US2004242494A1PendingUtilityA1
Caspase inhibitors and uses thereof
Priority: May 27, 2003Filed: May 27, 2004Published: Dec 2, 2004
Est. expiryMay 27, 2023(expired)· nominal 20-yr term from priority
Inventors:Guy BrenchleyJean-Damien CharrierSteven DurrantRonald KnegtelMichael MortimoreJohn Studley
A61P 3/10A61P 5/14A61P 7/06A61P 7/02A61P 9/00A61P 7/00A61P 9/10A61P 37/04A61P 7/04A61P 37/08A61P 9/04A61P 35/04A61P 37/06A61P 37/00A61P 43/00A61P 25/32A61P 25/02A61P 35/00A61P 27/06A61P 25/00A61P 31/00A61P 31/20A61P 31/06A61P 31/12A61P 35/02A61P 25/16A61P 25/08A61P 31/14A61P 31/18A61P 25/28A61P 31/04A61P 27/02A61P 29/00A61P 25/04A61P 33/02A61P 25/14A61P 11/06A61P 11/16A61P 17/02A61P 17/06A61P 19/08A61P 15/00A61P 17/14A61P 19/02A61P 21/02A61P 19/10A61P 21/04A61P 19/06A61P 17/10A61P 21/00A61P 17/00A61P 1/04A61P 11/00A61P 1/18A61P 1/16A61P 13/12A61P 19/00A61P 17/04C07D 213/75C07D 213/82C07D 405/12C07D 417/12C07D 213/74
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Claims
Abstract
The present invention provides a compound of formula I: wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as defined herein. The present invention also provides pharmaceutical compositions and methods using such compositions for treating a caspase-mediated diseases and processes for preparing the compounds of the invention.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of formula I:
wherein:
R 1 is R 6 C(O)—, HC(O)—, R 6 SO 2 —, R'OC(O)—, (R 6 ) 2 NC(O)—, (R 6 )(H)NC(O)—, R 6 C(O)C(O)—, R 6 —, (R 6 ) 2 NC(O)C(O)—, (R 6 )(H)NC(O)C(O)—, or R 6 OC(O)C(O)—;
R 2 is hydrogen, —CF 3 , -halo, —OR 7 , —NO 2 , —OCF 3 , —CN, or R 8 ;
R 3 is hydrogen or (C1—C4)-aliphatic-;
R 4 is —COOH or —COOR 8 ;
R 5 is —CH 2 F or —CH 2 O-2,3,5,6-tetrafluorophenyl;
R 6 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-, or two R 6 groups bound to the same atom form together with that atom a 3- to 10-membered aromatic or nonaromatic ring; wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 6 is substituted with up to 6 substituents independently selected from R;
R is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, ═NR 7 , ═N(OR 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(S)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 );
two R 7 groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, N(R), O, S, SO, or SO 2 , wherein the ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J 2 ; or
each R 7 is independently selected from:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein R 7 has up to 3 substituents selected independently from J 2 ; and
J 2 is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, ═N(R 7 ), ═NO(R 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(S)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 ) COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —CN, —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 ); and
R 8 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, or (C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3 aliphatic carbon atoms may be replaced with a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 8 is optionally substituted with up to 6 substituents independently selected from R.
2 . A compound of formula I:
wherein:
R 1 is R 6 C(O)—, R 6 SO 2 —, R 6 OC(O)—, (R 6 ) 2 NC(O)—, R 6 C(O)C(O)—, R 6 —, (R 6 ) 2 NC(O)C(O)—, or R 6 OC(O)C(O)—;
R 2 is hydrogen, —CF 3 , -halo, —OR 7 , —NO 2 , —OCF 3 , —CN, or R 8 ;
R 3 is hydrogen or (C1-C4)-aliphatic-;
R 4 is —COOH or —COOR 8 ;
R 5 is —CH 2 F or —CH 2 O-2,3,5,6-tetrafluorophenyl;
R 6 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-, or two R 6 groups bound to the same atom form together with that atom a 3- to 10-membered aromatic or nonaromatic ring; wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 6 is substituted with up to 6 substituents independently selected from R;
R is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —OR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 );
two R 7 groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, N(R), O, S, SO, or SO 2 , wherein the ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J 2 ; or
each R 7 is independently selected from:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein R 7 has up to 3 substituents selected independently from J 2 ; and
J 2 is halogen, —OR , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —CN, —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 ); and
R 8 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, or (C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3 aliphatic carbon atoms may be replaced with a group selected from O, N, N(R), S, SO, and SO 2 .
3 . The compound according to claim 1 or claim 2 , wherein R 5 is —CH 2 O-2,3,5,6-tetrafluorophenyl.
4 . The compound according to claim 1 or claim 2 , wherein R 5 is —CH 2 F.
5 . The compound according to any one of claims 1 - 4 , wherein R 1 is R 6 C(O)—.
6 . The compound according to any one of claims 1 - 4 , wherein R 1 is R 6 SO 2 —.
7 . The compound according to any one of claims 1 - 4 , wherein R 1 is R 6 —.
8 . The compound according to any one of claims 1 - 4 , wherein R 1 is (R 6 ) 2 NC(O)—.
9 . The compound according to any one of claims 1 - 4 , wherein R 1 is (R 6 )(H)NC(O)—.
10 . The compound according to any one of claims 1 - 4 , wherein R 1 is (R 6 )OC(O)—.
11 . The compound according to any one of claims 1 - 10 , wherein R 6 is (C1-C4)-aliphatic-, (C3-C10)-cycloaliphatic, (C3-C10)-heterocyclyl, (C5-C10)-heteroaryl, (C6-C10)-aryl-, or (C6-C10)-aryl-(C1-C12)-; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, N(R), S, SO, and SO 2 ; and
wherein R 6 is optionally substituted.
12 . The compound according to any one of claims 1 - 10 , wherein R 6 is (C1-C4)-aliphatic-, (C5-C10)-heteroaryl-, or (C6-C10)-aryl-, wherein the heteroaryl or aryl is optionally substituted or wherein each R 6 together with the N-atom is a (C3-C7)-cycloaliphatic group.
13 . The compound according to any one of claims 1 - 10 , wherein R 6 is (C1-C4)-aliphatic- or (C6-C10)-aryl-, wherein the aryl is optionally substituted or wherein each R 6 together with the N-atom is a (C3-C7)-cycloaliphatic group.
14 . The compound according to any one of claims 1 - 13 , wherein the aliphatic is (C1-C4)-alkyl-.
15 . The compound according to any one of claims 1 - 14 , wherein R 2 is hydrogen, CF 3 , or CH 3 .
16 . The compound according to any one of claims 1 - 15 , wherein R 2 is hydrogen or CF 3 .
17 . The compound according to any one of claims 1 - 16 , wherein R 3 is (C1-C4)-alkyl-.
18 . The compound according to any one of claims 1 - 17 , wherein R 3 is ethyl.
19 . A compound selected from Table 1.
20 . A pharmaceutical composition comprising:
a) a compound according to any one of claims 1 - 19 ; and b) a pharmaceutically acceptable carrier, adjuvant or vehicle.
21 . A method for treating IL-1 mediated disease, an apoptosis mediated disease, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, a disease associated with cell death, a viral mediated disease, or liver disease in a patient comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 - 19 or a pharmaceutical composition according to claim 20 .
22 . A method for treating rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, myasthenia gravis, autoimmune neutropenia, autoimmune hemolytic anemia, thrombocytopenia, juvenile rheumatoid arthritis, gout, Behcet's syndrome, Still's syndrome, macrophage activation syndrome, sarcoidosis, Muckle-Wells syndrome, familial cold urticaria, chronic infantile neurological cutaneous and articular syndrome, familial mediterranean fever, TNFR1-Associated Periodic Syndrome (TRAPS), Hyper-IgD periodic fever Syndrome (HIDS), Blau's syndrome, psoriasis, atopic dermatitis, scarring, alopecia, acne vulgaris, pemphigus, asthma, adult respiratory distress syndrome, cystic fibrosis, emphysema, chronic bronchitis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory peritonitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune gastritis, H.pylori -associated gastric and duodenal ulcer disease, diabetes, pancreatitis, glomerulonephritis, chronic active hepatitis, excess dietary alcohol intake disease, renal disease, polycystic kidney disease, burns, organ apoptosis after burn injury, haemorrhagic shock, organ failure, endometriosis, graft vs. host disease, organ transplant rejection, leukemia, myelodysplastic syndrome, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, chronic heart disease, acute heart disease, myocardial infarction, myocardial ischemia, congestive heart failure, atherosclerosis, coronary artery bypass graft (CABG), a complication associated with a coronary artery bypass graft, acute coronary syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy's disease, prion disease, cerebral ischemia, epilepsy, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related encephalitis, traumatic brain injury, spinal cord injury, neurological damage due to stroke, diabetic neuropathy, acute and chronic pain, uveitis, retinal disorders, diabetic retinopathy, glaucoma, keratitis, viral mediated disease, sepsis, septic shock, shigellosis, hepatitis-B, hepatitis-C, hepatitis-G, yellow fever, dengue fever, Japanese encephalitis, HIV infection, tuberculosis, meningitis, Pseudomonas infection, Acinetobacter infection, or aging in a patient comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 - 19 or a pharmaceutical composition according to claim 20 .
23 . The method according to claim 22 , wherein the disease is osteoarthritis, pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, graft vs. host disease, osteoporosis, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, Shigellosis, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, or neurological damage due to stroke.
24 . The method according to claim 22 , wherein said disease is a complication associated with a coronary artery bypass graft.
25 . A method for inhibiting a caspase-mediated function in a patient comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 - 19 or a pharmaceutical composition according to claim 20 .
26 . The method for decreasing IGIF or IFN-γ production in a patient comprising administering a pharmaceutically effective amount of a compound according to any one of claims 1 - 19 or a pharmaceutical composition according to claim 20 .
27 . A method of preserving cells, said method comprising the step of bathing the cells in a solution of the compound according to any one of claims 1 - 19 .
28 . The method according to claim 27 , wherein said cells are in:
a) an organ intended for transplant; or b) a blood product.
29 . A method of treating cancer using immunotherapy, wherein said immunotherapy comprises as a component thereof a compound according to any one of claims 1 - 19 .
30 . The method according to any one of claims 20 - 29 wherein the method comprises administering an additional therapeutic agent.
31 . A process for preparing a compound of formula (I):
R 1 is R 6 C(O)—, HC(O)—, R 6 SO 2 —, R 6 OC(O)—, (R 6 ) 2 NC(O)—, (R 6 )(H)NC(O)—, R 6 C(O)C(O)—, R 6 —, (R 6 ) 2 NC(O)C(O)—, (R 6 )(H)NC(O)C(O)—, or R 6 C(O)C(O)—;
R 2 is hydrogen, —CF 3 , -halo, —OR 7 , —NO 2 , —OCF 3 , —CN, or R 8 ;
R 3 is hydrogen or (C1-C4)-aliphatic-;
R 4 is —COOH or —COOR 8 ;
R 5 is —CH 2 F or —CH 2 O-2,3,5,6-tetrafluorophenyl;
R 6 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C0l)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-, or two R 6 groups bound to the same atom form together with that atom a 3- to 10-membered aromatic or nonaromatic ring; wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 6 is substituted with up to 6 substituents independently selected from R;
R is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, ═NR 7 , ═N(OR 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(S)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 );
two R 7 groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, N(R), O, S, SO, or SO 2 , wherein the ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J 2 ; or
each R 7 is independently selected from:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein R 7 has up to 3 substituents selected independently from J 2 ; and
J 2 is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, ═NR 7 , ═N(OR 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(S)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —CN, —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 ); and
R 8 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, or (C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3 aliphatic carbon atoms may be replaced with a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 8 is optionally substituted with up to 6 substituents independently selected from R;
comprising:
(a) reacting a compound of formula (III):
wherein:
R 9 is —NO 2 , —C(O)OR 10 , —CN, R 6 C(O)N(H)—, R 6 SO 2 N(H)—, R 6 OC(O)N(H)—, (R 6 ) 2 NC(O)N(H)—, R 6 C(O)C(O)N(H)—, R 6 N(H)—, (R 6 ) 2 NC(O)C(O)N(H)—, or R 6 OC(O)C(O)N(H)—;
R 10 is independently hydrogen, (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C0-C12)-aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3 aliphatic carbon atoms may be replaced with a group selected from O, N(H), N(R), S, SO, and SO 2 ; and wherein R 10 is optionally substituted with up to 6 substituents independently selected from R; and
R, R 2 , R 3 and R 6 are as defined above;
with a compound of formula (IV):
wherein Y is either a carbonyl group or an OH group; and
R 4 and R 5 are as defined above;
in the presence of coupling conditions and a solvent;
provided that if Y is an OH group, then the process further comprises (b) oxidizing the OH group to provide the compound of formula (I); and
provided that if R 9 is —NO 2 , —C(O)OR 10 , or —ON, the process comprises the further step of converting the —NO 2 , —C(O)OR 10 , or —CN into R 6 C(O)N(H)—, R 6 SO 2 N(H)—, R 6 OC(O)N(H)—, (R 6 ) 2 NC(O)N(H)—, R 6 C(O)C(O)N(H)—, R 6 N(H)—, (R 6 ) 2 NC(O)C(O)N(H)—, or R 6 OC(O)C(O)N(H)—.
32 . The process according to claim 31 , wherein the compound of formula (III):
wherein
R 2 is hydrogen, —CF 3 , -halo, —OR 7 , —NO 2 , —OCF 3 , —CN, or R 8 ;
R 3 is hydrogen or (C1-C4)-aliphatic-;
R 9 is —NO 2 , —C(O)OR 10 , —CN, R 6 C(O)N(H)—, R 6 SO 2 N(H)—, R 6 OC(O)N(H)—, (R 6 ) 2 NC(O)N(H)—, R 6 C(O)C(O)N(H)—, R 6 N(H)—, (R 6 ) 2 NC(O)C(O)N(H)—, or R 6 OC(O)C(O)N(H)—;
R 6 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-, or two R 6 groups bound to the same atom form together with that atom a 3- to 10-membered aromatic or nonaromatic ring; wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 6 is substituted with up to 6 substituents independently selected from R;
R is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO2, —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, ═NR 7 , ═N(OR 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 );
two R 7 groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, N(R), O, S, SO, or SO 2 , wherein the ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J 2 ; or
each R 7 is independently selected from:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein R 7 has up to 3 substituents selected independently 10 from J 2 ; and
J 2 is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , 13 R 7 , oxo, thioxo, ═NR 7 , ═N(OR 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(S)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 ) SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —CN, —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 ); and
R 8 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, or (C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3 aliphatic carbon atoms may be replaced with a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein
R 8 is optionally substituted with up to 6 substituents independently selected from R;
is prepared by a process comprising:
(c) reacting a compound of formula (V):
wherein:
R 10 is independently hydrogen, (C1-C12)-aliphatic-(C3-C1-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3 aliphatic carbon atoms may be replaced with a group selected from O , N, N(R), S, SO, and SO 2 ; and
R, R 2 , R 3 , and R 9 are as defined above;
in a solvent in the presence of deprotecting conditions.
33 . The process according to claim 32 , wherein the compound of formula (V):
wherein R 2 , R 3 , R 9 , and R 10 are as defined in claim 32;
is prepared by a process comprising:
(d) reacting a compound of formula (VI):
wherein R 2 and R 9 are as defined in claim 32;
with a compound of formula (VII):
wherein X is a suitable leaving group; and
R 3 and R 10 are as defined above;
in the presence of a solvent and a base.
34 . A process for preparing a compound of formula (VIII):
wherein:
R 2 is —CF 3 , —Cl, —OR 7 , —NO 2 , —OCF 3 , —CN, or R 8 ;
R 3 is hydrogen or (C1-C4)-aliphatic-;
R 9 is —NO 2 , —C(O)OR 10 , —CN, R 6 C(O)N(H)—, R 6 SO 2 N(H)—,
R 6 OC(O)N(H)—, (R 6 ) 2 NC(O)N(H)—, R 6 C(O)C(O)N(H)—, R 6 N(H)—,
(R 6 ) 2 NC(O)C(O)N(H)—, or R 6 OC(O)C(O)N(H)—;
R 10 is independently hydrogen, (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3 aliphatic carbon atoms may be replaced with a group selected from O, N(H), N(R), S, SO, and SO 2 ; and wherein R 10 is optionally substituted with up to 6 substituents independently selected from R;
R 6 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-, or two RE groups bound to the same atom form together with that atom a 3- to 10-membered aromatic or nonaromatic ring; wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 6 is substituted with up to 6 substituents independently selected from R;
R is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, ═NR 7 , ═N(OR 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(S)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 1 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR)R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) or —P(O)(H)(OR 7 );
two R 7 groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, N(R), O, S, SO, or SO 2 , wherein the ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J 2 ; or
each R 7 is independently selected from:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein R 7 has up to 3 substituents selected independently from J 2 ; and
J 2 is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, ═NR 7 , ═N(OR 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(S)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —CN, —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 ); and
R 8 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, or (C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3 aliphatic carbon atoms may be replaced with a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 8 is optionally substituted with up to 6 substituents independently selected from R;
comprising the step of (e) reacting a compound of formula (IX):
wherein R 2 and R 9 are as defined above;
with a compound of formula (VII):
wherein R 3 and R 10 are as defined above; and
X is a suitable leaving group;
in the presence of-a solvent and a base.
35 . A process for preparing a compound of formula (I):
wherein:
R 1 is R 6 C(O)—, R 6 SO 2 —, R 6 OC(O)—, (R 6 ) 2 NC(O)—, (R 6 )(H)NC(O)—,
R 6 C(O)C(O)—, R 6 —, (R 6 ) 2 NC(O)C(O)—, (R 6 )(H)NC(O)C(O)—, or
R 6 OC(O)C(O)—;
R 2 is hydrogen, —CF 3 , -halo, —OR 7 , —NO 2 , —OCF 3 , —CN, or R 8 ;
R 3 is hydrogen or (C1-C4)-aliphatic-;
R 4 is —COOH or —COOR 8 ;
R 5 is —CH 2 F or —CH 2 O-2,3,5,6-tetrafluorophenyl;
R 6 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl(C1-C12)-aliphatic-, or two R 6 groups bound to the same atom form together with that atom a 3- to 10-membered aromatic or nonaromatic ring; wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 6 is substituted with up to 6 substituents independently selected from R;
R is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, ═NR 7 , ═N(OR 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(S)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 );
two R 7 groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, N(R), O, S, SO, or SO 2 , wherein the ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J 2 ; or
each R 7 is independently selected from:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloaliphatic-,
(C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein R 7 has up to 3 substituents selected independently from J 2 ; and
J 2 is halogen, —OR 7 , —OC(O)N(R 7 ) 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 7 , oxo, thioxo, ═NR 7 , ═N(OR 7 ), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 7 ) 2 , —SR 7 , —SOR 7 , —SO 2 R 7 , —SO 2 N(R 7 ) 2 , —SO 3 R 7 , —C(O)R 7 , —C(O)C(O)R 7 , —C(O)C(O)OR 7 , —C(O)C(O)N(R 7 ) 2 , —C(O)CH 2 C(O)R 7 , —C(S)R 7 , —C(S)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)N(R 7 ) 2 , —OC(O)N(R 7 ) 2 , —C(S)N(R 7 ) 2 , —(CH 2 ) 0-2 NHC(O)R 7 , —N(R 7 )N(R 7 )COR 7 , —N(R 7 )N(R 7 )C(O)OR 7 , —N(R 7 )N(R 7 )CON(R 7 ) 2 , −N(R 7 )SO 2 R 7 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 7 )C(O)OR 7 , —N(R 7 )C(O)R 7 , —N(R 7 )C(S)R 7 , —N(R 7 )C(O)N(R 7 ) 2 , —N(R 7 )C(S)N(R 7 ) 2 , —N(COR 7 )COR 7 , —N(OR 7 )R 7 , —CN, —C(═NH)N(R 7 ) 2 , —C(O)N(OR 7 )R 7 , —C(═NOR 7 )R 7 , —OP(O)(OR 7 ) 2 , —P(O)(R 7 ) 2 , —P(O)(OR 7 ) 2 , or —P(O)(H)(OR 7 ); and
R 8 is (C1-C12)-aliphatic-(C3-C10)-cycloaliphatic-, (C6-C10)-aryl-, (C3-C10)-heterocyclyl-, (C5-C10)-heteroaryl-, (C3-C10)-cycloaliphatic-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, or (C5-C10)-heteroaryl(C1-C12)-aliphatic-, wherein up to 3 aliphatic carbon atoms may be replaced with a group selected from O, N, N(R), S, SO, and SO 2 ; and wherein R 8 is optionally substituted with up to 6 substituents independently selected from R;
comprising:
(a) reacting a compound of formula (III):
wherein:
R 9 is —NO 2 , —C(O)OR 10 , —CN, R 6 C(O)N(H)—, R 6 SO 2 N(H)—, R 6 OC(O)N(H)—, (R 6 ) 2 NC(O)N(H)—, R 6 C(O)C(O)N(H)—, R 6 N(H)—, (R 6 ) 2 NC(O)C(O)N(H)—, or R 6 OC(O)C(O)N(H)—; and
R 2 , R 10 and R 6 are as defined above;
with a compound of formula (X):
wherein Y is either a carbonyl group or an OH group; and
R 3 , R 4 and R 5 are as defined above;
in the presence of coupling conditions and a solvent;
provided that if Y is an OH group, then the process further comprises (b) oxidizing the OH group to provide the compound of formula (I); and
provided that if R 9 is —NO 2 , —C(O)OR 10 , or —CN, the process comprises the further step of converting the —NO 2 ,
—C(O)OR 10 , or —CN into R 6 C(O)N(H)—, R 6 SO 2 N(H)—,
R 6 OC(O)N(H)—, (R 6 ) 2 NC(O)N(H)—, R 6 C(O)C(O)N(H)—, R 6 N(H)—, (R 6 ) 2 NC(O)C(O)N(H)—, or R 6 OC(O)C(O)N(H)—.Join the waitlist — get patent alerts
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