IP Library › Granted Patent US 9,029,409

Granted Patent B2

US 9,029,409 · App. 13/460,158 · Granted May 12, 2015

Isoxazolines as therapeutic agents

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Patent No.: US 9,029,409
App. No.: 13/460,158
Granted: May 12, 2015
Kind: B2

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Abstract

The present invention provides compound of Formula (I) biologically active metabolites, pro-drugs, isomers, stereoisomers, solvates, hydrates and pharmaceutically acceptable salts thereof wherein the variables are defined herein. The compounds of the invention are useful for treating immunological conditions.

Claims (468)

1. A compound of Formula (I)

stereoisomers, and pharmaceutically acceptable salts thereof wherein

A is

X is phenyl, benzo[1,4]oxazin-3-onyl, benzoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzo furanyl, pyrazinonyl, pyridinyl, pyridonyl, or quinolinyl, each of which is optionally substituted with one or more substituents independently selected from Br, Cl, F, CF 3 , CN, COOH, OCF 3 , OH, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy;

Y is pyridazinonyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted by one or more substituents independently selected from CF 3 , halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy,

Z is —C(O)NH 2 , CN, —C(O)-morpholinyl, —C(O)-pyrrolidinyl, —C(O)—N(H)CH 2 CH 2 OH, (C 3 -C 6 )cycloalkyl, 1,4-dioxanyl, imidazolyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyrazolo[3,4-b]pyridinyl, pyridazinyl, pyridazinonyl, pyridinyl, pyridonyl, pyrimidinyl, pyrrolidinyl, tetrahydropyranyl, tetrazolyl, or thienyl, each of which is optionally substituted by one or more substituents independently selected from Br, Cl, F, CF 3 , CN, —C(O)OH, —C(O)OCH 3 , —C(O)CH 3 , —C(O)CH 2 OC(O)CH 3 , —C(O)C(CH 3 ) 3 , —C(O)C(H)(CH 3 ) 2 , —C(O)CH 2 CN, —C(O)CH 2 OH, —C(O)CH 2 OCH 3 , —C(O)CH 2 CH 2 N(CH 3 ) 2 , —C(O)C(CH 3 ) 2 OH, —C(O)OC(CH 3 ) 3 , —C(O)N(H)CH 2 CH 3 , —C(O)CH 2 N(CH 3 ) 2 , —C(O)CH 2 N(H)S(O) 2 CH 3 , —C(O)CH 2 N(H)C(O)CH 3 , —C(O)CH 2 N(H)C(O)N(H)CH 3 , —C(O)CH 2 OCH 3 , —C(O)CH 2 S(O) 2 CH 3 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —C(O)N(H)CH 3 , —C(O)N(H)CH 2 CH 3 , —C(O)N(H)CH(CH 3 ) 2 , —C(O)N(H)CH 2 CH 2 OH, —C(O)N(H)-isoxazolyl, —C(O)N(H)thiazolyl, —C(O)N(CH 3 )CH 2 CH 2 OH, —C(O)-cyclopropyl, —C(O)-cyclobutyl, —OCH 2 CH 2 OH, —OC(CH 3 ) 3 , —NH 2 , —N(CH 3 ) 2 , —N(H)C(O)CH 3 —, —N(H)C(O)CH 2 OH, —N(H)C(O)CH 2 CN, —N(H)C(O)C(CH 3 ) 2 OH, —N(H)C(O)C(H)(OH)CH 3 , —N(H)C(O)CH 2 N(CH 3 ) 2 , —N(H)C(O)CH 2 N(H)CH 3 , —N(H)C(O)(OH)CH 3 , —N(R c )C(O)N(R c )(R c ), —N(H)C(O)N(CH 3 ) 2 , —N(H)C(O)N(H)CH 3 —N(H)C(O)N(H)CH 2 CH 2 OH, —N(H)C(O)N(H)C(H)(CH 2 OH) 2 , —N(H)C(O)N(CH 3 )CH 2 CH 2 OH, —N(H)C(O)N(CH 3 )CH 2 C(H)(OH)CH 2 OH, —N(H)C(O)O(CH 3 ) 3 , —N(H)S(O) 2 NH 2 , —N(H)S(O) 2 CH 3 , —N(R c )S(O) 2 N(R c )(R c ), —NO 2 , 1,2,4-oxadiazolyl, oxo, —OH, —S(O) 2 (R c ), —S(O)CH 3 , —S(O)CH 2 CH 3 , —S(O)CH 2 CH 2 CH 3 , —S(O) 2 C(H)(CH 3 ) 2 , —S(O) 2 cyclopropyl, —S(O) 2 -imidazolyl, —S(O) 2 -isoxazolyl, —CH 2 CN, —CH 2 C(O)N(H)CH 3 , —CH 2 C(O)N(H)-cyclopropyl, —CH 2 OCH 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 OS(O) 2 -phenyl, —C(CH 3 )OH, —C(H)(CH 2 ) 2 OH, —CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —CH 2 N(H)C(O)CH 3 , —CH 2 N(H)C(O)C(H)(OH)CH 3 , —CH 2 N(H)C(O)CH 2 CN, —CH 2 N(H)C(O)CH 2 OH, —CH 2 N(H)C(O)C(CH 3 ) 2 OH, —CH 2 N(H)C(O)N(H)CH 3 , —CH 2 N(H)C(O)N(CH 3 ) 2 , —CH 2 S(O) 2 CH 3 , —CH 2 -morpholinyl, —CH 2 -thiomorpholinyl, —CH 2 -thiomorpholinyl 1,1-dioxide, morpholinyl, oxadiazolyl, oxazolyl, piperidinyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl;

R c is independently H, (C 1 -C 3 )alkyl or (C 3 -C 6 )cycloalkyl;

R e is H, —C(O)R c , (C 1 -C 6 )alkyl, (C 1 -C 6 )hydroxyalkyl, (C 3 -C 6 )cycloalkyl, heteroaryl optionally substituted with (C 1 -C 3 )alkyl, or heterocyclyl; or

R a is independently H, (C 1 -C 3 )alkyl or (C 3 -C 6 )cycloalkyl,

R b is independently H, CF 3 , (C 1 -C 3 )alkyl or (C 3 -C 6 )cycloalkyl;

R 1 is independently Br, Cl, F, (C 1 -C 3 )alkyl or (C 3 -C 6 )cycloalkyl;

m is 0, 1 or 2;

n is 0; and

p is 0 or 1.

2. The compound of claim 1 wherein p is 0.

3. The compound of claim 2 wherein X is phenyl, benzo[1,4]oxazin-3-onyl, benzoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzo furanyl, pyrazinonyl, pyridinyl, or pyridonyl, each of which is optionally substituted with one or more substituents independently selected from Br, Cl, F, CF 3 , OCF 3 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy.

4. The compound of claim 3 wherein Y is pyrimidinyl optionally substituted by one or more substituents independently selected from CF 3 , or (C 1 -C 6 )alkyl.

