# US 8,541,418 B2 · Inhibitors of polo-like kinase

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- Number: US 8,541,418 B2
- Document ID: US8541418B2
- Status: Granted
- Kind: B2
- Application number: 12/974,622
- Filed: 2010-12-21
- Published: 2011-08-25
- Granted: 2013-09-24
- Earliest claimed: 2009-12-23
- Assignees: Elan Pharmaceutical Inc.
- Applicants: Robert A. Galemmo; Dean R. Artis; Xiaocong Michael Ye; Danielle Aubele; Anh Truong; Simeon Bowers; Roy K. Hom; Yong-Liang Zhu; R. Jeffrey Neitz; Jennifer Sealy; Marc Adler; Paul Beroza; John P. Anderson
- Inventors: Robert A. Galemmo; Dean R. Artis; Xiaocong Michael Ye; Danielle Aubele; Anh Truong; Simeon Bowers; Roy K. Hom; Yong-Liang Zhu; R. Jeffrey Neitz; Jennifer Sealy; Marc Adler; Paul Beroza; John P. Anderson
- Web page: https://patentgrep.com/patent/US8541418B2

## CPC

- C07D 475/00: Heterocyclic compounds containing pteridine ring systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- 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
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 475/04: with a nitrogen atom directly attached in position 2
- C07D 475/12: containing pteridine ring systems condensed with carbocyclic rings or ring systems
- C07D 487/14: Ortho-condensed systems
- C07D 498/14: Ortho-condensed systems
- 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 provides compounds having a structure according to Formula (I): or a salt or solvate thereof, wherein ring A, E1, E2, R1, R2, R3 and R4 are defined herein. The invention further provides pharmaceutical compositions including the compounds of the invention and methods of making and using the compounds and compositions of the invention, e.g., in the treatment and prevention of various disorders, such as Parkinson's disease.

## Claims

### Claim 1

A compound having a structure according to Formula (I):
or a salt thereof, wherein:
A is a ring selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6-membered heterocycloalkyl, and substituted or unsubstituted 5- or 6-membered heteroaryl;
E1 CR5, wherein R5 is selected from the group consisting of H, OH, unsubstituted C1-C3 alkoxy, unsubstituted C1-C3 alkyl, unsubstituted C2-C3 alkenyl, unsubstituted C2-C3 alkynyl, C1-C3 haloalkyl and halogen;
E2 is N;
R1 is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl;
R2 is selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl;
R3 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl;
or R2 and R3, together with the carbon atom to which they are attached, are optionally joined to form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl;
R4 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted 3- to 10-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and —NR25R26;
and
R25 and R26 are independently H, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C1-C10 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1 having a structure according to Formula (Ia):
or a salt thereof, wherein:
A, R1, R2, R3, R4 and R5 are defined as in claim 1.

### Claim 3 (depends on 2)

The compound of claim 2, wherein A is a member selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, N-alkyl-piperazinyl, oxazolidinyl, thiazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl and tetrazolyl, wherein A is substituted or unsubstituted.

### Claim 4 (depends on 3)

The compound of claim 3, wherein A is a substituted or unsubstituted ring selected from the group consisting of pyridyl, pyrazolyl and imidazolyl.

### Claim 5 (depends on 4)

The compound of claim 4, wherein A is a substituted or unsubstituted ring selected from the group consisting of pyridin-3-yl, pyridin-4-yl, pyrazol-4-yl and imidazol-1-yl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound has a structure selected from the group consisting of Formula (XIIa), Formula (XIIb), Formula (XIIc), Formula (XIId), Formula (XIIe), and Formula (XIIf):
or a salt thereof, wherein:
R2, R3 and R4 are defined as in claim 1;
R6 is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, aryl optionally substituted with one or more independently selected substituents R27, heteroaryl optionally substituted with one or more independently selected substituents R27, —CN, -halogen, —OR12, —SR12, —NR12R13, —C(O)R14, —C(O)NR12R13, —OC(O)NR12R13, —C(O)OR12, —NR15C(O)R14, —NR15C(O)OR12, —NR15C(O)NR12R13, —NR15C(S)NR12R13, —NR15S(O)2R14, —S(O)2NR12R13, —S(O)R14 and —S(O)2R14;
R10, R10a and R16 are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, aryl optionally substituted with one or more independently selected substituents R27, heteroaryl optionally substituted with one or more independently selected substituents R27, —CN, -halogen, —OR20, —SR20, —NR20R21, —C(O)R22, —C(O)NR20R21, —OC(O)NR20R21, —C(O)OR20, —NR23C(O)R22, —NR23C(O)OR20, —NR23C(O)NR20R21, —NR23C(S)NR20R21, —NR23S(O)2R22, —S(O)2NR20R21, —S(O)R22 and —S(O)2R22;
R11 is selected from the group consisting of H, —C(O)R22, substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, aryl optionally substituted with one or more independently selected substituents R27, 5- or 6-membered heteroaryl optionally substituted with one or more independently selected substituents R27, substituted or unsubstituted C3-C8 cycloalkyl and substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
each occurrence of R12, R13, R15, R20, R21 and R23 are independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, aryl optionally substituted with one or more independently selected substituents R27, 5- or 6-membered heteroaryl optionally substituted with one or more independently selected substituents R27, substituted or unsubstituted C3-C8 cycloalkyl and substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
each occurrence of R14 and R22 are independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3- to 6-membered heteroalkyl, aryl optionally substituted with one or more independently selected substituents R27, 5- or 6-membered heteroaryl optionally substituted with one or more independently selected substituents R27, substituted or unsubstituted C3-C8 cycloalkyl and substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
R27 at each occurrence is selected from the group consisting of C1-C10 alkyl optionally substituted with one or more independently selected substituents R28, 3- to 10-membered heteroalkyl optionally substituted with one or more independently selected substituents R28, C3-C8 cycloalkyl optionally substituted with one or more independently selected substituents R29, 3- to 8-membered heterocycloalkyl optionally substituted with one or more independently selected substituents R29, aryl optionally substituted with one or more independently selected substituents R29, heteroaryl optionally substituted with one or more independently selected substituents R29, —CN, —NO2, -halogen, —OR30, —SR30, —NR30R31, —C(O)R32, —C(O)NR30R31, —OC(O)NR30R31, —C(O)OR30, —OC(O)R32, —NR33C(O)R32, —NR33C(O)OR30, —NR33C(O)NR30R31, —NR33C(S)NR30R31, —NR33S(O)2R32, —S(O)2NR30R31, —S(O)R32 and —S(O)2R32;
R30, R31, R32, and R33, at each occurrence are independently selected from the group consisting of hydrogen, C1-C10 alkyl optionally substituted with one or more independently selected substituents R28, 3- to 12-membered heteroalkyl optionally substituted with one or more independently selected substituents R28, C3-C8 cycloalkyl optionally substituted with one or more independently selected substituents R29, 3- to 8-membered heterocycloalkyl optionally substituted with one or more independently selected substituents R29, aryl optionally substituted with one or more independently selected substituents R29, and heteroaryl optionally substituted with one or more independently selected substituents R29, provided that R32 is other than hydrogen;
R28 at each occurrence is independently selected from the group consisting of aryl optionally substituted with one or more independently selected substituents R39, heteroaryl optionally substituted with one or more independently selected substituents R39, —OR34, —SR34, —NHR34, —NR35R34, —C(O)R34, —C(O)OR34, —C(O)NHR34, —C(O)NR35R34, —NHC(O)R34, —NR34C(O)R34, —NHC(O)OR34, —NR34C(O)OR34, —NR34C(O)OH, —S(O)2R34, —S(O)2NHR34, —S(O)2NR35R34, —NHS(O)2R34, —NR34S(O)2R34, -halogen, —NHC(O)OH, —C(O)OH, —C(O)NH2, —S(O)2NH2, —CN, —NO2, ═O, —OH, ═NH, and —NH2;
R29 at each occurrence is independently —R28 or —R34;
R34 and R35 are independently selected from the group consisting of aryl optionally substituted with one or more independently selected substituents R39, heteroaryl optionally substituted with one or more independently selected substituents R39, and C1-C4 alkyl optionally substituted with one or more substituents independently selected from the group consisting of —F, —OH, —NH2, unsubstituted C1-C4 alkoxy, C1-C4 haloalkoxy, unsubstituted mono-alkylamino, unsubstituted di-alkylamino, and —NR36R37;
or —NR34R35 forms a 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with one or more unsubstituted C1-C4 alkyl; —NR36R37 forms a 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with one or more unsubstituted C1-C4 alkyl;
R39 at each occurrence is independently selected from the group consisting of —R44, —OR44, —SR44, —NHR44, —NR44R45, —C(O)R44, —C(O)OR44, —NHC(O)R44, —C(O)NHR45, —C(O)NR44R45, —S(O)2R44, —NHS(O)2R44, —S(O)2NHR45, —S(O)2NR44R45, -halogen, —C(O)OH, —C(O)NH2, —CN, —OH, and —NH2;
R44 and R45 are independently C1-C4 alkyl optionally substituted with one or more independently selected substituents independently selected from the group consisting of —F, —OH, —NH2, unsubstituted C1-C4 alkoxy, C1-C4 haloalkoxy, unsubstituted mono-alkylamino, unsubstituted di-alkylamino, and —NR46R47;
or —NR44R45 forms a 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with one or more unsubstituted C1-C4 alkyl; and
—NR46R47 forms a 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with one or more unsubstituted C1-C4 alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound has a structure according to Formula (XV):
or a salt thereof, wherein:
X1 is C or N and the dashed line represents a single or double bond;
A3 is a ring selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, thiazole, isothiazole, isoxazole, triazole, thiadiazole, benzimidazole, indole, pyrrolo[2,3-b]pyridine, quinoline, pyrrolidine, piperidine, piperazine, and dihydro-imidazole;
R74 is methyl;
R75 is hydrogen, methyl, ethyl, —CH2-cyclopropyl, or —CH2CF3;
R76 is methyl, ethyl, —CH2-cyclopropyl, or —CH2CF3;
or R75 and R76, together with the carbon atom to which they are attached, are optionally joined to form cyclobutyl;
R77 is selected from the group consisting of —NH2, —NHCH3, —NHcyclopropyl, pyrrolidine, —CH2-cyclopropyl, —CH(CH3)-cyclopropyl, cyclopropyl, cyclobutyl optionally substituted with 1 or 2 fluoro, cyclopentyl optionally substituted with 1 or 2 fluoro, isopropyl, —CH2CH2CF3, tetrahydropyran, tetrahydrofuran, oxetane, phenyl optionally substituted with 1 or 2 substituents R80, pyrazole optionally substituted with 1 substituent R81, and pyrimidine;
R78 is hydrogen, —Br, —CN, —CH3, —CH2CN, —CH2CH2NH2, —OH, —O−, ═O, —OCH3, -Obenzyl, —C(O)OH, —C(O)OCH3, —C(O)OCH2CH3, —C(O)NH2, —C(O)NHCH3, —C(O)N(CH3)2,
—NH2, ═NH, —NHCH3, —N(CH3)2, —NHS(O)2CH3, —S(O)2CH3, phenyl, thiazole, pyridine or pyrazine;
R79 is hydrogen, —Cl, —Br, —CH3, —CF3, —CH2NH2, —NH2, —CH2NHC(O)OCH3, —CH2NHC(O)CH3, —CH2NHC(O)phenyl, —CH2NHS(O)2CH3, —CH2NHS(O)2phenyl, —NHC(O)CH3, —NHC(O)OCH3, —NHC(O)phenyl, —NHS(O)2CH3, —NHS(O)2phenyl, —CH≡CHphenyl, cyclopropyl, cyclopentenyl, benzyl, phenyl optionally sub with 1, 2 or 3 substituents R82, pyridine optionally substituted with 1 fluoro, pyrimidine, pyrazine, pyridazine, pyrazole, thiazole, oxazole, thiophene optionally substituted with 1 chloro, pyrrolidine, oxazolidinone, pyrrolidinone, dihydropyran, tetrahydropyran, morpholine, 4-methyl-piperazine, pyrrolidine-dione, pyridinone, isoquinoline, or quinoline;
R80 at each occurrence is independently —C(O)NH2, fluoro, chloro, cyano, pyrazole, triazole, pyridine or pyrimidine;
R81 is methyl or 2-(trimethylsilyl)ethoxy)methyl, cyclopropyl, or —CH2-cyclopropyl; and
R82 at each occurrence is independently selected from the group consisting of fluoro, chloro, bromo, —S(O)2CH3, —OCF3, —CF3, —CN, pyridine, triazole, and pyrazole.

### Claim 8 (depends on 7)

The compound of claim 7, wherein the compound has a structure selected from the group consisting of Formula (XVa), Formula (XVb), Formula (XVc), Formula (XVd), and Formula (XVe),
or a salt thereof, wherein:
C is pyrazole, wherein R81 is bound to either of the nitrogens in the pyrazole ring;
Y is O or N—CH3; and
X1, A3, R74, R75, R76, R78, R79, R80 and R81 are as defined for claim 7.

### Claim 9 (depends on 8)

The compound of claim 8, wherein the compound has a structure selected from the group consisting of Formula (XVIa), Formula (XVIb), Formula (XVIc), Formula (XVId), and Formula (XVIe),
or a salt thereof, wherein:
X2 is C or N and the dashed line represents a single or double bond;
Y is O or N—CH3;
A4 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyridin-2-one, pyridin-4-imine, pyrazol-1-yl, pyrazol-4-yl, imidazol-1-yl, thiazol-5-yl, isothiazol-4-yl, isoxazol-4-yl, 1,2,4-triazol-1-yl, 1,2,3-thiadiazol-5-yl, indol-1-yl, indol-2-yl, indol-7-yl, piperazin-1-yl, 4,5-dihydro-1H-imidazol-1-yl;
B is selected from the group consisting of phenyl optionally substituted with 1, 2, or 3 substituents R89, pyridin-2-yl, 5-fluoro-pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, pyridazin-3-yl, pyrazol-1-yl, pyrazol-5-yl, pyrazol-4-yl, thiazol-2-yl, thiazol-4-yl, oxazol-2-yl, pyrrolidin-1-yl, oxazolidin-2-on-3-yl, 2-oxopyrrolidin-1-yl, tetrahydro-2H-pyran-4-yl, morpholin-4-yl, 4-methyl-piperazin-1-yl, quinolin-5-yl, and quinolin-3-yl;
C is pyrazole, wherein R88 is bound to either of the nitrogens in the pyrazole ring;
R83 is —CD3 or —CH3;
R84 is —CD2CD3 or —CH2CH3;
R85 is hydrogen, —CH3, —Br, —CN, or —NH2;
R86 is hydrogen, —F, —Cl, —C(O)NH2, or —CN;
R87 is hydrogen, —F, —Cl, —C(O)NH2, or —CN;
R88 is hydrogen, methyl, cyclopropyl, or —CH2-cyclopropyl; and
R89 at each occurrence is independently selected from the group consisting of fluoro, chloro, bromo, —S(O)2CH3, —OCF3, —CF3; —CN, pyridine, triazole, and pyrazole.

### Claim 10 (depends on 8)

The compound of claim 8, wherein the compound is selected from the group consisting of:
(7R)-7-ethyl-5-methyl-8-(tetrahydrofuran-3-yl)-2-(5-(thiazol-2-yl)-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-2-(2-(4-fluorophenyl)-1H-imidazol-1-yl)-5-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-2-(2-(4-fluorophenyl)-1H-imidazol-1-yl)-5-methyl-8-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-(2-phenyl-1H-imidazol-1-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-(1-methyl-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-2-(3-(2,4-difluorophenyl)-1H-pyrazol-4-yl)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-3-yl)-2-(1-methyl-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-3-yl)-2-(1-methyl-5-(thiazol-2-yl)-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-3-yl)-2-(3-phenylpyridin-4-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-3-yl)-2-(2-phenylpyridin-3-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-(2-phenylpyridin-3-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-4-yl)-2-(3-phenylpyridin-4-yl)-7,8-dihydropteridin-6(5H)-one,
(R)-7-ethyl-5-methyl-8-(1-methyl-1H-pyrazol-3-yl)-2-(2-phenyl-1H-imidazol-1-yl)-7,8-dihydropteridin-6(5H)-one,
(7R)-7-ethyl-5-methyl-2-(1-methyl-3-(thiazol-2-yl)-1H-pyrazol-4-yl)-8-(tetrahydrofuran-3-yl)-7,8-dihydropteridin-6(5H)-one, and
(7R)-7-ethyl-5-methyl-2-(1-methyl-5-(thiazol-2-yl)-1H-pyrazol-4-yl)-8-(tetrahydrofuran-3-yl)-7,8-dihydropteridin-6(5H)-one,
or a salt thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 6)

A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 7)

A pharmaceutical composition comprising a compound according to claim 7 and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 8)

A pharmaceutical composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier.