Indazoles

• US 8,846,935 B2
• Filed: 05/05/2011
• Issued: 09/30/2014
• Est. Priority Date: 05/07/2010
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: GlaxoSmithKline LLC (GSK plc)
• Inventors: Duquenne, Celine, Johnson, Neil, Knight, Steven D., Lafrance, Louis, Miller, William H., Newlander, Kenneth, Romeril, Stuart, Rouse, Meagan B., Tian, Xinrong, Verma, Sharad Kumar
• Primary Examiner(s): Murray, Jeffrey H
• Assistant Examiner(s): Masha, Oluwafemi
• Application Number:
  US13/696,436
• Publication Number:
  US 20130053383A1
• Time in Patent Office: 1,244 Days
• Field of Search: 548/361.1, 546/275.7, 546/256
• US Class Current: 546/275.7
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Herein are disclosed indazoles of formula (I)

where the various groups are defined herein, and which are useful for treating cancer.

Claims

1. A compound of formula (I):

2. The compound according to claim 1 wherein:

X and Z are selected independently from the group consisting of (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, aryl, —

NR^aR^b, and —

OR^a;

Y is H;

R¹ is (C₁-C₈)alkyl or (C₃-C₈)cycloalkyl;

R³ is hydrogen, (C₁-C₈)alkyl, or halo;

R⁶ is pyridinyl which is optionally substituted by 1, 2, or 3 groups independently selected from halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano, —

COR^a, —

CO₂R^a, —

CONR^aR^b, —

SR^a, —

SOR^a, —

SO₂R^a, —

SO₂NR^aR^b, nitro, —

NR^aR^b, —

NR^aC(O)R^b, —

NR^aC(O)NR^aR^b, —

NR^aC(O)OR^a, —

NR^aSO₂R^b, —

NR^aSO₂NR^aR^b, —

OR^a, —

OC(O)R^a, —

OC(O)NR^aR^b, aryl, and aryl(C₁-C₄)alkyl; and

R^a and R^b are each independently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₆-C₁₀)bicycloalkyl, or aryl, wherein said (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, or aryl group is optionally substituted by 1, 2, or 3 groups independently selected from halo, hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —

CO₂H, —

CO₂(C₁-C₄)alkyl, —

CONH₂, —

CONH(C₁-C₄)alkyl, —

CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —

SO₂(C₁-C₄)alkyl, —

SO₂NH₂, —

SO₂NH(C₁-C₄)alkyl, and —

SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl);

or R^a and R^b taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by 1, 2, or 3 groups independently selected from (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and (C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a (C₃-C₈)cycloalkyl, or aryl ring;

or R^a and R^b taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C₃-C₈)cycloalkyl or aryl ring;

wherein any aryl is selected from the group consisting of phenyl and naphthyridine;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein:

X is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, trifluoromethyl, tetrahydropyran, hydroxymethyl, methoxymethyl, or benzyl;

Y is H;

Z is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or benzyl;

R¹ is isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl or benzyl;

R³ is H, methyl, or Br; and

R⁶ is 3 pyridinyl, 4-pyridinyl, 2-(4-morpholinyl)-4-pyridinyl, 2-amino-4-pyridinyl, 5-(methyloxy)-3-pyridinyl, 5-(methylsulfonyl)-3-pyridinyl, 5-[(cyclopropylsulfonyl)amino]-6-(methyloxy)-3-pyridinyl, 5-[(phenylsulfonyl)amino]-3-pyridinyl, 6-(4-methyl-1-piperazinyl)-3-pyridinyl, 6-(4-morpholinyl)-3-pyridinyl, 6-(acetylamino)-3-pyridinyl, 6-(dimethylamino)-3-pyridinyl, 6-(methyloxy)-3-pyridinyl, 6-[(methylamino)carbonyl]-3-pyridinyl, 6-[(methylamino)sulfonyl]-3-pyridinyl, or 6-methyl-3-pyridinyl;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein:

X is (C₁-C₈)alkyl or (C₃-C₈)cycloalkyl;