5. The compound of claim 4 wherein Z is (C 3 -C 6 )cycloalkyl, 1,4-dioxanyl, morpholinyl, phenyl, piperidinyl, pyrazolyl, pyridazinyl, pyridazinonyl, pyridinyl, pyridonyl, pyrimidinyl, tetrahydropyranyl, tetrazolyl, or thienyl, each of which is optionally substituted by one or more substituents independently selected from Br, Cl, F, CF 3 , CH 3 , CN, —C(O)OH, —C(O)OCH 3 , —C(O)CH 3 , —C(O)CH 2 OC(O)CH 3 , —C(O)C(CH 3 ) 3 , —C(O)C(H)(CH 3 ) 2 , —C(O)CH 2 CN, —C(O)CH 2 OH, —C(O)CH 2 OCH 3 , —C(O)CH 2 CH 2 N(CH 3 ) 2 , —C(O)C(CH 3 ) 2 OH, —C(O)OC(CH 3 ) 3 , —C(O)N(H)CH 2 CH 3 , —C(O)CH 2 N(CH 3 ) 2 , —C(O)CH 2 N(H)S(O) 2 CH 3 , —C(O)CH 2 N(H)C(O)CH 3 , —C(O)CH 2 N(H)C(O)N(H)CH 3 , —C(O)CH 2 S(O) 2 CH 3 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —C(O)N(H)CH 3 , —C(O)N(H)CH 2 CH 3 , —C(O)N(H)CH(CH 3 ) 2 , —C(O)N(H)CH 2 CH 2 OH, —C(O)N(H)-isoxazolyl, —C(O)N(H)thiazolyl, —C(O)N(CH 3 )CH 2 CH 2 OH, —C(O)-cyclopropyl, —C(O)-cyclobutyl, —OCH 3 , —OCH 2 CH 2 OH, —OC(CH 3 ) 3 , —NH 2 , —N(CH 3 ) 2 , —N(H)C(O)CH 3 —, —N(H)C(O)CH 2 OH, —N(H)C(O)CH 2 CN, —N(H)C(O)C(CH 3 ) 2 OH, —N(H)C(O)C(H)(OH)CH 3 , —N(H)C(O)CH 2 N(CH 3 ) 2 , —N(H)C(O)CH 2 N(H)CH 3 , —N(H)C(O)(OH)CH 3 , —N(H)C(O)N(CH 3 ) 2 , —N(H)C(O)N(H)CH 3 —N(H)C(O)N(H)CH 2 CH 2 OH, —N(H)C(O)N(H)C(H)(CH 2 OH) 2 , —N(H)C(O)N(CH 3 )CH 2 CH 2 OH, —N(H)C(O)N(CH 3 )CH 2 C(H)(OH)CH 2 OH, —N(H)C(O)O(CH 3 ) 3 , —N(H)S(O) 2 NH 2 , —N(H)S(O) 2 CH 3 , —NO 2 , 1,2,4-oxadiazolyl, oxo, —OH, —S(O)CH 3 , —S(O)CH 2 CH 3 , —S(O)CH 2 CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 C(H)(CH 3 ) 2 , —S(O) 2 cyclopropyl, —S(O) 2 -imidazolyl, —S(O) 2 -isoxazolyl, —CH 2 CN, —CH 2 C(O)N(H)CH 3 , —CH 2 C(O)N(H)-cyclopropyl, —CH 2 OCH 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 OS(O) 2 -phenyl, —C(CH 3 ) 2 OH, —C(H)(CH 2 ) 2 OH, —CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —CH 2 N(H)C(O)CH 3 , —CH 2 N(H)S(O) 2 CH 3 , —CH 2 N(H)C(O)C(H)(OH)CH 3 , —CH 2 N(H)C(O)CH 2 CN, —CH 2 N(H)C(O)CH 2 OH, —CH 2 N(H)C(O)C(CH 3 ) 2 OH, —CH 2 N(H)C(O)N(H)CH 3 , —CH 2 N(H)C(O)N(CH 3 ) 2 , —CH 2 S(O) 2 CH 3 , —CH 2 -morpholinyl, —CH 2 -thiomorpholinyl, —CH 2 -thiomorpholinyl 1,1-dioxide, morpholinyl, oxadiazolyl, oxazolyl, piperidinyl, or (C 3 -C 6 )cycloalkyl.

6. The compound of claim 5 , wherein

X is phenyl, benzo[1,4]oxazin-3-onyl, benzoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzo furanyl, pyrazinonyl, or pyridinyl, each of which is optionally substituted with one or more substituents independently selected from Br, Cl, F, CF 3 , OCF 3 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy;

Y is 2-methylpyrimidinyl; and

Z is cyclohexyl, 1,4-dioxanyl, phenyl, pyridonyl, piperidinyl, or pyridinyl, each of which is optionally substituted by one or more substituents independently selected from Br, Cl, F, CF 3 , CH 3 , CN, —C(O)OH, —C(O)OCH 3 , —C(O)CH 3 , —C(O)CH 2 OC(O)CH 3 , —C(O)C(CH 3 ) 3 , —C(O)C(H)(CH 3 ) 2 , —C(O)CH 2 CN, —C(O)CH 2 OH, —C(O)CH 2 OCH 3 , —C(O)CH 2 CH 2 N(CH 3 ) 2 , —C(O)C(CH 3 ) 2 OH, —C(O)OC(CH 3 ) 3 , —C(O)N(H)CH 2 CH 3 , —C(O)CH 2 N(CH 3 ) 2 , —C(O)CH 2 N(H)S(O) 2 CH 3 , —C(O)CH 2 N(H)C(O)CH 3 , —C(O)CH 2 N(H)C(O)N(H)CH 3 , —C(O)CH 2 S(O) 2 CH 3 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —C(O)N(H)CH 3 , —C(O)N(H)CH 2 CH 3 , —C(O)N(H)CH(CH 3 ) 2 , —C(O)N(H)CH 2 CH 2 OH, —C(O)N(H)-isoxazolyl, —C(O)N(H)thiazolyl, —C(O)N(CH 3 )CH 2 CH 2 OH, —C(O)-cyclopropyl, —C(O)-cyclobutyl, —OCH 3 , —OCH 2 CH 2 OH, —OC(CH 3 ) 3 , —NH 2 , —N(CH 3 ) 2 , —N(H)C(O)CH 3 —, —N(H)C(O)CH 2 OH, —N(H)C(O)CH 2 CN, —N(H)C(O)C(CH 3 ) 2 OH, —N(H)C(O)C(H)(OH)CH 3 , —N(H)C(O)CH 2 N(CH 3 ) 2 , —N(H)C(O)CH 2 N(H)CH 3 , —N(H)C(O)(OH)CH 3 , —N(H)C(O)N(CH 3 ) 2 , —N(H)C(O)N(H)CH 3 —N(H)C(O)N(H)CH 2 CH 2 OH, —N(H)C(O)N(H)C(H)(CH 2 OH) 2 , —N(H)C(O)N(CH 3 )CH 2 CH 2 OH, —N(H)C(O)N(CH 3 )CH 2 C(H)(OH)CH 2 OH, —N(H)C(O)O(CH 3 ) 3 , —N(H)S(O) 2 NH 2 , —N(H)S(O) 2 CH 3 , —NO 2 , 1,2,4-oxadiazolyl, oxo, —OH, —S(O)CH 3 , —S(O)CH 2 CH 3 , —S(O)CH 2 CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 C(H)(CH 3 ) 2 , —S(O) 2 cyclopropyl, —S(O) 2 -imidazolyl, —S(O) 2 -isoxazolyl, —CH 2 CN, —CH 2 C(O)N(H)CH 3 , —CH 2 C(O)N(H)-cyclopropyl, —CH 2 OCH 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 OS(O) 2 -phenyl, —C(CH 3 ) 2 OH, —C(H)(CH 2 ) 2 OH, —CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —CH 2 N(H)C(O)CH 3 , —CH 2 N(H)S(O) 2 CH 3 , —CH 2 N(H)C(O)C(H)(OH)CH 3 , —CH 2 N(H)C(O)CH 2 CN, —CH 2 N(H)C(O)CH 2 OH, —CH 2 N(H)C(O)C(CH 3 ) 2 OH, —CH 2 N(H)C(O)N(H)CH 3 , —CH 2 N(H)C(O)N(CH 3 ) 2 , —CH 2 S(O) 2 CH 3 , —CH 2 -morpholinyl, —CH 2 -thiomorpholinyl, —CH 2 -thiomorpholinyl 1,1-dioxide, morpholinyl, oxadiazolyl, oxazolyl, piperidinyl, or (C 3 -C 6 )cycloalkyl.

7. A compound selected from the group consisting of:

6-(5-(1-Acetylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(methylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((5)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-Fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-(4-Carbamoylphenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(morpholine-4-carbonyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-(2H-tetrazol-5-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride;

6-(5-(1-(ethylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(cyclopropanecarbonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(2-acetamidoacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(2-cyanoacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(methylsulfonyl)acetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-hydroxy ethyl carbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(isoxazol-3-ylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(methylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(cyanomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-((S)-5-((2R,5S)-5-((methylsulfonyl)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

(2S,5R)-5-((S)-3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxane-2-carboxylic acid;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(morpholinomethyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-((S)-5-((2R,5S)-5-Carbamoyl-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1H-imidazol-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(4-(2-hydroxyethoxy)phenyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

