CN113549069A - Kinase inhibitor - Google Patents

Kinase inhibitor Download PDF

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Publication number
CN113549069A
CN113549069A CN202110836287.1A CN202110836287A CN113549069A CN 113549069 A CN113549069 A CN 113549069A CN 202110836287 A CN202110836287 A CN 202110836287A CN 113549069 A CN113549069 A CN 113549069A
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alkyl
radical
cycloalkyl
amino
substituted
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Inventor
赵兴东
李同双
张华杰
李志福
刘滨
刘启洪
谭锐
容悦
杨理君
陈志方
谭浩瀚
姜立花
刘研新
令狐莉
林敏�
孙婧
王为波
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Chongqing Fushang Yuanchuang Pharmaceutical Technology Co Ltd
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Shanghai Fochon Pharmaceutical Co Ltd
Fochon Pharmaceuticals Ltd
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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
The present application is a divisional application of chinese patent application No. 201680076568.9 entitled "class of kinase inhibitors" filed on 26.12.2016.
This application claims priority to U.S. provisional application 62/271,311, which is incorporated herein by reference in its entirety.
Technical Field
The present invention relates to a class of compounds or pharmaceutically acceptable salts which inhibit the activity of CDK4/6 kinase 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 provide the motive force 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. Uncontrolled proliferation is a characteristic of cancer cells, and CDK dysfunction occurs at high frequency in many solid tumors.
The role of CDKs and related proteins is critical in the coordination of proliferating cells and in driving the cell cycle. Thus, therapies that target-generic CDKs or specific CDKs to treat dysplastic diseases, such as cancer, have great potential. CDK inhibitors may also be used to treat other diseases such as viral infections, autoimmune diseases and neurodegenerative diseases. Targeted therapy of CDKs may also be used in combination with other therapeutic agents for the treatment of the above-mentioned diseases.
Therefore, compounds having CDK inhibitory activity are of great interest for the prevention and treatment of cancer. Although CDK4/6 inhibitors have been reported in the literature, e.g., WO2010020675 and WO2012064805, many inhibitors have low activity, short half-life or are toxic. Accordingly, there is an increasing need for novel inhibitors of CDK4/6 that have advantages in at least one of therapeutic efficacy, stability, selectivity, safety, pharmacodynamic profile and pharmacokinetic profile. Based on the situation, the invention provides a novel CDK4/6 inhibitor.
Disclosure of Invention
The invention relates to a novel 6-5 membered fused ring derivative, pharmaceutically acceptable salts thereof, a pharmaceutical composition thereof and application thereof as a medicament.
In one aspect, the invention provides a compound of formula (I):
Figure BDA0003177167530000021
or a pharmaceutically acceptable salt thereof, wherein
X is C or N;
y is C or N;
z is CR6O, S or NR7；
The 6-5 membered fused ring system A-B is selected from:
Figure BDA0003177167530000022
q is selected from aryl and heteroaryl;
w is CH or CRX；
R1Selected from hydrogen, halogen, hydroxy, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di (alkyl) amino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from RXSubstituted with the substituent(s);
R2selected from hydrogen, halogen, hydroxy, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di (alkyl) amino, heterocyclyl, aryl and heteroaryl is independentlySubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from RXSubstituted with the substituent(s);
R3and R4Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl and C3-10cycloalkyl-C1-4Alkyl, wherein each alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from RXSubstituted with the substituent(s);
or R3And R4Together with the N atom to which they are attached form a 4-12 membered ring containing 1,2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may optionally be substituted with 1,2 or 3RXSubstituted by groups;
each R5Independently selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, CN, NO2、-NRA1RB1、-ORA1、-S(O)rRA1、-S(O)2ORA1、-OS(O)2RA1、-P(O)RA1RB1、-P(O)(ORA1)(ORB1)、-C(O)RA1、-C(O)ORA1、-OC(O)RA1、-C(O)NRA1RB1、-NRA1C(O)RB1、-OC(O)NRA1RB1、-NRA1C(O)ORB1、-NRA1C(O)NRA1RB1、-NRA1C(S)NRA1RB1、-S(O)rNRA1RB1、-NRA1S(O)rRB1、-NRA1S(O)2NRA1RB1、-S(O)(＝NRE1)RB1、-N＝S(O)RA1RB1、-NRA1S(O)(＝NRE1)RB1、-S(O)(＝NRE1)NRA1RB1、-NRA1S(O)(＝NRE1)NRA1RB1、-C(＝NRE1)RA1、-C(＝N-ORB1)RA1、-C(＝NRE1)NRA1RB1、-NRA1C(＝NRE1)RB1and-NRA1C(＝NRE1)NRA1RB1Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one substituent such as 1,2,3 or 4 independently selected from RX;
R6selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, CN, NO2、-NRA2RB2、-ORA2、-S(O)rRA2、-S(O)2ORA2、-OS(O)2RA2、-P(O)RA2RB2、-P(O)(ORA2)(ORB2)、-C(O)RA2、-C(O)ORA2、-OC(O)RA2、-C(O)NRA2RB2、-NRA2C(O)RB2、-OC(O)NRA2RB2、-NRA2C(O)ORB2、-NRA2C(O)NRA2RB2、-NRA2C(S)NRA2RB2、-S(O)rNRA2RB2、-NRA2S(O)rRB2、-NRA2S(O)2NRA2RB2、-S(O)(＝NRE2)RB2、-N＝S(O)RA2RB2、-NRA2S(O)(＝NRE2)RB2、-S(O)(＝NRE2)NRA2RB2、-NRA2S(O)(＝NRE2)NRA2RB2、-C(＝NRE2)RA2、-C(＝N-ORB2)RA2、-C(＝NRE2)NRA2RB2、-NRA2C(＝NRE2)RB2and-NRA2C(＝NRE2)NRA2RB2Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from RXSubstituted with the substituent(s);
R7selected from hydrogen, halogen, C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, CN, -S (O)rRA3、-C(O)RA3、-CO2RA3and-C (O) NRA3RB3Wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from RXSubstituted with the substituent(s);
each RA1、RA2、RA3、RB1、RB2And RB3Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, 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 RXSubstituted with the substituent(s);
or each "RA1And RB1”、“RA2And RB2"or" RA3And RB3Taken 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 3RXSubstituted by groups;
each RE1And RE2Independently selected from hydrogen, C1-10Alkyl, CN, NO2、-ORa1、-SRa1、-S(O)rRa1、-C(O)Ra1、-S(O)rNRa1Rb1and-C (O) NRa1Rb1；
Each RXIndependently selected from C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, halogen, CN, NO2、-(CRc1Rd1)tNRa1Rb1、-(CRc1Rd1)tORb1、-(CRc1Rd1)tS(O)rRb1、-(CRc1Rd1)tS(O)2ORb1、-(CRc1Rd1)tOS(O)2Rb1、-(CRc1Rd1)tP(O)Ra1Rb1、-(CRc1Rd1)tP(O)(ORa1)(ORb1)、-(CRc1Rd1)tC(O)Ra1、-(CRc1Rd1)tC(O)ORb1、-(CRc1Rd1)tOC(O)Rb1、-(CRc1Rd1)tC(O)NRa1Rb1、-(CRc1Rd1)tNRa1C(O)Rb1、-(CRc1Rd1)tOC(O)NRa1Rb1、-(CRc1Rd1)tNRa1C(O)ORb1、-(CRc1Rd1)tNRa1C(O)NRa1Rb1、-(CRc1Rd1)tNRa1C(S)NRa1Rb1,-(CRc1Rd1)tS(O)rNRa1Rb1、-(CRc1Rd1)tNRa1S(O)rRb1、-(CRc1Rd1)tNRa1S(O)2NRa1Rb1、-(CRc1Rd1)tS(O)(＝NRe1)Rb1、-(CRc1Rd1)tN＝S(O)Ra1Rb1、-(CRc1Rd1)tNRa1S(O)(＝NRe1)Rb1、-(CRc1Rd1)tS(O)(＝NRe1)NRa1Rb1、-(CRc1Rd1)tNRa1S(O)(＝NRe1)NRa1Rb1、-(CRc1Rd1)tC(＝NRe1)Ra1、-(CRc1Rd1)tC(＝N-ORb1)Ra1、-(CRc1Rd1)tC(＝NRe1)NRa1Rb1、-(CRc1Rd1)tNRa1C(＝NRe1)Rb1And- (CR)c1Rd1)tNRa1C(＝NRe1)NRa1Rb1Wherein 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 RYSubstituted with the substituent(s);
each Ra1And Rb1Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, 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 RYSubstituted with the substituent(s);
or Ra1And Rb1Together 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 3RYSubstituted by groups;
each Rc1And Rd1Independently selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, 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 RYSubstituted with the substituent(s);
or Rc1And Rd1Together 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 3RYSubstituted by groups;
each Re1Independently selected from hydrogen, C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, CN, NO2、-ORa2、-SRa2、-S(O)rRa2、-C(O)Ra2、-C(O)ORa2、-S(O)rNRa2Rb2and-C (O) NRa2Rb2；
RYIndependently selected from C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, halogen, CN, NO2、-(CRc2Rd2)tNRa2Rb2、-(CRc2Rd2)tORb2、-(CRc2Rd2)tS(O)rRb2、-(CRc2Rd2)tS(O)2ORb2、-(CRc2Rd2)tOS(O)2Rb2、-(CRc2Rd2)tP(O)Ra2Rb2、-(CRc2Rd2)tP(O)(ORa2)(ORb2)、-(CRc2Rd2)tC(O)Ra2、-(CRc2Rd2)tC(O)ORb2、-(CRc2Rd2)tOC(O)Rb2、-(CRc2Rd2)tC(O)NRa2Rb2、-(CRc2Rd2)tNRa2C(O)Rb2、-(CRc2Rd2)tOC(O)NRa2Rb2、-(CRc2Rd2)tNRa2C(O)ORb2、-(CRc2Rd2)tNRa2C(O)NRa2Rb2、-(CRc2Rd2)tNRa2C(S)NRa2Rb2、-(CRc2Rd2)tS(O)rNRa2Rb2、-(CRc2Rd2)tNRa2S(O)rRb2、-(CRc2Rd2)tNRa2S(O)2NRa2Rb2、-(CRc2Rd2)tS(O)(＝NRe2)Rb2、-(CRc2Rd2)tN＝S(O)Ra2Rb2、-(CRc2Rd2)tNRa2S(O)(＝NRe2)Rb2、-(CRc2Rd2)tS(O)(＝NRe2)NRa2Rb2、-(CRc2Rd2)tNRa2S(O)(＝NRe2)NRa2Rb2、-(CRc2Rd2)tC(＝NRe2)Ra2,-(CRc2Rd2)tC(＝N-ORb2)Ra2、-(CRc2Rd2)tC(＝NRe2)NRa2Rb2、-(CRc2Rd2)tNRa2C(＝NRe2)Rb2And- (CR)c2Rd2)tNRa2C(＝NRe2)NRa2Rb2Wherein 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, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
each Ra2And Rb2Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, 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, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
or Ra2And Rb2Together 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 halogen, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino; each Rc2And Rd2Independently selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, 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, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, OH, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
or Rc2And Rd2Together 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, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkyl radicalsAmino and di (C)1-10Alkyl) amino;
each Re2Independently selected from hydrogen, CN, NO2、C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, -C (O) C1-4Alkyl, -C (O) C3-10Cycloalkyl, -C (O) OC1-4Alkyl, -C (O) OC3-10Cycloalkyl, -C (O) N (C)1-4Alkyl radical)2、-C(O)N(C3-10Cycloalkyl radicals2、-S(O)2C1-4Alkyl, -S (O)2C3-10Cycloalkyl, -S (O)2N(C1-4Alkyl radical)2and-S (O)2N(C3-10Cycloalkyl radicals2；
Each r is independently selected from 0, 1 and 2;
each t is independently selected from 0, 1,2,3, and 4;
m is selected from 0, 1,2 and 3.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another aspect, the present 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 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 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 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 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 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 a pharmaceutically acceptable salt thereof, in 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 chemotherapeutic agents to treat cell proliferative disorders.
In particular, wherein the cell proliferative disorder includes, but is not limited to, lymphoma, osteosarcoma, melanoma, or breast cancer, renal cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, neuronal cancer, lung cancer, uterine or gastrointestinal tumor.
In the above methods of using the compounds of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to a system comprising cells or tissues or to a subject, including a mammalian subject, such as a human or animal subject.
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. All patents, patent applications, published publications, and the like, referred to throughout this disclosure are incorporated by reference in their entirety unless otherwise indicated. As used herein, there are a number of definitions for the same term, which shall govern 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. As used herein, the singular includes the plural unless otherwise specified. 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, conventional techniques of mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacology, as used herein, are prior art. Unless specifically defined, the nomenclature, protocols, and techniques involved in analytical chemistry, synthetic organic chemistry, pharmaceutical and pharmaceutical chemistry described herein are known. 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 herein. 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, "Ci-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. C1-4，C1-10，C3-10And the like.
"alkyl", whether used alone or in combination with other terms, refers to branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atomsAnd (4) clustering. Unless otherwise indicated, "alkyl" means C1-10An alkyl group. For example, "C1-6C in alkyl1-6"refers to a linear or branched arrangement of groups having 1,2,3,4, 5 or 6 carbon atoms. For example, "C1-8Alkyl "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). Monocyclic and bridged hydrocarbons may 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 also be present. Thus, "C2－6Alkenyl "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, "C2-6Alkynyl radical"refers to alkynyl groups containing 2 to 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 another molecule through an oxygen atom. Alkoxy groups may be represented as-O-alkyl. "C1-10Alkoxy "refers to an alkoxy group containing 1 to 10 carbon atoms, and may be a straight chain or a branched structure. 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 another molecule through an oxygen atom. Cycloalkoxy can be represented as-O-cycloalkyl. "C3-10Cycloalkoxy "means a cycloalkoxy group containing 3 to 10 carbon atoms. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, and 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. An alkylthio group is attached to another molecule through a sulfur atom. Alkylthio groups may be represented by-S-alkyl. "C1-10Alkylthio "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 linked to another molecule through a sulfur atom. The cycloalkylthio group may be represented as-S-cycloalkyl. "C3-10Cycloalkylthio "means a cycloalkylthio group containing 3 to 10 carbon atoms. Cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, and cyclohexylthio, and the like.
"AlkylaminesGroup ", used alone or in combination with other terms, means an alkyl group attached to a nitrogen atom by a single bond. The alkylamino group is attached to another molecule through a nitrogen atom. Alkylamino can be represented as-NH (alkyl). "C1-10Alkylamino "refers to alkylamino groups containing 1 to 10 carbon atoms, which may be straight chain or branched. Alkylamino includes, but is 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 linked to another molecule through a nitrogen atom. The cycloalkylamino group may be represented as-NH (cycloalkyl). "C3-10Cycloalkylamino "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 another 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 atoms1-10Alkyl) amino, which may be linear or branched.
"aryl", used alone or in combination with other terms, 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 on the ring atoms, are named substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose name ends in "-yl", which are obtained by removing one more hydrogen atom from a carbon atom containing the valence electron of the radical, are named after the name of the monovalent radical plus "-idene", for example, naphthyl, which has two attachment sites, is called naphthylene. 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", used alone or in combination with other terms, 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 monovalent heteroaryl radicals ends with the "radical", which derives a divalent radical derived by removing a further hydrogen atom from the carbon atom containing the valence electron, by adding "idene" to the name of the monovalent radical, 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-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, 1, 4-piperazinyl and 2, 3-pyridazinyl. Morpholinyl is also contemplated, and 2-morpholinyl and 3-morpholinyl (oxygen position numbering is preferably 1) are also included. 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, but are not limited to:
Figure BDA0003177167530000111
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 C1-4Alkyl "in which" C1-4"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-C1-4Alkyl "in which" C1-4"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 "C3-10cycloalkyl-C1-4Alkyl "in which" C3-10"refers to the number of carbon atoms in the cycloalkyl moiety rather than the alkyl moiety. Wherein "C1-4"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-C1-4Alkyl "in which" C1-4"refers to the number of carbon atoms in the cycloalkyl moiety rather than in the heteroaryl moiety.
To avoid ambiguity, for example: when alkyl, cycloalkyl, heterocyclyl, aryl and/orWhen heteroaryl is substituted, it means that each of these groups is substituted individually or that these groups are mixed. That is: if R is1Is aryl-C1-4The alkyl, aryl moieties may be unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from RXMay also be unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from RXA 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, tripropylamine and tromethamine.
When the compounds disclosed herein are bases, it is desirable to prepare salts 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 a substituent attached to an amino group that blocks or protects the amino functionality on a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-Butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (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-nitrobenzenesulfinyl) 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-nitrophenylmercapto, 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, dibenzylphosphoryl, 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 1974Recommendations 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 to this, the correlationSynthetic procedures and intermediates are described, 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 standard compounds in 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-labelled parent compounds, and studying the in vivo metabolism of compounds (Blake et al, J. pharm. Sci.64,3,367-391 (1975)). Such metabolic studies are important for designing safe and effective therapeutic agents, and can be judged to be toxic or carcinogenic to the active compound administered to the patient in vivo 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))
Stable isotopic labels of 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 those of unlabeled molecules, while chemical and biological properties are the same, but with 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.
1. The present invention provides compounds of formula (I):
Figure BDA0003177167530000161
or a pharmaceutically acceptable salt thereof, wherein
X is C or N;
y is C or N;
z is CR6O, S or NR7；
The 6-5 membered fused ring system A-B is selected from:
Figure BDA0003177167530000162
q is selected from aryl and heteroaryl;
w is CH or CRX；
R1Selected from hydrogen, halogen, hydroxy, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di (alkyl) amino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from RXSubstituted with the substituent(s);
R2selected from hydrogen, halogen, hydroxy, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkyl ammonia, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, 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 RXSubstituted with the substituent(s);
R3and R4Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl and C3-10cycloalkyl-C1-4Alkyl, wherein each alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from RXSubstituted with the substituent(s);
or R3And R4Together with the N atom to which they are attached form a 4-12 membered ring containing 1,2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may optionally be substituted with 1,2 or 3RXSubstituted by groups;
each R5Independently selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, CN, NO2、-NRA1RB1、-ORA1、-S(O)rRA1、-S(O)2ORA1、-OS(O)2RA1、-P(O)RA1RB1、-P(O)(ORA1)(ORB1)、-C(O)RA1、-C(O)ORA1、-OC(O)RA1、-C(O)NRA1RB1、-NRA1C(O)RB1、-OC(O)NRA1RB1、-NRA1C(O)ORB1、-NRA1C(O)NRA1RB1、-NRA1C(S)NRA1RB1、-S(O)rNRA1RB1、-NRA1S(O)rRB1、-NRA1S(O)2NRA1RB1、-S(O)(＝NRE1)RB1、-N＝S(O)RA1RB1、-NRA1S(O)(＝NRE1)RB1、-S(O)(＝NRE1)NRA1RB1、-NRA1S(O)(＝NRE1)NRA1RB1、-C(＝NRE1)RA1、-C(＝N-ORB1)RA1、-C(＝NRE1)NRA1RB1、-NRA1C(＝NRE1)RB1and-NRA1C(＝NRE1)NRA1RB1Wherein 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 RXSubstituted by a substituent of；
R6Selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, CN, NO2、-NRA2RB2、-ORA2、-S(O)rRA2、-S(O)2ORA2、-OS(O)2RA2、-P(O)RA2RB2、-P(O)(ORA2)(ORB2)、-C(O)RA2、-C(O)ORA2、-OC(O)RA2、-C(O)NRA2RB2、-NRA2C(O)RB2、-OC(O)NRA2RB2、-NRA2C(O)ORB2、-NRA2C(O)NRA2RB2、-NRA2C(S)NRA2RB2、-S(O)rNRA2RB2、-NRA2S(O)rRB2、-NRA2S(O)2NRA2RB2、-S(O)(＝NRE2)RB2、-N＝S(O)RA2RB2、-NRA2S(O)(＝NRE2)RB2、-S(O)(＝NRE2)NRA2RB2、-NRA2S(O)(＝NRE2)NRA2RB2、-C(＝NRE2)RA2、-C(＝N-ORB2)RA2、-C(＝NRE2)NRA2RB2、-NRA2C(＝NRE2)RB2and-NRA2C(＝NRE2)NRA2RB2Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from RXSubstituted with the substituent(s);
R7selected from hydrogen, halogen, C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, CN, -S (O)rRA3、-C(O)RA3、-CO2RA3and-C (O) NRA3RB3Wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from RXSubstituted with the substituent(s);
each RA1、RA2、RA3、RB1、RB2And RB3Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, 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 RXSubstituted with the substituent(s);
or each "RA1And RB1”、“RA2And RB2"or" RA3And RB3Taken 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 3RXSubstituted by groups;
each RE1And RE2Independently selected from hydrogen, C1-10Alkyl, CN, NO2、-ORa1、-SRa1、-S(O)rRa1、-C(O)Ra1、-S(O)rNRa1Rb1and-C (O) NRa1Rb1；
Each RXIndependently selected from C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, halogen, CN, NO2、-(CRc1Rd1)tNRa1Rb1、-(CRc1Rd1)tORb1、-(CRc1Rd1)tS(O)rRb1、-(CRc1Rd1)tS(O)2ORb1、-(CRc1Rd1)tOS(O)2Rb1、-(CRc1Rd1)tP(O)Ra1Rb1、-(CRc1Rd1)tP(O)(ORa1)(ORb1)、-(CRc1Rd1)tC(O)Ra1、-(CRc1Rd1)tC(O)ORb1、-(CRc1Rd1)tOC(O)Rb1、-(CRc1Rd1)tC(O)NRa1Rb1、-(CRc1Rd1)tNRa1C(O)Rb1、-(CRc1Rd1)tOC(O)NRa1Rb1、-(CRc1Rd1)tNRa1C(O)ORb1、-(CRc1Rd1)tNRa1C(O)NRa1Rb1、-(CRc1Rd1)tNRa1C(S)NRa1Rb1,-(CRc1Rd1)tS(O)rNRa1Rb1、-(CRc1Rd1)tNRa1S(O)rRb1、-(CRc1Rd1)tNRa1S(O)2NRa1Rb1、-(CRc1Rd1)tS(O)(＝NRe1)Rb1、-(CRc1Rd1)tN＝S(O)Ra1Rb1、-(CRc1Rd1)tNRa1S(O)(＝NRe1)Rb1、-(CRc1Rd1)tS(O)(＝NRe1)NRa1Rb1、-(CRc1Rd1)tNRa1S(O)(＝NRe1)NRa1Rb1、-(CRc1Rd1)tC(＝NRe1)Ra1、-(CRc1Rd1)tC(＝N-ORb1)Ra1、-(CRc1Rd1)tC(＝NRe1)NRa1Rb1、-(CRc1Rd1)tNRa1C(＝NRe1)Rb1And- (CR)c1Rd1)tNRa1C(＝NRe1)NRa1Rb1Wherein 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 RYSubstituted with the substituent(s);
each Ra1And Rb1Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, 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 RYSubstituted with the substituent(s);
or Ra1And Rb1Together 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 3RYSubstituted by groups;
each Rc1And Rd1Independently selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one, such as 1,2, g,3 or 4, independently selected from RYSubstituted with the substituent(s);
or Rc1And Rd1Together 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 3RYSubstituted by groups;
each Re1Independently selected from hydrogen, C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, CN, NO2、-ORa2、-SRa2、-S(O)rRa2、-C(O)Ra2、-C(O)ORa2、-S(O)rNRa2Rb2and-C (O) NRa2Rb2；
RYIndependently selected from C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, halogen, CN, NO2、-(CRc2Rd2)tNRa2Rb2、-(CRc2Rd2)tORb2、-(CRc2Rd2)tS(O)rRb2、-(CRc2Rd2)tS(O)2ORb2、-(CRc2Rd2)tOS(O)2Rb2、-(CRc2Rd2)tP(O)Ra2Rb2、-(CRc2Rd2)tP(O)(ORa2)(ORb2)、-(CRc2Rd2)tC(O)Ra2、-(CRc2Rd2)tC(O)ORb2、-(CRc2Rd2)tOC(O)Rb2、-(CRc2Rd2)tC(O)NRa2Rb2、-(CRc2Rd2)tNRa2C(O)Rb2、-(CRc2Rd2)tOC(O)NRa2Rb2、-(CRc2Rd2)tNRa2C(O)ORb2、-(CRc2Rd2)tNRa2C(O)NRa2Rb2、-(CRc2Rd2)tNRa2C(S)NRa2Rb2、-(CRc2Rd2)tS(O)rNRa2Rb2、-(CRc2Rd2)tNRa2S(O)rRb2、-(CRc2Rd2)tNRa2S(O)2NRa2Rb2、-(CRc2Rd2)tS(O)(＝NRe2)Rb2、-(CRc2Rd2)tN＝S(O)Ra2Rb2、-(CRc2Rd2)tNRa2S(O)(＝NRe2)Rb2、-(CRc2Rd2)tS(O)(＝NRe2)NRa2Rb2、-(CRc2Rd2)tNRa2S(O)(＝NRe2)NRa2Rb2、-(CRc2Rd2)tC(＝NRe2)Ra2,-(CRc2Rd2)tC(＝N-ORb2)Ra2、-(CRc2Rd2)tC(＝NRe2)NRa2Rb2、-(CRc2Rd2)tNRa2C(＝NRe2)Rb2And- (CR)c2Rd2)tNRa2C(＝NRe2)NRa2Rb2Wherein 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, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) ammoniaSubstituent substitution of the group;
each Ra2And Rb2Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, 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, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
or Ra2And Rb2Together 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 halogen, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, OH, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
each Rc2And Rd2Independently selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, 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, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
or Rc2And Rd2Together 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, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
each Re2Independently selected from hydrogen, CN, NO2、C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, -C (O) C1-4Alkyl, -C (O) C3-10Cycloalkyl, -C (O) OC1-4Alkyl, -C (O) OC3-10A cycloalkyl group, a,-C(O)N(C1-4Alkyl radical)2、-C(O)N(C3-10Cycloalkyl radicals2、-S(O)2C1-4Alkyl, -S (O)2C3-10Cycloalkyl, -S (O)2N(C1-4Alkyl radical)2and-S (O)2N(C3-10Cycloalkyl radicals2；
Each r is independently selected from 0, 1 and 2;
each t is independently selected from 0, 1,2,3, and 4;
m is selected from 0, 1,2 and 3.
2.1A compound or a pharmaceutically acceptable salt thereof, wherein the fused ring system A-B is selected from
Figure BDA0003177167530000211
Figure BDA0003177167530000212
3.2A compound or a pharmaceutically acceptable salt thereof, wherein the fused ring system A-B is
Figure BDA0003177167530000213
4.2 or a pharmaceutically acceptable salt thereof, wherein R6Selected from hydrogen and C1-10Alkyl, preferably R6Is hydrogen.
A compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein W is selected from the group consisting of CH and CRX。
A compound of 6.5 or a pharmaceutically acceptable salt thereof, wherein W is CH.
7.5 or a pharmaceutically acceptable salt thereof, wherein W is CRXWherein R isXSelected from halogens.
A compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Q is selected from aryl and heteroaryl.
A compound of 9.8 or a pharmaceutically acceptable salt thereof, wherein Q is selected from heteroaryl.
A compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein Q is selected from pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl.
A compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein Q is selected from pyridin-2-yl, pyrimidin-2-yl, pyridazin-3-yl, and pyrazin-2-yl.
A compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R1Selected from heterocyclyl, wherein heterocyclyl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from RXIs substituted with the substituent(s).
13.12 or a pharmaceutically acceptable salt thereof, wherein R1Is a heterocyclic group, wherein the heterocyclic group is unsubstituted or is independently selected from R by 1 or 2XIs substituted with the substituent(s).
14.13 or a pharmaceutically acceptable salt thereof, wherein R1Is selected from unsubstituted or substituted by 1 or 2 independently selected from RXSubstituted by substituents
Figure BDA0003177167530000214
Wherein R isXIs independently selected from C1-10Alkyl, heterocyclyl, -NRa1Rb1、-(CRc1Rd1)tORb1Wherein alkyl and heterocyclyl are unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from RYIs substituted with the substituent(s). Preferably RXIndependently selected from methyl, ethyl, isopropyl, propyl, heterocyclic radical, NRa1Rb1、-(CRc1Rd1)tORb1The heterocyclic radical is unsubstituted or is independently selected from R by 1 or 2YIs substituted with the substituent(s). More preferably Ra1And Rb1Independently selected from hydrogen and C1-10Alkyl, most preferably Ra1And Rb1Independently selected from hydrogen, methyl and ethyl, Rc1And Rd1Is hydrogen and t is 1.
15.1-14 or a pharmaceutically acceptable salt thereof, wherein R2Is selected from C3-10Cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from RXIs substituted with the substituent(s).
