INHIBITORS OF C-FMS KINASE

• US 20070249608A1
• Filed: 04/18/2007
• Published: 10/25/2007
• Est. Priority Date: 04/20/2006
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Wilson, Kenneth, Meegalla, Sanath K., Illig, Carl R., Wall, Mark, Chen, Jinsheng, Ballentine, Shelley K., DesJarlais, Renee Louise
• Granted Patent: US 8,815,867 B2
• Time in Patent Office: Days
• US Class Current: 514/235.800
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• 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 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 207/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/90 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• 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 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 493/08 : Bridged systems
• CPC Class Codes: C12N 9/99 : Enzyme inactivation by chemical treatment

Abstract

The invention is directed to compounds of Formula I:

wherein Z, X, J, R² 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.

Claims

1. The novel compounds of Formula I

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

W is

wherein each R⁴ is independently H, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃, SC_(1-4)alkyl, SOC_(1-4)alkyl, SO₂C_(1-4)alkyl, —

C_(1-3)alkyl, —

CO₂R^d, CONR^eR^f, C≡

CR^g, 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, —

CH₂OH, or —

CH₂CH₂OH;

R² 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 CH₃;

J is CH, or N;

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 —

(CH₂)_n—

, where n is 2 or 3;

R³ is H, C_(1-4)alkyl, CH₂CH₂NH₂, CH₂CH₂OR^a, —

COCH₃, CONH₂, or CO₂R^a;

R⁹ is H, C_(1-4)alkyl, OR^a, —

NA¹A², NA¹SO₂C_(1-4)alkyl, NA¹COC_(1-4)alkyl, —

NHCH₂CH₂OCH₂CH₃, —

N(CH₂CH₂OH)₂, —

N(CH₃)CH₂CH₂OCH₃, —

NHCH₂CH₂SO₂CH₃, —

NHCH₂CON(CH₃)₂, or R³ and R⁹ may be taken together to form oxo, —

OCH₂CH₂O—

, or —

OCH₂C(R^a)₂CH₂O—

;

R¹⁰ is H, —

C_(1-4)alkyl, —

OR^a, —

CN, —

NA¹A², —

SO₂CH₃, —

COOR^a, —

CO₂CH₃, —

CH₂—

NA¹A², —

CONA¹A², —

CH₂OR^a, —

OC_(1-4)alkylOR^a, —

NHCH₂CH₂CO₂R_a, —

NHCH₂CH₂OR^a, —

NR^aCH₂CH₂NA¹A², —

OC_(1-4)alkylNA¹A², —

OCH₂CO₂R^a, —

CH₂CO₂R^a, —

CH₂CH₂SO₂C_(1-4)alkyl, —

SO₂CH₂CH₂NA¹A², —

SOCH₂CH₂NA¹A², —

SCH₂CH₂NA¹A², —

NHSO₂CH₂CH₂NA¹A², phenyl, imidazolyl, thiazolyl, 4H-[1,2,4]oxadiazol-5-onyl, 4H-pyrrolo[2,3-b]pyrazinyl, pyridinyl, [1,3,4]oxadiazolyl, 4H-[1,2,4]triazolyl, tetrazolyl, pyrazolyl, [1,3,5]triazinyl, and [1,3,4]thiadiazolyl;

A¹ is H, —

C_(1-4)alkyl, or CH₂CH₂OR^a;

A² is H, —

C_(1-4)alkyl, CORA, CH₂CON(CH₃)₂, —

CH₂CH₂OR^a, —

CH₂CH₂SC_(1-4)alkyl, —

CH₂CH₂SOC_(1-4)alkyl, or —

CH₂CH₂SO₂C_(1-4)alkyl;

alternatively, A¹ and A² 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; and

R^bb is H, —

C_(1-4)alkyl, —

CH₂CH₂OCH₂CH₂OCH₃, —

CH₂CO₂H, —

C(O)C_(1-4)alkyl, or —

CH₂C(O)C_(1-4)alkyl.

2. A compound of claim 1, wherein:

W is

R² is

Z is H;

X is

wherein R¹⁰ is H, —

CO₂H, —

CN, —

OH, —

CH₂NH₂, —

NA¹A², —

OCH₂CH₂NA¹A², or —

NR^aCH₂CH₂NA¹A²;

A¹ is H, or —

CH₃;

A² is H, —

CH₂CH₂OCH₃, —

COCH₃, or —

CH₃;

alternatively, A¹ and A² may be taken together with their attached nitrogen to form a heterocyclic ring selected from the following;

R^a is H, or —

C_(1-4)alkyl;

R^aa is H, or —

C_(1-4)alkyl;

R^bb is H, —

C_(1-4)alkyl, —

CH₂CO₂H or —

COCH₃;

R^z is H, —

CH₃, or may be taken together as —

CH₂CH₂—

;

R³ is H, —

COCH₃, —

CH₃, —

CO₂CH₃, —

CONH₂, or —

CO₂H; and

R⁹ is H, —

OH, —

N(CH₃)₂, —

N(CH₂CH₃)₂, morpholinyl, N-methyl-piperazinyl, N-ethyl-piperazinyl, —

NHCH₂CH₂OCH₂CH₃, —

N(CH₂CH₂OH)₂, —

N(CH₃)CH₂CH₂OCH₃, —

NHCH₂CH₂SO₂CH₃, —

NHCH₂CON(CH₃)₂, or R⁹ may be taken together with R³ to form oxo, or —

OCH₂CH₂O—

.

3. A compound of claim 2, wherein:

W is

R² is

X is

wherein R¹⁰ is H, —

CO₂H, —

CN, —

OH, —

CH₂NH₂, —

NA¹A², —

OCH₂CH₂NA¹A², or —

NR^aCH₂CH₂NA¹A²;

A¹ is H, or —

CH₃;

A² is H, —

CH₂CH₂OCH₃, —

COCH₃, or —

CH₃;

alternatively, A¹ and A² may be taken together with their attached nitrogen to form a heterocyclic ring selected from the following;

R^bb is H, —

C_(1-4)alkyl, —

CH₂CO₂H or —

COCH₃;

R^z is H, —

CH₃, or may be taken together as —

CH₂CH₂—

;

R³ is H, —

COCH₃, —

CH₃, —

CO₂CH₃, —

CONH₂, or —

CO₂H; and

R⁹ is H, —

OH, —

N(CH₃)₂, —

N(CH₂CH₃)₂, morpholinyl, N-methyl-piperazinyl, N-ethyl-piperazinyl, —

NHCH₂CH₂OCH₂CH₃, —

N(CH₂CH₂OH)₂, —

N(CH₃)CH₂CH₂OCH₃, —

NHCH₂CH₂SO₂CH₃, —

NHCH₂CON(CH₃)₂, or R⁹ may be taken together with R³ to form oxo, or —

OCH₂CH₂O—

.

4. A compound of claim 3, wherein:

W is

R² is

X is

wherein R¹⁰ is H, —

CO₂H, —

CN, —

OH, —

CH₂NH₂, —

NA¹A², —

OCH₂CH₂NA¹A², or —

NR^aCH₂CH₂NA¹A²;

A¹ is H, or —

CH₃;

A² is H, —

CH₂CH₂OCH₃, —

COCH₃, or —

CH₃;

alternatively, A¹ and A² may be taken together with their attached nitrogen to form a heterocyclic ring selected from the following;

R^bb is H, —

C_(1-4)alkyl, —

CH₂CO₂H or —

COCH₃;

R^z is H, —

CH₃, or may be taken together as —

CH₂CH₂—

;

R³ is H, —

COCH₃, —

CH₃, —

CO₂CH₃, —

CONH₂, or —

CO₂H; and

R⁹ is H, —

OH, —

N(CH₃)₂, —

N(CH₂CH₃)₂, morpholinyl, N-methyl-piperazinyl, N-ethyl-piperazinyl, —

NHCH₂CH₂OCH₂CH₃, —

N(CH₂CH₂OH)₂, —

N(CH₃)CH₂CH₂OCH₃, —

NHCH₂CH₂SO₂CH₃, —

NHCH₂CON(CH₃)₂, or R⁹ may be taken together with R³ to form oxo, or —

OCH₂CH₂O—

.

5. A compound of claim 4, wherein:

W is

R² is

X is

wherein R¹⁰ is —

CN, or —

OH; and

R³ is —

COCH₃, or —

CO₂H.

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

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

and solvates, hydrates, tautomers and pharmaceutically acceptable salts 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 method for inhibiting protein tyrosine kinase activity, comprising contacting the kinase with an effective inhibitory amount of at least one compound of claim 1.

12. A method according to claim 11, wherein the protein tyrosine kinase is c-fms.

13. A method of treating inflammation in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 1.

14. A method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 1.

15. A method of treating cardiovascular disease in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 1.

16. A method of treating diseases with an inflammatory component including glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia or Alzheimer'"'"'s dementia in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of claim 1.

17. A method of treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain in a mammal, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of claim 1.

18. A method of treating 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, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of claim 1.

19. A method of treating and of preventing metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, and hairy cell leukemia, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of claim 1.

20. A method of treating autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and other forms of inflammatory arthritis, psoriasis, Sjogren'"'"'s syndrome, multiple sclerosis, or uveitis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of at least one compound of claim 1.

21. A compound selected from the group consisting of:

and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.