# US 2014/0155386 A1 · Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors

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- Number: US 2014/0155386 A1
- Document ID: US20140155386A1
- Status: Published application
- Kind: A1
- Application number: 14/094,392
- Filed: 2013-12-02
- Published: 2014-06-05
- Earliest claimed: 2006-12-29
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Dane Goff; Jing Zhang; Rajinder Singh; Sacha Holland; Jiaxin Yu; Pingyu Ding; Joane Litvak
- Web page: https://patentgrep.com/patent/US20140155386A1

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 27/02: Ophthalmic agents
- A61P 27/12: for cataracts
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 249/14: Nitrogen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 453/06: containing isoquinuclidine ring systems
- C07D 471/18: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Bridged bicyclic aryl or heteroaryl substituted triazoles and pharmaceutical compositions containing the compounds are disclosed as being useful in inhibiting the activity of the receptor protein tyrosine kinase Axl. Methods of using the compounds in treating diseases or conditions associated with Axl activity are also disclosed.

## Claims

### Claim 1

A compound of formula (Ia):
R1, R4 and R5 are each hydrogen;
R2 is phenyl optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR14, —R15—N(R14)C(O)R14, —R15—N(R14)S(O)tR14 (where t is 1 or 2), —R15—S(O)tOR14 (where t is 1 or 2), —R15—S(O)pR14 (where p is 0, 1 or 2), and —R15—S(O)tN(R14)2 (where t is 1 or 2), where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain;
R3 is a bridged bicyclic heteroaryl of formula (II):
where:
m and n are independently 1 to 2;
q and r are independently 0 to 2;
A1, A3 and each A4 are each independently C(R8)2;
the A2 to which (A4)r is attached is N and the other A2 is C(R8)2; and
B1 is N, B2 is the carbon directly bonded to the nitrogen to which R3 is attached,
B3 is C(R13) and B4 is C(R13);
each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R11—OR9, —R11—CN, —R11—NO2, —R11—N(R9)2, —R11—C(O)OR9 and —R11—C(O)N(R9)2;
each R8 is independently selected from the group consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, —R10—OR9, —R10—OC(O)—R9, —R10—N(R6)R7, —R10—C(O)R9, —R10—C(O)OR9, —R10—C(O)N(R6)R7, —R10—N(R6)C(O)OR14, —R10—N(R6)C(O)R9, —R10—N(R6)S(O)tR9 (where t is 1 or 2), —R10—S(O)tOR9 (where t is 1 or 2), —R10—S(O)pR9 (where p is 0, 1 or 2), and —R10—S(O)tN(R6)R7 (where t is 1 or 2), or two R8's on adjacent carbons can combine to form a double bond;
each R9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, and optionally substituted cycloalkylalkyl;
each R10 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
each R11 is an optionally substituted straight or branched alkylene chain; and
each R13 is independently selected from the group consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R10—OR9, —R10—OC(O)—R9, —R10—N(R6)R7, —R10—C(O)R9, —R10—C(O)OR9, —R10—C(O)N(R6)R7, —R10—N(R6)C(O)OR14, —R10—N(R6)C(O)R9, —R10—N(R6)S(O)tR9 (where t is 1 or 2), —R10—S(O)tOR9 (where t is 1 or 2), —R10—S(O)pR9 (where p is 0, 1 or 2), and —R10—S(O)tN(R6)R7 (where t is 1 or 2);
as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 selected from:
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-thiophen-2-yl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-pyridin-4-yl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(3-carboxypiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-bicyclo[2.2.1]heptan-2-yl piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-cyclohexyl piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-ethyloxycarbonylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-carboxymethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-(4-trifluoromethylphenyl)-I-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(4-ethyloxycarbonylpiperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(4-carboxypiperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-((2S)-2-methyloxycarbonylpyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine);
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-((2S)-2-carboxypyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-(4-methoxyphenyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-pyridin-3-yl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-thiophen-3-yl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-((3S)-3-methyloxycarbonyl-4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-((3S)-3-carboxy-4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; and
1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-methyl-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

### Claim 3 (depends on 2)

The compound of claim 2 which is 1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof.

### Claim 4

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of formula (Ia):
R1, R4 and R5 are each hydrogen;
R2 is phenyl optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR14, —R15—N(R14)C(O)R14, —R15—N(R14)S(O)tR14 (where t is 1 or 2), —R15—S(O)tOR14 (where t is 1 or 2), —R15—S(O)pR14 (where p is 0, 1 or 2), and —R15—S(O)tN(R14)2 (where t is 1 or 2), where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain;
R3 is a bridged bicyclic heteroaryl of formula (II):
where:
m and n are independently 1 to 2;
q and r are independently 0 to 2;
A1, A3 and each A4 are each independently C(R8)2;
the A2 to which (A4)r is attached is N and the other A2 is C(R8)2; and
B1 is N, B2 is the carbon directly bonded to the nitrogen to which R3 is attached, B3 is C(R13) and B4 is C(R13);
each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R11—OR9, —R11—CN, —R11—NO2, —R11—N(R9)2, —R11—C(O)OR9 and —R11—C(O)N(R9)2;
each R8 is independently selected from the group consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, —R10—OR9, —R10—OC(O)—R9, —R10—N(R6)R7, —R10—C(O)R9, —R10—C(O)OR9, —R10—C(O)N(R6)R7, —R10—N(R6)C(O)OR14, —R10—N(R6)C(O)R9, —R10—N(R6)S(O)tR9 (where t is 1 or 2), —R10—S(O)tOR9 (where t is 1 or 2), —R10—S(O)pR9 (where p is 0, 1 or 2), and —R10—S(O)tN(R6)R7 (where t is 1 or 2), or two R8's on adjacent carbons can combine to form a double bond;
each R9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, and optionally substituted cycloalkylalkyl;
each R10 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
each R11 is an optionally substituted straight or branched alkylene chain; and
each R13 is independently selected from the group consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R10—OR3, —R10—OC(O)—R9, —R10—N(R6)R7, —R10—C(O)R9, —R10—C(O)OR9, —R10—C(O)N(R6)R7, —R10—N(R6)C(O)OR14, —R10—N(R6)C(O)R9, —R10—N(R6)S(O)tR9 (where t is 1 or 2), —R10—S(O)tOR9 (where t is 1 or 2), —R10—S(O)pR3 (where p is 0, 1 or 2), and —R10—S(O)tN(R6)R7 (where t is 1 or 2);
as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof.

### Claim 5

A method of inhibiting Axl activity in a cell, wherein the method comprises contacting the cell with an effective amount of a compound of formula (Ia):
R1, R4 and R5 are each hydrogen;
R2 is phenyl optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR14, —R15—N(R14)C(O)R14, —R15—N(R14)S(O)tR14 (where t is 1 or 2), —R15—S(O)tOR14 (where t is 1 or 2), —R15—S(O)pR14 (where p is 0, 1 or 2), and —R15—S(O)tN(R14)2 (where t is 1 or 2), where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain;
R3 is a bridged bicyclic heteroaryl of formula (II):
where:
m and n are independently 1 to 2;
q and r are independently 0 to 2;
A1, A3 and each A4 are each independently C(R8)2;
the A2 to which (A4)r is attached is N and the other A2 is C(R8)2; and
B1 is N, B2 is the carbon directly bonded to the nitrogen to which R3 is attached, B3 is C(R13) and B4 is C(R13);
each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R11—OR9, —R11—CN, —R11—NO2, —R11—N(R9)2, —R11—C(O)OR9 and —R11—C(O)N(R9)2;
each R8 is independently selected from the group consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, —R10—OR9, —R10—OC(O)—R9, —R10—N(R6)R7, —R10—C(O)R9, —R10—C(O)OR9, —R10—C(O)N(R6)R7, —R10—N(R6)C(O)OR14, —R10—N(R6)C(O)R9, —R10—N(R6)S(O)tR9 (where t is 1 or 2), —R10—S(O)tOR9 (where t is 1 or 2), —R10—S(O)pR3 (where p is 0, 1 or 2), and —R10—S(O)tN(R6)R7 (where t is 1 or 2), or two R8's on adjacent carbons can combine to form a double bond;
each R9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, and optionally substituted cycloalkylalkyl;
each R10 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain;
each R11 is an optionally substituted straight or branched alkylene chain; and
each R13 is independently selected from the group consisting of hydrogen, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R10—OR9, —R10—OC(O)—R9, —R10—N(R6)R7, —R10—C(O)R9, —R10—C(O)OR9, —R10—C(O)N(R6)R7, —R10—N(R6)C(O)OR14, —R10—N(R6)C(O)R9, —R10—N(R6)S(O)tR9 (where t is 1 or 2), —R10—S(O)tOR9 (where t is 1 or 2), —R10—S(O)pR9 (where p is 0, 1 or 2), and —R10—S(O)tN(R6)R7 (where t is 1 or 2);
as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The method of claim 5 wherein the cell is a mammalian cell.

### Claim 7 (depends on 6)

The method of claim 6 wherein the Axl activity in the mammalian cell is associated with a disease or condition in a mammal.

### Claim 8 (depends on 7)

The method of claim 7 wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, vascular disease, vascular injury, psoriasis, visual impairment due to macular degeneration, diabetic retinopathy, retinopathy of prematurity, kidney disease, osteoporosis, osteoarthritis, cataracts, breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma, melanoma, prostate carcinoma, sarcoma, gastric cancer, uveal melanoma, myeloid leukemia, lymphoma and endometriosis.

### Claim 9 (depends on 8)

The method of claim 8 wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, vascular disease, vascular injury, psoriasis, visual impairment due to macular degeneration, diabetic retinopathy, retinopathy of prematurity, kidney disease, osteoporosis, osteoarthritis and cataracts.

### Claim 10 (depends on 8)

The method of claim 8, wherein the disease or condition is selected from the group consisting of breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma, melanoma, prostate carcinoma, sarcoma, gastric cancer and uveal melanoma.

### Claim 11 (depends on 8)

The method of claim 8, wherein the disease or condition is myeloid leukemia or lymphoma.

### Claim 12 (depends on 8)

The method of claim 8 wherein the disease or condition is endometriosis.