16.15 ofA compound or a pharmaceutically acceptable salt thereof, wherein R2Selected from the group consisting of cyclopentyl, cyclohexyl, and 4-methylcyclohexyl.
A compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R3And R4Independently selected from hydrogen and C1-10An alkyl group.
A compound of 18.17 or a pharmaceutically acceptable salt thereof, wherein R3And R4Is methyl.
A compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R5Selected from hydrogen, halogen and C1-10Alkyl, wherein R is preferred5Are hydrogen and halogen.
20. A compound selected from
1-cyclopentyl-N, N-dimethyl-6- ((5-piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-6- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (piperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (1-methylpiperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-6- ((5- (1-ethylpiperidin-4-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5-piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-6- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-morpholineproperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-6- ((5- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino-N, N-dimethyl-1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) -5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) -5- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
5- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) thieno [2,3-c ] pyridine-2-carboxamide,
5- ((5- (4-isopropylpiperidin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (dimethylamino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (3- (hydroxymethyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (3- (hydroxymethyl) -4-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (4-ethyl-3- (hydroxymethyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (3- (methoxymethyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (3- (methoxymethyl) -4-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (4-ethyl-3- (methoxymethyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (piperidin-4-yl) piperazin-1-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (1-ethylpiperidin-4-yl) piperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (piperidin-4-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (1-methylpiperidin-4-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (1-ethylpiperidin-4-yl) pyrimidin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4-morpholinylpiperidin-1-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((3-fluoro-5- (piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((3-fluoro-5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4-ethylpiperazin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((3-fluoro-5- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(S) -3-cyclopentyl-5- ((3-fluoro-5- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(S) -3-cyclopentyl-5- ((3-fluoro-5- (hexahydropyrazino [2,1-c ] [1,4] oxazin-8 (1H) -yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((3-fluoro-5- (hexahydropyrazino [2,1-c ] [1,4] oxazin-8 (1H) -yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((3-fluoro-5- (3-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (3, 4-dimethylpiperazin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (4-ethyl-3-dimethylpiperazin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(S) -3-cyclopentyl-5- ((3-fluoro-5- (3-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(S) -3-cyclopentyl-5- ((5- (3, 4-dimethylpiperazin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(S) -3-cyclopentyl-5- ((5- (4-ethyl-3-methylpiperazin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((3-fluoro-5- (3- (methoxymethyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((3-fluoro-5- (3- (methoxymethyl) -4-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (4-ethyl-3- (methoxymethyl) piperazin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((3-fluoro-5- (3- (hydroxymethyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((3-fluoro-5- (3- (hydroxymethyl) -4-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (4-ethyl-3- (hydroxymethyl) piperazin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
(S) -3-cyclopentyl-5- ((3-fluoro-5- (2-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((3-fluoro-5- (2-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (2, 4-dimethylpiperazin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (4-ethyl-2-methylpiperazin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (3- (fluoromethyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (3- (fluoromethyl) -4-methylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
(R) -3-cyclopentyl-5- ((5- (4-ethyl-3- (fluoromethyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (piperidin-4-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (1-methylpiperidin-4-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (1-ethylpiperidin-4-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (1-ethylpiperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((3-fluoro-5- (4- (piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((3-fluoro-5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((3-fluoro-5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) -3-fluoropyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4-morpholinylpiperidin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((3-fluoro-5- (4-morpholinylpiperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (piperazin-1-yl) piperidin-1-yl) pyrazin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyrazin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) pyrazin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4-morpholinylpiperidin-1-yl) pyrazin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((6- (4-morpholinylpiperidin-1-yl) pyridazin-3-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (piperidin-4-yl) piperazin-1-yl) pyrazin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-N, N-dimethyl-5- ((5- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyrazin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (1-ethylpiperidin-4-yl) piperazin-1-yl) pyrazin-2-yl) amino) -N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-4-fluoro-N, N-dimethyl-5- ((5- (4- (piperidin-4-yl) piperazin-1-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-4-fluoro-N, N-dimethyl-5- ((5- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) pyrimidin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4- (1-ethylpiperidin-4-yl) piperazin-1-yl) pyrimidin-2-yl) amino) -4-fluoro-N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-4-fluoro-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-4-fluoro-N, N-dimethyl-5- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-5- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -4-fluoro-N, N-dimethylthiophene [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-4-fluoro-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-4-fluoro-5- ((3-fluoro-5- (4- (piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthieno [2,3-c ] pyridine-2-carboxamide,
3-cyclopentyl-4-fluoro-N, N-dimethyl-5- ((5- (4-morpholinylpiperidin-1-yl) pyridin-2-yl) amino) thieno [2,3-c ] pyridine-2-carboxamide,
or a pharmaceutically acceptable salt thereof.
21. The present invention provides a pharmaceutical composition comprising a compound of any one of 1-20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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: instructions for what disease state the composition is to be applied to, information stored on the composition, dosage information, and 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 or variant of any of the above embodiments.
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., brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, ovary, prostate, colon, epidermis, esophagus, testicular, gynecological, or thyroid cancer); 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 compounds and variants of any one of the above embodiments as medicaments. In another aspect, the invention relates to the use of compounds and variants of any one of the above embodiments for the preparation of a medicament for inhibiting CDK 4/6.
In another aspect, the invention relates to the use of compounds and variants of any one of the above embodiments for the preparation of a medicament for the treatment of the pathology and/or symptomology of a disease state 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 viscosity increasing agents including, but not limited to, sodium carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizing agents 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 palmitateIsopropyl myristate, isopropyl myristate,
Figure BDA0003177167530000291
M2375 (polyoxyethylene glycerol),
Figure BDA0003177167530000292
M1944 CS (unsaturated polyglycolyzed glyceride prepared by alcoholysis of oleum Armeniacae amarum, containing glyceride and polyethylene glycol ester), LABRASOLTM(saturated PEGylated glycerides prepared by alcoholysis of TCM, containing glycerides and polyethylene glycol esters; all available from GaKefosse, France), and/or
Figure BDA0003177167530000293
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 oil 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, may also be 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 the present 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, therapies that can be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of the diseased area, 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) 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.
BiTE antibodies are bispecific antibodies that attack cancer cells by binding to T cells and cancer cell surface antigens. In addition, T cells attack the target cancer cells again. Examples of the BiTE antibody include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103), and the like. Without being limited by theory, one of the mechanisms in which T cells induce apoptosis of target cells is by exocytosis of the cell granules, which includes perforin and granzyme B. In this regard, Bcl-2 has been shown to attenuate apoptosis induced by perforin and granzyme B. These data indicate that inhibition of Bcl-2 enhances the cytotoxic effects of T cells when directed against cancer cells (v.r. sutton, d.l. vaux and j.a. trapani, j.of Immunology 1997,158(12), 5783).
sirnas are molecules with endogenous RNA bases or chemically modified nucleotides. This modification does not abolish cellular activity, but rather increases stability and/or cellular potency. Examples of chemical modifications include phosphorothioate groups, 2' -deoxynucleotides, 2-OCH-containing groups3Radical (I)The ribonucleotide of (1), 2 '-F-ribonucleotide, 2' -methoxyethyl ribonucleotide, a combination thereof and the like. The sirnas can be of varying lengths (e.g., 10-200 base pairs) and structures (e.g., hairpins, single/double strands, bulges, cuts/gaps, mismatches) and processed in cells to silence active genes. Double stranded sirna (dsrna), can have the same number of nucleotides on each strand (blunt end) or at an asymmetric end (overhang). The 1-2 nucleotide overhang may be present on the sense strand and/or the antisense strand, and may be present at the 5 'and/or 3' -end of the designated strand. For example, targeting Mcl-1 by siRNA was shown to enhance the activity of ABT-263, (i.e., N- (4- (4- ((2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4- (((1R) -3- (morpholin-4-yl) -1- ((phenylsulfanyl) methyl) -propyl) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide, or ABT-737 (i.e., N- (4- (4- ((4' -chloro (1, R-biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4- ((R-biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4 (1R) -3- (dimethylamino) -1- ((phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide).
Multivalent binding proteins comprise two or more antigen binding sites. Multivalent binding proteins are engineered into normally non-naturally occurring antibodies with three or more antigen binding sites. "Multispecific binding protein" refers to a protein that is capable of binding 2 or more related or unrelated target proteins. A Dual Variable Domain (DVD) binding protein is a tetravalent or multivalent binding protein comprising two or more antigen binding sites. Thus, DVDs can be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding 2 or more antigens). A DVD-binding protein comprising two DVD polypeptide heavy chains and 2 DVD polypeptide light chains is referred to as DVD Ig. In each half of the DVD Ig, 1 DVD polypeptide heavy chain, 1 DVD polypeptide light chain, and 2 antigen binding sites are included. Each binding site comprises 1 heavy chain variable domain and 1 light chain variable domain, and the total number of CDRs per antibody binding site is 6.
Alkylating agents include: altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brositallicin, busulfan, carboquone, carmustine (BCNU), phenylbutyric acidNitrogen mustard,
Figure BDA0003177167530000321
(lanreotide, VNP40101M), cyclophosphamide, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), macsfamide, melphalan, dibromomannitol, dibromodulcitol, nimustine, mechlorethamine N-oxide, ramustine, temozolomide, thiotepa, temozolomide, and other active compounds,
Figure BDA0003177167530000322
(bendamustine), busulfan, trofosfamide, and the like.
Angiogenesis inhibitors include: endothelial specific receptor tyrosine kinase (Tie-2) inhibitors, Epidermal Growth Factor Receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, inhibitors of matrix metalloproteinase-2 (MMP-2), inhibitors of matrix metalloproteinase 9(MMP-9), Platelet Derived Growth Factor Receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors, and the like.
The antimetabolite comprises
Figure BDA0003177167530000324
(Pemetrexed disodium, LY231514, MTA), 5-azacitidine,
Figure BDA0003177167530000323
(Capecitabine), carmofur,
Figure BDA0003177167530000325
(cladribine), clofarabine, cytarabine octadecylphosphate, cytarabine, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-1-beta-D-ribofuranosyl imidazole-4-carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil, alone or in combination with leucovorin,
Figure BDA0003177167530000326
(gemcitabine), hydroxyurea,
Figure BDA0003177167530000327
(melphalan), mercaptopurine, 6-mercaptopurine nucleosides, methotrexate, mycophenolic acid, nelarabine, loratrexone, octadecyl phosphate, pellitrexol, pentostatin, raltitrexed, ribavirin, triapine, trimetrexate, S-1, thiazolorfurin, tegafur, TS-1, vidarabine, UFT, and the like.
Antiviral agents include ritonavir, hydroxychloroquine, and the like.
Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, Aurora A specific inhibitors, Aurora B specific inhibitors, and panaurora kinase inhibitors, among others.
Bcl-2 protein inhibitors include AT-101((-) gossypol),
Figure BDA0003177167530000328
(G3139 or Orimerson (targeting Bcl-2 antisense oligonucleotide)), IPI-194, IPI-565, N- (4- (4- ((4 '-chloro (1,1' -biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4- (((1R) -3- (dimethylamino) -1- ((phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) (ABT-737), N- (4- (4- ((2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4- (((1R) -3- (morpholin-4-yl) -1- ((phenylsulfanyl) methyl) propyl) amino) -3- ((trifluoromethyl) -sulfonyl) benzenesulfonamide (ABT-263), GX-070(obatoclax), and the like.
Bcr-Abl kinase inhibitors include
Figure BDA0003177167530000331
(BMS-354825)、
Figure BDA0003177167530000332
(imatinib), and the like.
CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, Fragran flatness, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709, and the like.
COX-2 inhibitors include ABT-963,
Figure BDA0003177167530000333
(etoricoxib),
Figure BDA0003177167530000334
(valdecoxib), BMS347070,
Figure BDA0003177167530000335
(celecoxib), COX-189 (lumiracoxib), CT-3,
Figure BDA0003177167530000336
(deracoxib), JTE-522, 4-methyl-2- (3, 4-dimethylphenyl) -1- (4-sulfamoylphenyl-1H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614,
Figure BDA0003177167530000337
(rofecoxib), and the like.
The EGFR inhibitor comprises ABX-EGF, anti-EGFR immunoliposome, EGF vaccine, EMD-7200,
Figure BDA0003177167530000338
(cetuximab), HR3, IgA antibodies,
Figure BDA0003177167530000339
(gefitinib) is added to the composition,
Figure BDA00031771675300003310
(erlotinib or OSI-774), TP-38, EGFR fusion protein,
Figure BDA00031771675300003311
(lapatinib), and the like.
ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),
Figure BDA00031771675300003313
(trastuzumab),
Figure BDA00031771675300003314
(lapatinib),
Figure BDA00031771675300003312
(2C4, pertuzumab), TAK-165, GW-572016 (ionofanib), GW-282974, EKB-569, PI-166, dHER2(HER2 vaccine), APC-8024(HER-2 vaccine), anti-HER/2 neu bispecific antibody, B7.HER2IgG3, AS HER2 trifunctional bispecific antibody, monoclonal antibody AR-209, monoclonal antibody 2B-1, and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
The HSP-90 inhibitor comprises 17-AAG-NAB, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953,
Figure BDA00031771675300003315
(HSP90 human recombinant antibody), NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090VER49009, etc.
The inhibitor for inhibiting apoptosis protein includes HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242, etc.
Antibody drug conjugates include anti-CD 22-MC-MMAF, anti-CD 22-MC-MMAE, anti-CD 22-MCC-DM1, CR-011-vcMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75, and similar death receptor pathway activators including TRAIL, antibodies or other drugs targeting TRAIL or death receptors (e.g., DR4 and DR5), such as Apomab, cetostearl, ETR2-ST01, GDC0145 (lexamumab), HGS-1029, LBY-135, PRO-1762, and trastuzumab.
Kinesin inhibitors include Eg5 inhibitors, such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A, etc.
JAK-2 inhibitors include CEP-701 (lestaurtinib), XL019, INCBO18424 and the like.
MEK inhibitors include ARRY-142886, ARRY-438162, PD-325901, PD-98059, and the like.
mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, sirolimus, ATP-competitive TORC1/TORC2 inhibitors including PI-103, PP242, PP30, Torin 1, and the like.
The non-steroidal anti-inflammatory drug comprises
Figure BDA0003177167530000341
(disalicylate),
Figure BDA0003177167530000345
(diflunisal) and (bis (flunivalin),
Figure BDA0003177167530000342
(ibuprofen),
Figure BDA0003177167530000343
(ketoprofen),
Figure BDA0003177167530000344
(nabumetone),
Figure BDA0003177167530000346
(piroxicam), ibuprofen cream,
Figure BDA00031771675300003411
(naproxen) and
Figure BDA00031771675300003410
(naproxen),
Figure BDA0003177167530000347
(diclofenac),
Figure BDA00031771675300003412
(Xiaoyantong),
Figure BDA00031771675300003414
(sulindac),
Figure BDA0003177167530000349
(tolmetin),
Figure BDA0003177167530000348
(Etodolac),
Figure BDA00031771675300003413
(ketorolac),
Figure BDA00031771675300003415
(oxaprozin), and the like.
PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
The platinum chemotherapeutic drugs comprise cisplatin,
Figure BDA00031771675300003416
(oxaliplatin), eptaplatin, lobaplatin, nedaplatin,
Figure BDA00031771675300003417
(carboplatin), satraplatin, picoplatin, and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Phosphatidylinositol-3-kinase (PI3K) inhibitors include wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765, and the like.
Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1, and the like.
VEGFR inhibitors include
Figure BDA00031771675300003418
(bevacizumab), ABT-869, AEE-788, ANGIOZYMETM(ribozyme against angiogenesis (ribozyme pharmaceutical company (Border, Colorado) and Kalon (Elmerrilage, Calif.)), Astinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (Pagatanib), Dogemini (Sorafenib, BAY43-9006), Pazopanib (GW-786034), Watalanb (PTK-787, ZK-222584), Sotanium
Figure BDA00031771675300003419
(the amount of sunitinib in the composition,SU-11248)、VEGF trap、ZACTIMATM(vandetanib, ZD-6474) and the like. The antibiotics include the inserted antibiotics aclarubicin, actinomycin D, amrubicin, anamycin, adriamycin,
Figure BDA00031771675300003420
(bleomycin), daunorubicin, and,
Figure BDA00031771675300003421
Or
Figure BDA00031771675300003422
(Liposomal doxorubicin), elsamitrucin, epirubicin, glanbuicin, and,
Figure BDA00031771675300003423
(idarubicin), mitomycin C, nemorubicin, neocarzinostatin, pelomycin, pirarubicin, rebeccamycin, styrene polymer (stimalamer), streptozocin, and related compounds,
Figure BDA00031771675300003424
(valrubicin), and/or (zinostatin).
The topoisomerase inhibitor comprises aclacinomycin, 9-aminocamptothecin, amsacrine, becatecarin, belotene, BN-80915, and,
Figure BDA00031771675300003425
(irinotecan hydrochloride), camptothecin,
Figure BDA00031771675300003426
(dexrazoxane or dexrazoxane)), diflutecan, edotecarin,
Figure BDA00031771675300003427
Or
Figure BDA00031771675300003428
(epirubicin), etoposide, irinotecan, 10-hydroxycamptothecin, gemmacetan, lurtotecan, mitoxantroneRubitecan, pirarubicin, pixantrone, rubitecan, sobuzosin, SN-38, afluposide, topotecan, and the like.
The antibody comprises
Figure BDA00031771675300003429
(bevacizumab), an antibody specific for CD40, chTNT-1/B, denosumab, Dermatocet,
Figure BDA00031771675300003430
(cetuximab),
Figure BDA00031771675300003433
(zanolimumab), IGF 1R-specific antibody, lintuzumab,
Figure BDA00031771675300003431
(Edamuzumab),
Figure BDA00031771675300003432
(WX G250)、
Figure BDA00031771675300003434
(rituximab), (CTLA-4 mab), trastuzumab, CD20 type I and type II antibodies, and the like.
The hormone therapy comprises
Figure BDA0003177167530000351
(anastrozole),
Figure BDA0003177167530000355
(exemestane), azoxifene,
Figure BDA0003177167530000352
(bicalutamide),
Figure BDA0003177167530000354
(cetrorelix), degarelix, lorelin,
Figure BDA0003177167530000353
(trilostane), dexamethasone,
Figure BDA0003177167530000357
(flutamide),
Figure BDA0003177167530000356
(Raloxifene), AFEMATM(Fang),
Figure BDA0003177167530000358
(toremifene),
Figure BDA00031771675300003510
(fulvestrant),
Figure BDA0003177167530000359
(letrozole), formestane, glucocorticoid,
Figure BDA00031771675300003511
(cholecalciferol) in the presence of,
Figure BDA00031771675300003514
(sevelamer carbonate), lasofoxifene, leuprorelin acetate, and,
Figure BDA00031771675300003512
(megestrol),
Figure BDA00031771675300003513
(mifepristone), NILANDRONTM(nilutamide),
Figure BDA00031771675300003524
(tamoxifen citrate), PLENAXISTM(Abarelix), prednisone,
Figure BDA00031771675300003516
(finasteride), trilostane, and,
Figure BDA00031771675300003515
(buserelin),
Figure BDA00031771675300003517
(luteinizing hormone releasing hormone (LHRH)), (LHRH),
Figure BDA00031771675300003520
(implantation of histrelin),
Figure BDA00031771675300003518
(trilostane),
Figure BDA00031771675300003519
(fosrelin, goserelin) and the like.
Deltoid and retinoids include seocalcitol (EB1089, CB1093), lasiocalcitol (KH1060), fenretinide, tretinoin, and retinoids,
Figure BDA00031771675300003521
(aliretinoin 9-cis-retinoic acid or alitretinoin),
Figure BDA00031771675300003523
(Liposomal retinoic acid),
Figure BDA00031771675300003522
(bexarotene), LGD-1550, and the like.
PARP inhibitors include ABT-888 (Veripanib), Olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231, and the like.
Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine, and the like. Proteasome inhibitors include
Figure BDA00031771675300003525
(bortezomib), MG132, NPI-0052, PR-171, and the like.
The immune preparation includes interferon and other immune enhancers. The interferon comprises interferon alpha, interferon alpha-2A, interferon alpha-2 b, interferon beta, interferon gamma-LA,
Figure BDA00031771675300003526
(interferon gamma-LB) or interferon gamma-NL, combinations thereof, and the like. The other reagents include
Figure BDA00031771675300003527
(IFN-a), BAM-002 (oxidized glutathione),
Figure BDA00031771675300003528
(tasonermin) and (tasonermin),
Figure BDA00031771675300003529
(tositumomab),
Figure BDA00031771675300003530
(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), dacarbazine, dinil interleukin, epratuzumab,
Figure BDA00031771675300003531
(Legionsin), lentinan, leukocyte interferon-alpha, imiquimod, MDX-010(CTLA-4 antibody), melanoma vaccine, mitumomab, morastidine, MYLOTARGTM(Jimumab ozomicin),
Figure BDA00031771675300003532
(filgrastim), OncoVAC-CL,
Figure BDA00031771675300003533
(oregovomab)、pemtumomab(Y-muHM FGL)、
Figure BDA00031771675300003534
(xipracet-T), sargrastim, schizophyllan or cezopyran, teichosine (teceleukin),
Figure BDA00031771675300003535
(Bacillus Calmette-Guerin), ubenimex,
Figure BDA00031771675300003536
(immunotherapy, Lorus pharmaceutical Co., Ltd.), Z-100(Maruyama Specified Substance (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), (Sigma-Rad),
Figure BDA00031771675300003537
(aldesleukin aldesukin) and (de-leukin-aldesukin-aldesleukin-aldeskin-aldes,
Figure BDA00031771675300003538
(thymalfasin),
Figure BDA00031771675300003539
(daclizumab),
Figure BDA00031771675300003540
(90Y-ibritumomab) and the like.
Bioresponse modifiers are drugs used to modify biological defense mechanisms or biological responses, such as survival, growth or differentiation of tissue cells of an organism to direct it to have anti-tumor activity, including Coriolus versicolor, lentinan, sizofren, streptolysin PF-3512676(CpG-8954), ubenimex, and the like.
The pyrimidine analogs include cytarabine (ara C or arabinoside C), cytosine arabinoside, doxifluridine, and,
Figure BDA0003177167530000362
(fludarabine), 5-FU (5-fluorouracil), floxuridine,
Figure BDA0003177167530000361
(gemcitabine),
Figure BDA0003177167530000363
(Raltitrexed), TROXTELTM(triacetyluridine troxacitabine) and the like.
The purine analogues include
Figure BDA0003177167530000364
(thioguanine) and
Figure BDA0003177167530000365
(6-mercaptopurine).
The antimitotic agent comprises batabulin, epothilone D (KOS-862), N- (2- ((4-hydroxyphenyl) amino) pyridin-3-yl) -4-methylbenzenesulfonamide, ixabepilone (BMS247550), paclitaxel, and combinations thereof,
Figure BDA0003177167530000366
(docetaxel), PNU100940(109881), patupulon, XRP-9881(larotaxel loxel), vinflunine, ZK-EPO (synthetic epothilone), and the like.
Ubiquitin ligase inhibitors include MDM2 inhibitors such as nutlin, NEDD8 inhibitors such as MLN4924 and the like. The compounds of the invention may also be used as radiosensitizers to enhance the efficacy of radiation therapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed source radiotherapy, open source radiotherapy, and the like.
In addition, the compounds of formula (I) may be used in combination with chemotherapeutic agents, e.g., ABRAXANETM(ABI-007), ABT-100 (farnesyltransferase inhibitors),
Figure BDA0003177167530000367
(Ad5CMV-p53 vaccine),
Figure BDA0003177167530000368
Or
Figure BDA0003177167530000369
(lovastatin) Anpril
Figure BDA00031771675300003610
(unequal molecule mismatching polyinosinic polycytidylic acid, a synthetic RNA),
Figure BDA00031771675300003611
(Exishulin),
Figure BDA00031771675300003612
(pamidronic acid), parthenolide derivative, L-asparaginase, alpha-glucosidaseTametamet (l-methyl-3, 17-dione-androst-l, 4-diene),
Figure BDA00031771675300003613
(tazarotene), AVE-8062 (combretastatin derivatives), BEC2 (mitumomab), cachectin (tumor necrosis factor), kavaxin (canvaxin) (vaccines),
Figure BDA00031771675300003619
(tumor vaccine),
Figure BDA00031771675300003620
(simon interleukin),
Figure BDA00031771675300003614
(di-hydrochloramine),
Figure BDA00031771675300003618
(human papillomavirus vaccines),
Figure BDA00031771675300003617
(C:
Figure BDA00031771675300003615
(cyclophosphamide); h:
Figure BDA00031771675300003621
(hydroxydoxorubicin); o vincristine
Figure BDA00031771675300003616
P is prednisone), CYPATTM(Cycloprogestin acetate), tubulin A4P, DAB (389) EGF (His-Ala hEGF-catalyzed and ectopic diphtheria toxin site linked by fusion) or TransMID-107RTM(diphtheria toxin), dacarbazine, dactinomycin, 5, 6-dimethylxanthone-4-acetic acid (DMXAA), eniluracil, EVIZONTM(squalamine lactic acid),
Figure BDA00031771675300003622
(T4N5 liposome lotion), round skin spongeEster, DX-8951f (irinotecan methanesulfonic acid), enzastaurin, EPO906 (epothilone B),
Figure BDA00031771675300003624
(tetravalent human papilloma virus (Types 6,11,16,18) recombinant vaccines)
Figure BDA00031771675300003623
Figure BDA00031771675300003625
GMK (ganglioside conjugate vaccine),
Figure BDA00031771675300003626
(prostate cancer vaccine), clopidogrel, histrelin, hydroxyurea, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintrekin besedotox), IL-13-Pseudomonas exotoxin, interferon-alpha, interferon gamma, JUNO VANTMOr MEPACTTM(mivakutide), lonafarnib, 5, 10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine),
Figure BDA00031771675300003627
(AE-941)、
Figure BDA00031771675300003630
(Trimeleguraldehyde),
Figure BDA00031771675300003631
(pentostatin),
Figure BDA00031771675300003628
(ribonucleases),
Figure BDA00031771675300003629
(melanoma vaccine therapy),
Figure BDA00031771675300003632
(IL-2 vaccine), ORATHECINTM(rubitecan),
Figure BDA00031771675300003634
(antibody-based cell pharmaceuticals),
Figure BDA00031771675300003633
MAb (murine monoclonal antibody), Taxol, PANDIMEXTM(the aglycone of ginsenoside includes 20(S aglycon saponin) protopanaxadiol (aPPD) and 20(S) panaxatriol (aPPT)), panitumumab, and,
Figure BDA00031771675300003635
(research cancer vaccine), pemetrexed, PEG interferon A, phenytol, procarbazine, rebimastat, and,
Figure BDA0003177167530000371
(Cartesian) to,
Figure BDA0003177167530000372
(lenalidomide), RSR13 (ethacrylonil), SOMATULINE
Figure BDA00031771675300003711
(lanreotide),
Figure BDA0003177167530000373
(Avermectin A), staurosporine (streptomycete staurosporine), talabostat (PT100),
Figure BDA0003177167530000374
(Bexarotene),
Figure BDA0003177167530000379
(DHA-taxol),
Figure BDA00031771675300003710
(Camphor, TLK286), tetramifene,
Figure BDA0003177167530000378
(temozolomide), timifene, thalidomide,
Figure BDA0003177167530000375
(STn-KLH), nolatrexed (2-amino-3, 4-dihydro-6-methyl-4-oxo-5- (4-pyridylthio) quinazoline dihydrochloride), TNFaradETM(adenovirus vector: tumor necrosis factor-alpha containing the gene)
Figure BDA0003177167530000376
Or
Figure BDA0003177167530000377
(bosentan), tretinoin (Lontin-A), tetrandrine,
Figure BDA00031771675300003712
(arsenic trioxide),
Figure BDA00031771675300003713
ukrain (alkaloid derivative from Chelidonium majus), Iressay bead (anti-alpha V beta 3 antibody),
Figure BDA00031771675300003714
(motesafen gadolinium) XINLAYTM(atrasentan), XYOTAXTM(paclitaxel polyglutamic acid),
Figure BDA00031771675300003715
(Tripex), ZD-6126,
Figure BDA00031771675300003716
(dexrazoxane),
Figure BDA00031771675300003717
(zoledronic acid), zorubicin, and the like.
Examples
There are various methods for synthesizing the compound of formula (I) 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 pharmaceutically acceptable salts thereof may also be obtained by synthesis in other synthetic schemes.
In certain compounds of formula (I), the attachment of atoms to other atoms may result in the presence of particular stereoisomers (e.g. chiral centres). The synthesis of a compound of formula (I) 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) 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) 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 the compounds of formula (I) are described in the definitions section herein. In addition, salt forms of the compounds of formula (I) can also be prepared by using salts of the starting materials or intermediates.
The free acid or base of the compound of formula (I) 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) 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) 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 a pharmaceutically acceptable salt thereof may be prepared by methods known in the art. For example, the N-oxide can be obtained by reacting a non-oxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, peroxymaleic acid (permaleic acid), perbenzoic acid, peracetic acid, m-chloroperoxybenzoic acid, etc.) in an inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at a temperature of approximately 0 to 80 ℃. Alternatively, the N-oxides of the compounds of formula (I) may also be prepared from the N-oxides of the starting materials.
The non-oxidized form of the compound of formula (I) can be prepared by reacting the N-oxide with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide and the like) in a suitable inert organic solvent (such as acetonitrile, ethanol, dioxane aqueous solution and the like) at 0-80 ℃.
Protected derivatives of compounds of formula (I) 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. Unless otherwise indicated, standard single or three letter abbreviations 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 (liter), mL (mL), μ L (microliter), psi (pounds per square inch), M (moles), mM (mmol), i.v. (intravenous), Hz (Hertz), MHz (megahertz), mol (moles), mmol (millimole), RT (ambient temperature), min (min), h (hour), mp (melting point), TLC (thin layer chromatography), Rt (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 (ethylene glycol dimethyl ether), DCM (dichloromethane), DCE (dichloroethane), DMF (N, N-dimethylformamide), DMPU (N, N-dimethyl propenylurea), CDI (1, 1-carbonyldiimidazo), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et2O (diethyl ether), EDCI (1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (tert-butoxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMSE (2- (trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilyl), TBS (tert-butyldimethylsilyl), DMAP (4-dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethylhexylcarbodiimide)Base), tBu (tert-butyl), HPLC (high performance liquid chromatography), BOP (bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride), TBAF (tetrabutylammonium fluoride), mCPBA (m-chloroperoxybenzoic 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 Bruker Avance 400 NMR spectrometer. Chemical shifts are expressed in ppm. The coupling constants are all in hertz (Hz). The apparent multiplicities are described in split mode and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplicities) and br (broad)
Low resolution Mass Spectrometry (MS) and compound purity data were from shimadzu mass spectrometry single-pole rod systems equipped with an electrospray ion detector (ESI), ultraviolet detectors (220 and 254nm) and 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
At least one compound of formula (I) and/or a pharmaceutically acceptable salt 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.
Protection of reactive functional groups may be necessary in reactions such as those described below to prevent these reactive groups from participating in other undesirable 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 synthetic procedures or by methods exemplified herein.
The synthetic route for the compounds of formula I of the present invention is shown in scheme 1. The intermediate of formula II is reacted with an amino-arene (formula III) to produce the compound of formula I via Buchwald amination or other amination coupling conditions reported in the literature.
Figure BDA0003177167530000391
Synthesis scheme 1
As an example of the preparation of the compound of formula II, one synthetic route for the compound of formula IIa is shown in FIG. 2. The compound with the formula IIa-B is prepared by taking aminoheteroarene IIa-A as a starting material through reductive amination or N-alkylation reaction reported in the literature. Halogenation of the compound IIa-B to IIa-C followed by transition metal catalyzed coupling, such as the Sonogashira reaction, produces alkynes IIa-E. Cyclization of IIa-E under the action of a base, such as TBAF, affords azaindole IIa-F. IIa-F is subjected to hydroxyl oxidation to obtain an intermediate IIa through removing a protective group on an oxygen atom and oxidizing the hydroxyl group to obtain amide.
Figure BDA0003177167530000392
Synthesis scheme 2
As another example of the preparation of the compound of formula II, one synthetic route for the compound of formula IIb is shown in FIG. 3. The IIb-A is lithiated and then reacts with IIb-B through Weinreb to prepare IIb-C, and the IIb-C is converted into IIb-E through halogen substitution and in-situ cyclization reactions of a one-pot method. The ester group of IIb-E is converted to an amide to provide an intermediate of formula IIb.
Figure BDA0003177167530000401
Synthesis scheme 3
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-chloro-1-cyclopentyl-N, N-dimethyl-1-hydro-pyrrolo [3, 2-c)]Pyridine-2-carboxamides (intermediate A))
Figure BDA0003177167530000402
2-chloro-N-Cyclopentyl pyridine-4-amine (A-1)
To a solution of 2-chloro-4-aminopyridine (10g,0.079mol) and cyclopentanone in isopropyl acetate (150mL) was added TFA (30mL,0.395mol) and sodium triacetoxyborohydride (50g,0.24mol) at room temperature, and reacted at this temperature for 24 hours. The reaction solution was poured into aqueous sodium hydrogencarbonate (2N,150mL), extracted with ethyl acetate (3 × 150mL), washed with saturated brine, and the dried and concentrated residue was purified by silica gel column chromatography (eluent: N-hexane/ethyl acetate ═ 15:1-10:1-5:1)) to give the title compound 2-chloro-N-cyclopentylpyridin-4-amine (a-1). MS-ESI (M/z):197[ M +1 [)]+。
2-chloro-N-cyclopentyl-5-iodopyridin-4-amine (A-2)
To a solution of 2-chloro-N-cyclopentylpyridin-4-amino (7.2g,0.037mol) in DMF (70mL) at room temperature was added N-iodosuccinimide (12g,0.055mol) and reacted at 60 ℃ for 12 hours. The reaction solution was poured into an aqueous sodium sulfite solution (2N,200mL), extracted with ethyl acetate (3 × 150mL), washed with saturated brine, and the dried and concentrated residue was purified by silica gel column chromatography (eluent: N-hexane/ethyl acetate: 30:1-20:1-1:1)) to give 2-chloro-N-cyclopentyl-5-iodopyridin-4-amine (a-2). MS-ESI (M/z):323[ M +1 ]]+
2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-4-amine (A- 3)
To contain threeEthylamine (2.5mL,18mmol) in DMF (15mL) was added 2-chloro-N-cyclopentyl-5-iodopyridin-4-amine (A-2) (1.17g,3.6mmol), 2- (prop-2-yn-1-yloxy) tetrahydro-2 h-pyran (0.61g,4.4mmol) and cuprous iodide (0.13g,0.67 mmol). Bis (triphenylphosphine) palladium dichloride (0.25g,0.36mmol) was added under nitrogen blanket, then replaced again with nitrogen and heated at 80 ℃ overnight. The reaction system was extracted with ethyl acetate (250mL), washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: N-hexane/ethyl acetate from 10:1 to 6:1) to give the title compound 2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-4-amine (a-3). MS-ESI (M/z):335[ M +1 ]]+。
6-chloro-1-cyclopentyl-2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-pyrrolo [3,2-c]Pyridine (A- 4)
To a solution of 2-chloro-N-cyclopentyl-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-4-amine (A-3) (0.88g,0.26mmol) in anhydrous tetrahydrofuran (20mL) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (13mL,13mmol) and then heated at 65 ℃ for two hours. The solvent was concentrated off and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate from 6:1 to 5:1) to give the title compound 6-chloro-1-cyclopentyl-2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-pyrrolo [3,2-c]Pyridine (A-4). MS-ESI (M/z):335[ M +1 ]]+。
(6-chloro-1-cyclopentyl-1H-pyrrole [3, 2-c)]Pyridin-2-yl) methanol (A-5)
To 6-chloro-1-cyclopentyl-2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-pyrrolo [3,2-c]To a solution of pyridine (A-4) (430mg,1.29mmol) in methanol (15mL) was added p-toluenesulfonic acid monohydrate (110mg,1.29 mmol). The reaction mixture was then stirred at room temperature overnight. The solvent was concentrated off, the residue was extracted with ethyl acetate (100mL), washed with water, saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound (6-chloro-1-cyclopentyl-1H-pyrrolo [3, 2-c)]Pyridin-2-yl) methanol (A-5) was used as crude product in the next step without further purification. MS-ESI (M/z):251[ M +1]+。
6-chloro-1-cyclopentyl-N, N-dimethyl-1H-pyrrolo [3,2-c]Pyridine-2-carboxamides (intermediate A))
(6-chloro-1-cyclopentyl-1H-pyrrole [3, 2-c)]Pyridin-2-yl) methanol (A-5) (300mg,1.2mmol), sodium cyanide (100mg,2.04mmol),2M dimethylamine in tetrahydrofuran (3mL,6mmol) were mixed in anhydrous DMF (20mL) and stirred at room temperature for 10 min before manganese dioxide (0.3g,3.45mmol) was added. Thirty minutes later, manganese dioxide (4.8g,55.2mmol) and 2M dimethylamine in tetrahydrofuran (3.5mL,7mmol) were added in three portions every two hours. After the reaction was complete, the reaction mixture was filtered through celite and washed with ethyl acetate. The solvent was concentrated and removed, followed by extraction with ethyl acetate (150mL), water, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration. The residue was purified by silica gel column chromatography (eluent: N-hexane/ethyl acetate from 4:1 to 1:1) to give 6-chloro-1-cyclopentyl-N, N-dimethyl-1H-pyrrolo [3,2-c ]]Pyridine-2-carboxamide (intermediate a). MS-ESI (M/z):292(M +1)+。
Intermediate B
5-bromo-3-cyclopentyl-N, N-dimethylthiophene [2,3-c]Pyridine-2-carboxamides (B)
Figure BDA0003177167530000421
N-methoxy-N-methylcyclopentylformamide (B-1)
N-methoxy-N-methylcyclopentylformamide (B-1) was prepared according to patent US 2009/62342.
(2-bromo-5-chloropyridin-4-yl) (cyclopentyl) methanone (B-2)
To a solution of diisopropylamine (4.87mL,34.5mmol) in tetrahydrofuran (80mL) under nitrogen was added butyllithium (2.5M in hexane, 13.4mL,33.6mmol) at-5 ℃. The reaction solution was stirred at-5 ℃ for 30 minutes. The reaction mixture was cooled to-78 ℃ and a solution of 2-bromo-5-chloropyridine (5.76g,30.0mmol) in tetrahydrofuran (80mL) was added dropwise. After stirring for 30 min, N-methoxy-N-methylcyclopentylformamide (B-1,4.94g,31.5mmol) was added dropwise. The reaction solution is at-78Stir for 30 minutes, warm slowly to room temperature and stir for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. Washing the extract with saturated brine, and washing with Na2SO4And (5) drying. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and eluted with 2-5% ethyl acetate-hexane to give (2-bromo-5-chloropyridin-4-yl) (cyclopentyl) methanone (B-2). MS-ESI (M/z):288, 290 and 292(1:1.2:0.4,100%), [ M +1]+。
5-bromo-3-cyclopentylthiophene [2,3-c]Pyridine-2-carboxylic acid (B-3)
To a solution of (2-bromo-5-chloropyridin-4-yl) (cyclopentyl) methanone B-2(1.44 g,5.00mmol) and methyl thioglycolate (0.556g,5.25mmol) in DMF (15mL) at room temperature was added NaH (60%, 400mg,10.0 mmol). The mixture was stirred at room temperature for 15 minutes and then heated at 60 ℃ for 1 hour. After cooling to room temperature, 5N NaOH (5mL) was added. Stirred at room temperature for 1 hour. The reaction solution was diluted with water and adjusted to pH 3-4 with 1N HCl. The mixture was extracted with ethyl acetate (2X 50 mL). The extract was washed with saturated brine and MgSO4And (5) drying. Vacuum evaporating solvent to obtain 5-bromo-3-cyclopentyl thiophene [2,3-c ]]Pyridine-2-carboxylic acid (B-3). MS-ESI (M/z):328and 328(1:1, 100%), [ M + 1%]+. Directly used for the next reaction.
5-bromo-3-cyclopentyl-N, N-dimethylthiophene [2,3-c]Pyridine-2-carboxamides (B)
To 5-bromo-3-cyclopentylthiophene [2,3-c]Pyridine-2-carboxylic acid (B-3) (1.63g,5.00mmol), dimethylamine hydrochloride (0.815g,10.0mmol), EDCI (1.44g,7.50mmol) and HOBT hydrate (1.15g,7.50mmol) in anhydrous DMF (50mL) was added DIPEA (2.61mL,15.0 mmol). The mixture was stirred at room temperature for 5 hours. Diluting with water, and extracting with ethyl acetate. Washing the extract with saturated brine and Na2SO4And (5) drying. The solvent was distilled off under reduced pressure. Purifying the residue with silica gel column chromatography, eluting with 50% ethyl acetate-hexane to obtain 5-bromo-3-cyclopentyl-N, N-dimethylthiophene [2,3-c ]]Pyridine-2-carboxamide (B). MS-ESI (M/z):353 and 355(1:1, 100%), [ M + 1%]+。
Intermediate C
5-bromo-N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) thiophene [2,3-c]Pyridine-2-carboxamides (C)
Figure BDA0003177167530000431
(1r,4r)-N-methoxy-N, 4-dimethylcyclohexane-1-carboxamide (C-1)
(1r,4r) -N-methoxy-N, 4-dimethylcyclohexane-1-carboxamide (C-1) was synthesized according to the procedure described in US 2014/0179680. MS-ESI (M/z):186[ M +1 ]]+.
5-bromo-N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) thiophene [2,3-c]Pyridine-2-carboxamides (C)
5-bromo-N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) thiophene [2,3-c]Pyridine-2-carboxamide (C) was prepared as intermediate B by replacing N-methoxy-N-methylcyclopentylcarboxamide (B-1) with (1r,4r) -N-methoxy-N, 4-dimethylcyclohexane-1-carboxamide (C-1). MS-ESI (M/z):381[ M +1 ]]+.
Example 1
1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine (II) Pyridine-2-carboxamide (1)
Figure BDA0003177167530000432
Tert-butyl 4- (2-aminopyrimidin-5-yl) piperazine-1-carboxylate (1a)
2-amino-5-bromopyrimidine (3.5g,20.1mmol), N-Boc-piperazine (8.2g,44.1mmol), sodium tert-butoxide (3.3g,34.4mmol), tris (dibenzylideneacetone) dipalladium 0.92g,1.0mmol) and 2-di-tert-butylphosphine-2' - (N, N-dimethylamino) biphenyl (1.37g,4.0mmol) were added to toluene (150mL) and mixed with stirring, heated to 110 ℃ under nitrogen and reacted overnight. The reaction was cooled to room temperature and filtered through a buchner funnel pad with celite and the filtrate was concentrated. The residue was dissolved with 0.5N hydrochloric acid (200mL) and extracted with ethyl acetate (2X 100 mL). The aqueous phase was basified with sodium hydroxide, adjusted to pH 4 and treated with dichloromethane (3X 150mL)) And (4) extracting. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give tert-butyl 4- (2-aminopyrimidin-5-yl) piperazine-1-carboxylate (1 a). MS-ESI (M/z) 280[ M +1 ]]+.
Tert-butyl 4- (2- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino) Pyrimidin-5-yl) piperazine-1-carboxylic acid ester (1b)
Under the protection of nitrogen, 6-chloro-1-cyclopentyl-N, N-dimethyl-1H-pyrrole [3,2-c]Pyridine-2-carboxamide (intermediate a) (120mg,0.41mmol), tert-butyl 4- (2-aminopyrimidin-5-yl) piperazine-1-carboxylate (1a) (250mg,0.89mmol), tris (dibenzylideneacetone) dipalladium (38mg,0.042mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (48mg,0.083mmol) and cesium carbonate (270mg,0.83mmol) were mixed in dioxane (12mL) and stirred at 100 ℃ overnight. The solvent was concentrated and removed, followed by extraction with ethyl acetate (100mL), washing with water and saturated brine, drying over anhydrous sodium sulfate, and concentration. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol from 100:1 to 50:1) to give the title compound tert-butyl 4- (2- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino) pyrimidin-5-yl) piperazine-1-carboxylate (1 b). MS-ESI (M/z):535[ M +1 ]]+。
1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine (II) Pyridine-2-carboxamide (1)
To tert-butyl 4- (2- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c) at 0 deg.C]Pyridin-6-yl) amino) pyrimidin-5-yl) piperazine-1-carboxylate (1b) (51mg,0.096mmol) in dichloromethane (5mL) was added TFA (1.5 mL). The reaction system was warmed to room temperature and reacted for 2 hours, extracted with dichloromethane (2X 50mL), washed successively with saturated sodium bicarbonate solution (20mL), water, saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol/aqueous ammonia 125:11.5:1) to give 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine-2-carboxamide (1). MS-ESI (M/z):435[ M +1 [)]+。
Example 2
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrole [3, 2-c]pyridine-2-carboxamide (2)
Figure BDA0003177167530000441
To 1-cyclopentyl-N, N-dimethyl-6- ((5 (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrole [3,2-c at 0 ℃]To a solution of pyridine-2-carboxamide (1) (11mg,0.025mmol) in 1, 2-dichloroethane (3mL) were added formaldehyde (37% aqueous solution, 10. mu.L), sodium triacetoxyborohydride (54mg,0.25mmol), and then reacted at this temperature for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution (10mL) and extracted with dichloromethane (2X 30 mL). Dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol 15:1) to give 1-cyclopentyl-N, N-dimethyl-6- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c-]Pyridine-2-carboxamide (2). MS-ESI (M/z):449[ M +1 ]]+。
Example 3
1-cyclopentyl-6- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-1H-pyrrole [3, 2-c]pyridine-2-carboxamide (3)
Figure BDA0003177167530000451
To 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrole [3,2-c at 0 ℃]To a solution of pyridine-2-carboxamide (1) (8.2mg,0.019mmol) in 1, 2-dichloroethane (3mL) were added acetaldehyde (40% aqueous solution, 10. mu.L), sodium triacetoxyborohydride (40mg,0.19mmol), and then reacted at this temperature for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution (10mL)) and extracted with dichloromethane (2X 30 mL). Dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/methanol 15:1)) To obtain 1-cyclopentyl-6- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-1H-pyrrole [3, 2-c)]Pyridine-2-carboxamide (3). MS-ESI (M/z):463[ M +1 [)]+。
Example 4
1-cyclopentyl-N, N-dimethyl-6- ((5- (piperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine (II) Pyridine-2-carboxamide (4)
Figure BDA0003177167530000452
Tert-butyl 4- (2-aminopyrimidin-5-yl) -3, 6-dihydropyridine-1- (2H) -carboxylic acid ester (4a)
Under the protection of nitrogen, 5-bromopyrimidine-2-amine (900mg,5.17mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate, (1.9g,6.15mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (209mg,0.29mmol) and potassium carbonate (2.2g,15.9mmol) were mixed in a mixed solution of dioxane (57mL) and water (9.5mL) and stirred at 80 ℃ overnight. The solvent was concentrated and removed, followed by extraction with ethyl acetate (100mL), washing with water and saturated brine, drying over anhydrous sodium sulfate, and concentration. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol from 100:1 to 50:1) to give the title compound tert-butyl 4- (2-aminopyrimidin-5-yl) -3, 6-dihydropyridine-1- (2H) -carboxylate (4 a). MS-ESI (M/z):277[ M +1 ]]+。
Tert-butyl 4- (2-aminopyrimidin-5-yl) -piperidine-1-carboxylic acid ester (4b)
To a solution of tert-butyl 4- (2-aminopyrimidin-5-yl) -3, 6-dihydropyridine-1- (2H) -carboxylate (4a) (303mg,1.1mmol) in ethanol (50mL) was added 10% Pd/C (60% water, 303mg), then the gas was replaced, and after replacement, the mixture was hydrogenated at normal pressure overnight. After completion of the reaction, the reaction mixture was filtered through celite and washed with ethyl acetate. The solvent was concentrated off and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol from 100:1 to 50:1) to give the title compound tert-butyl 4- (2-aminopyrimidin-5-yl) -piperidine-1-carboxylate (4 b). MS-ESI (m/z):279[M+1]+。
Tert-butyl 4- (2- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino) Pyrimidin-5-yl) piperidine-1-carboxylic acid ester (4c)
Tert-butyl 4- (2- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino) pyrimidin-5-yl) piperidine-1-carboxylate (4c) was prepared by following the synthesis of (1b) in example 1, replacing tert-butyl 4- (2-aminopyrimidin-5-yl) piperazine-1-carboxylate (1a) with tert-butyl 4- (2-aminopyrimidin-5-yl) -piperidine-1-carboxylate (4 b). MS-ESI (M/z):534[ M +1 [)]+。
1-cyclopentyl-N, N-dimethyl-6- ((5- (piperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine (II) Pyridine-2-carboxamide (4)
1-cyclopentyl-N, N-dimethyl-6- ((5- (piperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine-2-carboxamide (4) was prepared as in example 1 from tert-butyl 4- (2- ((1-cyclopentyl-2- (dimethylaminoacyl) -1 h-pyrrole [3, 2-c)]Pyridin-6-yl) amino) pyrimidin-5-yl) piperazine-1-carboxylic acid ester (1b) was changed to tert-butyl 4- (2- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridyl-6-yl) amino) pyrimidin-5-yl) piperidine-1-carboxylate (4 c). MS-ESI (M/z):434[ M +1 [)]+。
Example 5
1-cyclopentyl-N, N-dimethyl-6- ((5- (1-methylpiperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrole [3, 2-c]pyridine-2-carboxamide (5)
Figure BDA0003177167530000461
1-cyclopentyl-N, N-dimethyl-6- ((5- (1-methylpiperidin-4-yl) pyrimidin-2-yl) amino-1H-pyrrolo [3, 2-c)]Pyridine-2-carboxamide (5) was prepared as in example 2 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Change of pyridine-2-carboxamide (1) to 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrole [3,2-c]Pyridine-2-carboxamide (4). MS-ESI (M/z):448[ M +1 ]]+。
Example 6
1-cyclopentyl-6- ((5- (1-ethylpiperidin-4-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-1H-pyrrole [3, 2-c]pyridine-2-carboxamide (6)
Figure BDA0003177167530000471
1-cyclopentyl-6- ((5- (1-ethylpiperidin-4-yl) pyrimidin-2-yl) amino-N, N-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine-2-carboxamide (6) was prepared as in example 3 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Change of pyridine-2-carboxamide (1) to 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Pyridine-2-carboxamide (4). MS-ESI (M/z):462[ M + 1[ ]]+。
Example 7
1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine (II) Pyridine-2-carboxamide (7)
Figure BDA0003177167530000472
Tert-butyl 4- (6- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino) Pyridin-3-yl) piperazine-1-carboxylic acid ester (7a)
Tert-butyl 4- (6- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Preparation of pyridin-6-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (7a) tert-butyl 4- (2-aminopyrimidin-5-yl) piperazinyl-1-carboxylate (1a) was changed to tert-butyl 4- (6-aminopyridin-3-yl) -piperidine-1-carboxylate (obtained according to the procedure in US 2013/0116262) according to the synthesis of (1b) in example 1. MS-ESI (M/z):534[ M +1 [)]+。
1-cyclopentyl-N, N-dimethyl6- ((5-piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine (II) Pyridine-2-carboxamide (7)
1-cyclopentyl-N, N-dimethyl-6- ((5-piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine-2-carboxamide (7) was prepared as in example 1 from tert-butyl 4- (2- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino) pyrimidin-5-yl) piperazine-1-carboxylic acid ester (1b) was changed to tert-butyl 4- (6- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino) pyridin-3-yl) piperazine-1-carboxylic acid ester (7 a). MS-ESI (M/z):434[ M +1 [)]+。
Example 8
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrole [3, 2-c]pyridine-2-carboxamide (8)
Figure BDA0003177167530000481
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino-1H-pyrrolo [3, 2-c)]Pyridine-2-carboxamide (8) was prepared as in example 2 by reacting 1-cyclopentyl-N, N-dimethyl-6- ((5 (-piperazin-1-yl) pyrimidin-2-yl) amino-1H-pyrrolo [3, 2-c)]Change of pyridine-2-carboxamide (1) to 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine-2-carboxamide (7). MS-ESI (M/z):448[ M +1 ]]+。
Example 9
1-cyclopentyl-6- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-1H-pyrrole [3, 2-c]pyridine-2-carboxamide (9)
Figure BDA0003177167530000482
1-cyclopentyl-6- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-1H-pyrrolo [3, 2-c)]Process for preparing pyridine-2-carboxamides (9)As in example 3, 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Change of pyridine-2-carboxamide (1) to 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine-2-carboxamide (7). MS-ESI (M/z):462[ M + 1[ ]]+。
Example 10
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-morpholinepropydin-1-yl) pyridin-2-yl) amino) -1H-pyrrole [3, 2-c]pyridine-2-carboxamide (10)
Figure BDA0003177167530000491
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-morpholinopiperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrole [3,2-c]Preparation of pyridine-2-carboxamide (10) Synthesis of (1b) in example 1, tert-butyl 4- (2-aminopyrimidin-5-yl) piperazinyl-1-carboxylate (1a) was changed to 5- (4-morpholinopiperidin-1-yl) -pyridin-2-amine. MS-ESI (M/z):518[ M +1 [)]+。
Example 11
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H- Pyrrole [3,2-c ]]Pyridine-2-Carboxamides(11)
Figure BDA0003177167530000492
Tert-butyl 4- (1- (6- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino Yl) pyridin-3-yl) piperidin-4-yl) piperazine-1-carboxylic acid ester (11a)
Tert-butyl 4- (1- (6- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Preparation of pyridin-6-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazine-1-carboxylate (11a) Synthesis of (1b) in example 1, tert-butyl 4- (2-aminopyrimidin-5-yl) piperazine-1-carboxylate (1a) was changed to tert-butyl 4- (1- (6-aminopyridin-3-yl) -piperidin-4-yl) Piperazine-1-carboxylic acid ester. MS-ESI (M/z):617[ M +1 ]]+。
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H- Pyrrole [3,2-c ]]Pyridine-2-carboxamide (11)
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrole [3,2-c]Pyridine-2-carboxamide (11) was prepared as in example 1 from tert-butyl 4- (2- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino) pyrimidin-5-yl) piperazine-1-carboxylic acid ester (1b) was changed to tert-butyl 4- (1- (6- ((1-cyclopentyl-2- (dimethylaminoacyl) -1H-pyrrole [3, 2-c)]Pyridin-6-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazine-1-carboxylate (11 a). MS-ESI (M/z):517[ M + 1%]+。
Example 12
1-cyclopentyl-N, N-dimethyl-6- ((5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) 1H-pyrrolo [3,2-c ] yl]Pyridine compound-2-carboxamide (12)
Figure BDA0003177167530000501
1-cyclopentyl-N, N-dimethyl-6- ((5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrole [3,2-c]Pyridine-2-carboxamide (12) was prepared as in example 2 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Pyridine-2-carboxamide (1) Change to 1-cyclopentyl-N, N-dimethyl-6- ((5- (4-piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine-2-carboxamide (11). MS-ESI (M/z):531[ M +1 [)]+。
Example 13
1-cyclopentyl-6- ((5- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl radical-1H-pyrrole [3,2-c]Pyridine-2-carboxamide (13)
Figure BDA0003177167530000502
1-cyclopentyl-6- ((5- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-1H-pyrrole [3,2-c]Pyridine-2-carboxamide (13) was prepared as in example 3 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Pyridine-2-carboxamide (1) Change to 1-cyclopentyl-N, N-dimethyl-6- ((5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c]Pyridine-2-carboxamide (11). MS-ESI (M/z):545[ M +1 [)]+。
Example 14
3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c]Pyridine- 2-carboxamide (14)
Figure BDA0003177167530000511
Tert-butyl 4- (2- ((3-cyclopentyl-2- (dimethylcarbamoyl) thiophene [2, 3-c)]Pyridin-5-yl) amino) pyrimidines Pyridin-5-yl) piperazine-1-carboxylic acid ester (14a)
To 5-bromo-3-cyclopentyl-N, N-dimethylthiophene [2,3-c ]]Pyridine-2-carboxamide (B) (353mg,1.00mmol) in dioxane (10mL) was added tert-butyl 4- (2-aminopyrimidin-5-yl) piperazine-1-carboxylate (307mg,1.10mmol), Pd2(dba)3(55mg,0.060mmol), xantphos (69.5mg,0.120mmol) and cesium carbonate (652mg, 2.00 mmol). The mixture was heated at 100 ℃ for 5 hours under nitrogen. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate (2X 30 mL). Washing the extract with saturated brine and Na2SO4And (5) drying. The solvent was distilled off under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with 40-80% ethyl acetate-hexane to obtain tert-butyl 4- (2- ((3-cyclopentyl-2- (dimethylcarbamoyl) thiophene [2, 3-c)]Pyridin-5-yl) amino) pyrimidin-5-yl) piperazine-1-carboxylic acid ester (14 a). MS-ESI (M/z):552[ M +1 ]]+。
3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c]Pyridine- 2-carboxamide (14)
To 4- (2- ((3-cyclopentyl-2- (dimethylcarbamoyl) thiophene [2, 3-c)]Pyridin-5-yl) amino) pyrimidin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (14a) (430mg,0.780mmol) in dichloromethane (8mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with 94:5:1 dichloromethane-methanol-ammonia water to obtain 3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (14). MS-ESI (M/z):452[ M +1 [)]+。
Example 15
3-cyclopentyl-N, N-dimethyl-5- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c] Pyridine-2-carboxamide (15)
Figure BDA0003177167530000512
3-cyclopentyl-N, N-dimethyl-5- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (15) was prepared as in example 2 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Replacement of pyridine-2-carboxamide (1) with 3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c ]]Pyridine-2-carboxamide (14), MS-ESI (M/z):466[ M +1]+.
Example 16
3-cyclopentyl-5- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethylthiophene [2, 3-c)] Pyridine-2-carboxamide (16)
Figure BDA0003177167530000521
3-cyclopentyl-5- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethylthiophene [2, 3-c)]Pyridine-2-carboxamide (16)Prepared as in example 3 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Replacement of pyridine-2-carboxamide (1) with 3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c ]]Pyridine-2-carboxamide (14), MS-ESI (M/z):480[ M +1]+.
Example 17
3-cyclopentyl-5- ((5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethylthia-ne Thiophene [2,3-c ]]Pyridine-2-carboxamide (17)
Figure BDA0003177167530000522
(5-bromo)Pyrimidines-2-yl) carbamic acid tert-butyl ester (17a)
(5-Bromopyrimidin-2-yl) carbamic acid tert-butyl ester(17a) The preparation process of (a) is described in document US 2014/100366. MS-ESI (M/z):274[ M +1 ]]+.MS-ESI(m/z):274[M+1]+.
(5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-yl) aminomethylcarboxylic acid tert-butyl ester (17b)
(5-Bromopyrimidin-2-yl) carbamic acid tert-butyl ester(17a) (360mg,0.96mmol), N, N-dimethylaminopiperidin-4-amine (246mg,1.92mmol), tris (dibenzylideneacetone) dipalladium (44mg,0.048mmol),4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (56mg,0.096mmol), sodium tert-butoxide (184mg,1.92mmol) dispersed in toluene (11mL), heated to 110 ℃ under nitrogen, cooled to room temperature after 18 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol (10:1)) to give tert-butyl (5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-yl) carbamate (17 b). MS-ESI (M/z) 322[ M +1 ]]+。
5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-amine (17c)
(5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-yl) carbamic acid tert-butyl ester 17b (100mg) was dissolved in 3mL of dichloromethane at room temperature1.5mL of trifluoroacetic acid was slowly added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure to give the desired compound 5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-amine (17c) which was used in the next reaction without purification. MS-ESI (M/z):222[ M +1 [)]+。
3-cyclopentyl-5- ((5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethylthia-ne Thiophene [2,3-c ]]Pyridine-2-carboxamide (17)
3-cyclopentyl-5- ((5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethylthiophene [2, 3-c)]Pyridine-2-carboxamide (17) was prepared as in 14a, substituting tert-butyl 4- (2-aminopyrimidin-5-yl) piperazine-1-carboxylate (1a) with 5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-amine (17 c). MS-ESI (M/z):494[ M +1 ]]+。
Example 18
N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) -5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) Thiophene [2,3-c ]]Pyridine-2-carboxamide (18)
Figure BDA0003177167530000531
N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) -5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (18) was prepared as in example 1, starting from 6-chloro-1-cyclopentyl-N, N-dimethyl-1H-pyrrolo [3,2-c ]]Replacement of pyridine-2-carboxamide (intermediate A) with 5-bromo-N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) thiophene [2,3-c]Pyridine-2-carboxamide (intermediate C). MS-ESI (M/z) 480[ M +1 ]]+。
Example 19
N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) -5- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) Amino) thiopheno [2,3-c]Pyridine-2-carboxamide (19)
Figure BDA0003177167530000541
N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) -5- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (19) was prepared as in example 2 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Replacement of pyridine-2-carboxamide (1) with N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) -5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (18). MS-ESI (M/z):494[ M +1 ]]+。
Example 20
5- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-3- ((1r,4r) -4-methylcyclo Hexyl) thiophene [2,3-c]Pyridine-2-carboxamide (20)
Figure BDA0003177167530000542
5- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) thiophene [2, 3-c)]Pyridine-2-carboxamide (20) was prepared as in example 3 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Replacement of pyridine-2-carboxamide (1) with N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) -5- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (18). MS-ESI (M/z):508[ M +1]+.
Example 21
5- ((5- (4-isopropylpiperidin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-3- ((1r,4r) -4-methyl Cyclohexyl) thiophene [2,3-c]Pyridine-2-Carboxamides(21)
Figure BDA0003177167530000543
5- ((5- (4-isopropylpiperidin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) thiophene [2, 3-c)]Process for preparing pyridine-2-carboxamides (21)The preparation process is as in example 17, mixing 5-bromo-3-cyclopentyl-N, N-dimethylthiophene [2,3-c ]]Replacement of pyridine-2-carboxamide (intermediate B) with 5-bromo-N, N-dimethyl-3- ((1r,4r) -4-methylcyclohexyl) thiophene [2,3-c]Pyridine-2-carboxamide (intermediate C). MS-ESI (M/z):521[ M +1 ]]+。
Example 22
3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyridin-2-yl) amino) thiophene [2,3-c]Pyridine- 2-carboxamide (22)
Figure BDA0003177167530000551
4- (6- ((3-cyclopentyl-2- (dimethylcarbamoyl) thiophene [2, 3-c)]Pyridin-5-yl) amino) pyridine-3- Yl) piperazine-1-carboxylic acid tert-butyl ester (22a)
To 5-bromo-3-cyclopentyl-N, N-dimethylthiophene [2,3-c ]]Pyridine-2-carboxamide (B) (88.3mg,0.250mmol) in dioxane (2.5mL) was added tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (69.5mg,0.250mmol), Pd2(dba)3(13.7mg,0.015mmol), xantphos (17.4mg,0.030mmol) and cesium carbonate (163mg,0.500 mmol). The mixture was heated at 100 ℃ for 8 hours under nitrogen. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate (2X 10 mL). Washing the extract with saturated brine and Na2SO4And (5) drying. The solvent was distilled off under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with 60-80% ethyl acetate-hexane to obtain 4- (6- ((3-cyclopentyl-2- (dimethylcarbamoyl) thiophene [2, 3-c)]Pyridin-5-yl) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (22 a). MS-ESI (M/z) 551[ M +1 ]]+。
3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyridin-2-yl) amino) thiophene [2,3-c]Pyridine- 2-carboxamide (22)
To 4- (6- ((3-cyclopentyl-2- (dimethylcarbamoyl) thiophene [2, 3-c)]Pyridin-5-yl) amino) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (22a) (122mg,0.222mmol) in dichloromethane (2mL)Trifluoroacetic acid (1.5mL) was added to the solution. The mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with 94:5:1 dichloromethane-methanol-ammonia water to obtain 3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyridin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (22). MS-ESI (M/z):451[ M +1 [)]+。
Example 23
3-cyclopentyl-N, N-dimethyl-5- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) thiophene [2,3-c] Pyridine-2-carboxamides (23)
Figure BDA0003177167530000561
3-cyclopentyl-N, N-dimethyl-5- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (23) was prepared as in example 2 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Replacement of pyridine-2-carboxamide (1) with 3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyridin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (22). MS-ESI (M/z):465[ M +1 ]]+。
Example 24
3-cyclopentyl-5- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2, 3-c)] Pyridine-2-carboxamide (24)
Figure BDA0003177167530000562
3-cyclopentyl-5- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2, 3-c)]Pyridine-2-carboxamide (24) was prepared as in example 3 from 1-cyclopentyl-N, N-dimethyl-6- ((5- (piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3, 2-c)]Replacement of pyridine-2-carboxamide (1) with 3-cyclopentyl-N, N-dimethyl-5- ((5- (piperazin-1-yl) pyridin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (22). MS-ESI (M/z) 479[ M +1 ]]+。
Example 25
3-cyclopentyl-5- ((5- (4- (dimethylamino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthia-ne Thiophene [2,3-c ]]Pyridine-2-carboxamide (25)
Figure BDA0003177167530000563
3-cyclopentyl-5- ((5- (4- (dimethylamino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethylthiophene [2, 3-c)]Pyridine-2-carboxamide (25) was prepared in the same manner as in example 17 except that tert-butyl 4- (2-aminopyrimidin-5-yl) piperazine-1-carboxylate (1a) was replaced with tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate. MS-ESI (M/z):493[ M +1 ]]+。
Examples 26-31 listed in Table 1 were prepared essentially according to the same procedures as example 22, or using similar synthetic strategies or methods, according to literature procedures and with the necessary modifications to prepare the corresponding aminopyridines, e.g., acylation and reductive amination. The names and structures of examples 26-31 are given in Table 1.
TABLE 1
Figure BDA0003177167530000571
Figure BDA0003177167530000581
Figure BDA0003177167530000591
Figure BDA0003177167530000601
Figure BDA0003177167530000611
Figure BDA0003177167530000621
Figure BDA0003177167530000631
Figure BDA0003177167530000641
Figure BDA0003177167530000651
Figure BDA0003177167530000661
Example 91
3-cyclopentyl-4-fluoro-N, N-dimethyl-5- ((5- (4- (piperidin-4-yl) piperazin-1-yl) pyrimidin-2-yl) amino Yl) thiophene [2,3-c]Pyridine-2-carboxamide (91)
Figure BDA0003177167530000662
2- (benzyloxy) -5-bromopyrimidine (91a)
2- (benzyloxy) -5-bromopyrimidine (91a) was prepared as described in WO 200469805.
4- (piperazin-1-yl) piperidine-1-carboxylic acid benzyl ester (91b)
Benzyl 4- (piperazin-1-yl) piperidine-1-carboxylate (91b) was prepared as described in document US 200749581.
Benzyl 4- (4- (2- (benzyloxy) pyrimidin-5-yl) piperazin-1-yl) piperidine-1-carboxylate (91c)
To 2- (benzyloxy) -5-bromoTo a solution of pyrimidine (91a) (2.65g,10.0mmol) in toluene (50mL) was added benzyl 4- (piperazin-1-yl) piperidine-1-carboxylate (91b) (3.03g,10.0mmol), Pd2(dba)3(460mg,0.50mmol), Johnphos (600mg,2.00mmol) and sodium tert-butoxide (1.44g,15.0 mmol). The mixture was reacted at 55 ℃ for 3 hours under nitrogen. The mixture was cooled to room temperature, diluted with water (100mL) and extracted with dichloromethane (3X 50 mL). The extract was dried over sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: 1-2.5% methanol/dichloromethane) to give benzyl 4- (4- (2- (benzyloxy) pyrimidin-5-yl) piperazin-1-yl) piperidine-1-carboxylate (91 c). MS-ESI (M/z):488[ M +1 ]]+。
4- (4- (2-Chloropyrimidin-5-yl) piperazin-1-yl) piperidine-1-carboxylic acid benzyl ester (91d)
To a solution of benzyl 4- (4- (2- (benzyloxy) pyrimidin-5-yl) piperazin-1-yl) piperidine-1-carboxylate (91c) (1.0g,2.1mmol) in phosphorus oxychloride (20ml) at room temperature was added N, N-diethylaniline (0.34g,2.3 mmol). The mixture was reacted at 100 ℃ overnight and the phosphorus oxychloride was evaporated under reduced pressure. The residue was extracted with saturated sodium bicarbonate solution (50mL) and dichloromethane (3X 50 mL). The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 1-2.5% methanol/dichloromethane) to give benzyl 4- (4- (2-chloropyrimidin-5-yl) piperazin-1-yl) piperidine-1-carboxylate (91 d). MS-ESI (M/z) 416[ M +1 ]]+。
4- (4- (2- ((3-cyclopentyl-2- (dimethylcarbamoyl) -4-fluorothiophene [2, 3-c)]Pyridin-5-yl) amino group) Pyrimidin-5-yl) piperazin-1-yl) piperidine-1-carboxylic acid benzyl ester (91e)
To a solution of benzyl 4- (4- (2-chloropyrimidin-5-yl) piperazin-1-yl) piperidine-1-carboxylate (91d) (33mg,0.078mmol) in toluene (1mL) was added 5-amino-3-cyclopentyl-4-fluoro-N, N-dimethylthiophene [2,3-c]Pyridine-2-carboxamide (D) (24mg,0.078mmol), Pd2(dba)3(15mg,0.016mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (20mg,0.031mmol) and sodium tert-butoxide (15mg,0.16 mmol). The mixture was reacted at 100 ℃ for 5 hours under nitrogen. After cooling to room temperature, the mixture was diluted with water (10mL) and extracted with dichloromethane (3X 10 mL). The extract is processed by sulfurDrying sodium salt, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 7% methanol/dichloromethane) to give 4- (4- (2- ((3-cyclopentyl-2- (dimethylcarbamoyl) -4-fluorothiophene [2, 3-c)]Pyridin-5-yl) amino) pyrimidin-5-yl) piperazin-1-yl) piperidine-1-carboxylic acid benzyl ester (91 e). MS-ESI (M/z):687[ M +1 ]]+。
3-cyclopentyl-4-fluoro-N, N-dimethyl-5- ((5- (4- (piperidin-4-yl) piperazin-1-yl) pyrimidin-2-yl) amino Yl) thiophene [2,3-c]Pyridine-2-carboxamide (91)
4- (4- (2- ((3-cyclopentyl-2- (dimethylcarbamoyl) -4-fluorothiophene [2, 3-c)]Pyridin-5-yl) amino) pyrimidin-5-yl) piperazin-1-yl) piperidine-1-carboxylic acid benzyl ester (91e) (30mg,0.096mmol) in concentrated hydrochloric acid (0.5mL) was stirred at room temperature for 1 hour, basified with saturated sodium bicarbonate solution (20mL) and extracted with dichloromethane (3 × 20 mL). The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluent: 125:11.5:1 dichloromethane/methanol/aqueous ammonia) to give 3-cyclopentyl-4-fluoro-N, N-dimethyl-5- ((5- (4- (piperidin-4-yl) piperazin-1-yl) pyrimidin-2-yl) amino) thiophene [2,3-c]Pyridine-2-carboxamide (91). MS-ESI (M/z):553[ M +1 ]]+。
TABLE 2
Figure BDA0003177167530000681
Cell proliferation assay
The method A comprises the following steps:
BE (2) -C cells (
Figure BDA0003177167530000691
Numbering: CRL-2268) was inoculated into 96-well plates at 5000/well, with 150. mu.l of medium per well. Compound dilution: prepare 20mM compound DMSO stock solution. On the day of dosing, compound stock solutions were freshly prepared as working solutions (4 × final concentration) with the media. 50 μ l of the compound mixture and 150 μ l of cells were added to each well. The test compound was added 24 hours after the inoculation of BE (2) -C cells. 72 hours after administration, cell proliferation was detected using MTS kit according to the instructionsReproductive ability. IC of compound was calculated using GraphPad Prism 5.0 software50。
The compounds prepared as described above were assayed according to the biological method described herein, and the results are shown in Table 3.
TABLE 3
Examples BE(2)-C IC50(nM) Examples BE(2)-C IC50(nM) Examples BE(2)-C IC50(nM)
1 2095 14 156 23 28
2 4055 15 109 24 23
3 3192 16 118 25 28
4 10554 17 130 26 326
5 2549 18 64 27 65
6 2814 19 81 28 61
7 370 20 117 29 250
8 419 21 132 30 120
9 268 22 53 31 83
The method B comprises the following steps:
MTS kit is commercially available from Promega, DMEM, standard fetal bovine serum and penicillin-streptomycin mixture from Gibco and Dimethylsulfoxide (DMSO) from Sigma.
BE (2) -C (ATCC: CRL-2268) cell models were established based on the experimental mechanism to investigate whether compounds could inhibit CDK4/6 activity in cells. In the assay, compounds were tested for their inhibitory activity against CDK4/6 by inhibiting BE (2) -C cell proliferation. The BE (2) -C cells are cultured in a culture flask containing 10% fetal bovine serum in a DMEM medium to 40-80%, then the cells are collected and seeded into a 96-well plate at a concentration of 3000 cells/well, and the 96-well plate is placed at 37 ℃ and 5% CO2Incubate overnight in the incubator. Compounds were added to 96-well plates to a final concentration of 10000, 3333, 1111, 270, 123.5, 41.2, 13.7, 4.6 and 1.5nM, and the 96-well plates were placed at 37 ℃ with 5% CO2Incubate for 48 h. The medium was removed, 100. mu.L of mixed medium containing 20. mu.L of MTS was added to each well and incubated for 2h, 25. mu.L of 10% SDS was added to each well to terminate the reaction, and the absorbance was measured at 490 and 650nm (reference wavelength). IC of compound was calculated using GraphPad Prism 5.0 software50。
The compounds prepared above were assayed according to the biological method described herein, and the results are shown in Table 4.
TABLE 4
Examples BE(2)-C IC50(nM) Examples BE(2)-C IC50(nM) Examples BE(2)-C IC50(nM)
33 217 54 721 72 23
34 69 55 870 73 37
35 191 56 325 75 790
36 66 57 255 76 37
37 174 58 455 77 48
39 33 59 512 79 725
40 57 60 386 81 67
41 52 61 278 82 978
42 77 62 85 83 156
43 775 63 213 84 33
46 214 64 47 85 11
47 428 65 284 86 39
48 229 66 18 87 412
49 67 67 134 88 672
50 207 68 74 89 50
51 242 69 20 90 13
52 298 70 68
53 887 71 151

Claims (10)

1. A compound of formula (I)
Figure FDA0003177167520000011
Or a pharmaceutically acceptable salt thereof, wherein
X is C;
y is N;
z is CR6；
The 6-5 membered fused ring system A-B is selected from:
Figure FDA0003177167520000012
q is selected from aryl and heteroaryl;
w is CH or CRX；
R1Selected from hydrogen, halogen, hydroxy, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein each of 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 group independently selected from RXSubstituted with the substituent(s);
R2selected from hydrogen, halogen, hydroxy, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkyl ammonia, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, di (alkyl) amino, heterocyclyl, aryl and heteroaryl is each unsubstituted or substituted with at least one group independently selected from RXSubstituted with the substituent(s);
R3and R4Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl and C3-10cycloalkyl-C1-4Alkyl, wherein each alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or substituted with at least one independently selected from RXSubstituted with the substituent(s);
or R3And R4Together with the N atom to which they are attached form a 4-12 membered ring containing 1,2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may optionally be substituted with 1,2 or 3RXSubstituted by groups;
each R5Independently selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, CN, NO2、-NRA1RB1、-ORA1、-S(O)rRA1、-S(O)2ORA1、-OS(O)2RA1、-P(O)RA1RB1、-P(O)(ORA1)(ORB1)、-C(O)RA1、-C(O)ORA1、-OC(O)RA1、-C(O)NRA1RB1、-NRA1C(O)RB1、-OC(O)NRA1RB1、-NRA1C(O)ORB1、-NRA1C(O)NRA1RB1、-NRA1C(S)NRA1RB1、-S(O)rNRA1RB1、-NRA1S(O)rRB1、-NRA1S(O)2NRA1RB1、-S(O)(＝NRE1)RB1、-N＝S(O)RA1RB1、-NRA1S(O)(＝NRE1)RB1、-S(O)(＝NRE1)NRA1RB1、-NRA1S(O)(＝NRE1)NRA1RB1、-C(＝NRE1)RA1、-C(＝N-ORB1)RA1、-C(＝NRE1)NRA1RB1、-NRA1C(＝NRE1)RB1and-NRA1C(＝NRE1)NRA1RB1Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one RXSubstituted with the substituent(s);
R6selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, CN, NO2、-NRA2RB2、-ORA2、-S(O)rRA2、-S(O)2ORA2、-OS(O)2RA2、-P(O)RA2RB2、-P(O)(ORA2)(ORB2)、-C(O)RA2、-C(O)ORA2、-OC(O)RA2、-C(O)NRA2RB2、-NRA2C(O)RB2、-OC(O)NRA2RB2、-NRA2C(O)ORB2、-NRA2C(O)NRA2RB2、-NRA2C(S)NRA2RB2、-S(O)rNRA2RB2、-NRA2S(O)rRB2、-NRA2S(O)2NRA2RB2、-S(O)(＝NRE2)RB2、-N＝S(O)RA2RB2、-NRA2S(O)(＝NRE2)RB2、-S(O)(＝NRE2)NRA2RB2、-NRA2S(O)(＝NRE2)NRA2RB2、-C(＝NRE2)RA2、-C(＝N-ORB2)RA2、-C(＝NRE2)NRA2RB2、-NRA2C(＝NRE2)RB2and-NRA2C(＝NRE2)NRA2RB2Wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is notSubstituted or substituted by at least one member independently selected from RXSubstituted with the substituent(s);
R7selected from hydrogen, halogen, C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, CN, -S (O)rRA3、-C(O)RA3、-CO2RA3and-C (O) NRA3RB3Wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one group independently selected from RXSubstituted with the substituent(s);
each RA1、RA2、RA3、RB1、RB2And RB3Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one RXSubstituted with the substituent(s);
or each "RA1And RB1”、“RA2And RB2"or" RA3And RB3Taken 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, which ring may optionally be interrupted by 1,2 or 3RXSubstituted by groups;
each RE1And RE2Independently selected from hydrogen, C1-10Alkyl, CN, NO2、-ORa1、-SRa1、-S(O)rRa1、-C(O)Ra1、-S(O)rNRa1Rb1and-C (O) NRa1Rb1；
Each RXIndependently selected from C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, halogen, CN, NO2、-(CRc1Rd1)tNRa1Rb1、-(CRc1Rd1)tORb1、-(CRc1Rd1)tS(O)rRb1、-(CRc1Rd1)tS(O)2ORb1、-(CRc1Rd1)tOS(O)2Rb1、-(CRc1Rd1)tP(O)Ra1Rb1、-(CRc1Rd1)tP(O)(ORa1)(ORb1)、-(CRc1Rd1)tC(O)Ra1、-(CRc1Rd1)tC(O)ORb1、-(CRc1Rd1)tOC(O)Rb1、-(CRc1Rd1)tC(O)NRa1Rb1、-(CRc1Rd1)tNRa1C(O)Rb1、-(CRc1Rd1)tOC(O)NRa1Rb1、-(CRc1Rd1)tNRa1C(O)ORb1、-(CRc1Rd1)tNRa1C(O)NRa1Rb1、-(CRc1Rd1)tNRa1C(S)NRa1Rb1,-(CRc1Rd1)tS(O)rNRa1Rb1、-(CRc1Rd1)tNRa1S(O)rRb1、-(CRc1Rd1)tNRa1S(O)2NRa1Rb1、-(CRc1Rd1)tS(O)(＝NRe1)Rb1、-(CRc1Rd1)tN＝S(O)Ra1Rb1、-(CRc1Rd1)tNRa1S(O)(＝NRe1)Rb1、-(CRc1Rd1)tS(O)(＝NRe1)NRa1Rb1、-(CRc1Rd1)tNRa1S(O)(＝NRe1)NRa1Rb1、-(CRc1Rd1)tC(＝NRe1)Ra1、-(CRc1Rd1)tC(＝N-ORb1)Ra1、-(CRc1Rd1)tC(＝NRe1)NRa1Rb1、-(CRc1Rd1)tNRa1C(＝NRe1)Rb1And- (CR)c1Rd1)tNRa1C(＝NRe1)NRa1Rb1Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one RYSubstituted with the substituent(s);
each Ra1And Rb1Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one RYSubstituted with the substituent(s);
or Ra1And Rb1Together 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 3RYSubstituted by groups;
each Rc1And Rd1Independently selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one RYSubstituted with the substituent(s);
or Rc1And Rd1Together 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 3RYSubstituted by groups;
each Re1Independently selected from hydrogen, C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, CN, NO2、-ORa2、-SRa2、-S(O)rRa2、-C(O)Ra2、-C(O)ORa2、-S(O)rNRa2Rb2and-C (O) NRa2Rb2；
RYIndependently selected from C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl-C1-4Alkyl, halogen, CN, NO2、-(CRc2Rd2)tNRa2Rb2、-(CRc2Rd2)tORb2、-(CRc2Rd2)tS(O)rRb2、-(CRc2Rd2)tS(O)2ORb2、-(CRc2Rd2)tOS(O)2Rb2、-(CRc2Rd2)tP(O)Ra2Rb2、-(CRc2Rd2)tP(O)(ORa2)(ORb2)、-(CRc2Rd2)tC(O)Ra2、-(CRc2Rd2)tC(O)ORb2、-(CRc2Rd2)tOC(O)Rb2、-(CRc2Rd2)tC(O)NRa2Rb2、-(CRc2Rd2)tNRa2C(O)Rb2、-(CRc2Rd2)tOC(O)NRa2Rb2、-(CRc2Rd2)tNRa2C(O)ORb2、-(CRc2Rd2)tNRa2C(O)NRa2Rb2、-(CRc2Rd2)tNRa2C(S)NRa2Rb2、-(CRc2Rd2)tS(O)rNRa2Rb2、-(CRc2Rd2)tNRa2S(O)rRb2、-(CRc2Rd2)tNRa2S(O)2NRa2Rb2、-(CRc2Rd2)tS(O)(＝NRe2)Rb2、-(CRc2Rd2)tN＝S(O)Ra2Rb2、-(CRc2Rd2)tNRa2S(O)(＝NRe2)Rb2、-(CRc2Rd2)tS(O)(＝NRe2)NRa2Rb2、-(CRc2Rd2)tNRa2S(O)(＝NRe2)NRa2Rb2、-(CRc2Rd2)tC(＝NRe2)Ra2,-(CRc2Rd2)tC(＝N-ORb2)Ra2、-(CRc2Rd2)tC(＝NRe2)NRa2Rb2、-(CRc2Rd2)tNRa2C(＝NRe2)Rb2And- (CR)c2Rd2)tNRa2C(＝NRe2)NRa2Rb2Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently unsubstituted or substituted with at least one group independently selected from OH, CN, amino, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
each Ra2And Rb2Independently selected from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is each unsubstituted or substituted with at least one group independently selected from halogen, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
or Ra2And Rb2Together 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 halogen, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
each Rc2And Rd2Independently selected from hydrogen, halogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio radical, C1-10Alkylamino radical, C3-10Cycloalkylamino, di (C)1-10Alkyl) amino, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl is each unsubstituted or substituted with at least one group independently selected from halogen, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
or Rc2And Rd2Together 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, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, hydroxy, C1-10Alkoxy radical, C3-10Cycloalkoxy, C1-10Alkylthio radical, C3-10Cycloalkylthio, amino, C1-10Alkylamino radical, C3-10Cycloalkylamino and di (C)1-10Alkyl) amino;
each Re2Independently selected from hydrogen, CN, NO2、C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl radical, C1-10Alkoxy radical, C3-10Cycloalkoxy, -C (O) C1-4Alkyl, -C (O) C3-10Cycloalkyl, -C (O) OC1-4Alkyl, -C (O) OC3-10Cycloalkyl, -C (O) N (C)1-4Alkyl radical)2、-C(O)N(C3-10Cycloalkyl radicals2、-S(O)2C1-4Alkyl, -S (O)2C3-10Cycloalkyl, -S (O)2N(C1-4Alkyl radical)2and-S (O)2N(C3-10Cycloalkyl radicals2；
Each r is independently selected from 0, 1 and 2;
each t is independently selected from 0, 1,2,3, and 4;
m is selected from 0, 1,2 and 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is selected from heteroaryl.
3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein R1Is a heterocyclic group, wherein the heterocyclic group is unsubstituted or substituted with at least one group independently selected from RXIs substituted with the substituent(s).
4.A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2Is selected from C3-10Cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with at least one group independently selected from RXIs substituted with the substituent(s).
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R3And R4Independently selected from hydrogen and C1-10An alkyl group.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R5Selected from hydrogen, halogen and C1-10An alkyl group.
7. A compound selected from
1-cyclopentyl-N, N-dimethyl-6- ((5-piperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-6- ((5- (4-ethylpiperazin-1-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (piperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (1-methylpiperidin-4-yl) pyrimidin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-6- ((5- (1-ethylpiperidin-4-yl) pyrimidin-2-yl) amino) -N, N-dimethyl-1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5-piperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-6- ((5- (4-ethylpiperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-morpholineproperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4-piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-N, N-dimethyl-6- ((5- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
1-cyclopentyl-6- ((5- (4- (4-ethylpiperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino-N, N-dimethyl-1H-pyrrolo [3,2-c ] pyridine-2-carboxamide,
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
9. A method of treating, ameliorating or preventing a disorder responsive to inhibition of CDK4/6 comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
10. Use of a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a cell proliferation abnormality.
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