Inhibitors of c-fms kinase

Patent metadata

Field	Value
Publication number	US-9452996-B2
Application number	US-201514927855-A
Country	US
Kind code	B2
Filing date	Oct 30, 2015
Priority date	Apr 20, 2006
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

The invention is directed to compounds of Formula I:

wherein Z, X, J, R 2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including arthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

First claim

We claim:

1. A compound of Formula I

or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein:
W is

wherein each R 4 is independently H, F, Cl, Br, I, OH, OCH 3 , OCH 2 CH 3 , SC (1-4) alkyl, SOC (1-4) alkyl, SO 2 C (1-4) alkyl, —C (1-3) alkyl, CO 2 R d , CONR e R f ,

or CN;
wherein R d is H, or —C (1-3) alkyl;
R e is H, or —C (1-3) alkyl;
R f is H, or —C (1-3) alkyl; and
R g is H, —CH 2 OH, or —CH 2 CH 2 OH;

R 2 is cycloalkyl, spiro-substituted cycloalkenyl, heterocyclyl, spirosubstituted piperidinyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or dihydropyranyl, any of which may be independently substituted with one or two of each of the following: chloro, fluoro, hydroxy, C (1-3) alkyl, and C (1-4) alkyl;
Z is H, F, or CH 3 ;
J is N;
X is —C (1-6) alkylR 1 , alkenyl, propenyl-NA 1 A 2 , —CH═CH—CO 2 R a wherein said CH═CH bond includes both E and Z stereochemistry, —C (1-4) alkylR 3 R 4a , or CH 2 -heteroaryl-C (1-4) alkyl-R 1 ;
wherein:
R 1 is —CN, —SO 2 NA 1 A 2 , —SO 2 R a , —SCH 2 CH 2 NA 1 A 2 , —SOCH 2 CH 2 NA 1 A 2 , —SO 2 CH 2 CH 2 NA 1 A 2 , —S—C(O)C (1-4) alkyl, —S—CH 2 -4-methoxy phenyl, —OC (1-4) alkylNA 1 A 2 , —NA 1 A 2 , —NHSO 2 R a , —NHCOR a , —NHSO 2 CH 2 CH 2 NA 1 A 2 , —NHCOCH 2 CH 2 NA 1 A 2 , —CONH 2 , —CONHCH 2 CH 2 CH 2 OH, —CONHCH 2 CH 2 N(C (1-4) alkyl) 2 , —NHCONH 2 , —NHCONHCH 2 CH 2 OH, —NHCOCONH 2 , —NR a CH 2 CH 2 NA 1 A 2 , CO 2 R a , pyridyl, —OCH 2 CH 2 OR a , —OCH 2 CH 2 OCH 2 CH 2 NA 1 A 2 , —OCH 2 CH 2 NA 1 CH 2 CH 2 OR a , —NA 1 CH 2 CH 2 OCH 2 CH 2 OR a , —OCOR a , or —CH 2 OCOCH 3 ;
A 1 is H or —C (1-4) alkyl;
A 2 is —C (1-4) alkyl, —CH 2 CH 2 OR a , —COR a , —CH 2 CH 2 SC (1-4) alkyl, —CH 2 CH 2 SOC (1-4) alkyl, pyridyl, 2-methyl pyridyl, —CH 2 CH 2 OCH 2 CH 2 OR a , or —CH 2 CH 2 SO 2 C (1-4) alkyl;
alternatively, A 1 and A 2 may be taken together with their attached nitrogen to form a heterocyclic ring selected from the following:

wherein:
R a is H or C (1-4) alkyl;
R aa is H or C (1-4) alkyl;
R b is H, —C (1-4) alkyl, alkoxyether, —C(O)C (1-4) alkyl, —C (1-4) alkyl-OH, —C (1-4) alkyl-O-C (1-4) alkyl, —C (1-4) alkyl-C(O)O-C (1-4) alkyl, —C (1-4 )alkylC(O)OH, —C (1-4) alkylC(O)ONa, or —CH 2 C(O)C (1-4) alkyl; and

R 3 and R 4a are independently —CH 2 OH, —OCH 3 , —CH 2 OCH 3 , —CO 2 H, —CO 2 C (1-4) alkyl, OC(O)C (1-4) alkyl, or —OH.

2. The compound of claim 1 , wherein:
R 2 is

X is —C (1-6) alkylR 1 , alkenyl, propenyl-NA 1 A 2 , —CH═CH—CO 2 R a , —C (1-4) alkylR 3 R 4a , or —CH 2 -heteroaryl-C (1-4) alkyl-R 1 ;
wherein:
R 1 is —CN, —SO 2 NA 1 A 2 , —SO 2 R a , —SCH 2 CH 2 NA 1 A 2 , —SOCH 2 CH 2 NA 1 A 2 , —SO 2 CH 2 CH 2 NA 1 A 2 , —S—C(O)C (1-4) alkyl, —S—CH 2 -4-methoxy phenyl, —OC (1-4) alkylNA 1 A 2 , —NA 1 A 2 , —NHSO 2 CH 3 , —NHCOCH 3 , —CONH 2 , —CONHCH 2 CH 2 CH 2 OH, —CONHCH 2 CH 2 N(C (1-4) alkyl) 2 , —NHCONH 2 , —NHCONHCH 2 CH 2 OH, —NHCOCONH 2 , —NR a CH 2 CH 2 NA 1 A 2 , —CO 2 R a , pyridyl, —OCOCH 3 , or —CH 2 OCOCH 3 ;
A 1 is H or —C (1-4) alkyl;
A 2 is —C (1-4) alkyl, —CH 2 CH 2 OR a , —COR a , —CH 2 CH 2 SC (1-4) alkyl, —CH 2 CH 2 SOC (1-4) alkyl, pyridyl, 2-methyl pyridyl, or —CH 2 CH 2 SO 2 C (1-4) alkyl;
alternatively, A 1 and A 2 may be taken together with their attached nitrogen to form a heterocyclic ring selected from the following:

wherein:
R a is H or C (1-4) alkyl;
R b is H, —C (1-4) alkyl, alkoxyether, —C(O)C (1-4) alkyl, —C (1-4) alkyl-OH, —C (1-4) alkyl-O-C (1-4) alkyl, —C (1-4) alkyl-C(O)O-C (1-4) alkyl, —C (1-4) alkylC(O)OH, —C (1-4) alkylC(O)ONa, or —CH 2 C(O)C (1-4) alkyl; and

R 3 and R 4a are independently —CH 2 OH, —OCH 3 , —CH 2 OCH 3 , —CO 2 H, —CO 2 C (1-4) alkyl, —OC(O)C (1-4) alkyl, or —OH.

3. The compound of claim 2 wherein:
R 2 is

X is —C (1-5) alkylR 1 , alkenyl, propenyl-NA 1 A 2 , —CH═CH—CO 2 R a , —C (1-4) alkylR 3 R 4a , or —CH 2 -heteroaryl-C (1-4) alkyl-R 1 ;
wherein:
R 1 is —CN, —SO 2 NA 1 A 2 , —SO 2 R a , —SCH 2 CH 2 NA 1 A 2 , —SOCH 2 CH 2 NA 1 A 2 , —SO 2 CH 2 CH 2 NA 1 A 2 , —S—C(O)C (1-4) alkyl, —S—CH 2 -4-methoxy phenyl, —OC (1-4) alkylNA 1 A 2 , —NA 1 A 2 , —NHSO 2 CH 3 , —NHCOCH 3 , —CONH 2 , —CONHCH 2 CH 2 CH 2 OH, CONHCH 2 CH 2 N(C (1-4) alkyl) 2 , —NHCONH 2 , —NHCONHCH 2 CH 2 OH, —NHCOCONH 2 , —NR a CH 2 CH 2 NA 1 A 2 , —CO 2 R a , pyridyl, —OCOCH 3 , or —CH 2 OCOCH 3 ;
A 1 is H or —C (1-4) alkyl;
A 2 is —C (1-4) alkyl, —CH 2 CH 2 OR a , —COR a , —CH 2 CH 2 SC (1-4) alkyl, —CH 2 CH 2 SOC (1-4) alkyl, pyridyl, 2-methyl pyridyl, or —CH 2 CH 2 SO 2 C (1-4) alkyl;
alternatively, A 1 and A 2 may be taken together with their attached nitrogen to form a heterocyclic ring selected from the following:

wherein:
R a is H or C (1-4) alkyl;
R b is H, —C (1-4) alkyl, alkoxyether, —C(O)C (1-4) alkyl, —C (1-4) alkyl-OH, —C (1-4) alkyl-O-C (1-4) alkyl, —C (1-4) alkyl-C(O)O-C (1-4) alkyl, —C (1-4) alkylC(O)OH, —C (1-4) alkylC(O)ONa, or —CH 2 C(O)—C (1-4) alkyl; and

R 3 and R 4a are independently —CH 2 OH, —OCH 3 , —CH 2 OCH 3 , —CO 2 H, —CO 2 C (1-4) alkyl, OC(O)C (1-4) alkyl, or —OH.

4. The compound of claim 3 wherein:
W is

R 2 is

Z is H;
X is —C (1-5) alkylR 1 , —CH═CH—CO 2 H wherein said CH═CH bond has E stereochemistry, —C (1-4) alkylR 3 R 4a , propenyl-NA 1 A 2 , or propenyl;
wherein:
R 1 is —SO 2 NA 1 A 2 , —S—C(O)CH 3 , —S—CH 2 -4-methoxy phenyl, —OC (1-4) alkylNA 1 A 2 , —NA 1 A 2 , —NHCH 2 CH 2 NA 1 A 2 , —NHSO 2 CH 3 , —NHCOCH 3 , —CONH 2 , —CONHCH 2 CH 2 CH 2 OH, —CONHCH 2 CH 2 N(CH 3 ) 2 , —NHCONH 2 , —NHCONHCH 2 CH 2 OH, —NHCOCONH 2 , —CO 2 R a , or pyridyl;
A 1 is H or —C (1-4) alkyl;
A 2 is —C (1-4) alkyl, —CH 2 CH 2 OR a , —COCH 3 , —CH 2 OCH 3 , —CH 2 CH 2 SC (1-4) alkyl, pyridyl, 2-methyl pyridyl, or —CH 2 CH 2 SO 2 C (1-4) alkyl;
alternatively, A 1 and A 2 may be taken together with their attached nitrogen to form a heterocyclic ring selected from the following:

wherein:
R a is H or C (1-4) alkyl;
R b is H, —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 C(O)OCH 2 CH 3 , —CH 2 C(O)OH, —CH 2 C(O)ONa, —C(O)CH 3 , or —C (1-4) alkyl; and

R 3 and R 4a are independently

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Illig Carl R
• Ballentine Shelley K
• Chen Jinsheng
• Desjarlais Renee Louise
• Meegalla Sanath K
• Wall Mark
• Wilson Kenneth

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title