# US 10,501,459 B2 · Substituted imidazo[1,2-a]pyridines as bromodomain inhibitors

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- Number: US 10,501,459 B2
- Document ID: US10501459B2
- Status: Granted
- Kind: B2
- Application number: 15/770,121
- Filed: 2016-10-20
- Published: 2018-11-01
- Granted: 2019-12-10
- Earliest claimed: 2015-10-21
- Assignees: Neomed Institute
- Applicants: NEOMED Institute
- Inventors: Mehrnaz Pourashraf; Marc-Andre Beaulieu; Stephen Claridge; Malken Bayrakdarian; Shawn Johnstone; Jeffrey S. Albert; Andrew Griffin
- Web page: https://patentgrep.com/patent/US10501459B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 35/02: specific for leukemia
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This application relates to substituted imidazopyridines, compositions comprising them and their uses in the treatment of diseases and conditions in which inhibition of a bromodomain is indicated. For example, the application relates to substituted imidazopyridines of Formula I and to their use as bromodomain inhibitors. The present application is also related to the treatment or prevention of proliferative disorders, auto-immune disorders, inflammatory disorders, dermal disorders, and neoplasms, including tumors and/or cancers.

## Claims

### Claim 1

A compound of Formula I:
wherein:
R1 is an unsubstituted group selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl, C3-C10cycloalkylC1-C6alkyl-, C3-C10heterocycloalkylC1-C6alkyl-, C6-C10arylC1-C6alkyl-, C5-C10heteroarylC1-C6alkyl-, C(O)Ra, ORa, NHRa, N(Ra)2, C(O)NH2, C(O)NHRa, C(O)N(Ra)2, NHC(O)Ra, N(Ra)C(O)Ra, NHC(O)NHRa, N(Ra)C(O)NHRa, NHC(O)N(Ra)2, N(Ra)C(O)N(Ra)2, NHSO2Ra, N(Ra)SO2Ra, NHSO2NHRa, N(Ra)SO2NHRa, NHSO2N(Ra)2, N(Ra)SO2N(Ra)2, SO2Ra, SO2NH2, SO2NHRa, and SO2N(Ra)2; or
R1 is a group selected from C3-C10cycloalkyl, C3-C10heterocycloalkyl, C3-C10cycloalkylC1-C6alkyl-, C3-C10heterocycloalkylC1-C6alkyl-, C6-C10arylC1-C6alkyl- and C5-C10heteroarylC1-C6alkyl- which is substituted with one or more group(s) selected from halogen and alkoxy; or
R1 is a branched or linear C1-C6alkyl group substituted with one or more group(s) selected from halogen, OH, NH2, CN, C3-C10cycloalkyl, C3-C10heterocycloalkyl optionally substituted with an oxo group, C6-C10aryl, C5-C10heteroaryl, C(O)Ra, ORa, NHRa, N(Ra)2, C(O)NH2, C(O)NHRa, C(O)N(Ra)2, NHC(O)Ra, N(Ra)C(O)Ra, NHC(O)NHRa, N(Ra)C(O)NHRa, NHC(O)N(Ra)2, N(Ra)C(O)N(Ra)2, NHSO2Ra, N(Ra)SO2Ra, NHSO2NHRa, N(Ra)SO2NHRa, NHSO2N(Ra)2, N(Ra)SO2N(Ra)2, SO2Ra, SO2NH2, SO2NHRa, and SO2N(Ra)2;
each Ra is independently an unsubstituted group selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl, C3-C10cycloalkylC1-C6alkyl-, C3-C10heterocycloalkylC1-C6alkyl-, C6-C10aryl, C5-C10heteroaryl, C6-C10arylC1-C6alkyl-, and C5-C10heteroarylC1-C6alkyl-; or
Ra is independently a group selected from C1-C6alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl, C3-C10cycloalkylC1-C6alkyl-, C3-C10heterocycloalkylC1-C6alkyl-, C6-C10aryl, C5-C10heteroaryl, C6-C10 arylC1-C6alkyl-, and C5-C10heteroarylC1-C6alkyl- which is substituted with one or more group(s) selected from halogen, alkyl and alkoxy;
R2 is H, NH2, CN or a group selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, C5-C10heteroaryl, C(O)Ra, ORa, SRa, NHRa, N(Ra)2, C(O)NH2, C(O)NHRa, C(O)N(Ra)2, NHC(O)Ra, SO2Ra, SO2NHRa, SO2N(Ra)2, NHSO2Ra, N(Ra)SO2Ra, NHSO2NHRa, N(Ra)SO2NHRa, NHSO2N(Ra)2, and N(Ra)SO2N(Ra)2;
R3 and R6 are each independently H, halogen, NH2, CN or a group selected from C1-C6alkyl, C(O)Ra, ORa, NHRa, N(Ra)2, C(O)NH2, C(O)NHRa, C(O)N(Ra)2, and NHC(O)Ra; and
one of R4 and R5 is H, halogen, NH2, CN or a group selected from C1-C6alkyl, C(O)Ra, NH2, NHRa, N(Ra)2, C(O)NH2, C(O)NHRa, C(O)N(Ra)2, and NHC(O)Ra; and the other of R4 and R5 is a group of Formula II:
wherein:
R7 and R10 are each independently H, halogen, CN, or a group selected from C1-C6alkyl, C3-C6cycloalkyl, OC1-C6alkyl, OC3-C6cycloalkyl, SC1-C6alkyl, SC3-C6cycloalkyl, NHC1-C6alkyl, NHC3-C6cycloalkyl, N(C1-C6alkyl)2, NHC(O)C1-C6alkyl and NHC(O)C3-C6cycloalkyl;
R8 is halogen, CN, or a group selected from C1-C6alkyl, C3-C6cycloalkyl, OC1-C6alkyl, OC3-C6cycloalkyl, SC1-C6alkyl, SC3-C6cycloalkyl, NHC1-C6alkyl, NHC3-C6cycloalkyl, N(C1-C6alkyl)2, NHC(O)C1-C6alkyl and NHC(O)C3-C6cycloalkyl;
R9 is a C1-C3alkyl or C3-C5cycloalkyl group; and
X1, X2, and X3 are each selected from a nitrogen or carbon atom, wherein when X1, X2, or X3 is a nitrogen atom, then the R7, R8, or R10 attached thereto is absent, provided that at least two of X1, X2, and X3 are carbon atoms;
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl in the definitions of R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently optionally substituted with one or more substituents selected from halogen, OH, NH2, CN, C1-C6alkyl, C1-C6alkoxy, C3-C10heterocycloalkyl and C6-C10aryl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is a compound of Formula IIIa or Formula IIIb:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R9 is an unsubstituted C1-C3alkyl or unsubstituted C3-C5cycloalkyl group; R7 and R10 are each H and R8 is Cl, CN, C1-C3alkyl, cyclopropyl, NHC1-C3alkyl, or N(C1-C3alkyl)2.

### Claim 4 (depends on 2)

The compound of claim 2, wherein R8 and R9 are each independently selected from methyl, ethyl, isopropyl, fluoroethyl, difluoromethyl, trifluoromethyl, cyclopropyl, or difluorocyclopropyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is an unsubstituted, branched or linear C1-C6alkyl group or a branched or linear C1-C6alkyl substituted with one or more group(s) selected from halogen, OH, NH2, CN, C3-C10cycloalkyl, C3-C10heterocycloalkyl optionally substituted with an oxo group, C6-C10aryl, C5-C10heteroaryl, C(O)Ra, ORa, NHRa, N(Ra)2, C(O)NH2, C(O)NHRa, C(O)N(Ra)2, NHC(O)Ra, N(Ra)C(O)Ra, NHC(O)NHRa, N(Ra)C(O)NHRa, NHC(O)N(Ra)2, N(Ra)C(O)N(Ra)2, NHSO2Ra, N(Ra)SO2Ra, NHSO2NHRa, N(Ra)SO2NHRa, NHSO2N(Ra)2, N(Ra)SO2N(Ra)2, SO2Ra, SO2NH2, SO2NHRa, and SO2N(Ra)2.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1 is selected from C(O)Ra, ORa, NHRa, N(Ra)2, C(O)NHRa, C(O)N(Ra)2, SO2Ra, SO2NHRa, and SO2N(Ra)2.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 is selected from C(O)C3-C10 heterocycloalkyl, ORa, NHRa, N(Ra)2, C(O)NHRa, SO2(C3-C10heterocycloalkyl), and SO2NHRa.

### Claim 8 (depends on 1)

The compound of claim 1, wherein each Ra is independently selected from an unsubstituted group selected from C1-C6alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl, or C5-C10heteroaryl; or each Ra is independently a group selected from C1-C6alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl, C6-C10aryl and C5-C10heteroaryl which is substituted with one or more group(s) selected from halogen and alkoxy.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R2 is H, C1-C6alkyl, C3-C10cycloalkyl, or C3-C10heterocycloalkyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R2 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, piperidinyl, or pyrrolidinyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R2 is H or methyl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R3 is H or C1-C6alkyl and R6 is H or C1-C6alkyl.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is a group of Formula II and R5 is H or C1-C3 alkyl.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is a group of Formula II and R4 is H or C1-C3 alkyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein X1, X2 and X3 are all carbon atoms.

### Claim 16 (depends on 15)

The compound of claim 15, wherein R7 and R10 are each H and R8 is Cl, CN, C1-C3alkyl, cyclopropyl, NHC1-C3alkyl, or N(C1-C3alkyl)2 wherein the alkyl and cyclopropyl are optionally substituted with halogen.

### Claim 17 (depends on 1)

The compound of claim 1, wherein X1 is a nitrogen atom and R10 is absent, and X2 and X3 are carbon atoms.

### Claim 18 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

### Claim 19 (depends on 1)

A method for inhibiting bromodomain activity in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 1.

### Claim 20 (depends on 19)

The method of claim 19, wherein the subject has a disease or condition selected from the group consisting of an auto-immune disorder, an inflammatory disorder, a dermal disorder, and a neoplasm.

### Claim 21 (depends on 20)

The method of claim 20, wherein the disease or condition is a neoplasm.

### Claim 22 (depends on 20)

The method of claim 20, wherein the disease or condition is a hematopoietic neoplasm.

### Claim 23 (depends on 20)

The method of claim 20, wherein the disease or condition is a solid neoplasm.

### Claim 24 (depends on 19)

The method of claim 19, wherein the subject has a cancer.

### Claim 25 (depends on 24)

The method of claim 24, wherein the cancer is bladder cancer, leukemia, lymphoma, brain cancer, central nervous system cancer, breast cancer, cervix cancer, colorectal cancer, colon cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer or gastric cancer.

### Claim 26 (depends on 24)

The method of claim 24, wherein the cancer is breast cancer, bladder cancer, colon cancer, lung cancer, lymphoma, leukemia, mesothelioma, ovarian cancer or prostate cancer.

### Claim 27 (depends on 24)

The method of claim 24, wherein the cancer is prostate cancer.