃ CN (116.34 g,548.92 mmol) and the reaction was stirred overnight at 30 ℃. The reaction mixture was taken up with saturated NaHCO ₃ Quench and extract twice with DCM. The combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether containing DCM (0-25%) to give 1- (tert-butyl) 2-methyl 5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-1, 2-dicarboxylate (20 g, 21.65%). LC/MS (ESI) M/z 418 (M+H) ⁺ 。

Step 6: (2-chloro-3-fluoropyridin-4-yl) carbamic acid tert-butyl ester

To a solution of 2-chloro-3-fluoroisonicotinic acid (180 g,1 mol) and t-BuOH (1300 mL) in toluene (1300 mL) was added TEA (428 mL). The mixture was stirred at 110 ℃ for 0.5 hours, then D was added dropwise to the mixture after the mixture cooledPPA (332 mL). The reaction mixture was stirred at 110℃for 6 hours. The reaction mixture was then concentrated and diluted with water and extracted with EA. The combined organics were washed with brine, dried over Na ₂ SO ₄ Dried, concentrated, and the desired product (193 g, 76%) was obtained.

MS calculated: 246.06, MS (ESI): 247.0[ M+H ]] ⁺

Step 7: 2-chloro-3-fluoropyridin-4-amine

A solution of tert-butyl (2-chloro-3-fluoropyridin-4-yl) carbamate (193 g,0.78 mol) in dioxane/HCl (1L) was stirred overnight at room temperature. The reaction mixture was then concentrated and the residue was dissolved in water (2000 ml), extracted once with MTBE (1000 ml), dropped, then saturated NaHCO was added ₃ Aqueous solution (200 mL) up to pH>7, extracted with EA (1500 ml. Times.3). The combined organic layers were washed with saturated NaCl, over Na ₂ SO ₄ Dried and concentrated, and the desired product (93 g, 81%) was obtained.

MS(ESI):147[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ7.67(d,J＝5.4Hz,1H),6.73–6.65(m,1H),6.58(s,2H)。

Step 8:5- (((2-chloro-3-fluoropyridin-4-yl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione

A solution of 2-chloro-3-fluoropyridin-4-amine (29 g,198.6 mmol) in trimethyl orthoformate (200 mL) was stirred at 80℃for 2 hours. To the mixture was added 2, 5-dimethoxy aniline (28.6 g,198.6 mmol). The reaction was stirred at 80℃for 16 hours. The mixture was cooled to room temperature and diluted with 5% etoac/hexanes (300 mL) and filtered to give the desired product (48 g, yield: 80.7%) which was used in the next step without further purification.

MS(ESI):301[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ11.42(d,J＝12.8Hz,1H),8.60(d,J＝13.2Hz,1H),8.24(d,J＝5.6Hz,1H),7.27(d,J＝10.4Hz,1H),1.77(s,6H)。

Step 9: 7-chloro-8-fluoro-1, 6-naphthyridin-4-ol

A solution of phenyl ether (450 mL) was heated at 210 ℃. 5- (((2-chloro-3-fluoropyridin-4-yl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (48 g,160 mmol) was added to the reaction. The mixture was stirred at 210℃for 0.3 h. The reaction was cooled to room temperature and washed with hexane. The mixture was filtered off and the residue was purified by a silica gel column (DCM: meoh=30:1) to give the desired product (13.5 g, yield: 42.4%).

MS(ESI):199.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.39(s,1H),8.84(s,1H),7.95(d,J＝7.2Hz,1H),6.23(d,J＝7.6Hz,1H)。

Step 10: 7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-ol

To 7-chloro-8-fluoro-1, 6-naphthyridin-4-ol (13.5 g,67.8 mmol) at room temperature in H ₂ SO ₄ HNO was added to the solution in (90 mL) ₃ (30 mL). The mixture was stirred at 80℃for 2 hours. The reaction mixture was quenched with ice water and the pH was adjusted to about 7 with solid NaOH. The reaction was extracted with EA (600 ml x 2). The combined organic layers were washed with brine (400 mL. Times.2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the desired product (13.2 g, yield: 79.7%), which was used in the next step without further purification.

MS calculated: 242.98, MS (ESI): 244.0[ M+H ]] ⁺ 。

Step 11:4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine

To 7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-ol (13.2 g,54.2 mmol) in POCl ₃ DIEA (21 g,0.1622 mmol) was added to a solution of (130 mL) and the mixture was stirred at 105℃for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with ice water (200 ml) and 1M NaOH (aq) was added until PH>7 (kept below 5 ℃ C.) then extracted with EtOAc (200 ml x 2), the combined organic layers were washed with brine (200 ml x 2) over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give the desired product (13.5 g, yield: 93.7%), which was used in the next step without further purification.

MS calculated: 260.95, MS (ESI): 262.0[ M+H ]] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ9.48(s,2H)。

Step 12:1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylic acid methyl ester

To 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine (2.61 g,10 mmol) in CH ₃ To a solution in CN (30 mL) was added methyl 5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (3.03 g,10 mol) and NaHCO ₃ (1.68 g,20 mmol). The reaction was stirred at 55℃for 16 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by a silica gel column (EA: pe=1:3) to give the desired product (2.27 g, yield: 43%). MS calculated: 528.1, MS (ESI): 529.2[ M+H ] ] ⁺ 。

Step 13:2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To a mixture of methyl 1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (cyanomethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (3.7 g,7 mmol) in EtOH (60 mL) and saturated aqueous ammonium chloride solution (60 mL) was added iron powder (2.0 g,35 mmol) at room temperature and the reaction was heated to 80 ℃ and stirred under nitrogen atmosphere for 16 hours. The reaction solution was filtered while still hot, water (100 ml) was added to the filtrate and extracted with EtOAc (200 ml x 3), the combined extracts were washed with water and brine, and dried over Na ₂ SO ₄ Dried, filtered, concentrated under reduced pressure, and the residue was purified by SGC (EA: pe=1:3) to give the title product (1.1 g, yield: 43%).

MS calculated: 466.1, MS (ESI): 467.2[ M+H ]] ⁺ 。

Step 14:2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] at room temperature under a nitrogen atmosphere ]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (1.1 g,2.36 mmol) in DMF (15 mL) was added Cs in sequence ₂ CO ₃ (1.53 g,4.72 mmol) and MeI (503 mg,3.54 mmol) and then the reaction was stirred at room temperature under nitrogen for 2 hours. Water (100 ml) was added, stirred at room temperature for 20 minutes, filtered, and the solid was washed with water and dried under reduced pressure to give the title product (880 mg, yield: 78%).

MS calculated: 480.2, MS (ESI): 481.2[ M+H ]] ⁺ 。

Step 15:2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (10- (4-methoxybenzyl) -7-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-2, 3,4,7, 8a,9,10,11, 12-decahydro-1H-pyrazino [1',2':4, 5) at room temperature under a nitrogen atmosphere]Pyrazino [2,3-c ]][1,7]Naphthyridin-11-yl) acetonitrile (240 mg,0.5 mmol), 2- (8-chloronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (288 mg,1 mmol) and K ₂ CO ₃ (207 mg,1.5 mmol) in dioxane (4 mL) and H ₂ Pd (PPh) was added to a solution in O (1 ml) ₃ ) ₄ (58 mg,0.05 mmol) and then the reaction was heated to 100℃and stirred under nitrogen for 16 hours. After cooling to room temperature, water (5 ml) was added, extracted with EtOAc (10 ml x 3), the combined extracts were washed with water and brine, and dried over Na ₂ SO ₄ Drying, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by TLC (PE: etoac=1:1) to give the title product (180 mg crude, yield: 29.7%). MS calculated: 606.2, MS (ESI): 607.2[ M+H ]] ⁺ 。

Step 16:2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (180 mg, about 50% purity, 0.15 mmol) in TFA (10 mL) was added methyl (phenyl) sulfane (0.1 mL). The mixture is put under N ₂ Stirring is carried out for 3 hours at 50℃under an atmosphere. Concentrating the reaction mixture to obtain a residueAnd the remainder. The residue was quenched with water and taken up in solid NaHCO ₃ The pH was adjusted to about 7. The reaction was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was purified by TLC (DCM: meoh=10:1) to give the desired product (120 mg, yield: 83.3%). MS calculated: 486.1, MS (ESI): 487.2[ M+H ]] ⁺ 。

Step 12:2- (10-propenoyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile (120 mg,0.173 mmol) in DCM (5 mL) was added dropwise acryloyl chloride (32 mg,0.36 mmol) and TEA (54 mg,0.54 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour. The reaction was concentrated under reduced pressure (below 20 ℃) and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give the two isomers (example 1a:2.7 mg/example 1b:16.5 mg).

Example 1A: MS calculated: 540.2, MS (ESI): 541.3[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ9.31(s,1H),8.70(s,1H),8.07(d,J＝8.0Hz,1H),7.92(d,J＝8.0Hz,1H),7.63 -7.61(m,2H),7.53-7.51(m,1H),7.45–7.43(m,1H),6.88–6.82(m,1H),6.25(d,J＝16.8Hz,1H),5.80(d,J＝10.8Hz,1H),4.50–4.41(m,4H),3.58–3.55(m,2H),3.48(s,3H),2.88–2.85(m,2H)。

Example 1b ms calculated: 540.2, MS (ESI): 541.3[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ9.49(s,1H),9.05(m,1H),8.18(d,J＝8.0Hz,1H),8.05(d,J＝8.0Hz,1H),7.74 -7.70(m,2H),7.63-7.61(m,1H),7.56-7.53(m,1H),7.13–7.10(m,1H),6.33(d,J＝16.8Hz,1H),5.88(d,J＝10.4Hz,1H),4.98–4.96(m,2H),4.17 -4.06(m,1H),4.03 -3.99(m,1H),3.90 -3.81(m,1H),3.79-3.71(m,1H),3.61(s,3H)。

Example 2:

2- (10-propenoyl-4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1:2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] at room temperature under a nitrogen atmosphere ]Pyrazino [2,3-c ]][1,6]Naphthyridin-11-yl) acetonitrile (240 mg,0.27 mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (314 mg,1 mmol) and K ₂ CO ₃ (207 mg,1.5 mmol) in dioxane (4 mL) and H ₂ To a solution in O (1 ml) was added Ruphos-G2-Pd (39 mg,0.05 mmol), and the reaction was then heated to 100℃and stirred under nitrogen for 2 hours. After cooling to room temperature, water (5 ml) was added, extracted with EtOAc (10 ml x 3), the combined extracts were washed with water and brine, and dried over Na ₂ SO ₄ Drying, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by TLC (PE: etoac=1:1) to give the title product (200 mg, yield: 61.9%).

MS(ESI):557.2[M+H] ⁺ 。

Step 2:2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (180 mg,0.32 mmol) in TFA (10 mL) was added methyl (phenyl) sulfane (0.1 mL). The mixture is put under N ₂ Stirring is carried out for 3 hours at 50℃under an atmosphere. The reaction mixture was concentrated to give a residue. The residue was quenched with water and taken up in solid NaHCO ₃ The pH was adjusted to about 7. The reaction was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was purified by TLC (DCM: meoh=8:1) to give the desired product (120 mg, yield: 85.6%).

MS(ESI):437.2[M+H] ⁺ 。

Step 3: acrylic acid 2- (10-propenoyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-3-yl) -3-fluorophenyl ester

To a solution of 2- (4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile (110 mg,0.20 mmol) in DCM (5 mL) was added dropwise acryloyl chloride (38 mg,0.42 mmol) and TEA (60 mg,0.60 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour. The reaction was concentrated under reduced pressure (below 20 ℃ C.) and the residue was used directly in the next step without further purification (140 mg crude, yield: 100%).

MS(ESI):545.3[M+H] ⁺ 。

Step 4:2- (10-propenoyl-4-fluoro-3- (2-fluoro-6-hydroxyphenyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To acrylic acid 2- (10-propenoyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5 ]Pyrazino [2,3-c ]][1,6]Naphthyridin-3-yl) -3-fluorophenyl ester (140 mg crude, 0.20 mmol) in THF (4 mL) and H ₂ LiOH.H was added to a solution in O (1 ml) ₂ O (21 mg,0.5 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure (below 20 ℃) and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give 2 isomers [ example 2A:5.6mg, example 2B:6.7mg]。

Example 2A: MS (ESI): 491.3[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,MeOD)δ9.33(s,1H),8.93(s,1H),7.38-7.35(m,1H),7.00-7.02(m,1H),6.84-6.75(m,2H),6.76(d,J＝8.4Hz,1H),5.90(d,J＝10.8Hz,1H),4.59-4.40(m,3H),4.22-4.18(m,1H),3.61(s,3H),3.34 -3.30(m,2H),2.94-2.93(m,2H)

Example 2b ms (ESI): 491.3[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,MeOD)δ9.45(s,1H),9.09(s,1H),7.37-7.33(m,1H),7.18-7.11(m,1H),6.85-6.75(m,2H),6.30(d,J＝16.8Hz,1H),5.88(d,J＝12.0Hz,1H),5.03 -4.87(m,2H),4.09-4.02(m,1H),3.99-3.97(m,1H),3.77-3.74(m,1H),3.61(s,3H),3.54 -3.50(m,1H),3.36-3.32(m,2H)

Example 3:

2- (10-propenoyl-4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1:2- (4-fluoro-10- (4-methoxybenzyl) -3- (3- (methoxymethoxy) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (10- (4-methoxybenzyl) -7-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-2, 3,4,7, 8a,9,10,11, 12-decahydro-1H-pyrazino [1',2':4, 5) at room temperature under a nitrogen atmosphere]Pyrazino [2,3-c ]][1,7]Naphthyridin-11-yl) acetonitrile (240 mg,0.5 mmol), 2- (3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (314 mg,1 mmol) and K ₂ CO ₃ (207 mg,1.5 mmol) in dioxane (4 mL) and H ₂ Pd (PPh) was added to a solution in O (1 ml) ₃ ) ₄ (58 mg,0.05 mmol) and then the reaction was heated to 100℃and stirred under nitrogen for 16 hours. After cooling to room temperature, water (5 ml) was added, extracted with EtOAc (10 ml x 3), the combined extracts were washed with water and brine, and dried over Na ₂ SO ₄ Drying, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by TLC (PE: etoac=1:1) to give the title product (200 mg, yield: 63.3%).

MS(ESI):633.3[M+H] ⁺ 。

Step 2:2- (4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (4-fluoro-10- (4-methoxybenzyl) -3- (3- (methoxymethoxy) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (180 mg,0.28 mmol) in TFA (10 mL) was added methyl (phenyl) sulfane (0.1 mL). The mixture is put under N ₂ Stirring is carried out for 3 hours at 50℃under an atmosphere. The reaction mixture was concentrated to give a residue. The residue was quenched with water and taken up in solid NaHCO ₃ The pH was adjusted to about 7. The reaction was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was purified by TLC (DCM: meoh=10:1) to afford the desired product (110 mg, yield: 84.6%).

MS(ESI):469.3[M+H] ⁺ 。

Step 3: acrylic acid 4- (10-propenoyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-3-yl) naphthalen-2-yl ester

To a solution of 2- (4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile (100 mg,0.173 mmol) in DCM (5 mL) was added dropwise acryloyl chloride (32 mg,0.36 mmol) and TEA (54 mg,0.54 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour. The reaction was concentrated under reduced pressure (below 20 ℃ C.) and the residue was used directly in the next step without further purification (120 mg crude, yield: 100%).

MS(ESI):577.4[M+H] ⁺ 。

Step 4:2- (10-propenoyl-4-fluoro-3- (3-hydroxynaphthalen-1-yl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To acrylic acid 4- (10-propenoyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]Pyrazino [2,3-c ] ][1,6]Naphthyridin-3-yl) naphthalen-2-yl ester (120 mg crude, 0.173 mmol) in THF (4 mL) and H ₂ LiOH H was added to the solution in O (1 ml) ₂ O (21 mg,0.5 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure (below 20 ℃) and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give 2 isomers [ example 3A:6.5mg, example 3B:35.8mg]。

Example 3A: MS (ESI): 523.3[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,MeOD)δ9.26(s,1H),δ8.23(s,1H),7.66(d,J＝8.4Hz,1H),7.43(d,J＝8.4Hz 1H),7.33–7.31(m,1H),7.19–7.12(m,3H),7.10–6.86(m,1H),6.23(d,J＝16.8Hz,1H),5.77(d,J＝12Hz,1H),4.80–4.71(m,1H),4.38–4.26(m,3H),4.14–4.11(m,1H),3.34(s,3H),3.25–3.20(m,2H),2.82(d,J＝5.2Hz,1H)

Example 3b ms (ESI): 523.3[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,MeOD)δ9.26(s,1H),δ8.23(s,1H),7.65(d,J＝8.4Hz,1H),7.44(d,J＝8.4Hz 1H),7.34–7.32(m,1H),7.18–7.12(m,3H),7.09–6.86(m,1H),6.22(d,J＝16.8Hz,1H),5.78(d,J＝12Hz,1H),4.38–4.26(m,3H),4.14–4.11(m,1H),3.34(s,3H),3.25–3.20(m,2H),2.82(m,2H)。

Example 4:

2- (10-propenoyl-4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1:2- (4-fluoro-10- (4-methoxybenzyl) -7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (10- (4-methoxybenzyl) -7-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-2, 3,4,7, 8a,9,10,11, 12-decahydro-1H-pyrazino [1',2':4, 5) at room temperature under a nitrogen atmosphere]Pyrazino [2,3-c ]][1,7]Naphthyridin-11-yl) acetonitrile (240 mg,0.5 mmol), 4, 5-tetramethyl-2- (8-methylnaphthalen-1-yl) -1,3, 2-dioxaborolan (268 mg,1 mmol) and K ₂ CO ₃ (207 mg,1.5 mmol) in dioxane (4 mL) and H ₂ Pd (PPh) was added to a solution in O (1 ml) ₃ ) ₄ (58mg，0.05mmol) The mixture was then heated to 100 ℃ and stirred under nitrogen for 16 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (50 ml x 3). The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE: etoac=1:1) to give the title product (120 mg, yield: 41%).

MS(ESI):587.3[M+H] ⁺ 。

Step 2:2- (4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (120 mg,0.25 mmol) in TFA (4 mL) was added anisole (0.1 mL). The mixture is put under N ₂ Stirring is carried out for 3 hours at 50℃under an atmosphere. The reaction mixture was concentrated to give a residue. The residue was quenched with water and taken up in solid NaHCO ₃ The pH was adjusted to about 7. The mixture was extracted with EA (30 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated and the residue was purified by preparative TLC (DCM: meoh=10:1) to give the desired product (80 mg, yield: 80%).

MS(ESI):467.1[M+H] ⁺ 。

Step 3:2- (10-propenoyl-4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To a solution of 2- (4-fluoro-7-methyl-3- (8-methylnaphthalen-1-yl) -8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile (80 mg,0.17 mmol) in DCM (5 mL) was added dropwise acryloyl chloride (32 mg,0.36 mmol) and TEA (54 mg,0.54 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure (below 20 ℃) and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give the title product (example 4A:1.9mg; example 4B:2.1mg, yield: 4.5%).

Example 4A: MS calculated: 520.2, MS (ESI): 521.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ9.27(s,1H),8.94(s,1H),8.00(d,J＝8.5Hz,1H),7.83(d,J＝8.3Hz,1H),7.60–7.53(m,1H),7.53–7.44(m,1H),7.44–7.38(m,1H),7.29–7.26(m,1H),6.75(dd,J＝16.7,10.5Hz,1H),6.45(d,J＝17.1Hz,1H),5.88(d,J＝10.6Hz,1H),4.90(br s,1H),4.54–4.26(m,3H),4.26–4.05(m,2H),3.63(s,3H),2.92–2.71(m,2H),2.00(d,J＝3.5Hz,3H)。

Implementation of the embodimentsExample 4B:MS calculated: 520.2, MS (ESI): 521.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ9.47(s,1H),9.01(s,1H),8.00(d,J＝8.2Hz,1H),7.83(d,J＝8.0Hz,1H),7.59–7.53(m,1H),7.53–7.44(m,1H),7.42(t,J＝7.5Hz,1H),7.27–7.25(m,1H),7.05–6.92(m,1H),6.42(d,J＝16.8Hz,1H),5.89(d,J＝10.6Hz,1H),5.11–4.88(m,2H),3.87–3.83(m,3H),3.61(s,3H),3.49–3.46(m,1H),3.26–3.24(m,1H),2.94–2.90(m,1H),1.99(d,J＝6.4Hz,3H)。

Example 5:

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol

Step 1:2- (3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (500 mg,1.04 mmol) in TFA (10 mL) was added anisole (1 drop). The mixture is put under N ₂ Stirring is carried out for 2 hours at 50℃under an atmosphere. The reaction mixture was concentrated. The residue was quenched with water and taken up in solid NaHCO ₃ The pH was adjusted to about 7. The mixture was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (30 ml x 3), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated to give the desired product (380 mg, crude product) which was used in the next step without further purification.

MS(ESI):361.1[M+H] ⁺ 。

Step 2:2- (10-propenoyl-3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] at 0 DEG C]Pyrazino [2,3-c ]][1,6]A solution of naphthyridin-11-yl) acetonitrile (380 mg,1.05 mmol) in DCM (10 mL) was added dropwise acryloyl chloride (190 mg,2.1 mmol) and TEA (318 mg,3.15 mmol). The mixture was stirred at room temperature for 1 hour. Will react with H ₂ O (15 mL) was quenched and extracted with DCM (15 mL. Times.3). The combined organic layers were washed with brine (15 ml x 2), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated and the crude product was purified by preparative TLC (PE: ea=3:1) to give the desired product (310 mg, yield: 71%).

MS(ESI):415.1[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ9.18(s,1H),8.97(s,1H),7.04–6.70(m,1H),6.47–6.38(m,1H),5.88(dd,J＝10.6,1.6Hz,1H),5.07–4.84(m,2H),4.27–4.07(m,1H),3.93–3.87(m,1H),3.76–3.66(m,1H),3.61(s,3H),3.52–3.39(m,1H),3.33–3.23(m,1H),2.94–2.83(m,1H)。

Step 3: t2- (10-propenoyl-4-fluoro-7-methyl-8-oxo-3- (8- ((triisopropylsilane) ethynyl) naphthalen-1-yl) -8,8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (10-propenoyl-3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4, 5)]Pyrazino [2,3-c ]][1,6]Naphthyridin-11-yl) acetonitrile (150 mg,0.36 mmol), triisopropyl ((8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (314 mg,0.72 mmol) in dioxane (10 mL) and water (2 mmol) Pd (dtbpf) Cl was added ₂ (24mg，0.036mmol)、K ₃ PO ₄ (229 mg,1.08 mmol). The reaction mixture was stirred under nitrogen at 100 ℃ for 16 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 ml x 3), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated and the crude product was purified by preparative TLC (PE: ea=3:1) to give the desired product (48 mg, yield: 20%).

MS(ESI):687.4[M+H] ⁺ 。

Step 4:2- (10-propenoyl-3- (8-ethynylnaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (10-propenoyl-4-fluoro-7-methyl-8-oxo-3- (8- ((triisopropylsilane) ethynyl) naphthalene-1-yl) -8,8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (40 mg,0.058 mmol) in DMF (5 mL) was added CsF (26 mg,0.174 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 ml x 3), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (containing 0.05% nh ₄ OH in water/MeCN) to give the title product (5 mg, yield: 16%).

MS(ESI):531.2[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ9.39(d,J＝9.6Hz,1H),9.08(d,J＝6.4Hz,1H),8.15–8.04(m,2H),7.77–7.60(m,3H),7.55–7.48(m,1H),7.19–7.08(m,1H),6.29(d,J＝17.0Hz,1H),5.87(d,J＝12.1Hz,1H),5.05(s,1H),4.95(d,J＝14.6Hz,1H),4.08(br s,1H),4.01–3.92(m,1H),3.79–3.69(m,1H),3.60(s,3H),3.54–3.33(m,3H)。

Example 6:

2- (10-propenoyl-3- (8-ethynyl-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1: tert-butyldimethyl ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- ((triisopropylsilane) ethynyl) naphthalen-2-yl) oxy) silane

Trifluoromethanesulfonic acid 3- ((tert-butyldimethylsilyl) oxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl ester (1.5 g,2.559 mmol), bis (pinacolato) diborane (1.95 g,7.677 mmol), acOK (750 mg,7.677 mmol) and Pd (dppf) Cl ₂ (372mg,0.510 mmol) in toluene (50 mL) in N ₂ Stirred overnight at 110 ℃ under an atmosphere. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The mixture was extracted with EtOAc (100 ml x 3). The combined organic layers were washed with brine (50 ml x 2), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (50:1) to give the desired product (412 mg, yield: 28%).

¹ H NMR(400MHz,DMSO-d6)δ7.66(d,J＝8.1Hz,1H),7.43(d,J＝6.8Hz,1H),7.25(m,1H),7.20–7.14(m,1H),6.99(d,J＝2.5Hz,1H),1.12(s,12H),0.94–0.86(m,21H),0.77(s,9H),0.03(s,6H)。

Step 2:2- (10-propenoyl-4-fluoro-3- (3-hydroxy-8- ((triisopropylsilane) ethynyl) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

2- (10-propenoyl-3-chloro-4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4, 5)]Pyrazino [2,3-c ]][1,6]Naphthyridin-11-yl) acetonitrile (80 mg,0.192 mmol), tert-butyldimethyl ((4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- ((triisopropylsilane) ethynyl) naphthalen-2-yl) oxy) silane (216 mg, 0.284 mmol), K ₃ PO ₄ (120 mg,0.576 mmol) and Pd (dtbpf) Cl ₂ (12 mg,0.019 mmol) in 1, 4-dioxane (5 mL) and H ₂ Solution in O (1 mL) in N ₂ Stirred overnight at 90 ℃ under an atmosphere. The reaction mixture was cooled to room temperature and diluted with water (40 mL). The mixture was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (30 ml x 2), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EA (1:5) to give the desired product (30 mg, yield: 22%).

MS(ESI):703.3[M+H] ⁺ 。

Step 4:2- (10-propenoyl-3- (8-ethynyl-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (10-propenoyl-4-fluoro-3- (3-hydroxy-8- ((triisopropylsilane) ethynyl) naphthalen-1-yl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (27 mg,0.038 mmol) in DMF (1.5 mL) was added CsF (29 mg,0.192 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 ml x 3), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (water/MeCN with 0.05% NH4 OH) to give the title product (5.38 mg, yield: 25%).

MS(ESI):547.3[M+H] ⁺ 。

¹ H NMR(400MHz,MeOD)δ9.33(d,J＝7.6Hz,1H),9.06(d,J＝5.3Hz,1H),7.73–7.57(m,1H),7.32–7.27(m,1H),7.27–7.22(m,1H),7.17–7.14(m,2H),7.13–7.10(m,1H),6.28(d,J＝16.9Hz,1H),5.86(d,J＝11.0Hz,1H),5.06(s,1H),4.94(m,2H),4.13–4.03(m,1H),4.02–3.90(m,1H),3.76–3.66(m,1H),3.59(s,3H),3.50–3.40(m,2H),3.36–3.33(m,1H)。

Example 7:

Step 1: 1-bromo-8-chloro-3- (methoxymethoxy) naphthalene

At N ₂ To a solution of 4-bromo-5-chloronaphthalen-2-ol (400 mg,1.56 mmol) in DCM (10 mL) was added DIEA (410 mg,3.15 mmol) and MOMBr (390 mg,3.15 mmol) DIEA at 0deg.C under an atmosphere. The mixture was stirred at 0 ℃ for 2 hours. After dilution with water, the mixture was extracted with DCM. The combined organics were washed with brine, dried over Na ₂ SO ₄ And (5) drying. After concentration, the crude product was purified by preparative TLC to give the desired product (400 mg, yield: 85%). ¹ H NMR(400MHz,DMSO-d6)δ7.92(dd,J＝8.3,1.0Hz,1H),7.75(d,J＝2.6Hz,1H),7.64–7.58(m,2H),7.50–7.44(m,1H),5.35(s,2H),3.43(s,3H)。

Step 2:2- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan

To 1-bromo-8-chloro-3- (methoxymethoxy) naphthalene (400 mg,1.3 mmol), 4', 5', to a solution of 5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (660 mg,2.6 mmol) and KOAc (254 mg,2.6 mmol) in DMF (6 mL) was added Pd (dppf) Cl ₂ (95 mg,0.13 mmol) and then the reaction mixture was stirred under nitrogen at 90℃for 24 hours. Water (30 ml) was added and the mixture extracted with EtOAc (20 ml. Times.3). The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE: etoac=30:1) to give the title product (330 mg, yield: 70%). ¹ H NMR(400MHz,DMSO-d6)δ7.85(dd,J＝8.2,1.0Hz,1H),7.57–7.51(m,2H),7.49–7.42(m,1H),7.27(d,J＝2.5Hz,1H),5.35(s,2H),3.43(s,3H),1.37(s,12H)。

Step 3:2- (3- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (10- (4-methoxybenzyl) -7-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-2, 3,4,7, 8a,9,10,11, 12-decahydro-1H-pyrazino [1',2':4, 5) at room temperature under a nitrogen atmosphere]Pyrazino [2,3-c ]][1,7]Naphthyridin-11-yl) acetonitrile (240 mg,0.5 mmol), 2- (8-chloro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (330 mg,0.94 mmol) and K ₂ CO ₃ (207 mg,1.5 mmol) in dioxane (4 mL) and H ₂ Pd-Ruphos-G4 (50 mg,0.05 mmol) was added to a solution in O (1 ml), and the mixture was heated to 100deg.C and stirred under nitrogen for 16 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (40 ml x 3). The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE: etoac=1:1) to give the title product (200 mg, yield: 60%).

MS(ESI):667.1[M+H] ⁺ 。

Step 4:2- (3- (8-chloro-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (200 mg,0.3 mmol) in TFA (4 mL) was added anisole (0.1 mL). The mixture is put under N ₂ Stirring is carried out for 3 hours at 50℃under an atmosphere. The reaction mixture was concentrated to give a residue. Will remain behindThe material was quenched with water and taken up in solid NaHCO ₃ The pH was adjusted to about 7. The mixture was extracted with EA (30 ml x 3). The combined organic layers were washed with brine (40 ml x 2), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated and the crude product was purified by preparative TLC (DCM: meoh=10:1) to give the desired product (105 mg, yield: 70%).

MS(ESI):503.2[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ9.40(d,J＝6.3Hz,1H),9.04(s,1H),7.75–7.66(m,1H),7.39–7.34(m,2H),7.34–7.31(m,1H),7.21(d,J＝2.7Hz,1H),4.11(d,J＝13.6Hz,1H),3.67–3.55(m,4H),3.52–3.44(m,2H),3.35(d,J＝13.2Hz,1H),2.72–2.57(m,1H),2.57–2.44(m,2H)。

Step 5: acrylic acid 4- (10-propenoyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-3-yl) -5-chloronaphthalen-2-yl ester

To a solution of 2- (3- (8-chloro-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile (100 mg,0.2 mmol) in DCM (5 mL) was added dropwise acryloyl chloride (54 mg,0.60 mmol) and TEA (60 mg,0.60 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour. The mixture was concentrated under reduced pressure to give the crude title product, which was used directly in the next step.

MS(ESI):611.1[M+H] ⁺ 。

Step 6:2- (10-propenoyl-3- (8-chloro-3-hydroxynaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To acrylic acid 4- (10-propenoyl-11- (cyanomethyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]Pyrazino [2,3-c ]][1,6]Naphthyridin-3-yl) -5-chloronaphthalen-2-yl ester (150 mg crude, 0.20 mmol) in THF (4 mL) and H ₂ LiOH H was added to the solution in O (1 mL) ₂ O (21 mg,0.5 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure (below 20 ℃) and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give the title product (for two steps, example 7a:1.5 mg/example 7b:4.6mg, yield: 5.4%, over two steps).

Example 7A: MS calculated: 556.1, MS (ESI): 557.1[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ9.25–9.12(m,1H),8.90(s,1H),7.66–7.64(m,1H),7.35–7.29(m,2H),7.25–7.13(m,2H),6.79–6.65(m,1H),6.42(d,J＝16.2Hz,1H),5.93–5.80(m,1H),5.00–4.74(m,1H),4.44–4.20(m,2H),4.24–4.00(m,2H),3.84–3.80(m,1H),3.60(s,3H),2.97–2.60(m,2H)。

Implementation of the embodimentsExample 7B: ¹ H NMR(400MHz,CDCl ₃ )δ9.46–9.22(m,1H),9.06–8.84(m,1H),7.61–7.58(m,1H),7.28–7.26(m,1H),7.24–7.03(m,3H),6.99–6.87(m,1H),6.39(d,J＝9.1.0Hz,1H),5.92–5.80(m,1H),5.00–4.71(m,2H),3.93–3.65(m,2H),3.62–3.31(m,4H),3.24–3.22(m,2H),2.85–2.81(m,1H)。

example 8:

2- (10-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1: 5-chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene

To a mixture of 1-bromo-3-chloro-2, 4-difluorobenzene (25 g,110 mmol) and furan (15 g,220 mmol) in toluene (250 ml) was added n-BuLi (2.50M, 52.8mL,132 mmol) dropwise over 0.5 hours at-15 ℃. The mixture was warmed to room temperature and stirring was continued for 12 hours. Subsequently, the mixture was quenched with water (200 ml) and filtered. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (200 ml x 2). The combined organic layers were taken up over Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: ea=10:1) to give 5-chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene (8.1 g,37% yield).

¹ H NMR(400MHz,CDCl ₃ )δ7.09(d,J＝5.2Hz,2H),7.06–7.01(m,1H),6.73(dd,J＝9.5,7.7Hz,1H),5.88(s,1H),5.74(s,1H)。

Step 2: 8-chloro-7-fluoronaphthalen-1-ol

A mixture of 5-chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene (15 g,76.3 mmol) in concentrated hydrochloric acid (34 g, 931mmol) and ethanol (110 ml) was heated and stirred at 80℃for 6 hours. Subsequently, the reaction mixture was concentrated under vacuum. The residue was taken up in saturated NaHCO ₃ The aqueous solution was adjusted to a pH of about 7 and extracted with ethyl acetate (250 ml x 2). The combined organic layers were taken up over Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated in vacuo. The residue was triturated with petroleum ether (500 mL) and then filtered and the filter cake dried under vacuum to give the desired product (13 g,86% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.89(s,1H),7.73(dd,J＝9.1,5.5Hz,1H),7.42–7.33(m,2H),7.27(t,J＝7.8Hz,1H),7.09–7.04(m,1H)。

Step 3: trifluoro-methanesulfonic acid 8-chloro-7-fluoronaphthalen-1-yl ester

8-chloro-7-fluoronaphthaleneA mixture of 1-ol (13 g,66.1 mmol), DIEA (51.3 g,396.6 mmol) and 4A MS (120 g) in dichloromethane (150 ml) was stirred at 20℃for 10 min. To this suspension cooled to-40 ℃ was added dropwise trifluoromethanesulfonic anhydride (24.2 g,85.9 mmol). After 20 min, the reaction mixture was diluted with water (150 mL) and the organic layer was collected. The aqueous layer was then extracted with ethyl acetate (150 ml x 2). The combined organic layers were taken up over Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE/ea=10:1) to give the desired product (18.5 g,85% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.88(dd,J＝8.1,0.9Hz,1H),7.83(dd,J＝9.0,5.3Hz,1H),7.58(d,J＝7.7Hz,1H),7.50(t,J＝8.0Hz,1H),7.42(t,J＝8.7Hz,1H)。

Step 4:2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan

Triflic acid 8-chloro-7-fluoronaphthalen-1-yl ester (13.3 g,40.5 mmol), (PinB) ₂ (20.6 g,81 mmol), KOAc (19.9 g,202.5 mmol) and Pd (dppf) Cl ₂ (2.96 g,4.05 mmol) in DMF (150 mL) was purged with nitrogen and the mixture was then stirred at 80℃for 12 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (150 ml x 2). The combined organic layers were washed with brine (150 mL), and dried over Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE: ea=10:1) to give the desired product (9.6 g,74% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.85(d,J＝8.2Hz,1H),7.75(dd,J＝9.0,5.5Hz,1H),7.70(d,J＝6.8Hz,1H),7.50–7.43(m,1H),7.32(t,J＝8.7Hz,1H),1.45(s,6H),1.26(s,6H)。

Step 5:2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (10- (4-methoxybenzyl) -7-methyl-6- (((S) -1-methylpyrrolidin-2-yl) methoxy) -8-oxo-2, 3,4,7, 8a,9,10,11, 12-decahydro-1H-pyrazino [1',2':4, 5) at room temperature under a nitrogen atmosphere]Pyrazino [2,3-c ]][1,7]Naphthyridin-11-yl) acetonitrile (480 mg,1.0 mmol), 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (610 mg,2 mmol) and K ₂ CO ₃ (414 mg,3.0 mmol) in dioxane (8 mL) and H ₂ To a solution in O (2 ml) was added RuPhos-Pd-G4 (85 mg,0.1 mmol), and the reaction was then heated to 100℃and stirred under nitrogen for 16 hours. After cooling, water (40 ml) was added and the mixture was extracted with EtOAc (50 ml x 3). The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ Dried, filtered and the filtrate concentrated under reduced pressure. The residue was purified by preparative TLC (PE: etoac=1:1) to give the title product (240 mg, yield: 38.4%). MS (ESI): 625.2[ M+H ]] ⁺ 。

Step 6:2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (240 mg,0.38 mmol) in TFA (6 mL) was added methyl (phenyl) sulfane (0.2 mL). The mixture is put under N ₂ Stirring is carried out for 3 hours at 50℃under an atmosphere. The reaction mixture was concentrated. The residue was diluted with water and taken up in solid NaHCO ₃ The pH was adjusted to about 7. The mixture was extracted with EA (30 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ And (5) drying. After filtration, the filtrate was concentrated and purified by preparative TLC (DCM: meoh=10:1) to give the desired product (155 mg, yield: 80%). MS (ESI): 505.1[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ9.36(d,J＝10.2Hz,1H),8.98(d,J＝7.4Hz,1H),8.02(d,J＝7.8Hz,1H),7.91(dd,J＝9.0,5.5Hz,1H),7.71–7.56(m,2H),7.44–7.36(m,1H),3.87–3.72(m,2H),3.64(s,3H),3.59–3.50(m,2H),3.50–3.34(m,2H),3.29–3.11(m,1H),3.05–2.87(m,1H)。

Step 7:2- (10-propenoyl-3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] at 0 DEG C]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (70 mg,0.139 mmol) in DCM (3 mL) was added TEA (30 mg,0.3 mmol) and the mixture was stirred at 0deg.C for 5 min before the addition of acryloyl chloride (25 mg,0.28 mmol). The resulting mixture was stirred at 0℃for 30 minutes. The reaction was concentrated under reduced pressure (below 20 ℃) and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give the two isomers (example 8A:5.5 mg/example 8B:22.9 mg). MS calculated: 558.1, MS (ESI): 559.1[ M+H ]] ⁺ 。

Example 8A: ¹ H NMR(400MHz,CDCl ₃ )δ9.49–9.24(m,1H),8.93(s,1H),8.03(d,J＝8.0Hz,1H),7.91(dd,J＝9.2,5.5Hz,1H),7.78–7.56(m,2H),7.42(t,J＝8.8Hz,1H),6.85–6.69(m,1H),6.44(d,J＝16.8Hz,1H),5.88(d,J＝10.5Hz,1H),4.88–4.80(m,1H),4.61–3.90(m,5H),3.62(s,3H),3.07–2.68(m,2H)。

example 8B: ¹ H NMR(400MHz,CDCl ₃ )δ9.49(s,1H),8.99(d,J＝13.5Hz,1H),8.02(d,J＝7.6Hz,1H),7.91(dd,J＝9.0,5.5Hz,1H),7.74–7.57(m,2H),7.45–7.36(m,1H),7.06–6.92(m,1H),6.42(d,J＝16.9Hz,1H),5.99–5.74(m,1H),5.13–4.90(m,2H),4.08–3.89(m,2H),3.87–3.71(m,1H),3.61–3.56(m,4H),3.37–3.21(m,1H),2.95(d,J＝13.3Hz,1H)。

example 22:

2- (10-propenoyl-3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1:2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3-chloro-4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] ]Pyrazino [2,3-c ]][1,6]Naphthyridin-11-yl) acetonitrile (240 mg,0.5 mmol) and 2- (3-chloro-2- (trifluoromethyl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (306 mg,1.0 mmol) in dioxane/H ₂ K was added to the solution in O (5 mL/1 mL) ₂ CO ₃ (207 mg,1.5 mmol) and Pd (PPh) ₃ ) ₄ (116 mg,0.1 mmol). The mixture is put under N ₂ Stirring is carried out for 16 hours at 100℃under an atmosphere. The reaction mixture was then concentrated and diluted with water and extracted with EA. The combined organics were washed with brine, dried over Na ₂ SO ₄ Dried, concentrated, and purified by preparative TLC to give the desired product (269 mg, crude).

MS(ESI):625.1[M+H] ⁺ 。

Step 2:2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]Naphthyridin-11-yl) acetonitrile, 2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (269 mg, crude) in TFA (5 mL) was added PhSMe (0.1 mL). The reaction mixture was stirred at 50℃for 3 hours. The reaction mixture was then concentrated and the residue was taken up with saturated NaHCO ₃ The aqueous solution is adjusted to pH>7. The resulting solution was extracted with EA. The combined organic layers were washed with saturated NaCl, over Na ₂ SO ₄ Drying and concentrating. The crude product was purified by preparative TLC to give the desired product (116 mg, yield: 46%,2 steps).

MS(ESI):505.1[M+H] ⁺ 。

Step 3:2- (10-propenoyl-3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (3-chloro-2- (trifluoromethyl) phenyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4, 5) at 0 ℃]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (90 mg,0.178 mmol) in DCM (5 mL) was added TEA (40 mg,0.4 mmol) and acryloyl chloride (20 mg,0.22 mmol). The reaction mixture was then taken up in N ₂ Stirring was carried out at 0℃for 0.5 hours under an atmosphere. The reaction was concentrated under reduced pressure and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give the two isomers (example 22A:10 mg/example 22B:20 mg).

MS(ESI):559.2[M+H] ⁺ 。

Example 22A: ¹ H NMR(400MHz,CDCl ₃ )δ9.20(s,1H),8.92(s,1H),7.68(d,J＝8.1Hz,1H),7.59(t,J＝7.9Hz,1H),7.41(d,J＝7.5Hz,1H),6.75(dd,J＝16.7,10.6Hz,1H),6.45(d,J＝16.7Hz,1H),5.88(d,J＝11.5Hz,1H),4.90(br s,1H),4.55–4.23(m,3H),4.24–4.02(m,2H),3.62(s,3H),3.10–2.63(m,2H)。

example 22B: ¹ H NMR(400MHz,CDCl ₃ )δ9.41(s,1H),9.00(s,1H),7.69(d,J＝8.0Hz,1H),7.59(t,J＝7.4Hz,1H),7.41(s,1H),6.98(dd,J＝16.3,10.7Hz,1H),6.42(d,J＝16.7Hz,1H),5.89(d,J＝10.8Hz,1H),5.16–4.84(m,2H),4.04–3.69(m,3H),3.61(s,3H),3.59–3.40(m,1H),3.37–3.20(m,1H),3.01–2.82(m,1H)。

the following compounds were prepared according to the above method using different starting materials.

Compound 10A:

¹ H NMR(400MHz,MeOD)δ9.39(s,1H),8.94(s,1H),8.03(dd,J＝21.4,7.9Hz,2H),7.70–7.63(m,3H),7.55(t,J＝7.4Hz,1H),7.47(t,J＝7.6Hz,1H),6.97(dd,J＝16.8,10.7Hz,1H),6.34(d,J＝16.5Hz,1H),5.88(d,J＝10.8Hz,1H),4.60–4.44(m,2H),4.39-4.36(m,2H),4.27–4.18(m,1H),3.76–3.62(m,1H),3.60(s,3H),2.92(d,J＝5.9Hz,2H)。

compound 10B:

¹ H NMR(400MHz,DMSO-d ₆ )δ9.49(s,1H),9.22(s,1H),8.09(dd,J＝16.6,7.9Hz,2H),7.74–7.66(m,3H),7.59(t,J＝7.5Hz,1H),7.54–7.48(m,1H),7.07(dd,J＝16.8,10.6Hz,1H),6.20(dd,J＝16.8,2.2Hz,1H),5.87–5.72(m,1H),4.96–4.77(m,2H),4.13–4.05(m,1H),3.90–3.60(m,2H),3.53(s,3H),3.48–3.41(m,1H),3.40–3.34(m,2H)。

compound 11:

¹ H NMR(400MHz,DMSO)δ10.02(s,1H),8.70(s,1H),8.47(d,J＝8.1Hz,1H),8.16(dd,J＝9.0,5.0Hz,1H),8.04(d,J＝8.1Hz,1H),7.74(t,J＝7.8Hz,1H),7.57(dd,J＝12.2,9.1Hz,1H),7.02(d,J＝17.3Hz,1H),6.21–6.15(m,1H),5.81(d,J＝12.2Hz,1H),4.71(d,J＝15.6Hz,2H),3.96(s,1H),3.55(s,3H),2.75(d,J＝13.6Hz,2H),2.69–2.66(m,1H),2.42(dd,J＝12.0,2.6Hz,2H),2.33(s,1H)。

Compound 146:

¹ H NMR(400MHz,MeOD)δ9.48(s,1H),9.09(s,1H),7.72(dd,J＝7.9,1.0Hz,1H),7.42(d,J＝6.6Hz,1H),7.30(t,J＝7.7Hz,1H),7.22–6.63(m,1H),6.26(d,J＝17.5Hz,1H),5.82(d,J＝10.6Hz,1H),4.61–4.35(m,5H),4.03(s,1H),3.84(d,J＝17.0Hz,1H),3.66(s,1H),3.59(s,3H),3.41(s,1H)。

compound 148A:

¹ H NMR(400MHz,CD ₃ OD)δ9.37(s,1H),8.88(s,1H),8.06(d,J＝7.9Hz,1H),7.88(d,J＝8.3Hz,1H),7.62–7.58(m,1H),7.54–7.42(m,2H),7.31(d,J＝5.8Hz,1H),7.02–6.91(m,1H),6.34(d,J＝17.4Hz,1H),5.88(d,J＝12.0Hz,1H),4.62–4.53(m,1H),4.52–4.44(m,2H),4.44–4.31(m,2H),3.59(d,J＝2.5Hz,3H),3.51–3.42(m,1H),3.02–2.89(m,2H)。

compound 149A:

¹ H NMR(400MHz,MeOD)δ9.34(d,J＝3.8Hz,1H),8.95(s,1H),8.06(dd,J＝7.4,2.1Hz,1H),7.93(dd,J＝9.0,5.8Hz,1H),7.62–7.52(m,2H),7.36(t,J＝9.2Hz,1H),6.96(ddd,J＝16.8,10.7,2.0Hz,1H),6.34(d,J＝15.9Hz,1H),5.87(d,J＝12.3Hz,1H),4.82–4.06(m,6H),3.61(t,J＝4.1Hz,3H),3.04–2.76(m,2H),1.83(dd,J＝5.1,2.5Hz,3H)。

compound 149B:

¹ H NMR(400MHz,MeOD)δ9.46(d,J＝3.8Hz,1H),9.14(d,J＝28.5Hz,1H),8.07(dd,J＝6.0,4.0Hz,1H),7.93(dd,J＝9.0,5.9Hz,1H),7.62–7.50(m,2H),7.36(t,J＝9.3Hz,1H),7.12(dd,J＝16.3,10.7Hz,1H),6.28(dd,J＝16.9,1.7Hz,1H),5.86(d,J＝12.3Hz,1H),5.03–4.91(m,2H),4.81(s,1H),4.07(s,1H),4.02–3.91(m,1H),3.83–3.70(m,1H),3.62–3.44(m,4H),3.38–3.33(m,2H),3.28–3.24(m,1H),1.82(d,J＝1.9Hz,3H)。

compound 151A:

¹ H NMR(400MHz,MeOD)δ9.34(d,J＝5.4Hz,1H),8.16–8.08(m,1H),7.95–7.87(m,1H),7.77–7.65(m,2H),7.58–7.48(m,1H),6.97(dd,J＝16.8,10.7Hz,1H),6.34(d,J＝17.1Hz,1H),5.88(d,J＝10.9Hz,1H),4.63–4.15(m,6H),3.60(s,3H),3.03–2.83(m,2H)。

compound 151B:

¹ H NMR(400MHz,MeOD)δ9.46(s,1H),9.10(d,J＝4.9Hz,1H),8.20–8.05(m,1H),7.99–7.84(m,1H),7.79–7.65(m,2H),7.59–7.46(m,1H),7.23–7.04(m,1H),6.29(d,J＝16.7Hz,1H),5.87(d,J＝11.9Hz,1H),5.12–4.91(m,2H),4.09(s,1H),4.04–3.93(m,1H),3.86–3.68(m,1H),3.61(s,3H),3.57–3.43(m,1H),3.41–3.34(m,2H)。

compound 169:

¹ H NMR(400MHz,DMSO-d ₆ )δ9.73–9.53(m,1H),9.31–9.19(m,1H),8.29–8.19(m,1H),8.19–8.09(m,1H),7.83–7.71(m,1H),7.71–7.57(m,1H),7.56–7.43(m,1H),7.12–6.83(m,1H),6.16(d,J＝17.0Hz,1H),5.77(d,J＝10.1Hz,1H),5.00–4.67(m,1H),4.44(d,J＝11.5Hz,1H),4.23–4.03(m,1H),3.63(d,J＝12.3Hz,1H),3.53(s,3H),3.29–2.83(m,2H),1.11–0.92(m,3H)。

compound 174A:

¹ H NMR(400MHz,CDCl ₃ )δ9.21(s,1H),8.91(s,1H),7.33(d,J＝7.3Hz,1H),7.26(d,J＝14.9Hz,1H),7.13(d,J＝7.4Hz,1H),6.75(dd,J＝16.7,10.6Hz,1H),6.45(dd,J＝16.7,1.4Hz,1H),5.88(dd,J＝10.6,1.5Hz,1H),4.92(s,1H),4.43(s,2H),4.29(dd,J＝13.9,5.4Hz,1H),4.22–4.04(m,2H),3.62(s,3H),3.05–2.88(m,2H),2.87(d,J＝7.1Hz,1H),2.76(dd,J＝17.1,3.6Hz,1H),1.90(t,J＝7.2Hz,2H),1.14(s,3H),1.01(s,3H)。

compound 174B:

¹ H NMR(400MHz,CDCl ₃ )δ9.41(s,1H),8.99(s,1H),7.33(d,J＝7.4Hz,1H),7.26(d,J＝14.9Hz,1H),7.10(d,J＝7.4Hz,1H),7.04–6.91(m,1H),6.42(dd,J＝16.8,1.4Hz,1H),5.98–5.78(m,1H),5.18–4.83(m,2H),3.86(d,J＝9.4Hz,2H),3.74(d,J＝12.3Hz,1H),3.61(s,3H),3.47(d,J＝9.0Hz,1H),3.28(dd,J＝16.8,7.5Hz,1H),2.97(dd,J＝15.4,6.1Hz,3H),1.90(t,J＝7.2Hz,2H),1.10(s,3H),1.03(s,3H)。

compound 175:

¹ H NMR(400MHz,MeOD)δ9.43(d,J＝6.7Hz,1H),9.09(s,1H),8.14–8.10(m,1H),8.07(d,J＝8.3Hz,1H),7.76–7.61(m,3H),7.56–7.49(m,1H),7.14(dd,J＝16.8,10.7Hz,1H),6.26(d,J＝17.0Hz,1H),5.82(d,J＝10.6Hz,1H),4.99–4.88(m,1H),4.63–4.39(m,1H),4.10(d,J＝41.8Hz,1H),3.84(d,J＝12.2Hz,1H),3.65(s,1H),3.60(s,3H),3.45(d,J＝23.8Hz,1H),3.22–3.01(m,1H),2.89(d,J＝51.8Hz,1H)。

compound 176A:

¹ H NMR(400MHz,MeOD)δ9.27(d,J＝9.1Hz,1H),8.92(d,J＝2.7Hz,1H),8.13(t,J＝7.7Hz,2H),7.74–7.66(m,2H),7.45(t,J＝9.0Hz,1H),6.95–6.85(m,1H),6.32(d,J＝18.4Hz,1H),5.84(d,J＝10.6Hz,1H),4.71–4.62(m,1H),4.58(s,2H),4.39–4.32(m,2H),4.03–3.90(m,1H),3.61(s,3H),3.48(d,J＝1.9Hz,1H),3.15(d,J＝15.5Hz,1H),1.35(d,J＝15.6Hz,1H),1.23(s,3H)。

compound 176B:

¹ H NMR(400MHz,MeOD)δ9.40(d,J＝7.1Hz,1H),9.07(d,J＝3.3Hz,1H),8.13(t,J＝7.7Hz,2H),7.74–7.66(m,2H),7.45(t,J＝8.9Hz,1H),7.12(dd,J＝16.9,10.5Hz,1H),6.80(s,1H),6.24(d,J＝16.7Hz,1H),5.81(d,J＝10.1Hz,1H),5.38(d,J＝14.8Hz,1H),4.54(d,J＝30.1Hz,1H),4.08(s,1H),3.98(d,J＝13.9Hz,1H),3.60(s,3H),3.45(dd,J＝60.4,35.7Hz,3H),3.15(s,1H),1.61(t,J＝16.1Hz,3H)。

compound 177:

¹ H NMR(400MHz,MeOD)δ9.44(d,J＝6.6Hz,1H),9.10(s,1H),8.14(dd,J＝12.5,5.1Hz,2H),7.75–7.67(m,2H),7.45(t,J＝8.3Hz,1H),7.21–6.63(m,1H),6.26(d,J＝16.9Hz,1H),5.83(d,J＝11.3Hz,1H),4.93(d,J＝13.1Hz,1H),4.49(s,1H),4.05(s,1H),3.84(d,J＝10.1Hz,1H),3.67(s,1H),3.60(s,3H),3.45(d,J＝22.1Hz,1H),3.15(s,2H)。

compound 180:

¹ H NMR(400MHz,CDCl ₃ )δ10.08(s,1H),9.47(s,1H),9.15-9.13(m,1H),7.35(dd,J＝15.3,8.1Hz,1H),7.19–6.97(m,1H),6.94–6.70(m,2H),6.16(d,J＝16.6Hz,1H),5.76(d,J＝8.9Hz,1H),4.74(d,J＝14.6Hz,1H),4.31(d,J＝11.9Hz,1H),4.10-4.05(m,1H),3.79–3.56(m,2H),3.51(s,3H),3.01-2.97(m,1H),2.72-2.67(m,1H)。

compound 181:

¹ H NMR(400MHz,MeOD)δ9.55(s,1H),9.14(s,1H),8.13(d,J＝7.8Hz,1H),8.04(d,J＝8.2Hz,1H),7.69–7.62(m,1H),7.62–7.52(m,2H),7.52–7.46(m,1H),7.22–6.69(m,1H),6.28(d,J＝16.6Hz,1H),5.95–5.59(m,2H),5.15–4.90(m,1H),4.60–4.36(m,1H),4.22–4.01(m,1H),3.91–3.80(m,1H),3.75–3.66(m,1H),3.62(s,3H),3.51–3.40(m,1H),3.27–3.11(m,1H),3.03–2.75(m,2H)。

compound 182:

¹ H NMR(400MHz,MeOD)δ9.49–9.31(m,1H),9.07(s,1H),7.82(d,J＝8.3Hz,1H),7.49(d,J＝7.1Hz,1H),7.43–7.36(m,1H),7.37–7.30(m,1H),7.28–7.02(m,2H),6.26(d,J＝17.0Hz,1H),5.82(d,J＝10.6Hz,1H),4.97–4.87(m,2H),4.49(d,J＝12.5Hz,1H),4.02(d,J＝11.0Hz,1H),3.82(d,J＝10.9Hz,1H),3.63(s,1H),3.58(s,3H),3.47–3.32(m,1H),3.13(dd,J＝21.5,11.3Hz,1H)。

compound 183:

¹ H NMR(400MHz,MeOD)δ9.42(d,J＝8.8Hz,1H),9.09(s,1H),7.87(dd,J＝8.9,5.8Hz,1H),7.44–7.03(m,4H),6.26(d,J＝16.9Hz,1H),5.82(d,J＝10.5Hz,1H),4.92(d,J＝14.9Hz,1H),4.50(d,J＝13.7Hz,1H),4.03(d,J＝7.5Hz,1H),3.83(d,J＝11.0Hz,1H),3.69(d,J＝33.2Hz,1H),3.59(s,3H),3.49–3.34(m,1H),3.22–3.01(m,2H)。

compound 185A:

¹ H NMR(400MHz,MeOD)δ9.49–9.45(m,1H),8.99(s,1H),8.24(d,J＝8.7Hz,1H),8.09(d,J＝8.4Hz,1H),7.91(d,J＝8.4Hz,1H),7.66(t,J＝7.5Hz,1H),7.52(t,J＝7.5Hz,1H),7.47–7.40(m,1H),7.00(dd,J＝16.8,10.9Hz,1H),6.69(td,J＝54.8,7.5Hz,1H),6.37(d,J＝16.8Hz,1H),5.90(d,J＝11.1Hz,1H),4.96–4.86(m,1H),4.66–4.47(m,2H),4.46–4.37(m,2H),4.35–4.24(m,1H),3.63(s,3H),2.96(d,J＝4.9Hz,2H)。

compound 185B:

¹ H NMR(400MHz,MeOD)δ9.60–9.54(m,1H),9.13(d,J＝4.6Hz,1H),8.24(d,J＝8.5Hz,1H),8.09(dd,J＝8.2,3.9Hz,1H),7.91(dd,J＝8.7,4.7Hz,1H),7.70–7.63(m,1H),7.54–7.44(m,1H),7.42–7.34(m,1H),7.15(dd,J＝16.5,11.2Hz,1H),6.67(td,J＝55.0,7.0Hz,1H),6.31(d,J＝16.8Hz,1H),5.89(d,J＝10.7Hz,1H),5.05–4.92(m,2H),4.13–3.95(m,2H),3.86–3.77(m,1H),3.63(s,3H),3.57–3.45(m,1H),3.45–3.36(m,2H)。

compound 186A:

¹ H NMR(400MHz,CD ₃ OD)δ9.41(s,1H),8.95(s,1H),7.98(d,J＝8.2Hz,1H),7.76–7.67(m,2H),7.61–7.52(m,2H),7.44(t,J＝7.2Hz,1H),6.97(dd,J＝16.8,10.7Hz,1H),6.34(d,J＝16.9Hz,1H),5.88(dd,J＝10.7,1.4Hz,1H),4.86(s,1H),4.60–4.44(m,2H),4.43–4.32(m,2H),4.30–4.19(m,1H),3.60(s,3H),2.92(d,J＝5.7Hz,2H)。

compound 186B:

¹ H NMR(400MHz,CD ₃ OD)δ9.53(s,1H),9.10(s,1H),7.98(d,J＝8.3Hz,1H),7.74(dd,J＝9.6,2.3Hz,1H),7.68(d,J＝8.6Hz,1H),7.61–7.50(m,2H),7.44(t,J＝7.6Hz,1H),7.13(dd,J＝16.8,10.7Hz,1H),6.29(d,J＝16.7Hz,1H),5.87(d,J＝10.7Hz,1H),5.08–4.91(m,2H),4.13–3.94(m,2H),3.79(dd,J＝12.6,4.2Hz,1H),3.61(s,3H),3.55–3.47(m,1H),3.35(d,J＝6.8Hz,2H)。

compound 187A:

¹ H NMR(400MHz,CD ₃ OD)δ9.52(s,1H),8.78(s,1H),8.29(s,1H),8.13(d,J＝8.1Hz,1H),7.88(s,1H),7.82(d,J＝8.5Hz,1H),7.70–7.58(m,2H),7.11(t,J＝56.0Hz,1H),7.01–6.88(m,1H),6.36(d,J＝16.6Hz,1H),5.90(d,J＝10.8Hz,1H),4.91-4.85(m,2H),4.66–4.40(m,4H),3.58(s,3H),2.99-2.95(m,2H)。

compound 187B:

¹ H NMR(400MHz,CD ₃ OD)δ9.55(s,1H),9.07(s,1H),8.26(s,1H),8.12(d,J＝8.0Hz,1H),7.83(s,1H),7.74(d,J＝8.3Hz,1H),7.65(t,J＝7.5Hz,1H),7.59-7.54(m,1H),7.17-7.14(m,1H),7.06(t,J＝56.0Hz,1H),6.29(d,J＝16.7Hz,1H),5.87(d,J＝11.2Hz,1H),5.17–4.93(m,4H),4.13(s,1H),4.01(d,J＝14.1Hz,1H),3.87(d,J＝8.5Hz,1H),3.65-3.62(m,1H),3.60(s,3H)。

example 23:

2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (2-fluoroacryloyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1:2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (2-fluoroacryloyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] at 0 DEG C]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-11-yl) acetonitrile (120 mg,0.173 mmol) and 2-fluoroacrylic acid (32 mg,0.36 mmol) in DMF (5 mL) was added HATU (136 mg,0.36 mmol) and TEA (54 mg,0.54 mmol). The mixture was stirred from 0 ℃ for 2 hours to room temperature. After dilution with water, the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Drying and filtering. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give the title product (example 23A:2.1 mg/example 23B:5.1 mg).

Example 23A: MS (ESI): 559.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ9.41–9.27(m,1H),8.95(s,1H),8.05(d,J＝6.7Hz,1H),7.91(d,J＝8.1Hz,1H),7.71–7.64(m,2H),7.56(d,J＝7.2Hz,1H),7.45(t,J＝7.7Hz,1H),5.63–5.45(m,1H),5.37–5.29(m,1H),4.83–4.80(m,1H),4.59–4.54(m,1H),4.29–4.25(m,2H),4.27–3.98(m,2H),3.62(s,3H),3.09–2.90(m,2H)。

Example 23B: MS (ESI): 559.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ9.39(d,J＝12.3Hz,1H),9.01(d,J＝6.1Hz,1H),8.06–8.00(m,1H),7.91(dd,J＝8.2,1.1Hz,1H),7.67–7.57(m,2H),7.56–7.51(m,1H),7.47–7.40(m,1H),5.68–5.48(m,1H),5.42–5.32(m,1H),5.19–4.88(m,2H),4.07–3.78(m,2H),3.65–3.62(m,1H),3.61(s,3H),3.57–3.30(m,1H),3.29–3.14(m,1H),3.14–3.00(m,1H)。

Example 24:

2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (2-fluoroacryloyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1:2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-10- (2-fluoroacryloyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] at 0 DEG C]Pyrazino [2,3-c ]][1,6]A solution of naphthyridin-11-yl) acetonitrile (100 mg,0.198 mmol) in DCM (4 mL) was added TEA (70 mg,0.69 mmol) followed by 2-fluoroacrylic acid (35.6 mg, 0.390 mmol) and HATU (113 mg,0.30 mmol). The mixture was stirred at 0 ℃ for 1 hour. The reaction was concentrated under reduced pressure (below 20 ℃) and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give the two isomers (example 24A:3.0 mg/example 24B:22.3 mg). MS (ESI): 577.1[ M+H ] ] ⁺ 。

Example 24A: ¹ H NMR(400MHz,CDCl ₃ )δ9.22(d,J＝14.4Hz,1H),8.95(s,1H),8.06–7.98(m,1H),7.91(dd,J＝8.9,5.4Hz,1H),7.66(dd,J＝29.9,6.9Hz,2H),7.41(t,J＝8.3Hz,1H),5.53(d,J＝47.4Hz,1H),5.39–5.27(m,1H),4.73(d,J＝98.5Hz,2H),4.06(dd,J＝143.0,73.9Hz,4H),3.65(d,J＝13.5Hz,3H),3.13–2.71(m,2H)。

example 24B: ¹ H NMR(400MHz,CDCl ₃ )δ9.22(d,J＝14.4Hz,1H),8.95(s,1H),8.06–7.98(m,1H),7.91(dd,J＝8.9,5.4Hz,1H),7.66(dd,J＝29.9,6.9Hz,2H),7.41(t,J＝8.3Hz,1H),5.53(d,J＝47.4Hz,1H),5.39–5.27(m,1H),4.73(d,J＝98.5Hz,2H),4.06(dd,J＝143.0,73.9Hz,4H),3.65(d,J＝13.5Hz,3H),3.13–2.71(m,2H)。

example 25:

2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -10- (4- (dimethylamino) but-2-enoyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1:2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -10- (4- (dimethylamino) but-2-enoyl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] at 0 DEG C]Pyrazino [2,3-c ]][1,6]A solution of naphthyridin-11-yl) acetonitrile (70 mg,0.139 mmol) in DMA (3 mL) was added SOCl sequentially ₂ (33 mg,0.278 mmol) and (E) -4- (dimethylamino) but-2-enoic acid (46 mg,0.278 mmol). The mixture was stirred at 0 ℃ for 1 hour. The reaction was concentrated under reduced pressure (below 20 ℃) and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give the two isomers (example 25a:4.4 mg/example 25b:17.3 mg). MS (ESI): 616.1[ M+H ]] ⁺ 。

Example 25A: ¹ H NMR(400MHz,CDCl ₃ )δ9.25(d,J＝14.8Hz,1H),8.92(s,1H),8.01(d,J＝7.8Hz,1H),7.95–7.84(m,1H),7.65(dt,J＝15.1,7.4Hz,2H),7.40(d,J＝3.0Hz,1H),6.93(s,2H),4.90(s,1H),4.55–3.98(m,4H),3.67–3.58(m,3H),3.53(s,1H),3.16–2.82(m,2H),2.81–2.62(m,3H),2.58(s,4H)。

example 25B: ¹ H NMR(400MHz,CDCl ₃ )δ9.22(d,J＝14.4Hz,1H),8.95(s,1H),8.06–7.98(m,1H),7.91(dd,J＝8.9,5.4Hz,1H),7.66(dd,J＝29.9,6.9Hz,2H),7.41(t,J＝8.3Hz,1H),5.53(d,J＝47.4Hz,1H),5.39–5.27(m,1H),4.73(d,J＝98.5Hz,2H),4.06(dd,J＝143.0,73.9Hz,4H),3.65(d,J＝13.5Hz,3H),3.13–2.71(m,2H)。

example 26:

(S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -10- (4- (dimethylamino) but-2-enoyl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

Step 1: (S) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) 3-methyl ester

To a solution of 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine (2 g,7.63 mmol) and DIPEA (3.74 mL,22.89 mmol) in dioxane (30 mL) was added (S) -piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) 3-methyl ester (1.86 g,7.63 mmol) at 0 ℃ and the reaction mixture was stirred overnight at 50 ℃. The reaction mixture was diluted with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether containing 0% to 30% ethyl acetate to give (S) -1- (tert-butyl) 3-methyl 4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) ester (1.6 g, 44.61%). LC/MS ESI (m/z): 470[ M+H ]] ⁺ 。

Step 2: (S) -3-chloro-4-fluoro-8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridine-10-carboxylic acid tert-butyl ester

To (S) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridine-4-To a solution of 1- (tert-butyl) 3-methyl piperazine-1, 3-dicarboxylate (1.6 g,3.41 mmol) in EtOH (50 mL) and water (10 mL) was added Fe (1.9 g,34.05 mmol) and NH ₄ Cl (3.6 g,68.11 mmol). The reaction mixture was stirred at 80℃for 3 hours. The mixture is then filtered and the solvent is removed from the liquid phase. The residue was diluted with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried, and concentrated to give (S) -3-chloro-4-fluoro-8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5] ]Pyrazino [2,3-c ]][1,6]Naphthyridine-10-carboxylic acid tert-butyl ester (1.3 g, 93.61%). LC/MS ESI (m/z): 408[ M+H ]] ⁺ 。

Step 3: (S) -3-chloro-4-fluoro-7-methyl-8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridine-10-carboxylic acid tert-butyl ester

To (S) -3-chloro-4-fluoro-8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5]Pyrazino [2,3-c ]][1,6]Naphthyridine-10-carboxylic acid tert-butyl ester (1.3 g,3.19 mmol) and Cs ₂ CO ₃ (3.1 g,9.57 mmol) in DMF (20 mL) was added CH ₃ I (1.13 g,7.97 mmol) and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried, and concentrated to give (S) -3-chloro-4-fluoro-7-methyl-8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]Naphthyridine-10-carboxylic acid tert-butyl ester (1.0 g, 74.37%). LC/MS ESI (m/z): 422[ M+H ]] ⁺

Step 4: (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridine-10-carboxylic acid tert-butyl ester

To (S) -3-chloro-4-fluoro-7-methyl-8-oxo-7, 8a,9,11,12-hexahydro-10H-pyrazino [1',2':4,5]Pyrazino [2,3-c ] ][1,6]Naphthyridine-10-carboxylic acid tert-butyl ester (240 mg,0.57 mmol), K ₂ CO ₃ (236 mg,1.71 mmol) and 2- (8-chloro-7-fluoronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (349 mg,1.14 mmol) in dioxane (5 mL) and H ₂ RuPhos-Pd-G was added to a solution in O (1 mL) ₄ (50 mg,0.06 mmol). The mixture is then taken up in N ₂ Stirred overnight at 100 ℃. The reaction was diluted with ice-water and then extracted twice with EA. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether containing 0% to 50% ethyl acetate to give the title compound (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4, 5)]Pyrazino [2,3-c ]][1,6]Naphthyridine-10-carboxylic acid tert-butyl ester (120 mg, 37.27%). LC/MS ESI (m/z): 566[ M+H ]] ⁺ 。

Step 5: (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

To (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5]Pyrazino [2,3-c ]][1,6]To a solution of tert-butyl naphthyridine-10-carboxylate (120 mg,0.21 mmol) in dioxane (5 mL) was added HCl/dioxane (4M, 5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give the title compound (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4, 5) ]Pyrazino [2,3-c ]][1,6]Naphthyridin-8 (8 aH) -one (HCl salt, 85mg, 79.87%). LC/MS ESI (m/z): 466[ M+H ]] ⁺ 。

Step 6: (S) -3- (8-chloro-7-fluoronaphthalen-1-yl) -10- (4- (dimethylamino) but-2-enoyl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

To a suspension of (S) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one (HCl salt, 65mg,0.13 mmol) and DIPEA (0.06 mL,0.39 mmol) in DMF (5 mL) was added HATU (99 mg,0.26 mmol) and (E) -4- (dimethylamino) but-2-enoic acid (34 mg,0.26 mmol) under nitrogen. The reaction mixture was stirred at 60 ℃ overnight. The mixture was quenched with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column (dichloromethane containing 0% to 20% methanol) to give a crude product which was further purified by preparative HPLC to give the title product (12.9 mg, 17.23%).

LC/MS ESI(m/z):577[M+H] ⁺ 。

¹ H NMR(400MHz,MeOD)δ9.48(s,1H),9.12(s,1H),8.20–8.05(m,2H),7.76–7.63(m,2H),7.54(t,J＝8.6Hz,1H),7.15(d,J＝14.8Hz,1H),6.77(s,1H),4.60–4.49(m,2H),4.06(s,1H),3.87(d,J＝12.3Hz,1H),3.68(s,2H),3.59(s,3H),3.11(d,J＝14.7Hz,1H),2.63(d,J＝59.8Hz,6H),2.15(dd,J＝38.9,31.3Hz,2H)。

Example 36:

2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-10- (3- (pyridin-2-yl) acryloyl) -8,8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

Step 1:2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-10- (3- (pyridin-2-yl) acryloyl) -8,8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) acetonitrile

To 2- (3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] at 0 DEG C]Pyrazino [2,3-c ]][1,6]A solution of naphthyridin-11-yl) acetonitrile (100 mg,0.20 mmol) in DMA (3 mL) was added SOCl sequentially ₂ (47.6 mg,0.4 mmol) and (E) -3- (pyridin-2-yl) acrylic acid (59.6 mg,0.4 mmol). The mixture was stirred at 0 ℃ for 2 hours. The reaction was concentrated under reduced pressure (below 20 ℃) and the residue was purified by preparative HPLC (0.05% formic acid in water/MeCN) to give the title product (17.1 mg).

MS(ESI):518.3[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ9.43(d,J＝13.5Hz,1H),9.01(s,1H),8.72(s,1H),8.04(s,1H),7.91(d,J＝7.4Hz,1H),7.84(s,2H),7.74(s,1H),7.65(d,J＝6.8Hz,2H),7.55(d,J＝7.5Hz,2H),7.44(dd,J＝7.9,3.8Hz,2H),5.23(d,J＝32.4Hz,2H),3.93(s,2H),3.74(d,J＝44.8Hz,1H),3.61(s,3H),3.33(dd,J＝36.1,27.1Hz,2H),3.01(s,1H)。

Compound 28A:

¹ H NMR(400MHz,CD ₃ OD)δ9.46–9.33(m,1H),9.17–9.02(m,1H),8.14(d,J＝8.1Hz,1H),8.02(d,J＝8.1Hz,1H),7.79–7.63(m,2H),7.63–7.54(m,2H),7.53-7.48(m,1H),7.12–6.82(m,1H),5.26–4.97(m,2H),4.81–4.42(m,2H),4.11–3.88(m,2H),3.82–3.62(m,1H),3.60(d,J＝4.1Hz,3H),3.43–3.33(m,2H),3.28–3.10(m,1H)。

compound 29A:

¹ H NMR(400MHz,CD ₃ OD)δ9.41(d,J＝3.5Hz,1H),9.09(d,J＝4.9Hz,1H),8.15(d,J＝7.8Hz,1H),8.02(d,J＝8.2Hz,1H),7.74–7.64(m,2H),7.64–7.56(m,2H),7.54–7.48(m,1H),6.16(d,J＝6.1Hz,1H),5.03–4.93(m,1H),4.83–4.76(m,1H),4.62–4.54(m,1H),4.09–4.03(m,1H),3.95–3.87(m,1H),3.85–3.69(m,2H),3.67(s,3H),3.64–3.62(m,1H),3.62(s,3H),3.56–3.39(m,2H)。

compound 51A:

¹ H NMR(400MHz,CDCl ₃ )δ9.00(s,1H),8.62(s,1H),7.93-7.91(m,1H),7.81(d,J＝8.1Hz,1H),7.60–7.50(m,2H),7.46(d,J＝7.1Hz,1H),7.35-7.32(m,1H),6.62–6.52(m,1H),6.36(d,J＝16.4Hz,1H),5.79(d,J＝9.7Hz,1H),5.25–4.62(m,1H),4.50–4.01(m,1H),3.95–3.47(m,4H),3.24–3.11(m,2H),3.07(s,3H),2.75–2.44(m,2H)。

compound 51B:

¹ H NMR(400MHz,CDCl ₃ )δ9.17(s,1H),8.83(s,1H),8.00(s,1H),7.87(d,J＝7.5Hz,1H),7.61-7.57(m,2H),7.51(s,1H),7.40(s,1H),6.61-6.59(m,1H),6.43(d,J＝16.2Hz,1H),5.87(d,J＝10.0Hz,1H),5.31–4.74(m,1H),4.62–3.99(m,1H),3.99–3.62(m,2H),3.59–3.29(m,4H),3.20(s,3H),3.15–3.05(m,2H)。

compound 52:

¹ H NMR(400MHz,CD3OD)δ9.24(s,1H),8.75(s,1H),8.13(d,J＝8.2Hz,1H),8.01(d,J＝8.1Hz,1H),7.72–7.61(m,2H),7.56(t,J＝6.5Hz,1H),7.49-7.45(m,1H),6.89–6.80(m,1H),6.32(d,J＝16.7Hz,1H),5.87(d,J＝10.6Hz,1H),5.19–4.99(m,1H),4.40(d,J＝9.7Hz,2H),4.21–3.78(m,2H),3.76–3.61(m,1H),3.60–3.44(m,2H),3.42–3.33(m,2H)。

compound 65:

¹ H NMR(400MHz,MeOD)δ9.46–9.27(m,1H),9.21–8.96(m,1H),8.15(d,J＝8.0Hz,1H),8.03(d,J＝7.9Hz,1H),7.65(ddd,J＝20.9,10.9,5.4Hz,3H),7.51(t,J＝7.9Hz,1H),7.19–6.84(m,1H),6.30(t,J＝19.6Hz,1H),5.86(d,J＝10.7Hz,1H),4.36(d,J＝27.7Hz,2H),4.08(s,2H),3.68(d,J＝23.7Hz,1H),3.49(d,J＝9.9Hz,1H),3.40(s,2H),2.70(s,2H),2.38–2.30(m,6H),2.19(t,J＝7.5Hz,1H),2.03(s,2H)。

compound 70:

¹ H NMR(400MHz,MeOD)δ9.35(dd,J＝50.6,4.6Hz,1H),9.23–8.99(m,1H),8.15(d,J＝8.0Hz,1H),8.02(d,J＝8.1Hz,1H),7.72–7.57(m,3H),7.51(t,J＝7.8Hz,1H),7.04(ddd,J＝67.8,16.7,10.5Hz,1H),6.31(t,J＝20.3Hz,1H),5.87(d,J＝10.9Hz,1H),4.25(d,J＝6.3Hz,2H),4.09(s,1H),3.97(dd,J＝19.3,9.0Hz,1H),3.83–3.73(m,1H),3.54(d,J＝8.2Hz,1H),3.38–3.33(m,2H),2.44(dd,J＝20.4,14.4Hz,2H),2.28(d,J＝16.5Hz,6H),2.23–2.14(m,1H),2.04–1.87(m,3H)。

compound 71:

¹ H NMR(400MHz,MeOD)δ9.41(d,J＝4.3Hz,1H),9.15(d,J＝6.6Hz,1H),8.15(d,J＝8.2Hz,1H),8.03(d,J＝7.1Hz,1H),7.72–7.59(m,3H),7.51(t,J＝7.8Hz,1H),7.12(dd,J＝16.7,10.7Hz,1H),6.29(d,J＝16.8Hz,1H),5.87(d,J＝10.8Hz,1H),4.27(s,2H),4.10(s,1H),4.02–3.95(m,1H),3.81(dd,J＝12.8,8.0Hz,1H),3.46(d,J＝9.1Hz,1H),3.35(d,J＝6.0Hz,2H),2.62(s,6H),2.01(dd,J＝14.8,7.0Hz,4H),1.83(s,4H)。

compound 144:

¹ H NMR(400MHz,CD ₃ OD)δ9.18(d,J＝37.9Hz,1H),8.84(s,1H),8.44(s,1H),8.12(d,J＝8.1Hz,1H),8.01-7.98(m,1H),7.66-7.62(m,2H),7.60–7.54(m,1H),7.51–7.42(m,1H),6.95–6.77(m,2H),5.33–4.92(m,1H),4.83–4.64(m,2H),4.32–4.03(m,1H),4.02–3.82(m,1H),3.82–3.64(m,2H),3.63–3.58(m,1H),3.57(s,2H),3.50–3.39(m,2H),3.22(s,3H),2.60(s,6H)。

compound 147A:

¹ H NMR(400MHz,MeOD)δ9.38(s,1H),8.95(s,1H),8.03(dd,J＝21.3,7.8Hz,2H),7.70–7.67(m,2H),7.64(d,J＝7.2Hz,1H),7.55(t,J＝7.4Hz,1H),7.49–7.44(m,1H),5.58–5.34(m,2H),4.93–4.88(m,1H),4.57–4.49(m,1H),4.45–4.36(m,2H),4.36–4.17(m,2H),3.60(s,3H),3.02–2.91(m,2H)。

compound 147B:

¹ H NMR(400MHz,DMSO)δ9.49(s,1H),9.22(s,1H),8.09(dd,J＝17.2,7.4Hz,2H),7.75–7.70(m,2H),7.68(d,J＝6.9Hz,1H),7.59(t,J＝7.1Hz,1H),7.52(t,J＝7.4Hz,1H),5.54–5.29(m,2H),4.93–4.73(m,2H),4.14–3.94(m,2H),3.72–3.64(m,1H),3.63–3.55(m,2H),3.54(s,3H),3.44–3.37(m,1H)。

compound 150A:

¹ H NMR(400MHz,CDCl ₃ )δ9.51–9.20(m,1H),8.99(d,J＝30.1Hz,1H),8.00–7.93(m,1H),7.82(dd,J＝8.9,5.9Hz,1H),7.62–7.49(m,2H),7.31(t,J＝9.1Hz,1H),5.65–5.45(m,1H),5.34(ddd,J＝16.7,12.0,3.6Hz,1H),5.17–4.78(m,1H),4.69–4.53(m,1H),4.30–4.12(m,2H),4.10–3.81(m,1H),3.63(s,3H),3.32–2.72(m,2H),1.90–1.82(m,3H)。

compound 150B:

¹ H NMR(400MHz,CDCl ₃ )δ9.42(d,J＝5.7Hz,1H),9.03(s,1H),8.01–7.93(m,1H),7.82(dd,J＝8.6,5.9Hz,1H),7.60–7.49(m,2H),7.31(dd,J＝11.8,6.6Hz,1H),5.57(dd,J＝47.0,3.7Hz,1H),5.43–5.30(m,1H),5.03(d,J＝50.7Hz,2H),4.05–3.65(m,3H),3.62(s,3H),3.46(d,J＝36.6Hz,1H),3.23(dd,J＝16.7,7.1Hz,1H),3.05(d,J＝5.4Hz,1H),1.90–1.81(m,3H)。

compound 152A:

¹ H NMR(400MHz,MeOD)δ9.33(d,J＝4.4Hz,1H),8.96(s,1H),8.12(d,J＝7.4Hz,1H),7.98–7.84(m,1H),7.78–7.64(m,2H),7.60–7.46(m,1H),5.67–5.29(m,2H),5.05–4.87(m,1H),4.66–4.47(m,1H),4.49–4.28(m,3H),4.27–4.14(m,1H),3.60(s,3H),3.18–2.77(m,2H)。

compound 152B:

¹ H NMR(400MHz,MeOD)δ9.43(s,1H),9.12(s,1H),8.13(d,J＝7.4Hz,1H),7.90(ddd,J＝9.0,4.9,1.6Hz,1H),7.78–7.64(m,2H),7.61–7.47(m,1H),5.57–5.32(m,2H),5.09–4.93(m,1H),4.17–4.00(m,2H),3.83–3.70(m,1H),3.61(s,3H),3.53–3.42(m,1H),3.38–3.34(m,1H)。

compound 154A:

¹ H NMR(400MHz,DMSO)δ9.37(d,J＝8.6Hz,1H),9.31(s,1H),9.01(d,J＝3.0Hz,1H),8.32(dd,J＝7.1,2.4Hz,2H),7.86–7.78(m,2H),5.51(d,J＝2.8Hz,1H),5.47–5.37(m,1H),4.90–4.83(m,1H),4.50–4.34(m,2H),4.28(s,1H),4.16–4.08(m,2H),3.51(d,J＝3.2Hz,3H),3.08–3.01(m,1H),2.95(s,1H),2.00(dd,J＝14.4,6.7Hz,1H),1.87(d,J＝5.9Hz,3H)。

compound 154B:

P2： ¹ H NMR(400MHz,DMSO)δ9.42(d,J＝7.2Hz,1H),9.32(s,1H),9.23(s,1H),8.36–8.30(m,2H),7.87–7.79(m,2H),5.52–5.30(m,2H),4.93–4.70(m,2H),4.15–3.98(m,2H),3.59(s,3H),3.53(s,3H),2.00(dd,J＝14.1,6.5Hz,1H),1.86(s,3H)。

compound 155A:

P1： ¹ H NMR(400MHz,DMSO)δ9.20(dd,J＝206.3,8.5Hz,1H),8.58–8.15(m,2H),7.68(ddt,J＝25.1,20.3,7.3Hz,2H),7.21(s,1H),6.67(s,1H),5.82(s,1H),5.44–5.16(m,3H),4.82–4.63(m,1H),4.27(d,J＝16.0Hz,1H),3.45(d,J＝12.9Hz,2H),2.87–2.54(m,2H),2.04–1.92(m,3H),1.75–1.32(m,4H)。

compound 155B:

P2： ¹ H NMR(400MHz,MeOD)δ9.53–9.51(m,1H),9.14–9.10(m,1H),8.14–8.04(m,1H),7.68–7.47(m,2H),5.34(t,J＝4.7Hz,2H),4.05(d,J＝12.6Hz,1H),3.82(d,J＝3.7Hz,1H),3.61(s,2H),3.48(dt,J＝4.2,1.3Hz,1H),3.13(dt,J＝3.5,1.7Hz,1H),2.59(d,J＝0.5Hz,1H),2.21–2.16(m,3H),2.06–1.99(m,4H),1.60(dd,J＝11.2,4.6Hz,3H)。

compound 156A:

¹ H NMR(400MHz,DMSO)δ9.46–9.27(m,2H),8.98(s,1H),7.50–7.35(m,1H),7.28(dd,J＝10.1,8.1Hz,2H),5.57–5.33(m,2H),4.84(dd,J＝21.0,10.4Hz,1H),4.53–4.00(m,5H),3.51(s,3H),3.12–3.00(m,1H),2.91(dd,J＝17.3,6.4Hz,1H),1.84(d,J＝5.1Hz,1H),0.64–0.53(m,2H),0.29(d,J＝4.0Hz,2H)。

Compound 156B:

¹ H NMR(400MHz,DMSO)δ9.40(s,3H),9.19(s,1H),7.42(dd,J＝13.4,7.8Hz,1H),7.29(dd,J＝12.6,5.7Hz,2H),5.56–5.27(m,2H),5.02–4.62(m,2H),4.17–3.90(m,2H),3.57(s,1H),3.51(s,4H),3.25–3.12(m,2H),1.92–1.78(m,1H),0.60(d,J＝8.2Hz,2H),0.29(d,J＝4.2Hz,2H)。

compound 157A:

¹ H NMR(400MHz,MeOD)δ9.51–9.36(m,1H),8.97(s,1H),8.51(d,J＝8.5Hz,1H),8.28(d,J＝6.2Hz,1H),8.10(d,1H),7.92(d,1H),7.62(d,J＝6.3Hz,1H),5.47–5.30(m,2H),4.46–4.36(m,2H),4.23(dd,J＝14.1,6.6Hz,1H),3.61(s,4H),3.05(s,3H),3.01–2.86(m,2H),2.23(dd,J＝26.3,6.3Hz,1H),2.02(d,J＝8.7Hz,1H),0.89(d,J＝7.2Hz,1H)。

compound 157B:

¹ H NMR(400MHz,MeOD)δ9.51(d,J＝11.9Hz,1H),9.13(s,1H),8.43(dd,J＝48.4,7.1Hz,1H),8.20(dd,J＝51.8,7.2Hz,1H),8.07–7.83(m,2H),7.80–7.51(m,1H),5.51–5.24(m,2H),4.48–4.28(m,1H),4.06(s,1H),3.78(s,1H),3.64(s,3H),3.48(s,2H),3.03(s,3H),2.36–2.15(m,2H),0.90(s,1H)。

compound 158:

¹ H NMR(400MHz,MeOD)δ9.36(d,J＝39.4Hz,1H),9.03(d,J＝67.7Hz,1H),7.81(td,J＝8.0,5.5Hz,1H),7.57–7.47(m,1H),7.40(d,J＝7.7Hz,1H),5.55–5.28(m,2H),4.98(dd,J＝18.7,12.9Hz,2H),4.54(d,J＝29.7Hz,1H),4.39–4.01(m,2H),3.74(d,J＝17.5Hz,1H),3.59(s,3H),3.39(dd,J＝43.1,15.1Hz,2H)。

compound 159A:

¹ H NMR(400MHz,MeOD)δ9.49(s,1H),9.41(dd,J＝40.6,2.9Hz,1H),9.02(t,J＝34.4Hz,1H),8.58(d,J＝22.1Hz,1H),8.34–8.19(m,1H),7.91(dd,J＝7.5,1.1Hz,1H),7.75(td,J＝7.9,2.0Hz,1H),5.61–5.26(m,2H),4.65–4.11(m,4H),3.61(d,J＝3.5Hz,3H),3.35(s,2H),3.13–2.80(m,2H)。

compound 159B:

¹ H NMR(400MHz,MeOD)δ9.52–9.43(m,2H),9.13(s,1H),8.55(d,J＝25.7Hz,1H),8.28(d,J＝8.1Hz,1H),7.90(t,J＝7.1Hz,1H),7.75(td,J＝7.9,1.7Hz,1H),5.52–5.34(m,2H),4.99(s,1H),4.05(d,J＝5.8Hz,2H),3.78(s,1H),3.60(s,3H),3.40(d,J＝38.0Hz,4H)。

compound 160A:

¹ H NMR(400MHz,MeOD)δ9.48(d,J＝1.9Hz,1H),9.38(s,1H),9.14(s,1H),8.41(d,J＝18.2Hz,1H),8.13(d,J＝7.7Hz,1H),7.71–7.61(m,2H),5.55–5.33(m,2H),4.95(s,1H),4.06(s,2H),3.78(s,1H),3.61(s,3H),3.40(d,J＝62.7Hz,4H),2.02(s,3H)。

compound 160B:

¹ H NMR(400MHz,MeOD)δ9.38(d,J＝5.0Hz,2H),8.97(d,J＝1.7Hz,1H),8.42(d,J＝20.2Hz,1H),8.13(d,J＝8.0Hz,1H),7.71–7.60(m,2H),5.43(ddd,J＝32.8,21.4,4.0Hz,2H),4.89(dd,J＝11.7,5.5Hz,1H),4.52(d,J＝13.3Hz,1H),4.41(dt,J＝9.3,5.9Hz,3H),4.29–4.17(m,1H),3.61(d,J＝2.0Hz,3H),2.96(dtd,J＝24.7,17.2,6.1Hz,2H),2.03(d,J＝7.0Hz,3H)。

compound 161A:

¹ H NMR(400MHz,CDCl ₃ )δ9.44–9.26(m,1H),9.00–8.76(m,1H),7.82(d,J＝8.3Hz,1H),7.69–7.58(m,1H),7.56–7.48(m,1H),6.42–6.17(m,1H),5.69–5.27(m,2H),5.17–5.03(m,1H),4.85–4.56(m,2H),4.49–3.80(m,1H),3.69–3.55(m,3H),3.43(s,1H),2.68(s,2H)。

compound 161B:

¹ H NMR(400MHz,CDCl ₃ )δ9.49–9.12(m,1H),9.08–8.86(m,1H),7.82(d,J＝7.3Hz,1H),7.63(t,J＝7.5Hz,1H),7.54–7.43(m,1H),5.74–5.24(m,2H),4.94–4.54(m,2H),4.35–4.10(m,2H),4.00(s,1H),3.86–3.54(m,5H),3.43(s,2H),3.31–2.69(m,2H)。

compound 162A:

¹ H NMR(400MHz,CDCl ₃ )δ9.23(s,1H),8.96(s,1H),8.02–7.95(m,1H),7.87–7.79(m,1H),7.55–7.43(m,2H),7.37–7.29(m,1H),5.64–5.28(m,2H),4.84(s,1H),4.64–4.54(m,1H),4.33–3.98(m,4H),3.66–3.63(m,3H),2.96–2.74(m,2H),2.61–2.48(m,1H),2.28–2.09(m,1H),0.81(t,J＝7.4Hz,3H)。

compound 162B:

¹ H NMR(400MHz,CDCl ₃ )δ9.42(s,1H),9.04(s,1H),7.99(d,J＝7.8Hz,1H),7.83(dd,J＝8.9,5.9Hz,1H),7.57–7.43(m,2H),7.32(t,J＝9.3Hz,1H),5.67–5.34(m,2H),5.04(d,J＝56.0Hz,2H),3.95–3.42(m,7H),3.26–3.01(m,2H),2.52(s,1H),2.17(s,1H),0.88–0.73(m,4H)。

compound 163:

¹ H NMR(400MHz,MeOD)δ9.19(d,J＝5.4Hz,1H),8.86(s,1H),8.03(d,J＝8.1Hz,1H),7.91(dd,J＝8.9,6.0Hz,1H),7.56–7.28(m,3H),5.41(dd,J＝27.9,3.8Hz,1H),5.33(s,1H),3.74(dd,J＝20.0,11.2Hz,4H),3.53(d,J＝9.4Hz,1H),3.49–3.31(m,4H),3.29–3.04(m,4H),2.50(dt,J＝14.2,7.7Hz,1H),2.22–2.08(m,1H),0.74(td,J＝7.4,4.3Hz,3H)。

compound 164A:

¹ H NMR(400MHz,MeOD)δ9.32(d,J＝5.7Hz,1H),8.92(d,J＝1.5Hz,1H),8.15(dd,J＝7.5,2.0Hz,1H),8.07(dd,J＝8.1,5.6Hz,1H),7.77–7.62(m,2H),7.51(t,J＝8.8Hz,1H),6.80(dd,J＝11.0,3.3Hz,1H),4.62–4.30(m,5H),4.21(ddd,J＝19.6,14.0,5.7Hz,1H),3.58(d,J＝5.2Hz,3H),2.92(dtd,J＝24.5,17.3,6.1Hz,2H),2.13–1.93(m,1H),1.35–1.24(m,2H),1.09–0.89(m,2H)。

compound 164B:

¹ H NMR(400MHz,MeOD)δ9.40(d,J＝5.6Hz,1H),9.10(d,J＝5.0Hz,1H),8.25–8.13(m,1H),8.08(dd,J＝9.1,5.6Hz,1H),7.72–7.62(m,2H),7.52(t,J＝8.8Hz,1H),6.70(dd,J＝11.0,5.6Hz,1H),4.04(d,J＝7.1Hz,2H),3.60(s,4H),3.42(dd,J＝31.6,13.3Hz,5H),2.10(dd,J＝7.2,3.5Hz,1H),1.38–1.21(m,2H),1.01(dd,J＝7.4,4.2Hz,2H)。

compound 165A:

¹ HNMR(400MHz,MeOD)δ9.31(dd,J＝10.9,3.9Hz,1H),8.94(d,J＝12.9Hz,1H),8.16(d,J＝2.0Hz,1H),8.11–8.05(m,1H),7.71(dd,J＝14.0,6.0Hz,2H),7.53(td,J＝8.9,2.5Hz,1H),4.84–4.62(m,2H),4.60–4.49(m,1H),4.48–4.17(m,3H),3.62–3.59(m,3H),3.08–2.74(m,2H),2.12(d,J＝2.7Hz,3H)。

compound 165B:

¹ H NMR(400MHz,CDCl ₃ )δ9.42(d,J＝8.8Hz,1H),9.03(dd,J＝10.0,4.8Hz,1H),8.01(dd,J＝7.3,2.0Hz,1H),7.94–7.77(m,1H),7.72–7.54(m,2H),7.39(t,J＝8.7Hz,1H),5.07–4.95(m,1H),3.97–3.79(m,2H),3.76–3.65(m,1H),3.61(s,3H),3.49–3.33(m,1H),3.23(ddd,J＝33.7,16.5,10.4Hz,2H),3.09–2.84(m,1H),2.15(s,3H)。

compound 166A:

¹ H NMR(400MHz,MeOD)δ9.31(d,J＝6.2Hz,1H),8.93(s,1H),8.21–8.11(m,1H),8.11–8.03(m,1H),7.77–7.63(m,2H),7.52(td,J＝8.9,2.3Hz,1H),6.72(dd,J＝14.8,1.5Hz,1H),6.42(dd,J＝14.9,10.1Hz,1H),4.42(dd,J＝87.5,53.3Hz,6H),3.60(d,J＝3.8Hz,3H),3.07–2.74(m,2H),1.83–1.70(m,1H),0.99(dd,J＝10.6,5.0Hz,2H),0.67(d,J＝4.2Hz,2H)。

compound 166B:

¹ HNMR(400MHz,MeOD)δ9.43(d,J＝3.8Hz,1H),9.07(d,J＝5.6Hz,1H),8.15(dd,J＝10.0,2.4Hz,1H),8.10–8.05(m,1H),7.72–7.63(m,2H),7.51(t,J＝8.9Hz,1H),6.87(d,J＝15.0Hz,1H),6.37(dd,J＝14.8,10.1Hz,1H),4.95(d,J＝11.1Hz,2H),4.58(s,1H),4.04(s,1H),3.91(s,1H),3.67(s,1H),3.59(s,3H),3.54–3.34(m,2H),1.75(s,1H),0.99(d,J＝6.9Hz,2H),0.67(s,2H)。

compound 167A:

¹ H NMR(400MHz,CDCl ₃ )δ9.19(d,J＝3.8Hz,1H),8.95(s,1H),8.02(d,J＝9.1Hz,1H),7.91(dd,J＝9.0,5.6Hz,1H),7.63(t,J＝6.5Hz,2H),7.41(td,J＝8.7,3.3Hz,1H),6.70–6.53(m,1H),6.45(dd,J＝16.4,9.2Hz,1H),6.12(dd,J＝14.3,9.7Hz,1H),4.57(d,J＝35.9Hz,1H),4.31(dd,J＝15.1,7.9Hz,1H),4.22–4.14(m,1H),4.13–3.98(m,2H),3.86(dd,J＝21.4,13.0Hz,1H),3.62(s,3H),3.01–2.61(m,2H)。

compound 167B:

¹ HNMR(400MHz,CDCl ₃ )δ9.46(d,J＝3.7Hz,1H),9.06(d,J＝3.2Hz,1H),8.02(d,J＝8.0Hz,1H),7.91(dd,J＝9.0,5.5Hz,1H),7.64(dd,J＝15.8,6.9Hz,2H),7.40(t,J＝8.7Hz,1H),6.75–6.65(m,1H),6.36(d,J＝16.5Hz,1H),6.06(dd,J＝9.9,2.1Hz,1H),4.69(t,J＝13.2Hz,1H),4.26(s,1H),3.77(d,J＝24.0Hz,1H),3.66(d,J＝4.6Hz,3H),3.64–3.56(m,2H),3.56–3.42(m,1H),3.19–2.97(m,2H)。

compound 168A:

¹ H NMR(400MHz,CD ₃ OD)δ9.33(d,J＝32.6Hz,1H),8.84(d,J＝15.7Hz,1H),8.09(dd,J＝20.5,8.1Hz,2H),7.76–7.67(m,2H),7.67–7.61(m,1H),7.53(td,J＝8.0,3.0Hz,1H),6.05(d,J＝6.9Hz,1H),5.43–5.37(m,1H),5.28–5.03(m,2H),4.84–4.71(m,2H),4.56–4.42(m,1H),3.57(d,J＝5.1Hz,3H),3.52–3.37(m,1H),3.05–2.93(m,1H),2.87–2.56(m,2H)。

compound 168B:

¹ H NMR(400MHz,CD ₃ OD)δ9.37(d,J＝10.1Hz,1H),9.10(d,J＝5.5Hz,1H),8.09(dd,J＝19.9,8.0Hz,2H),7.77–7.59(m,3H),7.57–7.45(m,1H),5.54–5.31(m,2H),5.10–4.87(m,2H),4.24–3.92(m,2H),3.81–3.64(m,1H),3.60(s,3H),3.56–3.37(m,2H),3.36–3.32(m,1H),2.99–2.72(m,1H)。

compound 170A:

¹ H NMR(400MHz,CDCl ₃ )δ9.56–9.24(m,1H),8.84(s,1H),7.63(dd,J＝7.6,1.2Hz,1H),7.54(dd,1H),7.43–7.32(m,1H),6.41(d,J＝3.9Hz,1H),6.17(s,1H),5.50(dd,J＝47.4,3.5Hz,1H),5.26(s,1H),5.10(dd,J＝15.0,3.5Hz,1H),4.83–4.67(m,2H),4.58(d,J＝8.5Hz,1H),3.61(s,3H),3.39(s,1H),2.67(d,J＝5.3Hz,2H),2.30–2.13(m,1H),0.66(d,J＝8.3Hz,2H),0.25(s,2H)。

compound 170B:

¹ H NMR(400MHz,CDCl ₃ )δ9.41(s,1H),9.01(s,1H),7.63(dd,J＝7.7,1.3Hz,1H),7.51(dd,J＝8.5Hz,1H),7.41–7.31(m,1H),5.57(dd,J＝47.0,3.7Hz,1H),5.37(dd,J＝16.3,3.6Hz,1H),5.06(d,J＝58.6Hz,1H),3.86(d,J＝3.4Hz,1H),3.69(s,1H),3.62(s,3H),3.42(d,J＝29.1Hz,2H),3.24(dd,J＝16.9,7.3Hz,1H),3.08(s,1H),2.21(dd,J＝8.1Hz,1H),1.38–1.23(m,2H),0.64(d,J＝7.1Hz,2H),0.25(s,2H)。

compound 171A:

¹ H NMR(400MHz,CDCl ₃ )δ9.24(s,1H),9.01(t,J＝4.0Hz,1H),8.97(s,1H),8.12(d,J＝8.3Hz,1H),7.66(t,J＝7.7Hz,1H),7.43–7.32(m,2H),5.54(dd,J＝47.6,3.5Hz,1H),5.33(dd,J＝16.6,3.7Hz,1H),4.85(s,1H),4.60(d,J＝9.5Hz,1H),4.31–4.15(m,3H),4.02(dd,J＝26.4,17.3Hz,1H),3.64(s,3H),2.98–2.71(m,2H),2.03(d,J＝3.1Hz,3H)。

compound 171B:

¹ HNMR(400MHz,CDCl ₃ )δ9.44(d,J＝3.4Hz,1H),9.04(s,1H),8.99(dd,J＝12.6,4.3Hz,1H),8.12(dd,J＝8.3,4.0Hz,1H),7.65(t,J＝7.8Hz,1H),7.42–7.30(m,2H),5.57(dd,J＝47.0,3.7Hz,1H),5.38(d,J＝16.6Hz,1H),5.03(d,J＝51.2Hz,2H),3.85(s,2H),3.65(s,1H),3.63(d,J＝2.8Hz,3H),3.51–3.19(m,2H),3.01(s,1H),2.03(d,J＝4.1Hz,3H)。

compound 172A:

¹ H NMR(400MHz,CDCl ₃ )δ9.46(s,1H),8.95(d,J＝18.8Hz,1H),8.01(d,J＝8.0Hz,1H),7.90(dd,J＝9.0,5.5Hz,1H),7.64(dt,J＝26.7,7.5Hz,2H),7.40(t,J＝8.7Hz,1H),3.95(dt,J＝7.4,4.2Hz,1H),3.83–3.72(m,1H),3.69(dd,J＝6.0,3.8Hz,1H),3.63(t,J＝5.6Hz,3H),3.59(dd,J＝8.0,4.9Hz,2H),3.55–3.50(m,1H),3.48–3.38(m,1H),3.34–3.17(m,2H),3.05–2.89(m,1H),2.41(d,J＝2.1Hz,1H)。

compound 172B:

¹ H NMR(400MHz,CDCl ₃ )δ9.43(d,J＝9.8Hz,1H),9.03(s,1H),8.02(dd,J＝8.0,1.2Hz,1H),7.91(dd,J＝9.0,5.5Hz,1H),7.65(dt,J＝15.1,7.2Hz,2H),7.40(t,J＝8.7Hz,1H),3.81(d,J＝16.4Hz,1H),3.75(t,J＝8.3Hz,2H),3.65(dd,J＝7.7,2.1Hz,3H),3.60(dd,J＝8.8,2.5Hz,2H),3.28(ddd,J＝17.4,10.0,7.1Hz,2H),3.05(dt,J＝39.8,10.8Hz,1H),2.71–2.62(m,1H),2.54(dd,J＝27.6,19.6Hz,1H),2.44(dd,J＝5.4,2.4Hz,1H)。

compound 173:

¹ H NMR(400MHz,DMSO)δ9.37(d,J＝14.3Hz,1H),8.93(s,1H),8.73–8.31(m,1H),8.32–8.13(m,2H),7.83–7.39(m,3H),5.91–5.76(m,1H),5.46–5.12(m,3H),4.86–4.32(m,3H),3.47(d,J＝14.0Hz,3H),2.92–2.66(m,2H)。

compound 178:

¹ H NMR(400MHz,MeOD)δ9.44(d,J＝6.1Hz,1H),9.15(d,J＝4.5Hz,1H),8.17–8.10(m,2H),7.75–7.66(m,2H),7.45(t,J＝8.5Hz,1H),7.27–6.64(m,1H),6.25(d,J＝16.9Hz,1H),5.82(d,J＝11.0Hz,1H),4.93(d,J＝13.0Hz,1H),4.62–4.23(m,3H),4.04(s,1H),3.83(d,J＝12.4Hz,1H),3.63(s,1H),3.39(d,J＝11.1Hz,1H),3.19(t,J＝27.0Hz,2H),2.71(dd,J＝14.2,7.7Hz,2H),2.35(d,J＝17.6Hz,6H)。

compound 179:

¹ H NMR(400MHz,MeOD)δ9.44(d,J＝6.3Hz,1H),9.17(s,1H),8.14(dd,J＝12.4,5.1Hz,2H),7.74–7.65(m,2H),7.45(t,J＝8.5Hz,1H),7.20–6.70(m,1H),6.26(d,J＝16.8Hz,1H),5.82(d,J＝11.9Hz,1H),4.94(d,J＝14.0Hz,1H),4.52(s,1H),4.25(d,J＝5.7Hz,2H),4.05(s,1H),3.83(d,J＝13.6Hz,1H),3.68(d,J＝10.9Hz,1H),3.48(d,J＝1.6Hz,2H),3.14(d,J＝12.3Hz,1H),2.53(s,2H),2.33(d,J＝3.4Hz,6H),1.97(d,J＝7.3Hz,2H)。

compound 184A:

¹ H NMR(400MHz,MeOD)δ9.32(d,J＝5.4Hz,1H),8.94(s,1H),8.17(d,J＝9.5Hz,1H),8.14–8.05(m,1H),7.77–7.67(m,2H),7.53(td,J＝8.9,2.2Hz,1H),7.05–6.83(m,2H),5.20(dt,J＝12.9,6.4Hz,1H),5.09(d,J＝2.0Hz,1H),4.63–4.29(m,5H),3.60(d,J＝4.0Hz,3H),3.50–3.40(m,1H),3.15–2.78(m,2H),1.85(dd,J＝12.7,3.5Hz,2H)。

compound 184B:

¹ H NMR(400MHz,MeOD)δ9.44(d,J＝4.5Hz,1H),9.09(d,J＝5.7Hz,1H),8.20–8.14(m,1H),8.09(dd,J＝9.1,5.6Hz,1H),7.75–7.63(m,2H),7.53(t,J＝8.8Hz,1H),7.07(d,J＝15.7Hz,1H),6.87(dd,J＝38.1,23.0Hz,1H),5.22(d,J＝2.1Hz,1H),5.10(s,1H),5.02(d,J＝4.7Hz,1H),4.94(d,J＝14.8Hz,1H),4.86(s,2H),4.12–4.05(m,1H),4.02–3.93(m,1H),3.75(ddd,J＝23.7,12.5,4.0Hz,1H),3.60(s,3H),3.37(t,J＝7.0Hz,2H)。

compound 188:

¹ H NMR(400MHz,CDCl ₃ )δ9.46(s,1H),9.15(s,1H),8.42(s,1H),8.01(dd,J＝14.1,8.3Hz,2H),7.80–7.45(m,4H),7.12–6.94(m,1H),6.45–6.28(m,1H),5.87–5.73(m,1H),4.83(d,J＝82.9Hz,1H),4.40–4.08(m,2H),4.01–3.66(m,2H),3.60–3.46(m,1H),3.38–3.13(m,2H),3.06–2.92(m,1H),2.89–2.80(m,1H),2.78–2.63(m,6H),2.52–2.34(m,2H),1.52–1.32(m,2H),1.30–1.20(m,1H),1.16–1.04(m,1H)。

example 145:

10-propenoyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ((methylsulfonyl) methyl) -9,10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

Step 1: (2S, 5R) -5- (((methylsulfonyl) oxy) methyl) piperazine-1, 2, 4-tricarboxylic acid 1-benzyl 4- (tert-butyl) 2-methyl ester

At N ₂ To a stirred solution of 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- (hydroxymethyl) piperazine-1, 2, 4-tricarboxylic acid ester (660 mg,1.62 mmol) in DCM (10 mL) at 0deg.C was added TEA (491 mg,4.85 mmol) and MsCl (278 mg,2.42 mmol). The reaction was stirred at 0deg.C for 1 hour, then quenched with water (5 mL) and extracted with DCM (5 mL). The organic phase was treated with anhydrous Na ₂ SO ₄ Dried and concentrated to give (2 s,5 r) -5- (((methylsulfonyl) oxy) methyl) piperazine-1, 2, 4-tricarboxylic acid 1-benzyl 4- (tert-butyl) 2-methyl ester (884 mg, crude) as a yellow oil. LC/MS (ESI) (m/z): 487[ M+H ]] ⁺ 。

Step 2: (2S, 5R) -5- ((methylthio) methyl) piperazine-1, 2, 4-tricarboxylic acid 1-benzyl 4- (tert-butyl) 2-methyl ester

