Substituted pyrrolo[2,3-b]pyridines for treating cancer or inflammatory diseases

• US 9,499,551 B2
• Filed: 01/23/2015
• Issued: 11/22/2016
• Est. Priority Date: 01/24/2014
• Status: Active Grant

• Current Assignee: Aclaris Therapeutics, Inc. (Confluence Life Sciences, Inc.)
• Original Assignee: Confluence Life Sciences, Inc.
• Inventors: Jacobsen, Eric Jon, Blinn, James Robert, Springer, John Robert, Hockerman, Susan L.
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US14/604,016
• Publication Number:
  US 20150210705A1
• Time in Patent Office: 669 Days
• Field of Search: 544/333, 544/373, 546/113, 546/199, 546/276.7, 548/202, 548/373.1, 548/518, 548/950
• US Class Current: 1/1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Disclosed herein are substituted pyrrolopyridine and pyrrolopyrazine compounds and compositions useful in the treatment of TAK mediated diseases, such as cancer, having the structure of Formula (I):

wherein R¹, R², R³, and R⁴ are as defined in the detailed description. Methods of modulation of TAK activity in a human or animal subject are also provided, providing therapeutic benefit to subjects with disease conditions, especially cancer.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein the compound has formula (II)

3. The compound of claim 2, wherein the compound has formula (III):

4. The compound of claim 3, wherein:

R¹ is chosen from C_2-6 alkyl, OC_3-7 cycloalkyl, C_1-4 alkylamino, NH₂, NHC_1-6 alkyl, N(C_1-4 alkyl)₂, CN, aryl and heteroaryl;

wherein each alkyl, aryl or heteroaryl group of R¹ may be optionally substituted with one or more R⁵ substituents;

R² is chosen from hydrogen, fluoro, alkyl, C(O)R⁴, CN, C(O)NH₂, and C(O)NHCH₃;

R³ is chosen from C(O)R⁴, CN, C(O)NH₂, C(O)NHCH₃, C(O)alkyl, C(O)C_1-6alkylN(R⁴)₂, C(O)C_1-6 alkylOR⁴;

or when R² is C(O)R⁴, C(O)NH₂, C(O)NHCH₃, or CN, R³ is chosen from hydrogen, fluoro and CH₃;

each R⁴ is independently chosen from hydrogen, C_1-6 alkyl, and C_3-6 cycloalkyl;

wherein each R⁴ together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R⁵ substituents;

each R⁵ is independently chosen from C_1-4 alkyl, OH, OC_1-6 alkyl, CH₂aryl, CH₂heteroaryl, O(CH₂)_nC_3-6 cycloalkyl, C_1-4 alkylamino, NHC_3-7 cycloalkyl, N(R⁴)₂, NHC(O)alkyl, NHC(O)aryl, NHC(O)heteroaryl, CN, C(O)N(R⁴)₂, C(O)OC_1-6 alkyl, C(O)C_1-6 alkyl, C(O)C_3-7 cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, CN, S(O)₂CH₃, S(O)CH₃, SCH₃, aryl, and heteroaryl;

wherein each alkyl, aryl, heteroaryl or heterocyclyl of R⁵ may be optionally substituted with one or more R⁶;

each R⁶ is independently chosen from halo, C_1-4 alkyl, C_3-6 cycloalkyl, CF₃, OH, OCH₃ and CN;

R⁷ is chosen from hydrogen, C_1-6 alkyl, OC_1-6 alkyl, OC_3-7 cycloalkyl, C_1-4 alkylamino, NHC_1-6 alkyl, NHC_3-7 alkyl, CN, trifluoromethyl, halo, aryl and heteroaryl, wherein alkyl, aryl or heteroaryl groups of R⁷ may be optionally substituted with one or more R⁵ substituents; and

n is chosen from 0, 1, and 2.

5. The compound of claim 4, wherein:

R¹ is chosen from OC_3-7 cycloalkyl, NHC_1-6 alkyl, CN, aryl and heteroaryl;

wherein each alkyl, aryl or heteroaryl group of R¹ may be optionally substituted with one or more R⁵ substituents;

R² is chosen from hydrogen, fluoro, alkyl, C(O)R⁴, CN, C(O)NH₂, and C(O)NHCH₃;

R³ is chosen from C(O)R⁴, CN, C(O)NH₂, C(O)alkyl, C(O)C_1-6 alkylOR⁴;

or when R² is C(O)R⁴, C(O)NH₂, C(O)NHCH₃, or CN, R³ is chosen from hydrogen, fluoro and CH₃;

each R⁴ is independently chosen from hydrogen, C_1-6 alkyl, and C_3-6 cycloalkyl;

wherein each R⁴ together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R⁵ substituents;

each R⁵ is independently chosen from C_1-4 alkyl, OH, OC_1-6 alkyl, O(CH₂)_nC_3-6 cycloalkyl, C_1-4 alkylamino, NHC_1-6 alkyl, NHC_3-7 cycloalkyl N(C_1-4 alkyl)₂, NHC(O)alkyl, CN, trifluoromethyl, halo, aryl, and heteroaryl, wherein alkyl, aryl or heteroaryl groups of R⁵ may be optionally substituted with R⁶;

each R⁶ is independently chosen from halo, CF₃, OCH₃, and CN;

R⁷ is chosen from hydrogen, OC_1-6 alkyl, OC_3-7 cycloalkyl, NHC_1-6 alkyl, NHC_3-7 alkyl CN, trifluoromethyl, halo, aryl and heteroaryl wherein alkyl, aryl or heteroaryl groups of R⁷ may be optionally substituted with one or more R⁵ substituents; and

n is chosen from 0 and 1.

6. The compound of claim 1, wherein:

R¹ is chosen from OC_3-7 cycloalkyl, C_1-4 alkylamino, N(R⁴)₂, NH(CH₂)_nC_3-7 cycloalkyl, C(O)N(R⁴)₂, C(O)aryl, C(O)heteroaryl, CH₂aryl, CH₂heteroaryl, heterocyclyl, aryl and heteroaryl;

wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group of R¹ may be optionally substituted with one or more R⁵ substituents;

R² is chosen from hydrogen, fluoro, C(O)R⁴, CN, C(O)NH₂, and C(O)NHCH₃;

R³ is chosen from C(O)R⁴, CN, C(O)NH₂, C(O)NHCH₃, and C(O)alkyl;

or when R² is C(O)R⁴, C(O)NH₂, C(O)NHCH₃, or CN, then R³ is chosen from hydrogen and CH₃;

each R⁴ is independently chosen from hydrogen, C_1-6 alkyl, and C_3-6 cycloalkyl;

wherein each R⁴ together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R⁵ substituents;

each R⁵ is independently chosen from C_1-6 alkyl, (CH₂)_nC_3-7 cycloalkyl, OH, OC_1-6 alkyl, O-aryl, O(CH₂)_nC_3-6 cycloalkyl, C_1-4 alkylamino, NHC_3-7 cycloalkyl, N(R⁴)₂, NHC(O)alkyl, CN, C(O)N(R⁴)₂, C(O)C_1-4 alkyl, C(O)OC_1-6 alkyl, C(O)O-aryl, C(O)O-heteroaryl, C(O)CF₃, C(O)aryl, C(O)heteroaryl, C(O)heterocyclyl, trifluoromethyl, halo, S(O)₂CH₃, aryl, and heteroaryl;

wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R⁵ may be optionally substituted with one or more R⁶;

each R⁶ is independently chosen from halo, C_1-6 alkyl, C_3-6 cycloalkyl, CF₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₂F, O(CH₂)_nCF₃, and CN;

R⁷ is chosen from hydrogen, C_1-6 alkyl, and CN;

wherein alkyl, aryl or heteroaryl groups of R⁷ may be optionally substituted with one or more R⁵ substituents;

X is CR⁷;

Y is chosen from a bond, CH₂, C(O), and NHC(O); and

n is chosen from 0, 1, and 2.

7. The compound of claim 6, wherein:

R¹ is chosen from N(R⁴)₂, C(O)N(R⁴)₂, C(O)aryl, C(O)heteroaryl, heterocycle heterocyclyl, aryl and heteroaryl;

wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group of R¹ may be optionally substituted with one or more R⁵ substituents;

R² is chosen from hydrogen, C(O)R⁴, CN, C(O)NH₂, and C(O)NHCH₃;

R³ is chosen from C(O)R⁴, CN, C(O)NH₂, C(O)NHCH₃, and C(O)alkyl;

or when R² is C(O)R⁴, C(O)NH₂, C(O)NHCH₃, or CN, then R³ is chosen from hydrogen and CH₃;

each R⁴ is independently chosen from hydrogen, and C_1-6 alkyl;

wherein each R⁴ together with the atoms to which they are attached optionally form a heterocycloalkyl or heteroaryl ring, which may be optionally substituted with one or more R⁵ substituents;

each R⁵ is independently chosen from C_1-6 alkyl, (CH₂)_nC_3-7 cycloalkyl, OH, OC_1-6 alkyl, O(CH₂)_nC_3-6 cycloalkyl, C_1-4 alkylamino, NHC_3-7 cycloalkyl, N(R⁴)₂, NHC(O)alkyl, CN, C(O)N(R⁴)₂, C(O)C_1-4 alkyl, C(O)OC_1-6 alkyl, C(O)O-aryl, C(O)O-heteroaryl, C(O)CF₃, C(O)aryl, C(O)heteroaryl, trifluoromethyl, halo, S(O)₂CH₃, aryl, and heteroaryl;

wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl of R⁵ may be optionally substituted with one or more R⁶;

each R⁶ is independently chosen from halo, C_1-6 alkyl, C_3-6 cycloalkyl, CF₃, OCH₃, OCH₂CH₃, O(CH₂)_nCF₃, and CN;

R⁷ is hydrogen;

X is CR⁷;

Y is chosen from a bond, CH₂, and C(O); and

n is chosen from 0, 1, and 2.

8. A compound selected from the group consisting of:

9. The compound of claim 8, wherein the compound is selected from the group consisting of:

10. The compound of claim 9, wherein the compound is selected from the group consisting of: