# US 11,993,604 B2 · Substituted pyrazolo[4,3-H]quinazolines as protein kinase inhibitors

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- Number: US 11,993,604 B2
- Document ID: US11993604B2
- Status: Granted
- Kind: B2
- Application number: 17/711,535
- Filed: 2022-04-01
- Published: 2022-07-21
- Granted: 2024-05-28
- Earliest claimed: 2017-08-11
- Assignees: Shengke Pharmaceuticals (Jiangsu) Ltd.
- Applicants: Shengke Pharmaceuticals (Jiangsu) Ltd.
- Inventors: Bin Liu; Hang Cheng; Weiyan Xiong; Chenggang Zhang; Chengzhi Yu
- Web page: https://patentgrep.com/patent/US11993604B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A 1H-pyrazolo[4,3-H]quinazoline compound represented by formula (I) can be used for treating cell proliferation dysfunction, and is an broad-spectrum and strongly-active inhibitor for a cell cyclin-dependent kinase (CDK).

## Claims

### Claim 1

A method for inhibiting cyclin-dependent kinase (CDK) activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
A1 is N;
A2 is CR3;
A3 is CR3;
R1 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, NRbRc, ORa, SRa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of ═O and ═S; and
wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R2 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of ═O and ═S; and
wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R3 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, L′-C3-7 cycloalkyl, L′-3- to 11-membered heterocyclyl, L′-C6-10 aryl, or L′-5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, L′-C3-7 cycloalkyl, L′-3- to 11-membered heterocyclyl, L′-C6-10 aryl, or L′-5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R6 substituents;
R4 is C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R′ substituents;
R5 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, NRbRc, ORa, SRa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of ═O and ═S; and
wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
each R6 is independently H, C1-6 alkyl, C1-6 haloalkyl, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1, 2, or 3 independently selected R″ substituents; or
any two geminal R6 substituents, taken together with the carbon atom to which they are attached, independently form ═O or ═S;
each R′ is independently H, halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C(O)NRbRc, C(O)ORa, NRbRc, ORa, SRa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each R″ is independently H, halogen, L-CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, L-C(O)Ra, L-C(O)C1-6 alkylene-NRbRc, L-C(O)NRbRc, L-C(O)ORa, L-C(S)Ra, L-C(S)NRbRc, L-C(S)ORa, L-NRbRc, L-N(Rb)—C(O)Ra, L-N(Rb)—C(O)NRbRc, L-N(Rb)—C(O)ORa, L-N(Rb)—C(S)Ra, L-N(Rb)—C(S)NRbRc, L-N(Rb)—C(S)ORa, L-N(Rb)—S(O)mRa, L-N(Rb)—S(O)mNRbRc, L-ORa, L-OC1-6 alkylene-ORa, L-OC(O)Ra, L-OC(O)NRbRc, L-OC(S)Ra, L-OC(S)NRbRc, ═O, L-S(O)mRa, L-S(O)mNRbRc, L-S(O)mORa, L-C3-7 cycloalkyl, L-3- to 7-membered heterocyclyl, L-C6-10 aryl, or L-5- to 10-membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, L-C3-7 cycloalkyl, L-3- to 7-membered heterocyclyl, L-C6-10 aryl, and L-5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of L-CN, NO2, L-C(O)Ra, L-C(O)C1-6 alkylene-NRbRc, L-C(O)NRbRc, L-C(O)ORa, L-C(S)Ra, L-C(S)NRbRc, L-C(S)ORa, L-NRbRc, L-N(Rb)—C(O)Ra, L-N(Rb)—C(O)NRbRc, L-N(Rb)—C(O)ORa, L-N(Rb)—C(S)Ra, L-N(Rb)—C(S)NRbRc, L-N(Rb)—C(S)ORa, L-N(Rb)—S(O)mRa, L-N(Rb)—S(O)mNRbRc, L-ORa, L-OC1-6 alkylene-ORa, L-OC(O)Ra, L-OC(O)NRbRc, L-OC(S)Ra, L-OC(S)NRbRc, ═O, L-S(O)mRa, L-S(O)mNRbRc, and L-S(O)mORa;
each Ra is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each Rb is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each Rc is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or
each Rb and Rc, taken together with the nitrogen atom to which they are attached, independently forms a 3- to 7-membered heterocyclyl;
each L is independently a chemical bond, —C1-6 alkylene-, —C2-6 alkenylene-, or —C2-6 alkynylene-;
L′ is a chemical bond, —C1-6 alkylene-, —C2-6 alkenylene-, —C2-6 alkynylene-, —C(O)—, —C(O)NH—, or —NHC(O)—; and
each m is independently 0, 1, or 2.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the subject has a cyclin-dependent kinase (CDK)-mediated disease or disorder that is a cell proliferative disorder.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the cell proliferative disorder is selected from the group consisting of an autoimmune disorder, a cancer, a cardiovascular disorder, a chronic inflammatory disease, an infectious disease, and psoriasis.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the autoimmune disease is lupus.

### Claim 5 (depends on 3)

The method according to claim 3, wherein the cancer is a solid tumor or a hematological malignancy.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the solid tumor or hematological malignancy is selected from the group consisting of breast cancer, carcinoma of the bile duct, cervical cancer, colorectal cancer, dedifferentiated liposarcoma, endometrial cancer, gastric cancer, a gastrointestinal stromal tumor (GIST), glioma, hepatocellular carcinoma, leukemia, lung cancer, lymphoma, malignant rhabdomyoma, melanoma, mesothelioma, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, a prostatic tumor, renal cancer, sarcoma, thyroid cancer, and well-differentiated liposarcoma.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the leukemia is acute myeloid leukemia (AML).

### Claim 8 (depends on 6)

The method according to claim 6, wherein the lymphoma is selected from the group consisting of anaplastic large cell lymphoma, mantle cell lymphoma, and non-Hodgkin's lymphoma.

### Claim 9 (depends on 3)

The method according to claim 3, wherein the cardiovascular disorder is selected from the group consisting of atherosclerosis, intimal hyperplasia secondary to balloon angioplasty, restenosis, and vascular smooth muscle proliferation.

### Claim 10 (depends on 3)

The method according to claim 3, wherein the chronic inflammatory disease is glomerulonephritis or rheumatoid arthritis.

### Claim 11 (depends on 3)

The method according to claim 3, wherein the infectious disease is selected from the group consisting of a DNA virus infection, a fungal infection, a protozoan parasitic infection, and an RNA virus infection.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the DNA virus infection or RNA virus infection is herpes simplex virus (HSV) infection.

### Claim 13 (depends on 11)

The method according to claim 11, wherein the protozoan parasitic infection is a Plasmodium falciparum infection.

### Claim 14 (depends on 3)

The method according to claim 3, wherein the psoriasis is characterized by excessive proliferation of keratinocytes.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the compound is of formula (II):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R2 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R3 is:
R3a is H, halogen, CN, NO2, C1-6 alkyl, or C1-6 haloalkyl;
R3b is H, halogen, CN, NO2, C1-6 alkyl, or C1-6 haloalkyl;
R3c is H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
R3d is H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
R3e is H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
R3f is H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
R4 is C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 11-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each R″ is independently H, halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Ra, C(O)Ci-alkylene-NRbRc, C(O)NRbRc, C(O)ORa, C(S)Ra, C(S)NRbRc, C(S)ORa, NRbRc, N(Rb)—C(O)Ra, N(Rb)—C(O)NRbRc, N(Rb)—C(S)Ra, N(Rb)—C(S)NRbRc, ORa, OC1-6 alkylene-ORa, OC(O)Ra, OC(O)NRbRc, OC(S)Ra, OC(S)NRbRc, or SRa;
each Ra is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each Rb is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each Rc is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and
is the point of attachment to the pyridinyl ring.

### Claim 16 (depends on 15)

The method according to claim 15, wherein:
R3 is:
and
is the point of attachment to the pyridinyl ring.

### Claim 17 (depends on 15)

The method according to claim 15, wherein:
R2 is H, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
R3 is:
R3a is H; and
is the point of attachment to the pyridinyl ring.

### Claim 18 (depends on 15)

The method according to claim 15, wherein:
R2 is H, halogen, CN, C1-6 alkyl, C(O)Ra, or C6-10 aryl, wherein the C1-6 alkyl or C6-10 aryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R3 is:
R3a is H, halogen, or C1-6 alkyl;
R3b is H, halogen, or C1-6 alkyl;
R3c is H or C1-6 alkyl;
R3d is H or C1-6 alkyl;
R3e is H or C1-6 alkyl;
R3f is H or C1-6 alkyl;
R4 is C1-6 alkyl or C3-7 cycloalkyl;
each R″ is an independently selected ORa substituent;
each Ra is independently H or C1-6 alkyl; and
is the point of attachment to the pyridinyl ring.