To a solution of 1-benzyl 4- (tert-butyl) 2-methyl (2 s,5 r) -5- (((methylsulfonyl) oxy) methyl) piperazine-1, 2, 4-tricarboxylic acid (884 mg, crude) in DMF (5 mL) was added NaSMe (113 mg,1.62 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na ₂ SO ₄ Dried, and concentrated to dryness. The residue was purified by silica gel chromatography (PE: ea=2:1) to give (2 s,5 r) -5- ((methylthio) methyl) piperazine-1, 2, 4-tricarboxylic acid 1-benzyl ester 4- (tert-butyl) 2-methyl ester (112 mg,15.8% yield, over 2 steps) as a yellow oil. LC/MS (ESI) (m/z) 439[ M+H ]] ⁺ 。

Step 3: (2S, 5R) -5- ((methylsulfonyl) methyl) piperazine-1, 2, 4-tricarboxylic acid 1-benzyl 4- (tert-butyl) 2-methyl ester

To a stirred solution of 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ((methylthio) methyl) piperazine-1, 2, 4-tricarboxylic acid (112 mg,0.26 mmol) in DCM (10 mL) was added m-CPBA (130 mg,0.64 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. Saturated NaHCO for reaction ₃ (15 mL) washing over anhydrous Na ₂ SO ₄ Drying and concentrating to dryness. The residue was purified by silica gel column chromatography (PE: ea=1:1) to give (2 s,5 r) -5- ((methylsulfonyl) methyl) piperazine-1, 2, 4-tricarboxylic acid 1-benzyl ester 4- (tert-butyl) 2-methyl ester (110 mg,91.5% yield) as a yellow oil. LC/MS (ESI) (m/z) 471[ M+H ]] ⁺

Step 4: (3S, 6R) -6- ((methylsulfonyl) methyl) piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) 3-methyl ester

To a solution of 1-benzyl 4- (tert-butyl) 2-methyl (2S, 5R) -5- ((methylsulfonyl) methyl) piperazine-1, 2, 4-tricarboxylic acid (226 mg,0.48 mmol) in MeOH (10 mL) was added Pd/C (30 mg,10 wt%) at room temperature. The mixture is put in H ₂ Stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was concentrated to dryness to give 1- (tert-butyl) 3-methyl (160 mg,99.0% yield) piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) ester as a yellow oil. LC/MS (ESI) (m/z): 337[ M+H ]] ⁺

Step 5: (3S, 6R) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -6- ((methylsulfonyl) methyl) piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) 3-methyl ester

To a stirred solution of 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine (187 mg,0.71 mmol) and 1- (tert-butyl) 3-methyl (160 mg,0.48 mmol) of (3 s,6 r) -6- ((methylsulfonyl) methyl) piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) ester in dioxane (5 mL) was added DIEA (184 mg,1.43 mmol). Stirring at 50deg.C for 12 After an hour, the reaction mixture was diluted with EtOAc (15 mL), washed with water (15 mL), and dried over Na ₂ SO ₄ Drying and evaporating to dryness. The residue was purified by silica gel column chromatography (PE: etoac=2:1) to give 1- (tert-butyl) 3-methyl (171 mg,64.0% yield) 4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -6- ((methylsulfonyl) methyl) piperazine-1, 3-dicarboxylic acid as a yellow oil. LC/MS (ESI) (m/z): 562[ M+H ]] ⁺

Step 6: (8 aS, 11R) -3-chloro-4-fluoro-11- ((methylsulfonyl) methyl) -8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridine-10-carboxylic acid tert-butyl ester

1- (tert-butyl) 3-methyl (3S, 6R) -4- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -6- ((methylsulfonyl) methyl) piperazine-1, 3-dicarboxylic acid 1- (tert-butyl) ester (171 mg,0.30 mmol), iron powder (170 mg,3.04 mmol) and NH ₄ A mixture of Cl (163 mg,3.04 mmol) in EtOH (10 mL) and water (2 mL) was stirred at 80℃for 4 h. TLC (PE: etoac=1:1) indicated completion of the reaction. The reaction was immediately filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: etoac=1:1) to give (8 as,11 r) -3-chloro-4-fluoro-11- ((methylsulfonyl) methyl) -8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5] as a yellow oil ]Pyrazino [2,3-c ]][1,6]Naphthyridine-10-carboxylic acid tert-butyl ester (143 mg,94.0% yield). LC/MS (ESI) (m/z) 500[ M+H ]] ⁺

Step 7: (2R, 4 aS) -10-chloro-9-fluoro-6-methyl-2- ((methylsulfonyl) methyl) -5-oxo-1, 2, 4a,5, 6-hexahydro-3H-pyrazino [1',2':4,5] pyrazino [2,3-c ] quinoline-3-carboxylic acid tert-butyl ester

To (8 aS, 11R) -3-chloro-4-fluoro-11- ((methylsulfonyl) methyl) -8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5] at 0 DEG C]Pyrazino [2 ],3-c][1,6]To a solution of tert-butyl naphthyridine-10-carboxylate (143 mg,0.29 mmol) in DMF (5 mL) was added Cs ₂ CO ₃ (280 mg,0.86 mmol) and MeI (49 mg,0.34 mmol). The reaction was stirred at 0 ℃ for 30 minutes. LCMS showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ Dried, and concentrated to dryness. The residue was purified by silica gel column chromatography (DCM: meoh=20:1) to give (2 r,4 as) -10-chloro-9-fluoro-6-methyl-2- ((methylsulfonyl) methyl) -5-oxo-1, 2, 4a,5, 6-hexahydro-3H-pyrazino [1',2':4,5] as a yellow solid]Pyrazino [2,3-c ]]Quinoline-3-carboxylic acid tert-butyl ester (125 mg,85.0% yield). LC/MS (ESI) (m/z): 513[ M+H ]] ⁺

Step 8: (8 aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ((methylsulfonyl) methyl) -8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridine-10-carboxylic acid tert-butyl ester

To (2R, 4 aS) -10-chloro-9-fluoro-6-methyl-2- ((methylsulfonyl) methyl) -5-oxo-1, 2, 4a,5, 6-hexahydro-3H-pyrazino [1',2':4,5] at room temperature]Pyrazino [2,3-c ]]To a stirred solution of tert-butyl quinoline-3-carboxylate (120 mg,0.23 mmol) and 2- (8-chloronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (101 mg,0.35 mmol) in 1, 4-dioxane (10 mL) and water (2 mL) was added K ₂ CO ₃ (97 mg,0.70 mmol) and Ruphos Pd G4 (20 mg,0.02 mmol). The reaction is carried out in N ₂ Deaeration was carried out three times under an atmosphere and stirred at 100℃for 18 hours. The reaction was cooled to room temperature and filtered. The filtrate was diluted with EtOAc (15 mL), washed with brine (15 mL), and dried over anhydrous Na ₂ SO ₄ Drying and concentrating to dryness. The residue was purified by preparative TLC (PE: etoac=1:1) to give (8 as,11 r) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ((methylsulfonyl) methyl) -8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5 as a yellow oil]Pyrazino [2,3-c ]][1,6]Naphthyridine-10-carboxylic acid tert-butyl ester (40)mg,26.8% yield). LC/MS (ESI) (m/z): 640[ M+H ]] ⁺

Step 9: (8 aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ((methylsulfonyl) methyl) -9,10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

To (8 aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ((methylsulfonyl) methyl) -8-oxo-7, 8a,9,11, 12-hexahydro-10H-pyrazino [1',2':4,5]Pyrazino [2,3-c ]][1,6]A solution of naphthyridine-10-carboxylic acid tert-butyl ester (20 mg,0.03 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction was stirred at 25 ℃ for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give (8 aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ((methylsulfonyl) methyl) -9,10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] as a pink solid]Pyrazino [2,3-c ]][1,6]Naphthyridin-8 (8 aH) -one (16 mg,94.8% yield). LC/MS (ESI) (m/z) 540[ M+H ]] ⁺ 。

Step 10: (8 aS, 11R) -10-propenoyl-3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ((methylsulfonyl) methyl) -9,10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

At 0℃under N ₂ Downward (8 aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-7-methyl-11- ((methylsulfonyl) methyl) -9,10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5]Pyrazino [2,3-c ]][1,6]To a solution of naphthyridin-8 (8 aH) -one (16 mg,0.03 mmol) and DIEA (12 mg,0.09 mmol) in DCM (2 mL) was added a solution of acryloyl chloride (5 mg,0.05 mmol) in DCM (0.5 mL). The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic phase was treated with anhydrous Na ₂ SO ₄ Drying and concentrating to dryness. The residue was purified by preparative HPLC (column: gemini5um C18 x 21.2mm, h ₂ O(0.1％FA)/CH ₃ CN) to give the desired product (5.4 mg,30.7% yield). LC/MS (ESI) (m/z): 594.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,MeOD)δ9.48(d,J＝11.6Hz,1H),9.12(s,1H),8.14(d,J＝7.3Hz,1H),8.02(d,J＝7.2Hz,1H),7.74–7.61(m,2H),7.60–7.55(m,1H),7.50(t,J＝7.8Hz,1H),7.09(dd,J＝16.9,10.8Hz,1H),6.25(d,J＝17.0Hz,1H),5.84(d,J＝10.7Hz,1H),5.41–5.32(m,1H),4.58(s,1H),4.19–3.82(m,4H),3.79–3.69(m,1H),3.60(s,3H),3.29–3.21(m,1H),3.14(s,3H)。

Example 153:

(8 aS, 11S) -10-propenoyl-3- (8-chloronaphthalen-1-yl) -11- ((dimethylamino) methyl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

Step 1: (2S, 5R) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylic acid methyl ester

To a solution of (2 s,5 r) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-1, 2-dicarboxylic acid 1- (tert-butyl) 2-methyl ester (1 g,2.54 mmol) in dioxane (10 mL) was added HCl/dioxane (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give the title compound (2 s,5 r) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylic acid methyl ester (700 mg, 93.8%) as a white solid.

LC/MS ESI(m/z):295[M+H] ⁺

Step 2: (2S, 5R) -1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylic acid methyl ester

To a solution of 4, 7-dichloro-8-fluoro-3-nitro-1, 6-naphthyridine (623 mg,2.38 mmol) and DIPEA (1.18 mL,7.14 mmol) in dioxane (20 mL) was added methyl (2 s,5 r) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (700 mg,2.38 mmol) at 0 ℃ and the reaction mixture was stirred overnight at 50 ℃. The reaction mixture was diluted with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to give methyl (2 s,5 r) -1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylate (900 mg, 72.8%) as a yellow oil.

LC/MS ESI(m/z):520[M+H] ⁺

Step 3: (8 aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -9,10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

To (2S, 5R) -1- (7-chloro-8-fluoro-3-nitro-1, 6-naphthyridin-4-yl) -5- (hydroxymethyl) -4- (4-methoxybenzyl) piperazine-2-carboxylic acid methyl ester (900 mg,1.73 mmol) in EtOH (10 mL) and H ₂ To a solution in O (2 mL) were added Fe (967 mg,17.31 mmol) and NH ₄ Cl (1.8 g,34.62 mmol). The reaction mixture was stirred at 80℃for 3 hours. The mixture is then filtered and the solvent is removed from the liquid phase. The residue was diluted with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried, and concentrated to give (8 as,11 r) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -9,10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] as a brown solid]Pyrazino [2,3-c ]][1,6]Naphthyridin-8 (8 aH) -one (750 mg, 94.6%).

LC/MS ESI(m/z):458[M+H] ⁺

Step 4: (8 aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

To (8 aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -9,10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5 ]Pyrazino [2,3-c ]][1,6]Naphthyridin-8 (8 aH) -one (700 mg,1.53 mmol) and Cs ₂ CO ₃ (1.5 g,4.59 mmol) in DMF (20 mL) was added CH ₃ I (552 mg,3.82 mmol) and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried, and concentrated to give (8 aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4, 5) as a brown solid]Pyrazino [2,3-c ]][1,6]Naphthyridin-8 (8 aH) -one (650 mg, 90.1%).

LC/MS ESI(m/z):472[M+H] ⁺

Step 5: (8 aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

To (8 aS, 11R) -3-chloro-4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5]Pyrazino [2,3-c ]][1,6]Naphthyridin-8 (8 aH) -one (600 mg,1.27 mmol), K ₂ CO ₃ (879 mg,6.36 mmol) and 2- (8-chloronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (284 mg,2.54 mmol) in dioxane (10 mL) and H ₂ RuPhos Pd G4 (15 mg,0.02 mmol) was added to a solution in O (2 mL) and the mixture was taken up in N ₂ Stirred overnight at 100 ℃. The reaction was diluted with ice-water and then extracted twice with EA. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (8 as,11 r) -3- (8-chloronaphthalen-1-yl) -4-fluoro-11- (hydroxymethyl) -10-, as a yellow solid4-methoxybenzyl) -7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5]Pyrazino [2,3-c ]][1,6]Naphthyridin-8 (8 aH) -one (250 mg, 32.9%).

LC/MS ESI(m/z):598[M+H] ⁺

Step 6: ((8 aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) methylsulfonic acid methyl ester

To a solution of (8 as,11 r) -3- (8-chloronaphthalen-1-yl) -4-fluoro-11- (hydroxymethyl) -10- (4-methoxybenzyl) -7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one (220 mg,0.37 mmol), DIPEA (0.18 mL,1.10 mmol) in DCM (10 mL) was added MsCl (0.04 mL,0.55 mmol) at 0 ℃. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched with aqueous Na2CO3 and then extracted twice with EA. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (((8 as,11 r) -3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-11-yl) methanesulfonate as a yellow oil (240 mg, 96.5%).

LC/MS ESI(m/z):676[M+H] ⁺

Step 7: (8 aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ((dimethylamino) methyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

To a solution of (((8 aS, 11R) -3- (8-chloronaphthalen-1-yl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-8-oxo-8, 8a,9,10,11, 12-hexahydro-7H-pyrazino [1',2':4,5] pyrazin-2, 3-c ] [1,6] naphthyridin-11-yl) methanesulfonic acid methyl ester (240 mg,0.36 mmol) in THF (5 mL) was added dimethylamine (about 2.0M in THF) (1.78 mL,3.55 mmol). The reaction mixture was stirred overnight at 60 ℃ then the mixture was filtered and the solvent was removed from the liquid phase, the residue was diluted with water, the combined organic layers were washed with water and brine, dried and concentrated to give (8 aS, 11S) -3- (8-chloronaphthalen-1-yl) -11 dimethyl-fluoro-4-fluoro-10- (4-methoxybenzyl) -7-8, 8-oxo-8, 8a,9, 11, 12-hexahydro-pyrazino [1',2, 5] naphthyridin-11-yl) methanesulfonic acid methyl ester as a brown solid.

LC/MS ESI(m/z):625[M+H] ⁺

Step 8: (8 aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ((dimethylamino) methyl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

To (8 aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ((dimethylamino) methyl) -4-fluoro-10- (4-methoxybenzyl) -7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5]]Pyrazino [2,3-c ]][1,6]A solution of naphthyridin-8 (8 aH) -one (40 mg,0.06 mmol) in TFA (3 mL) was added anisole (0.07 mL,0.59 mmol). The reaction mixture was stirred at 40 ℃ overnight. The mixture was slowly poured into ice-cold saturated NaHCO ₃ In (3) stirring for 30 minutes. The mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (8 as,11 s) -3- (8-chloronaphthalen-1-yl) -11- ((dimethylamino) methyl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4, 5) as a yellow oil]Pyrazino [2,3-c ]][1,6]Naphthyridin-8 (8 aH) -one (35 mg, 88.4%).

LC/MS ESI(m/z):505[M+H] ⁺

Step 9: (8 aS, 11S) -10-propenoyl-3- (8-chloronaphthalen-1-yl) -11- ((dimethylamino) methyl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one

To a suspension of (8 aS, 11S) -3- (8-chloronaphthalen-1-yl) -11- ((dimethylamino) methyl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one (30 mg,0.07 mmol) and DIPEA (0.03 mL,0.15 mmol) in DCM (5 mL) was added dropwise under nitrogen and the reaction mixture was stirred at 0 ℃. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography to give a crude product which was further purified by preparative HPLC to give (8 as,11 s) -10-propenoyl-3- (8-chloronaphthalen-1-yl) -11- ((dimethylamino) methyl) -4-fluoro-7-methyl-9, 10,11, 12-tetrahydro-7H-pyrazino [1',2':4,5] pyrazino [2,3-c ] [1,6] naphthyridin-8 (8 aH) -one (5.3 mg, 13.8%).

LC/MS ESI(m/z):559[M+H] ⁺

¹ H NMR(400MHz,MeOD)δ9.50(t,J＝17.4Hz,1H),9.13(d,J＝5.8Hz,1H),8.15(d,J＝7.8Hz,1H),8.03(d,J＝7.4Hz,1H),7.71–7.58(m,3H),7.51(t,J＝7.8Hz,1H),7.07(dt,J＝137.6,68.8Hz,1H),6.25(dd,J＝16.9,1.8Hz,1H),5.80(t,J＝15.6Hz,1H),4.35(d,J＝15.4Hz,1H),3.96(dd,J＝11.1,3.9Hz,1H),3.84(d,J＝14.6Hz,1H),3.79–3.63(m,2H),3.59(d,J＝4.2Hz,3H),3.11(ddd,J＝14.9,11.8,8.1Hz,2H),2.96–2.82(m,1H),2.40(t,J＝9.1Hz,6H)。

Bioassays

The following assays were used to measure the effect of the compounds of the present specification.

Phosphate ERK 1/2 assay in H358:

h358 cells were cultured in RPMI-1640 and 10%1 foetal calf serum (FCS;) T75 in (a)The flask was grown until a confluence of about 80% was reached. On day 1, 6000 cells/well were seeded in 384 well plates and incubated at 37 ℃, 5% co 2. Diluted compound was added by Echo 550, final DMSO 0.5%, cells were incubated at 37 ℃, 5% co ₂ Incubate for 3 hours. The medium was then removed and the cells were fixed by Apricot with 3.7% formaldehyde in PBS (PFA). Washed once with PBS. Cells were permeabilized with cold 100% methanol and washed repeatedly with PBS once. Li-Cor blocking buffer was added to each well and incubated for 1.5 hours at RT. The blocking buffer was removed and a primary antibody mixture (rabbit anti-pERK, mouse anti-GAPDH) was added. Incubate overnight at 4 ℃. On day 2, a total of 3 washes with PBST (Tween-20-containing PBS) and then secondary antibody mixtures (goat anti-rabbit 800CW (in combination solution at 1:800 dilution) and goat anti-mouse 680RD (in combination solution at 1:800 dilution) were added and incubated at RT for 60 min in the absence of light.) the wash was repeated 3 times with PBST after the last wash the plate reverse side was centrifuged at 1000rpm to completely remove wash solution from the wells. The plate surface and } was cleaned with moist non-velvet tissue prior to plate scan >Imagers scan the bed (if applicable) to avoid any obstructions during the scan. The plate was scanned with detection in 700nm and 800nm channels.

Table a shows the results for the exemplary compounds.

Table A

The compounds of the present disclosure exhibit an IC of 0.5nM to 10000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-5000nM ₅₀ Values. One of the present disclosureThese compounds exhibit an IC of 1-4000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-3000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-2000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-1000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-500nM ₅₀ Values.

KRAS (G12C): SOS1 nucleotide exchange assay

GDP-loaded KRAS (G12C) was thawed and GDP-loaded KRAS (G12C) was diluted to 500nM in RBD-RAS binding buffer. Preparation of master mix (6 μl): 96 well x (1. Mu.l of diluted GDP-loaded KRAS (G12C), 500 nM+5. Mu.l RBD-RAS binding buffer). Mu.l of the master mix was added to each well. Serial dilutions of test compounds in DMSO were prepared at 200X test concentrations. The compound was then diluted 20-fold in deionized water to prepare a 10X intermediate solution. For positive and negative controls, water with 5% DMSO was used as 10X intermediate, so that all wells included the same amount of DMSO. Mu.l of 10 Xintermediate solution of test compound was added to the test wells. Mu.l of 5% DMSO was added to the positive control wells and the negative control wells. Plates were briefly centrifuged and incubated for 30 min at room temperature. GTP (10 mM) was thawed on ice and SOS1 was thawed. SOS1 was diluted at 5. Mu.M in RBD-RAS binding buffer. GTP (10 mM) and diluted SOS1 (5. Mu.M) were mixed at a ratio of 1:1. The exchange reaction was initiated by adding 2. Mu.l of GTP/SOS1 mixture to the test wells and the positive control wells. RBD-cRAF was thawed and diluted at 25nM in RBD-RAS binding buffer. After 30 min incubation with SOS1/GTP (RBD-RAS buffer of negative control), 1. Mu.l of diluted RBD-cRAF (25 nM) was added to all wells. Plates were briefly centrifuged and incubated for 30 min at room temperature. The 3X immune buffer was diluted in deionized water to prepare a 1X immune buffer. One volume of 3X immune buffer was added to two volumes of deionized water. Glutathione acceptor beads (perkinelmer#al109C) and nickel chelating donor beads (perkinelmer#as101d) were diluted 1:500 and 1:250, respectively, in 1x immunization buffer. It was necessary to add 20 μl of acceptor bead/donor bead mixture to each well. Thus, 16 μl of glutathione acceptor beads and 32 μl of nickel donor beads were added to 8ml of 1x immunization buffer). Incubate for 30 minutes at room temperature. The alpha count is read using a compatible reader.

3D cell viability assay

H358 (ATCC CRL-5807) cells were purchased from ATCC company, and each cell was cultured in a medium supplemented with 10% Fetal Bovine Serum (FBS) according to the manufacturer's recommended protocol. Cells were seeded at 1000 cells/well in each growth medium in 96-well tissue culture plates and allowed to adhere overnight on day 0. The following day after plating, cells were treated with a 9-point 3-fold dilution series of test compound (100 μl final volume per well) and after 5 days cell viability was monitored according to manufacturer's recommendations, with 50ml CellTiter-Glo reagent added, vigorously mixed, covered, and placed on a plate shaker for 20 minutes before assessing luminescence signals to ensure complete cell lysis.

KRAS-G12C/cRAF binding assay

Frozen reagents were thawed on ice. A working solution was prepared by diluting 500XTag2-KRAS-G12C protein stock (Cisbio, 63ADK000CB20 PEG) and 10mM GTP (Sigma, V900868) stock with dilution buffer (Cisbio, 62 DLBDDF). A working solution was prepared by diluting 100X anti-Tag 1-Eu3+ stock (Cisbio, 63ADK000CB20 PEG) and 50X anti-Tag 2-XL665 (Cisbio, 63ADK000CB20 PEG) with detection buffer (Cisbio, 62DB1 FDG). Compounds were diluted manually 10-fold in DMSO, 3-fold. Then 0.2 μl of compound was transferred to 384 assay plates by ECHO. mu.L of KRAS G12C & GTP at the indicated concentration was added to 384 assay plates and centrifuged at 1000RPM for 1 minute. mu.L of cRAF (Cisbio, 63ADK000CB20 PEG) at the indicated concentration was added to the assay plate and centrifuged at 1000RPM for 1 minute. Incubate at 25℃for 15 min. mu.L of the anti-Tag 1-Eu and anti-Tag 2-XL665 mixture was added to the assay plate. Centrifuge at 1000RPM for 1 minute and incubate at 4℃for 2 hours. The 665/615nm ratio on Envision was read. Data analysis: the ratio of each well was calculated (ratio 665nm/615 nm). The% inhibition is calculated as follows:

Inhibition% = 100- (signal) _cmpd -signal _{Ave_PC} ) (Signal) _{Ave_VC} -signal _{Ave_PC} )×100

Signal signal _{ave_pc} : average ratio of positive controls on the plate.

Signal signal _ave _vc : average ratio of negative controls on the plate.

IC50 was calculated and the effect dose curve for compound (cmpd) was plotted: IC50 was calculated by fitting the log of% inhibition and compound concentration to a nonlinear regression (dose response-variable slope) with Graphpad 8.0.

Y=bottom+ (top-bottom)/(1+10 ++logic 50-X schl slope)

X: logarithm of inhibitor concentration; y: inhibition%.

The cRAF binding assay was performed with the compounds of the present disclosure and reference compound 1AMG-510 (Soto Raxib). Table B shows the results for exemplary compounds and reference compound 1.

Table B

Examples numbering	cRAF binding assay IC50 (nM)
		Reference 1	2521
1A	48
		25A	55

The compounds of the present disclosure exhibit an IC of 0.5nM to 2000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-1000nM ₅₀ Values. Some compounds of the present disclosure exhibit an IC of 1-500nM ₅₀ Values.

DMPK study

DMPK studies were performed with the compound of the present disclosure and reference compound 1AMG-510 (sotorrag) and reference compound 2MRTX849 (adarag) using the following assays: a) The method comprises the following steps MDCK-MDR1 Pgp evaluation and b) MDCK-BCRP BCRP evaluation.

Measurement a): MDCK-MDR1 Pgp assessment

Efflux transport mediated by P-glycoprotein (Pgp) was assessed by MDCK-MDR1 cells. The final concentration of test and control compounds was 1 μm. The multi-well insert plate was incubated at 37℃for 2 hours.

Measurement b): MDCK-BCRP BCRP evaluation

Efflux transport mediated by Breast Cancer Resistance Protein (BCRP) was assessed by MDCK-BCRP cells. The final concentration of test and control compounds was 1 μm. The multi-well insert plate was incubated at 37℃for 1.5 hours.

The Efflux Ratio (ER) of glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) reflects the likelihood of compounds being pumped from the brain by BBB efflux transporters. Substrates for P-gp and/or BCRP generally have brain penetrating lesions.

According to table C, reference compounds 1 and 2 are strong Pgp and/or BCRP substrates, which prevent these compounds from entering the interstitial space of the brain. In contrast, the examples in table C show a great improvement in the tendency to external discharge.

Table C

For other example compounds, not shown in the results, a considerable improvement in the tendency of Pgp and BCRP to efflux was expected for all compounds. For some example compounds, the results for Pgp ER, BCRP ER were comparable to or even slightly better than those for the example compounds in table C.

The foregoing description is considered as illustrative only of the principles of the disclosure. Further, since numerous modifications and variations will be apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown and described above. Accordingly, all suitable modifications and equivalents may be resorted to as falling within the scope of the invention as defined by the appended claims.

Claims

1. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof,

wherein the method comprises the steps of

Is a single bond or a double bond;

g is C (R) ^a ) Or N;

z is

Each R ^b Independently is hydrogen, deuterium, halogen, cyano, alkyl, alkoxy, heteroalkyl, cycloalkyl, or heteroaryl, wherein the alkyl, the heteroalkyl, the cycloalkyl, and the heteroaryl are optionally substituted with one or more groups independently selected from: hydroxy, halogen, -NR ^c R ^d And heterocyclyl optionally substituted with one or more groups independently selected from hydroxy, halogen, cyano, and amino;

each R ^c Independently hydrogen, alkyl, alkenyl, alkynyl or haloalkyl;

R ^d Selected from the group consisting of: optionally heteroaryl or-N (R) ^c ) ₂ Substituted alkyl haloalkyl group,

-C(O)N(R ^c ) ₂ 、-(CH ₂ ) _n NHC (O) -alkyl, heterocyclyl, and heteroaryl, wherein the heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from: halo, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl, hydroxyalkyl, -O-haloalkyl, and-S-haloalkyl;

w is CR ^e Or N;

Q is CR ^f Or N;

e is a bond, -O-or-NHC (O) -;

R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b and R is ⁴ Each of which is independently absent OR selected from hydrogen, oxo, hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, -C (O) OR ^c 、-C(O)N(R ^c ) ₂ 、-N(R ^c ) ₂ Or heteroaryl, wherein the alkyl, alkenyl, alkynyl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: cyano, hydroxy, halogen, -OR ^c 、-N(R ^c ) ₂ or-SO ₂ (R ^c ) The method comprises the steps of carrying out a first treatment on the surface of the Or alternatively

R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Together with the carbon atoms to which they are attached, form an alkyl, alkenyl, cycloalkyl or heterocyclyl group, said alkyl, said cycloalkyl or said heterocyclyl group optionally being independently selected from one or more ofIs substituted by a group of: cyano, halogen, hydroxy, amino, alkoxy, alkyl, alkenyl or alkynyl;

L ² is a bond, -O-, -N (R) ⁱ ) -or-S (O) _v -；

L ³ is a bond, -C (O) -or alkyl;

n is 0, 1 or 2;

m is an integer from 0 to 4;

p is an integer from 0 to 2;

r is 1 or 2;

u is an integer from 0 to 4;

v is an integer from 0 to 2;

provided that it is

when (when)When it is a triple bond, then R ^a Absent, R ^b Exists and r is 1;

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein two of themAre all single bonds, G is C (R ^a ) And R is ^a Is hydrogen.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein two of themAre all single bonds and G is N.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N-C (O) -C (R ^a )＝C(R ^b ) _r 。

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N-SO ₂ C(R ^a )＝C(R ^b ) _r 。

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ^a Is hydrogen, deuterium, cyano, halogen or alkyl.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N-C (O) -c≡c (R ^b ) _r 。

8. A compound according to claim 1Or a pharmaceutically acceptable salt thereof, wherein Z is N-SO ₂ C≡C(R ^b ) _r 。

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N-C (R ^a )≡C(R ^b ) _r 。

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R ^b Independently is hydrogen, deuterium, alkyl, heteroalkyl, cycloalkyl or heteroaryl, wherein said alkyl, said heteroalkyl, said cycloalkyl and said heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of: halogen, -NR ^c R ^d And heterocyclyl optionally substituted with one or more groups selected from hydroxy, halogen, cyano and amino.

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein W is N.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein W is CR ^e 。

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R ^e Selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, -OR ^c Alkyl, alkenyl, and alkynyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more groups independently selected from the group consisting of: hydroxy, halogen, cyano, -OR ^c and-N (R) ^c ) ₂ 。

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is N.

15. A compound according to claim 1 or a pharmaceutically acceptable thereofWherein Q is CR ^f And R is ^f is-Y- (CH) ₂ ) _m -T-R ^g 。

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Y is a bond, -O-, or-S-.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein T is heterocyclyl optionally substituted with one or more groups independently selected from: hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

18. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein Y is-N (R ^c )-。

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein T is a bond.

20. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Y is alkynyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein T is a bond.

22. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein T is heterocyclyl optionally substituted with one or more groups independently selected from: oxo, hydroxy, halogen, cyano, amino, alkyl, hydroxyalkyl or heteroaryl.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein T is heterocyclyl selected from the group consisting of:

24. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R ^g Selected from the group consisting of: hydrogen, hydroxy, halogen, alkyl, -N (R) ^c ) ₂ OR-OR ^c 。

25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Independently selected from hydrogen, alkyl, or heteroalkyl, wherein the alkyl and the heteroaryl are optionally substituted with one or more groups independently selected from: cyano, hydroxy, halogen, -OR ^c 、-N(R ^c ) ₂ or-SO ₂ (R ^c )。

26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Together with the carbon atoms to which they are attached, form an alkyl group.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^1a And R is ^3a Together with the carbon atoms to which they are attached, form propyl or butyl.

28. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^1a And R is ⁴ Together with the carbon atoms to which they are attached, form propyl or butyl.

29. The compound according to claim 26An agent or a pharmaceutically acceptable salt thereof, wherein R ^2a And R is ^3a Together with the carbon atoms to which they are attached, form propyl or butyl.

30. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Together with the carbon atoms to which they are attached, form an alkenyl group.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R ^1a And R is ^3a Forms a butenyl group together with the carbon atoms to which they are attached.

32. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^1a And R is ⁴ Forms a butenyl group together with the carbon atoms to which they are attached.

33. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R ^2a And R is ^3a Forms a butenyl group together with the carbon atoms to which they are attached.

34. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ^3a 、R ^3b And R is ⁴ Together with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclyl group.

35. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^1a And R is ^1b Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

36. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^2a And R is ^2b Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

37. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^3a And R is ^3b Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

38. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^1a And R is ^2a Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

39. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^3a And R is ⁴ Together with the carbon atoms to which they are attached form C _3-6 Cycloalkyl or C _3-6 A heterocyclic group.

40. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ Is a key.

41. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ Is- [ C (R) ^h ) ₂ ] _u -*。

42. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ Is- [ C (R) ^h ) ₂ ] _u -C(O)-*。

43. The compound according to claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein R ^h Is hydrogen and u is 0, 1, 2 or 3.

44. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ is-N (R) ^c )C(O)-*。

45. The compound according to claim 44, wherein R ^c Is hydrogen.

46. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ is-S (O) _v -。

47. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ² Is a key.

48. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ² is-O-.

49. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ² is-N (R) ⁱ )-。

50. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein R ⁱ Is hydrogen, alkyl, cycloalkyl or-C (O) -heterocyclyl, wherein said alkyl and said cycloalkyl are optionally substituted with one or more R' ", and the heterocyclyl moiety in the-C (O) -heterocyclyl is optionally substituted with one or more moieties independently selected from alkyl or-N (R) ^c ) ₂ Is substituted with a group of (a).

51. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ¹ Is- [ C (R) ^h ) ₂ ] _u -*，L ² is-N (R) ⁱ ) -, u is 1, and R ^h And R is ⁱ Together with the carbon and nitrogen atoms to which they are attached, respectively, form a heteroaryl group, which heteroaryl group is optionally substituted with one or more groups independently selected from: cyano, halogen, hydroxy, haloalkyl, hydroxyalkyl, alkyl or-alkyl-N (R) ^c ) ₂ 。

52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl is triazolyl or imidazolyl.

53. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ³ Is a key.

54. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ³ is-C (O) -.

55. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L ³ Is an alkyl group.

56. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is optionally substituted with one or more R ^j Substituted aryl.

57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is an aryl group selected from phenyl, naphthyl or 2, 3-dihydro-1H-indenyl, each of which is optionally substituted with one or more R ^j And (3) substitution.

58. The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein R ^j Is hydroxy, halogen, amino, alkyl, alkynyl, haloalkyl or cycloalkyl.

59. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is optionally substituted with one or more R ^j Substituted heteroaryl groups.

60. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is a heteroaryl selected from the group consisting of: pyridyl, quinolinyl, isoquinolinyl, indazolyl or benzo [ b ]]A thienyl group, a hydroxyl group,each of which is optionally substituted with one or more R ^j And (3) substitution.

61. The compound of claim 60, or a pharmaceutically acceptable salt thereof, wherein R ^j Is hydroxy, halogen, amino, alkyl or alkynyl.

62. The compound of claim 1, having formula (Ia), formula (Ib) or formula (Ic):

or a pharmaceutically acceptable salt thereof,

63. The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein two ofAre all single bonds.

64. The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein Q is CR ^f 。

65. The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein Q is N.

66. The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein L ³ Is a key.

67. The chemical of any one of claims 62 to 66A compound or pharmaceutically acceptable salt thereof, wherein R ⁵ Is aryl or heteroaryl, each of which is optionally substituted with one or more R ^j And (3) substitution.

68. The compound of claim 67, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Selected from the group consisting of: phenyl, naphthyl, 2, 3-dihydro-1H-indenyl, pyridyl, quinolyl, isoquinolyl, indazolyl and benzo [ b ]]Thienyl, each of which is optionally substituted with one or more R ^j And (3) substitution.

69. The compound of any one of claims 62 to 68, or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1.

70. The compound of claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

71. A pharmaceutical composition comprising a compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

72. A method of inhibiting KRas G12C activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-70, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 71.

73. A method of treating KRas G12C-associated cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-70, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 71.

74. The method of claim 73, wherein the KRas G12C-related cancer is selected from the group consisting of:

(iii) Gastrointestinal cancer: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, schuvascular intestinal peptide tumor), small intestinal cancer (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma (Kaposi's ssarcoma), smooth myoma, hemangioma, lipoma, neurofibroma, fibroma), large intestinal cancer (adenocarcinoma, tubular adenoma, villial adenoma, hamartoma, smooth myoma);

(xi) Adrenal cancer: neuroblastoma.

75. The method of claim 74, wherein the cancer is non-small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

76. The method of claim 75, wherein the cancer is associated with brain metastasis.

77. A method of treating cancer in a subject in need thereof, the method comprising: (a) knowing that the cancer is associated with a KRas G12C mutation; and (b) administering to the subject an effective amount of a compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 71.

78. The method of any one of claims 72-77, wherein the administering is by a route selected from the group consisting of: parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, cerebrospinal, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous and topical administration.

79. The method of any one of claims 72-78, wherein the compound is administered simultaneously, separately or sequentially with one or more additional therapeutic agents.

80. The method of claim 79, wherein the one or more additional therapeutic agents are selected from an anti-PD-1 or PD-L1 antagonist, a MEK inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, an mTOR inhibitor, a VEGFR inhibitor, an EGFR antibody, a platinum agent, or pemetrexed (pemetrexed).

81. Use of a compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 71, in the manufacture of a medicament for the treatment of cancer.

82. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 71, for use in the treatment of cancer.