# US 10,369,153 B2 · Pyrrolopyrimidine compounds and uses thereof

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- Number: US 10,369,153 B2
- Document ID: US10369153B2
- Status: Granted
- Kind: B2
- Application number: 16/173,120
- Filed: 2018-10-29
- Published: 2019-02-28
- Granted: 2019-08-06
- Earliest claimed: 2010-08-20
- Assignees: Hutchison Medipharma Limited
- Applicants: Hutchison Medipharma Limited
- Inventors: Wei-Guo Su; Wei Deng; Jinshui Li; Jianguo Ji
- Web page: https://patentgrep.com/patent/US10369153B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07B 2200/07: Optical isomers
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present disclosure provides pyrrolopyrimidine compounds and methods of use therefor. For example, the disclosure provides certain pyrrolopyrimidine compounds capable of inhibiting JAK kinases. The disclosure further provides the pharmaceutical compositions containing these pyrrolopyrimidine compounds, and use of these pyrrolopyrimidine compounds in the treatment of disorders or diseases, such as inflammatory diseases and cancer.

## Claims

### Claim 1

A method of treating in a subject an inflammatory disease responsive to inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 comprising administering to said subject in need thereof an effective amount of a compound of formula (1):
wherein
R1 is chosen from hydrogen, alkyl, cycloalkyl and heterocycle, each of the said alkyl, cycloalkyl, and heterocycle, in R1 is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, —C(O)Ra, —C(O)ORb, —CN, —C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, —NRcRd, —NReC(O)Ra, —NReC(O)ORb, —NReC(O)NRcRd, —NReS(O)nRf, —NReS(O)nNRcRd, —NO2, —ORb, —S(O)nRf, and —S(O)nNRcRd;
R2 is
which is optionally substituted with one or more groups chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, —C(O)Ra, —C(O)ORb, —CN, —C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, —NRcRd, —NReC(O)Ra, —NReC(O)ORb, —NReC(O)NRcRd, —NReS(O)nRf, —NReS(O)nNRcRd, —NO2, —ORb, —S(O)nRf, and —S(O)nNRcRd;
m is 1;
n is chosen from 0, 1, and 2;
for each occurrence, Ra, Rb, Rc, Rd, Re and Rf are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted haloalkyl, optionally substituted heteroaryl and optionally substituted heterocycle,
or Rc and Rd, with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups chosen from halo, lower alkyl, hydroxy, and lower alkoxy, wherein the heterocycle ring further optionally comprises one or two additional heteroatoms chosen from N, O and S,
wherein each optionally substituted group above can be unsubstituted or independently substituted with at least one substituent independently chosen from C1-C4 alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, —OC1-C4 alkyl, —OC1-C4 alkylphenyl, —C1-C4 alkylOH, —C1-C4 alkyl-O—C1-C4 alkyl, —OC1-C4 haloalkyl, halo, —OH, —NH2, —C1-C4 alkyl-NH2, —N(C1-C4 alkyl)(C1-C4 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkylphenyl), —NH(C1-C4 alkylphenyl), cyano, nitro, oxo, —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —NHC(O)(phenyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(phenyl), —C(O)C1-C4 alkyl, —C(O)C1-C4 haloalkyl, —OC(O)(C1-C4 alkyl), —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2, —SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl), in which each of phenyl, aryl, heterocycle, and heteroaryl is optionally substituted by one or more groups chosen from halo, cycloalkyl, heterocycle, C1-C4 alkyl, C1-C4 haloalkyl-, —OC1-C4 alkyl, C1-C4 alkyl-OH, —C1-C4 alkyl-O—C1-C4 alkyl, —OC1-C4 haloalkyl, cyano, nitro, —NH2, —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2, SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl),
and/or at least one pharmaceutically acceptable salt thereof.

### Claim 2

A method of treating in a subject a cancer responsive to inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 comprising administering to said subject in need thereof an effective amount of a compound of formula (1):
wherein
R1 is chosen from hydrogen, alkyl, cycloalkyl and heterocycle, each of the said alkyl, cycloalkyl, and heterocycle, in R1 is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, —C(O)Ra, —C(O)ORb, —CN, —C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, —NRcRd, —NReC(O)Ra, —NReC(O)ORb, —NReC(O)NRcRd, —NReS(O)nRf, —NReS(o)nNRcRd, —NO2, —ORb, —S(O)nRf, and —S(O)nNRcRd;
R2 is
which is optionally substituted with one or more groups chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, (C(O)Ra, —C(O)ORb, —CN, —C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, —NRcRd, —NReC(O)Ra, —NReC(O)ORb, —NReC(O)NRcRd, —NReS(O)nRf, —NReS(O)nNRcRd, NO2, —ORb, —S(O)nRf, and —S(O)nNRcRd;
m is 1;
n is chosen from 0, 1, and 2;
for each occurrence, Ra, Rb, Rc, Rd, Re and Rf are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted haloalkyl, optionally substituted heteroaryl and optionally substituted heterocycle,
or Rc and Rd, with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups chosen from halo, lower alkyl, hydroxy, and lower alkoxy, wherein the heterocycle ring further optionally comprises one or two additional heteroatoms chosen from N, O and S,
wherein each optionally substituted group above can be unsubstituted or independently substituted with at least one substituent independently chosen from C1-C4 alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, —OC1-C4 alkyl, —OC1-C4 alkylphenyl, —C1-C4 alkyl-OH, —C1-C4 alkyl-O—C1-C4 alkyl, —OC1-C4 haloalkyl, halo, —OH, —NH2, —C1-C4 alkyl-NH2, —N(C1-C4 alkyl)(C1-C4 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkylphenyl), —NH(C1-C4 alkylphenyl), cyano, nitro, oxo, —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —NHC(O)(phenyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(phenyl), —C(O)C1-C4 alkyl, —C(O)C1-C4 haloalkyl, —OC(O)(C1-C4 alkyl), —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2, —SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl), in which each of phenyl, aryl, heterocycle, and heteroaryl is optionally substituted by one or more groups chosen from halo, cycloalkyl, heterocycle, C1-C4 alkyl, C1-C4 haloalkyl-, —OC1-C4 alkyl, C1-C4 alkyl-OH, —C1-C4 alkyl-O—C1-C4 alkyl, —OC1-C4 haloalkyl, cyano, nitro, —NH2, —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2, SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl),
and/or at least one pharmaceutically acceptable salt thereof.

### Claim 3

A method for treating in a subject a cancer responsive to inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 comprising:
(a) administering to said subject in need thereof an effective amount of a compound of formula (1):
wherein
R1 is chosen from hydrogen, alkyl, cycloalkyl and heterocycle, each of the said alkyl, cycloalkyl, and heterocycle, in R1 is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, —C(O)Ra, —C(O)ORb, —CN, —C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, —NRcRd, —NReC(O)Ra, —NReC(O)ORb, —NReC(O)NRcRd, —NReS(O)nRf, —NReS(o)nNRcRd, —NO2, —ORb, —S(O)nRf, and —S(O)nNRcRd;
R2 is
which is optionally substituted with one or more groups chosen from optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, (C(O)Ra, —C(O)ORb, —CN, —C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, —NRcRd, —NReC(O)Ra, —NReC(O)ORb, —NReC(O)NRcRd, —NReS(O)nRf, —NReS(O)nNRcRd, —NO2, —ORb, —S(O)nRf, and —S(O)nNRcRd;
m is 1;
n is chosen from 0, 1, and 2;
for each occurrence, Ra, Rb, Rc, Rd, Re and Rf are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted haloalkyl, optionally substituted heteroaryl and optionally substituted heterocycle,
or Rc and Rd, with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups chosen from halo, lower alkyl, hydroxy, and lower alkoxy, wherein the heterocycle ring further optionally comprises one or two additional heteroatoms chosen from N, O and S,
wherein each optionally substituted group above can be unsubstituted or independently substituted with at least one substituent independently chosen from C1-C4 alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, aryl-C1-C4 alkyl, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, —OC1-C4 alkyl, —OC1-C4 alkylphenyl, —C1-C4 alkyl-OH, —C1-C4 alkyl-O—C1-C4 alkyl, —OC1-C4 haloalkyl, halo, —OH, —NH2, —C1-C4 alkyl-NH2, —N(C1-C4 alkyl)(C1-C4 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkylphenyl), —NH(C1-C4 alkylphenyl), cyano, nitro, oxo, —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —NHC(O)(phenyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(phenyl), —C(O)C1-C4 alkyl, —C(O)C1-C4 haloalkyl, —OC(O)(C1-C4 alkyl), —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2, —SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl), in which each of phenyl, aryl, heterocycle, and heteroaryl is optionally substituted by one or more groups chosen from halo, cycloalkyl, heterocycle, C1-C4 alkyl, C1-C4 haloalkyl-, —OC1-C4 alkyl, C1-C4 alkyl-OH, —C1-C4 alkyl-O—C1-C4 alkyl, —OC1-C4 haloalkyl, cyano, nitro, —NH2, —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2, SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl),
and/or at least one pharmaceutically acceptable salt thereof, and
(b) administering to the subject an amount of anti-neoplastic agent, wherein said anti-neoplastic agent is different from said at least one compound of (a), and/or at least one pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound is selected from the group consisting of compounds 41, 42, 44, 58, 61, 66-78, 81-83, 87, 89-92, 96-102, 121, 123, 124, 126, 128, 137, 144-147, 149, 150, 155-160, 162, 168-178, 181, 183, 186, 188, 190-200, and 209-260.

### Claim 5 (depends on 2)

The method according to claim 2, wherein the compound is selected from the group consisting of compounds 41, 42, 44, 58, 61, 66-78, 81-83, 87, 89-92, 96-102, 121, 123, 124, 126, 128, 137, 144-147, 149, 150, 155-160, 162, 168-178, 181, 183, 186, 188, 190-200, and 209-260.

### Claim 6 (depends on 3)

The method according to claim 3, wherein the compound is selected from the group consisting of compounds 41, 42, 44, 58, 61, 66-78, 81-83, 87, 89-92, 96-102, 121, 123, 124, 126, 128, 137, 144-147, 149, 150, 155-160, 162, 168-178, 181, 183, 186, 488, 190-200, and 209-260.