# US 8,569,337 B2 · Tri-cyclic pyrazolopyridine kinase inhibitors

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- Number: US 8,569,337 B2
- Document ID: US8569337B2
- Status: Granted
- Kind: B2
- Application number: 12/670,989
- Filed: 2010-01-27
- Published: 2012-05-31
- Granted: 2013-10-29
- Earliest claimed: 2008-07-23
- Assignees: Vertex Pharmaceuticals Incorporated
- Applicants: Juan-Miguel Jimenez; John Studley; Ronald Knegtel; Luca Settimo; Christopher John Davis; Damien Fraysse; Philip N. Collier; Guy Brenchley; Dean Boyall; Andrew Miller; Heather Twin; Stephen Young
- Inventors: Juan-Miguel Jimenez; John Studley; Ronald Knegtel; Luca Settimo; Christopher John Davis; Damien Fraysse; Philip N. Collier; Guy Brenchley; Dean Boyall; Andrew Miller; Heather Twin; Stephen Young
- Web page: https://patentgrep.com/patent/US8569337B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/06: Antiasthmatics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D 239/24: having three or more double bonds between ring members or between ring members and non-ring members
- C07D 241/10: having three double bonds between ring members or between ring members and non-ring members
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds of tri-cyclic pyrazolopyridine useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions containing such compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

## Claims

### Claim 1

A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is —H, halogen, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO2, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;
R2 is —H, halogen , —CN, —NO2, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;
ring B is a pyridyl; and ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more Jc;
Y is —Y1-Q1;
Y1 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y1 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p—; and Y1 is optionally and independently substituted with one or more Jd;
Q1 is absent, or a C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q1 is optionally and independently substituted with one or more Jb; wherein when B is substituted with Y then Y1 and Q1 are not both absent;
ring C is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring C is optionally substituted with one Z and independently further optionally and independently substituted with one or more Jb;
Z is —Y2-Q2;
Y2 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y2 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p—; and Y2 is optionally and independently substituted with one or more Jd;
Q2 is absent, C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q2 is optionally and independently substituted with one or more Je; wherein when C is substituted with Z then Y2 and Q2 are not both absent;
each R′ is independently —H, or C1-C6 alkyl optionally and independently substituted with one or more Ja;
each Ja is independently halogen, —OR, —N(R)2, —C(O)R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —NRC(O)OR, —CN, —NO2, or oxo;
each Jb is independently halogen, —OR, —N(R)2, —C(O)R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —NRC(O)OR, —CN, —NO2, oxo, or C1-C6 alkyl optionally and independently substituted with one or more Ja; or
two Jb groups on the same atom can join together to form a C3-8 membered partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally and independently substituted with one or more Ja;
each Jc is independently halogen, —OR′, —N(R′)2, —C(O)R, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO2, or C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;
each Jd is independently halogen, —OH, —N(H)2, —C(O)H, —C(O)OH, —C(O)N(H)2, —NHC(O)H, —NHC(O)OH, —CN, or —NO2;
each Je is independently halogen, —OH, —N(H)2, —C(O)H, —C(O)OH, —C(O)N(H)2, —NHC(O)H, —NHC(O)OH, —CN, —NO2, oxo, C1-10 aliphatic, wherein up to three methylene units are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p— and the aliphatic group is optionally and independently substituted with one or more Jd, or Je is C3-8 cycloaliphatic optionally and independently substituted with one ore more Jb;
each R is independently —H or C1-C6 alkyl; and
each p is independently 0, 1, or 2.

### Claim 2 (depends on 1)

A compound of claim 1, represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is —H, halogen, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO2, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;
R2 is —H, halogen, —CN, —NO2, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;
ring B is pyridyl; and ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more Jc;
Y is —Y1-Q1;
Y1 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y1 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p—; and Y1 is optionally and independently substituted with one or more Jd;
Q1 is absent, or a C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q1 is optionally and independently substituted with one or more Jb; wherein Y1 and Q1 are not both absent;
ring C is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring C is optionally substituted with one Z and independently further optionally and independently substituted with one or more Jb;
Z is —Y2-Q2;
Y2 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y2 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p—; and Y2 is optionally and independently substituted with one or more Jd;
Q2 is absent, C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q2 is optionally and independently substituted with one or more Je; wherein Y2 and Q2 are not both absent;
each R′ is independently —H, or C1-C6 alkyl optionally and independently substituted with one or more Ja;
each Ja is independently halogen, —OR, —N(R)2, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —NRC(O)OR, —CN, —NO2, or oxo;
each Jb is independently halogen, —OR, —N(R)2, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —NRC(O)OR, —CN, —NO2, oxo, or C1-C6 alkyl optionally and independently substituted with Ja; or
two Jb groups on the same atom can join together to form a C3-8 membered partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally and independently substituted with one or more Ja; each Jc is independently halogen, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO2, or C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;
each Jd is independently halogen, —CN, or —NO2;
each Je is independently halogen, —CN, —NO2, oxo, C1-10 aliphatic, wherein up to three methylene units are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p— and the aliphatic group is optionally and independently substituted with one or more Jd, or Je is C3-8 cycloaliphatic optionally and independently substituted with one ore more Jb;
each R is independently —H or C1-C6 alkyl; and
each p is independently 0, 1, or 2.

### Claim 3 (depends on 2)

A compound of claim 2, represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is —H, halogen, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO2, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;
R2 is —H, halogen, —CN, —NO2, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;
ring B is pyridyl; and ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more Jc;
Y is —Y1-Q1;
Y1 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y1 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p—; and Y1 is optionally and independently substituted with one or more Jd;
Q1 is absent, or a C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q1 is optionally and independently substituted with one or more Jb; wherein Y1 and Q1 are not both absent;
ring C is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring C is optionally substituted with one Z and independently further optionally and independently substituted with one or more Jb;
Z is —Y2-Q2;
Y2 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y2 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p—; and Y2 is optionally and independently substituted with one or more Jd;
Q2 is absent, C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q2 is optionally and independently substituted with one or more Je; wherein Y2 and Q2 are not both absent;
each R′ is independently —H, or C1-C6 alkyl optionally and independently substituted with one or more Ja;
each Ja is independently halogen, —OR, —N(R)2, —C(O)OR, —C(O)N(R)2; —NRC(O)R, —NRC(O)OR, —CN, —NO2, or oxo;
each Jb is independently halogen, —OR, —N(R)2, —C(O)OR, —C(O)N(R)2; —NRC(O)R, —NRC(O)OR, —CN, —NO2, oxo, or C1-C6 alkyl optionally and independently substituted with Ja;
each Jc is independently halogen, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO2, or C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;
each Jd is independently halogen, —CN, or —NO2;
each Je is independently halogen, —CN, —NO2, oxo, C1-10 aliphatic, wherein up to three methylene units are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p— and the aliphatic group is optionally and independently substituted with one or more Jd, or Je is C3-8 cycloaliphatic optionally and independently substituted with one ore more Jb;
each R is independently —H or C1-C6 alkyl; and
each p is independently 0, 1, or 2.

### Claim 4 (depends on 3)

The compound of claim 3 wherein:
R1 is —H, halogen, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb; and
R2 is —H, halogen, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb.

### Claim 5 (depends on 4)

The compound of claim 4 wherein:
R2 is —H.

### Claim 6 (depends on 5)

The compound of claim 5 wherein:
R1 is —H, halogen or C1-C10 haloalkyl.

### Claim 7 (depends on 6)

The compound of claim 6 wherein the compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
each q is independently 0 or 1; and
each t is independently 0, or 1-4.

### Claim 8 (depends on 7)

The compound of claim 7, wherein:
ring C is selected from the group consisting of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazalolyl, oxadiazolyl, thiazolyl, thiadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, indolyl, indazolyl, benzimidazolyl, quinolyl, quinoxalyl, indolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, azabicyclopentyl, azabicyclohexyl, azabicycloheptyl, azabicyclooctyl, azabicyclononyl, azabicyclodecyl, diazabicyclohexyl, diazabicycloheptyl, azetidinyl, isoindolinyl, isoindolyl, dihydroindazolyl, dihydrobenzimidazolyl, morpholinyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydropyrazolyl, dihydroimidazolyl, octahydropyrrolopyrazyl, octahydropyrrolopyridyl, octahydropyridopyrazyl, octahydropyridopyridyl, diazabicyclooctyl, diazabicyclononyl, diazabicyclodecyl, thiazepanyl, and thiazocanyl wherein each ring is optionally substituted with one Z and independently further and optionally substituted with one or more Jb.

### Claim 9 (depends on 7)

The compound of claim 7, wherein
ring C is selected from the group consisting of cyclohexyl, diazabicyclooctyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazalolyl, oxadiazolyl, thiazolyl, azetidinyl, morpholinyl, azepanyl, diazabicycloheptyl, diazabicyclooctyl, indolyl, tetrahydropyridyl, dihydropyridyl, octahydropyrrolopyrazyl, octahydropyrrolopyridyl, octahydropyridopyrazyl, octahydropyridopyridyl, thiadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, diazepanyl, and oxazepanyl wherein each ring is optionally substituted with one Z and independently further and optionally substituted with one or more Jb.

### Claim 10 (depends on 7)

The compound of claim 7, wherein
ring C is selected from the group consisting of cyclohexyl, 3,8-diazabicyclo[3.2.1.]octane, phenyl, pyridyl, piperidinyl, piperazinyl, diazepanyl, pyrrolidinyl, pyrrolyl, pyrrazolyl, azetidinyl, morpholinyl, azepanyl, 2,5 diazabicycloheptyl, diazabicyclooctyl, indolyl, tetrahydropyridyl, octahydro-1H-pyrrolo[2,3-b]pyrazyl, octahydropyrrolo[1,2-a]pyrazyl, and oxazepanyl wherein each ring is optionally substituted with one Z and independently further and optionally substituted with one or more Jb.

### Claim 11 (depends on 7)

The compound of claim 7, wherein
ring C is selected from the group consisting of piperidinyl, piperazinyl, diazapanyl, pyrrolidinyl, azetidinyl, and azepanyl, wherein each ring is optionally substituted with one Z and independently further and optionally substituted with one or more Jb.

### Claim 12 (depends on 7)

The compound of claim 7, wherein ring C is represented a structural formula selected from the group consisting of:
q is 0 or 1; and
t is 0 or 1-4.

### Claim 13 (depends on 7)

The compound of claim 7, wherein ring C is represented by a structural formula selected from the group consisting of:
q is 0 or 1; and
t is 0 or 1-4.

### Claim 14 (depends on 13)

The compound of claim 13 wherein ring C is represented by a structural formula represented by:
q is 0 or 1; and
t is 0 or 1-4.

### Claim 15 (depends on 7)

The compound of claim 7, wherein ring C is represented by a structural formula selected from the group consisting of:
q is 0 or 1; and
t is 0 or 1-4.

### Claim 16 (depends on 15)

The compound of claim 15 wherein ring C is represented by a structural formula represented by:
q is 0 or 1; and
t is 0 or 1-4.

### Claim 17 (depends on 15)

The compound of claim 15 wherein ring C is represented by a structural formula represented by:
q is 0 or 1; and
t is 0 or 1-4.

### Claim 18 (depends on 17)

The compound of claim 17 wherein:
R1 is halogen or C1-C10 haloalkyl.

### Claim 19 (depends on 18)

The compound of claim 18 wherein:
ring B is pyridyl substituted with one Y and independently further and optionally and independently substituted with one or more Jc.

### Claim 20 (depends on 19)

The compound of claim 19 wherein:
ring B is pyridyl substituted with one Y.

### Claim 21 (depends on 7)

The compound of claim 7 wherein:
ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z and independently further and optionally substituted with one or more Jb.

### Claim 22 (depends on 21)

The compound of claim 21 wherein:
ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z.

### Claim 23 (depends on 7)

The compound of claim 7 wherein the compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
q is 1; and
each t is independently 0 or 1-4.

### Claim 24 (depends on 23)

The compound of claim 23 wherein:
ring B is pyridyl substituted with one Y and independently further and optionally and independently substituted with one or more Jc.

### Claim 25 (depends on 24)

The compound of claim 24 wherein:
ring B is pyridyl substituted with one Y.

### Claim 26 (depends on 25)

The compound of claim 25 wherein:
ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z and independently further and optionally substituted with one or more Jb.

### Claim 27 (depends on 26)

The compound of claim 26 wherein:
ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z.

### Claim 28 (depends on 7)

The compound of claim 7 wherein the compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
q is 1; and
each t is independently 0 or 1-4.

### Claim 29 (depends on 28)

The compound of claim 28 wherein:
ring B is pyridyl independently and optionally and independently substituted with one or more Jc.

### Claim 30 (depends on 29)

The compound of claim 29 wherein:
ring B is pyridyl.

### Claim 31 (depends on 30)

The compound of claim 30 wherein:
ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z and independently further and optionally substituted with one or more Jb.

### Claim 32 (depends on 30)

The compound of claim 30 wherein:
ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z.

### Claim 33 (depends on 7)

The compound of claim 7 wherein the compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
T is —CH2—, —CH(Jb)-, —C(Jb)2-, —NH— or —N(Jb)-;
t is 0, 1, or 2;
n is 0 or 1;
w is 0 or 1;
Jc is CN, F, Cl or CF3;
U is Z or Jb
Z is Y2-Q2;
Y2 is absent or C1-6 alkyl optionally and independently substituted with one or more Jd;
Q2 is C1-C6 cyloalkyl having 0-1 heteroatoms optionally and independently substituted with one or more Je;
Jb is F, —OR, —N(R)2, —C(O)N(R), C1-6 alkyl optionally and independently substituted with one or more Ja;
Ja is F, —OR, —N(R)2, or —C(O)N(R);
each R is independently —H or C1-C6 alkyl; and
each Jd and Je is independently —OH, —NH2 or F.

### Claim 34 (depends on 33)

The compound of claim 33 wherein the compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
T is CHNH2 or NH;
Jc is F or CF3;
U is Z or Jb
Z is Y2-Q2;
Y2 is absent or C1-6 alkyl optionally and independently substituted with one or more Jd;
Q2 is C 1-C6 cyloalkyl optionally and independently substituted with one or more Je;
Jb is C 1-6 alkyl optionally and independently substituted with one or more Ja;
Ja is —OH, —NH2 or F; and
each Jd and Je is independently —OH, —NH2 or F.

### Claim 35 (depends on 7)

The compound of claim 7 wherein the compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
T is —CH2—, —CH(Jb)-, —C(Jb)2-, —NH— or —N(Jb)-;
t is 0, 1, or 2;
w is 0 or 1;
Jc is CN, F, Cl, or CF3;
U is Z or Jb
Z is Y2-Q2;
Y2 is absent or C1-6 alkyl optionally and independently substituted with one or more Jd;
Q2 is C1-C6 cyloalkyl having 0-1 heteroatoms optionally and independently substituted with one or more Je;
Jb is F, —OR, —N(R)2, —C(O)N(R), C1-6 alkyl optionally and independently substituted with one or more Ja;
Ja is F, —OR, —N(R)2, or —C(O)N(R);
each R is independently —H or C1-C6 alkyl; and
each Jd and Je is independently —OH, —NH2 or F.

### Claim 36 (depends on 35)

The compound of claim 35 wherein:
T is —CHNH2—, or —NH—.

### Claim 37 (depends on 7)

The compound of claim 7 wherein the compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
T is —CH2—, —CH(Jb)-, —C(Jb)2-, —NH— or —N(Jb)-;
t is 0, 1, or 2;
w is 0 or 1;
Jc is CN, F, CF3; CH2OH, CH2(CH3)OH, or
U is Z or Jb
Z is Y2-Q2;
Y2 is absent or C1-6 alkyl optionally and independently substituted with one or more Jd;
Q2 is C1-C6 cyloalkyl having 0-1 heteroatoms optionally and independently substituted with one or more Je;
Jb is F, —OR, —N(R)2, —C(O)N(R), C1-6 alkyl optionally and independently substituted with one or more Ja;
Ja is F, —OR, —N(R)2, or —C(O)N(R);
each R is independently —H or C1-C6 alkyl; and
each Jd and Je is independently —OH, —NH2 or F.

### Claim 38 (depends on 37)

The compound of claim 37 wherein:
T is —CHNH2—, or —NH—.

### Claim 39 (depends on 7)

The compound of claim 7 wherein the compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
T is —CH2—, —CH(Jb)-, —C(Jb)2-, —NH— or —N(Jb)-;
t is 0, 1, or 2;
w is 0 or 1;
Jc is CN, F, Cl, or CF3;
U is Z or Jb
Z is Y2-Q2;
Y2 is absent or C1-6 alkyl optionally and independently substituted with one or more Jd;
Q2 is absent or C3-C8 cyloalkyl having 0-1 heteroatoms optionally and independently substituted with one or more Je;
Jb is F, —OR, —N(R)2, —C(O)N(R), C1-6 alkyl optionally and independently substituted with one or more Ja;
Ja is F, —OR, —N(R)2, or —C(O)N(R);
each R is independently —H or C1-C6 alkyl; and
each Jd and Je is independently —OH, —NH2 or F.

### Claim 40 (depends on 35)

The compound of claim 35 wherein:
T is —CHNH2—, or —NH—.

### Claim 41 (depends on 40)

The compound of claim 40, wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 42

A compound represented by a structural formula selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 43 (depends on 1)

A composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.