6-(5-(4-(2-hydroxyethoxy)phenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-methoxybenzyl)-2-methyl-6-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(4-(hydroxymethyl)phenyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-methoxybenzyl)-6-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-methoxybenzyl)-2-methyl-6-(5-(4-morpholinophenyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-methoxybenzyl)-2-methyl-6-(5-(4-(piperidin-1-yl)phenyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(4-(dimethylamino)phenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(3-(2-hydroxyethoxy)phenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-methoxybenzyl)-2-methyl-6-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-cyclohexyl-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(4-(hydroxymethyl)phenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(4-carbamoylphenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-cyclohexyl-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-acetylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(4-hydroxycyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

tert-butyl 4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(pyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(4-(hydroxymethyl)phenyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidin-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(4-(morpholinomethyl)phenyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-cyano-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(4-(thiomorpholinomethyl)phenyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-cyano-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(3-carbamoylphenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(3-(morpholinomethyl)phenyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(3-(methylcarbamoyl)phenyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

methyl 4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoate;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(4-(methylcarbamoyl)phenyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(thiophen-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(pyridin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-{5-[4-(1,1,1,-Dioxo-thiomorpholine-4-ylmethyl)phenyl]-4,5-dihydro-isoxazol-3-yl}-2-methyl pyrimidine-4-carboxylate;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-Fluoro-3-methoxybenzyl)-6-((S)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydro-isoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-(2-cyanoacetamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-((1r,4r)-4-(sulfamoylamino)cyclohexyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-yl)pyrimidine-4-carboxamide;

6-(3-(4-(2-hydroxyethoxy)phenyl)-4,5-dihydroisoxazol-5-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(3-phenyl-4,5-dihydroisoxazol-5-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(3-(4-(2-hydroxyethoxy)phenyl)-4,5-dihydroisoxazol-5-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-methoxybenzyl)-2-methyl-6-(3-phenyl-4,5-dihydroisoxazol-5-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(4-(2-hydroxyethylcarbamoyl)phenyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1-acetylpiperidin-4-yl)methyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(pyrimidin-5-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(4-(2-hydroxypropan-2-yl)phenyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-((1-(2-hydroxyacetyl)piperidin-4-yl)methyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-((1-(methylsulfonyl)piperidin-4-yl)methyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(2-carbamoylpyridin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1H-pyrazol-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-((R)-5-((1r,4R)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-((R)-5-((1r,4R)-4-(methylsulfonamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((1r,4R)-4-(2-hydroxyacetamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(pyrimidin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-Fluoro-3-methoxybenzyl)-2-methyl-6-(5-((1r,4r)-4-(methylsulfonamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-Fluoro-3-methoxybenzyl)-6-(5-((1r,4r)-4-(2-hydroxyacetamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-2-methyl-6-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(1-acetylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methylbenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-2-methyl-6-(5-(1-(methylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-6-(5-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(pyrazin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(3,4-difluorobenzyl)-2-methyl-6-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(1-acetylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(3,4-difluorobenzyl)-2-methylpyrimidine-4-carboxamide;

N-(3,4-difluorobenzyl)-2-methyl-6-(5-(1-(methylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(3,4-difluorobenzyl)-6-(5-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(ethylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-isobutyrylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(propylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-2-methyl-6-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(1-acetylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(3-chloro-4-fluorobenzyl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-(5-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-methoxybenzyl)-2-methyl-6-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(1-acetylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluorobenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-2-methyl-6-(5-(1-(methylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-6-(5-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-acetylpiperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(3-methoxybenzyl)-2-methyl-6-(5-(1-(methylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(cyclopropanecarbonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(dimethylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(ethylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(2-acetamidoacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(isopropylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(2-cyanoacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-methoxyacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(cyclobutanecarbonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(methylsulfonamido)acetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(5-cyanopyridin-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(5-(hydroxymethyl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(5-(methylcarbamoyl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-hydroxyethylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(3-methylureido)acetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(5-(1-hydroxyethyl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-hydroxyethyl)(methyl)carbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(isopropylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(1-methyl-1H-imidazol-2-ylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(1-methyl-1H-imidazol-4-ylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(1-(1,2-dimethyl-1H-imidazol-4-ylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(3,5-dimethylisoxazol-4-ylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(5-(methylsulfonyl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(5-acetylpyridin-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

((2S,5R)-5-(3-(6-(3-chloro-4-fluorobenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate;

N-(3-chloro-4-fluorobenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

((2S,5R)-5-((S)-3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate;

methyl 4-(3-(2-(3-methoxybenzylcarbamoyl)pyridin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoate;

N-(3-methoxybenzyl)-4-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-yl)picolinamide;

4-(5-(4-chlorophenyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-N-(3-methoxybenzyl)picolinamide;

4-(3-(2-(3-methoxybenzylcarbamoyl)pyridin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoic acid;

4-(5-(4-((dimethylamino)methyl)phenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)picolinamide;

4-(3-(2-(4-methoxybenzylcarbamoyl)pyridin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoic acid;

4-(5-(4-chlorophenyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)picolinamide;

N-(4-methoxybenzyl)-4-(5-(pyrazin-2-yl)-4,5-dihydroisoxazol-3-yl)picolinamide;

N-(4-methoxybenzyl)-4-(5-(4-methoxyphenyl)-4,5-dihydroisoxazol-3-yl)picolinamide;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-((R)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-6-((R)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-6-((S)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-((R)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-((R)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-((S)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(acetamidomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-((S)-5-((2R,5R)-5-(methylsulfonamidomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5)-5-((2R,5S)-5-(methylsulfonylmethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(thiazol-2-ylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-(Acetamidomethyl)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-((R)-5-((1r,4R)-4-(acetamidomethyl)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(5-(oxazol-5-yl)pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(6-(methylsulfonyl)pyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(6-acetylpyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)pyridazine-3-carboxamide 2,2,2-trifluoroacetate;

6-(5-(6-cyanopyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((1r,4R)-4-((2-hydroxyacetamido)methyl)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-((1r,4r)-4-((2-hydroxyacetamido)methyl)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(3-carbamoyl-1-methyl-1H-pyrazol-5-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1r,4r)-4((2-cyanoacetamido)methyl)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-N-methylpyridazine-3-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-((2-hydroxyacetamido)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(6-(oxazol-5-yl)pyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-6-((R)-5-((2R,5R)-5-(hydroxy methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(6-(hydroxymethyl)pyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-((1r,4r)-4-(3-(2-hydroxyethyl)ureido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-((1r,4r)-4-(3-(2-hydroxyethyl)-3-methylureido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(5-(methylsulfonyl)pyrazin-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(6-cyanopyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(3-(dimethylamino)propanoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-6-((5)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3,4-difluorobenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3,4-difluorobenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

5S)-5-((S)-3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-1,4-dioxane-2-carboxylic acid;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-((1r,4r)-4-(3-methylureido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-(3,3-dimethylureido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(3,4-dichlorobenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3,4-dichlorobenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-((2-cyanoacetamido)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-((2-hydroxy-2-methylpropanamido)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-((S)-5-((2R,5R)-5-((3-methylureido)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6((S)-5-((2R,5R)-5-((3,3-dimethylureido)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(pyrrolidine-1-carbonyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-(2-(dimethylamino)acetamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1H-pyrazolo[3,4-b]pyridin-5-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(bromomethyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-N-(2-hydroxyethyl)-4,5-dihydroisoxazole-5-carboxamide;

3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazole-5-carboxamide;

methyl 3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazole-5-carboxylate;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5S)-5-(2-hydroxypropan-2-yl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-((S)-5-((2R,5S)-5-(methylcarbamoyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-((1r,4r)-4-(methylcarbamoyl)cyclohexyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

6-(5-((1r,4r)-4-carbamoylcyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-((1r,4r)-4-(2-hydroxy-2-methylpropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-((4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-((3-(hydroxymethyl)pyrrolidin-1-yl)methyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

6-(5-((4-acetylpiperazin-1-yl)methyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

6-(5-(6-(dimethylamino)pyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(6-(pyrrolidin-1-yl)pyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

6-(5-((1r,4r)-4-(3-(1,3-dihydroxypropan-2-yl)ureido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-((1r,4r)-4-((2-hydroxyethyl)carbamoyl)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-(3-(2,3-dihydroxypropyl)-3-methylureido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-Acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methylbenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(6-cyanopyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methylbenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-((1r,4r)-4-(2-(methylamino)acetamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-2-methyl-6-((S)-5-((2R,5S)-5-((methylsulfonyl)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(acetamidomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methylbenzyl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(acetamidomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(3-chloro-4-fluorobenzyl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-2-methyl-6-((S)-5-((2R,5S)-5-((methylsulfonyl)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(3-methylbenzyl)pyrimidine-4-carboxamide;

6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(3-methylbenzyl)pyrimidine-4-carboxamide;

6-(5-(6-cyanopyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluorobenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

N-(3-chloro-4-fluorobenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(3,4-difluorobenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(6-cyanopyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(3,4-difluorobenzyl)-2-methylpyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

N-(3-chloro-4-fluorobenzyl)-6-(5-(6-cyanopyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(3-chloro-4-fluorobenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluorobenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(3,4-difluorobenzyl)-2-methylpyrimidine-4-carboxamide;

N-((2,3-dihydrobenzofuran-5-yl)methyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-fluorobenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-fluorobenzyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((2-methylbenzo[d]oxazol-5-yl)methyl)pyrimidine-4-carboxamide;

6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((2-methylbenzo[d]oxazol-5-yl)methyl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((5)-5-((2R,5R)-5-(methoxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((2R,5R)-5-(methoxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-(((S)-2-hydroxypropanamido)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(3,4-difluorobenzyl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-(5-((1S,4r)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)pyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-(5-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

tert-butyl ((1r,4r)-4-(3-(6-((4-fluoro-3-methoxybenzyl)carbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)cyclohexyl)carbamate;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(methylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(pyridin-4-ylmethyl)pyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(pyridin-4-ylmethyl)pyrimidine-4-carboxamide;

6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(pyridin-4-ylmethyl)pyrimidine-4-carboxamide;

6 6-(5-((1r,4r)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)pyrimidine-4-carboxamide;

N—((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)-2-methyl-6-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N—((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)-2-methyl-6-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyrimidine-4-carboxamide;

6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)pyrimidine-4-carboxamide;

6-(5-((1r,4r)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(quinolin-4-ylmethyl)pyrimidine-4-carboxamide;

(S)—N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-((S)-5-((1r,4S)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methylbenzyl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(quinolin-4-ylmethyl)pyrimidine-4-carboxamide;

6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(quinolin-4-ylmethyl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-((2-hydroxy-2-methylpropanamido)methyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(acetamidomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(3-chloro-4-fluorobenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(6-cyanopyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(3,4-difluorobenzyl)-2-methylpyrimidine-4-carboxamide 2,2,2-trifluoroacetate;

6-((S)-5-((1r,4S)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-meth ylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((1S,4S)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((1S,4R)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-Fluorobenzyl)-6-(5-((1S,4r)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-6-((S)-5-((1S,4S)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methylbenzyl)-6-((R)-5-((1S,4R)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-((S)-5-((1S,4S)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-((R)-5-((1S,4R)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-((2-oxo-1,2,3,4,4a,8a-hexahydroquinolin-7-yl)methyl)pyrimidine-4-carboxamide;

6-((R)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(3,4-difluorobenzyl)-2-methyl-6-(5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

(S)—N-(3,4-difluorobenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

(R)—N-(3,4-difluorobenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(6-methoxypyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

(S)—N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(methylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

(R)—N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(methylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-(methoxy(methylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-(5-chloro-1-(2-(methylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(6-methoxy-5,6-dihydropyridin-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-(2-(dimethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-((S)-5-((1s,4R)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)pyrimidine-4-carboxamide;

6-((R)-5-((1r,4R)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(methylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-(isopropylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-(5-((1S,4r)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)pyrimidine-4-carboxamide;

6-(5-(3-chloro-5-cyclopropyl-4-oxocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

(S)-6-(5-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

(R)-6-(5-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

(R)-6-(5-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

6-(5-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)pyrimidine-4-carboxamide;

6-(5-(1-(2-(cyclopropylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-1-methyl-6-oxo-5-(5-phenyl-4,5-dihydroisoxazol-3-yl)-1,6-dihydropyridazine-3-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(1-methoxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide; and

N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-(isopropylamino)allyl)-2-oxo-1,2-dihydropyridin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide; or

a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 wherein the compound is

N-(4-Fluoro-3-methoxybenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((S)-5-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

6-((R)-5-((1r,4R)-4-acetamidocyclohexyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-6-((R)-5-((1r,4R)-4-(2-hydroxyacetamido)cyclohexyl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(3-chloro-4-fluorobenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-6-((S)-5-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;

N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-((S)-5-((2R,5S)-5-(methylsulfonylmethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide;