CN108602799B - Kinase inhibitor - Google Patents

Abstract

The present invention relates to a class of CDK4/6 inhibitors, as well as pharmaceutical compositions and methods of use thereof.

Description

Kinase inhibitor

This application claims priority to U.S. provisional application 62/292,259, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to a class of compounds which inhibit the activity of CDK4/6 kinase, or a pharmaceutically acceptable salt thereof, and as medicaments for the treatment of hyperproliferative diseases, such as cancer and inflammation.

Background

Hyperproliferative diseases such as cancer and inflammation have attracted the academic community to provide effective treatments for them. And efforts have been made in this regard to identify and target specific mechanisms that play a role in proliferative diseases.

The development of tumors is closely related to the genetic variation and abnormal regulation of cyclin-dependent kinases (CDKs) and their regulatory proteins, suggesting that CDK inhibitors may be effective anticancer therapies.

CDKs are serine/threonine protein kinases that are the prime movers for cell cycle and cell proliferation. CDKs regulate the initiation, progression and completion of the mammalian cell cycle and are critical for cell growth. Most known CDKs, including CDK1 through CDK9, are involved directly or indirectly in cell cycle progression. CDKs directly involved in cell cycle progression, such as CDK1-4 and CDK6, are classified as G1, S or G2M phase enzymes. Abnormal proliferation is a characteristic of cancer cells, and CDK dysfunction occurs at high frequency in many solid tumors.

Such therapies that target general CDKs or specific CDKs for the treatment of dysplastic diseases, such as cancer treatment, have great potential. CDK inhibitors may also be used to treat other diseases such as viral infections, autoimmune diseases and neurodegenerative diseases. CDK targeted therapies may also be used in combination with other therapeutic agents for the treatment of the above-mentioned disorders.

Therefore, compounds having CDK inhibitory activity are of great interest for the prevention and treatment of cancer. Although inhibitors of CDK4/6 have been reported in the literature, e.g., WO 2010075074, many have short half-lives or are toxic. Thus, there is an increasing need for new CDK4/6 inhibitors that have advantages in at least one of therapeutic efficacy, stability, selectivity, safety, pharmacodynamic and pharmacokinetic properties. The present invention relates to a novel class of CDK4/6 inhibitors.

Disclosure of Invention

The invention relates to a novel 6-5-membered fused azole ring derivative, a pharmaceutical composition thereof and application thereof as a medicament.

In one aspect, the invention provides a compound of formula (I) or (II):

or a pharmaceutically acceptable salt thereof, wherein,

q is selected from aryl and heteroaryl;

each R¹Independently selected from hydrogen, halogen, hydroxy, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di (alkyl) amino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R^xSubstituted with the substituent(s);

each R²Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, CN, NO₂、-NR^A1R^B1、-OR^A1、-S(O)_rR^A1、-S(O)₂OR^A1、-OS(O)₂R^A1、-P(O)R^A1R^B1、-P(O)(OR^A1)(OR^B1)、-C(O)R^A1、-C(O)OR^A1、-OC(O)R^A1、-C(O)NR^A1R^B1、-NR^A1C(O)R^B1、-OC(O)NR^A1R^B1、-NR^A1C(O)OR^B1、-NR^A1C(O)NR^A1R^B1、-NR^A1C(S)NR^A1R^B1、-S(O)_rNR^A1R^B1、-NR^A1S(O)_rR^B1、-NR^A1S(O)₂NR^A1R^B1、-S(O)(＝NR^E1)R^B1、-N＝S(O)R^A1R^B1、-NR^A1S(O)(＝NR^E1)R^B1、-S(O)(＝NR^E1)NR^A1R^B1、-NR^A1S(O)(＝NR^E1)NR^A1R^B1、-C(＝NR^E1)R^A1、-C(＝N-OR^B1)R^A1、-C(＝NR^E1)NR^A1R^B1、-NR^A1C(＝NR^E1)R^B1and-NR^A1C(＝NR^E1)NR^A1R^B1Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^xSubstituted with the substituent(s);

each R³Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, CN, NO₂、-NR^A2R^B2、-OR^A2、-S(O)_rR^A2、-S(O)₂OR^A2、-OS(O)₂R^A2、-P(O)R^A2R^B2、-P(O)(OR^A2)(OR^B2)、-C(O)R^A2、-C(O)OR^A2、-OC(O)R^A2、-C(O)NR^A2R^B2、-NR^A2C(O)R^B2、-OC(O)NR^A2R^B2、-NR^A2C(O)OR^B2、-NR^A2C(O)NR^A2R^B2、-NR^A2C(S)NR^A2R^B2、-S(O)_rNR^A2R^B2、-NR^A2S(O)_rR^B2、-NR^A2S(O)₂NR^A2R^B2、-S(O)(＝NR^E2)R^B2、-N＝S(O)R^A2R^B2、-NR^A2S(O)(＝NR^E2)R^B2、-S(O)(＝NR^E2)NR^A2R^B2、-NR^A2S(O)(＝NR^E2)NR^A2R^B2、-C(＝NR^E2)R^A2、-C(＝N-OR^B2)R^A2、-C(＝NR^E2)NR^A2R^B2、-NR^A2C(＝NR^E2)R^B2and-NR^A2C(＝NR^E2)NR^A2R^B2Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XSubstituted with the substituent(s);

each R⁴Selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, CN, NO₂、-NR^A3R^B3、-OR^A3、-S(O)_rR^A3、-S(O)₂OR^A3、-OS(O)₂R^A3、-P(O)R^A3R^B3、-P(O)(OR^A3)(OR^B3)、-C(O)R^A3、-C(O)OR^A3、-OC(O)R^A3、-C(O)NR^A3R^B3、-NR^A3C(O)R^B3、-OC(O)NR^A3R^B3、-NR^A3C(O)OR^B3、-NR^A3C(O)NR^A3R^B3、-NR^A3C(S)NR^A3R^B3、-S(O)_rNR^A3R^B3、-NR^A3S(O)_rR^B3、-NR^A3S(O)₂NR^A3R^B3、-S(O)(＝NR^E3)R^B3、-N＝S(O)R^A3R^B3、-NR^A3S(O)(＝NR^E3)R^B3、-S(O)(＝NR^E3)NR^A3R^B3、-NR^A3S(O)(＝NR^E3)NR^A3R^B3、-C(＝NR^E3)R^A3、-C(＝N-OR^B3)R^A3、-C(＝NR^E3)NR^A3R^B3、-NR^A3C(＝NR^E3)R^B3and-NR^A3C(＝NR^E3)NR^A3R^B3Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XSubstituted with the substituent(s);

each R⁵Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, CN, NO₂、-NR^A4R^B4、-(CH₂)_tNR^A4R^B4、-OR^A4、-S(O)_rR^A4、-S(O)₂OR^A4、-OS(O)₂R^A4、-P(O)R^A4R^B4、-P(O)(OR^A4)(OR^B4)、-C(O)R^A4、-C(O)OR^A4、-OC(O)R^A4、-C(O)NR^A4R^B4、-NR^A4C(O)R^B4、-OC(O)NR^A4R^B4、-NR^A4C(O)OR^B4、-NR^A4C(O)NR^A4R^B4、-NR^A4C(S)NR^A4R^B4、-S(O)_rNR^A4R^B4、-NR^A4S(O)_rR^B4、-NR^A4S(O)₂NR^A4R^B4、-S(O)(＝NR^E4)R^B4、-N＝S(O)R^A4R^B4、-NR^A4S(O)(＝NR^E4)R^B4、-S(O)(＝NR^E4)NR^A4R^B4、-NR^A4S(O)(＝NR^E4)NR^A4R^B4、-C(＝NR^E4)R^A4、-C(＝N-OR^B4)R^A4、-C(＝NR^E4)NR^A4R^B4、-NR^A4C(＝NR^E4)R^B4and-NR^A4C(＝NR^E4)NR^A4R^B4Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XSubstituted with the substituent(s);

each R^A1、R^A2、R^A3、R^A4、R^B1、R^B2、R^B3And R^B4Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R^XSubstituted with the substituent(s);

or each "R^A1And R^B1”、“R^A2And R^B2”、“R^A3And R^B3"or" R^A4And R^B4Taken together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0,1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may optionally be interrupted by 1,2 or 3R^XSubstituted by groups;

each R^E1、R^E2、R^E3And R^E4Independently selected from hydrogen, C_1-10Alkyl, CN, NO₂、-OR^a1、-SR^a1、-S(O)_rR^a1、-C(O)R^a1、-C(O)OR^a1、-C(O)NR^a1R^b1and-S (O)_rNR^a1R^b1；

Each R^XIndependently selected from C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, halogen, CN, NO₂、-(CR^c1R^d1)_tNR^a1R^b1、-(CR^c1R^d1)_tOR^b1、-(CR^c1R^d1)_tS(O)_rR^b1、-(CR^c1R^d1)_tS(O)₂OR^b1、-(CR^c1R^d1)_tOS(O)₂R^b1、-(CR^c1R^d1)_tP(O)R^a1R^b1、-(CR^c1R^d1)_tP(O)(OR^a1)(OR^b1)、-(CR^c1R^d1)_tC(O)R^a1、-(CR^c1R^d1)_tC(O)OR^b1、-(CR^c1R^d1)_tOC(O)R^b1、-(CR^c1R^d1)_tC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)R^b1、-(CR^c1R^d1)_tOC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)OR^b1、-(CR^c1R^d1)_tNR^a1C(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(S)NR^a1R^b1、-(CR^c1R^d1)_tS(O)_rNR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)_rR^b1、-(CR^c1R^d1)_tNR^a1S(O)₂NR^a1R^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tN＝S(O)R^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tC(＝NR^e1)R^a1、-(CR^c1R^d1)_tC(＝N-OR^b1)R^a1、-(CR^c1R^d1)_tC(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(＝NR^e1)R^b1And- (CR)^c1R^d1)_tNR^a1C(＝NR^e1)NR^a1R^b1Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^YSubstituted with the substituent(s);

each R^a1And R^b1Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R^YSubstituted with the substituent(s);

or R^a1And R^b1Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0,1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may optionally be interrupted by 1,2 or 3R^YSubstituted by groups;

each R^c1And R^d1Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R^YSubstituted with the substituent(s);

or R^c1And R^d1Together with the carbon atom or atoms to which they are attached, form a 3-12 membered ring containing 0,1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may beOptionally substituted by 1,2 or 3R^YSubstituted by groups;

each R^e1Independently selected from hydrogen, C_1-10Alkyl radical, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, CN, NO₂、-OR^a2、-SR^a2、-S(O)_rR^a2、-C(O)R^a2、-C(O)OR^a2、-S(O)_rNR^a2R^b2and-C (O) NR^a2R^b2；

Each R^YIndependently selected from C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, halogen, CN, NO₂、-(CR^c2R^d2)_tNR^a2R^b2、-(CR^c2R^d2)_tOR^b2、-(CR^c2R^d2)_tS(O)_rR^b2、-(CR^c2R^d2)_tS(O)₂OR^b2、-(CR^c2R^d2)_tOS(O)₂R^b2、-(CR^c2R^d2)_tP(O)R^a2R^b2、-(CR^c2R^d2)_tP(O)(OR^a2)(OR^b2)、-(CR^c2R^d2)_tC(O)R^a2、-(CR^c2R^d2)_tC(O)OR^b2、-(CR^c2R^d2)_tOC(O)R^b2、-(CR^c2R^d2)_tC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)R^b2、-(CR^c2R^d2)_tOC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)OR^b2、-(CR^c2R^d2)_tNR^a2C(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(S)NR^a2R^b2、-(CR^c2R^d2)_tS(O)_rNR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)_rR^b2、-(CR^c2R^d2)_tNR^a2S(O)₂NR^a2R^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tN＝S(O)R^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tC(＝NR^e2)R^a2,-(CR^c2R^d2)_tC(＝N-OR^b2)R^a2、-(CR^c2R^d2)_tC(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(＝NR^e2)R^b2And- (CR)^c2R^d2)_tNR^a2C(＝NR^e2)NR^a2R^b2Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from OH, CN, amino, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

each R^a2And R^b2Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

or R^a2And R^b2Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0,1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may optionally be substituted with 1-2 heteroatoms independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

each R^c2And R^d2Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkyl radicalsAmino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

or R^c2And R^d2Together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0,1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may optionally be substituted by 1 or 2 heteroatoms independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

each R^e2Independently selected from hydrogen, CN, NO₂、C_1-10Alkyl radical, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, -C (O) C_1-4Alkyl, -C (O) C_3-10Cycloalkyl, -C (O) OC_1-4Alkyl, -C (O) OC_3-10Cycloalkyl, -C (O) N (C)_1-4Alkyl radical)₂、-C(O)N(C_3-10Cycloalkyl radicals₂、-S(O)₂C_1-4Alkyl, -S (O)₂C_3-10Cycloalkyl, -S (O)₂N(C_1-4Alkyl radical)₂and-S (O)₂N(C_3-10Cycloalkyl radicals₂；

m is selected from 0,1, 2,3 and 4;

n is selected from 0,1 and 2;

p is selected from 0,1 and 2;

each r is independently selected from 0,1 and 2;

each t is independently selected from 0,1, 2,3, and 4.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method for modulating CDK4/6, comprising administering to a system or subject in need thereof a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, thereby modulating CDK 4/6.

In another aspect, the invention also provides a method of treating, ameliorating or preventing a disorder responsive to inhibition of CDK4/6 comprising administering to a system or subject in need thereof an effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent, for treating the disorder described above.

Alternatively, the invention provides the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder mediated by CDK 4/6. In certain embodiments, the compounds may be used alone or in combination with a second therapeutic agent in the treatment of a CDK4/6 mediated disorder.

Alternatively, the present invention provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in the treatment of a CDK4/6 mediated disorder.

In particular, wherein the condition includes, but is not limited to, an autoimmune disease, a transplantation disease, an infectious disease, or a cell proliferative disorder disease.

In addition, the present invention provides methods of treating a cell proliferative disorder comprising administering to a system or subject in need thereof an effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, optionally in combination with a second therapeutic agent, to treat the disorder.

Alternatively, the present invention provides the use of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a cell proliferative disorder. In particular embodiments, the compounds can be used alone or in combination with a second therapeutic agent to treat a cell proliferative disorder.

In particular, wherein the cell proliferative disorder includes, but is not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of the breast, kidney, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tract.

In the above methods of using the compounds of the present invention, a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be administered to a system comprising cells or tissues, or to an individual including a mammalian individual, such as a human or animal individual.

Term(s) for

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this patent belongs. All patents, patent applications, published publications, etc. referred to herein are incorporated by reference in their entirety unless otherwise indicated. As used in this patent, the same terms are defined differently than the definitions in this section.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claims. In this application, the use of the singular includes the plural unless otherwise indicated. It is noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is also noted that "or" represents "and/or" unless stated otherwise. Furthermore, "comprising," "including," and like terms are not intended to be limiting.

Standard definitions of chemical terms are referred to in the reference books, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY, 4 th edition. Volumes "A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, the conventional techniques of mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet spectroscopy, and pharmacology used in this patent are prior art. Unless specifically defined, the nomenclature, protocols, and techniques involved in analytical chemistry, synthetic organic chemistry, pharmaceutical and pharmaceutical chemistry are those known in the art. Standard techniques are available for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and administration, and treatment of patients. The reaction and purification techniques may be carried out with reference to the manufacturer's instructions, or with reference to known, commonly used techniques, or with reference to the methods described in this patent. The techniques and procedures described above can be performed using methods that are conventional and well known in the literature cited in this specification. In the specification, groups and substituents may be selected by one skilled in the art to form stable structures and compounds.

When a substituent is referred to by a formula, the substituents in the formula are written from left to right as they are from right to left. As a non-limiting example, CH₂O and OCH₂The same is true.

As used herein, "optionally substituted" includes unsubstituted or substituted. "substituted" means that the hydrogen atom is replaced with a substituent. It is noted that substituents on a particular atom are constrained by their valency. In the definition section, "C_i-j"refers to a range including a start point and an end point, where i and j are both integers indicating the number of carbon atoms. E.g. C_1-4，C_1-10，C_3-10And the like.

"alkyl", alone or in combination with other terms, refers to branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Unless otherwise indicated, "alkyl" means C_1-10An alkyl group. For example, "C_1-6C in alkyl₁-C₆"refers to a linear or branched arrangement of groups having 1,2,3,4, 5 or 6 carbon atoms. For example, "C_1-8Alkyl "includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl.

"cycloalkyl" whether used alone or in combination with other terms, refers to a monocyclic or bridged hydrocarbon system. Monocyclic cycloalkyl groups contain 3 to 10 carbon atoms, no heteroatoms, no double bonds. Examples of monocyclic systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Monocyclic cycloalkyl contains one or two alkylene bridges, each of which contains 1,2 or 3 carbon atoms, which are bonded to two non-adjacent carbon atoms in the ring system. Representative examples of bridged ring hydrocarbon systems include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane, bicyclo [4.2.1] nonane, tricyclo [3.3.1.03,7] nonane, and tricyclo [3.3.1.13,7] decane (adamantane). The monocyclic and bridged hydrocarbon rings can be attached to the parent ring through any suitable atom in the ring system.

"alkenyl", alone or in combination with other terms, refers to a nonaromatic, straight chain, branched or cyclic hydrocarbon radical containing from 2 to 10 carbon atoms and having at least one carbon-carbon double bond. In some embodiments, 1 carbon-carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C_2－6Alkenyl "means alkenyl containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain a double bond, and substituted alkenyl groups, if indicated, may be substituted.

"alkynyl", whether used alone or in combination with other terms, refers to a straight, branched or cyclic hydrocarbon radical containing from 2 to 10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, there may be 3 carbon-carbon triple bonds. Thus, "C_2-6Alkynyl "refers to alkynyl groups containing 2-6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The straight, branched or cyclic portion of the alkynyl group may contain a triple bond, and a substituted alkynyl group, if indicated, may be substituted.

"halogen" means fluorine, chlorine, bromine, iodine.

"alkoxy", used alone or in combination with other terms, refers to an alkyl group attached to an oxygen atom by a single bond. The alkoxy group is attached to the molecule through an oxygen atom. Alkoxy groups may be represented as-O-alkyl. "C_1-10Alkoxy "means containing 1 to 10 carbon atomsAlkoxy, which may be linear or branched. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like.

"Cycloalkoxy", used alone or in combination with other terms, means a cycloalkyl group attached by a single bond to an oxygen atom. The cycloalkoxy group is attached to the molecule through an oxygen atom. Cycloalkoxy can be represented as-O-cycloalkyl. "C_3-10Cycloalkoxy "means a cycloalkoxy group containing 3 to 10 carbon atoms. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

"alkylthio", used alone or in combination with other terms, refers to an alkyl group attached by a single bond to a sulfur atom. Alkylthio groups are attached to the molecule through a sulfur atom. Alkylthio groups may be represented by-S-alkyl. "C_1-10Alkylthio "refers to an alkylthio group containing 1 to 10 carbon atoms and can be a straight chain or branched structure. Alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.

"Cycloalkylsulfanyl", used alone or in combination with other terms, means a cycloalkyl group attached by a single bond to a sulfur atom. The cycloalkylthio group is bonded to the molecule through a sulfur atom. The cycloalkylthio group may be represented as-S-cycloalkyl. "C_3-10Cycloalkylthio "means a cycloalkylthio group containing 3 to 10 carbon atoms. Cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.

"alkylamino", used alone or in combination with other terms, refers to an alkyl group attached to a nitrogen atom by a single bond. The alkylamino group is attached to the molecule through a nitrogen atom. Alkylamino can be represented as-NH (alkyl). "C_1-10Alkylamino "refers to alkylamino groups containing 1 to 10 carbon atoms, which may be straight chain or branched. Alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino and the like.

"Cycloalkylamino", used alone or in combination with other terms, refers to a cycloalkyl group attached to a nitrogen atom by a single bond. The cycloalkylamino group is attached to the molecule through a nitrogen atom. The cycloalkylamino group can representis-NH (cycloalkyl). "C_3-10Cycloalkylamino "refers to cycloalkylamino groups containing 3 to 10 carbon atoms. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino and the like.

"Di (alkyl) amino", used alone or in combination with other terms, refers to two alkyl groups attached to a nitrogen atom by a single bond. The di (alkyl) amino group is attached to the molecule through a nitrogen atom. The di (alkyl) amino group may be represented by-N (alkyl)₂. ' two (C)_1-10Alkyl) amino "means a di (C) group in which the two alkyl moieties each contain 1 to 10 carbon atoms_1-10Alkyl) amino, which may be linear or branched.

"aryl" includes: 5-and 6-membered aromatic carbocyclic rings, such as phenyl; bicyclic rings having at least one aromatic carbon ring, such as naphthyl, indane and 1,2,3, 4-tetrahydroquinoline, and tricyclic rings having at least one aromatic carbon ring, such as fluorene. Aryl substituents are considered to be linked through an aromatic ring if they are bicyclic or tricyclic and at least one of the rings is non-aromatic.

For example, aryl includes 5-and 6-membered aromatic carbocyclic rings fused to a 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, provided that the site of attachment is an aromatic carbocyclic ring. Divalent radicals, which are formed from substituted benzene derivatives and have free valence electrons present at the ring atoms, are designated as substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose name ends with "-yl", which are obtained by removing one more hydrogen atom from a carbon atom containing a free valence electron, are named after the name of the monovalent radical plus "-idene (-idene)", for example, naphthyl, which has two attachment sites, is called naphthylidene. The definition of aryl, however, does not include, nor overlap with, heteroaryl, and is defined individually as follows. Thus, if one or more aromatic carbocyclic rings are fused to an aromatic ring of a heterocyclic ring, the ring system formed should be considered heteroaryl as defined herein rather than aryl.

"heteroaryl" means

A 5-to 8-membered aromatic monocyclic ring, which contains 1 to 4, and in certain embodiments 1 to 3, heteroatoms selected from N, O and S, the remainder being carbon atoms;

an 8-to 12-membered bicyclic ring containing 1 to 4, and in certain embodiments 1 to 3, heteroatoms selected from N, O and S, the remainder being carbon atoms, and wherein at least one heteroatom is present in the aromatic ring; and

11-to 14-membered tricyclic rings. The ring contains from 1 to 4, and in certain embodiments from 1 to 3, heteroatoms selected from N, O and S, the remainder being carbon atoms, and at least one of the heteroatoms is present in the aromatic ring.

When the total number of S and O atoms in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 1.

Examples of heteroaryl groups include, but are not limited to (the numbering of the attachment site is preferred, as in position 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 1-pyrazolyl, 2, 3-pyrazolyl, 2, 4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolinyl, pyridazinyl (pyridizinyl), triazolyl, quinolinyl, pyrazolyl, and 5,6,7, 8-tetrahydroisoquinolinyl.

Further, heteroaryl groups include, but are not limited to, pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinolyl, and isoquinolyl groups. As defined below for heterocyclic groups, "heteroaryl" includes N-oxide derivatives of nitrogen-containing heteroaryl groups.

The nomenclature of a monovalent heteroaryl group ends with the "radical", the divalent group derived by removing a hydrogen atom from a carbon atom containing a free valence electron, is that name given to the monovalent group plus a "ene" (for example: the pyridyl group having two attachment sites is called a pyridylidene. The definition of heteroaryl does not include, nor overlap with, aryl as defined above.

If the heteroaryl substituent is a bicyclo or tricyclic ring, and at least one of the rings is non-aromatic or contains no heteroatoms, it is generally considered to be linked via an aromatic ring or a heteroatom-containing ring, respectively.

"heterocycle" (and derivatives thereof such as "heterocyclic" or "heterocyclyl") refers broadly to a single cyclic aliphatic hydrocarbon, typically having from 3 to 12 ring atoms, containing at least 2 carbon atoms, and further containing from 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and also to combinations comprising at least one of the foregoing heteroatoms. Alternatively, the heterocyclic ring as defined above may be a polycyclic ring system (e.g. bicyclic) wherein two or more rings are present in the form of a parallel or bridged ring or spiro ring wherein at least one ring contains one or more heteroatoms independently selected from oxygen, sulfur, nitrogen. "heterocycle" also refers to a 5-to 7-membered heterocyclic ring fused to 5-and 6-membered aromatic carbocyclic rings containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, provided that the site of attachment is on the heterocyclic ring. Heterocycles may be saturated or contain one to more double bonds (i.e., partially unsaturated). The heterocyclic ring may be substituted with oxo (oxo). Either the carbon atom or the heteroatom of the heterocycle may be the attachment site, provided that a stable structure is formed. When a substituent is present on the heterocycle, the substituent may be attached to any heteroatom or carbon atom on the heterocycle, provided that a stable chemical structure is formed. The heterocyclic and heteroaryl definitions described herein do not overlap.

Suitable heterocycles include, for example (attachment site is preferably 1) 1-pyrrolidinyl, 2,4- (imidazolinyl), 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl and 2, 5-piperazinyl, 1, 4-piperazinyl, 2, 3-pyridazinyl. Also contemplated are morpholinyl groups, including 2-morpholinyl and 3-morpholinyl (oxygen atom position numbering is preferably 1). Substituted heterocycles also include ring systems substituted with one or more oxo groups, such as piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1, 1-dioxo-1-thiomorpholinyl. The bis-heterocyclic compounds include, for example:

as used herein, "aryl-alkyl" refers to an aryl-substituted alkyl group. Exemplary aralkyl groups include benzyl, phenethyl, naphthylmethyl, and the like. In some embodiments, aralkyl groups contain 7 to 20 or 7 to 11 carbon atoms. When using "aryl radicals C_1-4Alkyl "in which" C_1-4"refers to the number of carbon atoms in the alkyl portion rather than the aryl portion.

As used herein, "heterocyclyl-alkyl" refers to a heterocyclyl-substituted alkyl group. When using "heterocyclyl-C_1-4Alkyl "in which" C_1-4"refers to the number of carbon atoms in the alkyl moiety rather than in the heterocyclyl moiety.

As used herein, "cycloalkyl-alkyl" refers to a cycloalkyl-substituted alkyl group. When using "C_3-10cycloalkyl-C_1-4Alkyl "in which" C_3-10"refers to the number of carbon atoms in the cycloalkyl moiety rather than the alkyl moiety. Wherein "C_1-4"refers to the number of carbon atoms in the alkyl moiety rather than the cycloalkyl moiety.

As used herein, "heteroaryl-alkyl" refers to heteroaryl-substituted alkyl. When using "heteroaryl-C_1-4Alkyl "in which" C_1-4"refers to the number of carbon atoms in the alkyl moiety rather than in the heteroaryl moiety.

To avoid ambiguity, for example: when alkyl, cycloalkyl, heterocyclyl, aryl and/or heteroaryl substituents thereof are mentioned, it is meant that each of these groups is substituted individually or that these groups are mixed. That is: if R is¹Is aryl-C_1-4The alkyl, aryl moieties may be unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R^xMay also be unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^xA substituent of (1).

"pharmaceutically acceptable salt" refers to salts with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. The salt of an inorganic base may be selected, for example, from: aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, and zinc salts. Further, the salt of a pharmaceutically acceptable inorganic base may be selected from ammonium, calcium, magnesium, potassium and sodium salts. One or more crystal structures may be present in the solid salt, as well as in the form of hydrates. The pharmaceutically acceptable salts of organic non-toxic bases may be selected, for example, from: primary, secondary and tertiary amine salts, the substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.

When the compound referred to in this patent is a base, it is necessary to prepare a salt thereof with at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids. For example, selected from the group consisting of acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. In some embodiments, these acids may be selected, for example: citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acids.

By "administering" or "administration" of a compound or a pharmaceutically acceptable salt thereof is meant providing a compound of the invention or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

An "effective amount" is an amount of a compound or a pharmaceutically acceptable salt thereof that is capable of eliciting a biological or medical response in a tissue, system, animal or human that is observable by a researcher, veterinarian, clinician or other clinician.

The "composition" includes: the invention may take the form of a kit, article of manufacture, or any combination thereof. The pharmaceutical composition comprises: products comprising the active ingredient and an inert ingredient as a carrier, as well as products produced by any two or more of the ingredients, directly or indirectly, by combination, complexation or aggregation, or by dissociation of one or more of the ingredients, or by other types of reactions or interactions of one or more of the ingredients.

By "pharmaceutically acceptable" is meant compatible with the other ingredients of the formulation and not unacceptably toxic to the subject.

"subject" refers to a subject having a disease, disorder, or the like, and includes mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian family: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cattle, horses, sheep's yang, goats, pigs; domestic animals such as rabbits, dogs, and cats; the experimental animals include rodents such as rats, mice, guinea pigs, and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In one embodiment of the invention, the mammal is a human.

"treating" includes alleviating, alleviating or ameliorating a disease or condition, preventing other conditions, ameliorating or preventing a metabolic factor underlying a condition, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, alleviating a disease or condition, promoting remission of a disease or condition, or arresting the signs of a disease or condition, and extends to include prevention. "treating" also includes achieving a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the condition being treated. In addition, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and amelioration of the disease in the patient is observed, although the patient may still be suffering from the underlying disease. Prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a disease, or the use of a patient presenting with one or more physiological conditions of a disease, although the disease has not yet been diagnosed.

"protecting group" (Pg) refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. For example, "amino protecting group" refers to an amino group attached to a compound that blocks or protects the compoundA substituent of a radical functional group. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-Butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and-9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a class of hydroxy substituents that are effective in blocking or protecting the hydroxy function. Suitable protecting groups include, but are not limited to, acetyl and silyl groups. "carboxy protecting group" refers to a class of carboxy substituents that function effectively to block or protect a carboxy group. Common carboxyl protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For general description and instructions for use of protecting groups, see references: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991。

"NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzoyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, t-pentyloxycarbonyl, t-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropyloxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, benzhydryl, trityl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N, n-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3-dimethyl-5-oxocyclohexylidene, diphenylphosphoryl, dibenzylphosphono, 5-methyl-2-oxo-2H-l, 3-dioxy-4-ylmethyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

"C (O) OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1-dimethylpropyl, n-butyl, t-butyl, phenyl, naphthyl, benzyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis (p-methoxyphenyl) methyl, acetylmethyl, phenacyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2, 2-trichloroethyl, 2- (trimethylsilyl) ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, Benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

"OH or SH" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 2,2, 2-tribromoethoxycarbonyl, 2- (trimethylsilane) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, N-phenyloxycarbonyl, N-O-carbonyl, N-phenyloxycarbonyl, N-O-carbonyl, N-O-C, O-C-O, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2, 2-trichloroethyl, 2-trimethylsilylethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2, 2-trichloro-ethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 1-dimethyl-2-propenyl, 3-methyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 2-ethoxymethyl, 2, 2-methyl, 2-ethoxymethyl, 2-methyl, and a, 1-ethoxyethyl group, methanesulfonyl group, p-toluenesulfonyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, diethylisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, diphenylmethylsilyl group and tert-butylmethoxyphenylsilyl group.

Geometric isomers may exist in the compounds of the present invention. Compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in either the E or Z configuration, where "E" represents the preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond and "Z" represents the preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, as defined by Cahn-Ingold-Prelog preference. The compounds of the invention may also exist as mixtures of "E" and "Z" isomers. The substituents around the cycloalkyl or heterocyclyl group may be in either the cis or trans configuration. In addition, the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. Two substituents around a single ring in an adamantane ring system are designated in either the Z or E relative configuration. See, for example, C.D.Jones, M.Kaselj, R.N.Salvatore, W.J.le Noble J.org.chem.1998,63, 2758-.

Compounds of the invention may contain asymmetrically substituted carbon atoms of R or S configuration, "R" and "S" are defined in IUPAC 1974 Recommendations for Section E, functional Stereochemistry, Pure appl. chem. (1976)45, 13-10. Compounds containing asymmetrically substituted carbon atoms are racemates if the amounts of R and S configuration are the same. If one of the configurations is present in a greater amount than the other configuration, the configuration of the chiral carbon atom is represented by the more abundant configuration, preferably with an enantiomeric excess of about 85-90%, more preferably about 95-99%, and even more preferably 99% or more. Thus, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotopically enriched or labelled compounds

The compounds of the invention may exist in isotopically-labelled or enriched forms containing one or more atoms of different mass and mass numbers from the atom mass and mass number most prevalent in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to,²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、³²P、³⁵S、¹⁸F、³⁶cl and¹²⁵I. other isotopes and/or other atoms containing these atoms are also within the scope of the present invention.

In another embodiment, the isotopically labeled compound comprises deuterium (A), (B), (C) and D) and (C)²H) Tritium (a)³H) Or¹⁴Isotope of C. Isotopically-labeled compounds of the present invention can be obtained by employing procedures well known to those skilled in the art. These isotopically labeled compounds can be obtained by substituting a non-labeling reagent with an isotopically labeled reagent by referring to the examples and reaction schemes of the present invention. In certain examples, compounds can be treated with isotopic labeling agents to replace atoms with isotopic atoms, e.g., replacement of hydrogen with deuterium can be accomplished by deuterated acids such as D₂SO₄/D₂And exchanging the action of O. In addition, relevant synthetic steps and intermediates can be found, for example, in Lizondo, J et al, Drugs Fut,21(11),1116 (1996); brickner, S J et al, J Med Chem,39(3),673 (1996); mallesham, B et al, Org Lett,5(7),963 (2003); PCT publication nos. WO1997010223, WO2005099353, WO1995007271, WO 2006008754; U.S. patent nos. 7538189, 7534814, 7531685, 7528131, 7521421, 7514068, 7511013; and U.S. patent application publication nos. 20090137457, 20090131485, 20090131363, 20090118238, 20090111840, 20090105338, 20090105307, 20090105147, 20090093422, 20090088416, and 20090082471, for specific methods see references.

Isotopically-labelled compounds of the present invention are useful as standards for binding assays for determining the effectiveness of CDK4/6 inhibitors. Isotopically-containing compounds are useful in pharmaceutical research, evaluating the mechanism of action and metabolic pathways of non-isotopically-labeled parent compounds, and investigating the in vivo metabolic turnover of compounds (Blake et al.J.pharm.Sci.64,3,367-391 (1975)). Such metabolic studies are important for the design of safe and effective therapeutic agents, and can be judged to be toxic or carcinogenic to the in vivo active compound administered to the patient or to the metabolite of the parent compound (Foster et al, Advances in Drug Research Vol.14, pp.2-36, Academic press, London, 1985; Kato et al, J.Labelled Comp.Radiopharmaceut.,36(10):927-932 (1995); Kushner et al, Can.J.Physiol.Pharmacol,77,79-88 (1999)).

In addition, drugs containing non-radioactive isotopes, such as deuterated drugs, known as "heavy drugs," are useful for treating diseases and disorders associated with CDK4/6 activity. The proportion of a certain isotope in a compound that exceeds its natural abundance is called enrichment. The amount of enrichment is, for example, from about 0.5, 1,2,3,4, 5,6,7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to 100 mol%. In mammals, the replacement of 15% of the common atoms with heavy isotopes is effective and can last from days to weeks, including rodents and dogs, with fewer adverse effects (zajka D M and Finkel a J, ann.n.y.acad.sci.196084: 770; Thomson J F, ann.new York acad.sci 196084: 736; Czakja D M et al, am.j.physiol.1961201: 357). Replacing up to 15-23% of the body fluids in humans with deuteration does not cause toxicity (Blagojevic N et al in "Dosimetry & Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O eds.1994.advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.23:251(1997))

Suitable stable isotopic labels for drugs can alter the physicochemical properties of the drug, such as pKa and liquid solubility. If isotopic substitution affects the region associated with ligand-receptor interaction, then these effects and changes may affect the pharmacodynamic response of the drug molecule. Certain physical properties of stable isotope-labeled molecules differ from unlabeled molecules, while chemical and biological properties are the same, but only one important difference: any chemical bond containing a heavy isotope and another atom is stronger than a light isotope due to the increased mass of the heavy isotope. Accordingly, the presence of isotopes at the metabolic or enzymatic conversion sites slows the reaction and may alter its pharmacokinetic or pharmacodynamic properties compared to non-isotopically labeled compounds.

In embodiment (1), the present invention provides a compound represented by formula (I) or (II):

or a pharmaceutically acceptable salt thereof, wherein,

q is selected from aryl and heteroaryl;

each R¹Independently selected from hydrogen, halogen, hydroxy, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di (alkyl) amino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R^xSubstituted with the substituent(s);

each R²Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, CN, NO₂、-NR^A1R^B1、-OR^A1、-S(O)_rR^A1、-S(O)₂OR^A1、-OS(O)₂R^A1、-P(O)R^A1R^B1、-P(O)(OR^A1)(OR^B1)、-C(O)R^A1、-C(O)OR^A1、-OC(O)R^A1、-C(O)NR^A1R^B1、-NR^A1C(O)R^B1、-OC(O)NR^A1R^B1、-NR^A1C(O)OR^B1、-NR^A1C(O)NR^A1R^B1、-NR^A1C(S)NR^A1R^B1、-S(O)_rNR^A1R^B1、-NR^A1S(O)_rR^B1、-NR^A1S(O)₂NR^A1R^B1、-S(O)(＝NR^E1)R^B1、-N＝S(O)R^A1R^B1、-NR^A1S(O)(＝NR^E1)R^B1、-S(O)(＝NR^E1)NR^A1R^B1、-NR^A1S(O)(＝NR^E1)NR^A1R^B1、-C(＝NR^E1)R^A1、-C(＝N-OR^B1)R^A1、-C(＝NR^E1)NR^A1R^B1、-NR^A1C(＝NR^E1)R^B1and-NR^A1C(＝NR^E1)NR^A1R^B1Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^xSubstituted with the substituent(s);

each R³Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, CN, NO₂、-NR^A2R^B2、-OR^A2、-S(O)_rR^A2、-S(O)₂OR^A2、-OS(O)₂R^A2、-P(O)R^A2R^B2、-P(O)(OR^A2)(OR^B2)、-C(O)R^A2、-C(O)OR^A2、-OC(O)R^A2、-C(O)NR^A2R^B2、-NR^A2C(O)R^B2、-OC(O)NR^A2R^B2、-NR^A2C(O)OR^B2、-NR^A2C(O)NR^A2R^B2、-NR^A2C(S)NR^A2R^B2、-S(O)_rNR^A2R^B2、-NR^A2S(O)_rR^B2、-NR^A2S(O)₂NR^A2R^B2、-S(O)(＝NR^E2)R^B2、-N＝S(O)R^A2R^B2、-NR^A2S(O)(＝NR^E2)R^B2、-S(O)(＝NR^E2)NR^A2R^B2、-NR^A2S(O)(＝NR^E2)NR^A2R^B2、-C(＝NR^E2)R^A2、-C(＝N-OR^B2)R^A2、-C(＝NR^E2)NR^A2R^B2、-NR^A2C(＝NR^E2)R^B2and-NR^A2C(＝NR^E2)NR^A2R^B2Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XSubstituted with the substituent(s);

each R⁴Selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, CN, NO₂、-NR^A3R^B3、-OR^A3、-S(O)_rR^A3、-S(O)₂OR^A3、-OS(O)₂R^A3、-P(O)R^A3R^B3、-P(O)(OR^A3)(OR^B3)、-C(O)R^A3、-C(O)OR^A3、-OC(O)R^A3、-C(O)NR^A3R^B3、-NR^A3C(O)R^B3、-OC(O)NR^A3R^B3、-NR^A3C(O)OR^B3、-NR^A3C(O)NR^A3R^B3、-NR^A3C(S)NR^A3R^B3、-S(O)_rNR^A3R^B3、-NR^A3S(O)_rR^B3、-NR^A3S(O)₂NR^A3R^B3、-S(O)(＝NR^E3)R^B3、-N＝S(O)R^A3R^B3、-NR^A3S(O)(＝NR^E3)R^B3、-S(O)(＝NR^E3)NR^A3R^B3、-NR^A3S(O)(＝NR^E3)NR^A3R^B3、-C(＝NR^E3)R^A3、-C(＝N-OR^B3)R^A3、-C(＝NR^E3)NR^A3R^B3、-NR^A3C(＝NR^E3)R^B3and-NR^A3C(＝NR^E3)NR^A3R^B3Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XSubstituted with the substituent(s);

each R⁵Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, CN, NO₂、-NR^A4R^B4、-(CH₂)_tNR^A4R^B4、-OR^A4、-S(O)_rR^A4、-S(O)₂OR^A4、-OS(O)₂R^A4、-P(O)R^A4R^B4、-P(O)(OR^A4)(OR^B4)、-C(O)R^A4、-C(O)OR^A4、-OC(O)R^A4、-C(O)NR^A4R^B4、-NR^A4C(O)R^B4、-OC(O)NR^A4R^B4、-NR^A4C(O)OR^B4、-NR^A4C(O)NR^A4R^B4、-NR^A4C(S)NR^A4R^B4、-S(O)_rNR^A4R^B4、-NR^A4S(O)_rR^B4、-NR^A4S(O)₂NR^A4R^B4、-S(O)(＝NR^E4)R^B4、-N＝S(O)R^A4R^B4、-NR^A4S(O)(＝NR^E4)R^B4、-S(O)(＝NR^E4)NR^A4R^B4、-NR^A4S(O)(＝NR^E4)NR^A4R^B4、-C(＝NR^E4)R^A4、-C(＝N-OR^B4)R^A4、-C(＝NR^E4)NR^A4R^B4、-NR^A4C(＝NR^E4)R^B4and-NR^A4C(＝NR^E4)NR^A4R^B4Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XSubstituted with the substituent(s);

each R^A1、R^A2、R^A3、R^A4、R^B1、R^B2、R^B3And R^B4Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R^XSubstituted with the substituent(s);

or each "R^A1And R^B1”、“R^A2And R^B2”、“R^A3And R^B3"or" R^A4And R^B4Taken together with the atom or atoms to which they are attached, form a 4-12 membered heterocyclic ring containing 0,1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may optionally be interrupted by 1,2 or 3R^XSubstituted by groups;

each R^E1、R^E2、R^E3And R^E4Independently selected from hydrogen, C_1-10Alkyl, CN, NO₂、-OR^a1、-SR^a1、-S(O)_rR^a1、-C(O)R^a1、-C(O)OR^a1、-C(O)NR^a1R^b1and-S (O)_rNR^a1R^b1；

Each R^XIndependently selected from C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, halogen, CN, NO₂、-(CR^c1R^d1)_tNR^a1R^b1、-(CR^c1R^d1)_tOR^b1、-(CR^c1R^d1)_tS(O)_rR^b1、-(CR^c1R^d1)_tS(O)₂OR^b1、-(CR^c1R^d1)_tOS(O)₂R^b1、-(CR^c1R^d1)_tP(O)R^a1R^b1、-(CR^c1R^d1)_tP(O)(OR^a1)(OR^b1)、-(CR^c1R^d1)_tC(O)R^a1、-(CR^c1R^d1)_tC(O)OR^b1、-(CR^c1R^d1)_tOC(O)R^b1、-(CR^c1R^d1)_tC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)R^b1、-(CR^c1R^d1)_tOC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)OR^b1、-(CR^c1R^d1)_tNR^a1C(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(S)NR^a1R^b1、-(CR^c1R^d1)_tS(O)_rNR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)_rR^b1、-(CR^c1R^d1)_tNR^a1S(O)₂NR^a1R^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tN＝S(O)R^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tC(＝NR^e1)R^a1、-(CR^c1R^d1)_tC(＝N-OR^b1)R^a1、-(CR^c1R^d1)_tC(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(＝NR^e1)R^b1And- (CR)^c1R^d1)_tNR^a1C(＝NR^e1)NR^a1R^b1Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^YSubstituted with the substituent(s);

each R^a1And R^b1Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R^YSubstituted with the substituent(s);

or R^a1And R^b1Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0,1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may optionally be substituted with 1,2 or 3 heteroatoms selected from R^YSubstituent group(s) takeGeneration;

each R^c1And R^d1Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R^YSubstituted with the substituent(s);

or R^c1And R^d1Together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0,1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may optionally be interrupted by 1,2 or 3R^YSubstituted by groups;

each R^e1Independently selected from hydrogen, C_1-10Alkyl radical, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, CN, NO₂、-OR^a2、-SR^a2、-S(O)_rR^a2、-C(O)R^a2、-C(O)OR^a2、-S(O)_rNR^a2R^b2and-C (O) NR^a2R^b2；

Each R^YIndependently selected from C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl-C_1-4Alkyl, halogen, CN, NO₂、-(CR^c2R^d2)_tNR^a2R^b2、-(CR^c2R^d2)_tOR^b2、-(CR^c2R^d2)_tS(O)_rR^b2、-(CR^c2R^d2)_tS(O)₂OR^b2、-(CR^c2R^d2)_tOS(O)₂R^b2、-(CR^c2R^d2)_tP(O)R^a2R^b2、-(CR^c2R^d2)_tP(O)(OR^a2)(OR^b2)、-(CR^c2R^d2)_tC(O)R^a2、-(CR^c2R^d2)_tC(O)OR^b2、-(CR^c2R^d2)_tOC(O)R^b2、-(CR^c2R^d2)_tC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)R^b2、-(CR^c2R^d2)_tOC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)OR^b2、-(CR^c2R^d2)_tNR^a2C(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(S)NR^a2R^b2、-(CR^c2R^d2)_tS(O)_rNR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)_rR^b2、-(CR^c2R^d2)_tNR^a2S(O)₂NR^a2R^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tN＝S(O)R^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tC(＝NR^e2)R^a2,-(CR^c2R^d2)_tC(＝N-OR^b2)R^a2、-(CR^c2R^d2)_tC(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(＝NR^e2)R^b2And- (CR)^c2R^d2)_tNR^a2C(＝NR^e2)NR^a2R^b2Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from OH, CN, amino, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

each R^a2And R^b2Independently selected from hydrogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

or R^a2And R^b2Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0,1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may optionally be substituted with 1 or 2 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorusHalogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

each R^c2And R^d2Independently selected from hydrogen, halogen, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio radical, C_1-10Alkylamino radical, C_3-10Cycloalkylamino, di (C)_1-10Alkyl) amino, heterocyclyl-C_1-4Alkyl, aryl-C_1-4Alkyl, heteroaryl and heteroaryl-C_1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

or R^c2And R^d2Together with the carbon atom or atoms to which they are attached, form a 3-12 membered ring containing 0,1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may optionally be substituted with 1 or 2 heteroatoms independently selected from halogen, CN, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, hydroxy, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, C_1-10Alkylthio radical, C_3-10Cycloalkylthio, amino, C_1-10Alkylamino radical, C_3-10Cycloalkylamino and di (C)_1-10Alkyl) amino;

each R^e2Independently selected from hydrogen, CN, NO₂、C_1-10Alkyl radical, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-4Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkoxy, -C (O) C_1-4Alkyl, -C (O) C_3-10Cycloalkyl, -C (O) OC_1-4Alkyl, -C (O) OC_3-10Cycloalkyl, -C (O) N (C)_1-4Alkyl radical)₂、-C(O)N(C_3-10Cycloalkyl radicals₂、-S(O)₂C_1-4Alkyl, -S (O)₂C_3-10Cycloalkyl, -S (O)₂N(C_1-4Alkyl radical)₂and-S (O)₂N(C_3-10Cycloalkyl radicals₂；

m is selected from 0,1, 2,3 and 4;

n is selected from 0,1 and 2;

p is selected from 0,1 and 2;

each r is independently selected from 0,1 and 2;

each t is independently selected from 0,1, 2,3, and 4.

In another embodiment (2), the present invention provides a compound of embodiment (1), or a pharmaceutically acceptable salt thereof, having the formula

In another embodiment (3), the present invention provides a compound of embodiment (1), or a pharmaceutically acceptable salt thereof, having the formula

In another embodiment (4), the present invention provides a compound of any one of embodiments (1) - (3), or a pharmaceutically acceptable salt thereof, wherein Q is heteroaryl.

In another embodiment (5), the present invention provides a compound of embodiment (4) or a medicament thereofA pharmaceutically acceptable salt wherein Q is independently selected from

In another embodiment (6), the present invention provides a compound of any one of embodiments (1) to (5), or a pharmaceutically acceptable salt thereof, wherein each R is⁵Is independently selected from C_1-10Alkyl, heterocyclyl-C_1-4Alkyl, -S (O)_rR^A4、-C(O)R^A4and-CH₂NR^A4R^B4Wherein alkyl and heterocyclyl are unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XIs substituted with the substituent(s).

In another embodiment (7), the present invention provides a compound of embodiment (6), or a pharmaceutically acceptable salt thereof, wherein each R is⁵Independently selected from methyl, ethyl,

Which is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XIs substituted with the substituent(s).

In another embodiment (8), the present invention provides a compound of embodiment (6), or a pharmaceutically acceptable salt thereof, wherein each R is⁵Is independently selected from S (O)₂R^A4and-C (O) R^A4Wherein each R is^A4Independently selected from heterocyclyl and heterocyclyl-C_1-4Alkyl, wherein each alkyl and heterocyclyl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XAnd each R is substituted^B4Is independently selected from C_1-10An alkyl group.

In another embodiment (9), the present invention provides a compound of embodiment (8), or a pharmaceutically acceptable salt thereof, wherein each R is⁵Is independently selected from S (O)₂R^A4and-C (O) R^A4Wherein each R is⁴Is independently selected from

Which is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XAnd each R is substituted^B4Is methyl.

In another embodiment (10), the present invention provides a compound of embodiment (6), or a pharmaceutically acceptable salt thereof, wherein each R is⁵Is independently selected from-CH₂NR^A4R^B4Wherein each R is^A4Is composed of

Which is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R^XAnd each R is substituted^B4Is methyl.

In another embodiment (11), the present invention provides a compound of any one of embodiments (6) to (10), or a pharmaceutically acceptable salt thereof, wherein each R is^XIndependently selected from methyl, ethyl, methoxymethyl, cyanoethyl and oxetan-3-yl.

In another embodiment (12), the present invention provides a compound of any one of embodiments (1) - (11), or a pharmaceutically acceptable salt thereof, wherein m is 1.

In another embodiment (13), the present invention provides a compound of any one of embodiments (1) - (12), or a pharmaceutically acceptable salt thereof, wherein R is¹Is hydrogen.

In another embodiment (14), the present invention provides a compound of any one of embodiments (1) - (13), or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen.

In another embodiment (15), the present invention provides a compound of any one of embodiments (1) - (14), or a pharmaceutically acceptable salt thereof, wherein R³Is independently selected from C_1-10An alkyl group.

In another embodiment (16), the present invention providesA compound of embodiment (15) or a pharmaceutically acceptable salt thereof, wherein R³Independently selected from methyl, isopropyl and tert-butyl.

In another embodiment (17), the present invention provides a compound of any one of embodiments (15) to (16), or a pharmaceutically acceptable salt thereof, wherein p is 2.

In another embodiment (18), the present invention provides a compound of any one of embodiments (1) - (17), or a pharmaceutically acceptable salt thereof, wherein R⁴Is a halogen.

In another embodiment (19), the present invention provides a compound of embodiment (18), or a pharmaceutically acceptable salt thereof, wherein each R is⁴Independently selected from fluorine and chlorine.

In another embodiment (20), the compounds provided herein are selected from

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

(S) -5-fluoro-N- (5- ((hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

(R) -5-fluoro-N- (5- ((hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5- (((1S,4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- (((1S,4S) -5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- (((1S,4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5- ((3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5- ((3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-N- (5- ((hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((5-ethylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5- ((2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5- ((2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((6-methyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((6-ethyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5- ((3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((9-ethyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) -6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

6-ethyl-N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

(6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (piperazin-1-yl) methanone,

(6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (4-methylpiperazin-1-yl) methanone,

(4-ethylpiperazin-1-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methanone,

(8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (2, 7-azaspiro [3.5] nonan-2-yl) methanone,

(6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methanone,

(7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methanone,

(6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methanone,

(5-Ethylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- (piperazin-1-ylsulfonyl) pyridin-2-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((4-methylpiperazin-1-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((4-ethylpiperazin-1-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5- ((3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-N- (5- ((hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((5-ethylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5- ((2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(R) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(R) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(R) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(R) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

N- (5- ((3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoropyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((3- (methoxymethyl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((3- (methoxymethyl) -4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((4-ethyl-3- (methoxymethyl) piperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

N- (5- ((3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoropyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- ((8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-fluoro-N- (5- (1- (4-methylpiperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- (1- (4-ethylpiperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-chloro-N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-chloro-N- (5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -5-chloro-N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

N- (5- ((3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

N- (5- ((3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

(R) -5-fluoro-N- (5- ((hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

N- (5- ((2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-N- (5- ((hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((5-ethylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

N- (5- ((2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((2-methyl-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((2-ethyl-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

N- (5- ((3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((9-ethyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(R) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(R) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (piperazin-1-yl) methanone,

(6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (4-methylpiperazin-1-yl) methanone,

(4-ethylpiperazin-1-yl) (6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(3, 8-diazabicyclo [3.2.1] octan-8-yl) (6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methanone,

(3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) (6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methanone,

(8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (2, 7-diazaspiro [3.5] nonan-2-yl) methanone,

(6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methanone,

(7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) (6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

(6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methanone,

(6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) methanone,

(5-Ethylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,

N- (5- ((3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

N- (5- ((2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-N- (5- ((hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((5-methylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((5-ethylhexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- ((4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

(R) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- ((methyl ((1-methylpyrol-2-yl) methyl) amino) methyl) pyridin-2-yl) pyrimidin-2-amine,

(R) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- ((hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

N- (5- ((3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- ((3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

(S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- ((3- (methoxymethyl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- ((3- (methoxymethyl) -4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

(S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((4-ethyl-3- (methoxymethyl) piperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

N- (5- (((1R,5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- (((1R,5S) -8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- (((1R,5S) -8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- (1- (4-methylpiperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- (1- (4-ethylpiperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-ethyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- (morpholinomethyl) pyridin-2-yl) pyrimidin-2-amine,

3- (4- ((6- ((4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) propionitrile,

N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (piperidin-4-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (1-methylpiperidin-4-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (1-ethylpiperidin-4-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

or a pharmaceutically acceptable salt thereof.

In another embodiment (21), the invention provides a pharmaceutical composition comprising a compound of any one of embodiments (1) - (20), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another embodiment (22), the invention provides a method of treating, ameliorating or preventing a disorder responsive to inhibition of cyclin dependent kinase 4/6, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments (1) - (20), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.

In another embodiment (23), the invention provides the use of a compound of any one of embodiments (1) to (20), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cell proliferative disorder.

In another aspect, the invention provides a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and instructions including one or more of the following: information on what state the composition is applied to, information stored on the composition, dosage information, and instructions on how to use the composition. In one particular variant, the kit comprises the compound in a multiple dose form.

In another aspect, the present invention provides an article of manufacture comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and a packaging material. In one variation, the packaging material includes a container containing the compound. In one particular variation, the container includes a label that identifies one or more of the following: instructions for what disease the compound applies to, stored information, dosage information, and/or how to use the compound. In another variation, the article of manufacture comprises the compound in a multiple dose form.

In another aspect, the invention provides a method of treatment comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method of inhibiting CDK4/6 kinase comprising contacting a compound disclosed herein, or a pharmaceutically acceptable salt thereof, with CDK 4/6.

In another aspect, the invention provides a method of inhibiting CDK4/6, comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in a subject to inhibit CDK4/6 activity in vivo.

In another aspect, the invention provides a method of inhibiting CDK4/6 comprising administering to a subject a first compound which converts in vivo to a second compound, wherein the second compound inhibits CDK4/6 activity in vivo and the second compound is a compound of any one of the above embodiments and variations thereof.

In another aspect, the invention provides a method of treating a disease state in which CDK4/6 activity contributes to the pathology and/or symptomology of the disease state, comprising causing a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in a subject.

In another aspect, the invention provides a method of treating a disease state in which CDK4/6 activity contributes to the pathology and/or symptomology of the disease state, the method comprising administering to a subject a first compound which converts in vivo to a second compound, wherein the second compound inhibits CDK4/6 activity in vivo. It is noted that the compound of the present invention may be the first or second compound.

In variations of each of the above methods, the disease state is selected from: cancerous proliferative diseases (e.g., cancers of the brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, ovary, prostate, colon, epidermis, esophagus, testis, gynecology, or thyroid); non-cancerous proliferative diseases (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, and Benign Prostatic Hypertrophy (BPH)); pancreatitis; kidney disease; pain; preventing implantation of blastocysts; treating diseases associated with angiogenesis or vasculogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid cancer); asthma; neutrophil chemotaxis (e.g., reperfusion injury from myocardial infarction and stroke and inflammatory arthritis); septic shock; t cell mediated diseases in which immunosuppression is of value (e.g. prevention of organ transplant rejection, graft versus host disease, lupus erythematosus, multiple sclerosis and rheumatoid arthritis); atherosclerosis; inhibiting keratinocytes responsive to the growth factor mixture; chronic Obstructive Pulmonary Disease (COPD) and other diseases.

In another aspect, the invention provides a method of treating a disease state in which mutations in the CDK4/6 gene contribute to the pathology and/or symptomology of the disease, such as melanoma, lung, colon and other types of tumors.

In another aspect, the present invention relates to the use of a compound of any one of the above embodiments and variations thereof as a medicament. In another aspect, the invention relates to the use of a compound of any one of the above embodiments and variations thereof as a medicament for inhibiting CDK 4/6.

In another aspect, the invention relates to the manufacture of a compound of any one of the above embodiments and variations thereof as a medicament for the treatment of pathological and/or symptomatic disease states caused by CDK4/6 activity.

Administration and pharmaceutical compositions

Generally, the compounds of the present invention will be administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, by any of the usual and acceptable means known in the art. The therapeutically effective amount may vary widely depending on the severity of the disease, age and relative health of the subject, the potency of the compound used and other factors known in the art. For example, for the treatment of neoplastic diseases and immune system diseases, the required dosage will vary depending upon the mode of administration, the particular condition being treated and the desired effect.

In general, satisfactory results are achieved at daily dosages of from 0.001 to 100mg/kg body weight, in particular from about 0.03 to 2.5mg/kg body weight. Daily doses for larger mammals, such as humans, may be administered in a convenient form, for example in divided doses up to four times a day or in sustained release form, from about 0.5mg to about 2000mg, or more specifically, from 0.5mg to 1000 mg. Suitable unit dosage forms for oral administration contain from about 1 to 50mg of the active ingredient.

The compounds of the present invention may be administered in the form of pharmaceutical compositions, by any conventional route; e.g., enterally, e.g., orally, e.g., in the form of tablets or capsules, parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g., in the form of a lotion, gel, ointment, or cream, or in the form of a nasal or suppository.

Pharmaceutical compositions containing a compound of the invention in free base or pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in conventional manner by means of mixing, granulating, coating, dissolving or lyophilizing processes. For example, pharmaceutical compositions comprising a compound of the invention in combination with at least one pharmaceutically acceptable carrier or diluent may be formulated in conventional manner by admixture with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1mg to about 500mg of active substance.

In one embodiment, the pharmaceutical composition is a solution, including a suspension or dispersion, such as an isotonic aqueous solution, of the active ingredient. In the case of lyophilized compositions comprising the active ingredient alone or in admixture with a carrier such as mannitol, dispersions or suspensions may be prepared prior to use. The pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbicides such as sorbic acid or benzoic acid. The solution or suspension may also contain a thickening agent including, but not limited to, sodium carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatin, or a solubilizing agent such as tween 80 (polyoxyethylene (20) sorbitan monooleate).

Suspensions in oils may contain, as oily component, vegetable oils, synthetic or semi-synthetic oils, commonly used for injection purposes. Examples include liquid fatty acid esters containing as the acid component a long chain fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, if desired, with antioxidants such as vitamin E, 3-carotene or 3, 5-di-tert-butylhydroxytoluene. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as mono-, di-or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof, ethylene glycol and glycerol.

Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, isopropyl myristate, isopropyl palmitate, isopropyl myristate, isopropyl palmitate, and isopropyl palmitate,

M2375 (polyoxyethylene glycerol),

M1944CS (unsaturated polyglycolyzed glycerides and mixtures containing glycerides and polyglycolyzed esters of almond oil by alcoholysis), LABRASOL^TM(saturated polyglycolized glycerides prepared by alcoholysis of TCM and containing glycerides and polyethylene glycol esters; both available from GaKefosse, France), and/or

812 (triglycerides of saturated fatty acids with chain lengths of C8 to C12, from huls AG, germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.

Pharmaceutical compositions for oral administration may be obtained, for example, by mixing the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules by adding further excipients, in the form of tablets or tablet cores.

Suitable carriers include, but are not limited to, fillers, for example sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, for example starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

The tablet cores may be provided with a suitable, optionally enteric, coating by using, inter alia, a concentrated sugar solution, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or a coating solution in a suitable organic solvent or solvent mixture, or, for enteric coatings, a solution of a suitable cellulose preparation, such as an acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate solution. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of the active ingredient.

Pharmaceutical compositions for oral administration may also include hard capsules, including gelatin or soft, sealed capsules containing gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules may contain the active ingredients in the form of granules, for example in admixture with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oils or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, to which stabilizers and detergents, for example of the fatty acid ester type of polyoxyethylene sorbitol, are added.

Pharmaceutical compositions suitable for rectal administration, for example suppositories, comprise a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

Pharmaceutical compositions suitable for parenteral administration may comprise the active ingredient in water-soluble form, for example as a water-soluble salt or as an aqueous injection suspension comprising a viscosity-increasing substance, for example sodium carboxymethylcellulose, an aqueous solution of sorbitol and/or dextran, if desired, and a stabilizer. The active ingredient, optionally together with excipients, may also be in a lyophilized form and may be prepared as a solution by addition of a suitable solvent prior to parenteral administration. The solutions used, for example for parenteral administration, can also be used as infusion solutions. Injectable preparations are generally prepared under sterile conditions, and filled, for example, in ampoules or vials, and in sealed containers.

The invention also provides a pharmaceutical combination, e.g. a kit, comprising a) a compound disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one auxiliary agent. The kit may contain instructions for its use.

Combination therapy

The compounds or pharmaceutically acceptable salts described in this disclosure may be used alone or in combination with other therapeutic agents.

For example, the therapeutic benefit of a compound of the invention may be enhanced by the use of an adjuvant drug (e.g., the therapeutic benefit of the adjuvant drug alone may be minimal, but the therapeutic benefit of the subject may be enhanced when used in combination with another drug), or, for example, the therapeutic benefit of the subject may be enhanced by the use of a compound of the invention in combination with another therapeutic agent that is also therapeutically effective. For example, in the treatment of gout, the compound of the invention may be used in combination with another drug for gout therapy to enhance clinical benefit. Alternatively, for example, if the adverse effect of using the compounds of the present invention is nausea, then an anti-nausea agent may be used in combination. Alternatively, combination therapies may include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of diseased areas, rest, dietary improvement, and the like. Regardless of the disease, disorder, or condition being treated, both therapies should have additive or synergistic effects to benefit the treatment of an individual.

Where the compounds described herein are used in combination with other therapeutic agents, the route of administration of the pharmaceutical compositions of the compounds described herein may be the same as the other drugs, or the route of administration may be different due to differences in physical and chemical properties. For example, oral administration of a compound described herein may produce and maintain good blood levels, while intravenous administration of another therapeutic agent may be required. Thus, the compounds described herein and another therapeutic agent may be administered simultaneously, sequentially or separately.

The compounds of formula (I) or (II) are expected to be effective in combination with one or more of the following: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, promoters of other apoptosis (e.g., Bcl-xL, Bcl-W, and Bfl-1) inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, antibodies to BiTE (bispecific T-cell engagers), antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 ErbB inhibitors, DVDs, leukemia virus oncogene homolog (2) receptor inhibitors, growth factor inhibitors, Heat Shock Protein (HSP) -90 inhibitors, histone acetylases (HDAC) inhibitors, hormonal therapies, immunological agents, inhibitors of apoptosis protein Inhibitors (IAPs), intercalating antibiotics, inhibitors of apoptosis proteins, and the like, Kinase inhibitors, kinesin inhibitors, JAK2 inhibitors, rapamycin inhibitors for mammals, micrornas, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, nonsteroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate) -ribose polymerase (PARP) inhibitors, platinum-based chemotherapeutic drugs, polo-like kinase (PLK) inhibitors, phosphoinositide 3 kinase (PI3K) inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoid/deltoid plant alkaloids, small interfering RNA (sirnas) inhibitors, topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like.

Examples

There are various methods for synthesizing the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and representative methods are listed in this example. However, it is to be noted that the compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof may also be obtained by synthesis by other synthetic schemes.

In certain compounds of formula (I) or (II), the attachment of an atom to another atom may result in the presence of a particular stereoisomer (e.g., a chiral center). The synthesis of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may result in a mixture of different isomers (enantiomers, diastereomers). Unless a particular configuration is specified, all recited compounds include different stereoisomers that may exist.

The compounds of formula (I) or (II) may also be prepared as pharmaceutically acceptable acid addition salts, for example by reacting the free base form of the compounds of the invention with a pharmaceutically acceptable inorganic or organic acid. Or a compound of formula (I) or (II) in free acid form with a pharmaceutically acceptable inorganic or organic base, to form a pharmaceutically acceptable base addition salt. Inorganic and organic acids and bases suitable for preparing pharmaceutically acceptable salts of compounds of formula (I) or (II) are described in the definitions section herein. Furthermore, salt forms of the compounds of formula (I) or (II) can also be prepared by using salts of the starting materials or intermediates.

The free acid or free base of the compounds of formula (I) or (II) may be prepared from the corresponding base addition salt or acid addition salt thereof. The acid addition salt forms of the compounds of formula (I) or (II) may be converted to the corresponding free base, for example by treatment with a suitable base such as ammonium hydroxide solution, sodium hydroxide and the like. The base addition salt forms of the compounds of formula (I) or (II) may be converted to the corresponding free acids, for example by treatment with a suitable acid, such as hydrochloric acid and the like.

An N-oxide of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may be prepared by methods known in the art. For example, the N-oxide may be obtained by reacting a non-oxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, peroxymaleic acid, perbenzoic acid, peracetic acid, m-chloroperoxybenzoic acid, and the like) in an inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at a temperature near 0 ℃. Alternatively, the N-oxides of the compounds of formula (I) or (II) may also be prepared from the N-oxides of the starting materials.

The non-oxidized compound of formula (I) or (II) can be prepared by reacting an N-oxide thereof with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide and the like) at 0-80 ℃ in a corresponding inert organic solvent (such as acetonitrile, ethanol, hydrated dioxane and the like).

Protected derivatives of compounds of formula (I) or (II) may be prepared by methods well known to those skilled in the art. For a detailed technical description of the addition and removal of protecting groups see: greene, Protecting Groups in Organic Synthesis,3rd edition, John Wiley & Sons, Inc.1999.

The labels and common sense, charts and examples used in these reactions are consistent with the current scientific literature, e.g., the journal of the American chemical Association or the journal of biochemistry. Standard single or three letter abbreviations, unless otherwise indicatedReferences generally refer to L-amino acid residues. All starting materials used were purchased from commercial suppliers and used without further purification unless otherwise indicated. For example, the following abbreviations are used in the examples and throughout the specification: g (g), mg (mg), L (L), mL (mL), μ L (μ L), psi (pounds per square inch), M (mol), mM (mmol), i.v. (i.v.), Hz (Hz), MHz (megahertz), mol (mol), mmol (mmol), RT (ambient temperature), min (min), h (h), mp (melting point), TLC (thin layer chromatography), Rr (retention time), RP (reversed phase), MeOH (methanol), i-PrOH (isopropanol), TEA (triethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), DME (1, 2-dimethyl ether), DCM (dichloromethane), DCE (dichloroethane), DMF (N, N-dimethylformamide), DMPU (N, N-dimethylpropylurea), CDI (1, 1-carbonyldiimidazole), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et₂O (diethyl ether), EDCI (1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (t-butyloxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMSE (2- (trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilyl), TBS (t-butyldimethylsilyl), DMAP (dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (t-butyl), HPLC (high performance liquid chromatography), BOP (bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride), AF (tetrabutylammonium fluoride), TBmC (m-chloroperbenzoic acid).

Ether or Et₂O is diethyl ether; brine is then a saturated aqueous NaCl solution. Unless otherwise indicated, all temperatures refer to degrees Celsius (degrees Celsius) and all reactions are carried out in an inert atmosphere at room temperature.

¹H NMR spectra were recorded using a Varian Mercury Plus 400 NMR spectrometer. Chemical shifts are expressed in ppm. The coupling constants are all in hertz (Hz). Apparent diversity is described in the split mode and is assigned as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) andbr (broad peak)

Low resolution Mass Spectrometry (MS) and compound purity data were from a single-pole system of Shimadzu mass spectrometry equipped with an electrospray ion detector (ESI), ultraviolet detectors (220 and 254nm) and an Evaporative Light Scattering Detector (ELSD). Thin layer chromatography was performed using 0.25mm Asahi-poise silica gel plate (60F-254), 5% ethanol phosphomolybdate solution, ninhydrin or p-methoxybenzaldehyde solution and observing under an ultraviolet lamp. Silica gel (200-300 mesh, Qingdao ocean chemical Co., Ltd.) was used for flash column chromatography.

Synthetic schemes

The compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof may be synthesized by various methods, some exemplary methods are provided below and in the examples. Other synthetic methods can be readily suggested by those skilled in the art based on the information disclosed herein.

It may be necessary to protect reactive groups in the reactions described below in order to prevent these reactive groups from participating in other undesired reactions: such as hydroxyl, amino, imino, mercapto or carboxyl groups, which are contained in the final product. Commonly used protecting Groups are referred to T.W.Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

The synthetic schemes for all compounds of the present invention are illustrated by the following schemes and examples. The starting materials used are commercially available or may be prepared according to established procedures or by methods exemplified herein.

The intermediates listed in the following synthetic schemes are either obtained from the literature or are synthesized according to established analogous synthetic methods.

As illustrated below, one synthetic route for the compounds of formula I or II of the present invention is shown in FIG. 1. The compounds of formula I or II can be synthesized from intermediates III to VIII shown in the synthetic schemes, which can be synthesized according to literature or methods well known to those skilled in the art. The pyrimidine intermediates of formula IV or V are prepared from pyrimidine intermediates of formula VI and heteroarene intermediates of formula VII or VIII by palladium-catalyzed coupling reactions, such as Suzuki reactions or according to other coupling conditions reported in the literature. The compounds of formula I or II are prepared by coupling of formula IV or V with an aminoarene of formula III, such as Buchwald amination or according to other coupling conditions reported in the literature.

As an example of the preparation of intermediate IV, one synthetic route for the compound of formula IVa is shown in scheme 2. Starting from commercially available diaminopyridine A. The intermediate IVa is prepared by subsequent reductive amination, imidazole formation and conversion of the halogen group to a group such as B or Sn followed by a palladium catalyzed coupling reaction.

One synthetic route for the intermediate Vb compounds is shown in scheme 3. Reacting ketone N with hydrazine to obtain an intermediate O, alkylating the intermediate O to obtain an intermediate P, converting a halogen group in the intermediate P into a group such as B or Sn, and then carrying out palladium-catalyzed coupling reaction to obtain an intermediate Vb.

In some cases, the above synthetic schemes may be ordered as appropriate in order to facilitate the reaction or to avoid the production of unnecessary reaction products. In order that the invention may be more fully understood, the following examples are set forth. These examples are only examples and should not be construed as limiting the invention.

Preparation of intermediates

Intermediate A

6- (2-chloro-5-fluoropyrimidin-4-yl) -1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridine (intermediate A)

³5-bromo-N-isopropylpyridine-2, 3-diamine (A-1)

To a solution of commercial 2, 3-diamino-5-bromopyridine (1.88g,10mmol, in plain translation 5-bromo-2, 3-diaminopyridine) (1.7 g,12mmol) and acetone (0.7g,12mmol) in isopropyl acetate (15mL) was added TFA (2.51g,22mmol) followed by NaBH (OAc) at 0 deg.C₃(3.18g,15 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with EtOAc (50 mL). With saturated NaHCO₃Washed with aqueous solution (30mL) and saturated brine (30mL), and then with Na₂SO₄And (5) drying. Filtering and rotary evaporating, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 9: 1-2: 1) to obtain 5-bromo-N as yellow solid³Isopropylpyridine-2, 3-diamine (A-1). MS-ESI (M/z) 230,232[ M + 1]]⁺。

6-bromo-1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridine (A-2)

5-bromo-N³Isopropylpyridine-2, 3-diamine (A-1) (1.2g,5.2mmol) and Ac₂A mixture of O (2.6g,26mmol) in HOAc (10mL) was stirred at 90 deg.C overnight. The solvent was spun down in vacuo and the residue was diluted with DCM (50 mL). Adjusting the pH value to 8-9 by NaOH (1N). The organic layer was separated. The extract was washed with saturated brine (50mL), Na₂SO₄And (5) drying. Filtering and concentrating, purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 5: 1-1: 2) to obtain 6-bromo-1-isopropyl-2-methyl-1H-imidazo [4,5-b ] as a yellow solid]Pyridine (A-2). MS-ESI (M/z) 254,256[ M + 1]]⁺。

6- (tri-n-butylstannyl) -1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridine (A-3)

to-bromo-1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridine (A-2) (0.5g,2mmol) in THF (10mL) was added (Bu)₃Sn)₂(2.32g,4mmol)，Pd(PPh₃)(OAc)₂(0.08g,0.1mmol) and TBAF (1.044g,8 mmol). Stirring at 70 ℃ for 4h under nitrogen protection. The mixture was concentrated and the residue was diluted with ethyl acetate (50 mL). Extraction ofThe material was washed with water (50mL), MgSO₄And (5) drying. Filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 9:1 to 1:1) to give 6- (tri-n-butylstannyl) -1-isopropyl-2-methyl-1H-imidazo [4,5-b ] as a yellow oil]Pyridine (A-3). MS-ESI (M/z) 466[ M + 1]]⁺。

6- (2-chloro-5-fluoropyrimidin-4-yl) -1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridine (intermediate A)

To 6- (tri-n-butylstannyl) -1-isopropyl-2-methyl-1H-imidazo [4,5-b]To a solution of pyridine (A-3) (0.455g,0.97mmol) and 2, 4-dichloro-5-fluoropyrimidine (0.25g,1.49mmol) in toluene (8mL) was added Pd (PPh)₃)₄(0.06g,0.05 mmol). Stirring at 110 ℃ for 4h under nitrogen protection. The mixture was concentrated. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate) to give 6- (2-chloro-5-fluoropyrimidin-4-yl) -1-isopropyl-2-methyl-1H-imidazo [4,5-b ] as a yellow solid]Pyridine (intermediate a). MS-ESI (M/z) 306[ M + 1]]⁺。

Intermediate B

5- (2-chloro-5-fluoropyrimidin-4-yl) -7-fluoro-3-isopropyl-1-methyl-3 a,7 a-dihydro-1H-indazole (intermediate) B)

5-bromo-2-chloronicotinic acid (isobutyl carbonate) anhydride (B-1)

To a solution of 5-bromo-2-chloronicotinic acid (10.0g,42.3mmol) in anhydrous THF (440mL) at 0 deg.C was added TEA (7.06mL,50.8mmol) followed by isobutyl chloroformate (6.64mL,50.76mmol) and a white precipitate formed rapidly. The mixture was stirred at 0 ℃ for 75 minutes. After filtration the solid was washed with THF (30 mL). The solution was concentrated to obtain 200mL of a solution containing 5-bromo-2-chloronicotinic acid (isobutylcarbonic acid) anhydride (B-1) which was used directly in the next reaction.

(5-bromo-2-chloropyridin-3-yl) methanol (B-2)

Water (10mL) was added to the above solution.After the mixture was cooled to 0 deg.C, NaBH was added₄(3.38g,89mmol), the mixture was stirred at 0 ℃ for 1 hour and then warmed to room temperature for more than 2 hours. Ethyl acetate was added to the reaction mixture, which was washed with water and saturated brine, dried over anhydrous potassium carbonate and sodium sulfate, and concentrated to give a crude product of (5-bromo-2-chloropyridin-3-yl) methanol (B-2) which was used directly in the next reaction.

5-bromo-2-chloro-3-pyridinecarboxaldehyde (B-3)

At-78 deg.C, to (COCl)₂To a solution of (2.95mL,34.84mmol) in anhydrous DCM (26mL) was added DMSO (4.94mL,69.7mmol) in DCM (45mL) dropwise and stirred at-78 deg.C for 10 min. A solution of (5-bromo-2-chloropyridin-3-yl) methanol (B-2) in DCM (45mL) was added dropwise. The mixture was stirred at-78 ℃ for 10 minutes. TEA (18.2mL,131mmol) was added dropwise and stirring continued at-78 deg.C for 1 hour. The mixture was allowed to warm to room temperature and stirred for 1 hour. After dilution with water (100mL), the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with 3-5% ethyl acetate in hexane to give 5-bromo-2-chloro-3-pyridinecarboxaldehyde (B-3) as a white solid. MS-ESI (M/z) 220[ M + 1]]⁺。

1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-ol (B-4)

In N₂To a solution of 5-bromo-2-chloro-3-pyridinecarboxaldehyde (B-3) (5.63g,25.53mmol) in dry THF (70mL) at-78 deg.C was added isopropyl magnesium chloride (15.3 mL of 2.0M solution in THF) dropwise at ambient temperature. The mixture was warmed to room temperature and stirred overnight. After water was added, the mixture was separated, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-ol (B-4). MS-ESI (M/z):264[ M +1 [)]⁺。

1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-one (B-5)

B-4(265mg,1mmol), PCC (431mg,2mmol) and SiO₂A mixture (0.5g) in DCM (8mL) was stirred at room temperature for 5 h. The mixture was filtered through celite and the residual solid was washed with DCM. Concentrating the filtrate, and separating the residue with silica gel columnPurifying by chromatography to obtain 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropane-1-one (B-5). MS-ESI (M/z):262[ M +1 [)]⁺。

5-bromo-3-isopropyl-1H-pyrazolo [3,4-b]Pyridine (B-6)

To a solution of 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-one (B-5) (177mg,0.674mmol) in isopropanol (2mL) was added hydrazine hydrate (0.5mL) at room temperature. The mixture was warmed to 80 ℃ and stirred overnight. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate ═ 1:1) to give 5-bromo-3-isopropyl-1H-pyrazolo [3, 4-b)]Pyridine (B-6). MS-ESI (M/z) 240[ M + 1]]⁺。

5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3,4-b]Pyridine (B-7)

To 5-bromo-3-isopropyl-1H-pyrazolo [3,4-b ] at 0 DEG C]Pyridine (B-6) (48mg,0.2mmol) in THF was added NaH (10mg, 60% in oil), stirred for 5 min and then MeI (25. mu.L, 0.4mmol) was added dropwise. The mixture was stirred at 0 ℃ for 20 minutes. The reaction was quenched with water. The mixture was extracted with ethyl acetate, washed with saturated brine and Na₂SO₄Drying and concentrating. Purifying the residue by silica gel column chromatography, eluting with 10-100% ethyl acetate hexane solution to obtain 5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b)]Pyridine (B-7), MS-ESI (M/z):254[ M + 1]]⁺And 5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3,4-b]Pyridine (B-7B). MS-ESI (M/z) 254[ M + 1]]⁺。

(3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b)]Pyridin-5-yl) boronic acid (B-8)

5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3,4-b]Pyridine (B-7) (724mg,2.85mmol), Biboronic acid pinacol ester (1.09g,4.27mmol), Pd (OAc)₂(64mg,0.28mmol)，Cy₃A mixture of P (160mg,0.57mmol) and KOAc (838mg,8.55mmol) in DMSO (10mL) was stirred under nitrogen at 100 ℃ for 2h in a sealed tube. The reaction was quenched with water. The mixture was extracted with DCM and the extract Na₂SO₄Dried and concentrated to give the title compound (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b)]Pyridin-5-yl) boronic acid (B-8). MS-ESI (M/z) 220[ M + 1]]⁺。

5- (2-chloro-5-fluoropyrimidin-4-yl) -7-fluoro-3-isopropyl-1-methyl-3 a,7 a-dihydro-1H-indazole (intermediate) B)

(3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b)]Pyridin-5-yl) boronic acid (B-8) (624mg,2.85mmol), 2, 4-dichloro-5-fluoropyrimidine (952mg,5.7mmol), Pd (PPh)₃)₂Cl₂(200mg,0.28mmol) and Na₂CO₃(906mg,8.55mmol) in DME/H₂The mixture of O (24ml/10ml) solution was stirred under nitrogen at 80 ℃ for 2 hours in a sealed tube. The reaction was quenched with water. The mixture was extracted with DCM and the combined organic layers were washed with Na₂SO₄Drying and concentrating. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate ═ 2:1) to give the title compound 5- (2-chloro-5-fluoropyrimidin-4-yl) -7-fluoro-3-isopropyl-1-methyl-3 a,7 a-dihydro-1H-indazole (intermediate B). MS-ESI (M/z) 306[ M + 1]]⁺。

Intermediate C

5- (2-chloro-5-fluoropyrimidin-4-yl) -3-isopropyl-1-methyl-1H-pyrazolo [3,4-b]Pyridine (intermediate C)

5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3,4-b]Pyridine (C-1)

To a solution of 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-one (B-5) (38mg,0.15mmol) and methylhydrazine sulfate (25mg,0.2mmol) in EtOH (2mL) was added TEA (50mg,5 mmol). The mixture was stirred at room temperature for 0.5 hour and then refluxed overnight. The mixture was cooled to room temperature and concentrated. The residue was diluted with DCM (20mL), washed successively with water and saturated brine (20mL), Na₂SO₄Drying and rotary steaming. Purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate: 100: 1-50: 1) to obtain5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3,4-b]Pyridine (C-1). MS-ESI (M/z) 254[ M + 1]]⁺。

(3-isopropyl-1H-pyrazolo [3, 4-b)]Pyridin-5-yl) boronic acid (C-2)

According to the synthesis method of B-8, 5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3, 4-B)]Replacement of pyridine (B-7) with 5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3,4-B]Pyridine (C-1) to prepare the title compound (C-2). MS-ESI (M/z) 220[ M + 1]]⁺。

5- (2-chloro-5-fluoropyrimidin-4-yl) -3-isopropyl-1-methyl-1H-pyrazolo [3,4-b]Pyridine (intermediate J)

(3-isopropyl-1-methyl-1H-pyrazolo [3, 4-B) according to the synthesis method of intermediate B]Replacement of pyridin-5-yl) boronic acid (B-8) with (3-isopropyl-1H-pyrazolo [3, 4-B)]Pyridin-5-yl) boronic acid (C-2) gave the title compound (intermediate C). MS-ESI (M/z) 306[ M + 1]]⁺。

Intermediate D

6-bromo-1-tert-butyl-2-methyl-1H-imidazo [4,5-b]Pyridine (intermediate D)

5-bromo-3-fluoropyridin-2-amine (D-1)

NBS (8.72g,49.0mmol) was added to a solution of 3-fluoropyridin-2-amine (11.0g,98.0mmol) in ACN (300mL) at 0 ℃ and stirred at ambient temperature for 1 hour. NBS (8.72g,49.0mmol) was added dropwise. The reaction mixture was concentrated and diluted with water (100 mL). Filtered through celite. The filter cake was washed with water and the filtrate was concentrated to give the title compound, 5-bromo-3-fluoropyridin-2-amine (D-1), as a crude product. MS-ESI (M/z):191[ M + 1]]⁺。

5-bromo-3-fluoro-2-nitropyridine (D-2)

To a mixture of 5-bromo-3-fluoropyridin-2-amine (D-1) (4.0g,21.0mmol) in concentrated sulfuric acid (20mL) at 0 deg.C was added H₂O₂(33mL,29.1mmol) in concentrated sulfuric acid (66 mL).The mixture was allowed to warm to room temperature and stirred overnight. Basified with dilute sodium carbonate solution at 0 ℃ to pH 7 and extracted with ethyl acetate. The organic layer was successively washed with Na₂S₂O₃Washing with saturated brine and Na₂SO₄And (5) drying. Filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 40:1) to give the title compound 5-bromo-3-fluoro-2-nitropyridine (D-2). MS-ESI (M/z) 220[ M + 1]]⁺。

5-bromo-N-tert-butyl-2-nitropyridin-3-amine (D-3)

A mixture of 5-bromo-3-fluoro-2-nitropyridine (D-2) (1.63g,7.38mmol), tert-butylamine (1.08g,14.8mmol) and TEA (1.49g,14.8mmol) in THF (30mL) was stirred at 45 deg.C overnight. Water and ethyl acetate were added. The aqueous layer was extracted with EtOAc (3X 30 mL). The organic layer was washed with saturated brine and Na₂SO₄Drying, concentration and purification of the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 30:1) gave the title compound 5-bromo-N-tert-butyl-2-nitropyridin-3-amine (D-3). MS-ESI (M/z):274[ M + 1]]⁺。

³5-bromo-N-tert-butylpyridine-2, 3-diamine (D-4)

A mixture of 5-bromo-N-tert-butyl-2-nitropyridin-3-amine (D-3) (1.3g,4.7mmol), aqueous NH4Cl (16mL) and Fe (2.6g,46mmol) in EtOH (16mL) was stirred at 75 ℃ for 40 min. The mixture was filtered and the filtrate extracted with DCM (3X 30 mL). The organic layer was washed with saturated brine and Na₂SO₄Drying and concentrating to obtain the title compound 5-bromo-N³-tert-butylpyridine-2, 3-diamine (D-4). MS-ESI (M/z) 244[ M + 1]]⁺。

6-bromo-1-tert-butyl-2-methyl-1H-imidazo [4,5-b]Pyridine (intermediate D)

5-bromo-N³-tert-butylpyridine-2, 3-diamine (D-4) (50mg,0.205mmol) and Ac₂A mixture of O (21. mu.l, 0.225mmol) in AcOH (1mL) was stirred at 90 ℃ overnight. The mixture was concentrated and the residue was washed with sodium bicarbonate solution (50mL) and then extracted with EtOAc (3 × 30 mL). The extract was extracted with water (2X 30mL) and saturated salt in that orderWashed with water (30mL), dried and concentrated to give the title compound 6-bromo-1-tert-butyl-2-methyl-1H-imidazo [4,5-b]Pyridine (intermediate D). MS-ESI (M/z) 268[ M + 1]]⁺。

Intermediate E

3-tert-butyl-2-methyl-5- (tributyltin) -2H-pyrazolo [3,4-b]Pyridine (intermediate E)

5-bromo-2-chloro-N-methoxy-N-methylnicotinamide (E-1)

The title compound 5-bromo-2-chloro-N-methoxy-N-methylnicotinamine (E-1) was prepared by replacing isobutyl chloroformate with dimethylhydroxylamine hydrochloride (translated as N-methoxymethylaminochloride, but not commonly) according to the synthetic method of B-1. MS-ESI (M/z):279[ M +1]⁺。

5-bromo-2-chloro-3-pyridinecarboxaldehyde (E-2)

DIBAL-H (70mL,105mmol) was added to a CDM (250mL) solution of 5-bromo-2-chloro-N-methoxy-N-methylnicotinamine (E-1) (11.8g,42mmol) at-78 deg.C, and the mixture was stirred at 0 deg.C for 0.5H. The mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 10:1) to give the title compound 5-bromo-2-chloro-3-pyridinecarboxaldehyde (E-2). MS-ESI (M/z) 220[ M + 1]]⁺。

1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-ol (E-3)

To a solution of 5-bromo-2-chloro-3-pyridinecarboxaldehyde (E-2) (2.1g,10mmol) in THF (60mL) at 0 deg.C was added tert-butylmagnesium chloride (50mL,50 mmol). The mixture was stirred at 0-10 ℃ for 2h, and the reaction was quenched with MeOH (10 mL). The mixture was concentrated to give the title compound 1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-ol (E-3). MS-ESI (M/z):278[ M +1]⁺。

1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-one (E-4)

According toSynthesis of B-5 substituting 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-ol (B-4) with 1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-ol (E-3) produced the title compound 1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-one (E-4). MS-ESI (M/z):276[ M +1 [)]⁺。

5-bromo-3-tert-butyl-1H-pyrazolo [3,4-b]Pyridine (E-5)

The title compound 5-bromo-3-tert-butyl-1H-pyrazolo [3,4-B ] was prepared according to the synthetic method of B-6 by replacing 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-one (B-5) with 1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-one (E-4)]Pyridine (E-5). MS-ESI (M/z) 254[ M + 1]]⁺。

5-bromo-3-tert-butyl-2-methyl-2H-pyrazolo [3,4-b]Pyridine (E-6)

To 5-bromo-3-tert-butyl-1H-pyrazolo [3,4-b ] at 0 DEG C]Pyridine (E-5) (320mg,1.3mmol) in THF (10ml) was added NaH (80mg, 60% in oil), stirred for 5 min and then MeI (370mg,2.6mmol) was added dropwise. The mixture was stirred at 0 ℃ for 20 minutes. The reaction was quenched with water. The mixture was extracted with ethyl acetate, washed with saturated brine and Na₂SO₄Drying and concentrating. Purifying the residue by silica gel column chromatography, eluting with 10-100% ethyl acetate in hexane to obtain 5-bromo-3-tert-butyl-2-methyl-2H-pyrazolo [3, 4-b)]Pyridine (E-6), MS-ESI (M/z):268[ M +1]⁺And 5-bromo-3-tert-butyl-1-methyl-1H-pyrazolo [3,4-b]Pyridine (E-6 b). MS-ESI (M/z) 268[ M + 1]]⁺。

3-tert-butyl-2-methyl-5- (tributyltin) -2H-pyrazolo [3,4-b]Pyridine (intermediate E)

5-bromo-3-tert-butyl-2-methyl-2H-pyrazolo [3,4-b]Pyridine (E-6) (134mg,0.5mmol), (Bu)₃Sn)₂(870mg,1.5mmol)，Pd(PPh₃)₄A mixture of (22mg,0.02mmol) and TEA (150mg,1.5mmol) in 1, 4-dioxane (5mL) was stirred at 80 deg.C overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound 3-tert-butyl-2-methyl-5- (tributyltin) -2H-pyrazolo[3,4-b]Pyridine (intermediate E). MS-ESI (M/z) 480[ M + 1]]⁺。

Example 1

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) -N- (5- (piperazin-1-ylmethyl) Yl) pyridin-2-yl) pyrimidin-2-amine (1)

Tert-butyl 4- ((6-bromopyridin-3-yl) methyl) piperazine-1-carboxylic acid ester (1a)

To a solution of 6-bromonicotinaldehyde (11.0g,59.1mmol) and 1-Boc-piperazine (10.0g,53.7mmol) in DCM (100mL) at 0 deg.C was added NaBH (OAc) in portions₃(13.6g,64.1 mmol). The mixture was allowed to warm to room temperature and stirred overnight. DCM (100mL) was added followed by aqueous NaOH (2N,100mL) at 0 ℃. The organic layer was separated and the aqueous layer was extracted with DCM (100 mL). The extract was washed with saturated brine (100mL) and Na₂SO₄Drying and concentrating to obtain a yellow oily crude product of tert-butyl 4- ((6-bromopyridine-3-yl) methyl) piperazine-1-carboxylic ester (1a), which is directly used for the next reaction. MS-ESI (M/z):356, 358[ M + 1]]⁺。

Tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b)

Under nitrogen protection, tert-butyl 4- ((6-bromopyridin-3-yl) methyl) piperazine-1-carboxylate (1a) (3.56g,10mmol), Cu₂O (0.50g,0.3mmol) in NH₃.H₂A mixture of O (20mL) and MeOH (20mL) was stirred in a sealed tube at 70 ℃ overnight. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. Diluted with aqueous NaOH (2N,50mL) and extracted with DCM (2X 100 mL). The extract was washed with saturated brine (100mL) and Na₂SO₄Drying, filtration and concentration gave a crude product as a yellow oil which was purified by recrystallization from MTBE to give tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1 b). MS-ESI (M/z):293[ M + 1]]⁺。

Tert-butyl 4- ((6- ((5-fluoro-4- (1-isopropyl-2)-methyl-1H-imidazo [4,5-b]Pyridin-6-yl) pyrimidine- 2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylic acid ester (1c)

6- (2-chloro-5-fluoropyrimidin-4-yl) -1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridine (intermediate A) (0.045g,0.15mmol), tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) (0.055g,0.18mmol), Pd₂(dba)₃(0.008g,0.015mmol), Xantphos (0.01g,0.015mmol) and Cs₂CO₃(0.103g,0.3mmol) in 1, 4-dioxane (3mL) under nitrogen stirring at 90 ℃ for 1 h. The mixture was cooled to room temperature and diluted with DCM (10 mL). Filtered through celite. The filtrate was concentrated and the residue was purified by preparative thin layer chromatography (eluent: DCM/MeOH ═ 20:1) to give tert-butyl 4- ((6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylic acid ester (1 c). MS-ESI (M/z):562[ M + 1]]⁺。

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) -N- (5- (piperazin-1-ylmethyl) Yl) pyridin-2-yl) pyrimidin-2-amine (1)

Tert-butyl 4- ((6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]A mixture of pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylate (1c) (0.03g,0.05mmol) in TFA (2mL) and DCM (4mL) was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum and the residue was diluted with water (10mL) and washed with DCM (10 mL). The pH of the water layer is adjusted to 11-12 by NaOH (2N). Extract with IPA/DCM (25%, 4X 20 mL). The extract was washed with saturated brine (40mL), Na₂SO₄Dried and concentrated. The residue was purified by preparative thin layer chromatography (eluent: DCM/MeOH ═ 10:1) to give 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (1). MS-ESI (M/z):462[ M + 1[ ]]⁺。

Example 2

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) -N- (5- ((4-methylpiperazine- 1-yl) methyl) pyridine-2-yl) pyrimidin-2-amine (2)

5- ((4-Methylpiperazin-1-yl) methyl) pyridin-2-amine (2a)

The title compound 5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-amine (2a) was prepared according to the synthesis of 1b substituting 1-Boc-piperazine with 1-methylpiperazine. MS-ESI (M/z):207[ M + 1]]⁺。

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) -N- (5- ((4-methylpiperazine- 1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (2)

The title compound 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b) was prepared according to the synthesis of 1c, substituting tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with 5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-amine (2a)]Pyridin-6-yl) -N- (5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (2). MS-ESI (M/z):476[ M +1 [)]⁺。

Example 3

N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazole Azolo [4,5-b ] s]Pyridin-6-yl) pyrimidin-2-amine (3)

5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (3a)

The title compound 5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (3a) was prepared according to the synthetic procedure of 1b substituting 1-Boc-piperazine with 1-ethylpiperazine. MS-ESI (M/z) 221[ M + 1]]⁺。

N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H' Mimi Azolo [4,5-b ] s]Pyridin-6-yl) pyrimidin-2-amine (3)

The title compound N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b) was prepared according to the synthesis of 1c by replacing tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with 5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (3a)]Pyridin-6-yl) pyrimidin-2-amine (3). MS-ESI (M/z) 490[ M + 1]]⁺。

Example 4

(S) -5-fluoro-N- (5- ((hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-iso-butyl) pyridine propyl-2-methyl-1H-imidazo [4,5-b]Pyridin-6-yl) pyrimidin-2-amine (4)

(tert-Butoxycarbonyl) -L-proline (4a)

(tert-Butoxycarbonyl) -L-proline (4a) was prepared as described in tetrahedron.2013,10,156.

Tert-butyl (S) -2- ((2-ethoxy-2-oxoethyl) carbamoyl) pyrrolidine-1-carboxylic acid ester (4b)

To a solution of (tert-butoxycarbonyl) -L-proline (4a) (21.5g,100mmol) in THF (200mL) at 0 deg.C was added CDI (17.8g,110mmol) in portions. The mixture was stirred at room temperature for 0.5 hour. Ethyl glycinate hydrochloride (15.3g,110mmol) was added at 0 ℃ followed by TEA (15.0g,150mmol) and the mixture was stirred at room temperature overnight. The solvent was spun dry in vacuo and the residue was diluted with ethyl acetate (250mL), followed by saturated NaHCO₃The solution (200mL), 10% citric acid (2X 200mL) and saturated brine (200mL) were washed with Na₂SO₄Drying and concentration gave the title compound tert-butyl (S) -2- ((2-ethoxy-2-oxoethyl) carbamoyl) pyrrolidine-1-carboxylate (4 b).

(S) -prolyl glycine ethyl ester trifluoroacetate salt (4c)

A mixture of tert-butyl (S) -2- ((2-ethoxy-2-oxoethyl) carbamoyl) pyrrolidine-1-carboxylate (4b) (24.8g,82.6mmol) and TFA (100mL) in DCM (125mL) was stirred at room temperature for 2h and concentrated to give the crude (S) -prolylglycine ethyl trifluoroacetate (4c) which was used directly in the next reaction. MS-ESI (M/z) 201[ M + 1]]⁺。

(S) -hexahydropyrrolo [1,2-a ] compounds]Pyrazine-1, 4-diones (4d)

A mixture of (S) -prolylglycine ethyl trifluoroacetate (4c) (40g,127mmol) in TEA (150mL) and MeOH (800mL) was refluxed overnight. The solvent was spun dry in vacuo and the residue was diluted with IPA (100 mL). Filtration and washing of the filter cake with n-hexane. Vacuum drying the solid to obtain (S) -hexahydropyrrolo [1,2-a]Pyrazine-1, 4-dione (4 d). MS-ESI (M/z) 154[ M + 1]]⁺。

Benzyl (S) -hexahydropyrrolo [1,2-a]Pyrazine-2 (1H) -carboxylic acid esters (4e)

To a suspension of LAH (5.9g,156mmol) in THF (60mL) was added dropwise (S) -hexahydropyrrolo [1,2-a ] solution]A solution of pyrazine-1, 4-dione (4d) (4.0g,26mmol) in THF (40mL) was refluxed for 16 hours. The reaction mixture was cooled to 0 ℃ and saturated NaHCO was added dropwise₃(100mL) and benzyl chloroformate (6.67g,39mmol) was added. The mixture was stirred at 0 ℃ for 1 hour and at room temperature for a further 2 hours. The reaction solution was extracted with chloroform (3X 200mL), and the extract was washed with saturated brine (400mL), Mg₂SO₄And (5) drying. Concentrated and the residue purified by column chromatography over silica gel (eluent: DCM/MeOH 25:1) to give benzyl (S) -hexahydropyrrolo [1,2-a ] benzene]Pyrazine-2 (1H) -carboxylate (4 e). MS-ESI (M/z):261[ M + 1]]⁺。

(S) -octahydropyrrolo [1, 2-a)]Pyrazine (4f)

Benzyl (S) -hexahydropyrrolo [1,2-a]A mixture of pyrazine-2 (1H) -carboxylate (4e) (5.0g,19mmol) and Pd/C (10%, 1.0g) in MeOH (50mL) was stirred under hydrogen at room temperature for 2H. The mixture was filtered through celite, and the filtrate was concentrated to give (S) -octahydropyrrolo [1,2-a ]]Crude pyrazine (4 f). MS-ESI (M/z) 127[ M + 1]]⁺。

(S) -2- ((6-bromopyridin-3-yl) methyl) octahydropyrrolo [1, 2-a)]Pyrazine (4g)

Following the synthesis of 1a, 1-Boc-piperazine was replaced with (S) -octahydropyrrolo [1,2-a ]]Pyrazine (4f) preparation of the title compound (S) -2- ((6-bromopyridin-3-yl) methyl) octahydropyrrolo [1, 2-a)]Pyrazine (4 g). MS-ESI (M/z):296,298[ M + 1]]⁺。

(S) -5- ((hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl) methyl) pyridin-2-amine (4H)

Replacement of tert-butyl 4- ((6-bromopyridin-3-yl) methyl) piperazine-1-carboxylate (1a) with (S) -2- ((6-bromopyridin-3-yl) methyl) octahydropyrrolo [1,2-a ] according to the Synthesis procedure of 1b]Pyrazine (4g) gave the title compound (S) -5- ((hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl) methyl) pyridin-2-amine (4H). MS-ESI (M/z):233[ M +1 [)]⁺。

(S) -5-fluoro-N- (5- ((hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-iso-butyl) pyridine propyl-2-methyl-1H-imidazo [4,5-b]Pyridin-6-yl) pyrimidin-2-amine (4)

Tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) was replaced with (S) -5- ((hexahydropyrrolo [1, 2-a) according to the synthetic method of 1c]Pyrazin-2 (1H) -yl) methyl) pyridin-2-amine (4H) and the title compound (S) -5-fluoro-N- (5- ((hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridin-6-yl) pyrimidin-2-amine (4). MS-ESI (M/z):502[ M +1 [)]⁺。

Example 5

(R) -5-fluoro-N- (5- ((hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1- isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridin-6-yl) pyrimidin-2-amine (5)

(R) -5- ((hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl) carboxamidesYl) pyridin-2-Amines (5a)

The title compound (R) -5- ((hexahydropyrrolo [1, 2-a) was prepared according to the 4h synthesis substituting the starting L-proline for D-proline]Pyrazin-2 (1H) -yl) methyl) pyridin-2-amine (5 a). MS-ESI (M/z):233[ M +1 [)]⁺。

(R) -5-fluoro-N- (5- ((hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1- isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridin-6-yl) pyrimidin-2-amine (5)

Tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) was replaced with (R) -5- ((hexahydropyrrolo [1, 2-a) according to the synthetic method of 1c]Pyrazin-2 (1H) -yl) methyl) pyridin-2-amine (5a), the title compound (R) -5-fluoro-N- (5- ((hexahydropyrrolo [1, 2-a)]Pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridin-6-yl) pyrimidin-2-amine (5). MS-ESI (M/z):502[ M +1 [)]⁺。

Example 6

N- (5- (((1S,4S) -2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) pyrimidin-2-amine (6)

Tert-butyl (1S,4S) -5- ((6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid Acid ester (6a)

To tert-butyl (1S,4S) -2, 5-diazabicyclo [2.2.1]To a solution of heptane-2-carboxylate (0.099g,0.5mmol), 5-bromo-2-pyridinecarboxaldehyde (0.093g,0.5mmol) and AcOH (0.03g,0.5mmol) in THF (1mL) was added sodium triacetoxyborohydride (0.159g,0.75 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was saturated NaHCO₃The solution was quenched, extracted with EtOAc, and the organic layer was washed with saturated brine (20mL), Na₂SO₄And (5) drying. Concentrating to obtain tert-butyl(1S,4S) -5- ((6-Bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid ester (6 a). MS-ESI (M/z) 368,390[ M + 1]]⁺。

Tert-butyl (1S,4S) -5- ((6-aminopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane-2- Carboxylic acid ester (6b)

Tert-butyl (1S,4S) -5- ((6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid ester (6a) (180mg,0.49mmol), NH₃·H₂O(4.5mL)，Cu₂A mixture of O (80.0mg,0.56mmol) in MeOH (1.5mL) was stirred in a sealed tube at 65 deg.C overnight. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was differentiated between DCM and NaOH (2N). The organic layer was separated, washed with saturated brine and Na₂SO₄Dried and concentrated, and the residue purified by column chromatography on silica gel (eluent: DCM: MeOH ═ 10:1) to give tert-butyl (1S,4S) -5- ((6-aminopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid ester (6 b). MS-ESI (M/z):305[ M +1 [)]⁺。

Tert-butyl (1S,4S) -5- ((6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridine-6- Yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylate (6c)

Replacement of tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with tert-butyl (1S,4S) -5- ((6-aminopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] according to the Synthesis method of 1c]Heptane-2-carboxylic acid ester (6b), the title compound tert-butyl (1S,4S) -5- ((6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b) was prepared]Pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid ester (6 c). MS-ESI (M/z):574[ M +1 [)]⁺。

N- (5- (((1S,4S) -2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) pyrimidin-2-amine (6)

According to the synthesis method of 1, tert-butyl 4-((6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b))]Pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylate (1c) was replaced with tert-butyl (1S,4S) -5- ((6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid ester (6c), the title compound N- (5- (((1S,4S) -2, 5-diazabicyclo [ 2.2.1) was prepared]Heptane-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridin-6-yl) pyrimidin-2-amine (6). MS-ESI (M/z):474[ M +1]⁺。

Example 7

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) -N- (5- (((1S,4S) -5-) Methyl-2, 5-diazabicyclo [2.2.1]Heptane-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (7)

(1S,4S) -2- ((6-Bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane (7a)

To tert-butyl (1S,4S) -5- ((6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1 at room temperature]To a solution of heptane-2-carboxylate (6a) (0.81g,2.2mmol) in DCM (6mL) was added TFA (4 mL). The mixture was stirred for 2 hours. With Na₂CO₃The solution was adjusted to pH 8. The mixture was extracted with DCM (3X 6 mL). The extract was washed with water and saturated brine (5mL) in this order, and Na₂SO₄Drying and concentrating to give (1S,4S) -2- ((6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Heptane (7a) (0.534 g). MS-ESI (M/z) 268[ M + 1]]⁺。

(1S,4S) -2- ((6-Bromopyridin-3-yl) methyl) -5-methyl-2, 5-diazabicyclo [2.2.1]Heptane (7b)

To (1S,4S) -2- ((6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1 at room temperature]To a solution of heptane (7a) (0.15g,0.56mmol) in DCM (2mL) was added formaldehyde (37%, 63 μ L) followed by NaBH (OAc)₃(0.273g,1.12 mmol). The mixture was stirred vigorously for 30 minutes. The mixture was saturated with Na₂CO₃The solution was quenched, extracted with DCM (2X 5mL), and the extract was washed successively with water and saturated brine (5mL), Na₂SO₄And (5) drying. Filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: DCM: MeOH ═ 10:1) to give (1S,4S) -2- ((6-bromopyridin-3-yl) methyl) -5-methyl-2, 5-diazabicyclo [2.2.1]Heptane (7 b). MS-ESI (M/z):282,284[ M + 1]]⁺。

5- (((1S,4S) -5-methyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) pyridin-2-amine (7c)

According to the synthesis of 6b, tert-butyl (1S,4S) -5- ((6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Replacement of Heptane-2-carboxylate (6a) with (1S,4S) -2- ((6-bromopyridin-3-yl) methyl) -5-methyl-2, 5-diazabicyclo [2.2.1]Heptane (7b) to prepare the title compound 5- (((1S,4S) -5-methyl-2, 5-diazabicyclo [ 2.2.1)]Heptan-2-yl) methyl) pyridin-2-amine (7 c). MS-ESI (M/z) 219[ M + 1]]⁺。

5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) -N- (5- (((1S,4S) -5-) Methyl-2, 5-diazabicyclo [2.2.1]Heptane-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (7)

Replacement of tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with 5- (((1S,4S) -5-methyl-2, 5-diazabicyclo [ 2.2.1) according to the Synthesis method of 1c]Heptane-2-yl) methyl) pyridin-2-amine (7c) the title compound 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b) was prepared]Pyridin-6-yl) -N- (5- (((1S,4S) -5-methyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (7). MS-ESI (M/z):488[ M + 1]]⁺。

Example 8

N- (5- (((1S,4S) -5-ethyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) pyridin-2-yl) - 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) pyrimidin-2-amine (8)

(1S,4S) -2- ((6-Bromopyridin-3-yl) methyl) -5-ethyl-2, 5-diazabicyclo [2.2.1]Heptane (8a)

To (1S,4S) -2- ((6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1 at room temperature]To a solution of heptane (7a) (0.10g,0.37mmol) and TEA (60. mu.L, 0.41mmol) in DMF (1mL) was added dropwise ethyl bromide (27. mu.L, 0.33 mol). The mixture was stirred for 3.5 hours. Extract with water (5mL) and DCM (5 mL). The extract was washed with water (2mL) and saturated brine (2mL) in this order, and then with Na₂SO₄Dried and concentrated. The residue was purified by silica gel column chromatography (eluent: DCM: MeOH ═ 10:1) to give (1S,4S) -2- ((6-bromopyridin-3-yl) methyl) -5-ethyl-2, 5-diazabicyclo [2.2.1]Heptane (8 a). MS-ESI (M/z):296,298[ M + 1]]⁺。

5- (((1S,4S) -5-Ethyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) pyridin-2-amine (8b)

According to the synthesis of 6b, tert-butyl (1S,4S) -5- ((6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1]Replacement of Heptane-2-carboxylate (6a) with (1S,4S) -2- ((6-bromopyridin-3-yl) methyl) -5-ethyl-2, 5-diazabicyclo [2.2.1]Heptane (8a) to prepare the title compound 5- (((1S,4S) -5-ethyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) pyridin-2-amine (8 b). MS-ESI (M/z):233[ M +1 [)]⁺。

N- (5- (((1S,4S) -5-ethyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) pyridin-2-yl) - 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b)]Pyridin-6-yl) pyrimidin-2-amine (8)

Replacement of tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with 5- (((1S,4S) -5-ethyl-2, 5-diazabicyclo [ 2.2.1) according to the Synthesis method of 1c]Heptane-2-yl) methyl) pyridin-2-amine (8b) to prepare the title compound N- (5- (((1S,4S) -5-ethyl-2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b]Pyridine compound-6-yl) pyrimidin-2-amine (8). MS-ESI (M/z):488[ M + 1]]⁺。

Examples 9-81 listed in Table 1 are prepared essentially according to the same procedures as examples 1-8, or using similar synthetic strategies or procedures, using starting materials that are either commercially available or are prepared according to literature procedures and mutatis mutandis. The names and structures of examples 9-81 are given in Table 1.

TABLE 1

Example 83

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b)]Pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl) Yl) pyridin-2-yl) pyrimidin-2-amine (83)

Tert-butyl 4- ((6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b)]Pyridin-5-yl) pyrimidine- 2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylic acid ester (83a)

The title compound tert-butyl 4- ((6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-B) was prepared according to the synthesis of 1c, reactants tert-butyl 4- ((6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1B) and 5- (2-chloro-5-fluoropyrimidin-4-yl) -7-fluoro-3-isopropyl-1-methyl-3 a,7 a-dihydro-1H-indazole (intermediate B)]Pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylic acid ester (83 a). MS-ESI (M/z):562[ M + 1]]⁺。

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b)]Pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl) Yl) pyridin-2-yl) pyrimidin-2-amine (83)

According to the synthesis method of 1, tert-butyl 4- ((6- ((5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b))]Pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylate (1c) was replaced with tert-butyl 4- ((6- ((5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b)]Pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylic acid ester (83a) the title compound 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b) was prepared]Pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl)) Pyridin-2-yl) pyrimidin-2-amine (83). MS-ESI (M/z):462[ M + 1[ ]]⁺。

Example 84

5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b)]Pyridin-5-yl) -N- (5- ((4-methylpiperazine- 1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (84)

To 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b) at room temperature]Pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (83) (17.8mg,0.0386mmol), NaBH (OAc)₃To a solution of (12.3mg,0.0579mmol) in DCE (1mL) was added dropwise HCHO (37% aqueous solution) (2 drops), and the mixture was stirred at room temperature for 4 hours. NaHCO for the mixture₃The solution was diluted and extracted with DCM. Extract Na₂SO₄Dried and concentrated. Purifying the residue by preparative thin layer chromatography to obtain 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b)]Pyridin-5-yl) -N- (5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (84). MS-ESI (M/z):476[ M +1 [)]⁺。

Example 85

N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyri-dine Azolo [3,4-b]Pyridin-5-yl) pyrimidin-2-amine (85)

To 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b) at room temperature]Pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (83) (17.8mg,0.0386mmol), NaBH (OAc)₃To a solution of (12.3mg,0.0579mmol) in DCE (1mL) was added dropwise MeCHO (40% aqueous solution) (2 drops), and the mixture was stirred at room temperature for 4 hours. NaHCO for the mixture₃The solution was diluted and extracted with DCM. Extract Na₂SO₄Dried and concentrated. Disabled personThe retentate was purified by preparative thin layer chromatography to give N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b)]Pyridin-5-yl) pyrimidin-2-amine (85). MS-ESI (M/z) 490[ M + 1]]⁺。

Example 86

5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b)]Pyridin-5-yl) -N- (5- ((4-methylpiperazine- 1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (86)

According to the synthesis of 1c, the reactant is 5- (2-chloro-5-fluoropyrimidin-4-yl) -3-isopropyl-1-methyl-1H-pyrazolo [3,4-b]Pyridine (intermediate C) and 5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-amine (2a) to prepare the title compound 5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b)]Pyridin-5-yl) -N- (5- ((4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (86). MS-ESI (M/z):476[ M +1 [)]⁺。

Example 87

N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-1-methyl-1H-pyri-dine Azolo [3,4-b]Pyridin-5-yl) pyrimidin-2-amine (87)

According to the synthesis of 1c, the reactant is 5- (2-chloro-5-fluoropyrimidin-4-yl) -3-isopropyl-1-methyl-1H-pyrazolo [3,4-b]Pyridine (intermediate C) and 5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (3a) to prepare the title compound N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b)]Pyridin-5-yl) pyrimidin-2-amine (87). MS-ESI (M/z):476[ M +1 [)]⁺。

Examples 88-156 listed in Table 2 were prepared using the methods described in examples 83-87, by substituting the corresponding aminopyridine and making the necessary modifications, or using similar synthetic strategies or methods.

TABLE 2

Cell proliferation assay

To test the in vitro inhibitory effect of compounds on CDK4/6 kinase, a BE (2) -C cell-based assay was established. In the present method, the inhibitory activity of a compound against CDK4/6 is determined by measuring the inhibitory effect on the proliferation of BE (2) -C cells. BE (2) -C cells were seeded into 96-well culture plates at 5000/well, and 150. mu.l of the medium was added per well. Compound dilution: each compound was diluted to 20mM with DMSO as a stock solution, and on the day of addition, a working solution of 4-fold final concentration was prepared on the medium. After 24 hours of BE (2) -C cell inoculation, 50. mu.l of compound working solution (duplicate wells for each compound) was added to each well. After 72 hours of incubation, the cell proliferation activity was measured by the MTS method.

The prepared compounds were tested according to the biological activity test method described above. The results are shown in Table 3.

TABLE 3

Examples	IC50(nM)	Examples	IC50(nM)	Examples	IC50(nM)	Examples	IC50(nM)
								1	857	49	728	91	574	126	192
2	343	54	58	92	124	129	464
								3	204	56	740	93	96	134	323
4	19	57	456	94	68	135	418
								5	49	58	279	95	768	136	46
7	583	59	37	96	51	137	28
								8	811	60	435	97	55	138	18
10	82	61	217	99	176	139	26
								11	60	62	251	100	74	140	38
13	546	63	91	102	74	141	102
								14	392	65	58	103	99	142	26
16	751	66	51	105	640	143	20
								19	396	68	58	106	177	144	31
20	272	69	31	107	178	145	16
								22	840	70	148	108	456	146	37
23	514	71	38	109	297	147	535
								27	91	72	25	110	165	148	51
28	15	73	901	111	253	149	27
								29	85	74	182	112	954	151	121
31	364	75	22	113	243	152	99
								32	273	77	624	114	61	153	51
34	473	78	59	116	228	154	13
								35	53	80	911	117	157	155	22
40	460	81	365	118	463	156	35
								41	332	84	64	119	42	157	30
43	662	85	19	120	46	159	44
								44	440	88	994	121	489	160	22
46	420	88	85	122	433
								47	152	89	28	125	309

Claims (20)

1. A compound of formula (I) or (II):

or a pharmaceutically acceptable salt thereof, wherein,

q is pyridine;

each R¹Is hydrogen;

each R²Is hydrogen;

each R³Is independently selected from C_1-10An alkyl group;

each R⁴Is halogen;

each R⁵Independently selected from methyl, ethyl,

Which is unsubstituted or substituted by at least one member independently selected from R^XSubstituted with the substituent(s);

each R^XIndependently selected from C_1-10Alkyl, wherein each alkyl is independently unsubstituted or substituted with 1 independently selected from R^YSubstituted with the substituent(s);

each R^YIndependently selected from- (CR)^c2R^d2)_tOR^b2；

Each R^b2Independently selected from C_1-10An alkyl group;

m is 1;

n is selected from 0,1 and 2;

p is 2;

t is 0;

with the proviso that the compound of the formula (I) is not

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one means 1,2,3 or 4.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula

(I)。

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula

(II)。

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Q is

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein each R⁵Is independently selected from

Which is unsubstituted or substituted with at least one, independently selected from R^XIs substituted with the substituent(s).

7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R⁵Is that

Which is unsubstituted or substituted by at least one member independently selected from R^XIs substituted with the substituent(s).

8. A compound of formula (I) or (II):

or a pharmaceutically acceptable salt thereof, wherein,

q is

Each R¹Is hydrogen;

each R²Is hydrogen;

each R³Is independently selected from C_1-10An alkyl group;

each R⁴Is halogen;

each R⁵Independently selected from methyl, ethyl and

which is unsubstituted or substituted by at least one member independently selected from R^XSubstituted with the substituent(s);

each R^XIndependently selected from C_1-10Alkyl, wherein each alkyl is independently unsubstituted or substituted with 1 independently selected from R^YSubstituted with the substituent(s);

each R^YIndependently selected from- (CR)^c2R^d2)_tOR^b2；

Each R^b2Independently selected from C_1-10An alkyl group;

m is 1;

n is selected from 0,1 and 2;

p is 2;

t is 0.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein at least one means 1,2,3 or 4.

10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, having the formula

(I)。

11. The compound of claim 8, or a pharmaceutically acceptable salt thereof, having the formula

(II)。

12. The compound of any one of claims 1-4 or 8-11, or a pharmaceutically acceptable salt thereof, wherein each R³Independently selected from methyl, isopropyl and tert-butyl.

13. The compound of any one of claims 1-4 or 8-11, or a pharmaceutically acceptable salt thereof, wherein each R⁴Independently selected from fluorine.

14. The compound of any one of claims 1-4 or 8-11, or a pharmaceutically acceptable salt thereof, wherein each R^XIs independently selected from C_1-10Alkyl and methoxymethyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R^XIs independently selected from C_1-10An alkyl group.

16. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein each R^XIndependently selected from methyl, ethyl and methoxymethyl.

17. A compound selected from

(S) -5-fluoro-N- (5- ((hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

(R) -5-fluoro-N- (5- ((hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-amine,

N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) pyrimidin-2-yl) -6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((4-ethyl-3- (methoxymethyl) piperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

4- (1- (tert-butyl) -2-methyl-1H-imidazo [4,5-b ] pyridin-6-yl) -N- (5- ((8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

(R) -5-fluoro-N- (5- ((hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (3-isopropyl-2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) pyrimidin-2-amine,

(R) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- ((hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,

4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -N- (5- ((3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,

(S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoro-N- (5- ((3- (methoxymethyl) -4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine

N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-ethyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine,

N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3,4-b ] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (1-ethylpiperidin-4-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine

Or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

19. Use of a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18, in the manufacture of a medicament for the treatment, amelioration or prevention of a condition that is responsive to inhibition of CDK4/6, wherein the compound or pharmaceutically acceptable salt thereof or pharmaceutical composition is optionally in combination with a second therapeutic agent.

20. Use of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18, in the manufacture of a medicament for treating a cell proliferation disorder.