### Claim 19 (depends on 15)

The method according to claim 15, wherein:
R2 is H, halogen, CN, C1-6 alkyl, C(O)Ra, or C6-10 aryl, wherein the C1-6 alkyl or C6-10 aryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R3 is:
R3a is H, halogen, or C1-6 alkyl;
R3b is H, halogen, or C1-6 alkyl;
R3c is H or C1-6 alkyl;
R3d is H or C1-6 alkyl;
R3e is H or C1-6 alkyl;
R3f is H or C1-6 alkyl;
R4 is C1-6 alkyl or C3-7 cycloalkyl;
each R″ is an independently selected ORa substituent;
each Ra is independently H or C1-6 alkyl; and
is the point of attachment to the pyridinyl ring.

### Claim 20 (depends on 15)

The method according to claim 15, wherein:
R2 is H, CN, C1-6 alkyl, C(O)Ra, or C6-10 aryl, wherein the C1-6 alkyl or C6-10 aryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R3 is:
R3a is H;
R3b is H, halogen, or C1-6 alkyl;
R3c is H or C1-6 alkyl;
R3d is H or C1-6 alkyl;
R3e is H or C1-6 alkyl;
R4 is C1-6 alkyl or C3-7 cycloalkyl;
each R″ is an independently selected ORa substituent;
each Ra is independently H or C1-6 alkyl; and
is the point of attachment to the pyridinyl ring.

### Claim 21 (depends on 15)

The method according to claim 15, wherein:
R2 is C(O)Ra, C(O)NRbRc, or C(O)ORa;
R3 is:
R3a is H;
R3b is H;
R4 is CH(CH3)2 or cyclopentyl; and
is the point of attachment to the pyridinyl ring.

### Claim 22 (depends on 15)

The method according to claim 15, wherein:
R2 is C(O)Ra;
R3 is:
R3a is H;
R3b is H;
R3c is H or C1-6 alkyl;
R4 is CH(CH3)2;
each Ra is independently H or C1-6 alkyl; and
is the point of attachment to the pyridinyl ring.

### Claim 23 (depends on 1)

The method according to claim 1, wherein the compound is of formula (II):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R2 is CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R3 is:
R3a is H;
R36 is H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
R3c is H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
R4 is C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 11-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each R″ is independently H, halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Ra, C(O)Ci-alkylene-NRbRc, C(O)NRbRc, C(O)ORa, C(S)Ra, C(S)NRbRc, C(S)ORa, NRbRc, N(Rb)—C(O)Ra, N(Rb)—C(O)NRbRc, N(Rb)—C(S)Ra, N(Rb)—C(S)NRbRc, ORa, OC1-6 alkylene-ORa, OC(O)R3, OC(O)NRbRc, OC(S)Ra, OC(S)NRbRc, or SRa;
each Ra is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each Rb is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each Rc is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; and
is the point of attachment to the pyridinyl ring.

### Claim 24 (depends on 23)

The method according to claim 23, wherein:
R2 is CN, C1-6 alkyl, C(O)Ra, or C6-10 aryl, wherein the C1-6 alkyl or C6-10 aryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R3 is:
R3a is H;
R3b is H;
R3c is H or C1-6 alkyl;
R4 is C1-6 alkyl or C3-7 cycloalkyl;
each R″ is an independently selected ORa substituent;
each Ra is independently H or C1-6 alkyl; and
is the point of attachment to the pyridinyl ring.

### Claim 25 (depends on 23)

The method according to claim 23, wherein:
R2 is C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, or C(O)ORa;
R3 is:
R4 is CH(CH3)2 or cyclopentyl; and
is the point of attachment to the pyridinyl ring.

### Claim 26 (depends on 23)

The method according to claim 23, wherein:
R2 is C1-6 alkyl, C(O)Ra, C(O)NRbRc, or C(O)ORa;
R3 is:
R3a is H;
R3b is H, C6 alkyl, or C1-6 haloalkyl;
R3c is C1-6 alkyl or C1-6 haloalkyl;
R7 is CH(CH3)2 or cyclopentyl;
each Ra is independently H, C1-6 alkyl, or C1-6 haloalkyl;
each Rb is independently H, C1-6 alkyl, or C1-6 haloalkyl;
each Rc is independently H, C1-6 alkyl, or C1-6 haloalkyl; and
is the point of attachment to the pyridinyl ring.

### Claim 27 (depends on 23)

The method according to claim 23, wherein:
R2 is C1-6 alkyl or C(O)Ra;
R3 is:
R3a is H;
R3b is H;
R3c is C1-6 alkyl;
R4 is CH(CH3)2 or cyclopentyl;
Ra is H or C1-6 alkyl; and
is the point of attachment to the pyridinyl ring.

### Claim 28 (depends on 1)

The method according to claim 1, wherein the compound is of formula (II):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R2 is H;
R3 is:
R3a is H;
R3b is C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
R3c is H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
R4 is CH(CH3)2; and
is the point of attachment to the pyridinyl ring.

### Claim 29 (depends on 28)

The method according to claim 28, wherein:
R3 is:
R3b is C1-6 alkyl or C1-6 haloalkyl;
R3c is C1-6 alkyl or C1-6 haloalkyl; and
is the point of attachment to the pyridinyl ring.

### Claim 30 (depends on 1)

The method according to claim 1, wherein the compound, or a pharmaceutically acceptable salt or stereoisomer thereof, is selected from the group consisting of:

### Claim 31

A method for inhibiting cyclin-dependent kinase (CDK) activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
A1 is N;
A2 is CR3;
A3 is CR3;
R1 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, NRbRc, ORa, SRa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of ═O and ═S; and
wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R2 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of ═O and ═S; and
wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
R3 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, L′-C3-7 cycloalkyl, L′-3- to 11-membered heterocyclyl, L′-C6-10 aryl, or L′-5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, L′-C3-7 cycloalkyl, L′-3- to 11-membered heterocyclyl, L′-C6-10 aryl, or L′-5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R6 substituents;
R4 is C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R′ substituents;
R5 is H, halogen, CN, C1-6 alkyl, C1-6 haloalkyl, C(O)Ra, C(O)NRbRc, C(O)ORa, NRbRc, ORa, SRa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
wherein the C3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of ═O and ═S; and
wherein the C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R″ substituents;
each R6 is independently H, C1-6 alkyl, C1-6 haloalkyl, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1, 2, or 3 independently selected R″ substituents; or
any two geminal R6 substituents, taken together with the carbon atom to which they are attached, independently form ═O or ═S;
each R′ is independently H, halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C(O)NRbRc, C(O)ORa, NRbRc, ORa, SRa, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each R″ is independently H, halogen, L-CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, L-C(O)Ra, L-C(O)C1-6 alkylene-NRbRc, L-C(O)NRbRc, L-C(O)ORa, L-C(S)Ra, L-C(S)NRbRc, L-C(S)ORa, L-NRbRc, L-N(Rb)—C(O)Ra, L-N(Rb)—C(O)NRbRc, L-N(Rb)—C(O)ORa, L-N(Rb)—C(S)Ra, L-N(Rb)—C(S)NRbRc, L-N(Rb)—C(S)ORa, L-N(Rb)—S(O)mRa, L-N(Rb)—S(O)mNRbRc, L-ORa, L-OC1-6 alkylene-ORa, L-OC(O)Ra, L-OC(O)NRbRc, L-OC(S)Ra, L-OC(S)NRbRc, ═O, L-S(O)mRa, L-S(O)mNRbRc, L-S(O)mORa, L-C3-7 cycloalkyl, L-3- to 7-membered heterocyclyl, L-C6-10 aryl, or L-5- to 10-membered heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, L-C3-7 cycloalkyl, L-3- to 7-membered heterocyclyl, L-C6-10 aryl, and L-5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of L-CN, NO2, L-C(O)Ra, L-C(O)C1-6 alkylene-NRbRc, L-C(O)NRbRc, L-C(O)ORa, L-C(S)Ra, L-C(S)NRbRc, L-C(S)ORa, L-NRbRc, L-N(Rb)—C(O)Ra, L-N(Rb)—C(O)NRbRc, L-N(Rb)—C(O)ORa, L-N(Rb)—C(S)Ra, L-N(Rb)—C(S)NRbRc, L-N(Rb)—C(S)ORa, L-N(Rb)—S(O)mRa, L-N(Rb)—S(O)mNRbRc, L-ORa, L-OC1-6 alkylene-ORa, L-OC(O)Ra, L-OC(O)NRbRc, L-OC(S)Ra, L-OC(S)NRbRc, ═O, L-S(O)mRa, L-S(O)mNRbRc, and L-S(O)mORa;
each Ra is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each Rb is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl;
each Rc is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl; or
each Rb and Rc, taken together with the nitrogen atom to which they are attached, independently forms a 3- to 7-membered heterocyclyl;
each L is independently a chemical bond, —C1-6 alkylene-, —C2-6 alkenylene-, or —C2-6 alkynylene-;
L′ is a chemical bond, —C1-6 alkylene-, —C2-6 alkenylene-, —C2-6 alkynylene-, —C(O)—, —C(O)NH—, or —NHC(O)—; and
each m is independently 0, 1, or 2.

### Claim 32 (depends on 31)

The method according to claim 31, wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.