Pyrrolopyridines useful as inhibitors of protein kinase

• US 20070135466A1
• Filed: 05/22/2006
• Published: 06/14/2007
• Est. Priority Date: 05/20/2005
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Ledeboer, Mark, Come, Jon, Arnost, Michael, Farmer, Luc, Wang, Tiansheng, Pierce, Albert, Bemis, Guy, Green, Jeremy, Wang, Jian, Marhefka, Craig, Wannamaker, Marion, Martinez-Botella, Gabriel, Bethiel, Randy, Salituro, Francesco, Stewart, Michelle
• Granted Patent: US 8,921,376 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 31/12 Antivirals
• 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 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 9/12 : Antihypertensives
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family and ROCK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

Claims

1. A compound of formula I

or a pharmaceutically acceptable salt thereof

wherein

Q is a 3-8 membered saturated, partially unsaturated, or unsaturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur;

or an 8-12 membered bicyclic ring having 0-6 heteroatoms selected from nitrogen, oxygen;

or sulfur;

wherein Q is optionally substituted with 1-10 occurrences of J^Q;

Z is a bond, NH, N(C_1-3aliphatic) or C═

(CH₂;

R¹ is —

(C_1-2 aliphatic)_p-R⁴ wherein each R¹ is optionally substituted with 1-3 occurrences of J;

R² is —

(C_1-2 aliphatic)_d-R⁵ wherein each R¹ is optionally substituted with 1-3 occurrences of J;

R³ is halogen, —

CN, —

NO₂ or —

(U)_m—

X, wherein

U is a C_1-6 aliphatic, wherein up to two methylene units are optionally and independently replaced by G^U and wherein U is optionally substituted with 1-4 J^U;

X is H, halogen, CN, NO₂, S(O)R, SO₂R, C_1-4 haloaliphatic, or a group selected from C_1-6 aliphatic, a C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

wherein said group is optionally substituted with 1-4 J^X;

G^U is —

NH—

, —

NR—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR—

, —

C(═

N—

CN)—

, —

NHCO—

, —

NRCO—

, —

NHC(O)O—

, —

NRC(O)O—

, —

SO₂NH—

, —

SO₂NR—

, —

NHSO₂—

, —

NRSO₂—

, —

NHC(O)NH—

, —

NRC(O)NH—

, —

NHC(O)NR—

, —

NRC(O)NR, —

OC(O)NH—

, —

OC(O)NR—

, —

NHSO₂NH—

, —

NRSO₂NH—

, —

NHSO₂NR—

, —

NRSO₂NR—

, —

SO—

, or —

SO₂—

;

R⁴ is H, halogen, CN, NH₂, NO₂, CF₃, C_1-3 aliphatic, cyclopropyl, NCH₃, OCH3, —

C(═

O)NH₂, —

C(═

O)CH₃, —

NC(═

O)CH₃, or OH;

R⁵ is H, halogen, CN, NH₂, NO₂, CF₃, C_1-2 aliphatic, cyclopropyl, NCH₃, OCH₃, —

C(═

O)NH₂, —

C(═

O)CH₃, —

NC(═

O)CH₃, or OH;

J^Q is halogen, OCF₃, —

(V_n)—

R″

, —

(V_n)—

CN, —

(V_n)—

NO₂, or —

(V_n)—

(C_1-4 haloaliphatic), wherein J^Q is not H;

V is a C_1-10 aliphatic, wherein up to three methylene units are replaced by G^V, wherein G^V is selected from —

NH—

, —

NR—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR—

, —

C(═

N—

CN). —

NHCO—

, —

NRCO—

, —

NHC(O)O—

, —

NRC(O)O—

, —

SO₂NH—

, —

SO₂NR—

, —

NHSO₂—

, —

NRSO₂—

, —

NHC(O)NH—

, —

NRC(O)NH—

, —

NHC(O)NR—

, —

NRC(O)NR, —

OC(O)NH—

, —

OC(O)NR—

, —

NHSO₂NH—

, —

NRSO₂NH—

, —

NHSO₂NR—

, —

NRSO₂NR—

, —

SO—

, or —

SO₂—

; and

wherein V is optionally substituted with 1-6 occurrences of J^V;

R″

is H, or is an optionally substituted group selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;

or two R″

groups, on the same substituent or different substituents, together with the atom(s) to which each R″

group is bound, form an optionally substituted 3-8 membered heterocyclyl;

wherein each optionally substituted R″

group is independently and optionally substituted with 1-6 occurrences of J^R;

R is an optionally substituted group selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;

or two R groups, on the same substituent or different substituents, together with the atom(s) to which each R group is bound, form an optionally substituted 3-8 membered heterocyclyl;

wherein each R group is independently and optionally substituted with 1-4 occurrences of JR;

J^V, J^U, J^X, and J^R are each independently selected from halogen, L, -(L_n)-R′

, -(L_n)-N(R′

)₂, -(L_n)-SR′

, -(L_n)-OR′

, -(L_n)-(C_3-10 cycloaliphatic), -(L_n)-(C_6-10 aryl), -(L_n)-(5-10 membered heteroaryl), -(L_n)-(5-10 membered heterocyclyl), oxo, C_1-4haloalkoxy, C_1-4haloalkyl, -(L_n)-NO₂, -(L_n)-CN, -(L_n)-OH, -(L_n)-CF₃, —

CO₂R′

, —

CO₂H, —

COR′

, —

COH, —

OC(O)R′

, or —

NC(O)R′

;

or two J^V, J^U, J^X, or J^R groups, on the same substituent or different substituents, together with the atom(s) to which each J^V, J^U, J^X, and J^R group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;

R′

is H or C_1-6 aliphatic;

or two R′

groups, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —

OR*, —

SR*, —

NO₂, —

CF₃, —

CN, CO₂R*, —

COR*, OCOR*, NHCOR*, wherein R* is H or C_1-6 aliphatic;

L is a C_1-6 aliphatic wherein up to three methylene units are replaced by —

NH—

, NR⁶—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O), —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR⁶—

, —

C(═

N—

CN), —

NHCO—

, —

NR⁶CO—

, —

NHC(O)O—

, —

NR⁶C(O)O—

, —

SO₂NH—

, —

SO₂NR⁶—

, —

NHSO₂—

, —

NR⁶SO₂—

, —

NHC(O)NH—

, —

NR⁶C(C)NH—

, —

NHC(O)NR⁶—

, —

NR⁶C(O)NR⁶, —

OC(O)NH—

, —

OC(O)NR⁶—

, —

NHSO₂NH—

, —

NR⁶SO₂NH—

, —

NHSO₂NR⁶—

, —

NR⁶SO₂NR⁶—

, —

SO—

, or —

SO₂—

;

R⁶ is selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;

or two R⁶ groups, on the same substituent or different substituents, together with the atom(s) to which each R⁶ group is bound, form a 3-8 membered heterocyclyl;

J is halogen, OCH₃, OH, NO₂, NH₂, SCH₃, NCH₃, CN, unsubstituted C_1-2aliphatic;

two J'"'"'s, together with the carbon to which they are attached, form a cyclopropyl ring or C═

O;

m, n, d, and p are each independently 0 or 1;

provided that

when R¹, R², and R³ are H and Z is a bond, then Q is not

—

NH-tBu, —

NH-phenyl or phenyl;

when R¹ and R² are H, R³ is H, COOEt or COOH, and Z is a bond, then Q is not

when R¹ is 1, R² is H, R³ is Br and Z is NH;

then Q is not

when R¹ and R³ are H, R² is H, Cl, F, Me or CF₃, and Z is NH;

then Q is not 2-fluoro-4-amino phenyl, 2-fluoro-4-nitro phenyl or

when R¹ and R³ are H, R² is H or Me, and Z is NH, then Q is not 2,6-fluoro-4-amino phenyl,

when R¹ and R³ are H, R² is Me, and Z is NH, then Q is not

when R¹, R² and R³ are H, and Z is NH;

then Q is not 3,5-difluoro phenyl, 4-amino phenyl, 4-nitro phenyl, 2-chloro-4-amino phenyl, 2-chloro-4-nitro phenyl, 3,4-methoxyphenyl,

when R¹ and R² are H, R³ is C(═

O)NH₂ and Z is NH, then Q is not 2-ethylphenyl;

and

when R¹, R², and R³ are H and Z is NCH₃;

when Q is not unsubstituted phenyl, 2-fluoro-4-amino phenyl, 2-fluoro-4-nitro phenyl or

5. The compound according to claim 1, wherein R¹ is H, halogen, CN, NH₂, NO₂, CF₃, CH₃, NCH₃, OCH₃, or OH.

9. The compound according to claim 1, wherein R² is H, halogen, CN, NH₂, NO₂, CF₃, CH₃, NCH₃, OCH₃, or OH.

13. The compound according to claim 1, wherein m is 0 and R³ is H, halogen, —

CN, —

NO₂ or X.

16. The compound according to claim 1, wherein m is 1 and U is an optionally substituted C_1-3 aliphatic, wherein up to two methylene units are optionally replaced with 0-2 G^U groups.

30. The compound according to claim 1, wherein Q is a 5-10 membered aryl or heteroaryl ring optionally substituted with 1-5 J^Q groups.

52. The compound according to claim 1, wherein Q is a 5-12 membered saturated or partially saturated monocyclic or bicyclic ring system optionally substituted with 1-5 J^Q groups.

67. The compound according to claim 1, wherein each occurrence of J^Q is independently selected from R″

, —

CH₂R″

, halogen, CN, NO₂, —

COR″

, —

COR⁸R″

, —

N(R′

)R″

, —

CH₂N(R′

)R″

, —

OR″

, —

CH₂OR″

, —

SR″

, —

CH₂SR″

, —

C(O)OR″

, —

NR′

COR″

, —

NR′

COR⁸R″

, —

NR′

COOR″

, —

NR′

COOR⁸R″

, —

CON(R′

)R″

, —

CON(R′

)R⁸R″

, —

SO₂N(R′

)R″

, —

SO₂N(R′

)R⁸R″

, —

CON(R′

)R⁸N(R′

)R″

, —

OR⁸OR″

, —

OR⁸N(R′

)R″

, —

NR′

CH(R⁸)R″

, —

NR′

CH(R⁸)C(O)OR″

, —

N(R′

)R⁸R″

, —

N(R′

)R⁸R″

, —

N(R′

)R⁸N(R′

)R″

, —

N(R′

)R⁸OR″

, —

NR′

CH(R⁸)R″

, —

NR′

CH₂C(O)N(R′

)R″

, or —

NR′

CH(R⁸)C(O)N(R′

)R″

, wherein R⁸ is H or an C_1-6 alkyl optionally substituted with 1-4 occurrences of J^V.

83. A compound according to claim 1, which is selected from Table 1 or Table 2.

85. A pharmaceutical composition comprising the compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

86. The composition according to claim 85, additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

87. A method of inhibiting ROCK kinase activity or JAK kinase activity in a biological sample, comprising contacting said biological sample with a compound according to claim 1, or with a composition comprising said compound.

88. A method of inhibiting ROCK kinase activity or JAK kinase activity in a patient, comprising administering to said patient a compound according to claim 1, or with a composition comprising said compound.

89. A method of treating or lessening the severity of a disease, condition or disorder is selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, a psychotic disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder in a patient, comprising the step of administering to said patient a compound according to claim 1, or with a composition comprising said compound.

96. A method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, a myeloproliferative disease or an immunologically mediated disorder in a patient, comprising the step of administering to said patient a compound according to claim 1, or with a composition comprising said compound.

2. A compound of formula I-a

or a pharmaceutically acceptable salt thereof

wherein

Q is a 3-8 membered saturated, partially saturated, or unsaturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur;

or an 8-12 membered bicyclic ring having 0-6 heteroatoms selected from nitrogen, oxygen, or sulfur;

wherein Q is optionally substituted with 1-10 occurrences of J^Q;

R¹ is —

(C_1-2 aliphatic)_p-R⁴ wherein each R¹ is optionally substituted with 1-3 occurrences of J;

R² is —

(C_1-2 aliphatic)_d-R⁵ wherein each R¹ is optionally substituted with 1-3 occurrences of J;

R³ is halogen, —

CN, —

NO₂ or —

(U)_m—

X, wherein

U is a C_1-6 aliphatic, wherein up to two methylene units are optionally and independently replaced by G^U and wherein U is optionally substituted with 1-4 J^U;

X is H, halogen, CN, NO₂, S(O)R, SO₂R, C_1-4 haloaliphatic, or a group selected from C_1-6 aliphatic, a C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

wherein said group is optionally substituted with 1-4 J^X;

G^U is —

NH—

, —

NR—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR—

, —

C(═

N—

CN)—

, —

NHCO—

, —

NRCO—

, —

NHC(O)O—

, —

NRC(O)O—

, —

SO₂NH—

, —

SO₂NR—

, —

NHSO₂—

, —

NRSO₂—

, —

NHC(O)NH—

, —

NRC(O)NH—

, —

NHC(O)NR—

, —

NRC(O)NR, —

OC(O)NH—

, —

OC(O)NR—

, —

NHSO₂NH—

, —

NRSO₂NH—

, —

NHSO₂NR—

, —

NRSO₂NR—

, —

SO—

, or —

SO₂—

;

R⁴ is H, halogen, CN, NH₂, NO₂, CF₃, C_1-3 aliphatic, cyclopropyl, NCH₃, OCH₃, —

C(═

O)NH₂, —

C(═

O)CH₃, —

NC(═

O)CH₃, or OH;

R⁵ is H, halogen, CN, NH₂, NO₂, CF₃, C_1-3 aliphatic, cyclopropyl, NCH₃, OCH₃, —

C(═

O)NH₂, —

C(═

O)CH₃, —

NC(═

O)CH₃, or OH;

J^Q is halogen, OCF₃, —

(V_n)—

R″

, —

(V_n)—

CN, —

(V_n)—

NO₂, or —

(V_n)—

(C_1-4 haloaliphatic), wherein J^Q is not H;

V is a C_1-10 aliphatic, wherein up to three methylene units are replaced by G^V, wherein G^V is selected from —

NH—

, —

NR—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR—

, —

C(═

N—

CN), —

NHCO—

, —

NRCO—

, —

NHC(O)O—

, —

NRC(O)O—

, —

SO₂NH—

, —

SO₂NR—

, —

NHSO₂—

, —

NRSO₂—

, —

NHC(O)NH—

, —

NRC(O)NH—

, —

NHC(O)NR—

, —

NRC(O)NR, —

OC(O)NH—

, —

OC(O)NR—

, —

NHSO₂NH—

, —

NRSO₂NH—

, —

NHSO₂NR—

, —

NRSO₂NR—

, —

SO—

, or —

SO₂—

; and

wherein V is optionally substituted with 1-6 occurrences of J^V;

R″

is H, or is an optionally substituted group) selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;

or two R″

groups, on the same substituent or different substituents, together with the atom(s) to which etch R″

group is bound, form an optionally substituted 3-8 membered heterocyclyl;

wherein each optionally substituted R″

group is independently and optionally substituted with 1-6 occurrences of J^R;

R is an optionally substituted group selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;

or two R groups, on the same substituent or different substituents, together with the atom(s) to which each R group is bound, form an optionally substituted 3-8 membered heterocyclyl;

wherein each R group is independently and optionally substituted with 1-4 occurrences of J^R;

J^V, J^U, J^X, and J^R are each independently selected from halogen, L, -(L_n)-R′

, -(L_n)-N(R′

)₂, -(L_n)-SR′

, -(L_n)-OR′

, -(L_n)-(C_3-10 cycloaliphatic), -(L_n)-(C_6-10 aryl), -(L_n)-(5-10 membered heteroaryl), -(L_n)-(5-10 membered heterocyclyl), oxo, C_1-4haloalkoxy, C_1-4haloalkyl, -(L_n)-NO₂, -(L_n)-CN, -(L_n)-OH, -(L_n)-CF₃, —

CO₂R′

, —

CO₂H, —

COR′

, —

COH, —

OC(O)R′

, or —

NC(O)R′

;

or two J^V, J^U, J^X, or J^R groups, on the same substituent or different substituents, together with the atom(s) to which each J^V, J^U, J^X, and J^R group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;

R′

is H or C_1-6 aliphatic;

or two R′

groups, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —

OR*, —

SR*, —

NO₂, —

CF₃, —

CN, —

CO₂R*, —

COR*, OCOR*, NHCOR*, wherein R* is H or C_1-6 aliphatic;

L is a C_1-6 aliphatic wherein up to three methylene units are replaced by —

NH—

, —

NR⁶—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR⁶—

, —

C(═

N—

CN), —

NHCO—

, —

NR⁶CO—

, —

NHC(O)O—

, —

NR⁶C(O)O—

, —

SO₂NH—

, —

SO₂NR⁶—

, —

NHSO₂—

, —

NR⁶SO₂—

, —

NHC(O)NH—

, —

NR⁶C(O)NH—

, —

NHC(O)NR⁶—

, —

NR⁶C(O)NR⁶, —

OC(O)NH—

, —

OC(O)NR⁶—

, —

NHSO₂NH—

, —

NR⁶SO₂NH—

, —

NHSO₂NR⁶—

, —

NR⁶SO₂NR⁶—

, —

SO—

, or —

SO₂—

;

R⁶ is selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;

or two R⁶ groups, on the same substituent or different substituents, together with the atom(s) to which each R⁶ group is bound, form a 3-8 membered heterocyclyl;

J is halogen, OCH3, OH, NO₂, NH₂, SCH₃, NCH₃, CN, unsubstituted C_1-2aliphatic;

two J'"'"'s, together with the carbon to which they are attached, form a cyclopropyl ring or C═

O;

m, n, d, and p are each independently 0 or 1;

provided that

when R¹, R², and R³ are H, then Q is not

—

NH-tBu, —

NH-phenyl or phenyl; and

when R¹ and R² are H, and R³ is H, COOEt or COOH, then Q is not

3. A compound of formula I-b

or a pharmaceutically acceptable salt thereof

wherein

Q is a 3-8 membered saturated, partially saturated, or unsaturated monocyclic ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur;

or an 8-12 membered bicyclic ring having 6 heteroatoms selected from nitrogen, oxygen, or sulfur;

wherein Q is optionally substituted with 1-10 occurrences of J^Q;

Z′

is NH, N(C_1-3aliphatic) or C═

CH₂;

R¹ is —

(C_1-2 aliphatic)_p-R⁴ wherein each R¹ is optionally substituted with 1-3 occurrences of J;

R² is —

(C_1-2 aliphatic)_d-R⁵ wherein each R¹ is optionally substituted with 1-3 occurrences of J;

R³ is halogen, —

CN, —

NO₂ or —

(U)_m—

X, wherein

U is a C_1-6 aliphatic, wherein up to two methylene units are optionally and independently replaced by G^U and wherein U is optionally substituted with 1-4 J^U;

X is H, halogen, CN, NO₂, S(O)R, SO₂R, C_1-4 haloaliphatic, or a group selected from C_1-6 aliphatic, a C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl;

wherein said group is optionally substituted with 1-4 J^X;

G^U is —

NH—

, —

NR—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR—

, —

C(═

N—

CN)—

, —

NHCO—

, —

NRCO—

, —

NHC(O)O—

, —

NRC(O)O—

, —

SO₂NH—

, —

SO₂NR—

, —

NHSO₂—

, —

NRSO₂—

, —

NHC(O)NH—

, —

NRC(O)NH—

, —

NHC(O)NR—

, —

NRC(O)NR, —

OC(O)NH—

, —

OC(O)NR—

, —

NHSO₂NH—

, —

NRSO₂NH—

, —

NHSO₂NR—

, —

NRSO₂NR—

, —

SO—

, or —

SO₂—

;

R⁴ is H, halogen, CN, NH₂, NO₂, CF₃, C_1-3 aliphatic, cyclopropyl, NCH₃, OCH₃, —

C(═

O)NH₂, —

C(═

O)CH₃, —

NC(═

O)CH₃, or OH;

R⁵ is H, halogen, CN, NH₂, NO₂, CF₃, C_1-3 aliphatic, cyclopropyl, NCH₃, OCH3, —

C(═

O)NH₂, —

C(═

O)CH₃, —

NC(═

O)CH₃, or OH;

J^Q is halogen, OCF₃, —

(V_n)—

R″

, —

(V_n)—

CN, —

(V_n)—

NO₂, or —

(V_n)—

(C_1-4 haloaliphatic), wherein J^Q is not H;

V is a C_1-10 aliphatic, wherein up to three methylene units are replaced by G^V, wherein G^V is selected from —

NH—

, —

NR—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR—

, —

C(═

N—

CN), —

NHCO—

, —

NRCO—

, —

NHC(O)O—

, —

NRC(O)O—

, —

SO₂NH—

, —

SO₂NR—

, —

NHSO₂—

, —

NRSO₂—

, —

NHC(O)NH—

, —

NRC(O)NH—

, —

NHC(O)NR—

, —

NRC(O)NR, —

OC(O)NH—

, —

OC(O)NR—

, —

NHSO₂NH—

, —

NRSO₂NH—

, —

NHSO₂NR—

, —

NRSO₂NR—

, —

SO—

, or —

SO₂—

; and

wherein V is optionally substituted with 1-6 occurrences of J^V;

R″

is H, or is an optionally substituted group selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;

or two R″

groups, on the same substituent or different substituents, together with the atom(s) to which each R″

group is bound, form an optionally substituted 3-8 membered heterocyclyl;

wherein each optionally substituted R″

group is independently and optionally substituted with 1-6 occurrences of J^R;

R is an optionally substituted group selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, or 0.5-10 membered heterocyclyl;

or two R groups, on the same substituent or different substituents, together with the atom(s) to which each R group is bound, form an optionally substituted 3-8 membered heterocyclyl;

wherein each R group is independently and optionally substituted with 1-4 occurrences of J^R;

J^V, J^U, J^X, and J^R are each independently selected from halogen, L, -(L_n)-R′

, -(L_n)-N(R′

)₂, -(L_n)-SR′

, -(L_n)-OR′

, -(L_n)-(C_3-10 cycloaliphatic), -(L_n)-(C_6-10 aryl), -(L_n)-(5-10 membered heteroaryl), -(L_n)-(5-10 membered heterocyclyl), oxo, C_1-4haloalkoxy, C_1-4haloalkyl, -(L_n)-NO₂, -(L_n)-CN, -(L_n)-OH, -(L_n)-CF₃, —

CO₂R′

, —

CO₂H, —

COR′

, —

COH, —

OC(O)R′

, or —

NC(O)R′

;

or two J^V, J^U, J^X, or J^R groups, on the same substituent or different substituents, together with the atom(s) to which each J^V, J^U, J^X, and J^R group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;

R′

is H or C_1-6 aliphatic;

or two R′

groups, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —

OR*, —

SR*, —

NO₂, —

CF₃, —

CN, —

CO₂R*, —

COR*, OCOR*, NHCOR*, wherein R* is H or C_1-6 aliphatic;

L is a C_1-6 aliphatic wherein up to three methylene units are replaced by —

NH—

, —

NR⁶—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(O)NH—

, —

C(O)NR⁶—

, —

C(═

N—

CN), —

NHCO—

, —

NR⁶CO—

, —

NHC(O)O—

, —

NR⁶C(O)O—

, —

SO₂NH—

, —

SO₂NR⁶—

, —

NHSO₂—

, —

NR⁶SO₂—

, —

NHC(O)NH—

, —

NR⁶C(O)NH—

, —

NHC(O)NR⁶—

, —

NR⁶C(O)NR⁶, —

OC(O)NH—

, —

OC(O)NR⁶—

, —

NHSO₂NH—

, —

NR⁶SO₂NH—

, —

NHSO₂NR⁶—

, —

NR⁶SO₂NR⁶—

, —

SO—

, or —

SO₂—

;

R⁶ is selected from C_1-6 aliphatic, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;

or two R⁶ groups, on the same substituent or different substituents, together with the atom(s) to which each R⁶ group is bound, form a 3-8 membered heterocyclyl;

J is halogen, OCH₃, OH, NO₂, NH₂, SCH₃, NCH₃, CN, unsubstituted C_1-2aliphatic;

two J'"'"'s, together with the carbon to which they are attached, form a cyclopropyl ring or C═

O;

m, n, d, and p are each independently 0 or 1;

provided that

when R¹ is I, R² is H, R³ is Br and Z′

is NH, then Q is not

when R¹ and R³ are H, R² is H, Cl, F, Me or CF₃, and Z′

is NH;

then Q is not 2-fluoro-4-amino phenyl, 2-fluoro-4-nitro phenyl or

when R¹ and R³ are H, R² is H or Me, and Z is NH, then Q is not 2,6-fluoro-4-amino phenyl,

when R¹ and R³ are H, R² is Me, and Z′

is NH, then Q is not

when R¹, R² and R³ are H, and Z′

is NH;

then Q is not 3,5-difluoro phenyl, 4-amino phenyl, 4-nitro phenyl, 2-chloro-4-imino phenyl, 2-chloro-4-nitro phenyl, 3,4-methoxyphenyl,

when R¹ and R² are H, R³ is C(═

O)NH₂ and Z′

is NH, then Q is not 2-ethylphenyl;

and

when R¹, R², and R³ are H and Z′

is NCH₃;

then Q is not unsubstituted phenyl, 2-fluoro-4-amino phenyl, 2-fluoro-4-nitro phenyl or

4. (canceled)

6-8. -8. (canceled)

10-12. -12. (canceled)

14-15. -15. (canceled)

17-29. -29. (canceled)

31-51. -51. (canceled)

53-66. -66. (canceled)

68-82. -82. (canceled)

84. (canceled)

90-95. -95. (canceled)

97-100. -100. (canceled)