Inhibitors of c-fms kinase

Patent metadata

Field	Value
Publication number	US-9403804-B2
Application number	US-201414336014-A
Country	US
Kind code	B2
Filing date	Jul 21, 2014
Priority date	Apr 20, 2006
Publication date	Aug 2, 2016
Grant date	Aug 2, 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, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; 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 rheumatoid arthritis, and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.

First claim

The claimed invention is:

1. A compound of Formula I

or a 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 , C≡CR g , or CN;
wherein
R d is H, or —C (1-3) alkyl;
R e is H, or —C (11-3) 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, phenyl, 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 CH;
X is

R z is H or —C (1-4) alkyl, wherein both R z may have either syn or anti stereochemistry; alternatively both R z in a syn relationship may be taken together to form —(CH 2 ) n —, where n is 2 or 3;
R 3 is H, C (1-4) alkyl, CH 2 CH 2 NH 2 , CH 2 CH 2 OR a , —COCH 3 , CONH 2 , or CO 2 R a ;
R 9 is H, C (1-4) alkyl, OR a , —NA 1 A 2 , NA 1 SO 2 C (1-4) alkyl, NA 1 COC (1-4) alkyl, —NHCH 2 CH 2 OCH 2 CH 3 , —N(CH 2 CH 2 OH) 2 , —N(CH 3 )CH 2 CH 2 OCH 3 , —NHCH 2 CH 2 SO 2 CH 3 , or —NHCH 2 CON(CH 3 ) 2 , or R 3 and R 9 may be taken together to form oxo;
R 10 is H, —C (1-4) alkyl, —OR a , —CN, —NA 1 A 2 , —SO 2 CH 3 , —COOR a , —CO 2 CH 3 , —CH 2 —NA 1 A 2 , —CONA 1 A 2 , —CH 2 OR a , —OC (1-4) alkylOR a , —NHCH 2 CH 2 CO 2 R a , —NHCH 2 CH 2 OR a , —NR a CH 2 CH 2 NA 1 A 2 , —OC (1-4) alkylNA 1 A 2 , —OCH 2 CO 2 R a , —CH 2 CO 2 R a , —CH 2 CH 2 SO 2 C (1-4) alkyl, —SO 2 CH 2 CH 2 NA 1 A 2 , —SOCH 2 CH 2 NA 1 A 2 , —SCH 2 CH 2 NA 1 A 2 , —NHSO 2 CH 2 CH 2 NA 1 A 2 , or phenyl;

A 1 is H, —C (1-4) alkyl, or CH 2 CH 2 OR a ;
A 2 is H, —C (1-4) alkyl, COR a , CH 2 CON(CH 3 ) 2 , —CH 2 CH 2 OR a , —CH 2 CH 2 SC (1-4) alkyl, —CH 2 CH 2 SOC (1-4) alkyl, or —CH 2 CH 2 SO 2 C (1-4) alkyl;
wherein R a is H or C (1-4) alkyl.

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

R e is

Z is H;
X is

wherein R 10 is H, —CO 2 H, —CN, —OH, —CH 2 NH 2 , —NA 1 A 2 , —OCH 2 CH 2 NA 1 A 2 , or —NR a CH 2 CH 2 NA 1 A 2 ;
A 1 is H, or —CH 3 ;
A 2 is H, —CH 2 CH 2 OCH 3 , —COCH 3 , or —CH 3 ;
R a is H, or —C (1-4) alkyl;

R z is H, —CH 3 , or may be taken together as —CH 2 CH 2 —;
R 3 is H, —COCH 3 , —CH 3 , —CO 2 CH 3 , —CONH 2 , or —CO 2 H; and

R 9 is H, —OH, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NHCH 2 CH 2 OCH 2 CH 3 , —N(CH 2 CH 2 OH) 2 , —N(CH 3 )CH 2 CH 2 OCH 3 , —NHCH 2 CH 2 SO 2 CH 3 , or —NHCH 2 CON(CH 3 ) 2 , or R 9 may be taken together with R 3 to form oxo.

3. The compound of claim 2 , wherein:
W is

R 2 is

X is

wherein R 10 is H, —CO 2 H, —CN, —OH, —CH 2 NH 2 , —NA 1 A 2 , —OCH 2 CH 2 NA 1 A 2 , or —NR a CH 2 CH 2 NA 1 A 2 ;
A 1 is H, or —CH 3 ;
A 2 is H, —CH 2 CH 2 OCH 3 , —COCH 3 , or —CH 3 ;

R z is H, —CH 3 , or may be taken together as —CH 2 CH 2 —;
R 3 is H, —COCH 3 , —CH 3 , —CO 2 CH 3 , —CONH 2 , or —CO 2 H; and
R 9 is H, —OH, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NHCH 2 CH 2 OCH 2 CH 3 , —N(CH 2 CH 2 OH) 2 , —N(CH 3 )CH 2 CH 2 OCH 3 , —NHCH 2 CH 2 SO 2 CH 3 , —NHCH 2 CON(CH 3 ) 2 , or R 9 may be taken together with R 3 to form oxo.

4. The compound of claim 3 , wherein:
W is

R 2 is

X is

wherein R 10 is H, —CO 2 H, —CN, —OH, —CH 2 NH 2 , —NA 1 A 2 , —OCH 2 CH 2 NA 1 A 2 , or —NR a CH 2 CH 2 NA 1 A 2 ;
A 1 is H, or —CH 3 ;
A 2 is H, —CH 2 CH 2 OCH 3 , —COCH 3 , or —CH 3 ;

Rz is H, —CH 3 , or may be taken together as —CH 2 CH 2 —;
R 3 is H, —COCH 3 , —CH 3 , —CO 2 CH 3 , —CONH 2 , or —CO 2 H; and

R 9 is H, —OH, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NHCH 2 CH 2 OCH 2 CH 3 , —N(CH 2 CH 2 OH) 2 , —N(CH 3 )CH 2 CH 2 OCH 3 , —NHCH 2 CH 2 SO 2 CH 3 , or —NHCH 2 CON(CH 3 ) 2 , or R 9 may be taken together with R 3 to form oxo.

5. The compound of claim 4 , wherein:
W is

R 2 is

X is

wherein R 10 is —CN, or —OH; and
R 3 is —COCH 3 , or —CO 2 H.

6. The compound of claim 1 selected from the group consisting of:

7. The compound of claim 1 selected from the group consisting of:

or a tautomer or pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and from about 0.5 mg to about 10 g of at least one compound of claim 1 .

10. A dosage form according to claim 9 adapted for parenteral or oral administration.

11. A compound selected from the group consisting of:

or a tautomer or pharmaceutically acceptable salt thereof.

Assignees

• Janssen Pharmaceutica Nv

Inventors

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

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/02

  Immunomodulators · 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