Y is H;

Z is (C₁-C₃)alkyl;

R¹ is (C₃-C₈)alkyl or (C₃-C₈)cycloalkyl;

R³ is hydrogen, (C₁-C₃)alkyl, or halo;

R⁶ is pyridinyl which is optionally substituted by 1, 2, or 3 groups independently selected from —

O(C₁-C₆)alkyl(R^c)_1-2, —

S(C₁-C₆)alkyl(R^c)_1-2, —

(C₁-C₆)alkyl(R^c)_1-2, halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano, —

COR^a, —

CO₂R^a, —

CONR^aR^b, —

SR^a, —

SOR^a, —

SO₂R^a, —

SO₂NR^aR^b, nitro, —

NR^aR^b, —

NR^aC(O)R^b, —

NR^aC(O)NR^aR^b, —

NR^aC(O)OR^a, —

NR^aSO₂R^b, —

NR^aSO₂NR^aR^b, —

OR^a, —

OC(O)R^a, —

OC(O)NR^aR^b, aryl, and aryl(C₁-C₄)alkyl;

R^a and R^b are each independently hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₆-C₁₀)bicycloalkyl, or aryl, wherein said (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, or aryl group is optionally substituted by 1, 2, or 3 groups independently selected from halo, hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —

CO₂H, —

CO₂(C₁-C₄)alkyl, —

CONH₂, —

CONH(C₁-C₄)alkyl, —

CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —

SO₂(C₁-C₄)alkyl, —

SO₂NH₂, —

SO₂NH(C₁-C₄)alkyl, and —

SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl);

or R^a and R^b taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted by 1, 2, or 3 groups independently selected from (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and (C₁-C₄)alkoxy(C₁-C₄)alkyl; and

each R^c is independently —

NR^aSO₂R^b, —

SOR^a, —

SO₂R^a, —

NR^aC(O)OR^a, —

NR^aR^b, or —

CO₂R^a;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 which is:

N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

1-isopropyl-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indazole-4-carboxamide;

1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

N-((4-ethyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-4-carboxamide;

6-[6-(dimethylamino)-3-pyridinyl]-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide;

1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

6-(6-amino-3-pyridinyl)-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide;

1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-[6-(methyloxy)-3-pyridinyl]-1H-indazole-4-carboxamide;

1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(2-methyl-3-pyridinyl)-1H-indazole-4-carboxamide;

1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(6-methyl-3-pyridinyl)-1H-indazole-4-carboxamide;

6-[6-(dimethylamino)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide;

N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(trifluoromethyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-methoxypyridin-3-yl)-1H-indazole-4-carboxamide;

1-cyclopentyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-4-carboxamide;

1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

1-isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-6-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-indazole-4-carboxamide;

3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-[6(1-piperazinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

6-(6-(dimethylamino)pyridin-3-yl)-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide;

N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-4-carboxamide;

N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indazole-4-carboxamide;

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-6-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-indazole-4-carboxamide;

N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxamide;

N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxamide;

N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-(6-methyl-3-pyridinyl)-1H-indazole-4-carboxamide;

6-[6-(dimethylamino)-3-pyridinyl]-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide;

3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(3-pyridinyl)-1H-indazole-4-carboxamide;

or

3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 which is:

N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-indazole-4-carboxamide;

N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

6-[6-(acetylamino)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide;

N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(3-pyridinyl)-1H-indazole-4-carboxamide;

N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(methyloxy)-3-pyridinyl]-1H-indazole-4-carboxamide;

1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-carboxamide;

1-(1-methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-carboxamide;

1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(6-methyl-3-pyridinyl)-1H-indazole-4-carboxamide;

1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-carboxamide;

1-cyclopentyl-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(6-methyl-3-pyridinyl)-1H-indazole-4-carboxamide;

1-cyclopentyl-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(3-pyridinyl)-1H-indazole-4-carboxamide;

1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(3-pyridinyl)-1H-indazole-4-carboxamide;

or

1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-indazole-4-carboxamide;

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.