HK1213560B

HK1213560B - C-linked heterocycloalkyl substituted pyrimidines and their uses

Info

Publication number: HK1213560B
Application number: HK16101494.1A
Authority: HK
Inventors: 弗雷德里克．科恩; 斯纳赫尔．帕特尔
Original assignee: 豪夫迈‧罗氏有限公司
Priority date: 2013-05-01
Filing date: 2014-04-29
Publication date: 2019-06-14

Description

C-linked heterocycloalkyl substituted pyrimidines and their use

Technical Field

The present invention relates to organic compounds useful for therapy and/or prophylaxis in mammals, and in particular to DLK inhibitors useful for the treatment of neurodegenerative diseases and disorders.

Background

Neuronal or axonal degeneration plays a key role in the normal development of the nervous system and is a hallmark of many neurodegenerative diseases including, for example, Amyotrophic Lateral Sclerosis (ALS), glaucoma (glaucomia), Alzheimer's disease, and Parkinson's disease, as well as traumatic injuries to the brain and spinal cord. A recent patent publication WO2011/050192 (incorporated herein by reference) describes the role of dual leucine zipper kinase (DLK), also known as MAP3K12, in neuronal cell death. Neurodegenerative diseases and injuries are devastating to patients and caregivers, and also result in a significant financial burden, currently costing more than billions of dollars per year in the united states alone. The latest treatments for these diseases and conditions are inadequate. The urgency of the problems arising from these diseases is increased by the fact that: many of these diseases are age-related and thus their incidence increases rapidly with demographic changes. There is a great need to develop effective methods to treat neurodegenerative diseases and nervous system injuries, including, for example, by inhibitors of DLK in neurons.

Summary of The Invention

In one aspect, the present invention provides compounds of formula I and formula I-I and embodiments thereof. In the compounds of the formula I-I

R1 is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, 3-10 membered cycloalkylA 3-10 membered heterocycloalkyl, a 6-10 membered aryl, a 5-10 membered heteroaryl, -OR1a, -SR1a, -N (H) (R1a), and-N (R1a) (R1b), wherein R1a and R1b are each independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, and wherein the aliphatic and aromatic moieties of R1 are independently further substituted with 0 to 5 RA1 substituents selected from the group consisting of: -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-4 alkyl, C1-4 haloalkyl, C1-4 heteroalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 dialkylamino, R1C-C (═ O) -, R1C-C (═ O) N (H) -, R1C-C (═ O) N (R1d) -, R1C-C (═ O) O-, R1C-S (O)1-2-, R1C-S (O)1-2N (R1d) -, R1C-S (O)1-2N (H) -, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl, wherein R1c is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C5-6 heteroaryl, 3-7 membered heterocycloalkyl, phenyl and 3-6 membered cycloalkyl, R1d is selected from the group consisting of: hydrogen, C1-3 alkyl and C1-3 haloalkyl, and wherein the 5-6 membered heteroaryl, phenyl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl of the RA1 substituent are substituted with 0-4 substituents selected from: -F, -Cl, -Br, I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino and C1-4 dialkylamino; r2 is selected from the group consisting of: hydrogen, C1-6 alkyl and C1-6 haloalkyl; r3 is selected from the group consisting of: -F, -Cl, -Br, -I, - (X3)0-1-CN, - (X3)0-1-NO2, - (X3)0-1-SF5, - (X3)0-1-OH, - (X3)0-1-NH2, - (X3)0-1-N (H) (R3a), - (X3)0-1-N (R3b) (R3a), - (X3)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, - (X3)0-1-3-7 membered cycloalkyl, - (X3)0-1-3-7 membered heterocycloalkyl, - (X3)0-1-5-6 membered heteroaryl, - (X3) 0-1-C3 aryl, - (X3)0-1-C (═ Y3) N (H) (R3 3), - (X3)0-1-C (═ Y3) NH 3, - (X3)0-1-C (═ Y3) N (R3 3), - (X3)0-1-C (═ Y3) OR 33, - (X3)0-1-C (═ Y3) OH, - (X3)0-1-N (H) C (═ Y3) (R3 3), - (X3)0-1-N (R3 3) C (═ Y3) (R3 3), X3)0-1-N (H) C (═ Y3) OR 3) OR 0-1-N (R3) C (═ Y3) R3) X3) OR (3) X3) N (3) R3) N (3) 3), - (X3)0-1-N (H) S (O)1-2R3a, - (X3)0-1-N (R3b) S (O)1-2R3a, - (X3)0-1-S (O)0-1N (H) (R3a), - (X3)0-1-S (O)0-1N (R3b) (R3a), - (X3)0-1-S (O)0-1NH2, - (X4)0-1-S (═ O) (═ NR3b) R3a, - (X a) 0-1-C (═ Y a) H, - (X a) 0-1-C (═ NOH) R3a, - (X a) 0-1-C (═ NOR 3) R3R a, - (X a) 0-1-NHC (═ NHC) (NHC) R3-a, - (NHC (a) X a) 0-a, - (NHC (a) X a) N (NHC) (a) X a) N3-a, - (a) N a) 0-1-3-a, - (a), - (X3)0-1-NHC (═ Y3) N (R3b) (R3a), - (X a) 0-1-N (R3a) C (═ Y a) N (H) (R3a), - (X a) 0-1-N (R3a) C (═ Y a) NH a, - (X a) 0-1-OC (═ Y a) R3a, - (X a) 0-1-OC (═ Y a) H, - (X a) 0-1-OC (═ Y a) OR3a, - (X a) 0-1-OP (═ Y a) (OR3a), - (X a) -SC (═ Y a) OR3 OR a and- (X a) -SC (═ Y a) N (R3a) (R a), wherein X a is selected from the group consisting of: c1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene, R3a and R3b are each independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 3-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, C6 aryl, C6 aryl-C1-4 alkyl and benzyl; y3 is O, NR3d or S, wherein R3d is hydrogen or C1-6 alkyl; wherein the aliphatic or aromatic moiety of R3 is independently further substituted with 0 to 4 RA3 substituents selected from the group consisting of: -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C (═ O) N (H) (C1-6 alkyl), -C (═ O) N (C1-6 alkyl) 2, -C (═ O) NH2, -C (═ O) OC1-6 alkyl, -C (═ O) OH, -N (H) C (═ O) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) (C1-6 alkyl), -N (H) C (═ O) OC1-6 alkyl, -N (C1-6 alkyl) C (═ O) OC1-6 alkyl, -S (O)1-2C1-6 alkyl, -N (H) S (O)1-2C1-6 alkyl, -N (C1-6 alkyl) S (O)1-2C1-6 alkyl, -S (O)0-1N (H) (C1-6 alkyl), -S (O)0-1N (C1-6 alkyl) 2, -S (O)0-1NH2, -C (═ O) C1-6 alkyl, -C (═ NOH) C1-6 alkyl, -C (═ NOC1-6 alkyl) C1-6 alkyl, -NHC (═ O) N (H) (C1-6 alkyl), -NHC (═ O) N (C1-6 alkyl) 2, -NHC (═ O) NH2, -N (C1-6 alkyl) C (═ O) N (H) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) NH2, -OC (═ O) C1-6 alkyl, -OC (═ O) OC1-6 alkyl, -OP (═ O) (OC1-6 alkyl) 2, -SC (═ O) OC1-6 alkyl, and-SC (═ O) N (C1-6 alkyl) 2; prepare forOptionally, any two R3 substituents located on adjacent atoms are optionally combined to form a 5-6 membered heteroaryl ring, said 5-6 membered heteroaryl ring comprising 1-2 heteroatoms selected from N, O and S and further comprising 0 to 4R 3a substituents; m is an integer of 0 to 4; by structureThe ring represented is a4 to 10 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3R 4 groups; r4 is selected from the group consisting of: -F, -Cl, -Br, -I, - (X4)0-1-CN, - (X4)0-1-NO2, - (X4)0-1-SF5, - (X4)0-1-OH, - (X4)0-1-NH2, - (X4)0-1-N (H) (R4a), - (X4)0-1-N (R4b) (R4a), - (X4)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, - (X4)0-1- (3-10 membered heterocycloalkyl), - (X4)0-1- (5-10 membered heteroaryl), - (X4)0-1- (3-7 membered cycloalkyl), - (X4)0-1-C (═ Y4) N (H) (R4a), - (X a) 0-1-C (═ Y a) NH a, - (X a) 0-1-C (═ Y a) N (R4a), - (X a) 0-1-C (═ Y a) OR4a, - (X a) 0-1-C (═ Y a) OH, - (X a) 0-1-N (H) C (═ Y a) (R4a), - (X a) 0-1-N (R4a) C (═ Y a) (R4a), OR a) 0-1-N (H) C (═ Y a) OR4 OR 0-1-N (R a) N (a) Y a) OR (a) X a) N (a) OR a) N (a) X a) N (a) 1-a, - (X4)0-1-N (H) S (O)1-2R4a, - (X4)0-1-N (R4b) S (O)1-2R4a, - (X4)0-1-S (O)0-1N (H) (R4a), - (X4)0-1-S (O)0-1N (R4b) (R4a), - (X4)0-1-S (O)0-1NH2, - (X4)0-1-S (═ O) ((NR 4b) R4a, - (X4)0-1-C (═ Y4) R4 4, - (X4)0-1-C (═ Y4) H, - (X4)0-1-C (═ NOH) R4 (NOR 4) 1-2R 4R 4, - (X4)0-1-C (═ Y4) H, - (X4) 0-1-N4) (N4) N4, - (X4) 0-1-N4 (N4), - (X) 0-1-NHC (═ Y) NH, - (X) 0-1-NHC (═ Y) N (R4), - (X) 0-1-NR 4(═ Y) N (H) (R4), - (X) 0-1-N (R4) C (═ Y) NH, - (X) 0-1-OC (═ Y) R4, - (X) 0-1-OC (═ Y) H, - (X) 0-1-OC (═ Y) OR4, - (X) 0-1-OP (═ Y) (OR 4), - (Y) OR4 and-SC (═ Y) N (R4), wherein each occurrence of R4 and R4 is independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 6-10 membered aryl, 3-7 membered cycloalkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, 6-10 membered aryl-C1-4 alkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 3-7 membered heterocycloalkyl-C1-4 alkyl, and X4 is selected from the group consisting ofGroup (2): c1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene; y4 is O, NR4C or S, wherein R4C is hydrogen or C1-6 alkyl; wherein the aromatic and aliphatic moieties of R4 are independently further substituted with 0 to 4 RA4 substituents selected from the group consisting of: -F, -Cl, -Br, I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C (═ O) N (H) (C1-6 alkyl), -C (═ O) N (C1-6 alkyl) 2, -C (═ O) NH2, -C (═ O) OC1-6 alkyl, -C (═ O) OH, -N (H) C (═ O) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) (C1-6 alkyl), -N (H) C (═ O) OC1-6 alkyl, -N (C1-6 alkyl) C (═ O) OC1-6 alkyl, -S (O)1-2C1-6 alkyl, -N (H) S (O)1-2C1-6 alkyl, -N (C1-6 alkyl) S (O)1-2C1-6 alkyl, -S (O)0-1N (H) (C1-6 alkyl), -S (O)0-1N (C1-6 alkyl) 2, -S (O)0-1NH2, -C (═ O) C1-6 alkyl, -C (═ NOH) C1-6 alkyl, -C (═ NOC1-6 alkyl) C1-6 alkyl, -NHC (═ O) N (H) (C1-6 alkyl), -NHC (═ O) N (C1-6 alkyl) 2, -NHC (═ O) NH2, -N (C1-6 alkyl) C (═ O) N (H) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) NH2, -OC (═ O) C1-6 alkyl, -OC (═ O) OC1-6 alkyl, -OP (═ O) (OC1-6 alkyl) 2, -SC (═ O) OC1-6 alkyl, and-SC (═ O) N (C1-6 alkyl) 2;

n is an integer of 0 to 5; r5 is absent or selected from the group consisting of: hydrogen, C1-6 alkyl, C1-6 haloalkyl, -OH, OR5a, -CN, and halogen, wherein R5a is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl and C1-6 heteroalkyl; or optionally, R4 and R5 are optionally combined to form a 5-7 membered cycloalkyl or heterocycloalkyl and are independently further substituted with 0-4 RA4 substituents; r6 is hydrogen, -F, -Cl, -Br, -I, C1-3 alkyl or C1-3 haloalkyl. In the compounds of formula I:

r1, R2, R3, R4, R5, R6, m, n, and combinations thereofThe rings represented, all as described for the compounds of formula I-I, with the proviso that the compound of formula I is not: 1- (3- (2-methyl-6- ((4-methylpyridin-2-yl) amino) pyrimidin-4-yl) piperidin-1-yl) -2-phenylethanone.

In another aspect, the invention provides pharmaceutical compositions comprising compounds of formula I and formula I-I.

In another aspect, the invention provides methods of using compounds of formula I and formula I-I in vivo and in vitro settings.

Detailed Description

A. Definition of

Unless otherwise specified, the term "alkyl", alone or as part of another substituent, as described herein, means a straight or branched chain hydrocarbon group having the specified number of carbon atoms (i.e., C1-8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers to an unsaturated alkyl group having more than one double bond. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having more than one triple bond. Examples of such unsaturated alkyl groups include ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers. The term "cycloalkyl", "carbocyclic" or "carbocycle" refers to a hydrocarbon ring system having a total of 3 to 10 ring atoms (i.e., 3-10 membered cycloalkyl) and either being fully saturated for 3-5 membered cycloalkyl or having no more than one double bond between ring vertices and saturated for 6-or more membered cycloalkyl or having no more than two double bonds between ring vertices. As described herein, "cycloalkyl," "carbocyclic," "or" carbocyclic "also means bicyclic, polycyclic, and spirocyclic hydrocarbon ring systems such as, for example, bicyclic[2.2.1]Heptane, pinane, bicyclo [2.2.2]Octane, adamantane, norbornene, spiro C_5-12Alkanes, and the like. As described herein, the terms "alkenyl," "alkynyl," "cycloalkyl," "carbocycle," "carbocyclic," "and" carbocyclic, "are intended to include mono-and polyhalogenated variants thereof.

Unless otherwise specified, the term "heteroalkyl," by itself or in combination with another term, means a stable straight or branched chain hydrocarbon radical consisting of the stated number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N and S may be located at any internal position of the heteroalkyl group. The heteroatom Si may be located anywhere in the heteroalkyl group, including where the alkyl group is attached to the remainder of the molecule. "heteroalkyl" may include up to three units of unsaturation, and also includes mono-and polyhalogenated variants, or combinations thereof. Examples include-CH 2-CH2-O-CH3, -CH2-CH2-O-CF3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, -S (O) -CH3, -CH2-CH2-S (O)2-CH3, -CH-O-CH 3, -Si (CH3)3, -CH 2-CH-N-OCH 3 and-CH-N (CH3) -CH 3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and-CH 2-O-Si (CH3) 3.

The terms "heterocycloalkyl", "heterocyclic (heterocycle)," or "heterocycle" refer to a saturated or partially unsaturated ring system radical having a total number of ring atoms of 3 to 10 and containing one to five heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized as ring atoms. Unless otherwise indicated, the "heterocycloalkyl", "heterocyclic (heterocyclic)," or "heterocyclic" ring system may be a monocyclic, bicyclic, spiro or polycyclic ring system. A "heterocycloalkyl", "heterocyclic" or "heterocyclic" group may be attached to the rest of the molecule through one or more ring carbons or heteroatoms. Non-limiting examples of "heterocycloalkyl", "heterocyclic (heterocylic)," or "heterocyclic (heterocylic)" rings include pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2, 4(1H, 3H) -dione, 1, 4-dioxane, morpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro [3.3] heptane, (1R, 5S) -3-azabicyclo [3.2.1] octane, (1S, 4S) -2-azabicyclo [2.2.2] octane, (1R, 4R) -2-oxa-5-azabicyclo [2.2.2] octane, and the like. "heterocycloalkyl", "heterocyclic" or "heterocyclic" may include mono-and polyhalogenated variants thereof.

The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, for example-CH 2CH2CH2CH 2-. Typically, the alkyl (or alkylene) groups will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds, respectively. "alkylene," "alkenylene," and "alkynylene" are also meant to include mono-and polyhalogenated variants.

The term "heteroalkylene" by itself or as part of another substituent means a saturated or unsaturated or polyunsaturated divalent radical derived from heteroalkyl, for example-CH 2-CH2-S-CH2CH 2-and-CH 2-S-CH2-CH2-NH-CH2-, -O-CH2-CH ═ C H-, -CH2-CH ═ C (H) CH2-O-CH 2-and-S-CH 2-C.ident.C-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). The term "heteroalkylene" is also meant to include mono-and polyhalogenated variants.

The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense and refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively, and further include mono-and polyhalogenated variants thereof. Further, for dialkylamino groups, the alkyl moieties can be the same or different.

Unless otherwise specified, the terms "halo" or "halogen," by itself or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom. Furthermore, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-4 haloalkyl" is meant to include trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

Unless otherwise indicated, the term "aryl" means a polyunsaturated, typically aromatic, hydrocarbon ring which may be a single ring or multiple rings (up to three rings) fused together. The term "heteroaryl" refers to an aromatic ring containing one to five heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, and the likeOxazole, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidyl, pyrazolopyrimidyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl,azolyl radical, isoOxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. The optional substituents for each of the above-mentioned aryl and heteroaryl ring systems may be selected from the group of acceptable substituents described further below.

In some embodiments, the above terms (e.g., "alkyl," "aryl," and "heteroaryl") are intended to include both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

Substituents for alkyl groups (including those groups often referred to as alkylene, alkenyl, alkynyl, heteroalkyl, and cycloalkyl) can range in number from zero to (2 m' +1), including but not limited to a variety of groups: -halogen, -OR ', -NR ' R ', -SR ', -SiR ' R ' ", -OC (O) R ', -C (O) R ', -CO2R ', -CONR ' R ', -OC (O) NR ' R ', -NR" C (O) R ', -NR ' "C (O) NR ' R ', -NR" C (O)2R ', -NHC (NH2) ═ NH, -NR ' C (NH2) ═ NH, -NHC (NH2) ═ NR ', -NR ' "C (NR ' R '), -N-CN, -NR '" C (NR ' R '), -NOR ', -NHC (NH2) ═ NR ', -S (O) R ', -S (O)2NR ' R ', -NR ' S (O)2R ', -S (O) S (NR ' R ', -S (O)2NR ' R ', -S (O)2R ', -S (O '), -CN, -NO2, - (CH2)1-4-OR ", - (CH2)1-4-NR 'R", - (CH2) 1-4-SR', - (CH2)1-4-SiR 'R' R '", - (CH2)1-4-OC (O) R', - (CH2)1-4-C (O) R ', - (CH2)1-4-CO 2R', - (CH2)1-4CONR 'R", where m' is the total number of carbon atoms in such group. R ', R "and R'" each independently refer to a group comprising: for example, hydrogen, unsubstituted C1-6 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C1-6 alkyl, C1-6 alkoxy or C1-6 thioalkoxy groups, or unsubstituted aryl-C1-4 alkyl groups, unsubstituted heteroaryl, substituted heteroaryl, and the like. When R 'and R' are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR' R "is meant to include 1-pyrrolidinyl and 4-morpholinyl. For alkyl groups, including heteroalkyl groups, other substituents of the alkylene group include, for example, O, NR ', -N-OR ', -N-CN, ═ NH, where R ' includes substituents as described above. When a substituent for an alkyl group (including those groups often referred to as alkylene, alkenyl, alkynyl, heteroalkyl, and cycloalkyl) comprises an alkylene, alkenylene, alkynylene linkage (e.g., - (CH2) 1-4-NR' R "for alkylene), the alkylene linkage also includes halo variations. For example, when used as part of a substituent, the linker "- (CH2) 1-4-" is meant to include difluoromethylene, 1, 2-difluoroethylene, and the like.

Similarly, substituents for aryl and heteroaryl groups are diverse and are generally selected from groups including, but not limited to, the following in numbers ranging from zero to the total number of open valences on the aromatic ring system: -halogen, -OR ', -OC (O) R ', -NR ' R ', -SR ', -R ', -CN, -NO2, -CO2R ', -CONR ' R ', -C (O) R ', -OC (O) NR ' R ', -NR "C (O) NR" R ', -NHC (NH2) ═ NH, -NR ' C (NH2) ═ NH, -NHC (NH2) ═ NR ', -S (O) R ', -S (O)2NR ' R ', -NR ' S (O)2R ', -N3, perfluoro-C1-4 alkoxy and perfluoro-C1-4 alkyl, - (CH2)1-4-OR ', - (CH2)1-4-NR ' R ', - (CH2)1-4-SR ', - (CH2)1-4-SiR ' R ' R ', - (CH2)1-4-OC (O) R ', - (CH2)1-4-C (O) R ', - (CH2)1-4-CO2R ', - (CH2)1-4CONR ' R '; and wherein R ', R ", and R'" are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) -C1-4 alkyl, and unsubstituted aryloxy-C1-4 alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom through an alkylene chain of 1 to 4 carbon atoms. When a substituent for an aryl or heteroaryl group contains an alkylene, alkenylene, alkynylene linker (e.g., - (CH2) 1-4-NR' R "for alkylene), the alkylene linker also includes halo variations. For example, when used as part of a substituent, the linker "- (CH2) 1-4-" is meant to include difluoromethylene, 1, 2-difluoroethylene, and the like.

As described herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

As described herein, the term "chiral" refers to a molecule having the non-superimposable nature of a mirror pair, while the term "achiral" refers to a molecule that can be superimposed with its mirror pair.

As described herein, the term "stereoisomer" refers to a compound having the same chemical composition, but which differs with respect to the spatial arrangement of the atoms or groups.

Wavy lines intersecting bonds in chemical structures as described hereinRefers to the point of attachment of the atom to which the wavy bond is attached to the rest of the molecule or the rest of a fragment of the molecule in a chemical structure.

As described herein, the recitation of a group (e.g., Xd) in parentheses followed by a subscript integer range (e.g., (Xd)0-2) means that the group may have the number of occurrences as specified by the integer range. For example, (Xd)0-1 means that the group Xd may be absent or may be present once.

"diastereomer" refers to a stereoisomer having more than two chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography.

"enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The stereochemical definitions and conventions used herein are generally in accordance with S.P. Parker, eds., McGraw-HillDirectionbearing of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and hindered isomers, as well as mixtures thereof, such as racemic mixtures, form part of the invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In the description of the optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule to its chiral center. The prefixes d and l or (+) and (-) are used to indicate signs of polarized light rotation caused by the compound, with (-) or l indicating that the compound is levorotatory. Compounds with (+) or d prefix are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Particular stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which lacks optical activity.

As described herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that may be interconverted by low energy barriers. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions by proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include reorganized interconversions by bonding of some of the electrons.

As described herein, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex when the solvent molecule is water.

As described herein, the term "protecting group" refers to a substituent that is typically used to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (9-fluoromethyleneoxycarbonyl, Fmoc). Similarly, "hydroxy-protecting group" refers to a hydroxy group substituent that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl groups. "carboxy-protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfinyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl, and the like. For a general description of protecting groups and their use, see p.g.m.wuts and t.w.greene, Greene's Protective group in Organic Synthesis 4 th edition, Wiley-Interscience, new york, 2006.

As described herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

As described herein, the term "pharmaceutically acceptable salt" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganese, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine (procaine), purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as salts derived from relatively nontoxic organic acids such as acetates, propionates, isobutyrates, malonates, benzoates, succinates, suberates, fumarates, mandelates, phthalates, benzenesulfonates, p-tolylsulfonates, citrates, tartrates, methanesulfonates and the like. Also included are Salts of amino acids such as arginine Salts and the like, and Salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge, S.M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention comprise both basic and acidic functionalities that allow the compounds to be converted into one of a base addition salt or an acid addition salt.

The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compounds in prodrug form. As described herein, the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vitro environment by chemical or biochemical means. For example, a prodrug may be slowly converted to a compound of the invention when placed in a transdermal patch reservoir (transdermal patch reservoir) with a suitable enzyme or chemical agent.

the prodrugs of the present invention include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently linked through an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of a compound of the present invention, the amino acid residues include, but are not limited to, the 20 naturally occurring amino acids represented by the three letter symbols and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosine, isobornysine, γ -carboxyglutamic acid, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, p-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and t-butylglycine.

Additional types of prodrugs are also included. For example, the free carboxyl groups of the compounds of the invention may be derivatized as amides or alkyl esters. As another example, as in Fleisher, d, et al, (1996) Improved oral drug delivery: solubility limits overcom by the use of the drugs Advanced drug delivery Reviews, 19: 115, compounds of the present invention containing a free hydroxyl group can be derivatized into prodrugs by converting the hydroxyl group to a group such as, but not limited to, a phosphate, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethoxymethoxycarbonyl group. Also included are carbamate prodrugs of hydroxyl and amino groups, carbonate prodrugs which are hydroxyl groups, sulfonates and sulfates. Also included are derivatives of hydroxy groups as (acyloxy)) methyl and (acyloxy) ethyl ethers, wherein the acyl group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or wherein the acyl group is an amino acid ester as described above prodrugs of this type are described in J.Med.chem., (1996), 39: 10 more specific examples include replacement of the hydrogen atom of an alcohol group with groups such as (C1-6) alkanoyloxymethyl, 1- ((C1-6) alkanoyloxy) ethyl, 1-methyl-1- ((C1-6) alkanoyloxy) ethyl, (C1-6) alkoxycarbonyloxymethyl, N- (C1-6) alkoxycarbonylaminomethyl, succinyl, (C1-6) alkanoyl, α -amino (C1-4) alkanoyl, aroyl and α -aminoacyl, or α -aminoacyl- α -aminoacyl, wherein each α -aminoacyl group is independently selected from naturally occurring L-amino acids, P (O) (OH)2, -P (O) (C1) alkyl-366)₂Or a sugar group (a group resulting from removal of a hydroxyl group of the hemiacetal form of the sugar).

For additional examples of prodrug derivatives, see, e.g., a) Design of produgs, edited by h.bundgaard, (Elsevier, 1985) and Methods in Enzymology, volume 42, pages 309-396, edited by k.widder, et al (Academic Press, 1985); b) a Textbook of Drug Design and development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 "Design and application of Prodrugs," H.Bundgaard pages 113-191 (1991); c) bundgaard, Advanced drug delivery Reviews, 8: 1-38 (1992); d) bundgaard, et al, Journal of pharmaceutical sciences, 77: 285 (1988); and e) n.kakeya, et al, chem.pharm.bull, 32: 692(1984), each of which is specifically incorporated herein by reference.

Furthermore, the present invention provides metabolites of the compounds of the present invention. As described herein, "metabolite" refers to a product produced by the metabolism of a specified compound or salt thereof in vivo. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound.

Typically by preparing a radiolabel of a compound of the invention (e.g.,¹⁴c or³H) Isotopes which are parenterally administered to an animal such as a rat, mouse, guinea pig, monkey, or to a human in detectable doses (e.g., greater than about 0.5mg/kg), for sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and for their conversion products to be isolated from urine, blood or other biological samples to identify the metabolites. These products are easy to isolate because they are labelled (others are isolated by using antibodies capable of binding epitopes present in the metabolite). The metabolite structure is determined in a conventional manner, for example, by MS, LC/MS or NMR analysis. Typically, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites, provided they are not otherwise found in vivo, are useful in diagnostic assays for the administration of therapeutic doses of the compounds of the invention.

Certain compounds of the present invention may exist in unsolvated as well as solvated forms (including hydrated forms). In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are all intended to be included within the scope of the present invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at more than one atom that constitute such compounds. For example, the invention also includes isotopically-labeled variations of the invention identical to those recited herein, but for the fact that more than one atom is replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as described are contemplated as being within the scope of the compounds of the invention and uses thereof. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H ("D"), 3H, 11C, 13C, 14C, 13N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36C1, 123I, and 125I. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H or 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for facilitating their preparation and detectability. Further substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from better metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and is therefore preferred in some circumstances. Positron emitting isotopes such as 15O, 13N, 11C and 18F are useful in Positron Emission Tomography (PET) studies to detect substrate receptor occupancy. In general, isotopically labeled compounds of the present invention can be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures analogous to those disclosed in the schemes and/or in the examples herein below.

The terms "treatment" and "treating" refer to both therapeutic treatment and/or prophylactic treatment or prophylactic measure, wherein the object is to prevent or slow down (reduce) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of a disease or disorder, stabilized (i.e., not worsening) state of a disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. "treatment" may also mean an extended survival rate compared to the expected survival rate if not receiving treatment. Those in need of treatment include those already with the disease or condition as well as those predisposed to the disease or condition or those for which the disease or condition is to be prevented.

The phrase "therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a particular disease (disorder), condition (condition), or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly reduce or delay neuronal cell death.

The term "administering" as described herein refers to contacting a neuron or portion thereof with a compound described herein. This includes administering the compound to a subject in which the neuron or portion thereof is present, and introducing the inhibitor into a medium in which the neuron or portion thereof is cultured.

The term "patient" as described herein refers to any mammal, including humans, higher non-human primates, rodent livestock and farm animals such as cows, horses, dogs and cats. In one embodiment, the patient is a human patient.

The term "bioavailability" refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates a measure of the time (rate) and total amount (degree) of drug from an administered dosage form to the total circulation.

The phrases "preventing axonal degeneration," "preventing neuronal degeneration," "preventing CNS neuronal degeneration," "inhibiting axonal degeneration," "inhibiting neuronal degeneration," as described herein, include (i) the ability to inhibit or prevent axonal or neuronal degeneration in a patient diagnosed with or at risk of developing a neurodegenerative disease and (ii) the ability to inhibit or prevent further axonal or neuronal degeneration in a patient who has suffered from or has symptoms of a neurodegenerative disease. Preventing axonal or neuronal degeneration includes reducing or inhibiting axonal or neuronal degeneration, which may be characterized by complete or partial inhibition of neuronal or axonal degeneration. This can be assessed, for example, by analyzing neurobiological function. The terms listed above also include in vitro and in vitro methods. Further, the phrases "preventing neuronal degeneration" and "inhibiting neuronal degeneration" include such inhibition in terms of whole neurons or portions thereof, such as neuronal cell bodies, axons and dendrites. Administration of one or more agents as described herein can result in a neurological disorder in the subject or population secondary to a disease, condition, or neurological condition treated that has a major impact outside the nervous system, as compared to a control subject or population that does not receive one or more agents described herein; nervous system injury, pain, caused by physical, mechanical or chemical trauma; and vision-related neurodegeneration; loss of memory; or psychosis (e.g., tremors (tremators), bradykinesia (slowness of movement), ataxia (ataxia), loss of balance (loss of balance), depression (depression), decreased cognitive function (degraded cognitive function), short-term memory loss (short term memory loss), long-term memory loss (long term memory loss), confusion (deficiency), personality changes (change in personality), language disorders (language disorders), sensory loss of perception (loss of sensory perception), contact sensitivity (sensitivity), numb limbs in excesses, muscle weakness (muscle weaknesses), muscle paralysis (muscle spasms), headache (muscle spasms), muscle spasms (muscle spasms), impaired appetite, flank, rapid heart rate, dizziness, blurred vision (blurry vision), visual shadows or blind areas (shadows of vision), amethorphism (metamophopsia), color vision impairment (impaired vision), a reduced recovery of visual function after exposure to bright light, and a reduced visual contrast sensitivity (loss of visual contrast sensitivity)) of at least 10% (e.g., a reduction of at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 100%). Administration of one or more agents as described herein can result in at least a 10% reduction (e.g., at least a 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even a 100% reduction) in the number of neurons (or their neuron bodies, axons, or dendrites) that are degenerated in the neuron population or in the subject as compared to the number of neurons (or their neuron bodies, axons, or dendrites) that are degenerated in the neuron population or subject without administration of one or more agents described herein. Administration of one or more agents as described herein can result in the development of a neurological disorder in a subject or population of subjects, as compared to a subject or population not treated with one or more compounds described herein; secondary to a disease, condition, treated neurological condition having a major impact outside the nervous system; nervous system injury, pain, caused by physical, mechanical, or chemical trauma; vision-related neurodegeneration; loss of memory; or at least a 10% reduction in the likelihood of psychosis (e.g., at least a 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even a 100% reduction).

The term "neuron" as described herein refers to a nervous system cell, which includes a central cell body or cell body (soma), and two types of extensions or protrusions: dendrites, by which most neuronal signals are generally transmitted to the cell body, and axons, by which most neuronal signals are generally transmitted from the cell body to effector cells, such as target neurons or muscles. Neurons can transmit information from tissues and organs into the central nervous system (afferent or sensory neurons) and transmit signals from the central nervous system to effector cells (efferent or motor neurons). Other neurons, called interneurons, connect neurons within the central nervous system (brain and spine). Some specific examples of types of neurons that can receive treatment according to the invention include cerebellar granule neurons, dorsal root ganglion neurons, and cortical neurons.

B. Compound (I)

In one aspect, the present invention provides compounds of formula (I)

In formula I, R1 is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OR1a, -SR1a, -N (H) (R1a), and-N (R1a) (R1b), wherein R1a and R1b are each independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, and wherein the aliphatic and aromatic moieties of R1 are independently further substituted with 0 to 5 RA1 substituents selected from the group consisting of: -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-4 alkyl, C1-4 haloalkyl, C1-4 heteroalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 dialkylamino, R1C-C (═ O) -, R1C-C (═ O) N (H) -, R1C-C (═ O) N (R1d) -, R1C-C (═ O) O-, R1C-S (O)1-2-, R1C-S (O)1-2N (R1d) -, R1C-S (O)1-2N (H) -, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl, wherein R1c is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C5-6 heteroaryl, 3-7 membered heterocycloalkyl, phenyl and 3-6 membered cycloalkyl, R1d is selected from the group consisting of: hydrogen, C1-3 alkyl and C1-3 haloalkyl, and wherein the 5-6 membered heteroaryl, phenyl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl of the RA1 substituent are substituted with 0-4 substituents selected from: -F, -Cl, -Br, I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino and C1-4 dialkylamino. In formula I, R2 is selected from the group consisting of: hydrogen, C1-6 alkyl and C1-6 haloalkyl. R3 is selected from the group consisting of: -F, -Cl, -Br, -I, - (X3)0-1-CN, - (X3)0-1-NO2, - (X3)0-1-SF5, - (X3)0-1-OH, - (X3)0-1-NH2, - (X3)0-1-N (H) (R3a), - (X3)0-1-N (R3b) (R3a), - (X3)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, - (X3)0-1-3-7 membered cycloalkyl, - (X3)0-1-3-7 membered heterocycloalkyl, - (X3)0-1-5-6 membered heteroaryl, - (X3) 0-1-C3 aryl, - (X3)0-1-C (═ Y3) N (H) (R3 3), - (X3)0-1-C (═ Y3) NH 3, - (X3)0-1-C (═ Y3) N (R3 3), - (X3)0-1-C (═ Y3) OR 33, - (X3)0-1-C (═ Y3) OH, - (X3)0-1-N (H) C (═ Y3) (R3 3), - (X3)0-1-N (R3 3) C (═ Y3) (R3 3), X3)0-1-N (H) C (═ Y3) OR 3) OR 0-1-N (R3) C (═ Y3) R3) X3) OR (3) X3) N (3) R3) N (3) 3), - (X3)0-1-N (H) S (O)1-2R3a, - (X3)0-1-N (R3b) S (O)1-2R3a, - (X3)0-1-S (O)0-1N (H) (R3a), - (X3)0-1-S (O)0-1N (R3b) (R3a), - (X3)0-1-S (O)0-1NH2, - (X4)0-1-S (═ O) ((NR 3b) R3a, - (X3)0-1-C (═ Y3) R3 3, - (X3)0-1-C (═ Y3) H, - (X3)0-1-C (═ NOH) R3 (X3)0-1-N (R3) 1-2R 3R 3, - (X3) 0-1-N3 (N3) 0-1-N3, - (3) 3R 3), - (X) 0-1-NHC (═ Y) NH, - (X) 0-1-NHC (═ Y) N (R3), - (X) 0-1-N (R3) C (═ Y) N (H) (R3), - (X) 0-1-N (R3) C (═ Y) NH, - (X) 0-1-OC (═ Y) R3, - (X) 0-1-OC (═ Y) H, - (X) 0-1-OC (═ Y) OR3, - (X) 0-1-OP (═ Y) (OR 3), - (X) -SC (═ Y) OR3, and- (X) -SC (═ Y) N (R3), wherein X is selected from the group consisting of: c1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene, R3a and R3b are each independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 3-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, C6 aryl, C6 aryl-C1-4 alkyl and benzyl; y3 is O, NR3d or S, wherein R3d is hydrogen or C1-6 alkyl; wherein the aliphatic or aromatic moiety of R3 is independently further substituted with 0 to 4 RA3 substituents selected from the group consisting of: -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C (═ O) N (H) (C1-6 alkyl), -C (═ O) N (C1-6 alkyl) 2, -C (═ O) NH2, -C (═ O) OC1-6 alkyl, -C (═ O) OH, -N (H) C (═ O) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) (C1-6 alkyl), -N (H) C (═ O) OC1-6 alkyl, -N (C1-6 alkyl) C (═ O) OC1-6 alkyl, -S (O)1-2C1-6 alkyl, -N (H) S (O)1-2C1-6 alkyl, -N (C1-6 alkyl) S (O)1-2C1-6 alkyl, -S (O)0-1N (H) (C1-6 alkyl), -S (O)0-1N (C1-6 alkyl) 2, -S (O)0-1NH2, -C (═ O) C1-6 alkyl, -C (═ NOH) C1-6 alkyl, -C (═ NOC1-6 alkyl) C1-6 alkyl, -NHC (═ O) N (H) (C1-6 alkyl), -NHC (═ O) N (C1-6 alkyl) 2, -NHC (═ O) NH2, -N (C1-6 alkyl) C (═ O) N (H) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) NH2, -OC (═ O) C1-6 alkyl, -OC (═ O) OC1-6 alkyl, -OP (═ O) (OC1-6 alkyl) 2, -SC (═ O) OC1-6 alkyl, and-SC (═ O) N (C1-6 alkyl) 2; alternatively, any two R3 substituents located on adjacent atoms are optionally combined to form a 5-6 membered heteroaryl ring, the 5-6 membered heteroaryl ring comprising 1-2 heteroatoms selected from N, O and S and further comprising 0 to 4R 3a substituents;

m is an integer of 0 to 4.

In formula I, is represented byThe ring represented is a4 to 10 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3R 4 groups;

r4 is selected from the group consisting of: -F, -Cl, -Br, -I, - (X4)0-1-CN, - (X4)0-1-NO2, - (X4)0-1-SF5, - (X4)0-1-OH, - (X4)0-1-NH2, - (X4)0-1-N (H) (R4a), - (X4)0-1-N (R4b) (R4a), - (X4)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, - (X4)0-1- (3-10 membered heterocycloalkyl), - (X4)0-1- (5-10 membered heteroaryl), - (X4)0-1- (3-7 membered cycloalkyl), - (X4)0-1-C (═ Y4) N (H) (R4a), - (X a) 0-1-C (═ Y a) NH a, - (X a) 0-1-C (═ Y a) N (R4a), - (X a) 0-1-C (═ Y a) OR4a, - (X a) 0-1-C (═ Y a) OH, - (X a) 0-1-N (H) C (═ Y a) (R4a), - (X a) 0-1-N (R4a) C (═ Y a) (R4a), OR a) 0-1-N (H) C (═ Y a) OR4 OR 0-1-N (R a) N (a) Y a) OR (a) X a) N (a) OR a) N (a) X a) N (a) 1-a, - (X4)0-1-N (H) S (O)1-2R4a, - (X4)0-1-N (R4b) S (O)1-2R4a, - (X4)0-1-S (O)0-1N (H) (R4a), - (X4)0-1-S (O)0-1N (R4b) (R4a), - (X4)0-1-S (O)0-1NH2, - (X4)0-1-S (═ O) ((NR 4b) R4a, - (X4)0-1-C (═ Y4) R4 4, - (X4)0-1-C (═ Y4) H, - (X4)0-1-C (═ NOH) R4 (NOR 4) 1-2R 4R 4, - (X4)0-1-C (═ Y4) H, - (X4) 0-1-N4) (N4) N4, - (X4) 0-1-N4 (N4), - (X) 0-1-NHC (═ Y) NH, - (X) 0-1-NHC (═ Y) N (R4), - (X) 0-1-NR 4(═ Y) N (H) (R4), - (X) 0-1-N (R4) C (═ Y) NH, - (X) 0-1-OC (═ Y) R4, - (X) 0-1-OC (═ Y) H, - (X) 0-1-OC (═ Y) OR4, - (X) 0-1-OP (═ Y) (OR 4), - (Y) OR4 and-SC (═ Y) N (R4), wherein each occurrence of R4 and R4 is independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 6-10 membered aryl, 3-7 membered cycloalkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, 6-10 membered aryl-C1-4 alkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 3-7 membered heterocycloalkyl-C1-4 alkyl, and X4 is selected from the group consisting of: c1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene; y4 is O, NR4C or S, wherein R4C is hydrogen or C1-6 alkyl; wherein the aromatic and aliphatic moieties of R4 are independently further substituted with 0 to 4 RA4 substituents selected from the group consisting of: -F, -Cl, -Br, I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C (═ O) N (H) (C1-6 alkyl), -C (═ O) N (C1-6 alkyl) 2, -C (═ O) NH2, -C (═ O) OC1-6 alkyl, -C (═ O) OH, -N (H) C (═ O) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) (C1-6 alkyl), -N (H) C (═ O) OC1-6 alkyl, -N (C1-6 alkyl) C (═ O) OC1-6 alkyl, -S (O)1-2C1-6 alkyl, -N (H) S (O)1-2C1-6 alkyl, -N (C1-6 alkyl) S (O)1-2C1-6 alkyl, -S (O)0-1N (H) (C1-6 alkyl), -S (O)0-1N (C1-6 alkyl) 2, -S (O)0-1NH2, -C (═ O) C1-6 alkyl, -C (═ NOH) C1-6 alkyl, -C (═ NOC1-6 alkyl) C1-6 alkyl, -NHC (═ O) N (H) (C1-6 alkyl), -NHC (═ O) N (C1-6 alkyl) 2, -NHC (═ O) NH2, -N (C1-6 alkyl) C (═ O) N (H) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) NH2, -OC (═ O) C1-6 alkyl, -OC (═ O) OC1-6 alkyl, -OP (═ O) (OC1-6 alkyl) 2, -SC (═ O) OC1-6 alkyl, and-SC (═ O) N (C1-6 alkyl) 2. In formula I, n is an integer of 0 to 5. In formula I, R5 is absent or selected from the group consisting of: hydrogen, C1-6 alkyl, C1-6 haloalkyl, -OH, OR5a, -CN, and halogen, wherein R5a is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl and C1-6 heteroalkyl; or optionally, R4 and R5 are optionally combined to form a 5-7 membered cycloalkyl or heterocycloalkyl and are independently further substituted with 0-4 RA4 substituents. R6 is hydrogen, -F, -Cl, -Br, -I, C1-3 alkyl or C1-3 haloalkyl; and with the proviso that the compound of formula I is not:

1- (3- (2-methyl-6- ((4-methylpyridin-2-yl) amino) pyrimidin-4-yl) piperidin-1-yl) -2-phenylethanone.

In another aspect, the invention provides compounds of formula (I-I)

In formula I-I, R1 is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OR1a, -SR1a, -N (H) (R1a), and-N (R1a) (R1b), wherein R1a and Rib are each independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, and wherein the aliphatic and aromatic moieties of R1 are independently further substituted with 0 to 5 RA1 substituents selected from the group consisting of: -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-4 alkyl, C1-4 haloalkyl, C1-4 heteroalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 dialkylamino, R1C-C (═ O) -, R1C-C (═ O) N (H) -, R1C-C (═ O) N (R1d) -, R1C-C (═ O) O-, R1C-S (O)1-2-, R1C-S (O)1-2N (R1d) -, R1C-S (O)1-2N (H) -, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl, wherein R1c is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C5-6 heteroaryl, 3-7 membered heterocycloalkyl, phenyl and 3-6 membered cycloalkyl, R1d is selected from the group consisting of: hydrogen, C1-3 alkyl and C1-3 haloalkyl, and wherein the 5-6 membered heteroaryl, phenyl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl of the RA1 substituent are substituted with 0-4 substituents selected from: -F, -Cl, -Br, I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino and C1-4 dialkylamino. In formula I, R2 is selected from the group consisting of: hydrogen, C1-6 alkyl and C1-6 haloalkyl. R3 is selected from the group consisting of: -F, -Cl, -Br, -I, - (X3)0-1-CN, - (X3)0-1-NO2, - (X3)0-1-SF5, - (X3)0-1-OH, - (X3)0-1-NH2, - (X3)0-1-N (H) (R3a), - (X3)0-1-N (R3b) (R3a), - (X3)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, - (X3)0-1-3-7 membered cycloalkyl, - (X3)0-1-3-7 membered heterocycloalkyl, - (X3)0-1-5-6 membered heteroaryl, - (X3) 0-1-C3 aryl, - (X3)0-1-C (═ Y3) N (H) (R3 3), - (X3)0-1-C (═ Y3) NH 3, - (X3)0-1-C (═ Y3) N (R3 3), - (X3)0-1-C (═ Y3) OR 33, - (X3)0-1-C (═ Y3) OH, - (X3)0-1-N (H) C (═ Y3) (R3 3), - (X3)0-1-N (R3 3) C (═ Y3) (R3 3), X3)0-1-N (H) C (═ Y3) OR 3) OR 0-1-N (R3) C (═ Y3) R3) X3) OR (3) X3) N (3) R3) N (3) 3), - (X3)0-1-N (H) S (O)1-2R3a, - (X3)0-1-N (R3b) S (O)1-2R3a, - (X3)0-1-S (O)0-1N (H) (R3a), - (X3)0-1-S (O)0-1N (R3b) (R3a), - (X3)0-1-S (O)0-1NH2, - (X4)0-1-S (═ O) ((NR 3b) R3a, - (X3)0-1-C (═ Y3) R3 3, - (X3)0-1-C (═ Y3) H, - (X3)0-1-C (═ NOH) R3 (X3)0-1-N (R3) 1-2R 3R 3, - (X3) 0-1-N3 (N3) 0-1-N3, - (3) 3R 3), - (X) 0-1-NHC (═ Y) NH, - (X) 0-1-NHC (═ Y) N (R3), - (X) 0-1-N (R3) C (═ Y) N (H) (R3), - (X) 0-1-N (R3) C (═ Y) NH, - (X) 0-1-OC (═ Y) R3, - (X) 0-1-OC (═ Y) H, - (X) 0-1-OC (═ Y) OR3, - (X) 0-1-OP (═ Y) (OR 3), - (X) -SC (═ Y) OR3, and- (X) -SC (═ Y) N (R3), wherein X is selected from the group consisting of: c1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene, R3a and R3b are each independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 3-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, C6 aryl, C6 aryl-C1-4 alkyl and benzyl; y3 is O, NR3d or S, wherein R3d is hydrogen or C1-6 alkyl; wherein the aliphatic or aromatic moiety of R3 is independently further substituted with 0 to 4 RA3 substituents selected from the group consisting of: -F, -Cl, -Br, -I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C (═ O) N (H) (C1-6 alkyl), -C (═ O) N (C1-6 alkyl) 2, -C (═ O) NH2, -C (═ O) OC1-6 alkyl, -C (═ O) OH, -N (H) C (═ O) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) (C1-6 alkyl), -N (H) C (═ O) OC1-6 alkyl, -N (C1-6 alkyl) C (═ O) OC1-6 alkyl, -S (O)1-2C1-6 alkyl, -N (H) S (O)1-2C1-6 alkyl, -N (C1-6 alkyl) S (O)1-2C1-6 alkyl, -S (O)0-1N (H) (C1-6 alkyl), -S (O)0-1N (C1-6 alkyl) 2, -S (O)0-1NH2, -C (═ O) C1-6 alkyl, -C (═ NOH) C1-6 alkyl, -C (═ NOC1-6 alkyl) C1-6 alkyl, -NHC (═ O) N (H) (C1-6 alkyl), -NHC (═ O) N (C1-6 alkyl) 2, -NHC (═ O) NH2, -N (C1-6 alkyl) C (═ O) N (H) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) NH2, -OC (═ O) C1-6 alkyl, -OC (═ O) OC1-6 alkyl, -OP (═ O) (OC1-6 alkyl) 2, -SC (═ O) OC1-6 alkyl, and-SC (═ O) N (C1-6 alkyl) 2; alternatively, any two R3 substituents located on adjacent atoms are optionally combined to form a 5-6 membered heteroaryl ring, said 5-6 membered heteroaryl ring comprising 1-2 heteroatoms selected from N, O and S and further comprising 0 to 4R 3a substituents;

m is an integer of 0 to 4. In formula I, is represented byThe ring represented is a4 to 10 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3R 4 groups;

r4 is selected from the group consisting of: -F, -Cl, -Br, -I, - (X4)0-1-CN, - (X4)0-1-NO2, - (X4)0-1-SF5, - (X4)0-1-OH, - (X4)0-1-NH2, - (X4)0-1-N (H) (R4a), - (X4)0-1-N (R4b) (R4a), - (X4)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, - (X4)0-1- (3-10 membered heterocycloalkyl), - (X4)0-1- (5-10 membered heteroaryl), - (X4)0-1- (3-7 membered cycloalkyl), - (X4)0-1-C (═ Y4) N (H) (R4a), - (X a) 0-1-C (═ Y a) NH a, - (X a) 0-1-C (═ Y a) N (R4a), - (X a) 0-1-C (═ Y a) OR4a, - (X a) 0-1-C (═ Y a) OH, - (X a) 0-1-N (H) C (═ Y a) (R4a), - (X a) 0-1-N (R4a) C (═ Y a) (R4a), OR a) 0-1-N (H) C (═ Y a) OR4 OR 0-1-N (R a) N (a) Y a) OR (a) X a) N (a) OR a) N (a) X a) N (a) 1-a, - (X4)0-1-N (H) S (O)1-2R4a, - (X4)0-1-N (R4b) S (O)1-2R4a, - (X4)0-1-S (O)0-1N (H) (R4a), - (X4)0-1-S (O)0-1N (R4b) (R4a), - (X4)0-1-S (O)0-1NH2, - (X4)0-1-S (═ O) ((NR 4b) R4a, - (X4)0-1-C (═ Y4) R4 4, - (X4)0-1-C (═ Y4) H, - (X4)0-1-C (═ NOH) R4 (NOR 4) 1-2R 4R 4, - (X4)0-1-C (═ Y4) H, - (X4) 0-1-N4) (N4) N4, - (X4) 0-1-N4 (N4), - (X) 0-1-NHC (═ Y) NH, - (X) 0-1-NHC (═ Y) N (R4), - (X) 0-1-NR 4(═ Y) N (H) (R4), - (X) 0-1-N (R4) C (═ Y) NH, - (X) 0-1-OC (═ Y) R4, - (X) 0-1-OC (═ Y) H, - (X) 0-1-OC (═ Y) OR4, - (X) 0-1-OP (═ Y) (OR 4), - (Y) OR4 and-SC (═ Y) N (R4), wherein each occurrence of R4 and R4 is independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 6-10 membered aryl, 3-7 membered cycloalkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, 6-10 membered aryl-C1-4 alkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 3-7 membered heterocycloalkyl-C1-4 alkyl, and X4 is selected from the group consisting of: c1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene; y4 is O, NR4C or S, wherein R4C is hydrogen or C1-6 alkyl; wherein the aromatic and aliphatic moieties of R4 are independently further substituted with 0 to 4 RA4 substituents selected from the group consisting of: -F, -Cl, -Br, I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C (═ O) N (H) (C1-6 alkyl), -C (═ O) N (C1-6 alkyl) 2, -C (═ O) NH2, -C (═ O) OC1-6 alkyl, -C (═ O) OH, -N (H) C (═ O) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) (C1-6 alkyl), -N (H) C (═ O) OC1-6 alkyl, -N (C1-6 alkyl) C (═ O) OC1-6 alkyl, -S (O)1-2C1-6 alkyl, -N (H) S (O)1-2C1-6 alkyl, -N (C1-6 alkyl) S (O)1-2C1-6 alkyl, -S (O)0-1N (H) (C1-6 alkyl), -S (O)0-1N (C1-6 alkyl) 2, -S (O)0-1NH2, -C (═ O) C1-6 alkyl, -C (═ NOH) C1-6 alkyl, -C (═ NOC1-6 alkyl) C1-6 alkyl, -NHC (═ O) N (H) (C1-6 alkyl), -NHC (═ O) N (C1-6 alkyl) 2, -NHC (═ O) NH2, -N (C1-6 alkyl) C (═ O) N (H) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) NH2, -OC (═ O) C1-6 alkyl, -OC (═ O) OC1-6 alkyl, -OP (═ O) (OC1-6 alkyl) 2, -SC (═ O) OC1-6 alkyl, and-SC (═ O) N (C1-6 alkyl) 2. In formula I, n is an integer of 0 to 5. In formula I, R5 is absent or selected from the group consisting of: hydrogen, C1-6 alkyl, C1-6 haloalkyl, -OH, OR5a, -CN, and halogen, wherein R5a is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl and C1-6 heteroalkyl; or optionally, R4 and R5 are optionally combined to form a 5-7 membered cycloalkyl or heterocycloalkyl and are independently further substituted with 0-4 RA4 substituents. R6 is hydrogen, -F, -Cl, -Br, -I, C1-3 alkyl or C1-3 haloalkyl.

In one embodiment, in the compound of formula I or formula I-I, the compound is represented by the structureThe 4-to 10-membered heterocyclic ring represented comprises an optionally substituted ring selected from the group consisting of: morpholine, morpholone, piperazine, piperazinone, thiomorpholine, homopiperidine, homopiperidinone, piperidine, valerolactam, pyrrolidine, butyrolactam, azetidine, azetidinone, thiazelidine-1, 1-dioxide, isothiazolidine-1, 1-dioxide, pyridone, tetrahydropyran, oxetane and tetrahydrofuran, which are attached to the remainder of the compound represented by formula I.

In another embodiment, in the compound of formula I or formula I-I, the compound is represented by the structureThe 4 to 10 membered heterocyclic ring represented is selected from the group consisting of:

wherein the R4 substituent, if present, replaces a hydrogen atom attached to a carbon ring atom or a nitrogen ring atom in the 4-10 membered heterocycle.

wherein R4 attached to the nitrogen atom of the 4-to 10-membered heterocyclic ring is selected from the group consisting of: - (X4)0-1-CN, - (X4)0-1-NO2, - (X4)0-1-SF5, - (X4)0-1-OH, - (X4)0-1-NH2, - (X4)0-1-N (H) (R4a), - (X4)0-1-N (R4b) (R4a), - (X4)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, - (X4)0-1- (3-10 membered heterocycloalkyl), - (X4)0-1- (5-10 membered heteroaryl), - (X4)0-1- (3-7 membered cycloalkyl), - (X4)0-1-C (═ Y4) N (H) (R4 4), - (X4)0-1-C (═ Y4) NH 4, - (X4)0-1-C (═ Y4) N (R4 4), - (X4)0-1-C (═ Y4) OR 44, - (X4)0-1-C (═ Y4) OH, - (X4)0-1-N (H) C (═ Y4) (R4 4), - (X4)0-1-N (R4 4) C (═ Y4) (R4 4), - (X4)0-1-N (H) C (═ Y4) OR 44, - (X4)0-1-N (R4) Y4) Y (R4) N (R4) X4)0-1-N (4) Y4) OR (R4) N (4) N (R4) X4) N (R4) N (4) N (R4) X4) 1-4, - (X4)0-1-N (R4b) S (O)1-2R4a, - (X4)0-1-S (O)0-1N (H) (R4a), - (X4)0-1-S (O)0-1N (R4b) (R4a), - (X4)0-1-S (O)0-1NH2, - (X4)0-1-S (═ O) (═ NR4b) R4a, - (X a) 0-1-C (═ Y a) H, - (X a) 0-1-C (═ NOH) R4a, - (X a) 0-1-C (═ a) NOR 364, X a) 0-1-NHC (═ NHC) R4a, - (X a) N (NHC) 0-a) N a, - (a) X a) 0-a, - (NHC a) X a) N (NHC a) 0-a), - (X4)0-1-NHC (═ Y4) N (R4b) (R4a), - (X4)0-1-NR4aC (═ Y4) N (H) (R4 4), - (X4)0-1-N (R4 4) C (═ Y4) NH 4, - (X4)0-1-OC (═ Y4) R4 4, - (X4)0-1-OC (═ Y4) H, - (X4)0-1-OC (═ Y4) OR 44, - (X4)0-1-OP (═ Y4) (OR4 4), -SC (═ Y4) OR 44 and-SC (═ Y4) N (R4 4), wherein R4 and R4 are independently selected from the following groups each occurrence: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 6-10 membered aryl, 3-7 membered cycloalkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, 6-10 membered aryl-C1-4 alkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 3-7 membered heterocycloalkyl-C1-4 alkyl, and X4 is selected from the group consisting of: c1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene; y4 is O, NR4C or S, wherein R4C is hydrogen or C1-6 alkyl; wherein the aromatic and aliphatic moieties of R4 are independently further substituted with 0 to 4 RA4 substituents selected from the group consisting of: -F, -Cl, -Br, I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C (═ O) N (H) (C1-6 alkyl), -C (═ O) N (C1-6 alkyl) 2, -C (═ O) NH2, -C (═ O) OC1-6 alkyl, -C (═ O) OH, -N (H) C (═ O) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) (C1-6 alkyl), -N (H) C (═ O) OC1-6 alkyl, -N (C1-6 alkyl) C (═ O) OC1-6 alkyl, -S (O)1-2C1-6 alkyl, -N (H) S (O)1-2C1-6 alkyl, -N (C1-6 alkyl) S (O)1-2C1-6 alkyl, -S (O)0-1N (H) (C1-6 alkyl), -S (O)0-1N (C1-6 alkyl) 2, -S (O)0-1NH2, -C (═ O) C1-6 alkyl, -C (═ NOH) C1-6 alkyl, -C (═ NOC1-6 alkyl) C1-6 alkyl, -NHC (═ O) N (H) (C1-6 alkyl), -NHC (═ O) N (C1-6 alkyl) 2, -NHC (═ O) NH2, -N (C1-6 alkyl) C (═ O) N (H) (C1-6 alkyl), -N (C1-6 alkyl) C (═ O) NH2, -OC (═ O) C1-6 alkyl, -OC (═ O) OC1-6 alkyl, -OP (═ O) (OC1-6 alkyl) 2, -SC (═ O) OC1-6 alkyl, and-SC (═ O) N (C1-6 alkyl) 2; and the remaining R4 on the 4-10 membered heterocyclic ring, if present, are each independently selected from the group consisting of: -F, -Cl, -Br, I, - (X4)0-1-CN, - (X4)0-1-NO2, - (X4)0-1-SF5, - (X4)0-1-OH, - (X4)0-1-NH2, - (X4)0-1-N (H) (R4a), - (X4)0-1-N (R4b) (R4a), - (X4)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy and C1-6 alkylthio, wherein X4 is selected from the group consisting of: c1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene and R4a and R4b are each independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl and C1-6 heteroalkyl.

In another embodiment, in compounds of formula I or formula I-I, R4 is attached to the nitrogen atom (if present) of the 4-10 membered heterocyclic ring or to a carbon atom of the 4-10 membered heterocyclic ring, wherein R4 is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, - (X4)0-1- (3-10 membered heterocycloalkyl), - (X4)0-1- (5-10 membered heteroaryl), - (X4)0-1- (3-7 membered cycloalkyl), - (X4)0-1-S (O)1-2R4a and- (X4)0-1-C (═ Y4) R4a, wherein Y4 is O.

wherein R4 is selected from the group consisting of: -F, -Cl, -Br, -I, - (X4)0-1-CN, - (X4)0-1-NO2, - (X4)0-1-SF5, - (X4)0-1-OH, - (X4)0-1-NH2, - (X4)0-1-N (H) (R4a), - (X4)0-1-N (R4b) (R4a), - (X4)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy and C1-6 alkylthio, wherein X4 is selected from the group consisting of: c1-4 alkylene, C1-4 haloalkylene, C1-4 heteroalkylene, C2-4 alkenylene, and C2-4 alkynylene and R4a and R4b are each independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl and C1-6 heteroalkyl.

In another embodiment, in the compound of formula I or formula I-I, R5 is selected from the group consisting of: hydrogen, C1-4 alkyl, C1-4 haloalkyl, hydroxy, OR5a, -CN, -F, -Cl, -Br and-I.

In another embodiment, in the compound of formula I or formula I-I, wherein R1 is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, -OR1a, -SR1a, -N (H) (R1a), and-N (R1a) (R1b), methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, morpholine, homomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, azetidine, pyrrolidine, benzene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, oxetane, tetrahydrofuran, tetrahydropyran, -oxa-5-azabicyclo [2.2.1] heptane, 2-oxa-6-azaspiro [3.3] heptane, 8-oxa-3-azabicyclo [3.2.1] octane, 3-oxa-8-azabicyclo [3.2.1] octane, 7-oxabicyclo [2.2.1] heptane, 7-azabicyclo [2.2.1] heptane, norbornane, bicyclo [2.2.2] octane, 2-azabicyclo [2.2.2] octane, 2-oxabicyclo [2.2.2] octane, 2-oxa-5-azabicyclo [2.2.2] octane and 2, 5-diazabicyclo [2.2.2] octane, 5,6, 7, 8-tetrahydroimidazo [1, 2-a ] pyrazine, 4,5, 6, 7-tetrahydro-3H-imidazo [4, 5-c ] pyridine, wherein R1a and R1b are each independently selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl, and wherein the aliphatic and aromatic moieties of R1 are independently further substituted with 0 to 5 RA1 substituents selected from the group consisting of: -F, -Cl, -Br, I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, -O, C1-4 alkyl, C1-4 haloalkyl, C1-4 heteroalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 dialkylamino, R1C-C (═ O) -, -R1C-C (═ O) N (H) -, R1C-C (═ O) N (R1d) -, R1C-C (═ O) O-, R1C-S (O)1-2-, R1C-S (O)1-2N (R1d) -, R1C-S (O)1-2N (H) -, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl, wherein R1c is selected from the group consisting of: c1-6 alkyl, C1-6 haloalkyl, C5-6 heteroaryl, 3-7 membered heterocycloalkyl, phenyl and 3-6 membered cycloalkyl, R1d is selected from the group consisting of: hydrogen, C1-3 alkyl and C1-3 haloalkyl, and wherein the 5-6 membered heteroaryl, phenyl, 3-6 membered heteroaryl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl of the RA1 substituent are substituted with 0-4 substituents selected from: -F, -Cl, -Br, I, -CN, -NO2, -SF5, -OH, -NH2, -CF3, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino and C1-4 dialkylamino.

In another embodiment, in the compound of formula I or formula I-I, wherein R1 is selected from the group consisting of: pyrrolidin-1-yl, phenyl, piperidin-1-yl, pyrrol-1-yl, azetidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, 3-oxa-8-azabicyclo [3.2.1] oct-8-yl, 2-oxa-6-azaspiro [3.3] hept-6-yl, -8-oxa-3-azabicyclo [3.2.1] octane, methyl, isopropyl, isobutyl, cyclopropyl, pyrazol-1-yl, 4,5, 6, 7-tetrahydro-1H-imidazo [4, 5-c ] pyridin-5-yl, 3, 5,6, 7, 8, 8 a-hexahydroimidazo [1, 2-a ] pyrazin-7-yl, -N (H) R1a), and-N (R1a) (R1b), wherein R1a and R1b are each independently selected from the group consisting of: methyl, ethyl, propyl, butyl, methoxyethyl, ethoxyethyl, hydroxyethyl, methoxypropyl, ethoxypropyl and hydroxypropyl, wherein the aliphatic and/or aromatic moiety of R1 is substituted with 0 to 4 substituents selected from the group consisting of: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fluoro, chloro, bromo, iodo, cyano, methoxymethyl, methoxyethyl, methoxypropyl, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-methylpyrimidin-4-yl, 4-methyltriazol-3-yl, 1, 2, 4-triazol-3-yl, morpholinocarbonyl, morpholino, 2-methyl-pyrimidin-6-yl, 6-methyl-pyrimidin-2-yl, 4-methyl-1, 2, 4-triazol-3-yl, methylaminomethylcarbonyl and hydroxy.

In another embodiment, in the compounds of formula I, R3 is selected from the group consisting of: -F, -Cl, -Br, I, - (X3)0-1-CN, - (X3)0-1-NO2, - (X3)0-1-SF5, - (X3)0-1-OH, - (X3)0-1-NH2, - (X3)0-1-N (H) (R3a), - (X3)0-1-N (R3b) (R3a), - (X3)0-1-CF3, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, C1-6 alkylthio, - (X3)0-1-3-7 membered cycloalkyl, - (X3)0-1-3-7 membered heterocycloalkyl, - (X3)0-1-5-6 membered heteroaryl, - (X3) 0-1-C3 aryl, - (X3)0-1-C (═ Y3) N (H) (R3 3), - (X3)0-1-C (═ Y3) NH 3, - (X3)0-1-C (═ Y3) N (R3 3), - (X3)0-1-C (═ Y3) OR 33, - (X3)0-1-C (═ Y3) OH, - (X3)0-1-N (H) C (═ Y3) (R3 3), - (X3)0-1-N (R3 3) C (═ Y3) (R3 3), X3)0-1-N (H) C (═ Y3) OR 3) OR 0-1-N (R3) C (═ Y3) R3) X3) OR (3) X3) N (3) R3) N (3) 3), - (X3)0-1-N (H) S (O)1-2R3a, - (X3)0-1-N (R3b) S (O)1-2R3a, - (X3)0-1-S (O)0-1N (H) (R3a), - (X3)0-1-S (O)0-1N (R3b) (R3a), - (X3)0-1-S (O)0-1NH2, - (X3)0-1-C (═ Y3) R3a, - (X3)0-1-C (═ Y3) H, - (X3)0-1-NHC (═ Y3) N (H) (R3 3), - (X3)0-1-NHC (═ Y3) NH (X3) X3, - (X3)0-1-NHC (═ Y3) NH (3) X3) N (3) N3) (3), - (X3)0-1-N (R3a) C (═ Y3) N (H) (R3a), - (X3)0-1-N (R3a) C (═ Y3) NH2, wherein Y is O, or alternatively, any two R3 substituents located on adjacent atoms are optionally combined to form a 5-6 membered heteroaryl ring, said 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N, O and S and further containing 0 to 4R 3a substituents, and m is an integer from 1 to 4.

In another embodiment, in the compound of formula I or formula I-I, R3 is selected from the group consisting of: -F, -Cl, -Br, I, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkoxy, - (X3)0-1-N (H) C (═ Y3) (R3a), - (X3)0-1-N (R3b) C (═ Y3) (R3a), - (X3)0-1-C (═ Y3) N (H) (R3a), - (X3)0-1-C (═ Y3) NH2, - (X3)0-1-C (═ Y3) N (R3a) (R3b), thiophene, wherein if R3 is thiophene, or R3a and R3b are independently 3-to 7 membered cycloalkyl, 3-7 membered cycloalkyl-C1-4 alkyl, 3-to 7 membered heterocycloalkyl, 3-6-membered heterocycloalkyl, 3-to 1 membered heterocycloalkyl, 3-397-membered heterocycloalkyl, 3-to 397 membered heterocycloalkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl-C1-4 alkyl, C6 aryl, C6 aryl-C1-4 alkyl or benzyl, then the thiophene, 3-7 membered cycloalkyl-C1-4 alkyl, 3-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, C6 aryl, C6 aryl-C1-4 alkyl or benzyl is substituted with 0 to 4 RA3 substituents, or alternatively, any two R3 substituents located on adjacent atoms are optionally combined to form a thiazole ring further comprising 0 to 4R 3a substituents, and m is an integer from 1 to 4.

In another embodiment, in the compound of formula I or formula I-I, R3 is selected from the group consisting of: trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, tert-butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, thienyl and-C (═ O) NH 2.

In another embodiment, in the compound of formula I or formula I-I, the compound has a subformula selected from the group consisting of:

wherein R3 is selected from the group consisting of: methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclobutyl and methoxy.

In another embodiment, the compound of formula I or formula I-I is selected from the group of compounds in table a.

TABLE A

C. Synthesis of Compounds

For illustrative purposes, schemes 1-3 show general methods for preparing the compounds of the present invention as well as key intermediates. A more detailed description of the individual reaction steps is provided in the examples section below. One skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions. For example, the heterocycloalkyl ring containing X in compounds S1-i, S2-i, and S3-i may contain more than one heteroatom and may also be further substituted with additional substituents. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

In preparing compounds of formula I or I-I, it may be necessary to protect the remote functionality (e.g., primary or secondary amines) of the intermediate. The need for such protection will vary depending on the nature of the distal functionality and the conditions of the preparation process. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by those skilled in the art. For a general description of protecting Groups and their use, see t.w. greene, Protective Groups in Organic Synthesis, john wiley & Sons, new york, 1991.

The ring comprising X in schemes 1-3 represents a NH, O or S containing heterocyclic ring or substituted or oxidized variants thereof and R, R', R "represents a substituent on the compound that does not interfere with the synthetic steps listed in the schemes.

The compounds of the present invention can be prepared according to the synthetic methods outlined in scheme 1. In scheme 1, malonate derivatives are acylated with the cyclic acid S1-i in acetonitrile solvent (MeCN) in the presence of (CDI) carbonyldiimidazole and magnesium dichloride (MgCl2) to form the keto ester S1-ii. Condensation of the ketoester S1-ii with urea under basic reaction conditions yields the pyrimidinedione S1-iii, which can be further converted to the dichloro compound S1-iv after treatment with phosphorus oxychloride (POCl 3). Cross-coupling of 2-aminopyridine with dichloropyrimidine S1-iv palladium provided the N-heteroarylated product S1-v. Replacement of the remaining chlorine on S1-v with an alkylamine or dialkylamine under basic conditions gives compounds S1-vi. Where X in compounds S1-vi is a nitrogen atom protected with an acid labile functional group (e.g., tBoc), treatment of the compound with an acid results in loss of the protecting group, yielding compounds S1-vii, where X is-N (H) -and alkylation of the S1-vii with an alkyl halide, or with an aldehyde and hydride reducing agent under reductive amination conditions, or acylation conditions (e.g., R' C (═ O) Cl and schnixi base and DMAP) can provide compounds of formula I, e.g., compounds S1-viii.

Scheme 1

The compounds of the present invention can be prepared according to the synthetic methods outlined in scheme 2. In scheme 2, ketoester S2-i is condensed with an amidine compound to form the hydroxypyrimidine compound S2-ii using POCl₃After work-up, it is converted into the chloro derivative S2-iii. Palladium-mediated cross-coupling reactions between chloride S2-iii and 2-aminopyridine compounds yielded cross-coupled products S2-iv. In the case where X in compounds S2-iv is a nitrogen atom protected by an acid labile functional group (e.g., tBoc), treatment of the compounds with an acid (e.g., concentrated HCl solution) results in loss of the protecting group, yielding compounds S2-v, where X is-N (H) -, and alkylation of the S2-v compounds with an alkyl halide, or with an aldehyde and hydride reducing agent under reductive amination conditions, or acylation conditions (not shown), can provide compounds of formula I, e.g., compounds S2-vi.

Scheme 2

The compounds of the invention may be prepared as outlined in scheme 3. The 4-cyanopiperidine (piperidine) S3-i is deprotonated with tetramethyllithium piperidine and subjected to substitution/substitution with a trihalopyrimidine derivative to form the pyrimidine compound S3-ii. Palladium-mediated cross-coupling reactions between compounds S3-ii and 2-aminopyridine provided the coupling product S3-iii. Treatment of compounds S3-iii with alkyl or dialkylamine under basic conditions can result in substitution of the chlorine atom to give trisubstituted pyrimidine products S3-iv.

Scheme 3

D. Pharmaceutical compositions and administration

In addition to one or more of the compounds provided above (or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, isotope, pharmaceutically acceptable salt, or prodrug thereof), the present invention also provides compositions and medicaments comprising a compound of formula I or I-I (or any embodiment thereof) and at least one pharmaceutically acceptable carrier, diluent, or excipient. The compositions of the invention may be used to inhibit DLK activity in a patient (e.g., a human).

As described herein, the term "composition" is intended to encompass a product comprising the specified components in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified components in the specified amounts. By "pharmaceutically acceptable" it is meant a carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

In one embodiment, the present invention provides a pharmaceutical composition (or medicament) comprising a compound of formula I or I-I (or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, isotope, pharmaceutically acceptable salt, or prodrug thereof) and a pharmaceutically acceptable carrier, diluent, or excipient. In another embodiment, the invention provides the preparation of a composition (or medicament) comprising a compound of the invention. In another embodiment, the invention provides for the administration of compounds of formula I or I-I and compositions comprising compounds of formula I or I-I to patients in need thereof (e.g., human patients).

The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site at which the formulation is delivered, the method of administration, the timing of administration, and other factors known to the practitioner. The effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit DLK activity as required to prevent or treat an undesirable disease or disorder, such as, for example, neurodegeneration (neuro-degeneration), amyloidosis (amyloidosis), neurofibrillary tangle formation (formation of neurofibrillary tangles), or undesirable cell growth. For example, such an amount may be lower than an amount that is toxic to normal cells or the mammal as a whole.

In one embodiment, a therapeutically effective amount of a compound of the invention per dose administered parenterally will be in the range of about 0.01-100mg/kg, alternatively about, e.g., 0.1 to 20mg/kg patient body weight per day, with a typical starting range of 0.3 to 15 mg/kg/day for the compound used. In certain embodiments, the daily dose is administered as a single daily dose or as divided doses two to six times daily or in a sustained release form. In the case of a 70kg adult, the total daily dose will generally be from about 7mg to about 1,400 mg. The dosing regimen may be adjusted to provide the optimum therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain ingredients conventional in the manufacture of pharmaceuticals, for example, diluents, carriers, pH adjusting agents, sweeteners, fillers, and additional active agents.

The compounds of the invention may be administered by any suitable method, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and supradural and intranasal, and, if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional or subcutaneous administration.

Compositions comprising compounds of formula I or I-I are generally formulated as pharmaceutical compositions according to standard pharmaceutical practice. Typical formulations are prepared by mixing a compound of the invention with a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard c, et al, Ansel's pharmaceutical Dosage Forms and Drug Delivery systems, philiadelphia: lippincott, Williams & Wilkins, 2004; gennaro, Alfonso r., et al Remington: the scientific and Practice of pharmacy Philadelphia: lippincott, Williams & Wilkins, 2000; and Rowe, Raymond c. handbook of Pharmaceutical excipients, chicago, Pharmaceutical press, 2005. The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents (opacifying agents), glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide a pleasing appearance to the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as sugars, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the means and purpose for which the compounds of the present invention are to be employed. Solvents are generally selected according to a solvent (GRAS) deemed safe by one skilled in the art for administration to a mammal. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and the like, and mixtures thereof. The formulations may also include one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, masking agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents and other known additives to provide a pleasing appearance to the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of the drug (i.e., a medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate buffers, citrate buffers, and other organic acid buffers; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexa-hydrocarbyl quaternary ammonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other sugars, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants such as TWEEN^TM，PLURONICS^TMOr polyethylene glycol (PEG). The active pharmaceutical ingredients of the present invention (e.g., compounds of formula I or I-I) may also be encapsulated in microcapsules, e.g., hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, prepared, respectively, by coacervation techniques or by interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions (macroemulsions). This is achieved byThe technique is described in Remington: the Science and practice of Pharmacy: remington the Science and Practice of Pharmacy (2005), 21 st edition, Lippincott Williams&Wilkins, Philidelphia, PA..

Sustained release formulations of the compounds of the invention (e.g., compounds of formula I or I-I) may be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compound of formula I or I-I, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methacrylate), or poly (vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ -ethyl-L-glutamate (Sidman et al, Biopolymers 22: 547, 1983), non-degradable ethylene-vinyl acetate (Langer et al, J.biomed.Mater.Res.15: 167, 1981), degradable lactic-glycolic acid copolymers such as LUPRON DEPOT^TM(injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D- (-) -3-hydroxybutyric acid (EP 133,988A). Sustained release compositions also include liposome-entrapped compounds, which can be prepared by methods known per se (Epstein et al, Proc. Natl. Acad. Sci. U.S.A.82: 3688, 1985; Hwang et al, Proc. Natl. Acad. Sci. U.S.A.77: 4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A). Typically, liposomes are small (about 200-800 angstroms) monolayers, with lipid content greater than about 30 mol% cholesterol, the selected ratio being tailored for optimal treatment.

The formulations include those suitable for the routes of administration detailed herein. The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally described in Remington: the Science and Practice of Pharmacy: remington the Science and Practice of pharmacy (2005), 21 st edition, Lippincott Williams & Wilkins, Philidelphia, Pa. Such methods include the step of associating the active ingredient with the carrier which constitutes one or more accessory ingredients.

The formulations are generally prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents or excipients or finely divided solid carriers, diluents or excipients, or both, and then, if necessary, shaping the product. Typical formulations are prepared by mixing a compound of the invention with a carrier, diluent or excipient. The formulations may be prepared using conventional dissolution and mixing techniques. For example, the drug substance (i.e., a compound of the invention or a stable form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above.

In one example, a compound of formula I or I-I can be formulated by mixing the compound of formula I or I-I at ambient temperature, at a suitable pH, and in the required purity, with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to recipients at the dosages and concentrations used in galenic administration forms). The pH of the formulation depends primarily on the particular use and concentration of the compound, but preferably ranges from any point about 3 to about 8. In one example, a compound of formula I or I-I is formulated in acetate buffer at pH 5. In another embodiment, the compounds of formula I or I-I are sterile. The compounds may be stored, for example, as solid or amorphous compositions, lyophilized formulations, or aqueous solutions.

Formulations of a compound of the invention (e.g., a compound of formula I or I-I) suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of a compound of the invention.

Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally formulated to provide slow or controlled release of the active ingredient therefrom.

Tablets (tablets), troches (troches), lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g. gelatin capsules, syrups or elixirs for oral use may be prepared. Formulations of the compounds of the present invention (e.g., compounds of formula I or I-I) intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide the desired formulation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Examples of suitable oral administration forms are tablets comprising about 1mg, 5mg, 10mg, 25mg, 30mg, 50mg, 80mg, 100mg, 150mg, 250mg, 300mg and 500mg of a compound of the invention admixed with about 90-30mg of anhydrous lactose, about 5-40mg of croscarmellose sodium, about 5-30mg polyvinylpyrrolidone (PVP) K30, and about 1-10mg of magnesium stearate. The powder ingredients are first mixed together and then mixed with the PVP solution. The resulting composition may be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment. An example of an aerosol formulation may be prepared by dissolving, for example, 5 to 400mg of a compound of the invention in a suitable buffer, for example phosphate buffer, and if desired, adding a tonicity agent (tonicifier), for example a salt such as sodium chloride. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

For the treatment of the eye or other external tissues, e.g. mouth and skin, the formulation is preferably applied as a topical ointment or cream comprising the active ingredient in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredient may be employed with one of the ointment bases being miscible with paraffin or water. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include polyhydric alcohols, i.e., alcohols having more than two hydroxyl groups, such as propylene glycol, butane 1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycols (including PEG 400) and mixtures thereof. Topical formulations may suitably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsion of the invention may be constituted by known components in a known manner. Although the phase may comprise only emulsifiers, it suitably comprises a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both oil and fat. In summary, the emulsifier with or without stabilizer constitutes the so-called emulsifying wax, and the wax together with the oil and fat constitutes the so-called emulsifying ointment base which forms the oil dispersed phase of the cream formulation. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include60，80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, and glyceryl monostearateAnd sodium lauryl sulfate.

Aqueous suspensions of the compounds of the invention (e.g., compounds of formula I or I-I) contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of an alkylene oxide with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Formulations of the compounds of the invention (e.g., compounds of formula I or I-I) may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. Such suspensions may be formulated according to known procedures using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol, or as a lyophilized powder. Acceptable carriers and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may comprise from about 1 to 1000mg of the active substance in admixture with a suitable and convenient amount of carrier material which may vary from about 5 to about 95% (weight: weight) of the total composition. The pharmaceutical composition can be prepared to readily provide a measurable amount for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μ g of active ingredient per microliter of solution so that infusion at a rate of about 30mL/hr may occur in a suitable volume.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. Preferably the active ingredient is present in such a formulation at a concentration of about 0.5 to 20% w/w, such as about 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration to the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have a particle size, for example, in the range of 0.1 to 500 microns (including particle sizes in increments of microns such as between 0.1 and 500 microns, 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the lung vesicles. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds previously used to treat conditions as described below.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier for injections, for example water, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the type previously described. Preferred unit dose formulations are those containing a daily dose or unit daily sub-dose of the active ingredient as set out herein above, or a suitable fraction thereof.

Certain embodiments of the present invention provide compounds of formula I or I-I (or embodiments thereof) to cross the blood-brain barrier when the binding target is located in the brain. Certain neurodegenerative diseases are associated with an increase in permeability of the blood-brain barrier, so that compounds of formula I or I-I (or embodiments thereof) can be readily introduced into the brain. While the blood brain barrier is still intact, there are several approaches known in the art for transporting molecules across it, including but not limited to physical methods, lipid-based methods, and receptor and channel-based methods.

Physical methods of transporting a compound of formula I or I-I (or embodiments thereof) across the blood-brain barrier include, but are not limited to, bypassing the blood-brain barrier as a whole, or by establishing an opening at the blood-brain barrier.

Bypassing methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al, Gene therapy 9: 398-406, 2002), interstitial infusion/convection enhanced delivery (see, e.g., Bobo et al, Proc. Natl. Acad. Sci. U.S.A.91: 2076-2080, 1994), and transplantation of delivery devices in the brain (see, e.g., Gill et al, Nature Med.9: 589-595, 2003; and Glaidel Wafers^TMPharmaceutical), guildford. Methods of creating openings in a barrier include, but are not limited to, sonication (see, e.g., U.S. patent publication No. 2002/0038086), osmotic pressure (e.g., by applying hypertonic mannitol (Neuwelt, E.A., immunization of the Blo)od-Brain Barrier and its management, volumes 1 and 2, plenum Press, N.Y., 1989)), and permeabilization by, for example, bradykinin or permeabilizing agent A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

Lipid-based methods of transporting a compound of formula I or I-I (or embodiments thereof) across the blood-brain barrier include, but are not limited to, encapsulating a compound of formula I or I-I (or embodiments thereof) in a liposome coupled to an antibody-binding fragment that binds to a receptor on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. patent application publication No. 2002/0025313), and coating a compound of formula I or I-I (or embodiments thereof) with low-density lipoprotein particles (see, e.g., U.S. patent application publication No. 2004/0204354) or apolipoprotein E (see, e.g., U.S. patent application publication No. 2004/0131692).

Receptor and channel-based approaches to transport compounds of formula I or I-I (or embodiments thereof) across the blood-brain barrier include, but are not limited to, the use of glucocorticoid blockers to increase the permeability of the blood-brain barrier (see, e.g., U.S. patent application publication Nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. patent application publication No. 2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. patent application publication No. 2003/0073713); coating a compound of formula I or I-I (or embodiments thereof) with transferrin and modulating the activity of one or more transferrin receptors (see, e.g., U.S. patent application publication No. 2003/0129186) and cationizing antibodies (see, e.g., U.S. patent No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds may be administered continuously by infusion into a reservoir of the CNS, while bolus injections may be acceptable. The inhibitor may be administered to the ventricles or otherwise introduced into the CNS or spinal fluid. Administration can be by use of an indwelling catheter and continuous administration means such as a pump, or it can be by implantation, for example, intracerebral implantation of a sustained release carrier. More specifically, the inhibitor may be injected by chronic implantation of a cannula or by chronic infusion with the aid of an osmotic micro-pump. A subcutaneous pump may be used to deliver proteins through the tubules to the ventricles. The highly sophisticated pump can be refilled through the skin and its delivery rate can be set without surgical intervention. Examples of suitable administration regimens and delivery systems comprising subcutaneous pump devices or continuous intraventricular infusion via a fully implanted drug delivery system are e.g. those described by Harbaugh, j.neural trans, suppl.24: 271, 1987; and DeYebrenes et al, Mov.Disord.2: 143, 1987, for administering dopamine, dopamine agonists, and cholinergic agonists to alzheimer's patients and animal models of parkinson's disease.

The compounds of formula I or I-I (or embodiments thereof) for use in the present invention are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disorder to be treated, the particular mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the site of agent delivery, the method of administration, the timing of administration, and other factors known to the practitioner. The compounds of formula I or I-I (or embodiments thereof) need not be, but are optionally, formulated with one or more formulations currently used for the prevention or treatment of the disorder under consideration. The effective amount of such other formulations will depend on the amount of the compound of the invention present in the formulation, the type of condition or treatment, and other factors discussed above.

These are generally used at the same dose and in the route of administration as described herein, or about 1 to 99% of the dose described herein, or at any dose and by any route empirically/clinically determined to be appropriate.

For the prevention or treatment of disease, the appropriate dosage of a compound of formula I or I-I (or embodiments thereof) (either alone or in combination with other agents) will depend upon the type of disease to be treated, the nature of the compound, the severity and course of the disease, whether the compound is administered for prophylactic or therapeutic purposes, previous therapy, the patient's clinical history and response to the compound, and the judgment of the attending physician. The compounds are suitable for administration to a patient in a single or continuous therapy. Depending on the type and severity of the disease, about 1 μ g/kg to 15mg/kg (e.g., 0.1mg/kg-10mg/kg) of the compound may be a starting candidate dose for administration to a patient, whether, for example, by more than one divided administration, or by continuous infusion. Depending on the factors mentioned above, a typical daily dosage may range from about 1 μ g kg to 100mg/kg or more. For repeated administration over multiple days or longer, depending on the condition, treatment will generally continue until the desired suppression of disease symptoms occurs. A typical dose of a compound of formula I or I-I (or embodiments thereof) will range from about 0.05mg/kg to about 10 mg/kg. Thus, more than one dose (or any combination thereof) of about 0.5mg/kg, 2.0mg/kg, 4.0mg/kg or 10mg/kg may be administered to a patient. This dose may be administered intermittently, e.g., weekly or every three weeks (e.g., such that the patient receives about two to about twenty, or, e.g., about six doses of antibody). An initial higher loading dose may be administered followed by more than one lower dose. A typical dosing regimen comprises administration of an initial loading dose of about 4mg/kg, followed by a weekly maintenance dose of about 2mg kg of the compound. However, other dosing regimens may be used. This course of treatment is readily monitored by conventional techniques and assays.

Other typical daily dosages may range from, for example, about 1g/kg up to 100mg/kg or more (e.g., about 1 μ g kg to 1mg/kg, about 1 μ g/kg to about 5mg/kg, about 1mg kg to 10mg/kg, about 5mg/kg to about 200mg/kg, about 50mg/kg to about 150mg/mg, about 100mg/kg to about 500mg/kg, about 100mg/kg to about 400mg/kg, and about 200mg/kg to about 400mg/kg), depending on the factors mentioned above. Typically, the clinician will administer the compound until the dose reaches a dose that results in the amelioration or optimal elimination of one or more symptoms of the disease or disorder being treated. This course of treatment is easily monitored by routine assays. More than one agent provided herein can be administered together or at different times (e.g., one formulation is administered prior to administration of a second formulation). More than one agent can be administered to a subject using different techniques (e.g., one agent can be administered orally while a second agent is administered by intramuscular injection or intranasally). More than one agent may be administered such that the more than one agent simultaneously has a pharmacological effect in the subject. Alternatively, more than one agent may be administered such that the pharmacological activity of the first administered agent is ineffective prior to administration of more than one second administered agent (e.g., 1, 2,3, or4 second administered agents).

E. Adaptation and treatment methods

In another aspect, the invention provides methods of inhibiting dual leucine zipper kinase (DLK) in an in vitro (e.g., nerve graft for nerve transplantation) or in an in vivo environment (e.g., in a patient) by contacting DLK present in an in vitro or in vivo environment with a compound of formula I or I-I (or embodiments thereof). In these methods of the invention, inhibition of DLK signaling or expression with a compound of formula I or I-I (or embodiments thereof) results in a decrease in downstream JNK phosphorylation (e.g., a decrease in JNK2 and/or JNK3 phosphorylation), a decrease in JNK activity (e.g., a decrease in JNK2 and/or JNK3 activity), and/or a decrease in JNK expression (e.g., a decrease in JNK2 and/or JNK3 expression). Thus, administration of one or more compounds of formula I or I-I (or embodiments thereof) according to the methods of the invention may result in a reduction in kinase target activity downstream of the DLK signaling cascade, e.g., (I) a reduction in JNK phosphorylation, JNK activity, and/or JNK expression, (ii) a reduction in cJun phosphorylation, cJun activity, and/or cJun expression, and/or (iii) a reduction in p38 phosphorylation, p38 activity, and/or p38 expression.

The compounds of the invention may be used in methods of inhibiting neuronal or axonal degeneration. Thus, the inhibitors are useful for treating, for example, (i) a neurological disorder (e.g., a neurodegenerative disease), (ii) a neurological disorder secondary to a disease, condition, or treatment having a major effect on the exterior of the nervous system, (iii) damage to the nervous system caused by physical, mechanical, or chemical trauma, (iv) pain, (v) vision-related neurodegeneration, (vi) memory loss, and (vii) a psychiatric disorder. Non-limiting examples of some of these diseases, disorders, and injuries are provided below.

Examples of neurodegenerative diseases and disorders that may be prevented or treated according to the invention include Amyotrophic Lateral Sclerosis (ALS), trigeminal neuralgia (trigeminal neuraligia), glossopharyngeal neuralgia (glossopharyngel neuraligia), Bell's Palsy (Bell's Palsy), myasthenia gravis (myasthenia gravis), muscular dystrophy (muscular dystrophy), progressive muscular atrophy (progressive muscular dystrophy), primary lateral sclerosis (primary muscular sclerosis) (PLS), pseudobulbar Palsy (pseudobulbar Palsy), progressive bulbar Palsy (progressive bulbar Palsy), spinal muscular atrophy (spinal muscular atrophy), progressive bulbar Palsy (spinal muscular dystrophy) (e.g. cervical spondylotic disorder), cervical spondylotic disorder (cervical spondylotic disorder), cervical spondylotic disc disorder (cervical spondylotic disc disorder), peripheral Neuropathy (peripheral Neuropathy), porphyria (prophyria), mild cognitive impairment (mild cognitive impairment), Alzheimer's disease, Huntington's disease, Parkinson's disease, parkinsonism's superimposed syndrome (e.g., multiple system atrophy), progressive supranuclear palsy (progressive supranuclear palsy) and corticobasal degeneration (corticobasal degeneration), Lewy body dementia (marginal with Lewy body), frontotemporal dementia (front temporal sclerosis), demyelinating disease (e.g., cervical-spinal syndrome and cervical atrophy), and cervical-spinal muscular atrophy (also known as Sensory atrophy and muscular atrophy), hereditary Sensorimotor Neuropathy (HSMN) and Peroneal muscle atrophy (Peroneal musculantropy)), prion diseases (prion diseases) (e.g., Creutzfeldt-Jakob disease (Creutzfeldt-Jakob disease), Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (fractional family insomnia) (FFI) and Bovine Spongiform Encephalopathy (BSE), commonly referred to as mad cow disease), Pick's disease (Pick's disease), epilepsy (epilepy vda) and AIDS dementia complex (AIDS) (also referred to as HIV dementia (HIV dementia), HIV encephalopathy (HIV) and related cerebral palsy (HIV-associated dementia)).

the methods of the present invention may also be used for the prevention and treatment of vision-related neurodegeneration and related diseases and disorders, such as glaucoma (glaucopia), corneal dystrophy (corneal dystrophy), retinal pigment degeneration (retinitis pigmentosa), age-related macular degeneration (age-related macular degeneration) (AMD), wet or dry AMD-related photoreceptor degeneration (corneal receptor degeneration) and other retinal degeneration (retinal degeneration), optic nerve drusen (optic nerve traction), and optic nerve degeneration (optic nerve degeneration) (e.g. glaucoma), glaucoma (primary open-glaucoma), glaucoma (retinal glaucoma) and glaucoma), glaucoma (secondary open-retinal glaucoma), glaucoma (secondary corneal glaucoma), glaucoma (retinal ischemia-retinal glaucoma), glaucoma (secondary corneal glaucoma), glaucoma (retinal glaucoma), glaucoma (secondary corneal glaucoma), glaucoma (retinal cataract-retinal glaucoma), glaucoma (corneal glaucoma), glaucoma (corneal glaucoma), glaucoma, corneal glaucoma, glaucoma), glaucoma.

Examples of the types of pain that can be treated according to the methods of the invention include those associated with the following conditions: chronic pain, fibromyalgia (fibromyalgia), spinal pain (spinal pain), carpal tunnel syndrome (carpal tunnel syndrome), pain from cancer, arthritis (arthritis), sciatica (sciatic pain), headaches (headaches), pain from surgery, muscle spasms, back pain (back pain), visceral pain (visceral pain), pain from injury, toothache, neuralgia (neuralgia), such as pain from nerves or neuropathic pain, nerve infection or injury, shingles (shingles), herniated disc (herniated disc), ligament tears (trinigiment) and diabetes (diabetes).

Certain diseases and conditions that have a major impact outside the nervous system can lead to damage to the nervous system, which can be treated according to the methods of the present invention. Examples of such conditions include peripheral neuropathy (peripheral neuropathy) and neuralgia (neuropathic pain) caused by, for example, diabetes, cancer, AIDS, hepatitis, renal dysfunction, Colorado tick fever (Colorado tick fever), diphtheria (diphtheria), HIV infection, leprosy (leprosy), lyme disease (lyme disease), polyarteritis nodosa (polyarteritis nodosa), rheumatoid arthritis (rhamatoid arthritis), sarcoidosis (sarcoidosis), Sjogren syndrome (Sjogren syndrome), syphilis (syphilis), systemic lupus erythematosus (systemic lupus erythematosis), and amyloidosis (amyloidosis).

In addition, the methods of the invention may be used to treat nerve damage, such as peripheral neuropathy caused by exposure to toxic compounds, including heavy metals (e.g., lead, arsenic and mercury) and industrial solvents, as well as drugs, including chemotherapeutic agents (e.g., vincristine (vinrisine) and cisplatin), dapsone (dapsone), HIV drugs (e.g., Zidovudine (Zidovudine), Didanosine (Didanosine), Stavudine (Stavudine), Zalcitabine (Zalcitabine), Ritonavir (Ritonavir), and Amprenavir (Amprenavir)), cholesterol lowering drugs (e.g., Lovastatin, indapamide (indapamide), and Gemfibrozil (Gemfibrozil)), cardiac or blood pressure drugs (e.g., Amiodarone (amidarone), Hydralazine (Hydralazine), hexine (Hydralazine), and Metronidazole (Metronidazole).

The methods of the invention may also be used to treat nervous system injury caused by physical, mechanical, or chemical trauma. Thus, the methods may be used to treat peripheral nerve injury caused by physical injury (associated with, for example, burns, wounds, surgery, and accidents), ischemia (ischemia), chronic exposure to low temperatures (e.g., frost damage), and central nervous system injury due to, for example, stroke or intracranial hemorrhage, such as cerebral hemorrhage.

Further, the methods of the invention may be used to prevent or treat memory loss such as, for example, age-related memory loss. The types of memory that can be affected by the loss and thus treated according to the present invention include event memory, semantic memory, short term memory, and long term memory. Examples of memory loss related diseases and disorders that may be treated according to the present invention include mild cognitive impairment (cognitive impairment), alzheimer's disease, parkinson's disease, huntington's disease, chemotherapy, stress, stroke (stroke), and traumatic brain injury (e.g., concussion).

The methods of the invention may also be used to treat psychiatric disorders including, for example, schizophrenia (schizophrenia), delusional disorder (delusional disorder), schizoaffective disorder (schizoaffective disorder), schizophreniform disorder (schizophreniform), shared psychiatric disorder (shared psychiatric disorder), psychiatric disorder (psychosis), paranoid disorder (partial personal disorder), schizophreniform personal disorder (split personal disorder), borderline personal disorder (borderline personal disorder), antisocial personal disorder (anti-social personal disorder), self-social personal disorder (social personal disorder), obsessive personal disorder (social-social disorder), obsessive-compulsive disorder (obsessive-compulsive disorder), bipolar disorder (bipolar disorder), phobia (bipolar disorder), post-traumatic mental disorders (post-traumatic stress disorder), anxiety disorders (anxiety disorders), and impulse control disorders (e.g., kleptomania, pathological gambling, pyromania, and trichotillomania).

In addition to the in vivo methods described above, the methods of the invention may be used to treat nerves ex vivo, which may be helpful in the case of nerve grafts (nerve grafts) or nerve transplants (nerve transplants). Thus, the inhibitors described herein may be used as components of a medium for culturing neural cells in vitro.

Thus, in another aspect, the present invention provides a method of inhibiting or preventing degeneration of a Central Nervous System (CNS) neuron, or portion thereof, comprising administering to the CNS neuron a compound of formula I-I, or an embodiment thereof.

In one embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or portion thereof, said administering to a CNS neuron is performed in vitro.

In another embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or portion thereof, the method further comprises grafting (grafting) or transplanting (transplanting) the CNS neuron into a human patient after administration of the formulation.

In another embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or portion thereof, the CNS neuron is present in a human patient.

In another embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or a portion thereof, said administering to a CNS neuron comprises administering said compound of formula I-I, I or an embodiment thereof in a pharmaceutically acceptable carrier, diluent or excipient.

In another embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or a portion thereof, said administering to a CNS neuron is by a route of administration selected from the group consisting of: parenteral, subcutaneous, intravenous, intraperitoneal, intracerebral, intralesional, intramuscular, intraocular, intraarterial interstitial infusion and implanted delivery devices.

In another embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or portion thereof, the method further comprises administering one or more additional agents.

In another embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or a portion thereof, the administration of a compound of formula I-I, I or embodiments thereof results in a reduction of JNK phosphorylation, JNK activity and/or JNK expression.

In another embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or portion thereof, administration of a compound of formula I-I, I or embodiments thereof results in a decrease in cJun phosphorylation, cJun activity, and/or cJun expression.

In another embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or portion thereof, administration of a compound of formula I-I, I or embodiments thereof results in a reduction of p38 phosphorylation, p38 activity, and/or p38 expression.

In another embodiment, there is provided a method of inhibiting or preventing degeneration of Central Nervous System (CNS) neurons in a patient having or at risk of developing a neurodegenerative disease or disorder, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I-I, I or an embodiment thereof, or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a method of reducing or preventing one or more symptoms of a neurodegenerative disease or disorder in a patient suffering therefrom, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I-I, I or an embodiment thereof, or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a method of reducing the progression of a neurodegenerative disease or disorder in a patient having the neurodegenerative disease or disorder, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I-I, I or an embodiment thereof, or a pharmaceutically acceptable salt thereof.

In another embodiment, the neurodegenerative disease or disorder is selected from the group consisting of: alzheimer's disease, Huntington's disease, Parkinson's plus syndrome, Amyotrophic Lateral Sclerosis (ALS), ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, progressive amyotrophic lateral sclerosis (PLS), pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, invertebrate disc syndrome, cervical spondylosis, plexus disorders, thoracic outlet destruction syndrome, peripheral neuropathy, porphyria, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, frontotemporal dementia, demyelinating disease, Lankan-Barre syndrome, multiple sclerosis, progressive neurosurgical osteoporthias, prion disease, Creutzfeldt-Jakob disease, gerstmann-straussler syndrome (GSS), Fatal Familial Insomnia (FFI), bovine spongiform encephalopathy, pick's disease, epilepsy, AIDS dementia complex, nerve damage caused by exposure to toxic compounds selected from the group consisting of heavy metals, industrial solvents, drugs and chemotherapeutic agents; damage to the nervous system caused by physical, mechanical or chemical trauma, glaucoma, corneal network dystrophy, retinitis pigmentosa, age-related macular degeneration (AMD), wet or dry AMD-related photoreceptor degeneration, other retinal degenerations, optic nerve drusen, optic neuropathy and optic neuritis.

In another embodiment, the compounds of formula I-I are administered in combination with one or more additional agents.

The inhibitor may optionally be administered in combination or in cooperation with other agents known for the treatment of the relevant disease or condition. Thus, for example, in the treatment of ALS, the inhibitor may be administered in combination with Riluzole (Riluzole) (Rilutek), minocycline, insulin-like growth factor 1(IGF-1), and/or methylcobalamin. In another example, in the treatment of parkinson's disease, the inhibitor may be administered with levodopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and lisuride), dopa decarboxylase inhibitors (e.g., levodopa, benserazide, and carbidopa), and/or MAO-B inhibitors (e.g., selegiline and rasagiline). In a further example, in the treatment of alzheimer's disease, the inhibitor may be administered with an acetylcholinesterase inhibitor (e.g., donepezil (donepezil), galantamine (galantamine), and rivastigmine (rivastigmine)) and/or an NMDA receptor antagonist (e.g., memantine). Combination therapy may include simultaneous or sequential administration by the same or different routes as determined to be appropriate by one of skill in the art. The invention also includes pharmaceutical compositions and kits comprising a combination as described herein.

In addition to the combinations mentioned above, the invention includes combinations of inhibitors which are combinations of inhibitors of degeneration of different neuronal regions, including other combinations of the invention, and thus the invention includes combinations of (i) inhibition of neuronal cell body degeneration and (ii) inhibition of axonal degeneration inhibitors, for example, inhibitors of GSK and transcription are found to prevent neuronal cell body degeneration, while inhibitors of EGFR and p38MAPK are found to prevent axonal degeneration the invention thus includes inhibitor combinations of GSK and EGFR (and/or p38MAPK), combinations of transcription inhibitors and EGF (and/or p38MAPK), and further dual leucine zipper-dependent kinases (DLK), glycogen synthase kinase 3 β (GSK3), p38MAPK, EGFF, phosphoinositide 3-kinase (PI3K), cyclin-dependent kinase 5(cdk5), adenylate cyclase, c-Jun N-terminal kinase (jn) bck), BCL-2-related ion-related protein (Bax) kinase inhibitors, as described herein for any of these transcriptional protein kinase inhibitors, e G-05082, or any of these proteins which can be incorporated In the combination of calcium-dependent kinases described herein by reference proteins.

Combination therapy can provide "synergy" and exhibit "synergy", i.e., the effect obtained when the active ingredients are used together is better than the sum of the effects resulting from the separate use of the compounds. When the active ingredients are: (1) co-formulation and administration or delivery simultaneously in a combined, unit dose formulation; (2) delivered alternately or in parallel as separate formulations; or (3) by some other scheme, a synergistic effect can be obtained. When delivered in an alternating therapy, a synergistic effect may be obtained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes, separate pills or capsules, or in separate infusions. Typically, during alternation therapy, the effective dose of each active ingredient is administered sequentially (i.e., consecutively), whereas in combination therapy, the effective doses of two or more active ingredients are administered together.

F. Examples of the embodiments

The invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention. These examples are not intended to limit the scope of the invention, but rather to provide guidance to the skilled artisan in making and using the compounds, compositions, and methods of the invention. While particular embodiments of the present invention have been described, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

The chemical reactions in the described examples can be readily modified to prepare many other compounds of the present invention, and alternative methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, synthesis of compounds according to the present invention, which are not exemplified, can be successfully carried out by modifications apparent to those skilled in the art, e.g., by suitable protection of interfering groups, by use of other suitable reagents known in the art in addition to those described, and/or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered to have applicability for the preparation of other compounds of the invention. Accordingly, the following examples are provided to illustrate, but not to limit, the invention.

In the examples described below, all temperatures are expressed in degrees celsius unless otherwise indicated. Commercially available reagents are purchased from suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge and used without further purification unless otherwise indicated. The reactions set forth below are generally carried out under a positive pressure of nitrogen or argon or in dry tubes (unless otherwise indicated) in anhydrous solvents, and the reaction flasks are typically fitted with rubber septa for introducing substrates and reagents via syringe. The glassware was oven dried and/or heat dried. Column chromatography was carried out on a Biotage System (manufacturer: Dyax Corporation) with a silica column or on silica SEPOn cartridges (Waters); or alternatively column chromatography using an ISCO chromatography system with a silica gel column (manufacturer: Teledyne ISCO). Recording on a Varian instrument operating at 400MHz¹H NMR spectrum. Tetramethylsilane (TMS) was used as a reference standard (0ppm) in deuterated CDCl₃，d₆-DMSO，CH₃OD or d₆-in acetone solution¹H NMR spectrum (reported in ppm). When reporting the multiplicity of peaks, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad range), dd (doublet), dt (doublet triplet). Coupling constants, when given, are reported as Hertz (Hz).

The product formed in the reaction mixture was monitored by LC/MS, if possible. On an Agilent 1200 Series LC coupled with 6140 quadrupole mass spectrometer, a Supelco Ascentis Express C18 column was used with a linear gradient of 5% -95% acetonitrile/water (with 0.1% trifluoroacetic acid in each mobile phase) and held at 95% for 0.3 min, or a Phenomenex DNYC single C18 column was used with a linear gradient of 5% -95% acetonitrile/water (in each case) on a PE Sciex API 150 EXWith 0.1% trifluoroacetic acid in each mobile phase (over 5 minutes) and at 95% hold for 1 minute, high pressure liquid chromatography-mass spectrometry (LCMS) experiments were performed to determine retention time (R)_T) And the associated mass ions.

All abbreviations used to describe reagents, reaction conditions, or equipment used are consistent with the definitions set forth in "Standard abbreviations and acronyms (List of Standard abbreviations and acronyms)" published annually by Journal of organic Chemistry. The chemical name of each compound of the invention was obtained using the structural naming feature ChemBioDraw Version 11.0 or the compound naming program from Accelrys' Pipeline Pilot IUPAC.

Example 1

Preparation of 3- (2, 6-dichloropyrimidin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester:

step 1-synthesis of tert-butyl 3- (3-ethoxy-3-oxopropanoyl) pyrrolidine-1-carboxylate:

to a solution of pyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester (120g, 0.55mols) in anhydrous acetonitrile (1200mL) carbonyl diimidazole (110g, 0.67mols) was added in small portions at ambient temperature. The resulting mixture was stirred for 1 h. To the resulting vigorously stirred solution was added a mixture of potassium monoethylmalonate (95g, 0.55mols) and magnesium chloride (54g, 0.55 mols). The slurry was stirred at ambient temperature for 16 h. After the reaction is finishedThe solvent was evaporated in vacuo. The residue was diluted with cold water. The resulting mixture was neutralized with citric acid and extracted with dichloromethane (3 × 400 mL). The combined organic layers were evaporated to dryness. Purification by column chromatography (silica gel 60-120 mesh, ethyl acetate/hexanes) afforded 3- (2-ethoxycarbonyl-acetyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (138g, 87%):¹H NMR(300MHz，DMSO-d₆80 ℃ C. delta.1.2 (m, 3H), 1.41(s, 9H), 1.93-1.98(m, 1H), 2.07-2.11(m, 1H), 3.23-3.46(m, 5H), 3.64(m, 2H) and 4.09-4.15(m, 2H).

Step 2-synthesis of tert-butyl 3- (2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) pyrrolidine-1-carboxylate:

3- (2-ethoxycarbonyl-acetyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (100g, 0.35mols), and urea (126g, 2.1mols) were added to sodium ethoxide (913mL, 2.8mols, 21% ethanol solution) and the resulting mixture was refluxed for 72h (TLC control). After completion of the reaction, the solvent was evaporated in vacuo. The residue was dissolved in water. The resulting mixture was neutralized with citric acid and extracted with dichloromethane (3x300 mL). The combined organic layers were washed with water (2 × 300mL) and saturated brine solution (1 × 300mL) and evaporated to dryness. Purification by column chromatography (silica gel 60-120 mesh, methanol/chloroform) afforded 3- (2, 6-dihydroxy-pyrimidin-4-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (44g, 45%):¹H NMR(300MHz，DMSO-d₆) δ 1.38(s, 9H), 1.91-2.10(m, 2H), 3.00-3.23(m, 3H), 3.32(m, 1H), 3.56(m, 1H), 5.31(s, 1H), 10.83-10.85(br, 1H) and 10.98 (broad, 1H); LCMS: 279.9 (M-1).

Step 3Synthesis of tert-butyl 3- (2, 6-dichloropyrimidin-4-yl) pyrrolidine-1-carboxylate:

3- (2, 6-dihydroxy-pyrimidin-4-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (40g, 0.142mols) was placed in phosphorus oxychloride (200mL) and heated to reflux for 3 h. After completion of the reaction, the mixture was concentrated to 90% of the total volume and poured into crushed ice. Solid sodium bicarbonate was added slowly and the pH of the solution was adjusted to 9. Tetrahydrofuran (500mL) and di-tert-butyl dicarbonate (46.53g, 0.213mols) were added and the resulting mixture was stirred at ambient temperature for 16h (TLC control). After completion of the reaction, the mixture was filtered and the filtrate was extracted with dichloromethane (3 × 200 mL). The combined organic layers were washed with water (3 × 200mL), saturated brine solution (200mL) and evaporated to dryness. Purification by column chromatography (silica gel, 60-120 mesh, ethyl acetate/hexanes) afforded 3- (2, 6-dichloro-pyrimidin-4-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (20.8g, 46%):¹H NMR(400MHz，DMSO-d₆) δ 1.4(s, 9H), 2.05(m, 1H), 2.24(m, 1H), 3.27-3.70(m, 5H), and 7.8(s, 1H); LCMS: 316.3 (M-2).

The further compounds of the invention in table 1 below were prepared by the methods already described elsewhere in the application.

TABLE 1

Example 2

Preparation of (R) -2- (2-methylpyrrolidin-1-yl) -6- (piperidin-4-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) pyrimidin-4-amine:

step 1Synthesis of tert-butyl (R) -4- (2- (2-methylpyrrolidin-1-yl) -6- (4- (trifluoromethyl) pyridin-2-ylamino) pyrimidin-4-yl) piperidine-1-carboxylate:

the vial was loaded with example 1-d (1.00g, 3.01mmol), 2-amino-4- (trifluoromethyl) pyridine (537mg, 3.31mmol), tris (dibenzylideneacetone) dipalladium (0) (138mg, 0.15mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (180mg, 0.30mmol), and sodium tert-butoxide (420mg, 4.21 mmol). Capping the vials and applying N₂Purging, followed by addition of twoAlkane (6 mL). The resulting mixture was heated at 60 ℃ for 2 h. The dark mixture was diluted with 50% DCM/EtOAc (50mL) and filtered through paper. The filtrate was concentrated on Celite and chromatographed (24g SiO)₂Column, 0-50% ethyl acetate-heptane) to afford 820mg (53%) of the title compound as an off-white solid:¹H NMR(400MHz，CDCl₃)δ8.16(d，J＝5.3Hz，1H)，7.94(s，1H)，7.55(s，1H)，7.04(s，1H)，6.66(d，J＝5.2Hz，1H)，4.25(s，2H)，2.97-2.59(m，3H)，2.00-1.79(m，3H)，1.79-1.56(m，3H)，1.47(s，9H)，1.36-1.17(m，3H)，1.17-1.01(m，2H)，0.98-0.72(m，4H)；MS m/z＝459(M+H⁺)。

step 2Synthesis of tert-butyl (R) -4- (2- (2-methylpyrrolidin-1-yl) -6- (4- (trifluoromethyl) pyridin-2-ylamino) pyrimidin-4-yl) piperidine-1-carboxylate:

a solution of example 2-a (1.25g, 2.73mmol), (2R) -2-methylpyrrolidine (465mg, 5.46mmol) and dimethylformamide (5.0mL) in a sealed vial was dissolved in 80Heating at deg.C for 5 h. The reaction mixture is saturated with NH₄Aqueous Cl (50mL) was diluted and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with water (1x10mL), brine (1x10mL) and dried (Na)₂SO₄) Filtered and concentrated on Celite. By chromatography (SiO)₂40g column 0-40% ethyl acetate-heptane) to afford 1.00g (72%) of the title compound as a colorless solid:¹H NMR(400MHz，CDCl₃)δ8.85(s，1H)，8.36(d，J＝5.2Hz，1H)，7.24(s，1H)，7.08(d，J＝5.2Hz，1H)，5.85(s，1H)，4.40-4.26(m，1H)，4.26-4.09(m，2H)，3.67(ddd，J＝10.5，7.3，3.2Hz，1H)，3.62-3.44(m，1H)，2.82(t，J＝12.4Hz，2H)，2.54(tt，J＝11.6，3.6Hz，1H)，2.20-1.99(m，2H)，1.99-1.91(m，1H)，1.87(d，J＝13.4Hz，2H)，1.72(dd，J＝15.2，9.9Hz，3H)，1.48(s，9H)，1.28(d，J＝6.3Hz，4H)；MS m/z＝507(M+H⁺)。

step 3Synthesis of- (R) -2- (2-methylpyrrolidin-1-yl) -6- (piperidin-4-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) pyrimidin-4-amine (2-c). Adding 2-b (100mg, 0.22mmol) in twoA solution in alkane (2mL) and MeOH (1mL) was treated with a stream of HCl (g) for 10 seconds. The vial was capped and maintained at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to afford the title compound as a colorless solid:¹H NMR(400MHz，MeOD)δ8.62(d，J＝5.1Hz，1H)，7.45(d，J＝5.1Hz，1H)，4.63-4.44(m，1H)，3.84(t，J＝8.5Hz，1H)，3.58(d，J＝13.0Hz，2H)，3.25-3.05(m，3H)，2.36-2.06(m，5H)，2.06-1.80(m，3H)，1.36(d，J＝6.4Hz，3H)；MS m/z＝407(M+H⁺)。

the additional compounds of the invention in table 2 below were prepared by methods already described elsewhere in the application.

TABLE 2

Example 3

Preparation of (R) -1- (4- (2- (2-methylpyrrolidin-1-yl) -6- (4- (trifluoromethyl) pyridin-2-ylamino) pyrimidin-4-yl) piperidin-1-yl) ethanone

To a cooled (0 ℃ C.) solution of example 2-c (1.97mmol), 4- (dimethylamino) pyridine (49mg, 0.40mmol) and N, N-diisopropylethylamine (1.72mL, 9.90mmol) in acetonitrile (10mL) and dichloromethane (10mL) was added acetic anhydride (0.211mL, 2.17 mmol). The solution was kept at 0 ℃ for 1h and then 100mL of saturated NH was poured₄Aqueous Cl and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (1 × 10mL) and dried (Na)₂SO₄) Filtered and concentrated to a colorless solid. Purification by HPLC provided 430mg (49%) of the title compound as a colorless solid:¹H NMR(400MHz，CDCl₃)δ8.83(s，1H)，8.37(d，J＝5.2Hz，1H)，7.24(s，1H)，7.09(d，J＝5.1Hz，1H)，5.90(d，J＝30.7Hz，1H)，4.70(d，J＝12.6Hz，1H)，4.39-4.22(m，1H)，3.91(d，J＝13.5Hz，1H)，3.67(ddd，J＝10.2，7.3，3.1Hz，1H)，3.62-3.44(m，1H)，3.25-3.08(m，1H)，2.79-2.50(m，2H)，2.13(s，3H)，2.07(ddd，J＝13.5，9.1，4.4Hz，2H)，2.01-1.82(m，3H)，1.82-1.62(m，3H)，1.28(d，J＝6.3Hz，3H)；MS m/z＝449(M+H⁺)。

the additional compounds of the invention in table 3 below were prepared by methods already described elsewhere in the application.

TABLE 3

Example 4

Synthesis of (R) -6- (1-methylpiperidin-4-yl) -2- (2-methylpyrrolidin-1-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) pyrimidin-4-amine.

Formic acid at 25 ℃; 2- [ (2R) -2-Methylpyrrolidin-1-yl)]-6- (4-piperidinyl) -N- [4- (trifluoromethyl) -2-pyridinyl]Pyrimidin-4-amine (18 mg; 0.03978mmol) in 1, 4-bisTo the suspension of the alkane (300 equiv.; 11.93mmol) was added an aqueous solution of formaldehyde (37 mass%) (10.0 equiv.; 0.3978mmol) and the reaction was stirred at 60 ℃ for 2h to give a clear solution. After HPLC purification, the desired product was obtained (12.9mg, 78% yield) as a white powder:¹H NMR(400MHz，DMSO-d₆)δ10.11(s，1H)，8.85(s，1H)，8.50(d，J＝5.1Hz，1H)，7.25(d，J＝5.1Hz，1H)，6.29(s，1H)，4.28-4.13(m，1H)，3.51(dt，J＝16.1，7.8Hz，2H)，2.83(d，J＝11.3Hz，2H)，2.28(m，1H)，2.17(s，3H)，2.10-1.83(m，5H)，1.79-1.61(m，5H)，1.22(d，J＝6.3Hz，3H)；MS m/z＝421(M+H⁺)。

other compounds of the invention in table 4 below were prepared by the methods already described in the application.

TABLE 4

Example 5

Preparation of (R) -N- (4-cyclopropylpyridin-2-yl) -2- (2-methylpyrrolidin-1-yl) -6- (tetrahydro-2H-pyran-4-yl) -pyrimidin-4-amine.

Step 1Synthesis of (E) -2-chloro-N- (4-cyclopropylpyridin-2-yl) -6- (tetrahydro-2H-pyran-4-yl) -pyrimidin-4-amine.

The vial was loaded with example 1-f (250mg, 1.07mmol), 2-amino-4- (cyclopropyl) pyridine (160mg, 1.18mmol), tris (dibenzylideneacetone) dipalladium (0) (50mg, 0.054mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (64mg, 0.11mmol), and sodium tert-butoxide (150mg, 1.5 mmol). Capping the vials and applying N₂Purging, followed by addition of twoAlkane (2 mL). The resulting mixture was heated at 60 ℃ for 2 h. The dark mixture was diluted with 50% DCM/EtOAc (20mL) and filtered through paper. The filtrate was concentrated on Celite and chromatographed (12g SiO)₂Column, 0-50% ethyl acetate-heptane) to afford 106mg (30%) of the title compound as an off-white solid:¹H NMR(400MHz，CDCl₃)δ8.16(d，J＝5.3Hz，1H)，8.13-8.02(m，2H)，7.52(s，1H)，7.08(s，1H)，6.66(d，J＝5.3Hz，1H)，4.18-3.97(m，2H)，3.65-3.34(m，2H)，2.91-2.68(m，1H)，2.18(s，1H)，1.98-1.76(m，6H)，1.38-1.18(m，2H)，1.18-1.02(m，2H)，0.96-0.74(m，2H)；MS m/z＝329(M+H⁺)。

step 2Synthesis of- (R) -N- (4-cyclopropylpyridin-2-yl) -2- (2-methylpyrrolidin-1-yl) -6- (tetrahydro-2H-pyran-4-yl) -pyrimidin-4-amine. A solution of example 5-a (100mg, 0.30mmol), (2R) -2-methylpyrrolidine (51mg, 0.60mmol) and dimethylformamide (1.0mL) was heated at 80 ℃ for 7h in a sealed vial. The mixture was purified directly by HPLC to provide 62mg (54%) of the title compound as a colorless solid:¹H NMR(400MHz，DMSO-d₆)δ9.45(s，1H)，8.04(d，J＝5.2Hz，1H)，8.00(s，1H)，6.68(d，J＝5.0Hz，1H)，6.34(s，1H)，4.23(s，1H)，3.92(d，J＝11.3Hz，2H)，3.64-3.46(m，2H)，3.40(dt，J＝17.6，7.0Hz，2H)，2.62-2.52(m，1H)，2.15-1.95(m，2H)，1.95-1.80(m，2H)，1.79-1.56(m，5H)，1.24(d，J＝6.2Hz，3H)，1.14-0.95(m，2H)，0.76(d，J＝4.5Hz，2H)；MS m/z＝380.2(M+H⁺)。

other compounds of the invention in table 5 below were prepared by the methods already described in the application.

TABLE 5

Example 6

Preparation of 6- (1- ((1H-imidazol-2-yl) methyl) pyrrolidin-3-yl) -2- (3, 3-difluoropyrrolidin-1-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) pyrimidin-4-amine.

Compound 2-v (50mg, 0.11mmol), 1H-imidazole-2-carbaldehyde (13mg, 0.14mmol) and NaBH (CN) in DMF (5.0mL)₃(35mg, 0.56mmol) was stirred at 80 ℃ for 16 h. The mixture was directly purified by HPLC to give the title compound (3.5mg, 5.0%):¹H NMR(400MHz，MeOD)δ8.65(d，J＝5.2Hz，1H)，8.42(s，1H)，7.70(s，2H)，6.84(s，1H)，7.47-7.44(m，1H)，6.83(s，1H)，4.74-4.70(m，2H)，4.15-4.05(m，2H)，4.04-3.98(m，2H)，3.90-3.80(m，1H)，3.75-3.65(m，2H)，3.64-3.55(m，1H)，3.50-3.40(m，1H)，2.75-2.65(m，3H)，2.35-2.25(m，1H)；MS m/z＝495(M+H⁺)。

other compounds of the invention in table 6 below were prepared by the methods already described in the application.

TABLE 6

Example 7

Synthesis of 1- (3- (2- (1-methyl-1H-pyrazol-4-yl) -6- (4-methylpyridin-2-ylamino) pyrimidin-4-yl) piperidin-1-yl) ethanone.

Step 1Synthesis of tert-butyl (E) -3- (2- (1-methyl-1H-pyrazol-4-yl) -6- (4-methylpyridin-2-ylamino) pyrimidin-4-yl) piperidine-1-carboxylate.

Tert-butyl 3- (2-chloro-6- (4-methylpyridin-2-ylamino) pyrimidin-4-yl) piperidine-1-carboxylate (180mg, 0.45mmol), 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (187mg, 0.90mmol), Cs₂CO₃(293mg，0.90mmol)，Pd(dppf)Cl₂(16mg, 0.0225mmol) and bisalkane/H₂A mixture of O (6: 1) (8.0mL) was heated at 160 ℃ for 30mins under microwave. After removal of the solvent, the residue was purified by column (PE: EA ═ 2: 3) to give the title compound (170mg, yield: 74.9%): MS M/z 450.2(M + H)⁺)。

Step 2Synthesis of (E) -2- (1-methyl-1H-pyrazol-4-yl) -N- (4-methylpyridin-2-yl) -6- (piperidin-3-yl) pyrimidin-4-amine。

To a solution of compound 7-a (180mg, 040mmol) in EA (30.0mL) was added 4M HCl/EA (20 mL). The mixture was stirred at room temperature for 3 h. After removal of the solvent, the residue was lyophilized to yield the desired compound in quantitative yield:¹HNMR(400MHz，MeOD)δ8.52(s，1H)，8.40(d，J＝6.4Hz，1H)，8.23(s，1H)，7.30-7.26(m，2H)，6.86(s，1H)，3.93(s，3H)，3.56-3.53(m，1H)，3.39-3.31(m，2H)，3.24-3.22(m，1H)，3.05-3.02(m，1H)，2.51(s，3H)，2.12-2.06(m，1H)，1.97-1.96(m，1H)，1.87-1.80(m，2H)；MS m/z＝349.9(M+H⁺). Alternatively, the compound may be purified by HPLC.

Step 3Synthesis of (E) -1- (3- (2- (1-methyl-1H-pyrazol-4-yl) -6- (4-methylpyridin-2-ylamino) pyrimidin-4-yl) piperidin-1-yl) ethanone. To example 7-b (30mg, 0.068mmol), DCM (20mL) and Et₃To a mixture of N (0.5mL) was added acetyl chloride (5.3mg, 0.068 mmol). The mixture was stirred at room temperature for 15 min. The solvent was removed and the residue was purified by HPLC to give the title compound (12.9mg, 48.7%):¹H NMR(400MHz，CDCl₃)δ8.18-8.12(m，2H)，8.05(d，J＝2.4Hz，1H)，7.54-7.51(m，1H)，7.42-7.13(m，1H)，6.80(t，J＝6.0Hz，1H)，4.76-4.53(m，1H)，3.99-3.81(m，4H)，3.48-3.12(m，1H)，2.98-2.79(m，2H)，2.38(s，3H)，2.14(s，3H)，2.09-2.13(m，1H)，1.90-1.82(m，2H)，1.64-1.58(m，1H)；MS m/z＝392(M+H⁺)。

other compounds of the invention in table 7 below were prepared by the methods already described in the application.

TABLE 7

Example 8

Synthesis of 3- (6-chloro-2-cyclopentylpyrimidin-4-yl) azetidine-1-carboxylic acid tert-butyl ester.

Step 1Synthesis of tert-butyl (3- (2-cyclopentyl-6-hydroxypyrimidin-4-yl) azetidine-1-carboxylate.

In N₂Next, a mixture of tert-butyl 3- (3-ethoxy-3-oxopropanoyl) azetidine-1-carboxylate (3.25g, 12.0mmol), cyclopentane carboxamidine hydrochloride (4.45g, 30.0mmol), NaOMe (1.95g, 3eq) and anhydrous MeOH (200mL) was heated at reflux overnight. TLC (DCM: MeOH ═ 20: 1, R_f0.35) showed the reaction was complete and MeOH was removed under reduced pressure. Water was added and the pH adjusted to 5-6 with citric acid, extracted with DCM (60mLx 3), over Na₂SO₄Dried and concentrated. The residue is led toPurification by silica gel flash chromatography gave the desired product (2.8g, yield: 45.0%):¹H NMR(CDCl₃，400MHz)，δ：12.56(s，1H)，6.17(s，1H)，4.19-4.15(t，J＝8.4Hz，2H)，4.10-4.07(m，2H)，3.61-3.55(m，1H)，3.08-3.00(m，1H)，2.09-1.61(m，8H)，1.46(s，9H)。

step 2Synthesis of tert-butyl (3- (6-chloro-2-cyclopentylpyrimidin-4-yl) azetidine-1-carboxylate. In N₂Under the atmosphere, compound 8-a (20mmol), PPh₃(80mmol) and CCl₄(0.2mol) the mixture in DCE (100mL) was stirred at reflux for 2-3 hours. LCMS and TLC (PE: EA 5: 1, R)_f0.75) showed the reaction was complete. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography to give (1226.5mg, 35%) of the pure product:¹H NMR(400MHz，MeOD)，δppm：7.05(s，1H)，4.29-4.24(m，2H)，4.15-4.12(m，2H)，3.77-3.72(m，1H)，3.37-3.31(m，1H)，2.10-2.04(m，2H)，1.94-1.87(m，4H)，1.72-1.65(m，2H)，1.47(s，9H)。

other compounds of the invention in table 8 below were prepared by the methods already described in the application.

TABLE 8

Example 9

Preparation of 1-acetyl-4- (2- (3, 3-difluoropyrrolidin-1-yl) -6- (4- (trifluoromethyl) pyridin-2-ylamino) pyrimidin-4-yl) piperidine-4-carbonitrile.

Step 1Synthesis of tert-butyl (4-cyano-4- (2, 6-dichloropyrimidin-4-yl) piperidine-1-carboxylate.

To a solution of n-butyllithium (1.6mol/l in hexane; 4.5mL, 7.13mmol, 1.5 equiv.) in tetrahydrofuran (50mL) was added 2, 2, 6, 6-tetramethylpiperidine (1.07mL, 6.18mmol, 1.3 equiv.) at-78 deg.C, and the reaction was held at-78 deg.C for 5 minutes and then at 0 deg.C for 5 minutes, then cooled to-78 deg.C again. A solution of 1-N-Boc-4-cyano-piperidine (1.00 g; 4.76mmol) in tetrahydrofuran (50mL) was added dropwise over 5 minutes. The temperature was allowed to rise to-40 ℃ and a solution of 2, 4, 6-trichloropyrimidine (2.23mL, 19.0mmol, 4 equiv.) in tetrahydrofuran (20mL) was added rapidly. The reaction was allowed to warm to 25 ℃ and stirred for 4 h. The reaction was diluted with EtOAc and 10% citric acid and washed with water (2 ×) and brine until pH 7. After evaporation, the residue is chromatographed (24g SiO₂Column, 0-50% ethyl acetate-heptane) and provided 705mg (41% yield) of the title compound as a film which solidified during storage.¹H NMR(400MHz，CDCl₃)δ7.65(s，1H)，4.34(d，J＝7.1Hz，2H)，3.15(s，2H)，2.22(d，J＝4.3Hz，2H)，2.00(d，J＝13.2Hz，2H)，1.48(s，9H)；MS(M+H⁺)m/z＝357。

Step 2-4- (2-chloro-6- (4- (trifluoromethyl) pyridin-2-ylamino) pyrimidin-4-yl) -4-Synthesis of tert-butyl cyanopiperidine-1-carboxylate.

4-cyano-4- (2, 6-dichloropyrimidin-4-yl) piperidine-1-carboxylic acid tert-butyl ester (200mg, 0.55mmol), 2-amino-4- (trifluoromethyl) pyridine (180mg, 1.1mmol), Pd, at 80 ℃₂(dba)₃(50mg, 0.10eq), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (XantPhos, 68mg, 0.21eq), sodium tert-butoxide (109mg, 2.0eq) and 1, 4-bis (diphenylphosphino) were addedA mixture of alkanes (2.8mL) was heated for 30 min. The reaction was diluted with EtOAc and water and the final pH was adjusted to about 7 using 10% aqueous citric acid. The EtOAc layer was washed twice with water and once with brine, then over MgSO₄And (5) drying. After evaporation of the organic solvent, the residue is chromatographed (12g SiO₂Column, 0-30% EtOAc/DCM) and provided 163mg (53% yield) of the title compound as a yellow solid.¹H NMR(400MHz，CDCl₃)δ8.55(d，J＝5.2Hz，1H)，8.00(s，1H)，7.83(s，1H)，7.74(s，1H)，4.31(s，2H)，3.16(s，2H)，2.27(td，J＝13.2，4.3Hz，2H)，2.00(d，J＝13.2Hz，2H)，1.49(s，9H)；MS(M+H⁺)m/z＝483。

Step 3Synthesis of tert-butyl (4-cyano-4- (2- (3, 3-difluoropyrrolidin-1-yl) -6- (4- (trifluoromethyl) pyridin-2-ylamino) pyrimidin-4-yl) piperidine-1-carboxylate.

4- [ 2-chloro-6- [ [4- (trifluoromethyl) -2-pyridinyl ] at 65 ℃]Amino group]Pyrimidin-4-yl]-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (163mg, 0.29mmol), 3, 3-difluoropyrrolidine hydrochloride (64mg, 1.5eq), N, N-diisopropylethylamine (0.15ml, 3.0eq),and 1, 4-bisA solution of alkane (1.5ml) was heated for 2h while LCMS indicated completion of the reaction. The crude product was used directly in the next step without further purification. MS (M + H)⁺)m/z＝554。

Step 4Synthesis of (E) -4- (2- (3, 3-difluoropyrrolidin-1-yl) -6- (4- (trifluoromethyl) pyridin-2-ylamino) pyrimidin-4-yl) piperidine-4-carbonitrile.

Tert-butyl 4-cyano-4- (2- (3, 3-difluoropyrrolidin-1-yl) -6- (4- (trifluoromethyl) pyridin-2-ylamino) pyrimidin-4-yl) piperidine-1-carboxylate (50mg, 0.09mmol) and hydrogen chloride (4mol/l) were added to the solutionThe suspension in alkane (0.60mL, 25eq) was held at 25 ℃ for 2 h. After HPLC purification, 16.5mg (40% yield) of the title compound is obtained as a white powder.¹H NMR(400MHz，DMSO-d₆)δ10.53(s，1H)，8.70(s，1H)，8.55(d，J＝5.2Hz，1H)，7.34(d，J＝5.1Hz，1H)，6.84(s，1H)，3.92(t，J＝13.1Hz，2H)，3.76(t，J＝7.3Hz，2H)，3.03(d，J＝12.9Hz，2H)，2.77(t，J＝11.3Hz，2H)，2.64-2.52(m，2H)，2.03-1.82(m，4H)；MS(M+H⁺)m/z＝454。

Step 5Synthesis of (E) -1-acetyl-4- (2- (3, 3-difluoropyrrolidin-1-yl) -6- (4- (trifluoromethyl) pyridin-2-ylamino) pyrimidin-4-yl) piperidine-4-carbonitrile (10-e)

To 4- [2- (3, 3-difluoropyrrolidin-1-yl) -6- [ [4- (trifluoromethyl) -2-pyridinyl]Amino group]Pyrimidin-4-yl]To a solution of piperidine-4-carbonitrile (30 mg; 0.06617mmol) and DMAP (1.0mg, 0.007mmol, 0.10 equiv.) in N-ethyldiisopropylamine (0.035mL, 3.0 equiv.) and dichloromethane (1mL) was added acetic anhydride (0.0095mL, 0.09925mmol, 1.5 equiv.), and the reaction was takenStir at rt for 2 h. After HPLC purification, 23mg (70% yield) of the title compound are obtained as a white powder.¹H NMR(400MHz，CDCl₃)δ8.60(s，1H)，8.44(d，J＝5.1Hz，1H)，7.46(s，1H)，7.17(d，J＝5.1Hz，1H)，6.55(s，1H)，4.81(d，J＝14.3Hz，1H)，3.95(t，J＝12.9Hz，3H)，3.85(t，J＝7.2Hz，2H)，3.53(t，J＝13.5Hz，1H)，2.99(t，J＝13.3Hz，1H)，2.57-2.41(m，2H)，2.29-1.95(m，7H)；MS(M+H⁺)m/z＝496。

Other compounds of the invention in table 10 below were prepared by the methods already described in the application.

Watch 10

Example 11

Synthesis of 2-isopropyl-6- (1- (methylsulfonyl) azetidin-3-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) pyrimidin-4-amine.

To a solution of 6- (azetidin-3-yl) -2-isopropyl-N- (4- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-amine (0.037g, 0.1 mmoles) in anhydrous dimethylformamide (1mL), and triethylamine (0.042mL, 0.3 mmoles) was added methanesulfonyl chloride (0.015mL, 0.2 mmoles), and the mixture was stirred at ambient temperature for 16 h. After completion of the reaction, the solvent was evaporated in vacuo. The residue was purified by reverse phase HPLC chromatography (C1810. mu.M, 30X 100mm, 0.01% aqueous ammonium hydroxide/acetonitrile) to afford 2-isopropyl-6- (1- (methylsulfonyl) amideYl) azetidin-3-yl) -N- (4- (trifluoromethyl) pyridin-3-yl) pyrimidin-4-amine (12.5mg, 34%) as a white solid.¹H NMR(400MHz，DMSO-d₆)δ10.55(d，J＝14.9Hz，1H)，8.56(d，J＝5.2Hz，2H)，7.33(d，J＝5.8Hz，1H)，7.23(s，1H)，4.20-4.06(m，4H)，4.00-3.83(m，1H)，3.09(d，J＝11.1Hz，3H)，3.08-2.99(m，1H)，1.30(t，J＝7.4Hz，6H)；MS(M+H⁺)m/z＝416。

Example 12

DLK TR-FRET assay: in 384-well OptiPlates (Perkin Elmer), the medium containing the protein in kinase reaction buffer (50mM HEPES, pH 7.5, 0.01% Triton X-100, 0.01% bovine gamma-globulin, 2mM DTT, 10mM MgCl)₂And 1mM EGTA) 5nM of N-terminal GST-tag labeled DLK (catalytic domain amino acids 1-520) (Carna bioscience), 40nM of MKK4K131M substrate labeled with N-terminal HIS-tag, and 30 μ M ATP of DLK kinase reaction (20 μ L), and test compound diluted 1: 3 in series starting at 20 μ M were incubated at ambient temperature for 60 minutes. To quench the kinase reaction and detect phosphorylated MKK4, 15 μ L of TR-FRET antibody mixture containing 2nM anti-phosphorylated MKK4(Cisbio) labeled with Europium cryptate (europia cryptate) and 23nM anti-HIS labeled with D2 (Cisbio) in detection buffer (25mM Tris pH 7.5, 100mM NaCl, 100mM edta, 0.01% Tween-20 and 200mM KF) was added to the reaction mixture. The detection mixture was incubated at ambient temperature for 3 hours and TR-FRET was detected with an EnVision Multi-Label plate reader (Perkin-Elmer) using the LANCE/DELFIA Dual Enh labels from the Perkin-Elmer (excitation filter: UV2(TRF)320 and emission filters: APC 665 and Europium 615). Compounds of formula I as listed in Table A with K as provided in Table B below_is inhibits DLK kinase.

TABLE B

Example 13

Assay based on pJNK cells: HEK293 cells stably transfected with N-terminal Flag-tagged full-length DLK inducible by doxycycline were plated at a density of 7500 cells/well (40 μ Ι _) on 384-well Greiner bio-one μ clear plates coated with poly-D-lysine. Cells were incubated in DMEM (Dulbecco's Modified Eagle Medium) Medium containing 10% FBS and 2mM L-glutamine at 37 ℃ for 20-24 hours. 5 μ L of 60 μ M doxycycline was added to the cells at 37 ℃ to initiate DLK expression for 20 hours. For negative control wells, doxycycline was not added. mu.L of compound of formula I at various concentrations in DMEM were added to the cells and the compound-treated cells were incubated at 37 ℃ for 5.5 hours before fixation with 50. mu.L of 4% paraformaldehyde. The wells were washed twice with 40. mu.L PBS wash, followed by permeabilization with 0.1% Triton X-100. The cells were washed twice with 40 μ L PBS wash and then incubated in 20 μ L SuperBlock (ThermoScientific) for 1 hour at ambient temperature. Primary antibodies (1: 3000 mouse anti-Flag and 1: 1000 rabbit anti-pJNK in SuperBlock) were incubated with the fixed cells overnight at 4 ℃. Cells were washed twice with 40 μ L PBS before adding secondary antibodies (AlexaFluor 555 labeled anti-mouse and AlexaFluor488 labeled anti-rabbit diluted 1: 2000 in SuperBlock). The secondary antibodies were incubated for 2 hours at ambient temperature and protected from light. Cells were washed with 40. mu.L PBS, after which 20. mu.L Hoechst 33342 (1: 5000 in PBS) was added. The plates were sealed and stored in the dark at 4 ℃ until image analysis on an operathigh Content Screening System (Evotec). Three data points are reported: pJNK (average intensity within search template), DLK (average intensity of 1% of the brightest pixels within search template), and nuclear area.

Compounds of formula I the following Table B provides K_is inhibits phosphorylation of JNK.

Claims

1. A compound of formula (I)

Wherein

R¹Selected from the group consisting of: c_1-6Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 6-to 10-membered aryl, 5-to 10-membered heteroaryl, -OR^1a，-SR^1a，-N(H)(R^1a) and-N (R)^1a)(R^1b) Wherein R is^1aAnd R^1bEach independently selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, 3-to 10-membered cycloalkyl and 3-to 10-membered heterocycloalkyl, and wherein R¹Is further independently substituted by 0 to 5R selected from the group consisting of^A1Substituent group substitution: -F, -Cl, -Br, -I, -CN, -NO₂，-SF₅，-OH，-NH₂，-CF₃，＝O，C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_1-4Dialkylamino, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl, wherein R^A1Said 5-6 membered heteroaryl, phenyl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl of the substituents are substituted with 0-4 substituents selected from: -F, -Cl, -Br, I, -CN, -NO₂，-SF₅，-OH，-NH₂，-CF₃，C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino and C_1-4A dialkylamino group;

R²selected from the group consisting of: hydrogen, C_1-6Alkyl and C_1-6A haloalkyl group;

R³selected from the group consisting of: -F, -Cl, -Br, -I, - (X)³)_0-1-CN，-(X³)_0-1-NO₂，-(X³)_0-1-SF₅，-(X³)_0-1-OH，-(X³)_0-1-NH₂，-(X³)_0-1-N(H)(R^3a)，-(X³)_0-1-N(R^3b)(R^3a)，-(X³)_0-1-CF₃，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio group, - (X)³)_0-1-3-7 membered cycloalkyl, - (X)³)_0-1-3-7 membered heterocycloalkyl, - (X)³)_0-1-5-6 membered heteroaryl and- (X)³)_0-1-C₆Aryl radical, whereinX³Selected from the group consisting of: c_1-4Alkylene and C_1-4Halogenoalkylene, R^3aAnd R^3bEach independently selected from the group consisting of: c_1-6Alkyl and C_1-6A haloalkyl group;

m is an integer of 0 to 4;

by structureThe ring represented is a4 to 7 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O and S, said 4 to 7 membered heterocyclic ring being selected from the group consisting of:

wherein R is⁴Substituents, if present, replacing a carbon-bound hydrogen atom or a nitrogen ring atom-bound hydrogen atom of said 4-7 membered heterocyclic ring

R⁴Selected from the group consisting of: -F, -Cl, -Br, -I, - (X)⁴)_0-1-CN，-(X⁴)_0-1-NO₂，-(X⁴)_0-1-SF₅，-(X⁴)_0-1-OH，-(X⁴)_0-1-NH₂，-(X⁴)_0-1-N(H)(R^4a)，-(X⁴)_0-1-N(R^4b)(R^4a)，-(X⁴)_0-1-CF₃，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio group, - (X)⁴)_0-1- (3-to 10-membered heterocycloalkyl), - (X)⁴)_0-1- (5-to 10-membered heteroaryl), - (X)⁴)_0-1- (3-to 7-membered cycloalkyl), - (X)⁴)_0-1-C(＝Y⁴)N(H)(R^4a)，-(X⁴)_0-1-C(＝Y⁴)NH₂，-(X⁴)_0-1-C(＝Y⁴)N(R^4a)(R^4b)，-(X⁴)_0-1-C(＝Y⁴)OR^4a，-(X⁴)_0-1-C(＝Y⁴)OH，-(X⁴)_0-1-N(H)C(＝Y⁴)(R^4a)，-(X⁴)_0-1-N(R^4b)C(＝Y⁴)(R^4a)，-(X⁴)_0-1-N(H)C(＝Y⁴)OR^4a，-(X⁴)_0-1-N(R^4b)C(＝Y⁴)OR⁴And- (X)⁴)_0-1-S(O)_1-2R^4aWherein R is^4aAnd R^4bEach occurrence is independently selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, 6-to 10-membered aryl, 3-to 7-membered cycloalkyl, 5-to 10-membered heteroaryl, 3-to 7-membered heterocycloalkyl, 6-to 10-membered aryl-C_1-4Alkyl, 3-7 membered cycloalkyl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4Alkyl and 3-7 membered heterocycloalkyl-C_1-4Alkyl radical, and X⁴Selected from the group consisting of: c_1-4Alkylene and C_1-4A haloalkylene group; y is⁴Is O, NR^4cOr S, wherein R^4cIs hydrogen or C_1-6An alkyl group; wherein R is⁴Is further independently substituted by 0 to 4R selected from the group consisting of^A4Substituent group substitution: -F, -Cl, -Br, I, -CN, -NO₂，-SF₅，-OH，-NH₂，-CF₃，＝O，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C (═ O) N (H) (C)_1-6Alkyl group, -C (═ O) N (C)_1-6Alkyl radical)₂，-C(＝O)NH₂，-N(H)C(＝O)(C_1-6Alkyl group), -N (C)_1-6Alkyl) C (═ O) (C)_1-6Alkyl, -S (O)_1- ₂C_1-6Alkyl and-C (═ O) C_1-6An alkyl group;

n is an integer of 0 to 5;

R⁵absent or selected from the group consisting of: hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, -OH, OR^5a-CN and halogen, wherein R^5aSelected from the group consisting of: c_1-6Alkyl and C_1-6A haloalkyl group; or optionally, R⁴And R⁵Optionally combined to form a 5-7 membered cycloalkyl or heterocycloalkyl and independently further substituted with 0-4R^A4Substituent group substitution; and is

R⁶Is hydrogen, -F, -Cl, -Br, -I, C_1-3Alkyl or C_1-3A haloalkyl group.

2. The compound of claim 1, wherein the compound has the structureSaid 4 to 7 membered heterocyclic ring represented is selected from the group consisting of:

wherein R is attached to the nitrogen atom of the 4-to 7-membered heterocyclic ring⁴Selected from the group consisting of: - (X)⁴)_0-1-CN，-(X⁴)_0-1-NO₂，-(X⁴)_0-1-SF₅，-(X⁴)_0-1-OH，-(X⁴)_0-1-NH₂，-(X⁴)_0-1-N(H)(R^4a)，-(X⁴)_0-1-N(R^4b)(R^4a)，-(X⁴)_0-1-CF₃，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio group, - (X)⁴)_0-1- (3-to 10-membered heterocycloalkyl), - (X)⁴)_0-1- (5-to 10-membered heteroaryl), - (X)⁴)_0-1- (3-to 7-membered cycloalkyl), - (X)⁴)_0-1-C(＝Y⁴)N(H)(R^4a)，-(X⁴)_0-1-C(＝Y⁴)NH₂，-(X⁴)_0-1-C(＝Y⁴)N(R^4a)(R^4b)，-(X⁴)_0-1-C(＝Y⁴)OR^4a，-(X⁴)_0-1-C(＝Y⁴)OH，-(X⁴)_0-1-N(H)C(＝Y⁴)(R^4a)，-(X⁴)_0-1-N(R^4b)C(＝Y⁴)(R^4a)，-(X⁴)_0-1-N(H)C(＝Y⁴)OR^4a，-(X⁴)_0-1-N(R^4b)C(＝Y⁴)OR⁴And- (X)⁴)_0-1-S(O)_1-2R^4aWherein R is^4aAnd R^4bEach occurrence is independently selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, 6-to 10-membered aryl, 3-to 7-membered cycloalkyl, 5-to 10-membered heteroaryl, 3-to 7-membered heterocycloalkyl, 6-to 10-membered aryl-C_1-4Alkyl, 3-7 membered cycloalkyl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4Alkyl and 3-7 membered heterocycloalkyl-C_1-4Alkyl radical, and X⁴Selected from the group consisting of: c_1-4Alkylene and C_1-4A haloalkylene group; y is⁴Is O, NR^4cOr S, wherein R^4cIs hydrogen or C_1-6An alkyl group; wherein R is⁴Is further independently substituted by 0 to 4R selected from the group consisting of^A4Substituent group substitution: -F, -Cl, -Br, I, -CN, -NO₂，-SF₅，-OH，-NH₂，-CF₃，＝O，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, -C (═ O) N (H) (C)_1-6Alkyl group, -C (═ O) N (C)_1-6Alkyl radical)₂，-C(＝O)NH₂，-N(H)C(＝O)(C_1-6Alkyl group), -N (C)_1-6Alkyl) C (═ O) (C)_1-6Alkyl, -S (O)_1-2C_1-6Alkyl and-C (═ O) C_1-6An alkyl group; and the remaining R⁴Each, if present on said 4-7 membered heterocyclic ring, is independently selected from the group consisting of: -F, -Cl, -Br, I, - (X)⁴)_0-1-CN，-(X⁴)_0-1-NO₂，-(X⁴)_0-1-SF₅，-(X⁴)_0-1-OH，-(X⁴)_0-1-NH₂，-(X⁴)_0-1-N(H)(R^4a)，-(X⁴)_0-1-N(R^4b)(R^4a)，-(X⁴)_0-1-CF₃，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_1-6Alkylthio radical, wherein X⁴Selected from the group consisting of: c_1-4Alkylene and C_1-4Haloalkylene, and R^4aAnd R^4bEach independently selected from the group consisting of: c_1-6Alkyl and C_1-6A haloalkyl group.

3. The compound of claim 1, wherein R⁴To a nitrogen atom (if present) in said 4-7 membered heterocycle or to a carbon atom in said 4-7 membered heterocycle, wherein R⁴Selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio group, - (X)⁴)_0-1- (3-to 10-membered heterocycloalkyl), - (X)⁴)_0-1- (5-to 10-membered heteroaryl), - (X)⁴)_0-1- (3-to 7-membered cycloalkyl) and- (X)⁴)_0-1-S(O)_1-2R^4aWherein Y is⁴Is O.

4. The compound of claim 1, wherein the compound has the structureSaid 4 to 7 membered heterocyclic ring represented is selected from the group consisting of:

wherein R is⁴Selected from the group consisting of: -F, -Cl, -Br, -I, - (X)⁴)_0-1-CN，-(X⁴)_0-1-NO₂，-(X⁴)_0-1-SF₅，-(X⁴)_0-1-OH，-(X⁴)_0-1-NH₂，-(X⁴)_0-1-N(H)(R^4a)，-(X⁴)_0-1-N(R^4b)(R^4a)，-(X⁴)_0-1-CF₃，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy and C_1-6Alkylthio radical, wherein X⁴Selected from the group consisting of: c_1-4Alkylene and C_1-4Haloalkylene, and R^4aAnd R^4bEach independently selected from the group consisting of: c_1-6Alkyl and C_1-6A haloalkyl group.

5. The compound of claim 1, 2,3 or4, wherein R⁵Selected from the group consisting of: hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, hydroxy, OR^5a-CN, -F, -Cl, -Br and-I.

6. The compound of claim 1, 2,3 or4, wherein R¹Selected from the group consisting of: -OR^1a，-SR^1a，-N(H)(R^1a) and-N (R)^1a)(R^1b) Cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, morpholine, homomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, azetidine, pyrrolidine, benzene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, oxetane, tetrahydrofuran, tetrahydropyran, -oxa-5-azabicyclo [2.2.1]Heptane, 2-oxa-6-azaspiro [3.3]Heptane, 8-oxa-3-azabicyclo [3.2.1]Octane, 3-oxa-8-azabicyclo[3.2.1]Octane, 7-oxabicyclo [2.2.1]Heptane, 7-azabicyclo [2.2.1]Heptane, norbornane, bicyclo [2.2.2]Octane, 2-azabicyclo [2.2.2]Octane, 2-oxabicyclo [2.2.2]Octane, 2-oxa-5-azabicyclo [2.2.2]Octane and 2, 5-diazabicyclo [2.2.2]Octane, 5,6, 7, 8-tetrahydroimidazo [1, 2-a ]]Pyrazine, 4,5, 6, 7-tetrahydro-3H-imidazo [4, 5-c ]]Pyridine, wherein R^1aAnd R^1bEach independently selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, 3-to 10-membered cycloalkyl and 3-to 10-membered heterocycloalkyl, and wherein R¹Is further independently substituted by 0 to 5R selected from the group consisting of^A1Substituent group substitution: -F, -Cl, -Br, I, -CN, -NO₂，-SF₅，-OH，-NH₂，-CF₃，＝O，C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_1-4Dialkylamino, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl, wherein R^A1Said 5-6 membered heteroaryl, phenyl, 3-6 membered heteroaryl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl of substituents are substituted with 0-4 substituents selected from: -F, -Cl, -Br, I, -CN, -NO₂，-SF₅，-OH，-NH₂，-CF₃，C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino and C_1-4A dialkylamino group.

7. The compound of claim 6, wherein R¹Selected from the group consisting of: pyrrolidin-1-yl, phenyl, piperidin-1-yl, pyrrol-1-yl, azetidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, 3-oxa-8-azabicyclo [3.2.1]Oct-8-yl, 2-oxa-6-azaspiro [3.3]Hept-6-yl, -8-oxa-3-azabicyclo [3.2.1]Octane, cyclopropyl, pyrazol-1-yl, 4,5, 6, 7-tetrahydro-1H-imidazo [4, 5-c]Pyridin-5-yl, 3, 5,6, 7, 8, 8 a-hexaHydroimidazo [1, 2-a ] s]Pyrazin-7-yl, -N (H) R^1a) and-N (R)^1a)(R^1b) Wherein R is^1aAnd R^1bEach independently selected from the group consisting of: methyl, ethyl, propyl and butyl, wherein R¹Is substituted with 0 to 4 substituents selected from the group consisting of: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fluoro, chloro, bromo, iodo, cyano, methoxymethyl, methoxyethyl, methoxypropyl, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-methylpyrimidin-4-yl, 4-methyltriazol-3-yl, 1, 2, 4-triazol-3-yl, morpholinocarbonyl, morpholino, 2-methyl-pyrimidin-6-yl, 6-methyl-pyrimidin-2-yl, 4-methyl-1, 2, 4-triazol-3-yl, methylaminomethylcarbonyl and hydroxy.

8. The compound of claim 1, 2,3 or4, wherein R³Selected from the group consisting of: -F, -Cl, -Br, I, - (X)³)_0-1-CN，-(X³)_0-1-NO₂，-(X³)_0-1-SF₅，-(X³)_0-1-OH，-(X³)_0-1-NH₂，-(X³)_0-1-N(H)(R^3a)，-(X³)_0-1-N(R^3b)(R^3a)，-(X³)_0-1-CF₃，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio group, - (X)³)_0-1-3-7 membered cycloalkyl, - (X)³)_0-1-3-7 membered heterocycloalkyl, - (X)³)_0-1-5-6 membered heteroaryl and- (X)³)_0-1-C₆And (4) an aryl group.

9. The compound of claim 1, 2,3 or4, wherein R³Selected from the group consisting of: -F, -Cl, -Br, I, C_1-6Alkyl radical, C_1-6Haloalkyl and C_1-6An alkoxy group.

10. The compound of claim 9, wherein R3 is selected from the group consisting of: trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, tert-butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl and thienyl.

11. The compound of claim 1, 2,3 or4, wherein the compound of formula I has a subformula selected from the group consisting of:

12. the compound of claim 1, 2,3 or4, wherein the compound of formula I has a subformula selected from the group consisting of:

13. the compound of claim 1, 2,3 or4, wherein the compound of formula I has a subformula selected from the group consisting of:

wherein R is³Selected from the group consisting of: methyl, monofluoromethylDifluoromethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclobutyl and methoxy.

14. A compound selected from the group of compounds:

(4-methyl-pyridin-2-yl) - (6-piperidin-4-yl-2-pyrrolidin-1-yl-pyrimidin-4-yl) -amine;

{4- [6- (4-methyl-pyridin-2-ylamino) -2-pyrrolidin-1-yl-pyrimidin-4-yl ] -piperidin-1-yl } -phenyl-methanone;

(2-piperidin-1-yl-6-piperidin-3-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

(6-piperidin-3-yl-2-pyrrolidin-1-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

[ 6-piperidin-3-yl-2- (3-trifluoromethyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-piperidin-1-yl) -6-piperidin-3-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6-piperidin-3-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (2-methyl-pyrrolidin-1-yl) -6-piperidin-3-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

(2-azetidin-1-yl-6-piperidin-4-yl-pyrimidin-4-yl) - (4-methyl-pyridin-2-yl) -amine;

(4-methyl-pyridin-2-yl) - (2-piperidin-1-yl-6-piperidin-3-yl-pyrimidin-4-yl) -amine;

(4-methyl-pyridin-2-yl) - (2-piperidin-1-yl-6-piperidin-4-yl-pyrimidin-4-yl) -amine;

{3- [6- (4-methyl-pyridin-2-ylamino) -2-pyrrolidin-1-yl-pyrimidin-4-yl ] -piperidin-1-yl } -phenyl-methanone;

1- {3- [6- (4-methyl-pyridin-2-ylamino) -2-pyrrolidin-1-yl-pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

2- { methyl- [ 4-piperidin-3-yl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -amino } -ethanol;

2- { methyl- [ 4-pyrrolidin-3-yl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -amino } -ethanol;

[2- (3, 3-difluoro-azetidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6-piperidin-3-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (2-methyl-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

(2-pyrrolidin-1-yl-6-pyrrolidin-3-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

[ 6-piperidin-4-yl-2- (3-trifluoromethyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6-pyrrolidin-3-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-piperidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (4, 4-difluoro-piperidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[ 6-pyrrolidin-3-yl-2- (3-trifluoromethyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (1-methyl-1H-pyrazol-4-yl) -6-piperidin-3-yl-pyrimidin-4-yl ] - (4-methyl-pyridin-2-yl) -amine;

(4-methyl-pyridin-2-yl) - (2-piperidin-1-yl-6-pyrrolidin-3-yl-pyrimidin-4-yl) -amine;

{3- [ 2-azetidin-1-yl-6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -phenyl-methanone;

1- {4- [ 2-azetidin-1-yl-6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [6- (4-methyl-pyridin-2-ylamino) -2-piperidin-1-yl-pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

2- { methyl- [ 4-piperidin-4-yl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -amino } -ethanol;

{3- [2- (1-methyl-1H-pyrazol-4-yl) -6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -phenyl-methanone;

(4-methyl-pyridin-2-yl) - (6-piperidin-3-yl-2-pyrrolidin-1-yl-pyrimidin-4-yl) -amine;

(4-methyl-pyridin-2-yl) - (2-pyrrolidin-1-yl-6-pyrrolidin-3-yl-pyrimidin-4-yl) -amine;

{3- [6- (4-methyl-pyridin-2-ylamino) -2-pyrrolidin-1-yl-pyrimidin-4-yl ] -pyrrolidin-1-yl } -phenyl-methanone;

{3- [6- (4-methyl-pyridin-2-ylamino) -2-piperidin-1-yl-pyrimidin-4-yl ] -piperidin-1-yl } -phenyl-methanone;

{3- [6- (4-methyl-pyridin-2-ylamino) -2-piperidin-1-yl-pyrimidin-4-yl ] -pyrrolidin-1-yl } -phenyl-methanone;

1- {3- [2- (1-methyl-1H-pyrazol-4-yl) -6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [ 2-azetidin-1-yl-6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [ 2-azetidin-1-yl-6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {3- [6- (4-methyl-pyridin-2-ylamino) -2-pyrrolidin-1-yl-pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {3- [6- (4-methyl-pyridin-2-ylamino) -2-piperidin-1-yl-pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {4- [6- (4-methyl-pyridin-2-ylamino) -2-piperidin-1-yl-pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

(2-piperidin-1-yl-6-piperidin-4-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (2-methyl-pyrrolidin-1-yl) -6-pyrrolidin-3-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

(2-piperidin-1-yl-6-pyrrolidin-3-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-piperidin-1-yl) -6-pyrrolidin-3-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6-pyrrolidin-3-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

(4-methyl-pyridin-2-yl) - (2-phenyl-6-piperidin-3-yl-pyrimidin-4-yl) -amine;

(2-phenyl-6-piperidin-3-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {4- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

(2-methyl-6-pyrrolidin-3-yl-pyrimidin-4-yl) - (5-trifluoromethyl-pyridin-2-yl) -amine;

(5-methyl-pyridin-2-yl) - (2-methyl-6-pyrrolidin-3-yl-pyrimidin-4-yl) -amine;

[2- (1-methyl-1H-pyrazol-4-yl) -6-pyrrolidin-3-yl-pyrimidin-4-yl ] - (4-methyl-pyridin-2-yl) -amine;

4- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidine-4-carbonitrile;

1- {3- [6- (4-methyl-pyridin-2-ylamino) -2-phenyl-pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [ 2-phenyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [ 2-isopropyl-6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [ 2-isopropyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

(2-morpholin-4-yl-6-piperidin-4-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- ((R) -2-methyl-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- ((S) -2-methyl-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (1-methyl-1H-pyrazol-4-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-methyl-pyridin-2-yl) -amine;

{3- [2- (1-methyl-1H-pyrazol-4-yl) -6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -phenyl-methanone;

(2-azetidin-1-yl-6-piperidin-3-yl-pyrimidin-4-yl) - (4-methyl-pyridin-2-yl) -amine;

{3- [ 2-azetidin-1-yl-6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -phenyl-methanone;

3- {4- [6- (4-methyl-pyridin-2-ylamino) -2-piperidin-1-yl-pyrimidin-4-yl ] -piperidin-1-yl } -3-oxo-propionitrile;

1- {3- [2- (1-methyl-1H-pyrazol-4-yl) -6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {4- [6- (4-methyl-pyridin-2-ylamino) -2-pyrrolidin-1-yl-pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

(4-chloro-pyridin-2-yl) - [2- (3, 3-difluoro-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] -amine;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (1-methyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

(4-methyl-pyridin-2-yl) - [2- (2-methyl-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] -amine;

3- {3- [2- (1-methyl-1H-pyrazol-4-yl) -6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-oxo-propionitrile;

3- {4- [6- (4-methyl-pyridin-2-ylamino) -2-pyrrolidin-1-yl-pyrimidin-4-yl ] -piperidin-1-yl } -3-oxo-propionitrile;

(4-methoxy-pyridin-2-yl) - [2- (2-methyl-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] -amine;

(4-methoxy-pyridin-2-yl) - [2- (2-methyl-pyrrolidin-1-yl) -6-pyrrolidin-3-yl-pyrimidin-4-yl ] -amine;

(4-methoxy-pyridin-2-yl) - [2- (2-methyl-pyrrolidin-1-yl) -6-piperidin-3-yl-pyrimidin-4-yl ] -amine;

1- {4- [6- (4-methoxy-pyridin-2-ylamino) -2- (2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [6- (4-methoxy-pyridin-2-ylamino) -2- (2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

(2-morpholin-4-yl-6-piperidin-3-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

(2-morpholin-4-yl-6-pyrrolidin-3-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [ 2-morpholin-4-yl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [ 2-morpholin-4-yl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [ 2-morpholin-4-yl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

(4-methyl-pyridin-2-yl) - (2-morpholin-4-yl-6-piperidin-3-yl-pyrimidin-4-yl) -amine;

(4-methyl-pyridin-2-yl) - (2-morpholin-4-yl-6-piperidin-4-yl-pyrimidin-4-yl) -amine;

(4-methyl-pyridin-2-yl) - (2-morpholin-4-yl-6-pyrrolidin-3-yl-pyrimidin-4-yl) -amine;

1- {3- [6- (4-methyl-pyridin-2-ylamino) -2-morpholin-4-yl-pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [6- (4-methyl-pyridin-2-ylamino) -2-morpholin-4-yl-pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [6- (4-methyl-pyridin-2-ylamino) -2-morpholin-4-yl-pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {4- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

(4-cyclopropyl-pyridin-2-yl) - [2- (3, 3-difluoro-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] -amine;

[2- ((2R, 5R) -2, 5-dimethyl-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[6- (1-methyl-piperidin-3-yl) -2-phenyl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[6- (1-methyl-piperidin-3-yl) -2-phenyl-pyrimidin-4-yl ] - (4-methyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (1-methyl-piperidin-3-yl) -pyrimidin-4-yl ] - (4-methyl-pyridin-2-yl) -amine;

1- {3- [6- (4-methoxy-pyridin-2-ylamino) -2- (2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

[6- (1-methyl-piperidin-4-yl) -2- (2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] - (4-methyl-pyridin-2-yl) -amine;

1-acetyl-4- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidine-4-carbonitrile;

[2- (2-methyl-pyrrolidin-1-yl) -6- (1-methyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

3- {3- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -3-oxo-propionitrile;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (1-methyl-piperidin-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

3-oxo-3- {4- [ 2-pyrrolidin-1-yl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -propionitrile;

[2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {4- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

[6- (1-methyl-piperidin-4-yl) -2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

3- {4- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-oxo-propionitrile;

[6- (1-methyl-piperidin-4-yl) -2- ((R) -2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-isopropyl-pyridin-2-yl) -amine;

(4-cyclobutyl-pyridin-2-yl) - [2- (3, 3-difluoro-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] -amine;

3- {3- [ 2-cyclopropyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-oxo-propionitrile;

(2-cyclopropyl-6-piperidin-3-yl-pyrimidin-4-yl) - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {4- [2- ((R) -2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [2- ((S) -2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

3- {4- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-oxo-propionitrile;

1- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -2, 2-difluoro-ethanone;

1- {4- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -2, 2-difluoro-ethanone;

{3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } - (2-methyl-cyclopropyl) -methanone;

1- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

3- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-oxo-propionitrile;

1- {4- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -propan-1-one;

cyclopropyl- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -methanone;

cyclopropyl- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -methanone;

cyclopropyl- {4- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -methanone;

1- {3- [ 2-cyclopropyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-methoxy-propan-1-one;

1- {3- [ 2-isobutyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-methoxy-propan-1-one;

1- {3- [ 2-cyclopropyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -propan-1-one;

1- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -butan-1-one;

cyclobutyl- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -methanone;

2-cyclopropyl-1- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {3- [ 2-cyclopropyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -2, 2-difluoro-ethanone;

4- [2- ((R) -2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidine-4-carbonitrile;

[ 2-cyclopropyl-6- (1-methyl-piperidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

(4-tert-butyl-pyridin-2-yl) - [2- (3, 3-difluoro-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] -amine;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-thiophen-2-yl-pyridin-2-yl) -amine;

(4-cyclopropyl-pyridin-2-yl) - [2- ((R) -2-methyl-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] -amine;

(1-methyl-1H-imidazol-4-yl) - {3- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -methanone;

2-imidazol-1-yl-1- {3- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {3- [6- (4-trifluoromethyl-pyridin-2-ylamino) -2- (3-trifluoromethyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -propan-1-one;

1- {4- [6- (4-trifluoromethyl-pyridin-2-ylamino) -2- (3-trifluoromethyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [6- (4-cyclopropyl-pyridin-2-ylamino) -2- (3, 3-difluoro-pyrrolidin-1-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

4- [2, 6-bis- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -tetrahydro-pyran-4-carbonitrile;

4- [2- ((R) -2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -tetrahydro-pyran-4-carbonitrile;

4- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -tetrahydro-pyran-4-carbonitrile;

[2- (2-methoxymethyl-pyrrolidin-1-yl) -6-piperidin-4-yl-pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (2, 2-dimethyl-morpholin-4-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3-morpholin-4-yl-azetidin-1-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- [4- (tetrahydro-pyran-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

[2- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- ((S) -2-methyl-pyrrolidin-1-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- ((R) -2-methyl-pyrrolidin-1-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[ 2-morpholin-4-yl-6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-pyrrolidin-1-yl) -6- [1- (1H-imidazol-2-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -2, 2-difluoro-ethanone;

1- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidine-1-carbonyl } -cyclopropanecarbonitrile;

1- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -3-methoxy-propan-1-one;

{3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } - (1-methyl-cyclopropyl) -methanone;

2, 2-difluoro-1- {3- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {3- [6- (4-trifluoromethyl-pyridin-2-ylamino) -2- (3-trifluoromethyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {3- [6- (4-trifluoromethyl-pyridin-2-ylamino) -2- (3-trifluoromethyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -2, 2-difluoro-ethanone;

3- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -3-oxo-propionitrile;

1- {4- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-methoxy-propan-1-one;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {4- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -propan-1-one;

1- {4- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -propan-1-one;

{4- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } - (1-methyl-cyclopropyl) -methanone;

cyclopropyl- {4- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -methanone;

2-cyclopropyl-1- {4- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

2, 2-difluoro-1- {3- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

[6- (1-methyl-piperidin-3-yl) -2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

2, 2-difluoro-1- {3- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [6- (4-cyclopropyl-pyridin-2-ylamino) -2- ((R) -2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

2, 2-difluoro-1- {4- [2- (2-methoxymethyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [2- (3, 4-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

[2- (3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 4,6, 7-tetrahydro-imidazo [4, 5-c ] pyridin-5-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (5, 6-dihydro-8H-imidazo [1, 2-a ] pyrazin-7-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (4-morpholin-4-yl-piperidin-1-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- [4- (2-methyl-pyrimidin-4-yl) -piperidin-1-yl ] -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- [3- (4-methyl-pyrimidin-2-yl) -azetidin-1-yl ] -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- [2- (4-methyl-4H- [1, 2, 4] triazol-3-yl) -pyrrolidin-1-yl ] -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- [4- (4-methyl-4H- [1, 2, 4] triazol-3-yl) -piperidin-1-yl ] -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- [3- (4-methyl-4H- [1, 2, 4] triazol-3-yl) -piperidin-1-yl ] -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

morpholin-4-yl- {1- [4- (tetrahydro-pyran-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidin-3-yl } -methanone;

[2- [3- (2-methyl-pyrimidin-4-yl) -pyrrolidin-1-yl ] -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-ethyl-piperidin-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

{3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } - (tetrahydro-furan-3-yl) -methanone;

1- {4- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -2, 2-difluoro-ethanone;

{3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } - (tetrahydro-furan-2-yl) -methanone;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -3-methoxy-propan-1-one;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -3-dimethylamino-propan-1-one;

{3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } - (2-methyl-cyclopropyl) -methanone;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -butan-1-one;

{3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } - (1-methyl-cyclopropyl) -methanone;

cyclopropyl- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -methanone;

cyclobutyl- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -methanone;

2-cyclopropyl-1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

[6- (1-methyl-pyrrolidin-3-yl) -2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {4- [2- (2, 2-dimethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (2, 2-dimethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [2- (2, 6-dimethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (2, 6-dimethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (2, 6-dimethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {3- [2- (2, 6-dimethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -2, 2-difluoro-ethanone;

1- [4- [1- (2, 2-difluoro-acetyl) -piperidin-4-yl ] -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

1- [4- [1- (2, 2-difluoro-acetyl) -piperidin-3-yl ] -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

1- [4- (1-acetyl-piperidin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

1- [4- (1-acetyl-piperidin-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

1- {4- [2- (2-ethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (2-ethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

[6- (1-methyl-piperidin-4-yl) -2- (3-morpholin-4-yl-azetidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (2-ethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- [4- (1-methyl-piperidin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

1- {3- [2- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

2, 2-difluoro-1- {3- [2- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

[6- (1-methyl-piperidin-4-yl) -2- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {4- [2- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

2, 2-difluoro-1- {4- [2- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

[2-[1，4]oxazazepine-4-yl-6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl]- (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (2-methoxymethyl-pyrrolidin-1-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (5-methyl-iso-butyl)Azol-3-ylmethyl) -pyrrolidin-3-yl]-pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (5-methyl-3H-imidazol-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-)Azol-2-ylmethyl-pyrrolidin-3-yl) -pyrimidin-4-yl]- (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (2-methyl-1H-imidazol-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-)Azol-4-ylmethyl-piperidin-4-yl) -pyrimidin-4-yl]- (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-)Azol-2-ylmethyl-piperidin-4-yl) -pyrimidin-4-yl]- (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (4-methyl-1H-imidazol-2-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1H-imidazol-2-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (3-methyl-3H-imidazol-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (tetrahydro-furan-3-ylmethyl) -piperidin-4-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1H-imidazol-2-ylmethyl) -piperidin-4-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (tetrahydro-pyran-3-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1H-imidazol-4-ylmethyl) -piperidin-4-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (2H-pyrazol-3-ylmethyl) -piperidin-4-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1-methyl-1H-pyrazol-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-pyridin-3-ylmethyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1H-pyrazol-4-ylmethyl) -piperidin-4-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-pyridin-4-ylmethyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1-methyl-1H-imidazol-2-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidine-1-carbonyl } -cyclopropanecarbonitrile;

2, 2-difluoro-1- {4- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (2, 2-dimethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

1- {3- [2- (2, 2-dimethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -2, 2-difluoro-ethanone;

1- {3- [2- (2-ethyl-morpholin-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -2, 2-difluoro-ethanone;

1- [4- [1- (2, 2-difluoro-acetyl) -pyrrolidin-3-yl ] -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

[6- (1-methyl-pyrrolidin-3-yl) -2- (3-morpholin-4-yl-azetidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- [4- (1-acetyl-pyrrolidin-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

[2- (2, 2-dimethyl-morpholin-4-yl) -6- (1-methyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (2, 6-dimethyl-morpholin-4-yl) -6- (1-methyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- [4- (1-methyl-pyrrolidin-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

[6- (1-methyl-piperidin-3-yl) -2- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[6- (1-methanesulfonyl-piperidin-4-yl) -2- ((R) -2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1-methyl-5- [2- ((R) -2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -1H-pyridin-2-one;

1-methyl-4- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-2-one;

5- [6- (4-cyclopropyl-pyridin-2-ylamino) -2- ((R) -2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -1-methyl-1H-pyridin-2-one;

(4-cyclopropyl-pyridin-2-yl) - [2- ((R) -2-methyl-pyrrolidin-1-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] -amine;

{2- (3, 3-difluoro-pyrrolidin-1-yl) -6- [1- (1H-imidazol-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

3- {3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -3-oxo-propionitrile;

(3-methyl-3H-imidazol-4-yl) - {3- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -methanone;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (tetrahydro-furan-3-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-pyrimidin-5-ylmethyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1H-imidazol-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (2H-pyrazol-3-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-ethyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1H-pyrazol-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1-methyl-1H-pyrazol-3-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-propyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (2-methyl-2H-pyrazol-3-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-pyridin-2-ylmethyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (2-ethyl-morpholin-4-yl) -6- (1-methyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1-methyl-4- [2- ((R) -2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -1H-pyridin-2-one;

[ 2-isopropoxy-6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- ((R) -2-methoxymethyl-pyrrolidin-1-yl) -6- (tetrahydro-pyran-4-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [ 2-cyclopropyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -azetidin-1-yl } -ethanone;

[ 2-cyclopropyl-6- (1-methanesulfonyl-azetidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {4- [ 5-fluoro-2- ((R) -2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [2- ((R) -2-methoxymethyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [ 2-isopropoxy-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (2, 2, 2-trifluoro-ethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1H-imidazol-4-ylmethyl) -piperidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

3- {4- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-oxo-propionitrile;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -propan-1-one;

{3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } - (1-methyl-cyclopropyl) -methanone;

cyclopropyl- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -methanone;

2-cyclopropyl-1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

[6- (1-methyl-piperidin-3-yl) -2- (3-morpholin-4-yl-azetidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (8-oxa-3-aza-bicyclo [32.1] oct-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

2, 2-difluoro-1- {3- [2- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

[6- (1-methanesulfonyl-azetidin-3-yl) -2- ((R) -2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- ((R) -2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -azetidin-1-yl } -ethanone;

[6- (1-methanesulfonyl-pyrrolidin-3-yl) -2- (2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-methanesulfonyl-pyrrolidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (tetrahydro-furan-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [6- (4-methyl-pyridin-2-ylamino) -2- (tetrahydro-furan-3-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [2- (tetrahydro-furan-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {4- [6- (4-methyl-pyridin-2-ylamino) -2- (tetrahydro-furan-3-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (3-morpholin-4-yl-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

[ 2-cyclopentyl-6- (1-methanesulfonyl-piperidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[ 2-cyclobutyl-6- (1-methanesulfonyl-piperidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-azetidin-1-yl) -6- (1-methanesulfonyl-azetidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (2-methyl-2H-pyrazol-3-yl) -6- [1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (2-methyl-2H-pyrazol-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

{2- (3, 3-difluoro-pyrrolidin-1-yl) -6- [1- (2H-pyrazol-3-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[ 2-cyclopentyl-6- (1-oxetan-3-yl-piperidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

4- [2- (tetrahydro-furan-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-2-one;

[6- (1-methanesulfonyl-piperidin-4-yl) -2- (tetrahydro-furan-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [ 2-cyclopentyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

4- [2- (2-methoxymethyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-2-one;

[6- (1-cyclopropylmethyl-pyrrolidin-3-yl) -2- (3, 3-difluoro-azetidin-1-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (2, 5-dimethyl-2H-pyrazol-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

[6- (1-oxetan-3-yl-piperidin-4-yl) -2- (tetrahydro-furan-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[ 2-isopropyl-6- (1-oxetan-3-yl-azetidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2-(3, 3-difluoro-azetidin-1-yl) -6- (1-Azol-5-ylmethyl-piperidin-3-yl) -pyrimidin-4-yl]- (4-trifluoromethyl-pyridin-2-yl) -amine;

[6- (1-methanesulfonyl-piperidin-3-yl) -2- (tetrahydro-furan-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (2-methyl-2H-pyrazol-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

{2- (3, 3-difluoro-pyrrolidin-1-yl) -6- [1- (1H-pyrazol-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [ 2-cyclobutyl-6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -3-methoxy-propan-1-one;

[ 2-cyclobutyl-6- (1-oxetan-3-yl-piperidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [6- (4-cyclopropyl-pyridin-2-ylamino) -2- (3, 3-difluoro-azetidin-1-yl) -pyrimidin-4-yl ] -azetidin-1-yl } -ethanone;

[ 2-cyclopropyl-6- (1-oxetan-3-yl-azetidin-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (1-)Azol-5-ylmethyl-pyrrolidin-3-yl) -pyrimidin-4-yl]- (4-trifluoromethyl-pyridin-2-yl) -amine;

4- [2- (2-methyl-pyrrolidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-2-one;

2- {4- [6- (4-cyclobutyl-pyridin-2-ylamino) -2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanol;

1- {3- [2- (1-methyl-1H-pyrazol-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -pyrrolidin-1-yl } -ethanone;

[6- (1-oxetan-3-yl-piperidin-3-yl) -2- (tetrahydro-furan-3-yl) -pyrimidin-4-yl ] - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (3, 3-difluoro-azetidin-1-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -azetidin-1-yl } -ethanone;

1- [4- (1-methyl-piperidin-3-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-2-yl ] -azetidine-3-carbonitrile;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [1- (1H-pyrazol-4-ylmethyl) -piperidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {3- [2- (1-methyl-1H-pyrazol-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

{2- (3, 3-difluoro-azetidin-1-yl) -6- [ (R) -1- (2-methyl-1H-imidazol-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

[2- (2-methyl-pyrrolidin-1-yl) -6- (1-)Azol-5-ylmethyl-pyrrolidin-3-yl) -pyrimidin-4-yl]- (4-trifluoromethyl-pyridin-2-yl) -amine;

{2- (1-methyl-1H-pyrazol-4-yl) -6- [1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl ] -pyrimidin-4-yl } - (4-trifluoromethyl-pyridin-2-yl) -amine;

1- {4- [2- (1-methyl-1H-pyrazol-4-yl) -6- (4-trifluoromethyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } -ethanone;

(2-methoxy-4-methyl-phenyl) - {3- [6- (4-methyl-pyridin-2-ylamino) -2- (2-methyl-pyrrolidin-1-yl) -pyrimidin-4-yl ] -piperidin-1-yl } -methanone;

{3- [2- (3, 3-difluoro-pyrrolidin-1-yl) -6- (4-methyl-pyridin-2-ylamino) -pyrimidin-4-yl ] -piperidin-1-yl } - (2-methoxy-4-methyl-phenyl) -methanone;

n- (4-chloropyridin-2-yl) -2- (3, 3-difluoropyrrolidin-1-yl) -6- (1- (oxetan-3-yl) piperidin-4-yl) pyrimidin-4-amine.

15. A pharmaceutical composition comprising a compound of formula I-I and a pharmaceutically acceptable carrier, diluent or excipient, wherein in said compound of formula I-I

Wherein

R¹Selected from the group consisting of: c_1-6Alkoxy, 3-to 10-membered cycloalkyl, 3-to 10-membered heterocycloalkyl, 6-to 10-membered aryl, 5-to 10-membered heteroaryl, -OR^1a，-SR^1a，-N(H)(R^1a) and-N (R)^1a)(R^1b) Wherein R is^1aAnd R^1bEach independently selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, 3-to 10-membered cycloalkyl and 3-to 10-membered heterocycloalkyl, and wherein R¹Is further independently substituted by 0 to 5R selected from the group consisting of^A1Substituent group substitution: -F, -Cl, -Br, -I, -CN, -NO₂，-SF₅，-OH，-NH₂，-CF₃，＝O，C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_1-4Dialkylamino, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl, wherein R^A1Said 5-6 membered heteroaryl, phenyl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl of substituents are substituted with 0-4 substituents selected from: -F, -Cl, -Br, I, -CN, -NO₂，-SF₅，-OH，-NH₂，-CF₃，C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkyl ammoniaRadical and C_1-4A dialkylamino group;

R³selected from the group consisting of: -F, -Cl, -Br, -I, - (X)³)_0-1-CN，-(X³)_0-1-NO₂，-(X³)_0-1-SF₅，-(X³)_0-1-OH，-(X³)_0-1-NH₂，-(X³)_0-1-N(H)(R^3a)，-(X³)_0-1-N(R^3b)(R^3a)，-(X³)_0-1-CF₃，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio group, - (X)³)_0-1-3-7 membered cycloalkyl, - (X)³)_0-1-3-7 membered heterocycloalkyl, - (X)³)_0-1-5-6 membered heteroaryl and- (X)³)_0-1-C₆Aryl radical, wherein X³Selected from the group consisting of: c_1-4Alkylene and C_1-4Halogenoalkylene, R^3aAnd R^3bEach independently selected from the group consisting of: c_1-6Alkyl and C_1-6A haloalkyl group;

m is an integer of 0 to 4;

by structureThe ring represented is a4 to 7 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with 1 to 3R⁴Substituted by groups;

R⁴selected from the group consisting of: -F, -Cl, -Br, -I, - (X)⁴)_0-1-CN，-(X⁴)_0-1-NO₂，-(X⁴)_0-1-SF₅，-(X⁴)_0-1-OH，-(X⁴)_0-1-NH₂，-(X⁴)_0-1-N(H)(R^4a)，-(X⁴)_0-1-N(R^4b)(R^4a)，-(X⁴)_0-1-CF₃，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio group, - (X)⁴)_0-1- (3-to 10-membered heterocycloalkyl), - (X)⁴)_0-1- (5-to 10-membered heteroaryl), - (X)⁴)_0-1- (3-to 7-membered cycloalkyl), - (X)⁴)_0-1-C(＝Y⁴)N(H)(R^4a)，-(X⁴)_0-1-C(＝Y⁴)NH₂，-(X⁴)_0-1-C(＝Y⁴)N(R^4a)(R^4b)，-(X⁴)_0-1-C(＝Y⁴)OR^4a，-(X⁴)_0-1-C(＝Y⁴)OH，-(X⁴)_0-1-N(H)C(＝Y⁴)(R^4a)，-(X⁴)_0-1-N(R^4b)C(＝Y⁴)(R^4a)，-(X⁴)_0-1-N(H)C(＝Y⁴)OR^4a，-(X⁴)_0-1-N(R^4b)C(＝Y⁴)OR⁴And- (X)⁴)_0-1-S(O)_1-2R^4aWherein R is^4aAnd R^4bEach occurrence is independently selected from the group consisting of: c_1-6Alkyl radical, C_1-6Haloalkyl, 6-to 10-membered aryl, 3-to 7-membered cycloalkyl, 5-to 10-membered heteroaryl, 3-to 7-membered heterocycloalkyl, 6-to 10-membered aryl-C_1-4Alkyl, 3-7 membered cycloalkyl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4Alkyl and 3-7 membered heterocycloalkyl-C_1-4Alkyl radical, and X⁴Selected from the group consisting of: c_1-4Alkylene and C_1-4A haloalkylene group; y is⁴Is O, NR^4cOr S, wherein R^4cIs hydrogen or C_1-6An alkyl group; wherein R is⁴Is further independently substituted by 0 to 4R selected from the group consisting of^A4Substituent group substitution: -F, -Cl, -Br, I, -CN, -NO₂，-SF₅，-OH，-NH₂，-CF₃，＝O，C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, 3-6 membered cycloalkyl, 3-6 membered heteroCycloalkyl, -C (═ O) N (H) (C)_1-6Alkyl group, -C (═ O) N (C)_1-6Alkyl radical)₂，-C(＝O)NH₂，-N(H)C(＝O)(C_1-6Alkyl group), -N (C)_1-6Alkyl) C (═ O) (C)_1-6Alkyl) and-C (═ O) C_1-6An alkyl group;

n is an integer of 0 to 5;

R⁶Is hydrogen, -F, -Cl, -Br, -I, C_1-3Alkyl or C_1-3A haloalkyl group.

16. Use of a compound of formula I-I in the manufacture of a medicament for inhibiting or preventing degeneration of a Central Nervous System (CNS) neuron or a portion thereof, wherein the compound of formula I-I is as defined in claim 15.

17. Use of a compound of formula I-I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I-I is as defined in claim 15, in the manufacture of a medicament for inhibiting or preventing degeneration of Central Nervous System (CNS) neurons in a patient suffering from or at risk of developing a neurodegenerative disease or condition.

18. Use of a compound of formula I-I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I-I is as defined in claim 15, in the manufacture of a medicament for reducing or preventing one or more symptoms of a neurodegenerative disease or disorder in a patient suffering therefrom.

19. Use of a compound of formula I-I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I-I is as defined in claim 15, in the manufacture of a medicament for reducing the progression of a neurodegenerative disease or disorder in a patient suffering therefrom.

20. The use of claim 17, 18 or 19, wherein the neurodegenerative disease or disorder is selected from the group consisting of: alzheimer's disease, Huntington's disease, Parkinson's plus syndrome, Amyotrophic Lateral Sclerosis (ALS), ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, progressive amyotrophic lateral sclerosis (PLS), pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, invertebrate disc syndrome, cervical spondylosis, plexus disorders, thoracic outlet destruction syndrome, peripheral neuropathy, porphyria, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, frontotemporal dementia, demyelinating disease, Lankan-Barre syndrome, multiple sclerosis, progressive neurosurgical osteoporthias, prion disease, Creutzfeldt-Jakob disease, gerstmann-straussler syndrome (GSS), Fatal Familial Insomnia (FFI), bovine spongiform encephalopathy, pick's disease, epilepsy, AIDS dementia complex, nerve damage caused by exposure to toxic compounds selected from the group consisting of heavy metals, industrial solvents, drugs and chemotherapeutic agents; damage to the nervous system caused by physical, mechanical or chemical trauma, glaucoma, corneal network dystrophy, retinitis pigmentosa, age-related macular degeneration (AMD), wet or dry AMD-related photoreceptor degeneration, other retinal degenerations, optic nerve drusen, optic neuropathy and optic neuritis.