# US 2014/0155402 A1 · Bi-heteroaryl compounds as vps34 inhibitors

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- Number: US 2014/0155402 A1
- Document ID: US20140155402A1
- Status: Published application
- Kind: A1
- Application number: 14/173,072
- Filed: 2014-02-05
- Published: 2014-06-05
- Earliest claimed: 2010-12-21
- Assignees: Novartis AG
- Inventors: Ivan Cornella Taracido; Edmund Harrington; Ayako Honda; Erin Keaney
- Web page: https://patentgrep.com/patent/US20140155402A1

## CPC

- C07D 403/14: containing three or more hetero rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- 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 405/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- 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 includes novel methods of treating a disease or disorder characterized by hyperactivity of Vps34, and compound as Vps34 inhibitors; particularly compounds of Formula I: or a pharmaceutically acceptable salt thereof, as well as methods of treating a disease, disorder, or syndrome associated with Vps34 inhibition, particularly hyperproliferative diseases. The present invention also includes pharmaceutical compositions including compounds of formula I and pharmaceutically acceptable salts thereof.

## Claims

### Claim at position 1

1-19. (canceled)

### Claim 20

A method for the treatment of cancer in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R1 is C1-6alkyl, NR3R6, C1-6alkoxy, or —S—C1-6alkyl;
R2 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, a C6-14aryl group, a C3-14cycloalkyl group, a 5 to −14 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from N, O, and S, C1-6alkoxy, C2-6-alkenyloxy, C2-6-alkynyloxy, C1-6alkyl-O—R27, C1-6alkyl-C3-14cycloalkyl, C1-6alkyl-O—C0-6alkyl-C6-14aryl, C1-6alkyl-O—SiR8R9R10, halogen, or C1-6haloalkyl, wherein R2 may be unsubstituted or substituted with OH, C1-6alkoxy, or halogen;
R4 and R5 are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, a C6-14aryl group, a C3-14cycloalkyl group, a 3-14 membered cycloheteroalkyl group, a 5-14 membered heteroaryl group, C1-6alkoxy, OH, C1-6alkylNR11R12, C1-6alkyl-O—R13, C1-6alkyl-5-14 membered heteroaryl group, or C(O)—C1-6alkyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-14aryl group, C3-14cycloalkyl group, 3-14 membered cycloheteroalkyl group, 5-14 membered heteroaryl group, C1-6alkoxy, C1-6alkyl-NR11R12, C1-6alkylOR13, C1-6alkyl-5-14 membered heteroaryl group, or C(O)—C1-6alkyl may be optionally substituted by one or more from the group of halogen, a 5-14 membered heteroaryl group, OH, C1-6alkyl, C1-6haloalkyl, C1-6alkylOR27, C1-6alkoxy, NR14R15, CONR16R17, NR18COR19, NR20COOR21, COR22, COOR23, —CN, SO2R26, or NR24SO2R25;
R3 and R6 are independently H, C1-6alkyl, C1-6alkyl-aryl, C1-6alkoxy, a C3-14cycloalkyl group, a 3-14 membered cycloheteroalkyl group, a C6-14aryl group, a 5-14 membered heteroaryl group, or C1-6alkyl-O—R8, wherein C1-6alkyl, C1-6alkyl-aryl, C1-6alkoxy, a C3-14cycloalkyl group, a 3-14 membered cycloheteroalkyl group, a C6-14aryl group, a 5-14 membered heteroaryl group, or C1-6alkyl-O—R8, may be substituted by one of more of C1-6alkyl, or OH;
R11 and R12 are the same or different, and independently are selected from hydrogen, C1-6alkyl, a C3-8cycloalkyl group, a C6-14 aryl group, a 5-14 membered heteroaryl group, and a 3-14 membered cycloheteroalkyl group, or NR11R12 forms a non-aromatic four to seven membered ring optionally containing a second heteroatom selected from O, N and S, and optionally substituted by one or more substituents R28;
R7 and R7a are independently H or C1-6alkyl
n is 0, 1, or 2; and
R8, R9, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, and R27, and R28 are independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, a C6-14 aryl group, A C3-14 cycloalkyl group, a 3-14 membered cycloheteroalkyl group, or a 5-14 membered heteroaryl group.

### Claim 21 (depends on 20)

The method according to claim 20, wherein R1 is C1-6alkyl, NR3R6, or C1-6alkoxy, and R3 and R6 are independently H, C1-6alkyl, C1-6alkyl-aryl, a C3-14cycloalkyl group, C1-6alkylOH, C1-6alkylOC1-6alkyl, or a 3-14 membered cycloheteroalkyl group.

### Claim 22 (depends on 20)

The method according to claim 20 wherein R1 is methyl, ethyl, propyl, methoxy, ethoxy, methyl-phenyl, NH2, NH-pentyl-OH, NHbutyl, NHCH3, or NHisopropyl.

### Claim 23 (depends on 20)

The method according to claim 20 wherein R1 is NH2, NH-pentyl-OH, NHbutyl, NHCH3, or NHisopropyl.

### Claim 24 (depends on 20)

The method according to claim 20 wherein R2 is C1-6alkyl, a C3-14cycloalkyl group, or C1-6alkyl-C3-14cycloalkyl.

### Claim 25 (depends on 20)

The method according to claim 20 wherein R2 is methyl, ethyl, propyl, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, —CH2—O—CH3, —CH2-cyclopropyl, —CH2-cyclobutyl, —CH2-cyclopentyl, —CH2-cyclohexyl, —CH2CH2-cyclopropyl, —CH2CH2-cyclobutyl, —CH2CH2-cyclopentyl, —CH2CH2-cyclohexyl, or —CH2—O—CH2-phenyl.

### Claim 26 (depends on 20)

The method according to claim 20 wherein R2 is —CH2-cyclopropyl.

### Claim 27 (depends on 20)

The method according to claim 20 wherein R4 and R5 are independently H, a C6-14aryl group, C3-14cycloalkyl group, a 3-14 membered cycloheteroalkyl group, or a 5-14 membered heteroaryl group wherein said C6-14aryl group, C3-14cycloalkyl group, 3-14 membered cycloheteroalkyl group, or 5-14 membered heteroaryl group, is optionally mono- or di-substituted by one or more of halogen, OH, C1-6alkyl, C1-6haloalkyl, C1-6alkylOH, C1-6alkoxy, NR14R15, CONR16R17, NR18COR19, NR20COOR21, COR22, COOR23, or NR24SO2R25.

### Claim 28 (depends on 20)

The method according to claim 20 where one of R4 or R5 is H, and the other is methyl, ethyl, propyl, phenyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl, or pyridazinyl; each of which may be unsubstituted or substituted with one or more of halogen, a 5-14 membered heteroaryl group, OH, C1-6alkyl, C1-6haloalkyl, C1-6alkylOR27, C1-6alkoxy, NR14R15, CONR16R17, NR18COR19, NR20COOR21, COR22, COOR23, —CN, SO2R26, —O—, or NR24SO2R25.

### Claim 29 (depends on 20)

The method according to claim 20 where one of R4 and R5 is H, and the other is phenyl or pyridinyl, each of which may be unsubstituted or substituted with one or more of F, Cl, OH, methyl, ethyl, CN, or CF3.

### Claim 30 (depends on 20)

The method according to claim 20 where R7 is H and n is 0.

### Claim 31

A method for the treatment of cancer in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of Formula II,
or a pharmaceutically acceptable salt thereof, wherein
R1 is (C1-C6)alkyl, —OCH3, —NH2, —NH(C1-C6)alkyl, —NHCH2(phenyl), —NHCH2CH2OH, —NHCH2CH(OH)CH3, —NHCH(CH3)CH2OH, —NHCH2CH(CH3)2OH, —NHCH2CH2OCH3, —NH(C3-C6)cycloalkyl, phenethylamino-, tetrahydropyranylamino-, or —SCH3;
R2 is (C1-C6)alkyl, —CF3, —CH2(cyclopropyl), —CH2OH, or —CH2OCH2(phenyl);
R4 is H; and
R5 is
(i) —(CH2)n—R5a, where n is 0, 1 or 2 and R5a is pyridinyl, 6-methoxypyridin-3-yl, furanyl, imidazolyl, isoxazolyl, thiazolyl, thiadiazolyl, quinolinyl, 1H-indolyl, benzo[d][1,3]dioxolyl, morpholinyl, tetrahydropyranyl, or piperidinyl, where said chemical moiety is optionally substituted with a methyl or halo; or
(ii) (C1-C6)alkyl, (C3-C6)cycloalkyl, or phenyl, wherein said (C1-C6)alkyl, said (C3-C6)cycloalkyl, and said phenyl are optionally substituted with one to two substituents each independently selected from F, Cl, —CH3, —CN, —OH, —OCH3, —NHC(O)—(C1-C4)alkyl, —NH2, —N(CH3)2i—NHSO2CH3, —C(O)CH3, —C(O)OH, or —SO2CH3.

### Claim 32 (depends on 31)

The method according to claim 31 wherein n is 0.

### Claim 33 (depends on 20)

The method according to claim 20 wherein the compound of formula (I) is 1-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol having the following formula:
; or a pharmaceutically acceptable salt thereof.

### Claim 34 (depends on 20)

The method according to claim 20 wherein the compound of formula (I) is 4′-Cyclopropylmethyl-N2-pyridin-4-yl-[4,5′]bipyrimidinyl-2,2′-diamine having the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 35 (depends on 20)

The method according to claim 20 wherein the compound of formula (I) is 4′-Benzyloxymethyl-N2-pyridin-4-yl-[4,5]bipyrimidinyl-2,2′-diamine having the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 36 (depends on 20)

The method according to claim 20 wherein the compound of formula (I) is N2-(pyridin-4-yl)-4′-(trifluoromethyl)-4,5′-bipyrimidine-2,2′-diamine having the following formula:
or a pharmaceutically acceptable salt thereof.