Carboxamide-pyrimidine derivatives as SHP2 antagonists

Abstract

The present invention relates to a carboxamide-pyrimidine derivative represented by general formula I or a pharmaceutically acceptable salt thereof, the use of the compound of the present invention for treating hyperproliferative diseases and disorders in mammals (especially humans), and a pharmaceutical composition containing the compound, #imgabs0#

Description

[0001] The present invention relates to a carboxamide-pyrimidine derivative represented by the general formula I,

[0002]

[0003] The invention also relates to the use of the compounds of the invention in treating and / or preventing hyperproliferative diseases and disorders in mammals (especially humans), and pharmaceutical compositions containing such compounds. Background of the Invention

[0005] Src homology 2 (SH2) containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to a variety of cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signaling through the Ras mitogen-activated protein kinase, JAK-STAT, or phosphoinositide 3-kinase-AKT pathways. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2): one is the catalytic domain (PTP) and one is the C-terminal tail. These two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive, autoinhibitory configuration that is stabilized by a binding network involving residues from the N-SH2 and PTP domains. For example, exposure of the catalytic site by stimulation with cytokines or growth factors leads to enzymatic activation of SHP2.

[0006] SHP2 is widely expressed in various tissues and cell types. It plays an important role in regulating cellular biological processes in various signal transduction pathways and participates in the signal transduction pathways of various growth factors and cytokines. Within a single signal transduction pathway, SHP2 can simultaneously play a positive (signal enhancement) role and a negative (signal attenuation) role in the intracellular signal transduction process. It is believed that SHP2 acts by dephosphorylating its related signal transduction molecules, thereby attenuating the local signal transduction flow. However, the main role of SHP2 activity in most signal transduction pathways (e.g., growth factors, cytokines and extracellular matrix receptors) is to enhance signal transduction. For example, SHP2 is a positive regulator of the ERK / MAPK signal transduction pathway, which plays a key role in regulating cell proliferation and survival (KS Grossman et al., Adv. Cancer Res., 2010, 106, 53-89 and references cited therein).

[0007] Mutations in the PTPN11 gene that affect N-SH2 or PTP domain residues involved in the basal repression of SHP2 produce more activated forms of the SHP2 protein that result in unregulated or increased SHP2 activity. Such activating mutants of SHP2 are associated with developmental disorders such as Noonan syndrome, in which nearly all mutant forms of SHP2 show increased PTP activity. Activating SHP2 mutations have also been detected in juvenile myelomonocytic leukemia (e.g., Q506P), chronic myelomonocytic leukemia (e.g., Y63C), neuroblastoma (e.g., T507K), melanoma (e.g., RI38Q), acute myeloid leukemia (e.g., G503V), breast cancer, lung cancer (e.g., E76V), and colorectal cancer (e.g., E76G) (M. Bentires-Alj et al., in Cancer Res. 2004, 64, 8816-8820; and references cited therein). Other PTPN1 mutations associated with cancer are disclosed in WO 2015 / 107495 and references cited therein.

[0008] Mutations in the PTPN11 gene and subsequently SHP2 mutations have been identified in several human diseases, such as Noonan syndrome (NS), Leopard syndrome, diabetes, neutropenia (Kostmann's syndrome), systemic lupus erythematosus, neuroblastoma, melanoma, juvenile myelomonocytic leukemia, acute myeloid leukemia, juvenile leukemia, chronic myelomonocytic leukemia, and other cancers associated with SHP2 dysregulation, such as lung cancer, colon cancer, and breast cancer, such as HER2-positive breast cancer, triple-negative breast cancer, breast ductal carcinoma, breast invasive ductal carcinoma, non-small cell lung cancer (including lung adenocarcinoma), esophageal cancer, gastric cancer, head and neck squamous cell carcinoma (SCCHN), and colon cancer (N. Aceto et al. Nature Medicine, 2012, 28, 529-538; CM Furcht et al. Oncogene, 2013, 32, 2346-2355; VESchneeberger et al. Oncotarget, 2015, 6, 6191-6202; P. Cai et al., Biomedicine & Pharmacotherapy 2014, 6, 285-290; and references cited therein).

[0009] Therefore, SHP2 represents a highly attractive target for the development of novel therapeutics for the treatment of a variety of diseases.The compounds of the present invention fulfill the need for small molecules that inhibit SHP2 activity.

[0010] SHP2 phosphatase inhibitors are disclosed in, for example, WO 2015 / 107493, WO 2015 / 107494, WO 2015 / 107495, WO 2016 / 203404, WO 2016 / 203405, WO 2016 / 203406, WO2017 / 216706, WO2018 / 013597, WO2018 / 136264, WO2018 / 136265, WO2018 / 057884, WO2018 / 081091 and JG Fortanet et al., J. Med. Chem. 2016, doi: 10.1021 / acs.jmedchem.6b00600 and references cited therein. The effects of SHP2 phosphatase inhibition are described, for example, in Y.-NPChen et al., Nature, 2016, doi.10.1038 / nature / 18621; J. Wang et al., J. Clin. Invest., 2016, 126, 2077-2092; and references cited therein. SHP2 phosphatase inhibitors include, for example, 8-hydroxy-7-[(6-sulfo-2-naphthyl)azo]-5-quinolinesulfonic acid (NSC 87077) and SHP-099.

[0011] However, known compounds such as SHP-099 (or compounds disclosed in WO2015 / 107493) and / or RMC-4550 (compounds disclosed in WO2018 / 013597) do not exhibit high selectivity for hErg, which is extremely important for the safety of compounds for preventing or treating diseases.

[0012] In addition, compared with known compounds such as SHP-099 (or compounds disclosed in WO2015 / 107493) or RMC-4550 (compounds disclosed in WO2018 / 013597), the compounds of the present invention exhibit excellent pharmacokinetic properties (e.g., low clearance and / or high exposure).

[0013] Therefore, there remains a need for highly potent SHP2 inhibitors that do not exhibit the above mentioned drawbacks.A specific object of the present invention is to provide improved methods capable of preventing or treating hyperproliferative diseases and disorders in a host, and in particular to provide potent SHP2 antagonists for the treatment and prevention of such diseases. Summary of the invention

[0014] Surprisingly, it has been found that the carboxamide-pyrimidine derivatives according to the present invention are highly potent SHP2 inhibitors and are therefore useful in the treatment of hyperproliferative diseases and disorders, such as cancer.

[0015] In addition, the compounds of the present invention are highly potent inhibitors of ERK12, which is a target downstream form of SHP2 in the signaling pathway (as mentioned above, SHP2 is a positive regulator of the ERK / MAPK signaling pathway, and ERK phosphorylation depends on SHP2 activation), which plays a key role in regulating cell proliferation and survival. This also confirms that the compounds of the present invention can be used to treat hyperproliferative diseases and disorders, such as cancer.

[0016] At the same time, compared with the known SHP2 antagonists SHP-099, RMC-4550 and similar pyrimidine derivatives, the compounds of the present invention unexpectedly have very high selectivity for hErg (ion channel Kv11.1). The high hErg inhibitory activity of SHP-099, RMC-4550 and similar pyrimidine derivatives clearly points to the potential risk of cardiac toxicity, which can be avoided by the compounds of the present invention. The improved safety of the compounds of the present invention is combined with more desirable pharmacokinetic properties and enhanced target engagement (lower IC 50 The unexpected properties of the compounds of the present invention represent a significant advance in the desired field of SHP2 inhibitors.

[0017] The present invention relates to a carboxamide-pyrimidine derivative represented by the general formula I*,

[0018]

[0019] In the formula,

[0020] R1' is a monocyclic or bicyclic alkyl, heterocyclic, heteroaryl or bicyclic alkylaryl group containing 3 to 14 carbon atoms and 0 to 4 heteroatoms independently selected from N, O and S, said group being unsubstituted or substituted with CH2) n NH2, (CH2) n OH, (CH2) n CH3 or Hal is monosubstituted, disubstituted or trisubstituted,

[0021] X is a single bond, -NH- or -N(CH3)-, (CH2) n or O,

[0022] R2 is aryl or heteroaryl, S-aryl or S-heteroaryl, said group is unsubstituted or (CH2) n NH2, (CH2) n OH, COOH, CONH2, alkyl, =S, =O, =NH, CN or Hal monosubstituted, disubstituted or trisubstituted,

[0023] R3 is H, NH2, OH, Hal or alkyl,

[0024] Y is N or O,

[0025] R4, R5 are both H, or one of R4 and R5 is OH, COOH, NH2, CONH2 or methyl or ethyl, said group being unsubstituted or substituted by =S, =O, OH, COOH, =NH, NH2, CONH2,

[0026] Hal is F, Cl, Br or I,

[0027] n is 0, 1, 2 or 3,

[0028] and physiologically acceptable salts, derivatives, solvates, prodrugs, stereoisomers and atropisomers thereof, including mixtures thereof in various ratios.

[0029] The present invention preferably relates to a carboxamide-pyrimidine derivative represented by the general formula I,

[0030]

[0031] or a pharmaceutically acceptable salt thereof, wherein:

[0032] R1' is a monocycloalkyl, a bicycloalkyl, a monoheterocyclic radical or a biheterocyclic radical, any of which is optionally spiro-connected to a monocycloalkyl, a bicycloalkyl, a monoheterocyclic radical or a biheterocyclic radical, wherein each of the monocycloalkyl or bicycloalkyl and the monoheterocyclic radical or the biheterocyclic radical may be optionally and independently substituted by 1-3 groups selected from the following: C1-C6 alkyl, -F, -Cl, -CF3, -NH2, C1-C3 aminoalkyl, -OH, C1-C3 alkoxy, C1-C3 hydroxyalkyl and phenyl;

[0033] X is a bond, -NH- or -N(Me)-;

[0034] R2 is aryl or heteroaryl, which is substituted by 1-3 groups selected from the group consisting of -F, -Cl, -CF3, C1-C3 alkoxy and C1-C3 alkyl;

[0035] R3 is -H, -NH2, -OH, -Cl, -F, -Br or -CH3;

[0036] Y is -N-; and

[0037] R4 and R5 are independently -H, -NH2, -OH, C1-C3 alkyl or C1-C3 hydroxyalkyl.

[0038] The present invention preferably relates to a carboxamide-pyrimidine derivative represented by the general formula Ia,

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein R6, R7 and R8 are each independently selected from -H, -F, -Cl, -CF3, C1-C3 alkoxy and C1-C3 alkyl, and the remaining variables are as defined for the compound of formula I.

[0041] The present invention preferably relates to a carboxamide-pyrimidine derivative represented by the general formula Ib,

[0042]

[0043] or a pharmaceutically acceptable salt thereof, wherein:

[0044] When A is the point of attachment to the pyrimidine ring of Formula Ib, R1 is

[0045] R6, R7 and R8 are each independently selected from -H, -F, -Cl, -CF3, C1-C3 alkoxy and C1-C3 alkyl;

[0046] n is 0, 1, 2 or 3; and

[0047] R9, R10, R11, R12, R13, R14, R15 and R16, if present, are each independently selected from -H, C1-C3 alkyl, -NH2, -OH, -Cl, -F, -Br, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy and phenyl; or

[0048] Two of R9, R11, R13 and R16 taken together form a bridged bicyclic heterocyclic ring system optionally substituted with 1-3 substituents selected from the group consisting of C1-C3 alkyl, -NH2, -OH, -Cl, -F, -Br, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy and phenyl; or

[0049] Two of R9, R10, R11, R12, R13, R14, R15 and R16 attached to the same carbon atom together form a monocyclic or bicyclic spirocyclic group, which is optionally substituted with 1-3 substituents selected from the following: C1-C3 alkyl, -NH2, -OH, -Cl, -F, -Br, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy and phenyl; or

[0050] Two of R9, R10, R11, R12, R13, R14, R15 and R16 attached to adjacent carbon atoms together form a fused carbocyclic or heterocyclic group, which is optionally substituted with 1-3 substituents selected from the group consisting of C1-C3 alkyl, -NH2, -OH, -Cl, -F, -Br, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy and phenyl;

[0051] The remaining variables have the definitions described above for Formula I.

[0052] The present invention preferably relates to a carboxamide-pyrimidine derivative represented by the general formula Ic,

[0053]

[0054] The remaining variables have the same definitions as described above for Formula I.

[0055] The present invention preferably relates to a carboxamide-pyrimidine derivative represented by the general formula Id,

[0056]

[0057] The remaining variables have the same definitions as described above for Formula I.

[0058] The present invention preferably relates to a carboxamide-pyrimidine derivative represented by the general formula Ie,

[0059]

[0060] The remaining variables have the same definitions as described above for Formula I.

[0061] The present invention preferably relates to a carboxamide-pyrimidine derivative represented by the general formula If,

[0062]

[0063] The remaining variables have the same definitions as described above for Formula I.

[0064] The present invention preferably relates to compounds of the general formula I or general formula Ia, wherein R1 is one of the following structural formulas:

[0065] as well as

[0066] The structural formula is unsubstituted or mono-, di- or tri-substituted by the following groups: C1-C6 alkyl, -F, -Cl, -CF3, -NH2, C1-C3 aminoalkyl, -OH, C1-C3 alkoxy or C1-C3 hydroxyalkyl,

[0067] and wherein X, R2, R3, Y, R4 and R5 have the definitions disclosed above.

[0068] The present invention preferably relates to compounds of formula I or formula Ia, wherein X-R1 is one of the following structural formulas:

[0069]

[0070] as well as

[0071] wherein A represents the point of attachment to the pyrimidine ring and the remaining variables have the definitions described above for the general formula.

[0072] In one aspect of the present invention, X-R1 in Formula I or Formula Ia is selected from the group consisting of:

[0073] wherein A represents the point of attachment to the pyrimidine ring.

[0074] In one aspect of the present invention, X-R1 in Formula I or Formula Ia is selected from the group consisting of:

[0075] as well as wherein A represents the point of attachment to the pyrimidine ring.

[0076] In one aspect of the present invention, X-R1 in Formula I or Formula Ia is selected from the group consisting of:

[0077] wherein A represents the point of attachment to the pyrimidine ring.

[0078] The present invention preferably relates to a compound according to formula I or a pharmaceutically acceptable salt thereof, wherein R2 is phenyl, which is unsubstituted or mono-, di- or tri-substituted by -F, -Cl and / or -Br, and X, R1, R3, Y, R4 and R5 have the definitions disclosed above.

[0079] The present invention preferably relates to a compound according to formula I or a pharmaceutically acceptable salt thereof, wherein R2 is one of the following structural formulas:

[0080]

[0081] wherein X, R1, R3, Y, R4 and R5 have the definitions disclosed above.

[0082] The present invention preferably relates to a compound according to formula I or a pharmaceutically acceptable salt thereof, wherein R3 is -NH2, and X, R1, R2, Y, R4 and R5 have the definitions disclosed above.

[0083] The present invention preferably relates to a compound according to formula I or a pharmaceutically acceptable salt thereof, wherein R3 is -CH3, and X, R1, R2, Y, R4 and R5 have the definitions disclosed above.

[0084] The present invention preferably relates to a compound according to formula I or a pharmaceutically acceptable salt thereof, wherein R3 is -H, and X, R1, R2, Y, R4 and R5 have the definitions disclosed above.

[0085] The present invention preferably relates to a compound according to formula I or a pharmaceutically acceptable salt thereof, wherein R3 is -Cl, and X, R1, R2, Y, R4 and R5 have the definitions disclosed above.

[0086] The present invention preferably relates to a compound according to formula I or a pharmaceutically acceptable salt thereof, wherein X is a single bond, -NH- or -N(CH ３ )-, and wherein Y, R1, R2, R3, R4 and R5 have the definitions disclosed above.

[0087] One aspect of the present invention is a compound according to formula Ib or a pharmaceutically acceptable salt thereof, wherein

[0088] When A is the point of attachment to the pyrimidine ring of Formula Ib, R1 is

[0089] R6, R7 and R8 are each independently selected from -H, -F, -Cl, -CF3, C1-C3 alkoxy and C1-C3 alkyl;

[0090] n is 0, 1, 2 or 3; and

[0091] R9, R10, R11, R12, R13, R14, R15 and R16, if present, are each independently selected from -H, C1-C3 alkyl, -NH2, -OH, -Cl, -F, -Br, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy and phenyl; or

[0092] Two of R9, R11, R13 and R16 taken together form a bridged bicyclic heterocyclic ring system optionally substituted with 1-3 substituents selected from the group consisting of C1-C3 alkyl, -NH2, -OH, -Cl, -F, -Br, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy and phenyl; or

[0093] Two of R9, R10, R11, R12, R13, R14, R15 and R16 attached to the same carbon atom together form a monocyclic or bicyclic spirocyclic group, which is optionally substituted with 1-3 substituents selected from the following: C1-C3 alkyl, -NH2, -OH, -Cl, -F, -Br, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy and phenyl; or

[0094] Two of R9, R10, R11, R12, R13, R14, R15 and R16 attached to adjacent carbon atoms together form a fused carbocyclic or heterocyclic group, which is optionally substituted with 1-3 substituents selected from the following: C1-C3 alkyl, -NH2, -OH, -Cl, -F, -Br, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy and phenyl.

[0095] The present invention particularly preferably relates to compounds selected from the group consisting of:

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119] and pharmaceutically acceptable salts and atropisomers thereof, including mixtures thereof in various ratios.

[0120] All of the above embodiments for the above meanings of the variables (if any) in any of the general formulae I, Ia, Ib, Ic, Id, Ie and If should be understood in such a way that any of these specific embodiments can be combined with any possible embodiment to give the compounds of the invention.

[0121] Alkyl is a saturated straight or branched hydrocarbon chain and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl and the like.

[0122] Aminoalkyl is an alkyl group as described above, wherein the alkyl group is substituted with a -NH2 group.

[0123] Hydroxyalkyl is an alkyl group as described above, wherein the alkyl group is substituted with an -OH group.

[0124] Alkoxy refers to a group according to the general formula -O(CH2) n CH, is a saturated, unbranched or branched hydrocarbon chain containing at least 1 to 10 carbon atoms, wherein n in the general formula is 0 to 9. Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, and the like.

[0125] Cyclic alkyl or cycloalkyl refers to a saturated cyclic hydrocarbon chain having 3-15 carbon atoms and in the form of a bridged ring system, a monocyclic ring system, a bicyclic ring system and / or a spirocyclic ring system. Monocyclic cycloalkyl preferably has 3-7 C atoms and preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl may also represent partially unsaturated cyclic alkyl, such as cyclohexenyl or cyclohexynyl. When the cycloalkyl is part of a bicyclic ring system, at least one of the rings is a 3-7 membered cycloalkyl, which may be fused with a 5- or 6-membered heteroaryl, a phenyl, a 5-7 membered heterocyclyl or a 5-7 membered cycloalkyl. Examples of bicyclic ring systems that meet the definition of cycloalkyl include, for example, 2,3-dihydro-1H-indenyl, 4H,5H,6H-cyclopenta[d][1,3]thiazolyl, 1,2,3,4-tetrahydronaphthyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5H,6H,7H-cyclopenta(b)pyridinyl, 5H,6H,7H-cyclopenta(c)pyridinyl, and the like.

[0126] Aryl, Ar or aromatic ring represents a monocyclic or polycyclic aromatic or completely unsaturated cyclic hydrocarbon chain, for example unsubstituted phenyl, naphthyl or biphenyl, more preferably phenyl, naphthyl or biphenyl, each of which is mono-, di- or tri-substituted by, for example, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, sulfonylamino, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, dimethylsulfonylamino, phenylsulfonylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl, and / or amide.

[0127] Heterocycle and heterocyclyl refer to saturated or unsaturated non-aromatic monocyclic rings, or partially or completely non-aromatic ring systems that may be bridged, bicyclic ("fused") and / or spiro-connected. Heterocyclyl contains at least one heteroatom selected from O, S and N, and may further include oxidized forms of sulfur, i.e., SO and SO2. Monocyclic heterocyclyls are preferably 3-7 atoms and include azetidinyl, tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiolane, thiomorpholine, oxolane, oxane, azepane, and the like. When the heterocyclyl is part of a bicyclic ring system, at least one ring is a 3-7 membered heterocyclyl which may be fused to a 5- or 6-membered heteroaryl, phenyl, 5-7 membered heterocyclyl or 5-7 membered cycloalkyl. Examples of bicyclic ring systems that meet the definition of heterocyclyl include, for example, 2H,3H-furo[2,3-b]pyridine, 2H,3H-furo[2,3-c]pyridine, 2H,3H-furo[2,3-d]pyridine, 2,3-dihydrobenzofuran, octahydro-1H-isoindole, octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, 3-azabicyclo[3.1.0]hexane, 3,9-diazabicyclo[4.2.1]non-3-yl, and the like.

[0128] Heteroaryl refers to an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N. Heteroaryl thus includes heteroaryl groups fused to other types of rings, such as aryl, cycloalkyl and heterocycles that are not aromatic. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolyl, pyridazinyl, indazolyl, isoxazolyl, isoindolyl, dihydrobenzothiophenyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, The heterocyclic and heteroaryl groups include rings and ring systems containing 3 to 15 atoms, forming 1 to 3 rings.

[0129] Spirocyclic moieties refer to those in which two rings or ring systems are connected via a single common carbon atom. Spiro compounds can be completely carbocyclic (all carbon atoms) or heterocyclic (with one or more non-carbon atoms). Spirocyclic moieties comprising two rings are considered as bicyclic; Spirocyclic moieties in which a monocyclic ring is connected to a bicyclic moiety are considered as tricyclic moieties. Examples of spiral bicyclic moieties include 8-azaspiro [4.5] decane, 2-oxa-8-azaspiro [4.5] decane, 2-azaspiro [3.4] octane, 6-azaspiro [3.4] octane, 2-oxa-6-azaspiro [3.4] octane, 2-azaspiro [4.4] nonane, 1-oxa-9-azaspiro [5.5] undecane, 5-azaspiro [2.4] heptane , 1,3-dihydrospiro-[indene-2,4′-piperidine], 5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine], 3H-spiro[furano[2,3-b]pyridine-2,4′-piperidine], 3H-spiro[1-benzofuran-2,4′-piperidine], 4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidine], etc.

[0130] The compounds of the present invention may form atropisomers, which are conformational isomers associated with the pyrimidine moiety present in Formula I, Ia, Ib, Ic, Id, Ie and If. Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where energy differences due to steric strain or other contributing factors produce sufficiently high resistance to rotation to allow separation of individual conformers. Two different atropisomers are observed in the compounds of the present invention, for example when R2 is phenyl substituted with R6, R7 and R8, as shown below:

[0131] Depending on the orientation of the aryl or heteroaryl group and the substituent R3 on the pyrimidine ring, these forms are represented in the compound nomenclature as M or P forms. Examples of M and P forms are provided in the Examples section. Particularly preferred compounds are those having the following orientations:

[0132]

[0133] The invention furthermore relates to pharmaceutical preparations comprising a compound according to the invention and / or one of its physiologically acceptable salts.

[0134] The present invention also relates to such pharmaceutical preparations according to the invention, comprising further excipients and / or adjuvants.

[0135] Furthermore, the present invention relates to the above-mentioned pharmaceutical formulation according to the present invention, further comprising one or more additional therapeutic agents.

[0136] The compounds of the present invention can be used in their free base form. On the other hand, the present invention also includes the use of the compounds of the present invention in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic bases by following methods known in the art. The term pharmaceutical salt is used to refer to an ionizable drug that has been combined with a counterion to form a neutral complex. Converting the drug to a salt by this process can increase its chemical stability, make the complex easier to administer, and allow control of the pharmacokinetic properties of the agent. The selection of salts is now a common standard operation performed with ionizable small molecules during drug development, and in many cases, drug salts show better properties than the parent molecule. Most of the pharmaceutically acceptable salt forms of the compounds of the present invention are prepared by conventional methods.

[0137] In one embodiment, the pharmaceutically acceptable salt of the compound of the invention can be selected from hydrochloride, acetate, sodium, sulfate, phosphate or diphosphate, chloride, potassium, maleate, calcium, citrate, methanesulfonate, nitrate, tartrate, aluminum, gluconate, benzoate, benzenesulfonate and edisylate. In one aspect of this embodiment, the pharmaceutically acceptable salt is benzoate, benzenesulfonate or edisylate.

[0138] The pharmaceutically acceptable salts of the compounds of the invention include solvates of the salts. The term solvate refers to an adduct of inert solvent molecules of the compounds of the invention formed due to their mutual attraction. Solvates are, for example, hydrates, such as monohydrates or dihydrates or alcoholates, i.e. addition compounds with alcohols, such as methanol or ethanol.

[0139] The compounds of general formula I may have one or more chiral centers, so that the present invention also claims all stereoisomers, enantiomers, diastereomers, etc. of the compounds shown in general formula I. Therefore, the present invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds.

[0140] Compounds of the general formula I shall also include isotopically labeled forms thereof. Isotopically labeled forms of compounds of the general formula I differ from said compounds only in that one or more atoms of said compounds are replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atoms normally occurring in nature. Examples of isotopes that are readily available on the market and can be incorporated into compounds of the general formula I by known methods include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, respectively 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O.31 P. 32 P. 35 S. 18 F and 36 CI. Compounds of the general formula I, their prodrugs or pharmaceutically acceptable salts of any of them containing one or more of the above-mentioned isotopes and / or isotopes of other atoms are to be understood as part of the present invention. Isotopically labeled compounds of the general formula I can be used in a variety of advantageous ways. For example, in combination with 3 H or 14 Compounds of Formula 1 labeled with radioactive isotopes of C can be used in drug and / or substrate tissue distribution assays. These two radioactive isotopes are particularly preferred due to their simple preparation and good detectability, namely tritium ( 3 H) and carbon-14 ( 14 C). Due to the presence of deuterium ( 2 H) has a higher metabolic stability, and it is therapeutically beneficial to incorporate such isotopically labeled compounds into compounds of Formula I. Higher metabolic stability directly leads to an increase in half-life in vivo or a reduction in dosage, which in most cases represents a preferred embodiment of the present invention. Isotopically labeled compounds of Formula I can generally be prepared by carrying out the steps disclosed in the synthetic schemes and related descriptions in the Examples and Preparations section of this text, replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0141] In order to control the oxidative metabolism of compounds through the primary kinetic isotope effect, deuterium ( 2 H) is incorporated into a compound having the general formula I. The primary kinetic isotope effect is a change in the rate of a chemical reaction due to the replacement of an isotopic nucleus, which is caused by a change in the ground state energy required to form a covalent bond after said isotopic replacement. Replacement of a heavier isotope generally results in a decrease in the ground state energy of the chemical bond, thereby causing a decrease in the rate of the rate-limiting bond breaking reaction. If bond breaking occurs in or near the saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can be significantly altered. The explanation is as follows: If deuterium is bonded to a non-replaceable position on a carbon atom, the rate difference k is generally m / k d = 2-7. If this rate difference is successfully applied to a compound of formula I that is susceptible to oxidation, the in vivo properties of the compound can be significantly altered, thereby improving the pharmacokinetic properties.

[0142] Deuterium-hydrogen substitution in compounds of Formula I can also be used to favorably alter the metabolite profile of the starting compound to reduce or eliminate undesirable toxic metabolites. For example, if toxic metabolites are produced by oxidative carbon-hydrogen (CH) bond cleavage, it is reasonable to assume that deuterated analogs will significantly reduce or eliminate the production of undesirable metabolites, even if that particular oxidation reaction is not the rate-determining step. For more information on deuterium-hydrogen substitution in the prior art, see, for example, Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foste R, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33 (10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16 (4), 683-688, 1993.

[0143] The invention also relates to mixtures of compounds of the general formula I, for example mixtures of two atropisomers and / or two or more diastereomers, for example in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferably mixtures of two stereoisomeric compounds. In one embodiment of the invention, the mixture of atropisomers and / or diastereomers contains at least 80% of the desired conformation. In one aspect of this embodiment, the mixture of atropisomers and / or diastereomers contains at least 85% of the desired conformation. In another aspect of this embodiment, the mixture of atropisomers and / or diastereomers contains at least 90% of the desired conformation. In one aspect of this embodiment, the mixture of atropisomers and / or diastereomers contains at least 95% of the desired conformation. In one aspect of this embodiment, the mixture of atropisomers and / or diastereomers contains at least 98% of the desired conformation.

[0144] If desired, the starting materials are formed in situ, in such a way that they are not isolated from the reaction mixture but are immediately converted further into compounds of the general formula I.

[0145] Preferably, by solvolysis, especially hydrolysis or hydrogenolysis, handle so as to discharge the compound of general formula I from its functional derivative and obtain.The preferred initiator for solvolysis or hydrogenolysis is a compound containing corresponding protected amino, carboxyl and / or hydroxyl rather than one or more free amino groups, carboxyl and / or hydroxyl, preferably has an amino protecting group rather than the compound of the H atom bonded to the N atom.Other preferred initiators are to carry protected carboxyl rather than free carboxyl.A plurality of identical or different protected amino and / or hydroxyl groups can also be present in the molecule of the initiator.If the existing protecting groups are different from each other, they can be selectively cracked and removed so.

[0146] The term "amino-protecting group" is used in a general sense and relates to a group which is suitable for protecting (preventing) an amino group from chemical reactions but which is easily removable after the desired chemical reaction has taken place elsewhere in the molecule. Typical such groups are, in particular: unsubstituted or substituted acyl, unsubstituted or substituted aryl (e.g. 2,4-dinitrophenyl) or aralkyl (e.g. benzyl, 4-nitrobenzyl, trityl). Since the amino-protecting groups are removed after the desired reaction or reaction sequence, their type and size are not critical; however, preference is given to protecting groups having 1 to 20, in particular 1 to 8, carbon atoms. The term "acyl" is to be understood in the broadest sense in connection with the present process. It comprises acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, in particular alkoxycarbonyl, aryloxycarbonyl and in particular aralkyloxycarbonyl. Examples of such acyl groups are: alkyl acyl (e.g., acetyl, propionyl and butyryl); aralkyl acyl (e.g., phenylacetyl); aroyl (e.g., benzoyl and toluoyl); aryloxyalkanoyl (e.g., phenoxyacetyl); alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl); aralkyloxycarbonyl, (e.g., CBZ, 4-methoxybenzyloxycarbonyl and FMOC). Preferred amino protecting groups are CBZ, FMOC, benzyl and acetyl.

[0147] The term "acid protecting group" or "carboxyl protecting group" likewise means a general term and relates to a group suitable for protecting a -COOH group for chemical reactions but which is easily removable after the desired chemical reaction has taken place elsewhere in the molecule. Typically, esters are used rather than free acids, such as substituted and unsubstituted alkyl esters (e.g., methyl, ethyl, tert-butyl and substituted derivatives thereof), substituted and unsubstituted benzyl esters or silyl esters. The type and size of the acid protecting group are not critical; however, preferred are protecting groups having 1 to 20, especially 1 to 10, carbon atoms.

[0148] The term "hydroxyl-protecting group" likewise has a general meaning and relates to a group which is suitable for protecting a hydroxyl group for chemical reactions but which is easily removable after the desired chemical reaction has been completed elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl groups. The type and size of the hydroxyl-protecting group are not critical, since they are removed after the desired chemical reaction or reaction sequence; preference is given to groups having 1 to 20, in particular 1 to 10, carbon atoms. Examples of hydroxyl-protecting groups are, in particular: benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.

[0149] Other typical examples of amino-protecting groups, acid-protecting groups and hydroxy-protecting groups are found in, for example, “Greene's Protective Groups in Organic Synthesis”, 4th edition, Wiley-Interscience, 2007.

[0150] The obtained compounds according to the present invention can be separated (e.g., by centrifugation and washing) from the corresponding solutions in which they are prepared, and can be stored in another composition after separation, or they can be directly retained in the prepared solution. The obtained compounds according to the present invention can also be dissolved in the desired solvent for a specific purpose.

[0151] Conventional work-up steps, such as addition of water to the reaction mixture and extraction, enable the compounds to be obtained after removal of the solvent. For further purification of the product, subsequent distillation or crystallization or chromatographic purification may be advantageous.

[0152] It has surprisingly been found that compounds of general formula I may have advantageous efficacy, selectivity, pharmacokinetic properties, dosing regimens, lower toxicity and / or physical properties compared to prior art compounds.

[0153] The present invention also relates to the use of a compound according to the invention for the preparation of a medicament for the treatment of a disease caused, promoted and / or propagated by SHP2 or an agonist thereof.

[0154] Therefore, the present invention also particularly relates to a medicament for the treatment and / or prevention of physiological and / or pathophysiological conditions, the medicament comprising at least one compound of the present invention and / or one of its pharmaceutically acceptable salts. In particular, physiological and / or pathophysiological conditions associated with SHP2 are particularly preferred. Physiological and / or pathophysiological conditions are to be understood as meaning medically relevant physiological and / or pathophysiological conditions, such as diseases or illnesses and medical disorders, ailments, symptoms or complications, etc., in particular diseases.

[0155] The present invention also relates to a medicament for treating a physiological and / or pathophysiological condition selected from hyperproliferative diseases and disorders, the medicament comprising at least one compound of the present invention and / or one of its pharmaceutically acceptable salts. In one embodiment, the hyperproliferative disease or disorder is cancer.

[0156] Therefore, the present invention particularly preferably relates to a medicament comprising at least one compound according to the invention and / or one of its pharmaceutically acceptable salts, wherein the cancer is selected from acute and chronic lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, bladder cancer, brain cancer, breast cancer, uterine cancer, uterine hyperplasia, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, essential thrombocythemia, genitourinary cancer, glioma, glioblastoma, hairy cell leukemia, head and neck cancer, Hodgkin's disease, Kaposi's sarcoma, lung cancer, lymphoma, Malignant carcinoid tumor, malignant hypercalcemia, malignant melanoma, malignant pancreatic insulinoma, medullary thyroid cancer, melanoma, multiple myeloma, mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, polycythemia vera, primary brain cancer, primary macroglobulinemia, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, skin cancer, small cell lung cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer and Wilm's tumor. In one embodiment of the invention, the cancer is non-small cell lung cancer, small cell lung cancer, head and neck cancer, breast cancer, esophageal cancer, gastric cancer, colorectal cancer, glioblastoma, pancreatic cancer, osteogenic sarcoma, melanoma and renal cancer. In one aspect of this embodiment, cancer is head and neck cancer. In another aspect of this embodiment, cancer is lung cancer. In one aspect of this embodiment, lung cancer is non-small cell lung cancer. In another aspect of this embodiment, the lung cancer is small cell lung cancer. In another aspect of this embodiment, the cancer is colorectal cancer. In another aspect of this embodiment, the cancer is esophageal cancer. In another aspect of this embodiment, the cancer is gastric cancer.

[0157] The present invention also preferably relates to a medicament for the treatment of a physiological and / or pathophysiological condition selected from hyperproliferative and infectious diseases and disorders, the medicament comprising at least one compound of the present invention and / or one of its pharmaceutically acceptable salts, wherein the hyperproliferative disease or disorder is selected from age-related macular degeneration, Crohn's disease, cirrhosis, chronic inflammation-related disorders, proliferative diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, granulomatous diseases, immune hyperproliferation associated with organ or tissue transplantation and an immunoproliferative disease or disorder selected from inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), vascular hyperproliferation secondary to retinal hypoxia and vasculitis.

[0158] The above disclosed medicaments are intended to include the corresponding use of the compounds of the present invention for the preparation of medicaments for the treatment of the above physiological and / or pathophysiological conditions.

[0159] Furthermore, the medicaments disclosed above are intended to include corresponding methods for the treatment of the above physiological and / or pathophysiological conditions, wherein at least one compound according to the invention is administered to a patient in need of such treatment.

[0160] As described in the examples, the compounds of the present invention preferably exhibit advantageous biological activities that can be readily demonstrated in enzyme assays and animal tests. In such enzyme-based assays, the compounds of the present invention preferably exhibit and cause an inhibitory effect, which is generally indicated by an IC in a suitable range. 50 The values ​​are preferably in the micromolar range, more preferably in the nanomolar range.

[0161] The compounds of the invention can be administered to humans or animals, in particular mammals, such as apes, dogs, cats, rats or mice, and can be used for therapeutic treatment of the human or animal body and also for combating the above-mentioned diseases. They can also be used as diagnostic agents or reagents.

[0162] Furthermore, the compounds of the invention can be used to isolate SHP2 and study its activity or expression. In addition, they are particularly suitable for use in diagnostic methods for diseases associated with disturbed SHP2 activity. Therefore, the present invention also relates to the use of the compounds of the invention for isolating SHP2 and studying its activity or expression or as binders and inhibitors of SHP2.

[0163] For diagnostic purposes, the compounds of the invention may, for example, be radiolabeled. Examples of radiolabeled 3 H. 14 C. 231 I and 125 I. The preferred labeling method is the indogen method (Fraker et al., 1978). In addition, the compounds of the present invention can be labeled by enzymes, fluorophores and chromophores. Examples of enzymes are alkaline phosphatase, β-galactosidase and glucose oxidase, examples of fluorophores are fluorescein, examples of chromophores are luminol, and automatic detection systems for, for example, fluorescent staining are described in, for example, US 4,125,828 and US 4,207,554.

[0164] The present invention also relates to pharmaceutical preparations comprising at least one compound of formula I and / or a pharmaceutically acceptable salt thereof. In particular, the present invention also relates to pharmaceutical preparations comprising other excipients and / or adjuvants, and pharmaceutical preparations comprising at least one other pharmaceutically active compound.

[0165] In particular, the present invention also relates to a process for the preparation of a pharmaceutical preparation, characterized in that a compound of formula I and / or one of its pharmaceutically acceptable salts is formed into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant and optionally with one or more additional therapeutic agents.

[0166] The pharmaceutical preparations of the present invention can be used as drugs in human or veterinary medicine. The patient or host can belong to any mammalian species, such as primate species, especially humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental studies, where they provide models for treating human diseases.

[0167] Suitable carrier materials are organic or inorganic substances, which are suitable for enteral (e.g. oral), parenteral or topical administration and do not react with the novel compound, such as water, vegetable oil (e.g. sunflower oil or cod liver oil), benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (e.g. lactose or starch), magnesium stearate, talc, lanolin or vaseline. Due to professional knowledge, those skilled in the art are familiar with which adjuvant is suitable for the desired pharmaceutical preparation. In addition to solvents (e.g. water, physiological saline solution or alcohol (e.g. ethanol, propanol or glycerol), sugar solutions (e.g. glucose or mannitol solutions)) or mixtures of the solvents, gelling agents, tablet adjuvants and other active ingredient carriers, lubricants, stabilizers and / or wetting agents, emulsifiers, salts that affect osmotic pressure, antioxidants, dispersants, antifoaming agents, buffer substances, flavoring agents and / or spices or flavoring agents, preservatives, solubilizers or dyes may also be used. If desired, the preparation or medicine of the present invention may include one or more other active compounds, such as one or more vitamins.

[0168] If desired, the preparations or medicaments of the present invention may contain one or more other active compounds and / or one or more action enhancers (auxiliaries).

[0169] For the purposes of the present invention, the terms "pharmaceutical formulation" and "pharmaceutical preparation" are used synonymously.

[0170] As used herein, "pharmaceutically acceptable" refers to drugs, precipitating agents, excipients, adjuvants, stabilizers, solvents and other agents that facilitate administration of the pharmaceutical preparations derived therefrom to mammals without undesirable physiological side effects such as nausea, dizziness, digestive problems, and the like.

[0171] In pharmaceutical preparations for parenteral administration, isotonicity, normal hydration and tolerability as well as safety of the preparation (low toxicity), the adjuvants used and the primary packaging are required. Surprisingly, the compounds of the present invention preferably have the advantage that they can be used directly, and therefore, no further purification steps for removing toxicologically unacceptable agents (e.g. high concentrations of organic solvents or other toxicologically unacceptable adjuvants) are necessary before the compounds of the present invention are used in pharmaceutical formulations.

[0172] The present invention particularly preferably also relates to pharmaceutical preparations comprising at least one compound according to the invention in precipitated amorphous, precipitated crystalline or dissolved or suspended form and optionally excipients and / or adjuvants and / or further pharmaceutically active compounds.

[0173] The compounds according to the invention preferably allow the preparation of highly concentrated formulations without disadvantageous, undesirable aggregation of the compounds according to the invention. Thus, ready-to-use solutions having a high active ingredient content can be prepared with the aid of the compounds according to the invention with aqueous solvents or in aqueous media.

[0174] The compounds and / or their physiologically acceptable salts and solvates can also be lyophilized, the resulting lyophilizates being used, for example, for the preparation of injection preparations.

[0175] The pharmaceutical preparations according to the invention may also comprise a mixture of a plurality of compounds according to the invention.

[0176] The preparations of the invention are physiologically well tolerated, easy to prepare, accurately dispensed, and preferably stable in terms of assays, decomposition products and aggregates throughout storage and transport and during multiple freezing and thawing processes. They can preferably be stored in a stable manner at refrigerator temperature (2-8° C.) and room temperature (23-27° C.) and 60% relative atmospheric humidity (RH) for a period of at least three months to two years.

[0177] For example, the compounds of the present invention can be stored in a stable manner by drying and, if necessary, converted into ready-to-use pharmaceutical preparations by dissolving or suspending. Possible drying methods are, for example, but not limited to, the following examples: nitrogen drying, vacuum oven drying, freeze drying, washing with an organic solvent and then air drying, liquid bed drying, fluidized bed drying, spray drying, roller drying, layer drying, room temperature air drying, and other methods.

[0178] The term "effective amount" refers to the amount of a compound of Formula I or a pharmaceutically acceptable salt thereof that elicits the biological or medical response of a tissue, system, animal or human that is sought or desired, for example, by a researcher or physician.

[0179] In addition, the term "therapeutically effective amount" refers to an amount that has the following results, compared to a corresponding subject that has not received such an amount: improvement of one or more symptoms, cure or elimination of a disease, syndrome, disease condition, ailment, disorder, or prevention of side effects. "Therapeutically effective amount" also includes reducing the progression of a disease, ailment, or disorder. For cancer treatment, a "therapeutically effective amount" can reduce the tumor burden of the subject, delay the progression of the disease ("progression-free survival"), extend the life expectancy of the subject (increase overall survival), slow or prevent the metastasis of the primary tumor to other tissues and / or improve the quality of life of the subject receiving treatment. The term "therapeutically effective amount" also includes an amount that effectively improves normal physiological function.

[0180] One embodiment of the present invention is to use a preparation or medicine composed of a compound according to the present invention and / or a pharmaceutically acceptable salt thereof, the preparation being in a dosage between 0.1 and 500 mg per use unit, particularly between 1 and 300 mg. The daily dose is preferably between 0.001 and 250 mg / kg body weight, particularly between 0.01 and 100 mg / kg body weight. The preparation can be administered once or more per day, for example two, three or four times per day. However, the individual dosage of the patient depends on many individual factors, for example, depending on the efficacy, age, body weight, general health, sex, nutrition, administration time and method, excretion rate, combination with other drugs, and severity and duration of a particular disease of the particular compound used.

[0181] The measure of the absorption of a pharmaceutically active compound in an organism is its bioavailability. If a pharmaceutically active compound is delivered intravenously to an organism in the form of an injection solution, its absolute bioavailability, that is, the proportion of the drug that reaches the systemic blood, i.e., the main circulation, in an unchanged form, is 100%. In the case of oral administration of therapeutically active compounds, the active compound is usually in solid form in the preparation and must therefore first be dissolved so that it can overcome entry barriers, such as the gastrointestinal tract, oral mucosa, nasal membranes or skin, particularly the stratum corneum, or can be absorbed by the body. Data on pharmacokinetics, i.e., bioavailability data, can be obtained similarly to the methods of J. Shaffer et al., J. Pharm. Science S, 88 (1999), 313-318.

[0182] Otherwise, a medicament of this type can be prepared by one of the methods generally known in the pharmaceutical art.

[0183] The medicament may be adapted for administration by any desired suitable route, for example, by oral (including buccal or sublingual), rectal, pulmonary, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, especially intraarticular) routes. Medicaments of this type may be prepared by all methods known in the pharmaceutical art, for example, by combining the active compound with excipients or adjuvants.

[0184] Suitable for enteral administration (oral or rectal) are in particular tablets, dragees, capsules, syrups, juices, drops or suppositories, suitable for topical use are ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example in alcohols (such as ethanol or isopropanol), acetonitrile, DMF, dimethylacetamide, 1,2-propylene glycol or mixtures thereof with each other and / or with water) or powders. Liposomal preparations are also particularly suitable for topical use.

[0185] Of course, in addition to the ingredients specifically mentioned above, the medicament of the present invention may also contain other agents commonly used in the art in connection with a particular type of pharmaceutical preparation.

[0186] The invention also relates to a kit consisting of the following individual packages:

[0187] a) an effective amount of a compound of formula I and / or its physiologically acceptable salts, derivatives, solvates, prodrugs, stereoisomers and atropisomers, including mixtures thereof in various ratios, and

[0188] b) an effective amount of another pharmaceutically active compound.

[0189] The kit includes a suitable container, such as a box or carton, a single bottle, a bag or an ampoule. The kit may, for example, include separate ampoules, each ampoule containing an effective amount of a compound of Formula I and / or a pharmaceutically acceptable salt thereof in dissolved or lyophilized form and an effective amount of one or more additional therapeutic agents.

[0190] Additionally, the medicaments of the invention may be used to provide an additive or synergistic effect in certain known therapies, and / or to restore the efficacy of certain existing therapies.

[0191] In addition to the compounds of the present invention, the pharmaceutical preparations of the present invention may also comprise one or more additional therapeutic agents, such as other antitumor drugs for the treatment of cancer. In order to treat the other diseases mentioned, in addition to the compounds of the present invention, the pharmaceutical preparations of the present invention may also comprise other pharmaceutically active compounds known to those skilled in the art in their treatment.

[0192] In one embodiment, the compound of the present invention or its pharmaceutically acceptable salt is administered in combination with one or more additional therapeutic agents. In one aspect of the present invention, one or more additional therapeutic agents are EGFR inhibitors, MET inhibitors, PD-L1 inhibitors, MEK 1 / 2 inhibitors, TGF-βR pathway inhibitors, or combinations thereof. In another aspect of this embodiment, one or more additional therapeutic agents are Erbitux, tepotinib, avelumab, Muc1-TGFβR2 Nb, EGFR-Muc1-ADC, pimasertib, pembrolizumab, nivolumab, cemilimab, atezolizumab, durvalumab, or combinations thereof. In one aspect of this embodiment, one or more additional therapeutic agents are Erbitux, tepotinib, avelumab, pimasertib, or combinations thereof.

[0193] In a main embodiment, a method for enhancing the immune response of a host in need is provided. By reducing T cell tolerance, including by increasing IFN-γ release, by reducing regulatory T cell production or activation, or by increasing antigen-specific memory T cell production in the host, the immune response can be enhanced. In one embodiment, the method includes combining with an antibody or alternately administering the compound of the present invention to the host. In one aspect of this embodiment, the antibody is a therapeutic antibody. In a specific embodiment, a method for enhancing the efficacy of passive antibody therapy is provided, the method including combining with one or more passive antibodies or alternately administering the compound of the present invention. This method can improve the efficacy of antibody therapy for treating abnormal cell proliferative disorders (such as cancer), or can improve the efficacy of therapy in the treatment or prevention of infectious diseases. The compound of the present invention can be combined or alternately administered with antibodies such as rituximab, Herceptin or Erbitux.

[0194] In another major embodiment, there is provided a method of treating or preventing abnormal cellular proliferation, said method comprising administering to a host in need thereof a compound of the present invention in the substantial absence of another anticancer agent.

[0195] In another major embodiment, a method for treating or preventing abnormal cell proliferation in a host in need thereof is provided, the method comprising first administering a compound of the invention to the host, substantially in combination with a first anticancer agent, followed by administration of a second SHP2 antagonist. In one aspect of this embodiment, the second antagonist is administered substantially in the absence of another anticancer agent. In another major embodiment, a method for treating or preventing abnormal cell proliferation in a host in need thereof is provided, the method comprising administering a compound of the invention to the host, substantially in combination with a first anticancer agent, followed by administration of a second anticancer agent in the absence of an antagonist.

[0196] Therefore, the cancer treatment disclosed herein can be performed as a therapy utilizing the compounds of the present invention or in combination with surgery, radiation or chemotherapy. This type of chemotherapy may include the use of one or more additional therapeutic agents selected from the following groups:

[0197] (i) antiproliferative / antitumor / DNA damaging active compounds and combinations thereof for use in medical oncology, such as alkylating active compounds (e.g. cisplatin, parboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (e.g. antifolates, such as fluoropyrimidines, e.g. 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumor antibiotics (e.g. anthracyclines, such as doxorubicin, bleomycin, doxorubicin); compounds with antimitotic activity (e.g. vinca alkaloids, such as vincristine, vinblastine, vindesine and vinorelbine, and taxanes, such as paclitaxel and taxotere); topoisomerase inhibitors (e.g. epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell differentiation active compounds (e.g. all-trans retinoic acid, 13-cis-retinoic acid and retinamide);

[0198] (ii) cytostatically active compounds, such as antiestrogens (e.g. tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor modulators (e.g. fulvestrant), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprolide and buserelin), progestins (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorozole and exemestane) and inhibitors of 5α-reductase (e.g. finasteride);

[0199] (iii) active compounds that inhibit cancer invasion, including, for example, metalloproteinase inhibitors (such as marimastat) and inhibitors of urokinase plasminogen activator receptor function;

[0200] (iv) inhibitors of growth factor function, such as growth factor antibodies, growth factor receptor antibodies, such as the anti-ErbB2 antibody trastuzumab [Herceptin TM ] and the anti-erbbl antibody cetuximab [C225], farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine / threonate kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g. EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), inhibitors of the platelet-derived growth factor family, and inhibitors of the hepatocyte growth factor family, for example;

[0201] (v) anti-angiogenic active compounds, such as bevacizumab, angiostatin, endostatin, linomide, batimastat, captopril, cartilage-derived inhibitors, genistein, interleukin 12, fumonisin, medroxyprogesterone acetate, recombinant human platelet factor 4, teicogalan, thrombospondin, TNP-470, anti-VEGF monoclonal antibodies, soluble VEGF receptor chimeric proteins, anti-VEGF receptor antibodies, anti-PDGF receptors, integrin inhibitors, tyrosine kinase inhibitors, serine / threonine kinase inhibitors, antisense oligonucleotides, antisense oligodeoxynucleotides, siRNAs, anti-VEGF aptamers, pigment epithelium-derived factors and compounds disclosed in international patent applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354;

[0202] (vi) Vascular disrupting agents, such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[0203] (vii) antisense therapies, such as those directed against the above targets, e.g., ISIS 2503 (an anti-Ras antisense);

[0204] (viii) gene therapy approaches, including, for example, methods of replacing abnormal, modified genes (e.g., abnormal p53 or abnormal BRCA1 or BRCA2), GDEPT approaches (gene-directed enzyme prodrug therapy), such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase, and methods of improving a patient's tolerance to chemotherapy or radiation therapy, such as multidrug resistance therapy; and

[0205] (ix) immunotherapy methods, including, for example, ex vivo and in vivo methods for increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte macrophage colony stimulating factor, methods for reducing T cell anergy, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cells, and methods using anti-idiotypic antibodies;

[0206] (x) Chemotherapeutic agents, including, for example, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretinoin, amifostine, anastrozole, arsenic trioxide, asparaginase, BCG live, bevacizumab, bexarotene, bleomycin, bortezomib, busulfan, carlotestosterone, camptothecin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cinacalcet, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, actinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin, drostanolone, epirubicin, epoetin alfa, estramustine, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, and gemcitabine.

[0207] Additional therapeutic agents from Table 1 may preferably, but not exclusively, be combined with the compounds of Formula I.

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217] Even without further embodiments, it is assumed that a person skilled in the art will be able to use the above description in the broadest scope. Therefore, the preferred embodiments should only be considered as a descriptive disclosure which is absolutely not limiting in any way.

[0218] Therefore, the following examples are intended to illustrate the invention without limiting it. Unless otherwise indicated, percentage data represent weight percentages. All temperatures are expressed in degrees Celsius. "Conventional work-up": If necessary, water is added, if necessary, the pH is adjusted to a value between 2 and 10 depending on the composition of the final product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered, and evaporated, and the product is purified by chromatography on silica gel and / or by crystallization.

[0219] List of abbreviations

[0220] AUC Area under the plasma drug concentration-time curve

[0221] C max Maximum plasma concentration

[0222] CL clearance

[0223] CV Coefficient of variation

[0224] CYP Cytochrome P450

[0225] DMSO Dimethyl sulfoxide

[0226] %F Bioavailability

[0227] f a The absorbed fraction

[0228] iv intravenous

[0229] LC-MS / MS Liquid chromatography tandem mass spectrometry

[0230] LLOQ Lower limit of quantitation

[0231] NC Not calculated

[0232] NT Not tested

[0233] PEG Polyethylene glycol

[0234] Pgp permeability glycoprotein

[0235] PK Pharmacokinetics

[0236] po Oral (oral)

[0237] t 1 / 2 half life

[0238] t max Time to reach maximum plasma concentration of drug

[0239] UPLC Ultra-Performance Liquid Chromatography

[0240] V ss - Volume of distribution (at steady state)

[0241] v / v volume / volume

[0242] Example 1: Examples of compounds of the present invention

[0243] The present invention particularly relates to the compounds of Table 2 and physiologically acceptable salts, derivatives, solvates, prodrugs, stereoisomers and atropisomers thereof, including mixtures thereof in various ratios.

[0244] Table 2 - Examples of compounds of the invention

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278] Example 2: Preparation and analysis of the compounds of the present invention

[0279] The following abbreviations have the following meanings:

[0280] Boc tert-Butyloxycarbonyl

[0281] CBZ benzyloxycarbonyl

[0282] DNP 2,4-Dinitrophenyl

[0283] FMOC 9-Fluorenylmethoxycarbonyl

[0284] imi-DNP 2,4-dinitrophenyl at the 1-position of the imidazole ring

[0285] OMe Methyl Ester

[0286] POA Phenoxyacetyl

[0287] DCCI Dicyclohexylcarbodiimide

[0288] HOBt 1-Hydroxybenzotriazole

[0289] In general, compounds of the general formula (I) and related formulas according to the present invention can be prepared from readily available starting materials. If such starting materials are not commercially available, they can be prepared using standard synthetic techniques. In general, the synthetic route for any single compound of the general formula (I) or related formulas will depend on the specific substituents of each molecule, such factors as those of ordinary skill in the art understand. The following general methods and steps described in the examples below can be used to prepare compounds of the general formula (I) and related formulas. These methods are illustrative and are not meant to limit the possible methods that can be used by those skilled in the art to prepare the compounds disclosed herein. The reaction conditions (e.g., temperature, solvent, or co-reagent) described in the following flow are given only as examples and are not restrictive. It should be understood that, in the case of typical or preferred experimental conditions (i.e., reaction temperature, time, molar number of reagents, solvent, etc.), other experimental conditions may also be used unless otherwise stated. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art using conventional optimization steps. For all protection and deprotection methods, see Philip J. Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York (1994), and Theodora W. Greene and Peter GM Wuts, "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition (1999).

[0290] Depending on the properties of R1, R2, R3, R4, R5, X and Y, different synthetic schemes can be selected for the synthesis of compounds of general formula (I). In the steps shown in the following schemes, unless otherwise stated, R1, R2, R3, R4, R5, X and Y are defined as described above.

[0291] According to one method, a pyrimidine derivative according to formula 4, wherein R2 and R3 are as described above, R20 and R21 are H, substituted alkyl, heteroalkyl, or alkyl or heteroalkyl capable of combining to form a monocyclic or polycyclic ring, which may or may not be substituted, and R8 is COYR4R5, wherein Y, R4 and R5 are as described above, or CN can be prepared according to the reaction scheme described in Scheme 1.

[0292]

[0293] Solution 1

[0294] Pyrimidine 1, wherein R3 and R8 are as described above, LG1 is a leaving group (e.g., halogen or OMs, OTs, OTf), is heated with an amine NHR20R21 (wherein R20 and R21 are as described above) in a solvent, and a substitution reaction occurs in the presence or absence of a base to obtain a pyrimidine of formula 2 (wherein R3, R20, R21, and R8 are as defined above), wherein the solvent is, for example, but not limited to, methanol, ethanol, DMF, DMSO, and the base is, for example, TEA, DIEA, Cs2CO3, or K2CO3. Pyridine 2 is then subjected to halogenation conditions using, for example, NBS, NCS, or NIS to obtain an intermediate of formula 3 (wherein R3, R20, R21, and R8 are as described above and Hal is a halogen atom, such as Cl, Br, or I). Finally, pyrimidine 3 is subjected to a cross-coupling reaction using standard conditions known to those skilled in the art to obtain pyrimidine 4. In some embodiments, the cross-coupling reaction is a Suzuki reaction, but other cross-coupling reactions may be used.

[0295] Alternatively, the pyrimidine derivatives according to Formula 4 can be prepared according to the reaction scheme described in Scheme 2, wherein R2, R3, R20, R21, R8 are as defined above.

[0296]

[0297] Solution 2

[0298] In this reaction sequence, the thiomethyl compound 5 (wherein R3 and R8 are as defined above) is first subjected to a halogenation reaction and then subjected to cross-coupling conditions to obtain the intermediate compound 7 (wherein R2, R3, R8 are as defined above). The thiomethyl group is then oxidized to SO2Me using standard conditions well known to those skilled in the art, such as using mCPBA or H2O2, to obtain the intermediate 8 (wherein R2, R3 and R8 are as defined above). Finally, the intermediate 8 is subjected to a substitution reaction with NHR20R21 (wherein R20 and R21 are as defined above).

[0299] To obtain the final compounds of formula Ia, a final transformation of R8 may be necessary.

[0300] When R8 is COOR19, wherein R19 is H, alkyl, or cycloalkyl, when COOR19 is reacted with an amine HNR4R5 (wherein R4 and R5 are as described above) under conditions well known to those skilled in the art for preparing amides from amines and carboxylic acids or carboxylic acid derivatives, the final compound of formula I is generated, such as the use of standard coupling agents (e.g., DIC, EDC, TBTU, DECP), or other conditions as described in Scheme 3.

[0301]

[0302] Solution 3

[0303] When R8 is CN, the final compound of Formula I (wherein R2, R3, R4, R20 and R21 are as defined above) can be obtained by hydrolyzing the compound of Formula 4b (wherein R2, R3, R5 and R7 are as defined above) to form the acid of Formula 9 (wherein R, R3, R5, R7 are as defined above), followed by subjecting the acid of Formula 9 to an amide coupling reaction as described in Scheme 4. Alternatively, the compound of Formula 4b (wherein R2, R3, R5 and R7 are as defined above) can be directly hydrolyzed using conditions known to those skilled in the art, such as heating in DMF or DMSO in the presence of NaOH and H2O2 to obtain the compound of Formula Ib.

[0304]

[0305] Solution 4

[0306] For the synthesis of other compounds of Formula I, similar synthetic schemes should be used, with appropriate modifications made to the specific substituents of each molecule, and these factors are understandable to those of ordinary skill in the art.

[0307] According to further general procedures, compounds of formula I may be converted into alternative compounds of formula I using appropriate interconversion techniques, such as those described in the Examples hereinafter.

[0308] All NMR experiments were recorded on a Bruker Avance III 400 NMR spectrometer equipped with a Bruker PABBO BB-1H / DZGRD probe at 400 MHz for proton NMR or a Bruker Mercury Plus 300 NMRR spectrometer equipped with a Bruker 300 BBFO probe at 300 MHz for proton NMR. Most deuterated solvents typically contain 0.03% to 0.05% v / v tetramethylsilane, which was used as a reference signal ( 1 H and 13C is set to d 0.00). In the case of deuterated solvents without tetraalkylsilane, the residual non-deuterated solvent peak is used as a reference signal according to published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997). Chemical shifts are expressed in parts per million (ppm, delta units). Coupling constants are expressed in Hertz (Hz). Splitting patterns describe the apparent multiplicity and are expressed as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), qt (quintet) or brs (broad singlet).

[0309] The following abbreviations are used in the following text:

[0310] Ac (acetyl); ACN (acetonitrile); atm (atmospheric pressure); DIEA (diisopropylethylamine); °C (degrees Celsius); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); dppf (1,1′-bis(diphenylphosphino)ferrocene); EtOAc (ethyl acetate); g (gram); h (hour); HATU (N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethylammonium hexafluorophosphate); HOBt (hydroxybenzotriazole); azole); HPLC (high performance liquid chromatography); LC (liquid chromatography); LDA (lithium diisopropylamide); MeOH (methanol); min (minute); mL (milliliter); mmol (millimolar); MS (mass spectrometry); NBS (bromosuccinimide); NMR (nuclear magnetic resonance); O / N (overnight); PE (petroleum ether); RT (room temperature); TBDMS (tert-butyldimethylsilyl); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TMS (trimethylsilyl).

[0311] UPLC / MS analysis was performed on a Waters Aquity H equipped with an SQ detector (ESI), and LC-MS analysis was performed on an Agilent 1200 series mass spectrometer equipped with a quadrupole detector or a SHIMADZU LC-MS instrument consisting of a UFLC 20-AD system and a LCMS 2020 MS detector.

[0312] Microwave reactions were performed using a Biotage Initiator Microwave Synthesizer following standard protocols known in the art.

[0313] The compounds of the present invention can be prepared by several synthetic methods from readily available starting materials. Examples of synthetic routes are described in the following examples. Unless otherwise indicated, the compounds of the present invention obtained as racemic mixtures can be separated to provide enantiomerically enriched mixtures or pure enantiomers.

[0314] Unless otherwise stated, commercial starting materials used in the following experimental descriptions were purchased from Sigma-Aldrich or Fisher.

[0315] Intermediate 1: tert-butyl (1-(5-bromo-4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0316] Step 1: tert-Butyl (1-(4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0317]

[0318] A solution of 2-chloropyrimidine-4-carbonitrile (2 g, 14.3 mmol), cesium carbonate (11.62 g, 35.7 mol) and tert-butyl (4-methylpiperidin-4-yl)carbamate (3.38 g, 15.8 mmol) in DMF (30 mL) was stirred overnight at 110 ° C. The reaction mixture was filtered through a diatomaceous earth pad. The pad was washed with ethyl acetate (50 mL) and the filtrate was washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The title compound was obtained by flash chromatography on silica gel (petroleum ether: ethyl acetate, a gradient of 100: 0 to 50: 50) as a white solid (2 g, 66%). 1H NMR (400MHz, DMSO-d6): 8.61 (S, 1H), 7.10 (S, 1H), 6.60 (brS, 1H), 4.06 (m, 2H), 3.38 (m, 2H), 2.07 (m, 2H), 1.42 (m, 2H), 1.39 (S, 9H), 1.25 (S, 3H).

[0319] Step 2: tert-Butyl (1-(5-bromo-4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0320]

[0321] To a solution of tert-butyl (1-(4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate (2 g, 6.31 mmol) in anhydrous acetonitrile (30 mL) was added N-bromo-succinimide (1.2 g, 6.93 mmol) in portions at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then quenched with ice and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The title compound was obtained by flash chromatography on silica gel (petroleum ether: ethyl acetate, gradient from 100: 0 to 85: 15) as a white solid (2 g, 80%). 1H NMR (400MHz, DMSO-d6): 8.75 (S, 1H), 6.66 (brS, 1H), 4.01 (m, 2H), 3.35 (m, 2H), 2.08 (m, 2H), 1.43 (m, 2H), 1.39 (S, 9H), 1.22 (S, 3H).

[0322] Intermediate 2: tert-butyl N-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

[0323] Step 1: tert-Butyl N-[1-(4-amino-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

[0324]

[0325] A mixture of 6-amino-2-chloropyrimidine-4-carboxamide (700 mg, 3.20 mmol), tert-butyl N-(4-methylpiperidin-4-yl)carbamate (1.3 g, 5.76 mmol), TEA (822 mg, 7.72 mmol) in acetonitrile (11 mL) was heated at 80° C. for 18 hours in a sealed tube. The solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 90: 10) to give the title compound as a yellow solid (1.2 g, 100%). LC / MS (M+1): 351.2.

[0326] Step 2: tert-Butyl N-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

[0327]

[0328] NBS (243 mg, 1.30 mmol) was added in portions to a solution of tert-butyl N-[1-(4-amino-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate (400 mg, 1.14 mmol) in DMF (6 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then quenched with ice and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (420 mg, 80%). LC / MS (M+1): 429.2.

[0329] Intermediate 3: 5-bromo-2-(4-{[(tert-butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)pyrimidine-4-carboxylic acid methyl ester

[0330]

[0331] A mixture of methyl 5-bromo-2-chloropyrimidine-4-carboxylate (300 mg, 1.13 mmol), tert-butyl N-(4-methylpiperidin-4-yl)carbamate (307 mg, 1.36 mmol) and TEA (0.2 mL) in ACN (3 mL) was heated at 80° C. for 2 hours in a sealed tube. The solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 73: 27) to give the title compound as a yellow solid (495 mg, 96%). LC / MS (M+1): 429.2.

[0332] Intermediate 4: 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile

[0333] Step 1: 6-amino-2-(methylsulfanyl)pyrimidine-4-carbonitrile

[0334]

[0335] A mixture of 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (50 g, 285 mmol), KCN (37.1 g, 569 mmol), Pd2(dba)3 (15.6 g, 17.1 mmol), DPPF (12.6 g, 22.8 mmol) and tributyl(chloro)stannane (5.56 g, 17.1 mmol) in ACN (500 mL) was stirred at 15 ° C for 30 minutes and then heated to 80 ° C for 16 hours. The mixture was cooled to room temperature, poured into water (2.0 L) and extracted with ethyl acetate (1.5 L). The organic layer was washed with water (1.5 L), dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether / ethyl acetate / DCM, gradient from 8 / 1 / 0 to 4 / 1 / 1, containing 0.1% NH4OH) gave the title compound as a cream solid (28.6 g, 53%). 1 H NMR (400MHz DMSO-d6): 7.62 (brS, 2H), 6.63 (S, 1H), 2.40 (S, 3H).

[0336] Step 2: 6-Amino-5-bromo-2-(methylsulfanyl)pyrimidine-4-carbonitrile

[0337]

[0338] NBS (11.2 g, 62.9 mmol) was added portionwise to a solution of 6-amino-2-(methylsulfanyl)pyrimidine-4-carbonitrile (10.0 g, 60.2 mmol) in DMF (90 mL) at 5°C. The reaction mixture was stirred at the same temperature for 1 hour. The mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 0.5 M NaHCO3 solution (300 mL x 2), dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (7.78 g, 52.7%).

[0339] Step 3: 6-amino-5-(2,3-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-4-carbonitrile

[0340]

[0341] A mixture of 6-amino-5-bromo-2-(methylsulfanyl)pyrimidine-4-carbonitrile (1.55 g, 6.32 mmol), 2,3-(dichlorophenyl)boronic acid (3.02 g, 15.8 mmol), XPhos Palladacycle Gen 3 (267 mg, 316 umol) and K3PO4 (4.03 g, 18.9 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 95° C. for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with DCM (20 mL) and filtered. The filtrate was concentrated in vacuo and purified by RP-MPLC (TFA conditions) to give the title compound as a yellow solid (1.01 g, 48%). 1 H NMR (400MHz, CDCl3): 7.65 (dd, J=1.2, 8.0Hz, 1H), 7.41 (t, J=7.6Hz, 1H), 7.29 (dd, J=7.6, 8.0Hz, 1H), 5.04 (bR, 2H), 2.57 (S, 3H). LC / MS(M+1): 311.1.

[0342] Step 4: 6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile

[0343]

[0344] A solution of mCPBA (2.83 g; 12.65 mmol) in DCM (40 mL) was added to a solution of 6-amino-5-(2,3-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-4-carbonitrile (1.97 g; 6.32 mmol) in DCM (40 mL), maintained at 0° C. The reaction mixture was stirred at room temperature for 2 hours, cooled to 0° C., and then another solution of mCPBA (1.42 g; 6.32 mmol) in DCM (20 mL) was added to achieve complete conversion.

[0345] The reaction mixture was stirred at room temperature for an additional 2 hours. The white precipitate was then removed by filtration. The filtrate was concentrated, redissolved in DCM, filtered and concentrated. Purification by flash chromatography on silica gel (hexane: ethyl acetate, gradient from 60: 40 to 80: 20) gave the title compound as a white solid (1.5 g, 69%). 1H NMR (400 MHz, DMSO-d6) d8.73 (s, 1H), 7.85 (dd, J = 6.1, 3.5 Hz, 1H), 7.70 (s, 1H), 7.63-7.55 (m, 2H), 3.37 (s, 3H). LC / MS (M+1): 342.9.

[0346] Intermediate 5: {1-[4-amino-6-cyano-5-(2,3-dichloro-phenyl)-pyrimidin-2-yl]-4-methyl-piperidin-4-yl}-carbamic acid tert-butyl ester

[0347]

[0348] A solution of tert-butyl (4-methylpiperidin-4-yl)carbamate (Synthonix; 62 mg; 0.29 mmol) and potassium carbonate (101 mg; 0.73 mmol) in ACN (0.50 mL) and DMF (0.50 mL) was stirred at room temperature for 10 minutes, then 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (Intermediate 4; 50 mg; 0.15 mmol) was added. The reaction mixture was then heated at 100 °C for 66 hours. It was diluted with ethyl acetate (40 mL) and washed with water (2x10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Rapid purification by silica gel (hexane: ethyl acetate, gradient from 95: 5 to 40: 60) gave the title compound as a white foam. 1H NMR (400MHz, DMSO-d6) 7.72 (dd, J=8.0, 1.6Hz, 1H), 7.45 (t, J=7.8Hz, 1H), 7.38 (dd, J=7.7, 1.6Hz, 1H), 6. 56 (S, 2H), 4.08-3.93 (m, 2H), 3.40-3.24 (m, 2H), 2.04 (d, J=13.5Hz, 2H), 1.46-1.32 (m, 11H), 1.26 (S, 3H).

[0349] Intermediate 6: 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid

[0350]

[0351] A solution of tert-butyl N-[1-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate (Intermediate 5; 370 mg, 0.628 mmol) and NaOH (132 mg, 3.139 mmol) in water (5 mL) was stirred in an oil bath at 100°C for 16 h. The pH was adjusted to 4 by the addition of 1 M HCl solution, and the solution was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and purified by flash chromatography on C18 silica gel (ACN:water-0.5% HCl, gradient from 10% to 50% in 10 min) to give the title compound as a yellow solid (250 mg, 94%). Melting point: 179-181°C. 1H NMR (400MHz, DMSO-d6) 8.18 (S, 3H), 7.63-7.57 (m, 1H), 7.39-7.31 (m, 2H), 7.22 (S, 1H), 7.15 ( d, J=7.5Hz, 1H), 7.09 (S, 1H), 4.27 (d, J=13.9Hz, 1H), 2.55 (S, 0H), 1.71 (S, 4H), 1.39 (S, 3H). LC / MS(M+1): 396.1.

[0352] Intermediate 7: 6-amino-2-(4-{[(tert-butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylic acid

[0353]

[0354] A solution of tert-butyl N-[1-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate (Intermediate 5, 200 mg, 0.34 mmol) in aqueous NaOH (1 N solution, 4 mL) and ethanol (2 mL) was heated at 100°C for 16 hours. It was then diluted with water and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (ethyl acetate: methanol, 70: 30) gave the title compound as a white solid (140 mg, 69%). LC / MS (M+1): 496.1.

[0355] Intermediate 8: tert-Butyl N-[1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

[0356] Step 1: tert-Butyl N-[1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

[0357]

[0358] A solution of 2-chloro-6-methylpyrimidine-4-carbonitrile (1 g, 6.2 mmol), tert-butyl N-(4-methylpiperidin-4-yl)carbamate (1.7 g, 7.4 mmol) and TEA (0.1 mL) in ACN (15 mL) was heated at 80° C. for 2 hours. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (petroleum ether: ethyl acetate, gradient 0:0 to 50:50) to give the title compound as a yellow solid (1.9 g, 92%). LC / MS (M+1): 332.2.

[0359] Step 2: tert-Butyl N-[1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

[0360]

[0361] A solution of tert-butyl N-[1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate (1.9 g, 5.7 mmol) and NBS (1.6 g, 8.5 mmol) in DMF (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was then diluted with water (200 mL) and extracted with ethyl acetate (3x200 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (2.3 g, 96%). LC / MS (M+1): 410.2.

[0362] Intermediate 9: 7-Chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0363]

[0364] A mixture of 6-bromo-7-chloro-1H-indazole (300 mg, 1.23 mmol), Pd(dppf)Cl2.DCM (53 mg, 0.062 mmol), BPD (497 mg, 1.859 mmol) and potassium acetate (381 mg, 3.7 mmol) in dioxane (5 mL) was flushed with nitrogen and placed in a sealed tube and heated at 120°C for 2 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 50: 50) to give the title compound as a yellow oil (300 mg, 44%). LC / MS (M+1): 279.2.

[0365] Intermediate 10: 6-amino-5-(7-chloro-1H-indazol-6-yl)-2-methanesulfonyl-pyrimidine-4-carbonitrile

[0366]

[0367] The title compound was prepared as a yellow oil using 7-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate 9) as starting material according to the procedure described for Intermediate 4. LC / MS (M+1): 349.0.

[0368] Intermediate 11: tert-Butyl N-[(3S,4S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate

[0369] Step 1: tert-Butyl N-[(3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate

[0370]

[0371] A solution of 2-chloro-6-methylpyrimidine-4-carbonitrile (106 mg; 0.69 mmol), tert-butyl N-[(3S, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (125 mg; 0.46 mmol) and DIEA (0.4 mL, 2.31 mmol) in anhydrous DMSO (2.5 mL) was stirred at 70 ° C for 24 hours. The reaction mixture was diluted with (10 mL) and ethyl acetate (25 mL). The organic layer was washed with water (2x) and brine, dried over sodium sulfate, filtered and concentrated. The title compound was obtained by flash chromatography on silica gel (hexane: ethyl acetate, 95: 5 to 20: 80 gradient) as a yellow foam (175 mg, 98%). 1H NMR (Bruker400MHz, DMSO-d6): 7.03 (S, 1H), 6.98 (d, J=10.4Hz, 1H), 4.23-4.11 (m, 1H), 3.88 (dd, J=10.5, 5.1Hz, 1H), 3.85-3.78 (m, 1H), 3.78-3.63 (m, 3 H), 3.63-3.53 (m, 1H), 3.50 (d, J=8.4Hz, 1H), 2.34 (S, 3H), 1.69-1.51 (m, 3H) , 1.51-1.42 (m, 1H), 1.39 (S, 9H), 1.02 (d, J=6.3Hz, 3H); LC / MS (M+1): 388.2.

[0372] Step 2: tert-Butyl N-[(3S,4S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

[0373]

[0374] Keeping at 0 ℃, a solution of N-bromosuccinimide (121 mg; 0.68 mmol) in DMF (1.75 mL) was slowly added to a solution of tert-butyl N-[(3S, 4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (175 mg; 0.45 mmol) in DMF (1.75 mL). The reaction mixture was stirred at room temperature for 2 hours. It was then diluted with ethyl acetate (50 mL) and washed with water (2x25 mL) and brine (25 mL), dried over sodium sulfate, filtered and concentrated. The title compound was obtained as a white foam (158 mg, 75%) by flash chromatography on silica gel (hexane: ethyl acetate, gradient from 95: 5 to 50: 50). 1H NMR(Bruker 400MHz, DMSO-d6): 6.99 (d, J=10.5Hz, 1H), 4.22-4.12 (m, 1H), 3.88 (dd, J=10.5, 5.1Hz, 1H), 3.85-3.76 (m, 1H), 3.76-3.63 (m, 3H), 3 .60-3.47 (m, 2H), 2.48 (S, 3H), 1.69-1.52 (m, 3H), 1.52-1.43 (m, 1H), 1.40 (S, 9H), 1.03 (d, J=6.3Hz, 3H); LC / MS (M+1): 466.1, 468.1.

[0375] Intermediate 12: tert-Butyl N-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decane-1-yl]carbamate

[0376] Step 1: tert-Butyl N-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate

[0377]

[0378] The title compound was prepared as a yellow foam (172 mg, 98%) according to the procedure described in Step 1 of Intermediate 12 using 2-chloro-6-methylpyrimidine-4-carbonitrile (99 mg; 0.65 mmol) and tert-butyl N-[(1R)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate (125 mg; 0.43 mmol) as starting materials. 1H NMR (400MHz, DMSO-d6): 7.09-7.00 (m, 2H), 4.51-4.26 (m, 2H), 3.85 (q, J=9.3Hz, 1H), 3.18-2.94 (m, 2H), 2.48-2.36 (m, 2H), 2.34 (S, 3H), 2.31-1.95 (m, 2H), 1.62-1.38 (m, 4H), 1.34 (S, 9H), LC / MS (M+1): 408.1.

[0379] Step 2: tert-Butyl N-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate

[0380]

[0381] The title compound was prepared as a yellow solid (150 mg, 74%) using tert-butyl N-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate (170.00 mg; 0.42 mmol) as starting material according to the procedure described in Step 2 of Intermediate 12. LC / MS (M+1): 486.1, 488.1.

[0382] Intermediate 13: tert-Butyl N-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decane-1-yl]carbamate

[0383] Step 1: tert-Butyl N-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl]carbamate

[0384]

[0385] The title compound was prepared as a yellow foam (295 mg, 94%) according to the procedure described in Step 1 of Intermediate 12 using 2-chloro-6-methylpyrimidine-4-carbonitrile (258 mg; 1.68 mmol) and tert-butyl N-[(1R)-8-azaspiro[4.5]decan-1-yl]carbamate (214 mg; 0.84 mmol) as starting materials. 1H NMR (Bruker400MHz, DMSO-d6): 7.00 (S, 1H), 6.73 (d, J=9.3Hz, 1H), 4.45-4.13 (m, 2H), 3.57 (q, J=8.3Hz, 1H), 3.24-3.06 (m, 2H), 2.34 (S, 3H), 1.93-1.78 (m, 1H), 1.78-1.58 (m, 2H), 1.58-1.40 (m, 4H), 1.41-1.20 (m, 12H). LC / MS(M+1): 372.0.

[0386] Step 2: tert-Butyl N-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl]carbamate

[0387]

[0388] The title compound was prepared as a yellow foam (270 mg, 75%) according to the procedure described in Step 2 of Intermediate 12 using tert-butyl N-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl]carbamate (295 mg; 0.79 mmol) as starting material. LC / MS: 450.0, 452.0.

[0389] Intermediate 14: (3R)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine hydrochloride

[0390] Step 1: 2-(2-Fluorophenyl)-1,3-dithiane

[0391]

[0392] BF3.Et2O (25 mL, 197 mmol) was added to a solution of 2-fluoro-benzaldehyde (10.0 g, 76.5 mmol) and 1,3-propanedithiol (17.4 g, 153.1 mmol) in DCM (100 mL) at 25°C. The resulting mixture was stirred at 25°C for 16 hours. It was then concentrated in vacuo and purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 5: 1) to obtain the title compound as a cream solid (16.0 g, 95%). LC / MS (M+1): 215.

[0393] Step 2: 4-(2-Fluorobenzoyl)piperidin-4-ol

[0394]

[0395] Remaining at -78 ℃ and nitrogen atmosphere, a solution of 2- (2- fluorophenyl) -1,3- dithiane (10.0g, 40.7mmol) in THF (5mL) is added to a solution of LDA in THF (41mL, 2M). The resulting mixture is stirred at -20 ℃ for 30 minutes. Then a solution of 4- oxopiperidine -1- carboxylic acid tert-butyl ester (12.8g, 61.1mmol) in THF (5mL) is added dropwise at -78 ℃. After stirring at -78 ℃ for 1 hour, the reaction mixture is poured into NH4Cl saturated solution (100mL), extracted with ethyl acetate (3x100mL). The organic layers are combined, washed with brine (1x100ml), dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether:ethyl acetate, 1:1) gave tert-butyl 4-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate as a cream solid (15.0 g, 78%), LC / MS (M+1): 314.

[0396] A solution of tert-butyl 4-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate (15.0 g, 47.9 mmol), TBAB (4.63 g, 14.4 mmol), pyridine hydrobromide (15.3 g, 95.8 mmol) and pyridine (7.7 mL, 95.8 mmol) in DCM (200 mL) and H2O (40 mL) was stirred at 25°C for 16 hours. The resulting mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (DCM: methanol, 1:1) to give the title compound as a brown oil (10.4 g, 97%). LC / MS (M+1): 224.

[0397] Step 3: Spiro[1-benzofuran-2,4′-piperidin]-3-one

[0398]

[0399] A solution of 2-fluorobenzyl 4-(2-fluorobenzamide) (10.0 g, 40.3 mmol), t-BuOK (9.52 g, 80.6 mmol) and dioxane (100 mL) was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM: methanol, 1: 1) to give the title compound as a brown solid (8.0 g, 96%). LC / MS (M1): 204.

[0400] Step 4: (S)-2-methyl-N-[1′-[(S)-2-methylpropane-2-sulfinyl]spiro[1-benzofuran-2,4′-piperidinyl]-3-ylidene]propane-2-sulfinamide

[0401]

[0402] A mixture of Ti(OEt)4 (50 mL), (R)-2-methylpropane-2-sulfenamide (18.0 g, 140.7 mmol) and spiro[1-benzofuran-2,4-piperidin]-3-one (5.00 g, 23.4 mmol) was stirred at 90°C for 16 hours. It was then diluted with water (120 mL) and extracted with ethyl acetate (3 x 120 mL). The organic layers were combined, washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether: ethyl acetate, 1: 1) gave the title compound as a yellow solid (6.0 g, 60%). LC / MS (M+1): 411.

[0403] Step 5: (S)-2-methyl-N-[(3S)-1′-[(S)-2-methylpropane-2-sulfinyl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]propane-2-sulfinamide

[0404]

[0405] NaBH4 (1.87 g, 46.9 mmol) was added to a solution of (S)-2-methyl-N-[1-[(S)-2-methylpropane-2-sulfinyl]spiro[1-benzofuran-2,4-piperidinyl]-3-ylidene]propane-2-sulfinamide (4.00 g, 9.38 mmol) in THF (100 mL) and H2O (2.00 mL) at -50°C. The resulting mixture was stirred at 25°C for 2 hours. It was then quenched with saturated aqueous NH4Cl at 0°C and extracted with ethyl acetate (3x100 mL). The organic layers were combined, washed with brine (1x100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The title compound was obtained by flash chromatography on silica gel (petroleum ether: ethyl acetate, 1:1) as a yellow solid (2 g, 52%). LC / MS (M+1): 413.

[0406] Step 6: (3R)-3H-Spiro[1-benzofuran-2,4′-piperidin]-3-amine hydrochloride

[0407]

[0408] A mixture of HCl / methanol (10 mL, 6 M) and (S)-2-methyl-N-[(3S)-1-[(S)-2-methylpropane-2-sulfinyl]-3H-spiro[1-benzofuran-2,4-piperidin]-3-yl]propane-2-sulfinamide (700 mg, 1.70 mmol) was stirred at 25° C. for 2 hours. The resulting mixture was concentrated under reduced pressure. The solid was collected by filtration and washed with diethyl ether (3×10 mL) to give the title compound as a cream solid (300 mg, 85%). LC / MS (M+1): 205.

[0409] Intermediate 15: 3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-3-amine

[0410] Step 1: 3-(1,3-dithian-2-yl)-2-fluoropyridine

[0411]

[0412] To a solution of 2-fluoropyridine-3-carboxaldehyde (46.0 g, 349.3 mmol) and 1,3-propanedithiol (43.8 g, 384.2 mmol) in DCM (500 mL) was added dropwise BF3·Et2O (29 mL, 107.6 mmol, 0.31 eq., 47%) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3x200 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The title compound was obtained by flash chromatography on silica gel (petroleum ether: ethyl acetate, 10: 1) as a white solid (59 g, 63%). LC / MS (M+1): 216.

[0413] Step 2: tert-Butyl 4-[2-(2-fluoropyridin-3-yl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate

[0414]

[0415] Keep at -78 ℃, LDA solution (240mL, 2M solution in THF) is added dropwise to a solution of 3-(1,3-dithiane-2-yl)-2-fluoropyridine (59.0g, 220.3mmol) in THF (150mL). The resulting mixture is stirred at -20 ℃ for 60 minutes, and then a solution of 4-oxopiperidin-1-carboxylic acid tert-butyl ester (92.4g, 440.6mmol) in THF (30mL) is added at -78 ℃. The resulting mixture is stirred for another 1 hour at -78 ℃, and quenched with saturated NH4Cl solution (500mL) at 0 ℃. It is extracted with ethyl acetate (3x300mL). The organic layers are combined, dried over anhydrous Na2SO4, filtered and concentrated. The title compound is obtained as a white solid (80g, 87%) by flash chromatography on silica gel (petroleum ether: ethyl acetate, 5: 1). LC / MS: 359 (M+H-56).

[0416] Step 3: tert-Butyl 4-(2-fluoropyridine-3-carbonyl)-4-hydroxypiperidine-1-carboxylate

[0417]

[0418] A solution of tert-butyl 4-[2-(2-fluoropyridin-3-yl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate (90.0 g, 213.6 mmol), TBAB (21.7 g, 64.1 mmol), 2-[2]-tribromoethane-pyridine (143.8 g, 427.2 mmol) and pyridine (27.2 mL, 320.4 mmol, 1.50 equiv) in DCM (1 L) and H2O (200 mL) was stirred at room temperature for 10 hours. The reaction mixture was then extracted with DCM (3 x 300 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether: ethyl acetate, 2: 1) gave the title compound as a yellow solid (50.0 g, 71%). LC / MS: 269 (M+H-56).

[0419] Step 4: tert-Butyl 3-oxospiro[furo[2,3-b]pyridine-2,4-piperidin]-1-carboxylate

[0420]

[0421] Potassium tert-butoxide (6.51 g, 55.1 mmol) was added to a solution of tert-butyl 4-(2-fluoropyridine-3-carbonyl)-4-hydroxypiperidine-1-carboxylate (17.0 g, 50.1 mmol) in dioxane (170 mL) at room temperature. After stirring for 2 hours, the resulting mixture was poured into water (200 mL) and extracted with ethyl acetate (3x200 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The title compound was obtained by flash chromatography on silica gel (petroleum ether: ethyl acetate 5: 1) as a white solid (8.5 g, 53%). LC / MS: 249 (M+H-56).

[0422] Step 5: tert-Butyl 3-[[(R)-2-methylpropane-2-sulfinyl]imino]spiro[furo[2,3-b]pyridine-2,4′-piperidine]-1′-carboxylate

[0423]

[0424] A mixture of tert-butyl 3-oxospiro[furo[2,3-b]pyridine-2,4-piperidine]-1-carboxylate (8.50 g, 26.8 mmol), (R)-2-methylpropane-2-sulfinamide (20.5 g, 160.7 mmol) and Ti(OEt)4 (60 mL) was stirred at 90°C for 2 hours. The resulting mixture was cooled to room temperature and poured into water (150 mL). Filtered, the filtrate was extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by flash chromatography on silica gel (petroleum ether: ethyl acetate, 5: 1) gave the title compound as a yellow solid (11 g, 96%). LC / MS (M+1): 408.0.

[0425] Step 6: tert-Butyl 3-[[(S)-2-methylpropane-2-sulfinyl]amino]-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidine]-1′-carboxylate

[0426]

[0427] Sodium borohydride (4.66 g, 117 mmol) was added in portions to a solution of tert-butyl 3-[[(R)-2-methylpropane-2-sulfinyl]imino]spiro[furo[2,3-b]pyridine-2,4-piperidine]-1-carboxylate (10.0 g, 23.4 mmol) in THF (100 mL) and methanol (100 mL) at -50°C with stirring. The resulting mixture was stirred at -50°C for 1 hour and quenched with water (10 mL). The solvent was removed under reduced pressure, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (10 g, 62%). LC / MS (M+1): 410.0.

[0428] Step 7: 3H-Spiro[furo[2,3-b]pyridine-2,4′-piperidin]-3-amine

[0429]

[0430] A solution of HCl (gaseous) in 1,4-dioxane (100 mL) was added dropwise to a solution of tert-butyl 3-[[(S)-2-methylpropane-2-sulfinyl]amino]-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidine]-1′-carboxylate (10.0 g, 24.4 mmol) in DCM (60 mL) maintained at 0°C. After stirring at room temperature for 1 hour, the resulting mixture was concentrated under reduced pressure. The hydrochloride obtained was loaded onto SiliaBond propanesulfonic acid (SCX-2) resin pre-wetted with methanol and eluted with methanol until no HCl was detected. The free amine was then washed off with a 7M aqueous ammonia solution in methanol. The eluent was concentrated in vacuo to give the title compound as an orange oil (4.0 g, 77.7%). LC / MS (M+1): 206.

[0431] Intermediate 16: (4S)-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidinyl]-4-amine

[0432] Step 1: (4Z)-tert-butyl 2-chloro-4-{[(R)-2-methylpropane-2-sulfinyl]imino}-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidine]-1′-carboxylate

[0433]

[0434] A mixture of tert-butyl 2-chloro-4-oxo-6H-spiro[cyclopenta[d][1,3]thiazole-5,4-piperidine]-1-carboxylate (300 mg, 0.845 mmol) and (R)-2-methylpropane-2-sulfinamide (647 mg, 5.07 mmol) in Ti(OEt)4 (3.39 g, 14.1) was stirred at 90 °C under nitrogen atmosphere for 19 hours. Water (50 mL) was then added to quench the reaction and filtered. The filtrate was extracted with ethyl acetate (3x150 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether:ethyl acetate, gradient from 1:0 to 1:1) gave the title compound as a yellow solid (280 mg, 74%). LC / MS (M+1): 446.1.

[0435] Step 2: (4S)-tert-butyl 2-chloro-4-{[(R)-2-methylpropane-2-sulfinyl]amino}-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidine]-1′-carboxylate

[0436]

[0437] Maintaining at -50 ° C and argon atmosphere, sodium borohydride (70 mg, 1.78 mmol) was added in batches to a solution of (4Z)-2-chloro-4-[[(R)-2-ethylpropane-2-sulfinyl]imino]-6H-spiro[cyclopentadiene[d][1,3]thiazole-5,4-piperidine]-1-carboxylic acid tert-butyl ester (400 mg, 0.892 mmol) in THF (4.4 mL) and water (1.3 mL). The resulting mixture was stirred at -50 ° C and argon atmosphere for 2 hours, quenched with water (50 mL) and filtered. The filtrate was extracted with ethyl acetate (3x50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether:ethyl acetate, gradient from 1:0 to 0:1) gave the title compound as a yellow solid (200 mg, 50%), LC / MS (M+1): 448.1.

[0438] Step 3: (4S)-tert-butyl 4-{[(R)-2-methylpropane-2-sulfinyl]amino}-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidine]-1′-carboxylate

[0439]

[0440] A suspension of (4S)-tert-butyl 2-chloro-4-[[(R)-2-methylpropane-2-sulfinyl]amino]-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4-piperidine]-1-carboxylate (0.20 g, 0.446 mmol), Pd / C (0.10 g, 0.094 mmol, 10%) in methanol (10 mL) was stirred for 12 hours at 100°C under a hydrogen atmosphere. The mixture was filtered through a pad of celite and the filtrate was concentrated to give the title compound as a yellow solid (130 mg, 66%). LC / MS (M+1): 414.2.

[0441] Step 4: (4S)-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidinyl]-4-amine

[0442]

[0443] A solution of (4S)-tert-butyl 4-[[(R)-2-methylpropane-2-sulfinyl]amino]-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4-piperidine]-1-carboxylate (150 mg, 0.337 mmol) in methanol / HCl (4 mL, 26 mmol, 20%) was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was loaded onto SiliaBond propanesulfonic acid (SCX-2) resin pre-wetted with methanol, the resin was eluted with methanol and the free amine was washed off with methanol / NH3 (7 M). The title compound was obtained after removal of methanol under reduced pressure as a cream solid (65 mg, 89%). LC / MS (M+1): 210.1.

[0444] Compound 1: 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide

[0445] Step 1: tert-Butyl (1-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

[0446]

[0447] A solution of tert-butyl (1-(5-bromo-4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate (intermediate 1, 2 g, 5.06 mmol), 2,3-dichlorophenylboronic acid (0.967 g, 5.06 mmol) and cesium carbonate (4.1 g, 12.6 mmol) in a dioxane / water mixture (15:5 mL) was degassed with nitrogen for 3 minutes. Pd(PPh3)4 (0.58 g, 0.51 mmol) was added and the reaction mixture was heated overnight at 100°C under an inert atmosphere. The reaction mixture was dissolved in ethyl acetate (50 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The title compound was obtained as a white solid (1.6 g, 70%) by flash chromatography on silica gel (petroleum ether: ethyl acetate, gradient from 100:0 to 80:20). 1H NMR (400MHz, DMSO-d6): 8.68 (S, 1H), 8.80 (dd, J=2.0, 7.6Hz, 1H), 4.56 (m, 2H), 6.69 (b rS, 1H), 4.06 (m, 2H), 3.45 (m, 2H), 2.12 (m, 2H), 1.48 (m.2H), 1.40 (S, 9H), 1.27 (S, 3H).

[0448] Step 2: tert-Butyl N-{1-[4-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

[0449]

[0450] To a solution of tert-butyl (1-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate (0.2 g, 0.432 mmol) in DMSO (8 mL) was added hydrogen peroxide (0.4 mL, 30% aqueous solution) and potassium carbonate (0.119 g, 0.86 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with ethyl acetate (2x20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (0.18 g, 87%). LC / MS (M+1): 480.2.

[0451] Step 3: 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide hydrochloride

[0452]

[0453] Keeping at 0°C, HCl solution (2 mL, 4 M solution in dioxane) was added to a solution of tert-butyl N-{1-[4-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate (180 mg, 0.375 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. It was then concentrated under reduced pressure to give the title compound as a white solid (75 mg, 50%). 1H NMR (400MHz, DMSO-d6): 8.36 (S, 1H), 8.14 (m, 4H), 7.59 (m, 2H), 7.37 (t, J=9.2Hz , 1H), 7.26 (d, J=7.2Hz, 1H), 4.40 (m, 2H), 3.52 (m, 2H), 1.76 (m, 4H), 1.41 (S, 3H).

[0454] Compound 2: 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(3-chloro-phenyl)-pyrimidine-4-carboxylic acid amide

[0455] Step 1: tert-Butyl N-{1-[4-amino-6-carbamoyl-5-(3-chlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

[0456]

[0457] Under inert atmosphere, a solution of tert-butyl N-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate (Intermediate 2, 250 mg, 0.41 mmol), (3-chlorophenyl)boronic acid (137 mg, 0.83 mmol), Pd(PPh3)4 (34 mg, 0.03 mmol) and sodium carbonate (84 mg, 0.75 mmol) in water (2 mL) and dioxane (6 mL) was heated at 130°C for 30 minutes. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 50: 50) to give the title compound as a yellow solid (110 mg, 47%). LC / MS (M+1): 461.2.

[0458] Step 2: 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(3-chloro-phenyl)-pyrimidine-4-carboxylic acid amide

[0459]

[0460] A solution of tert-butyl N-[1-[4-amino-6-carbamoyl-5-(3-chlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate (200 mg, 0.37 mmol) and HCl (0.6 mL, 1.25 M solution in methanol) in methanol (6 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XBridge Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase: water (10 mM NH4HCO3 + 0.1% NH4OH) and ACN (8 min gradient: 18% ACN rising to 48%) to give the title compound as a white solid (31 mg, 23%). Melting point: 118-120°C. 1H NMR (300 MHz, CD3OD); 7.43-7.27 (m, 2H), 7.28-7.20 (m, 1H), 7.16 (m, 1H), 4.07-3.95 (m, 2H), 3.70 (m, 2H), 1.58 (m, 4H), 1.25 (d, J=1.3 Hz, 3H). LC / MS (M+1): 361.3.

[0461] Compound 3: 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide

[0462] Step 1: 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carbonitrile bistrifluoroacetate

[0463]

[0464] A solution of {1-[4-amino-6-cyano-5-(2,3-dichloro-phenyl)-pyrimidin-2-yl]-4-methyl-piperidin-4-yl}-carbamic acid tert-butyl ester (Intermediate 5; 34 mg; 0.07 mmol) and TFA (0.34 mL) in DCM (0.68 mL) was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure and excess TFA was removed by coevaporation with toluene to give the title compound as a white foam (42 mg, 97%). LC / MS (M+1): 377.1.

[0465] Step 2: 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide

[0466]

[0467] A solution of 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carbonitrile bistrifluoroacetate (35 mg; 0.06 mmol), sodium hydroxide (0.1 mL, 6M aqueous solution, 0.58 mmol) and hydrogen peroxide (30% by weight, 70 ul; 0.58 mmol) in DMF (1.40 mL) was heated in a microwave reactor at 100°C for 1 hour. Hydrogen peroxide and sodium hydroxide (equal amounts) were added twice and the reaction mixture was heated again at 100°C until complete conversion was obtained. The reaction mixture was filtered through a pad of celite and then purified by preparative HPLC (XBridge Prep C-18 OBD 10 uM, 30x250, water (0.1% ammonium hydroxide) and ACN, 15 min gradient: 30 to 80%) to give the title compound as a white amorphous foam (mixture of two atropisomers, 12 mg, 48%). 1H NMR (400MHz, DMSO-d6) 7.70 (S, 1H), 7.51 (dd, J=8.1, 1.6Hz, 1H), 7.28 (t, J=7.8Hz, 1H), 7.14 (S, 1H), 7.10 ( dd, J=7.6, 1.6Hz, 1H), 6.05 (S, 2H), 3.99-3.87 (m, 2H), 3.68-3.54 (m, 2H), 1.47-1.31 (m, 4H), 1.08 (S, 3H). LC / MS(M+1): 395.2.

[0468] Compounds 26 and 27: (4M)-6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide and (4P)-6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide

[0469]

[0470] A mixture of atropisomers 3 (200 mg) was separated by SFC ((R,R)WHELK-01 4.6x150 mm, 5 um, ethanol + 0.1% DEA:CO2, 10-50%).

[0471] First eluting isomer(Compound 26): white solid, 76 mg, RT = 3.42 min, ed = 99.7%, 1H NMR (300 MHz, DMSO-d6): 7.75-7.68 (m, 1H), 7.49 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.08 (dd, J = 7.7, 1.6 Hz, 1H), 6.07 (s, 2H), 3.96-3.85 (m, 2H), 3.68-3.53 (m, 2H), 1.59 (brS, 1H), 1.37 (q, J = 4.9, 4.4 Hz, 4H), 1.07 (s, 3H), melting point: 126-128°C.

[0472] The second eluting isomer ( Compound 27): white solid, 76 mg, RT = 3.79 min, ed = 98.2%, 1H NMR (300 MHz, DMSO-d6) 7.71 (s, 1H), 7.49 (dd, J = 8.1, 1.5 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.08 (dd, J = 7.7, 1.6 Hz, 1H), 3.91 (d, J = 13.6 Hz, 2H), 3.61 (dt, J = 13.1, 6.4 Hz, 2H), 1.61 (brS, 2H), 1.46-1.34 (m, 4H), 1.07 (s, 3H), melting point: 130-132°C.

[0473] Compound 4: 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide

[0474]

[0475] The title compound was prepared as a cream solid according to the procedure described above using tert-butyl N-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate (Intermediate 2, 500 mg, 1.1 mmol) and (3-fluorophenyl)boronic acid (243 mg, 1.7 mmol) as starting materials. 1H NMR (400Mz, DMSO-d6) 7.61 (S, 1H), 7.37 (q, J=7.6Hz, 1H), 7.16 (S, 1H), 7.09 (t, J=8.6Hz, 1H), 7.03-6.94 (m , 2H), 6.00 (brS, 2H), 3.90-3.90 (m, 2H), 3.62-3.45 (m, 2H), 1.75 (brS, 1H), 1.39-1.36 (m, 4H), 1.09 (S, 3H). LC / MS(M+1): 345.2.

[0476] Compound 5: 6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0477]

[0478] The title compound was prepared as a white powder according to the procedure described above using ((3S,4S)-3-methyl-2-oxa-8-aza-spiro[4.5]dec-4-yl)-carbamic acid tert-butyl ester (WUXI, 130 mg, 0.5 mmol) and 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (Intermediate 5, 110 mg, 0.3 mmol) as starting materials (30 mg, 20%, 3 steps). NMR (400MHz, DMSO-d6) 7.71 (S, 1H), 7.51 (dd, J=8.0, 1.5Hz, 1H), 7.28 (t, J=7.8Hz, 1H ), 7.15 (S, 1H), 7.10 (dd, J=7.6, 1.5Hz, 1H), 6.08 (S, 2H), 4.12 (m, 3H), 3.68 (d, J=8.4H z, 1H), 3.49 (d, J = 8.4Hz, 1H), 3.47-3.32 (m, 2H), 2.89 (d, J = 5.2Hz, 1H), 1.75-1.63 (m , 1H), 1.63-1.52 (m, 1H), 1.52-1.38 (m, 2H), 1.38-1.20 (m, 2H), 1.08 (d, J=6.4Hz, 3H). LC / MS(M+1): 451.1.

[0479] Compound 6: 6-amino-2-{9-amino-3-azabicyclo[3.3.1]nonan-3-yl}-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0480]

[0481] The title compound was prepared as a white powder (mixture of isomers - 1:1) according to the procedure described above using tert-butyl N-(3-azabicyclo[3.3.1]nonan-9-yl)carbamate (Achemblock) and 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (Intermediate 4) as starting materials. LC / MS (M+1): 421.3.

[0482] Compound 7: 6-amino-2-[(1R)-1-amino-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0483]

[0484] The title compound was prepared as a white powder according to the procedure described above using (R)-(8-Aza-spiro[4.5]dec-1-yl)-carbamic acid tert-butyl ester (WUXI) and 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (Intermediate 4) as starting materials. 1H NMR (400MHz, DMSO-d6) 7.50 (dd, J=8.1, 1.6Hz, 1H), 7.28 (t, J=7.9Hz, 1H), 7.09 (dd, J=7.6, 1.5Hz, 1H), 4.44 (t, J=12.2Hz, 2H), 3.00 (q , J=10.4Hz, 2H), 2.65 (t, J=7.3Hz, 1H), 1.91-1.71 (m, 2H), 1.69-1.56 (m, 1H), 1.56-1.42 (m, 3H), 1.42-1.25 (m, 2H), 1.25-1.08 (m, 2H). LC / MS(M+1): 435.1.

[0485] Compound 8: 6-amino-2-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0486]

[0487] The title compound was prepared as a white powder according to the procedure described above using ((R)-3,3-difluoro-8-aza-spiro[4.5]dec-1-yl)-carbamic acid tert-butyl ester (WUXI) and 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (Intermediate 4) as starting materials. 1H NMR (400MHz, DMSO-d6) d7.72 (S, 1H), 7.51 (dd, J=8.0, 1.5Hz, 1H), 7.28 (t, J=7.8Hz, 1H), 7.20-7.13 (m, 1H), 7.10 (dt, J=7.6, 1.4Hz, 1H), 6.0 9 (S, 2H), 4.54 (t, J=16.4Hz, 2H), 3.13-2.84 (m, 3H), 2.47-2.28 (m, 2H), 2.14-1.85 (m, 2H), 1.74-1.43 (m, 4H), 1.30 (dd, J=27.6, 13.3Hz, 2H). LC / MS(M+1): 471.1.

[0488] Compound 9: 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid methylamide

[0489]

[0490] Under nitrogen atmosphere, a solution of 6-amino-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxylic acid (Intermediate 6, 110 mg, 0.27 mmol) and SO2Cl2 (0.5 mL) in methanol (5 mL) was heated at 80°C for 4 hours. The solvent was removed under reduced pressure, and the residue was redissolved in a 2M solution of methylamine in THF (2 mL) and placed in a sealed reactor and heated at 90°C for 16 hours. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XBridge ShieldRP18 OBD column, 5 μm, 19*150 mm; water (10 mM NH4HCO3): ACN, 8 min gradient: 38% to 68%) to give the title compound as a white solid (12 mg, 24%). Melting point: 147-149℃; δ1H NMR (300MHz, DMSO-d6) 8.32 (d, J=5.0Hz, 1H), 7.49 (dd, J=8.1, 1.5Hz, 1H), 7.26 (t, J=7.9Hz, 1H), 7.05 (dd, J=7.6, 1. 6Hz, 1H), 6.07 (S, 2H), 4.02-3.92 (m, 2H), 3.64-3.53 (m, 2H), 2.71 (d, J=1.5Hz, 3H), 1.44-1.39 (m, 6H), 1.07 (S, 3H). LC / MS(M+1): 409.1.

[0491] Compound 10: 6-amino-2-[6-amino-7-hydroxy-1-(propan-2-yl)-2-azaspiro[3.4]octan-2-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0492]

[0493] The title compound was prepared as a white powder (mixture of two diastereomers) according to the procedure described above using rac-n-[(6R,7r)-7-hydroxy-1-(propan-2-yl)-2-azaspiro[3.4]octan-6-yl]carbamic acid tert-butyl ester hydrochloride (enamine) and 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (intermediate 4) as starting materials. LC / MS (M+1): 465.2.

[0494] Compound 11: 6-amino-2-[8-(aminomethyl)-6-azaspiro[3.4]octan-6-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0495]

[0496] The title compound was prepared as a white powder (mixture of isomers) according to the procedure described above using tert-butyl n-((6-azaspiro[3.4]octan-8-yl)methyl)carbamate (enamine) and 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (intermediate 4) as starting materials. 1H NMR(400MHz, DMSO-d6)d7.70(S, 1H), 7.54-7.47(m, 1H), 7.32-7.23(m, 1H), 7.17(S, 1H), 7.13-7.05( m, 1H), 6.03 (S, 2H), 3.76-3.38 (m, 4H), 2.84 (d, J=12.0Hz, 1H), 2.41-2.29 (m, 1H), 2.28-1.64 (m, 7H). LC / MS(M+1): 421.2.

[0497] Compound 12: 6-amino-2-[3-(aminomethyl)-8-azabicyclo[3.2.1]octan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0498]

[0499] The title compound was prepared as a white powder according to the procedure described above using tert-butyl n-((8-azabicyclo[3.2.1]octan-3-yl)methyl)carbamate (enamine) and 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (intermediate 4) as starting materials. 1H NMR (400MHz, methanol-d4)d 7.49 (dd, J=8.0, 1.6Hz, 1H), 7.29 (t, J=7.8Hz, 1H), 7.16 (dd, J=7.6, 1.6Hz, 1H), 4.80-4.74 (m, 2H), 2.48 (d , J=6.7Hz, 2H), 2.15-1.95 (m, 3H), 1.84 (d, J=7.5Hz, 2H), 1.73-1.62 (m, 2H), 1.48 (td, J=13.5, 2.9Hz, 2H). LC / MS(M+1): 421.2.

[0500] Compounds 13 and 14: 6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11s)-11-amino-9-azabicyclo[5.3.1]undec-9-yl]pyrimidine-4-carboxamide and 6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11r)-11-amino-9-azabicyclo[5.3.1]undec-9-yl]pyrimidine-4-carboxamide

[0501]

[0502] The title compound was prepared as a mixture of two diastereoisomers according to the procedure described above using tert-butyl n-(9-azabicyclo[5.3.1]undec-11-yl)carbamate oxalic acid (enamine) and 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (Intermediate 4) as starting materials. The two isomers were separated by preparative HPLC (XBridge Prep C-18 OBD 10 uM, 30x250.30-80% ACN / water / (0.1% ammonium hydroxide) / ACN, 15 min gradient: 30% to 80%).

[0503] First eluting isomer (arbitrary assignment): 6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11s)-11-amino-9-azabicyclo[5.3.1]undec-9-yl]pyrimidine-4-carboxamide; white powder (8.2 mg, 17%), 1H NMR (400 MHz, DMSO-d6) 7.66 (s, 1H), 7.51 (dd, J=8.0, 1.5 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.23-7.08 (m, 2H), 6.10 (s, 2H), 4.81 (dd, J=13.3, 6.3 Hz, 2H), 3.09 (t, J=6.0 Hz, 1H) , 2.85 (dd, J=13.5, 4.5Hz, 2H), 2.02 (d, J=3.1Hz, 1H), 1.95-1.73 (m, 3H), 1.73-1.56 ( m, 3H), 1.51 (dt, J=14.9, 7.5Hz, 2H), 1.29 (q, J=12.9, 12.5Hz, 2H), 1.19-1.00 (m, 1H). LC / MS(M+1): 449.5.

[0504] Second eluting isomer (arbitrary assignment): 6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11r)-11-amino-9-azabicyclo[5.3.1]undec-9-yl]pyrimidine-4-carboxamide, white powder (4.7 mg, 10%), 1H NMR (400MHz, methanol-d4) 7.48 (dd, J=8.0, 1.6Hz, 1H), 7.29 (t, J=7.8Hz, 1H), 7.17 (dd, J=7.6, 1.6Hz, 1H), 4.59-4.52 (m, 2H ), 3.47-3.42(m, 1H), 3.28-3.24(m, 1H), 2.01-1.90(m, 2H), 1.88-1.71(m, 4H), 1.61-1.39(m, 4H), 1.37-1.19(m, 2H). LC / MS: 449.2.

[0505] Compound 15: 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-hydroxypyrimidine-4-carboxamide

[0506] Step 1: tert-Butyl N-{1-[4-amino-6-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

[0507]

[0508] N-[1-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate (Intermediate 5, 371 mg, 0.78 mmol) was heated in ethanol (5 mL) and aqueous NaOH (0.8 mL, 2.2 M solution) at 100°C for 16 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 7 by the addition of 3M HCl solution. The resulting solution was extracted with ethyl acetate (30 mL) and the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (ethyl acetate: methanol, gradient 100: 0 to 80: 20) gave the title compound as a cream solid (180 mg, 49%). LC / MS: 495.1.

[0509] Step 2: 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-hydroxypyrimidine-4-carboxamide

[0510]

[0511] A solution of tert-butyl N-[1-[4-amino-6-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate (60 mg, 0.122 mmol) and NaNO2 (88 mg, 1.3 mmol) in THF (5 mL), water (3 mL) and concentrated HCl (1 mL) was stirred at 0 ° C for 4 hours. The solvent was removed under reduced pressure, and the residue was diluted with HCl aqueous solution (5M, 2 mL) and stirred at room temperature for 30 minutes. It was then poured into ice and extracted with ethyl acetate (3x30 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (XBridge OBD C18 column, 19*250 mm, 5 um; water (10 mM NH4HCO3) and ACN, 8 min gradient: 58% to 80%) gave the title compound as a yellow solid (4 mg, 8%). 1H NMR (400 MHz, methanol-d4) 7.48-7.47 (m, 1H), 7.45-7.44 (m, 1H), 7.28-7.23 (m, 1H), 4.41-4.20 (m, 2H), 3.51-3.38 (m, 2H), 1.92-1.81 (m, 4H), 1.54-1.50 (m, 3H), .LC / MS (M+1): 396.1.

[0512] Compound 16: 2-(4-amino-4-methyl-piperidin-1-yl)-6-chloro-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide

[0513]

[0514] Keeping at 0°C, a solution of NaNO2 (197 mg, 2.7 mmol) in water (1 mL) was added to tert-butyl N-[1-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate (Intermediate 5, 440 mg, 0.90 mmol) in aqueous HCl (6M solution, 5 mL, 29.6 mmol). The reaction mixture was stirred at 0°C for 30 minutes and then at room temperature for 4 hours. The reaction mixture was poured into ice and the pH was adjusted to 9 by adding aqueous NaOH (2 M). It was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether: ethyl acetate, 50: 50)) gave a yellow solid (210 mg), which was redissolved in ACN (4 mL) and aqueous NaOH (0.5 M, 4 mL). The reaction mixture was heated at 70°C for 1 hour. Diluted with water (15 mL) and then extracted with ethyl acetate (3x30 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (petroleum ether: ethyl acetate, 50: 50) gave the title compound as a yellow solid (80 mg, 51%). 1H NMR (400 MHz, methanol-d4) 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.17 (dd, J = 7.6, 1.6 Hz, 1H), 4.09-4.01 (m, 2H), 3.89 (d, J = 5.5 Hz, 2H), 1.65 (qdd, J = 13.2, 7.5, 4.3 Hz, 4H), 1.27 (s, 3H). LC / MS (M+1): 415.0.

[0515] Compound 17: 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid (2-hydroxy-ethyl)-amide

[0516]

[0517] The title compound was prepared as a white solid according to the procedure described above using 6-amino-2-(4-[[(tert-butoxy)carbonyl]amino]-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylic acid (Intermediate 7) and 2-aminoethan-1-ol as starting materials. Melting point: 125-127°C. 1H NMR (400 MHz, methanol-d4) 7.54-7.47 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.18-7.12 (m, 1H), 4.08-3.97 (m, 2H), 3.82-3.71 (m, 2H), 3.62-3.55 (m, 2H), 3.30 (d, J = 5.6 Hz, 2H), 1.68-1.53 ​​(m, 3H), 1.25 (s, 3H). LC / MS (M+1): 439.2.

[0518] Compound 18: 2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide

[0519] Step 1: tert-Butyl N-{1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

[0520]

[0521] Under nitrogen atmosphere, a mixture of tert-butyl N-[1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate (Intermediate 8, 2.3 g, 5.5 mmol), (2,3-dichlorophenyl)boronic acid (2.2 g, 11 mmol), Pd(PPh3)4 (1.34 g, 1.1 mmol) and NaHCO3 (2.43 g, 27.4 mmol) in dioxane (9 mL) and water (3 mL) was placed in a sealed reactor and heated at 110°C for 2 hours. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate, gradient from 100:0 to 50:50) to give the title compound as a yellow solid (3 g, 100%). LC / MS (M+1): 476.4.

[0522] Step 2: 2-(4-Amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide

[0523]

[0524] Under nitrogen atmosphere, a solution of tert-butyl N-[1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate (100 mg, 0.199 mmol) in concentrated HCl (3 mL) was stirred at room temperature for 16 hours. The crude mixture was directly purified by preparative HPLC (XBridge Prep OBD C18 column, 30*150 mm 5um; water (10 mM NH4HCO3) and ACN, 8 min gradient: 32% to 62%). The title compound was isolated as a yellow solid (25 mg, 31%). Melting point: 103-105°C. 1H NMR (400MHz, methanol-d4) 9.38 (S, 1H), 8.07 (d, J = 1.5Hz, 1H), 7.77 (d, J = 3.1Hz, 1H), 7.72 (d, J = 3.1Hz, 1H ), 7.64 (d, J=1.8Hz, 1H), 4.46 (d, J=12.7Hz, 2H), 3.67 (S, 2H), 2.03 (d, J=13.7Hz, 4H), 1.58 (S, 3H). LC / MS(M+1): 394.1.

[0525] Compounds 30 and 31: (4M)-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide and (4P)-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0526]

[0527] The mixture of atropisomers was separated from compound 18 (250 mg) by preparative HPLC (column: CHIRALPAK IG, 2x25 cm, 5 um, hexane + 8 mmol / L NH3. methanol:ethanol - 50%).

[0528] First eluting isomer (Compound 30): white solid, 60 mg, RT = 6.96 min, 1H NMR (300 MHz, DMSO-d6): 7.91 (s, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.28 (m, 2H), 7.18 (dd, J = 7.6, 1.6 Hz, 1H), 4.01 (d, J = 13.7 Hz, 2H), 3.70 (dt, J = 12.8, 6.3 Hz, 2H), 1.98 (s, 4H), 1.42 (d, J = 5.4 Hz, 4H), 1.10 (s, 3H); LC / MS (M+1): 394.1, melting point: 160-162°C.

[0529] The second eluting isomer (compound 31 ): white solid, 40 mg, RT = 14.5 min, 1H NMR (300 MHz, DMSO-d6): 7.91 (s, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.29 (m, 2H), 7.18 (dd, J = 7.6, 1.6 Hz, 1H), 4.03 (d, J = 13.4 Hz, 2H), 3.68 (dt, J = 13.1, 6.4 Hz, 2H), 1.98 (s, 3H), 1.78 (d, J = 9.2 Hz, 2H), 1.41 (d, J = 5.3 Hz, 4H), 1.09 (s, 4H). LC / MS (M+1): 394.1, melting point: 190-192°C.

[0530] Compound 19: 2-(4-amino-4-methyl-piperidin-1-yl)-6-chloro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide

[0531] Step 1: tert-Butyl N-{1-[4-amino-6-carbamoyl-5-(3-fluorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

[0532]

[0533] The title compound was prepared as a brown solid using tert-butyl N-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate (Intermediate 2) and (3-fluorophenyl)boronic acid as starting materials according to the procedure described for compound 2. LC / MS (M+1): 445.2.

[0534] Step 2: 2-(4-Amino-4-methyl-piperidin-1-yl)-6-chloro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide

[0535]

[0536] The title compound was prepared starting from tert-butyl N-[1-[4-amino-6-carbamoyl-5-(3-fluorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate according to the procedure described for compound 16. The title compound was isolated as a white solid. Melting point: 110-112°C. 1H NMR (400 MHz, methanol-d4) 7.53-7.39 (m, 1H), 7.42-7.36 (m, 1H), 7.16-6.99 (m, 5H), 4.55-4.45 (m, 3H), 3.54 (ddd, J = 14.1, 9.7, 3.9 Hz, 3H), 2.05 (s, 1H), 2.00-1.87 (m, 1H), 1.85 (ddd, J = 18.0, 8.3, 3.8 Hz, 5H), 1.54 (s, 4H). LC / MS (M+1): 364.0.

[0537] Compound 20: 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydroxyamide

[0538] Step 1: Methyl 6-amino-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylate

[0539]

[0540] A solution of 6-amino-2-(4-[[(tert-butoxy)carbonyl]amino]-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylic acid (Intermediate 7, 40 mg, 0.073 mmol) and SOCl2 (1 mL, 13.1 mmol) in methanol (4 mL) was stirred at 70°C for 2 hours. The solvent was then removed under reduced pressure to give the title compound as a brown solid (38 mg, 96%). LC / MS (M+1): 410.2.

[0541] Step 2: 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydroxyamide

[0542]

[0543] 6-amino-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylic acid methyl ester (33 mg, 0.1 mmol) and NH2OH (20 μl, 50% aqueous solution) were stirred in a solution at room temperature in methanol (1 mL) for 16 hours. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XBridge Shield RP18 OBD column, 5 um, 19*150 mm: water (10 mM NH4HCO3) and ACN, 8 minutes gradient: 25% to 55%) to give the title compound as a white solid (9 mg, 33%). 1H NMR (400MHz, DMSO-d6) 7.56-7.49 (m, 2H), 7.29 (t, J=7.9Hz, 2H), 7.12 (S, 1H), 7.12 (d, J=7.8Hz, 1H), 6.10 (S, 4H), 3.91 (d, J=12.6Hz, 4H), 3.64 (S, 5H), 1.39 (d, J=9.5Hz, 10H), 1.24 (S, 1H), 1.09 (S, 6H). LC / MS(M+1): 411.1.

[0544] Compound 21: 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydrazide

[0545] Step 1: tert-Butyl N-{1-[4-amino-5-(2,3-dichlorophenyl)-6-(hydrazinecarbonyl)-pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

[0546]

[0547] A solution of 6-amino-2-(4-{[(tert-butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylic acid (Intermediate 7, 50 mg, 0.084 mmol), HATU (50 mg, 0.126 mmol), DIEA (34 mg, 0.25 mmol) and hydrazine (6 ul) in DMF (5.0 mL) was stirred at 80 °C for 24 hours. The reaction mixture was diluted with water / ice (25 mL) and extracted with ethyl acetate (3x30 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether:ethyl acetate, 90:10) gave the title compound as a yellow solid (40 mg, 88%).

[0548] Step 2: 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydrazide

[0549]

[0550] A solution of tert-butyl N-[1-[4-amino-5-(2,3-dichlorophenyl)-6-(hydrazinecarbonyl)-pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate (40 mg, 0.074 mmol) in HCl (2 mL, 4N solution in dioxane) was stirred at room temperature for 4 hours. The solvent was then removed under reduced pressure and the crude product was purified by preparative HPLC (XBridge Prep OBD C18 column, 30x150mm 5um; water (10 mM NH4HCO3) and ACN, 8 min gradient: 30% to 60%). The title compound was isolated as a white solid (4.3 mg, 13%). Melting point: 171-173°C. 1H NMR (300 MHz, methanol-d4) 7.50 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 4.05 (dt, J = 13.9, 5.2 Hz, 2H), 3.69 (ddd, J = 13.1, 7.7, 4.3 Hz, 2H), 1.69-1.50 (m, 4H), 1.26 (s, 3H). LC / MS (M+1): 410.1.

[0551] Compound 22: 2-(4-amino-4-methyl-piperidin-1-yl)-6-fluoro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide

[0552]

[0553] A mixture of tert-butyl N-[1-[4-amino-6-carbamoyl-5-(3-fluorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate (prepared with compound 4 in step 1, 179 mg, 0.396 mmol), phenylboronic acid (3.0 mL), NaNO2 (139 mg, 1.9 mmol) and KF (117 mg, 1.9 mmol) was stirred at 0°C for 1 hour. The reaction was then quenched by adding NH4Cl aqueous solution (10 mL) and extracted with ethyl acetate (3x30 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product (50 mg) was purified by preparative HPLC (XBridge Prep OBD C18 column, 19x250 mm, 5 um; water (10 mM NH4HCO3) and ACN, 8 min gradient: 30% to 45%) to obtain the title compound as a white solid (8 mg, 5%). Melting point: 90-92° C. 1H NMR (400 MHz, methanol-d4) 7.45-7.35 (m, 1H), 7.17-7.05 (m, 3H), 4.03 (s, 2H), 3.85 (s, 2H), 1.72-1.55 (m, 4H), 1.28 (s, 3H). LC / MS (M+1): 348.1.

[0554] Compound 23: 6-amino-2-[4-(aminomethyl)-8-oxa-2-azaspiro[4.5]decane-2-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0555]

[0556] The title compound was prepared as a white powder according to the procedure described above using 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (intermediate 4) and tert-butyl n-((8-oxa-2-azaspiro[4.5]decan-4-yl)methyl)carbamate (enamine) as starting materials. 1H NMR (400MHz, DMSO-d6) 7.78 (S, 1H), 7.51 (dd, J=8.1, 1.6Hz, 1H), 7.28 (t, J=7.8Hz, 1H), 7.18 (S, 1H), 7.10 (dt, J=7.6, 1.5Hz, 1H), 6.04 (S, 2 H), 3.84-3.64 (m, 4H), 2.72-2.61 (m, 2H), 1.98-1.84 (m, 2H), 1.77 (dd, J=18.1, 6.4Hz, 2H), 1.55 (t, J=10.6Hz, 2H), 1.36 (t, J=16.2Hz, 3H). LC / MS(M+1): 451.3.

[0557] Compound 24: 2-[3a-(Aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0558]

[0559] The title compound was prepared as a white powder (mixture of isomers) according to the procedure described above using 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (intermediate 4) and tert-butyl N-(octahydro-1h-isoindol-3a-ylmethyl)-carbamate (enamine) as starting materials. 1H NMR (400MHz, DMSO-d6) 7.68 (S, 1H), 7.51 (dd, J=8.1, 1.6Hz, 1H), 7.28 (t, J=7.8Hz, 1H), 7.16 (S, 1H), 7 .13-7.07 (m, 1H), 6.00 (S, 2H), 3.71-3.35 (m, 4H), 2.64 (S, 1H), 2.10-1.99 (m, 1H), 1.66-1.22 (m, 9H). LC / MS(M+1): 435.

[0560] Compound 25: 2-(4-amino-4-methylpiperidin-1-yl)-5-(3-fluorophenyl)-6-hydroxypyrimidine-4-carboxamide hydrochloride

[0561]

[0562] A solution of 2-(4-amino-4-methylpiperidin-1-yl)-6-fluoro-5-(3-fluorophenyl)-pyrimidine-4-carboxamide (Example 36, 50 mg, 0.072 mmol) in concentrated HCl (1.0 mL) and water (2.0 mL) was stirred at 50 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and directly purified by preparative HPLC (XBridge Prep OBD C18 column, 19*250 mm, 5 um; water (10 mM NH4HCO3 and ACN, 8 min gradient: 58% to 80%) to afford the title compound as a white solid (8.6 mg, 31%). 1H NMR (400 MHz, DMSO-d6) 7.63 (S, 1H), 7.33-7.23 (m, 2H), 7.12-7.02 (m, 2H), 7.04-6.96 (m, 1H), 4.06 (S, 1H), 3.81 (S, 2H), 3.61 (S, 2H), 1.48 (S, 4H), 1.17 (S, 3H). LC / MS (M+1): 346.1.

[0563] Compounds 66 and 67: (5P)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide and (5M)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0564] Step 1: tert-Butyl N-[(3S,4S)-8-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

[0565]

[0566] A solution of 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (Intermediate 4, 1.50 g; 4.37 mmol), tert-butyl N-[(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (WUXI; 1.77 g; 6.56 mmol), DIEA (2.27 mL) in anhydrous DMSO (60 mL) was stirred at 70 °C for 6 hours. The reaction mixture was then diluted with water (300 mL) and ethyl acetate (800 mL). The organic layer was washed with water (2x300 mL) and brine (300 mL), dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (hexane: ethyl acetate, gradient: 95: 5 to 20: 80) gave the title compound as a white solid (2.07 g, 89%). 1H NMR (400MHz, DMSO-d6): 7.72 (dd, J=8.0, 1.6Hz, 1H), 7.45 (t, J=7.8Hz, 1H), 7.39 (dd, J=7.7, 1.7Hz, 1H), 6.97 (d, J=10.5Hz, 1H), 4.17 (p, J=6.2Hz, 1H), 3.89 (dd, J=10.6, 5.1Hz, 1H), 3.86-3.75 (m, 1H), 3.75-3.61 (m, 3H), 3.57-3.43 (m, 2H), 1. 68-1.50 (m, 3H), 1.50-1.31 (m, 10H), 1.03 (d, J=6.3Hz, 3H); LC / MS (M+1): 533.1.

[0567] Step 2: N-[(3S,4S)-8-[4-amino-6-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate

[0568]

[0569] A solution of tert-butyl N-[(3S,4S)-8-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (Intermediate 4; 2.0 g; 3.75 mmol), potassium carbonate (2.59 g; 18.75 mmol) and hydrogen peroxide 30% by weight (7.65 ml; 67.49 mmol) in DMSO (50 mL) was stirred at 50° C. for 4.5 hours. The reaction mixture was diluted with ethyl acetate (800 mL) and washed with a solution of sodium thiosulfate pentahydrate (50.25 g; 202.46 mmol) in water (500 mL). The organic layer was washed with water (2×400 mL) and brine (400 mL), dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (2.2 g, 95.8%). 1H NMR(Bruker 400MHz, DMSO-d6): 7.73 (S, 1H), 7.51 (dd, J=8.0, 1.5Hz, 1H), 7.28 (t, J=7.8Hz, 1H), 7.14 (S, 1H), 7.10 (dd, J=7.4, 1.2Hz, 1H), 6.97 (d, J=10.5Hz, 1H ), 6.08(S, 2H), 4.22-4.11(m, 1H), 3.96-3.78(m, 2H), 3.78-3.64(m, 3H), 3.61-3.47 (m, 2H), 1.69-1.50 (m, 4H), 1.40 (S, 9H), 1.03 (d, J=6.3Hz, 3H). LC / MS (M+1): 551.2.

[0570] Step 3: (5P)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide and (5M)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0571]

[0572] A solution of tert-butyl N-[(3S,4S)-8-[4-amino-6-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (2.20 g; 3.59 mmol; 1.00 eq.) in dichloromethane (44 mL) and TFA (22 mL) was stirred at room temperature for 1 hour. Toluene was added and the mixture was concentrated under reduced pressure. The operation was repeated twice. The crude residue (3.3 g) was purified by preparative SFC (column: Amylose 2, 250 x 21 mm, 5 microns, methanol + 20 mM NH4OH:CO2; 45-55).

[0573] The first elution fraction (Compound 67) (5M)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide: white amorphous solid; 637 mg (40%). RT = 4.04 min; ed = 100%; 1H NMR (400MHz, DMSO-d6): 7.71 (S, 1H), 7.51 (dd, J=8.1, 1.5Hz, 1H), 7.28 (t, J=7 .8Hz, 1H), 7.15 (S, 1H), 7.10 (dd, J=7.6, 1.5Hz, 1H), 6.08 (S, 2H), 4.16-3.99 ( m, 3H), 3.68 (d, J = 8.4Hz, 1H), 3.50 (d, J = 8.4Hz, 1H), 3.48-3.25 (m, 4H), 2.91 ( d, J=5.1Hz, 1H), 1.77-1.34 (m, 6H), 1.09 (d, J=6.4Hz, 3H); LC / MS (M+1): 451.0.

[0574] The first elution fraction(Compound 66) (5P)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide: white solid; 603 mg (37%). RT = 4.53 min; ed = 95%; 1H NMR (Bruker 400 MHz, DMSO-d6): 7.72 (S, 1H), 7.51 (dd, J = 8.0, 1.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.15 (S, 1H), 7.10 (dd, J = 7.7, 1.6 Hz, 1H), 6.08 (S, 2H), 4.15-3.99 (m, 3H), 3.68 (d, J=8.4Hz, 1H), 3.50 (d, J=8.4Hz, 1H), 3.48-3.34 (m, 4H), 2.90 (d, J=5.2Hz, 1H) , 1.75-1.63 (m, 1H), 1.63-1.53 ​​(m, 1H), 1.53-1.29 (m, 4H), 1.08 (d, J=6.4Hz, 3H). LC / MS(M+1): 451.0.

[0575] Compound 85: 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0576] Step 1: tert-Butyl N-[(3S,4S)-8-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate

[0577]

[0578] Under nitrogen atmosphere and atmospheric pressure, tert-butyl N-[(3S,4S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (108 mg; 0.23 mmol) was mixed with a solution of 2,3-dichlorophenylboronic acid (66 mg; 0.35 mmol) and cesium carbonate (151 mg; 0.46 mmol) in 1,4-dioxane (2.2 mL) and water (0.54 mL). The mixture was degassed for 10 minutes, then tetrakis(triphenylphosphine)palladium(0) (53 mg; 0.05 mmol) was added and stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). It was filtered through a pad of Celite and rinsed with ethyl acetate (10 mL). The filtrate was concentrated and purified by flash chromatography on silica gel (hexanes:ethyl acetate, gradient 95:5 to 20:80) to afford the title compound as a white solid (72 mg, 58%). 1H NMR(Bruker 400MHz, DMSO-d6): 7.80 (dd, J=6.4, 3.2Hz, 1H), 7.60-7.47 (m, 2H), 7.01 (d, J=10.5Hz, 1H), 4.18 (p, J=6.2Hz, 1H), 3.96-3.84 (m, 2H), 3.84-3.7 3 (m, 2H), 3.70 (d, J = 8.5Hz, 1H), 3.66-3.58 (m, 1H), 3.54 (d, J = 8.2Hz, 1 H), 2.12 (S, 3H), 1.75-1.44 (m, 4H), 1.40 (S, 9H), 1.03 (d, J=6.3Hz, 3H). LC / MS (M+1): 532.2.

[0579] Step 2: tert-Butyl N-[(3S,4S)-8-[4-carbamoyl-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate

[0580]

[0581] A solution of tert-butyl N-[(3S,4S)-8-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (100 mg; 0.19 mmol), potassium carbonate (130 mg; 0.94 mmol) and hydrogen peroxide 30% by weight (0.38 mL; 3.38 mmol) in DMSO (2.5 mL) was stirred at 50° C. for 6 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with a solution of sodium thiosulfate pentahydrate (2.52 g; 10.1 mmol) in water (25 mL). The organic layer was washed with water (2×25 mL) and brine (25 mL), dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (103 mg, 94%). LC / MS (M+1): 550.2.

[0582] Step 3: 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0583]

[0584] A solution of tert-butyl N-[(3S,4S)-8-[4-carbamoyl-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate (100.00 mg; 0.18 mmol; 1.00 eq.) in dichloromethane (2 mL) and TFA (1 mL) was stirred at room temperature for 1 hour. Toluene was added and the mixture was concentrated under reduced pressure. The operation was repeated twice. The crude product was then purified by preparative HPLC (XBridge Prep C-18 OBD 10uM, 30x250; ACN:water (containing 0.1% ammonium hydroxide), 15 min gradient: 20% to 60%) to give the title compound as a white powder (70 mg, 86%). 1H NMR (Bruker 400MHz, DMSO-d6): 7.93 (S, 1H), 7.58 (dd, J=8.0, 1.6Hz, 1H), 7.43-7.29 (m, 2H), 7.20 (dd, J=7.7, 1.6Hz, 1H), 4.23-4.10 (m, 2H), 4.08 (dd, J=6.5, 5.2Hz , 1H), 3.70 (d, J=8.4Hz, 1H), 3.61-3.42 (m, 3H), 2.93 (d, J=5.2Hz, 1H), 2.00 (S, 3H), 1.77-1.68 (m, 1H), 1.68-1.42 (m, 5H), 1.09 (d, J=6.4Hz, 3H); LC / MS (M+1):450.1.

[0585] Compounds 94 and 95: (5P)-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide and (5M)-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0586]

[0587] The two atropisomers were separated from compound 85 by SFC (column IA, 250 x 21 mm, 5 micron, methanol + 20 mM NH4OH:CO2, 30-70).

[0588] The first eluting isomer (Compound 94): white amorphous solid, 24 mg, RT = 3.32 min, ed = 100%, 1H NMR (Bruker 400 MHz, DMSO-d6): 7.93 (s, 1H), 7.58 (dd, J = 8.0, 1.5 Hz, 1H), 7.42-7.29 (m, 2H), 7.20 (dd, J = 7.6, 1.6 Hz, 1H), 4.24-4.02 (m, 3H), 3.70 (d, J = 8.4 Hz, 1H), 3.62-3.41 (m, 3H), 2.92 (d, J = 5.2 Hz, 1H), 2.00 (s, 3H), 1.80-1.33 (m, 6H), 1.09 (d, J = 6.4 Hz, 3H). LC / MS (M+1): 450.2.

[0589] The second eluting isomer ( Compound 95): white solid, 22 mg, RT = 3.67 min, ed = 100%, 1H NMR (400MHz, DMSO-d6): 7.93 (S, 1H), 7.58 (dd, J=8.0, 1.6Hz, 1H), 7.41-7.30 (m, 2H), 7.20 (dd, J=7.7, 1.6Hz, 1H), 4.27-3.99 (m, 3H), 3.71 (d, J=8. 5Hz, 1H), 3.65-3.39 (m, 3H), 2.94 (d, J=5.2Hz, 1H), 2.00 (S, 3H), 1.81-1. 35 (m, 5H), 1.35-1.17 (m, 1H), 1.09 (d, J=6.4Hz, 3H), LC / MS (M+1): 450.2.

[0590] Compounds 96 and 97: (5M)-2-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide and (5P)-2-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0591]

[0592] Using tert-butyl N-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate (150.00 mg; 0.31 mmol) and 2,3-dichlorophenylboronic acid (88.28 mg; 0.46 mmol) as starting materials, the title compound was prepared according to the procedure described for compound 85 as a white powder (65 mg, 44% in three steps, a mixture of two atropisomers).

[0593] The two atropisomers were separated by preparative SFC (column Cel4, 250 x 21 mm, 5 micron, methanol + 20 mM NH4OH:CO2).

[0594] The first eluting isomer ( Compound 96): white solid, 31 mg, RT=, ed=, 1H NMR (Bruker 400 MHz, DMSO-d6): 7.93 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.42-7.28 (m, 2H), 7.20 (d, J=7.6 Hz, 1H), 4.61 (dd, J=17.5, 13.3 Hz, 2H), 3.18-2.94 (m, 3H), 2.46-2.29 (m, 2H), 2.12-1.91 (m, 5H), 1.78-1.54 (m, 4H), 1.36 (dd, J=26.1, 13.4 Hz, 2H), LC / MS (M+1): 470.2.

[0595] The second eluting isomer ( Compound 97): white solid, 25 mg, RT=, ed=, 1H NMR (Bruker 400 MHz, DMSO-d6): 7.93 (s, 1H), 7.58 (dd, J=8.0, 1.5 Hz, 1H), 7.41-7.29 (m, 2H), 7.20 (dd, J=7.6, 1.6 Hz, 1H), 4.61 (dd, J=19.0, 14.6 Hz, 2H), 3.17-2.95 (m, 3H), 2.47-2.29 (m, 2H), 2.12-1.92 (m, 5H), 1.86-1.51 (m, 4H), 1.44-1.28 (m, 2H), LC / MS (M+1): 470.2.

[0596] Compounds 98, 104, 99, 105: (5P)-2-[(3aR, 6aS)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide, (5P)-2-[(3aS, 6aR)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide Pyrimidine-4-carboxamide, (5M)-2-[(3aR, 6aS)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide, (5M)-2-[(3aS, 6aR)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0597] Step 1: rac-2-[(3aS,6aR)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0598]

[0599] The title compound was prepared according to the procedure described for compound 85 using 6-amino-2-chloropyrimidine-4-carbonitrile (250 mg, 1.6 mmol) and racemic-tert-butyl n-([(3aR,6ar)-octahydrocyclopenta[c]pyrrol-3a-yl]methyl)carbamate hydrochloride (enamine, 895 mg, 3.2 mmol) as starting materials as a white amorphous solid (179 mg, 25%, 5 steps). 1H NMR (400MHz, DMSO-d6)d 7.69 (S, 1H), 7.51 (d, J=8.0Hz, 1H), 7.28 (t, J=7.8Hz, 1H), 7.21-7.04 (m, 2H), 6.02 (S, 2H), 3.80-3.36 (m, 4H), 3. 06 (d, J=6.1Hz, 2H), 2.56 (S, 2H), 2.35 (ddq, J=12.8, 8.4, 4.6, 4.1Hz, 1H), 1.95-1.37 (m, 6H); LC / MS (M+1): 421.1.

[0600] Step 2: Separation of the four isomers

[0601]

[0602] The isomers of racemic-2-[(3aS,6aR)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide were separated by preparative SFC (column: IG, 250x21 mm, 5 micron, methanol + 20 mM NH4OH:CO2, 30:70%).

[0603] Stereochemistry was assigned arbitrarily. Enantiomeric purity was assessed by SFC using chiral column IC (methanol + 20 mM NH4OH).

[0604] The first eluted fraction (compound 98): White amorphous solid, 26 mg, RT = 3.76 min, ed = 95.9%, 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.51 (dd, J = 8.1, 1.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.21-7.04 (m, 2H), 6.03 (s, 2H), 3. 65(ddd, J=35.0, 11.5, 6.8Hz, 2H), 3.26-3.19(m, 1H), 2.42-2.26(m, 1H), 1.93-1.4 0 (m, 8H), 1.24 (d, J=3.0Hz, 2H), 0.87 (dt, J=13.4, 7.2Hz, 1H), LC / MS (M+1): 421.1.

[0605] The second eluted fraction (Compound 104): White amorphous solid, 35 mg, RT = 3.82 min, ed = 97.3%, 1H NMR (400 MHz, DMSO-d6) δ 7.69 (S, 1H), 7.51 (dd, J = 8.1, 1.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.16 (S, 1H), 7.09 (dd, J = 7.6, 1.6 Hz, 1H), 6.02 (S, 2H), 3.81-3.54 (m, 2H), 2.56 (S, 2H), 2.43-2.19 (m, 2H), 1.95-1.36 (m, 8H), 1.36-1.13 (m, 1H); LC / MS (M+1): 421.0.

[0606] The third eluting fraction (Compound 99):White amorphous solid, 46 mg, RT = 4.14 min, ed = 95.1%, 1H NMR (400 MHz, DMSO-d6) δ 7.69 (S, 1H), 7.51 (dd, J = 8.1, 1.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.16 (S, 1H), 7.09 (dd, J = 7.6, 1.6 Hz, 1H), 6.02 (S, 2H), 3.81-3.54 (m, 2H), 2.56 (S, 2H), 2.43-2.19 (m, 2H), 1.95-1.36 (m, 8H), 1.36-1.13 (m, 1H); LC / MS (M+1): 421.0.

[0607] The fourth eluted fraction (Compound 105): White amorphous solid, 29 mg, RT = 4.2 min, ed = 95.4%, 1H NMR (400 MHz, DMSO-d6) d7.69 (S, 1H), 7.51 (dd, J = 8.1, 1.5 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.16 (S, 1H), 7.10 (dd, J = 7.6, 1.6 Hz, 1H), 6.02 (S, 2H), 3.77-3.54 (m, 2H), 2.56 (S, 2H), 2.43-2.22 (m, 2H), 1.94-1.41 (m, 8H), 1.24 (S, 1H). ); LC / MS (M+1): 421.1.

[0608] Compounds 100, 101, 102, 103: (5P)-2-[(3aR, 7aS)-3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide, (5P)-2-[(3aS, 7aR)-3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide )pyrimidine-4-carboxamide, (5M)-2-[(3aR,7aS)-3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide, (5M)-2-[(3aS,7aR)-3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0609] Step 1: 2-[3a-(Aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0610]

[0611] The title compound was prepared according to the procedure described for compound 85 using 6-amino-2-chloropyrimidine-4-carbonitrile (250 mg, 1.6 mmol) and tert-butyl n-(octahydro-1h-isoindol-3a-ylmethyl)carbamate (enamine, 823 mg, 3.2 mmol) as starting materials, as a white amorphous solid (128 mg, 19% for five steps). 1H NMR (400MHz, DMSO-d6) d7.68 (S, 1H), 7.50 (d, 1H), 7.28 (t, J=7.8Hz, 1H), 7.23-7.04 (m, 2H), 6.00 (S, 2H), 3. 70-3.34 (m, 4H), 2.63 (q, J=5.8Hz, 1H), 2.05 (dd, J=11.5, 5.8Hz, 2H), 1.72-1.20 (m, 8H); LC / MS (M+1): 435.1.

[0612] Step 2: Separation of the four isomers

[0613]

[0614]

[0615] The isomers of 2-[3a-(Aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide were separated by preparative SFC (column: IG, 250×21 mm, 5 μm, methanol+20 mM NH 4 OH:CO 2 , 30:70%).

[0616] Stereochemistry was assigned arbitrarily. Enantiomeric purity was assessed by SFC using chiral column IG (methanol + 20 mM NH4OH).

[0617] The first eluted fraction (Compound 100): White amorphous solid, 20 mg, RT = 3.67 min, ed = 95.0%, 1H NMR (400 MHz, DMSO-d6): 7.68 (S, 1H), 7.51 (dd, J = 8.0, 1.5 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.22-7.05 (m, 2H), 6.00 (S, 2H), 3.77-3.48 (m, 2H), 2.62 (d, J = 14.0 Hz, 2H), 2.04 (S, 2H), 1.69-1.17 (m, 10H), 0.95-0.74 (m, 1H). LC / MS (M+1): 435.0.

[0618] The second eluted fraction (Compound 101):White amorphous solid, 19 mg, RT = 3.59 min, ed = 93.4%, 1H NMR (400 MHz, DMSO-d6): 7.76-7.59 (m, 1H), 7.51 (dd, J = 8.1, 1.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.22-7.04 (m, 2H), 6.00 (s, 2H), 3.73-3.43 (m, 2H), 2.64 (d, J = 14.3 Hz, 1H), 2.15-1.89 (m, 2H), 1.40 (t, J = 56.6 Hz, 9H), 0.96-0.72 (m, 1H); LC / MS (M+1): 435.0.

[0619] The third eluted fraction (Compound 102): White amorphous solid, 20 mg, RT = 3.85 min, ed = 91.3%, 1H NMR (400 MHz, DMSO-d6): 7.68 (S, 1H), 7.51 (dd, J = 8.0, 1.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.22-7.01 (m, 2H), 6.00 (S, 2H), 3.73-3.43 (m, 2H), 2.64 (S, 2H), 2.03 (dt, J = 15.3, 7.2 Hz, 2H), 1.78-0.97 (m, 10H), 0.97-0.68 (m, 1H). LC / MS (M+1): 435.0.

[0620] The fourth eluted fraction (Compound 103): White amorphous solid, 16 mg, RT = 4.02 min, ed = 94.2%, 1H NMR (400 MHz, DMSO-d6): 7.68 (S, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.28 (q, J = 7.0, 6.3 Hz, 1H), 7.22-7.00 (m, 2H), 6.00 (S, 2H), 3.51 (S, 2H), 2.04 (S, 2H), 1.34 (d, J = 77.2 Hz, 11H), 0.85 (S, 2H); LC / MS (M+1): 435.1.

[0621] Compounds 113 and 114: (5P)-2-[(1R)-1-amino-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide and (5M)-2-[(1R)-1-amino-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0622]

[0623] Using tert-butyl N-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl]carbamate (Intermediate 13, 100 mg; 0.22 mmol) and 2,3-dichlorophenylboronic acid (64 mg; 0.33 mmol) as starting materials, the title compound was prepared according to the procedure described for compound 85 as a white powder (43 mg, 31% in three steps, a mixture of two atropisomers).

[0624] The two atropisomers were separated by preparative SFC (column Whelk-O, 250 x 21 mm, 5 micron, methanol + 20 mM NH4OH:CO2, 5-45).

[0625] The first eluting isomer ( Compound 113): white solid, 9 mg, RT = 3.51 min, ed = 100%, 1H NMR (400 MHz, DMSO-d6): 7.91 (s, 1H), 7.58 (dd, J = 8.0, 1.5 Hz, 1H), 7.43-7.29 (m, 2H), 7.20 (dd, J = 7.6, 1.6 Hz, 1H), 4.55 (t, J = 13.0 Hz, 2H), 3.15-3.05 (m, 2H), 2.78 (t, J = 7.4 Hz, 1H), 2.00 (s, 3H), 1.96-1.72 (m, 3H), 1.73-1.29 (m, 7H), 1.29-1.14 (m, 2H), LC / MS (M+1): 434.0.

[0626] The second eluting isomer ( Compound 114): white solid, 9 mg, RT = 4.03 min, ed = 94.3%, 1H NMR (400MHz, DMSO-d6): 7.90 (S, 1H), 7.58 (dd, J=8.1, 1.6Hz, 1H), 7.40-7.30 (m, 2H), 7.20 (dd, J=7.6, 1.6Hz, 1H), 4.54 (td, J=9.5, 5.1Hz, 2H), 3.20 -3.05 (m, 2H), 2.73 (t, J=7.4Hz, 1H), 2.00 (S, 3H), 1.94-1.76 (m, 2H), 1.7 5-1.47 (m, 5H), 1.46-1.31 (m, 2H), 1.31-1.13 (m, 3H), LC / MS (M+1): 434.0.

[0627] Compounds 117 and 118: (5P)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide and (5M)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0628] Step 1: 6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

[0629]

[0630] A solution of 6-amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile (75 mg; 0.22 mmol; 1.00 eq.), (3S)-1,3-dihydrospiro[indene-2,4′-piperidine]-3-amine dihydrochloride (Pharmablock, 90 mg; 0.33 mmol; 1.50 eq.) and potassium carbonate (151 mg; 1.09 mmol; 5.00 eq.) in acetonitrile (1.50 ml; 20.00 V) and N,N-dimethylformamide (0.75 ml; 10.00 V) was stirred at 100° C. for 18 hours. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (ethyl acetate:methanol, gradient 99:1 to 90:10) gave the title compound as a white solid (76 mg, 75%).

[0631] 1H NMR(Bruker 400MHz, DMSO-d6): 7.72 (dd, J=8.0, 1.7Hz, 1H), 7.45 (t, J=7.8Hz, 1H), 7.39 (dd, J=7.6, 1. 6Hz, 1H), 7.30 (dd, J=6.6, 1.7Hz, 1H), 7.22-7.10 (m, 3H), 7.00-6.57 (m, 2H), 4.44 (t, J=14. 2Hz, 2H), 3.83 (S, 1H), 3.21-3.02 (m, 3H), 2.62 (d, J=15.6Hz, 1H), 1.93-1.78 (m, 2H), 1.78- 1.67 (m, 1H), 1.59 (td, J=12.6, 4.3Hz, 1H), 1.48 (d, J=13.2Hz, 1H), 1.07 (d, J=13.3Hz, 1H). LC / MS(M+1): 465.2.

[0632] Step 2: (5P)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide and (5M)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0633]

[0634] A solution of 6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile (936 mg; 2.01 mmol), potassium carbonate (1.39 g; 10.1 mmol) and hydrogen peroxide 30% by weight (4.1 ml; 36.2 mmol) in DMSO (23 mL) was stirred at 50° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (800 mL) and washed with a solution of sodium thiosulfate pentahydrate (27 g; 109 mmol) in water (230 mL). The organic layer was washed with water (2×400 mL) and brine (400 mL), dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (970 mg).

[0635] The two atropisomers were separated by preparative SFC (column IC, 250 x 21 mm, 5 micron; methanol + 20 mM NH4OH:CO2, 45-55).

[0636] The first eluting isomer ( Compound 117): white solid, 309 mg, RT=6.62 min, ed=100%, LC / MS (M+1) 483.1.

[0637] The second eluting isomer (Compound 118): white solid, 328 mg, RT = 7.98 min, ed = 99.4%, 1H NMR (400 MHz, DMSO-d6): 7.74 (s, 1H), 7.53-7.50 (m, 1H), 7.37-7.25 (m, 2H), 7.25-7.15 (m, 4H), 7.12-7.10 (m, 1H), 6.12 (s, 2H), 4.54 (d, J=13.7Hz, 2H), 3.90 (S, 1H), 3.16-3.01 (m, 3H), 2.67 (d, J=15.6Hz, 1H), 1.79-1.68 (m, 1H), 1.64? 1.58 (m, 1H), 1.47 (d, J=13.0Hz, 1H), 1.12 (d, J=13.0Hz, 1H); LC / MS (M+1) 483.1.

[0638] Compounds 119 and 120: (M)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide and (P)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0639] Step 1: 6-Methyl-2-{1-oxo-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl}pyrimidine-4-carbonitrile

[0640]

[0641] Under nitrogen atmosphere, a solution of 2-chloro-6-methylpyrimidine-4-carbonitrile (120 mg, 0.742 mmol), 1H-spiro[indene-2,4-piperidin]-3-one hydrochloride (Pharmablock, 279 mg, 1.114 mmol) and DIEA (303 mg, 2.23 mmol) in acetonitrile (5.0 mL) was stirred at 80° C. for 2 hours. The resulting mixture was concentrated in vacuo and purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 1: 1) to afford the title compound as a white solid (200 mg, 84%); LC / MS (M+1): 319.0.

[0642] Step 2: 5-Bromo-6-methyl-2-{1-oxo-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl}pyrimidine-4-carbonitrile

[0643]

[0644] A solution of 6-methyl-2-[3-oxo-1H-spiro[indene-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile (180 mg, 0.565 mmol) and NBS (158 mg, 0.847) in DMF (5.0 mL) was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with ethyl acetate (3x30 mL). The organic layers were combined, washed with brine (1x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether: ethyl acetate, 5: 1) gave the title compound as a yellow solid (220 mg, 96.38%). LC / MS (M+1): 396.9.

[0645] Step 3: 5-(2,3-dichlorophenyl)-6-methyl-2-{3-oxo-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl}pyrimidine-4-carbonitrile

[0646]

[0647] Under nitrogen atmosphere, a mixture of 5-bromo-6-methyl-2-[3-oxo-1H-spiro[indene-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile (590 mg, 1.46 mmol), 2,3-dichlorophenylboronic acid (880 mg, 4.38 mmol), K3PO4 (978 mg, 4.38 mmol), XPhos Pd G3 (130 mg, 0.146 mmol) and XPhos (73 mg, 0.146 mmol) in 1,4-dioxane (5 mL) and water (3 mL) was stirred at 100° C. for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel Prep-TLC (petroleum ether: ethyl acetate, 1: 1) to give the title compound as a yellow solid (820 mg, 81%). LC / MS (M+1): 463.2.

[0648] Step 4: (R)-N-{1′-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-ylidene}-2-methylpropane-2-sulfenamide

[0649]

[0650] Under nitrogen atmosphere, a mixture of 5-(2,3-dichlorophenyl)-6-methyl-2-[3-oxo-1H-spiro[indene-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile (780 mg, 1.34 mmol) and (R)-2-methylpropane-2-sulfinamide (681 mg, 5.340 mmol) in Ti(OEt)4 (12.3 g, 53.5 mmol) was stirred at 90°C for 2 hours. The reaction mixture was diluted with water and ethyl acetate and filtered. The filter cake was washed with ethyl acetate (100 mL) and the filtrate was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate (3x120 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether: ethyl acetate, 1:1) gave the title compound as a yellow solid (800 mg, 64%). LC / MS (M+1): 566.2.

[0651] Step 5: (R)-N-[(3S)-1′-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfenamide

[0652]

[0653] A solution of NaBH4 (93 mg, 2.34 mmol) in water (1.3 mL) was slowly added to a solution of (R)-N-[1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-1H-spiro[indene-2,4-piperidin]-3-ylidene]-2-methylpropane-2-sulfinamide (440 mg, 0.468 mmol) in THF (8.8 mL) while maintaining at -50°C. The resulting mixture was stirred at 25°C under nitrogen atmosphere for 1 hour. The reaction was quenched by addition of water / ice (30 mL) and the aqueous layer was extracted with ethyl acetate (3x50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow oil (320 mg, 63%). LC / MS (M+1): 568.2.

[0654] Step 6: 5-(2,3-dichlorophenyl)-6-methyl-2-[(3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]pyrimidine-4-carboxamide

[0655]

[0656] A mixture of (R)-N-[(3S)-1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-1,3-dihydrospiro[indene-2,4-piperidin]-3-yl]-2-methylpropane-2-sulfinamide (300 mg, 0.275 mmol) and NaOH (200 mg, 4.750 mmol) in ethanol (5.00 mL) and water (5 mL) was placed in a 30 mL sealed tube and stirred at 70° C. under nitrogen atmosphere for 1 hour. The reaction mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (400 mg, 88%). LC / MS (M+1): 586.2.

[0657] Step 7: 2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0658]

[0659] A solution of 1,3-dihydrospiro[indene-2,4-piperidin]-1-yl]pyrimidine-4-carboxamide (100 mg, 0.17 mmol) and HCl (gaseous) in 1,4-dioxane (2.00 mL, 7.9 mmol, 12%) was stirred under nitrogen atmosphere at 70° C. for 1 hour. The solvent was removed under reduced pressure and the residue was purified by reverse phase flash chromatography on C18 silica gel (ACN: water + NH 4 OH, gradient: 0: 100 to 50: 50) to give the title compound as a white solid (50 mg, 60%). 1H NMR (400MHz, DMSO-d6): 7.94 (S, 1H), 7.58 (d, J=7.9Hz, 1H), 7.41-7.29 (m, 3H ), 7.24-7.14(m, 4H), 4.62(t, J=15.0Hz, 2H), 3.86(S, 1H), 3.17(S, 1H), 3.10 (d, J=15.7Hz, 1H), 2.66 (d, J=15.5Hz, 1H), 2.01 (S, 3H), 1.82-1.71 (m, 1H), 1 .64 (dd, J=13.7, 9.4Hz, 1H), 1.52 (d, J=13.1Hz, 1H), 1.13 (d, J=13.4Hz, 1H). LC / MS (M+1): 482.2.

[0660] Step 8: Separation of atropisomers: (5M)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide and (5P)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0661]

[0662] The atropisomers were separated from 2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide by preparative HPLC (column (R,R) whelk-O1, 4.6*50 mm, 3.5 um, hexane+0.1% DEA:ethanol, 50:50).

[0663] First eluting isomer (Compound 119): 29 mg, RT = 1.1 min, ed = 97.9; 1H NMR (400 MHz, DMSO-d6): 7.94 (s, 1H), 7.58 (dd, J = 8.1, 1.5 Hz, 1H), 7.41-7.29 (m, 3H), 7.19 (ddd, J = 15.5, 7.2, 2.8 Hz, 4H), 4.62 (t, J = 16.3 Hz, 2H), 3.86 (s, 1H), 3.25-3. 15 (m, 1H), 3.11 (d, J = 15.7Hz, 1H), 2.66 (d, J = 15.4Hz, 1H), 2.01 (S, 3H), 1.77 (t, J = 1 1.3Hz, 1H), 1.62 (d, J=11.9Hz, 1H), 1.52 (d, J=12.9Hz, 1H), 1.13 (d, J=13.0Hz, 1H). LC / MS(M+1): 481.2, melting point: 114-115°C.

[0664] Second eluting isomer (Compound 120): 19 mg, RT = 6.9 min, ed = 98.5, LC / MS (M+1): 481.2, melting point: 121-123°C.

[0665] Compound 121: 6-amino-2-[(4S)-4-amino-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0666] Step 1: 6-amino-2-[(4S)-4-amino-4,6-dihydrospiro[cyclopenta[d][1,3]thiazol-5,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

[0667]

[0668] A mixture of (4S)-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4-piperidin]-4-amine (Intermediate 16, 100 mg, 0.430 mmol), 6-amino-5-(2,3-dichlorophenyl)-2-methylsulfonylpyrimidine-4-carbonitrile (220 mg, 0.439 mmol) and K2CO3 (10 mg, 0.069 mmol) in ACN (4.0 mL) was stirred under nitrogen atmosphere at room temperature for 12 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate, 1:9) to give the title compound as a yellow solid (60 mg, 24%). LC / MS (M+1): 472.1.

[0669] Step 2: 6-amino-2-[(4S)-4-amino-4,6-dihydrospiro[cyclopenta[d][1,3]thiazol-5,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0670]

[0671] A solution of 6-amino-2-[(4S)-4-amino-4,6-dihydrospiro[cyclopenta[d][1,3]thiazol-5,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile (40 mg, 0.070 mmol), NaOH (73 mg, 1.73 mmol) in water (1 mL) and ethanol (1 mL) was stirred at 50°C for 1 hour. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (column XBridge, Prep C18 OBD, 19x150 mm, 5 um, water + 10 mmol NH4HCO3): ACN; 8 min gradient: 70:30 to 50:50) to give the title compound as a cream solid (5.6 mg, 16%). NMR (400MHz, DMSO-d6): 8.96 (S, 1H), 7.74 (S, 1H), 7.52 (dd, J=8.0, 1.5Hz, 1H), 7.2 9 (t, J=7.8Hz, 1H), 7.16 (S, 1H), 7.11 (d, J=7.5Hz, 1H), 6.11 (S, 1H), 4.44 (dd, J=21. 6, 14.3Hz, 2H), 3.98 (S, 1H), 3.25? 3.17 (m, 2H), 2.87 (d, J=15.3Hz, 1H), 2.75 (d, J=1 5.3Hz, 1H), 1.82-1.71 (m, 1H), 1.68-1.50 (m, 3H), 1.24 (S, 1H), LC / MS (M+1): 490.1.

[0672] Compound 122: 2-((S)-3-amino-3H-spiro[benzofuran-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0673] Step 1: 6-methyl-2-[3-oxospiro[1-benzofuran-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile

[0674]

[0675] A solution of 2-chloro-6-methylpyrimidine-4-carbonitrile (100 mg, 0.619 mmol), spiro[1-benzofuran-2,4-piperidin]-3-one (140 mg, 0.682 mmol) and DIEA (0.215 mL, 1.24 mmol, 2 equiv) in ACN (4.0 mL) was stirred at 80° C. for 2 hours. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1:1) to give the title compound as a yellow solid (120 mg, 54%). LC / MS (M+1): 321.

[0676] Step 2: 5-Bromo-6-methyl-2-[3-oxospiro[1-benzofuran-2,4′-piperidinyl]-1′-yl]pyrimidine-4-carbonitrile

[0677]

[0678] NBS (105 mg, 0.563 mmol) was added to a solution of 6-methyl-2-[3-oxospiro[1-benzofuran-2,4-piperidine]-1-yl]pyrimidine-4-carbonitrile (100 mg, 0.281 mmol) in DMF (5.0 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours. The mixture was then diluted with water (40 mL) and extracted with ethyl acetate (3x45 mL). The organic layers were combined, washed with brine (1x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (110 mg, 85% yield). LC / MS (M+1): 399, 401.

[0679] Step 3: 5-(2,3-dichlorophenyl)-6-methyl-2-{3-oxo-3H-spiro[1-benzofuran-2,4′-piperidine]-1′-yl}pyrimidine-4-carbonitrile

[0680]

[0681] A solution of 5-bromo-6-methyl-2-[3-oxospiro[1-benzofuran-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile (100 mg, 0.216 mmol), 2,3-dichlorophenylboronic acid (87 mg, 0.432 mmol), K3PO4 (145 mg, 0.648 mmol), XPhos (22 mg, 0.043 mmol) and XPhos Pd G3 (39 mg, 0.043 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 100°C for 2 hours. The resulting mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with DCM (5 mL), filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate, 1:1) to give the title compound as a yellow solid (95 mg, 78%). LC / MS (M+1): 465.

[0682] Step 4: (S)-N-((E)-1′-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-ylidene)-2-methylpropane-2-sulfenamide

[0683]

[0684] A mixture of 5-(2,3-dichlorophenyl)-6-methyl-2-[3-oxospiro[1-benzofuran-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile (90 mg, 0.18 mmol), (S)-2-methylpropane-2-sulfinamide (138 mg, 1.08 mmol) and Ti(OEt)4 (1 mL) was stirred at 90°C for 4 hours. The resulting mixture was cooled to room temperature, poured into a mixture of water (20 mL) and ethyl acetate (20 mL) and filtered. The two layers were separated from the filtrate and the aqueous phase was extracted with ethyl acetate (3x20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by flash chromatography on silica gel (petroleum ether: ethyl acetate, 1:1) as a cream solid (180 mg, 100% yield). LC / MS (M+1): 568.2.

[0685] Step 5: 2-((S)-3-((tert-Butylthio)amino)-3H-spiro[benzofuran-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0686]

[0687] Maintaining at -50 ° C and nitrogen atmosphere, NaBH4 (31 mg, 0.782 mmol) was added to a solution of (S)-N-[1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]spiro[1-benzofuran-2,4-piperidin]-3-ylidene]-2-methylpropane-2-sulfinamide (160 mg, 0.156 mmol) in THF (4.0 mL) and H2O (1.0 mL). The resulting mixture was stirred at 25 ° C for 1 hour. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3x10 mL). The organic layers were combined, washed with brine (1x30 mL), dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow solid (130 mg, 94% yield). LC / MS (M+1): 554, 556.

[0688] Step 6: 2-((S)-3-((tert-butylthio)amino)-3H-spiro[benzofuran-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0689]

[0690] A mixture of (S)-N-[(3S)-1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3H-spiro[1-benzofuran-2,4-piperidin]-3-yl]-2-methylpropane-2-sulfinamide (130 mg, 0.142 mmol), aqueous NaOH solution (1.5 mL, 2 M) and ethanol (3.0 mL) was stirred at 70 °C for 1 hour. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residual aqueous layer was extracted with ethyl acetate (3x5 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated, and purified by flash chromatography on silica gel (petroleum ether:ethyl acetate, 1:1) to obtain the title compound as a yellow solid (120 mg, 94% yield). LC / MS (M+1): 572, 574.

[0691] Step 7: 2-((S)-3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0692]

[0693] A mixture of 5-(2,3-dichlorophenyl)-6-methyl-2-[(3S)-3-[[(S)-2-methylpropane-2-sulfinyl]amino]-3H-spiro[1-benzofuran-2,4-piperidin]-1-yl]pyrimidine-4-carboxamide (70 mg, 0.113 mmol) and HCl / 1,4-dioxane (7 mL, 4M solution) was stirred at 25°C for 1 hour. The resulting mixture was concentrated in vacuo and purified by reverse phase chromatography (column: C18 silica gel; water + 10 mmol / L NH4HCO3:ACN, 40 min gradient: 0% to 70%) to give the title compound as a cream solid (45.7 mg, 84%) 1 H-NMR (400MHz, DMSO-d6): 8.00 (brS, 1H), 7.59 (dd, J=8.0, 1.2Hz, 1H), 7.41-7.33 (m, 3H), 7.22-7.14 (m, 2H), 6.88 (t, J =7.2Hz, 1H), 6.80 (d, J = 7.6Hz, 1H), 4.68-4.57 (m, 2H), 4.13 (S, 1H), 3.49-3.33 (m, 2H), 2.03 (S, 3H), 1.94-1.70 (m, 4H). LC / MS (M+1): m / z=484.1.

[0694] Compound 123: 6-amino-2-((R)-3-amino-3H-spiro[benzofuran-2,4′-piperidinyl]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide dihydrochloride

[0695] Step 1: 6-amino-2-[(3S)-3-amino-3H-spiro[1-benzofuran-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

[0696]

[0697] A solution of 6-amino-5-(2,3-dichlorophenyl)-2-methanesulfonylpyrimidine-4-carbonitrile (192 mg, 0.492 mmol), (3R)-3H-spiro[1-benzofuran-2,4′-piperidine]-3-amine (Intermediate 14, 204 mg, 0.985 mmol) and KCO (143 mg, 0.985 mmol) in DMF (10 mL) was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (DCM: methanol, 10: 1) gave the title compound as a yellow solid (100 mg, 29% yield). LC / MS: 467.

[0698] Step 2: 6-amino-2-((R)-3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide dihydrochloride

[0699]

[0700] A mixture of 6-amino-2-[(3R)-3-amino-3H-spiro[1-benzofuran-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile (30 mg, 0.043 mmol), aqueous NaOH solution (0.5 mL, 2 M) and ethanol (0.50 mL) was stirred at 70° C. for 30 minutes. The resulting mixture was cooled to room temperature and purified by reverse phase chromatography (column: C18 silica gel; water + 0.05% HCl:CH3CN, 40 min gradient: 0% to 70%) to give the title compound as a cream solid (6.6 mg, 26%). 1H-NMR (400MHz, DMSO-d6): 7.78 (S, 1H), 7.52 (dd, J=8.0, 1.6Hz, 1H), 7.33-7.27 ( m, 2H), 7.18-7.10 (m, 3H), 6.86 (t, J=7.6Hz, 1H), 6.78 (d, J=8.0Hz, 1H), 6.16 (br S, 2H), 4.57-4.47 (m, 2H), 4.08 (S, 1H), 3.25-3.20 (m, 2H), 1.90-1.80 (m, 1H), 1.78-1.68 (m, 3H), LC / MS (M+1): 485.2.

[0701] Compounds 124, 125, 126, 127: (4M)-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide, (4M)-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide pyrimidine-4-carboxamide, (4P)-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide, (4P)-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide`

[0702] Step 1: 2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

[0703]

[0704] A solution of 2-chloro-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile (1.10 g, 3.65 mmol), 3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-3-amine (Intermediate 15, 1.15 g, 5.47 mmol) and DIEA (1.81 mL, 11.0 mmol) in ACN (12 mL) was stirred at 80° C. for 0.5 h. The resulting mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (petroleum ether:ethyl acetate, 1:1) to afford the title compound as a yellow solid (1.4 g, 81%). LC / MS (M+1): 467.1.

[0705] Step 2: 2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

[0706]

[0707] A mixture of 2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile (0.80 g, 1.70 mmol), NaOH (0.16 g, 3.80 mmol), ethanol (4 mL) and H2O (4 mL) was stirred at 70° C. for 0.5 h. The mixture was cooled to room temperature, and 6 M HCl was added to neutralize the mixture to pH 7. The resulting mixture was concentrated under reduced pressure and purified by reverse phase chromatography (column: C18 silica gel; water + containing 10 mmol / L NH4HCO3:ACN, 30 min gradient: 10% to 50%) to give 2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide (700 mg, 79%) as a white solid. LC / MS (M+1): 485.

[0708] Step 3: Separation of isomers

[0709]

[0710] The first separation was carried out by preparation (column CHIRALPAK IC, 3x25cm, 5um, hexane+8mmol / LNH3.methanol:ethanol; 50%) to obtain two fractions: fraction A (130mg) (RT: 9.6min) and fraction B (300mg) (RT: 14.64min).

[0711] The isomers were separated from fraction A by preparative HPLC (column CHIRALPAK IA, 3 x 25 cm, 5 um, MTBE + 10 mM NH3-methanol:ethanol, 20%).

[0712] First eluting isomer (124): 56mg, RT: 11min, 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 2H), 7.72 (d, J = 7.2, 1H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.43-7.33 (m, 2H), 7.21 (dd, J = 8.0, 1.6 Hz, 1H), 6.92 (dd, J = 7.2, 5.2 Hz, 1H), 4.71-4.61 (m, 2H), 4.14 (s, 1H), 3.51-3.39 (m, 2H), 2.20 (brS, 2H), 2.03 (s, 3H), 1.94-1.77 (m, 4H); LC / MS (M+1): 485.1; RT = 1.82 min (analytical column - chiral pack IA, MtBE + 0.1% DEA: ethanol, 80: 20), purity: 100%.

[0713] Second eluting isomer (125) : 60mg, RT: 12.9min, 1 H NMR (400 MHz, DMSO-d6): 8.01-8.00 (m, 2H), 7.72 (d, J = 6.8 Hz, 1H), 7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.40-7.34 (m, 2H), 7.22 (dd, J = 7.6, 1.6 Hz, 1H), 6.92 (dd, J = 7.2, 5.2 Hz, 1H), 4.72-4.61 (m, 2H), 4.14 (s, 1H), 3.51-3.39 (m, 2H), 2.20 (br S, 2H), 2.03 (s, 3H), 1.96-1.76 (m, 4H); LC / MS (M+1): 485.1; RT = 2.26 min (analytical column - chiral pack IA, MtBE + 0.1% DEA: ethanol, 80: 20); purity: 99.5%.

[0714] The isomers were separated from fraction B by preparative HPLC (CHIRALPAK ID, 3x25 cm, 5 um, MTBE+10 mM NH3-methanol:ethanol, 15%).

[0715] First eluting isomer (126): 92mg, RT: 12.0min; 1H NMR (400MHz, DMSO-d6): 8.01-8.00 (m, 2H), 7.72 (d, J=6.4, 1H), 7.59 (dd, J=8.0, 1. 6Hz, 1H), 7.41-7.34 (m, 2H), 7.22 (dd, J=7.6, 1.6Hz, 1H), 6.91 (dd, J=7.2, 5.2Hz, 1H ), 4.72-4.61 (m, 2H), 4.14 (s, 1H), 3.49-3.39 (m, 2H), 2.15 (brS, 2H), 2.03 (s, 3H), 1.93-1.77 (m, 4H), RT = 2.33 min (analytical column - chiral pack AD, MtBE + 0.1% DEA: ethanol, 85: 15); purity: 100%.

[0716] Second eluting isomer (127): 111mg, RT: 15.5min, ed=99.1%, 1 H NMR (400 MHz, DMSO-d6): 8.01-8.00 (m, 2H), 7.71 (d, J = 6.8 Hz, 1H), 7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.40-7.34 (m, 2H), 7.22 (dd, J = 7.6, 1.2 Hz, 1H), 6.92 (dd, J = 6.8, 4.8 Hz, 1H), 4.71-4.61 (m, 2H), 4.14 (s, 1H), 3.49-3.39 (m, 2H), 2.19 (br S, 2H), 2.03 (s, 3H), 1.91-1.77 (m, 4H); LC / MS (M+1): 485.1; RT = 3.17 min (analytical column Chiralpak ID, MtB + 0.1% DEA: ethanol, 85: 15). Purity: 99.1.

[0717] Compounds 128, 129, 130, 131: (4P)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide, (4P)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide )pyrimidine-4-carboxamide, (4M)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (4M)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0718] Step 1: 6-amino-2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

[0719]

[0720] A solution of DIEA (1.06 mL, 6.13 mmol, 2.00 equiv), 6-amino-5-(2,3-dichlorophenyl)-2-methanesulfonylpyrimidine-4-carbonitrile (Intermediate 4, 1.04 g, 3.06 mmol) and 3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-3-amine (0.84 g, 3.89 mmol) in ethanol (12 mL) was stirred at 60° C. for 4 hours. The resulting mixture was concentrated in vacuo and purified by flash chromatography on silica gel (petroleum ether:ethyl acetate, 1:9) to afford the title compound as a yellow solid (900 mg, 47% yield). LC / MS (M+1): 468.

[0721] Step 2: 6-amino-2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

[0722] The title compound was prepared using 6-amino-2-[3-amino-3H-spiro[furano[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile (0.90 g, 1.47 mmol) as starting material according to the procedure described in step 2 of compound 124-127 as a cream solid (600 mg, 83%). LC / MS (M+1); 486.

[0723] Step 3: Separation of isomers

[0724]

[0725] The first separation was carried out by preparative HPLC (column: CHIRALPAK IA, 3x25 cm, 5 um; MTBE+10 mM NH3-methanol):ethanol, 15%) to obtain three fractions:

[0726] First elution fraction: 150 mg mixture of two isomers.

[0727] Second elution fraction (128): White solid, 68 mg, RT = 7.22 min, 1 H NMR (400MHz, DMSO-d6): 8.00 (dd, J=4.8, 1.2Hz, 1H), 7.78 (S, 1H), 7.71 (d, J=6.8Hz, 1H), 7.52 (dd, J=8.0, 1.2 Hz, 1H), 7.29 (t, J=7.6Hz, 1H), 7.18 (S, 1H), 7.12 (dd, J=7.6, 1.6Hz, 1H), 6.91 (dd, J=7.2, 5.2Hz, 1H), 6.17 (br S, 2H), 4.58-4.52 (m, 2H), 4.13 (S, 1H), 3.40-3.31 (m, 2H), 2.32 (br S, 2H), 1.95-1.85 (m, 1H), 1.79-1.72 (m, 3H). RT (analytical column-chiral pack IA, MtBE+0.1% DEA: ethanol=85:15)=1.98 min; purity: 95.1%.

[0728] The third elution fraction (129): White solid, 62 mg, RT = 9.57 min, 1H NMR (400MHz, DMSO-d6) δ8.00 (dd, J=4.8, 1.2Hz, 1H), 7.78 (S, 1H), 7.70 (d, J=6.8Hz , 1H), 7.52 (dd, J=8.0, 1.2Hz, 1H), 7.29 (t, J=8.0Hz, 1H), 7.18 (S, 1H), 7.12 (dd, J= 7.6, 1.6 Hz, 1H), 6.91 (dd, J = 7.2, 5.2 Hz, 1H), 6.17 (brS, 2H), 4.58-4.51 (m, 2H), 4.12 (s, 1H), 3.40-3.31 (m, 2H), 2.32 (brS, 1H), 1.95-1.85 (m, 1H), 1.79-1.72 (m, 3H). RT (analytical column-chiral pack IA, MtBE+0.1% DEA:ethanol=85:15)=2.45 min; purity: 92.7%.

[0729] Isomers were separated from the first eluted fraction by preparative HPL (CHIRALPAK IA, 3x25cm, 5um:Hex:DCM=3:1+10mM NH3-methanol):ethanol, 15%).

[0730] First eluting isomer (130): White solid, 46 mg, RT = 7.22 min, 1 H NMR (400MHz, DMSO-d6) δ7.99 (d, J=5.6Hz, 1H), 7.78 (S, 1H), 7.70 (d, J=6.8Hz, 1H), 7.52 (dd, J=8.0, 1.6Hz, 1H), 7.29 (t, J=8.0Hz, 1H), 7.18 (S, 1H), 7.11 (dd, J=7.0, 1.6Hz, 1H), 6.90 (dd, J=7.2, 5.2Hz, 1H), 6.17 (br S, 1H), 4.62-4.51 (m, 2H), 4.12 (S, 1H), 3.39-3.31 (m, 2H), 1.95-1.86 (m, 1H), 1.79-1.74 (m, 3H). RT = 2.81 min (analytical column - chiral pack IA, Hex: DCM = 3: 1 + 0.1% DEA: ethanol = 85: 15); purity: 92.3%.

[0731] Second eluting isomer (131): White solid, 39 mg, Rt = 13.8 min, 1H NMR (400MHz, DMSO-d6): 7.99 (d, J=3.6Hz, 1H), 7.78 (S, 1H), 7.70 (d, J=7.6Hz, 1 H), 7.52 (dd, J=8.0, 1.2Hz, 1H), 7.29 (t, J=8.0Hz, 1H), 7.18 (S, 1H), 7.11 (d, J= 7.6, 1H), 6.90 (dd, J=7.2, 5.2 Hz, 1H), 6.17 (brS, 1H), 4.62-4.51 (m, 2H), 4.11 (s, 1H), 3.35-3.31 (m, 2H), 2.10 (brS, 1H), 1.95-1.86 (m, 1H), 1.78-1.71 (m, 3H). RT=2.42 min (analytical column-chiral pack IA, Hex: DCM=3:1+0.1% DEA: ethanol=85:15); purity: 99.9%.

[0732] The compounds in Table 3 have been prepared following similar synthetic routes as described above:

[0733] Table 3

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746] Example 3: Testing the inhibitory activity of the compounds of the present invention against SHP2 and ERK12

[0747] SHP2 biochemical assay:

[0748] The inhibition of SHP2 by the compounds of the invention was monitored using the surrogate substrate DiFMUP after the protein was activated by a peptide with two appropriately spaced phosphotyrosines. Full-length SHP2 protein (recombinant human SHP-2, E. coli derived Ser2Arg593, N-terminal 6His tag from R&D systems; 0.0.24 nM) was incubated with the activation peptide IRSI_2pY (New England Peptide, 140 nM) and DiFMUP (Molecular Probes, 80 uM)) in the presence of compound (10 concentration ranges, highest concentration 50 μM) in buffer (HEPES pH 7.2 60 mM, DDT 5 mM, KCl 75 mM, NaCl 75 mM, EDTA 1 mM, Tween 20 0.05%) at room temperature for 60 minutes. The DiFMU product generated by the activation of SHP2 was monitored by measuring fluorescence using a PerkinElmer Envision plate reader. Inhibitor dose response curves were analyzed using Genedata Screener. IC of the compounds of the present invention 50 The ranges are shown in Table 3 below.

[0749] Cellular Assay of p-Erk in MDA-MB-468 and KYSE520:

[0750] The effects of SHP2 inhibitors on pERK levels were evaluated using the Mesoscale quantification platform with phosphorylation-specific antibodies. To measure changes in pERK levels using the mesoscale, 30,000 MDA-MB-468 and KYSE520 cells were seeded in 96-well tissue culture plates placed in a volume of 175 μl of culture medium. After incubation overnight at 37°C, various SHP2 inhibitors at different concentrations were added to each well, duplicate wells were kept on the plate and incubated with the compounds for 2 hours at 37°C and washed with ice-cold PBS buffer. The cells were then lysed in lysis buffer and processed and analyzed for p-ERK / ERK according to the manufacturer's instructions (Mesoscale discovery, cat No. K15107D-3). IC of the compounds of the invention 50 The ranges are shown in Table 4 below.

[0751] Table 4

[0752]

[0753]

[0754]

[0755]

[0756]

[0757] Example 4: In vitro safety - testing selectivity for hErg

[0758] Inhibition of ion channel hErg (or Kv11.1) currents can lead to QT interval prolongation, which can cause a potentially fatal ventricular tachyarrhythmia called torsade-de-points. This is one of the leading causes of cardiotoxicity, and hErg channel activity is often assessed early in the drug development process to mitigate cardiotoxicity risk.

[0759] hERG ion channel activity was assessed in a stable Kv11.1 (hERG) transfected human embryonic kidney cell line (HEK293) using the patch clamp technique. Whole-cell recordings were performed using the automatic patch clamp device PatchlinerTM from Nanion Technologies in Munich, as recommended by the manufacturer. Test compounds or reference quinidine at different concentrations were applied to whole-cell suspensions, and currents were measured using a pulse mode with a fixed amplitude. The effect on Kv11.1 (hERG) ion channel activity was determined based on the change in tail current intensity and Kv11.1 (hERG) ion channel activity between the control value (defined as 100%) and the test compound, and expressed as a percentage change in the COI control value.

[0760] Table 5 - In vitro safety profile

[0761]

[0762]

[0763] result

[0764] Compared with the known SHP2 inhibitors SHP-099 and RMC-4550, the compounds of the present invention have better hErg activity (Ki value in patch clamp assay) and cell activity (IC 50 This should translate into a reduced potential for cardiotoxicity when the drug is administered to subjects.

[0765] Example 5: Testing the pharmacokinetic properties of the compounds of the invention in mice

[0766] Female CD1 mice (n=3) received a single oral administration (by gavage) or intravenous (bolus) injection of the compound. Dosing vehicle was generally administered orally or intravenously, as 0.5% Methocel K4M / 0.25% Tween 20, 0.1M, pH 3.0 in sodium citrate buffer for oral administration; as 10% Kolliphor HS15 solution, 0.01M, pH 4.5 in sodium acetate buffer for intravenous administration. Serial blood samples were obtained from the animals under the tongue under isoflurane inhalation at 0.083 (iv), 0.25, 0.5, 1, 2, 4, 6 and 24 hours and further processed to obtain plasma. Samples were subjected to protein precipitation and analysis by LC / MS / MS.

[0767] Table 6 - PK data in mice

[0768]

[0769] result

[0770] In mouse PK, compared with the reference compound SHP-099, the compounds of the present invention (Nos. 27 and 95) showed lower clearance and higher exposure.

[0771] Example 6: Testing the inhibitory activity of the compounds of the present invention against the SHP2 active mutant E76K in the presence and absence of an activating peptide

[0772] Using the same conditions as described in Example 3, a series of compounds were tested in a biochemical assay using the auto-activating mutant protein SHP2 E76K with and without the addition of the activating peptide IRSI_2pY (New England Peptide, 140 nM).

[0773] Table 7

[0774]

[0775] *From LaRochelle JR et al., Nature comm., 2018, 9: 4508, 1-10.

[0776] Under conditions of strong SHP2 activation, the compounds of the invention retain potency in the nM range, whereas the known inhibitor SHP099 loses several logs of potency under similar conditions. This may be an advantage in treating cancers with strong activating SHP2 mutations.

[0777] Example 6: Activity in U937 cells

[0778] Selected compounds were tested in cytokine release assays using monocytes (U937) to test their anti-inflammatory properties. Cells were seeded in 96-well cell culture plates using serum-free medium. Cells were treated with the indicated concentrations of SHP-2 inhibitors for 30 minutes and then stimulated overnight with recombinant IL-6 (50 ng / mL). MCP-1 production in the culture supernatant was measured using an MCP-1 AlphaLISA kit (Perkin Elmer).

[0779] The mixture of compounds (117+118) inhibited the production of MCP-1 in U937 cells stimulated with IL-6. 50 =67nM (see Figure 1 ). This result indicates that the compounds of the invention should be useful for treating the hyperproliferative disorders associated with the immune system described herein.

[0780] Example 7: Injection bottle

[0781] A solution of 100 g of the compound of the present invention and 5 g of sodium dihydrogen phosphate in 3 L of redistilled water was adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, transferred to an injection bottle, lyophilized under aseptic conditions, and sealed under aseptic conditions. Each injection bottle contained 5 mg of the compound of the present invention.

[0782] Example 8: Solution Formulation

[0783] A solution was prepared from 1 g of the compound of the present invention, 9.38 g of NaH2PO4·2H2O, 28.48 g of Na2HPO4·12H2O and 0.1 g of benzalkonium chloride in 940 mL of redistilled water. The pH of the solution was adjusted to 6.8, and the solution was made up to 1 L and sterilized by radiation.

[0784] Example 9: Ampoule

[0785] A solution of 1 kg of the compound of the present invention in 60 L of redistilled water was sterile filtered, transferred into ampoules, lyophilized under aseptic conditions, and sealed under aseptic conditions. Each ampoule contained 10 mg of the compound of the present invention.

Claims

1. A compound according to the general formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1 is cyclohexyl or cyclopentyl, each of which is optionally substituted by 1 or 2 groups selected from the group consisting of -F, -NH2 and -CH2NH2, and X is -NH- or -N(Me)-; R2 is selected from phenyl, pyridine, indole, 2,1,3-benzoxadiazole and 1,3-benzodiazole, each of which is optionally and independently substituted with 1 to 3 groups selected from the following: -F, -Cl, -CF3, -OCH3 and -CH3; R3 is -H, -NH2, -OH, -Cl, -F, -Br or -CH3; Y is -N-; R4 and R5 are independently -H, -NH2, -OH, C1-C3 alkyl or C1-C3 hydroxyalkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from phenyl and pyridine, each of which is optionally and independently substituted with 1 to 3 groups selected from the following: -Cl, -F, -CF3 and -OCH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one of R4 and R5 is -H and the other is -OH.

4. The compound according to claim 1, which is represented by general formula (Ia): or a pharmaceutically acceptable salt thereof, wherein R6, R7 and R8 are each independently selected from -H, -F, -Cl, -CF3, -OCH3 and -CH3.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X-R1 is wherein A is the point of attachment to the pyrimidine ring.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is -NH- or -N(Me)-, wherein R1 is cyclopentyl substituted with one -CH2NH2 or cyclohexyl substituted with one -NH2.

7. The compound of claim 1, wherein R3 is -CH3.

8. The compound of claim 1, wherein R3 is -NH2.

9. The compound of claim 1, wherein R3 is -H.

10. The compound of claim 1, wherein R3 is -Cl.

11. A compound selected from the following group: 2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxamide; 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(3-chloro-phenyl)-pyrimidine-4-carboxylic acid amide; 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide; 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide; 6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro-[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-{9-amino-3-azabicyclo[3.3.1]nonan-3-yl}-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[(1R)-1-amino-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decane-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid methylamide; 6-amino-2-[6-amino-7-hydroxy-1-(propan-2-yl)-2-azaspiro[3.4]octan-2-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[8-(aminomethyl)-6-azaspiro[3.4]octan-6-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[3-(aminomethyl)-8-azabicyclo[3.2.1]octan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11s)-11-amino-1,7-dimethyl-9-azabicyclo[5.3.1]undec-9-yl]pyrimidine-4-carboxamide; 6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11r)-11-amino-1,7-dimethyl-9-azabicyclo[5.3.1]undec-9-yl]pyrimidine-4-carboxamide; 2-(4-Amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-6-hydroxy-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-4-methyl-piperidin-1-yl)-6-chloro-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide; 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid (2-hydroxy-ethyl)-amide; 2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-4-methyl-piperidin-1-yl)-6-chloro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide; 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydroxyamide; 6-amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydrazide; 2-(4-Amino-4-methyl-piperidin-1-yl)-6-fluoro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide; 6-amino-2-[4-(aminomethyl)-8-oxa-2-azaspiro[4.5]decan-2-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 2-[3a-(Aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 2-(4-Amino-4-methyl-piperidin-1-yl)-5-(3-fluoro-phenyl)-6-hydroxy-pyrimidine-4-carboxylic acid amide; (4P)-6-amino-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (4M)-6-amino-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 2-(3-Amino-cyclohexylamino)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 6-amino-2-[4-amino-4-(hydroxymethyl)piperidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (4M)-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (4P)-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; 2-[(4-Amino-cyclohexyl)-methyl-amino]-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(7-Amino-3-oxa-9-aza-bicyclo[3.3.1]non-9-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 6-amino-2-[8-(aminomethyl)-2-oxa-6-azaspiro[3.4]octan-6-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 2-((R)-6-Amino-2-aza-spiro[4.4]non-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(3-Aminomethyl-cyclopentylamino)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-((S)-6-Amino-2-aza-spiro[4.4]non-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 6-amino-2-{4-amino-1-oxa-9-azaspiro[5.5]undec-9-yl}-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[4-(3-aminooxan-2-yl)piperidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[3-(aminomethyl)-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[4-(aminomethyl)-4-methylpiperidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 2-(4-Amino-hexahydro-cyclopenta[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide hydrochloride; 2-(2-Aminomethyl-cyclopentylamino)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(3-Aminomethyl-3-fluoro-azetidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-4-methyl-azepan-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(2-Aminomethyl-azetidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; (4P)-2-[(3R)-3-(Aminomethyl)morpholin-4-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide hydrochloride; (4P)-2-[(3S)-3-(Aminomethyl)morpholin-4-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide hydrochloride; 6-amino-2-(4-aminoazepan-1-yl)-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; 6-amino-2-(4-amino-octahydro-1H-isoindol-2-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[(3R,4R)-3-(aminomethyl)-4-phenylpyrrolidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-({4-azaspiro[bicyclo[2.2.2]octane-2,2′-oxane]-4′-yl}amino)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-(4-amino-4-propylpiperidin-1-yl)-5-(2,3-dichloro-phenyl)pyrimidine-4-carboxamide; 6-amino-2-[3-(aminomethyl)-3-hydroxyazetidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[3-(aminomethyl)-3-methylazetidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 5-(2,3-Dichloro-phenyl)-6-methyl-2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidine-4-carboxylic acid amide; 2-(3-Amino-3-hydroxymethyl-azetidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(1-Amino-5-aza-spiro[2.4]hept-5-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-4-methyl-piperidin-1-yl)-5-(1H-benzimidazol-4-yl)-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-4-methyl-piperidin-1-yl)-5-benzo[1,2,5]-oxadiazol-4-yl-pyrimidine-4-carboxylic acid amide; 6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(7-chloro-1H-indazol-6-yl)-pyrimidine-4-carboxylic acid amide; 5-(2,3-Dichloro-phenyl)-6-methyl-2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidine-4-carboxylic acid amide; (5M)-6-amino-5-(2,3-dichlorophenyl)-2-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}-pyrimidine-4-carboxamide; 6-amino-2-{[(1R,2S)-2-aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5P)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5M)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; 2-(3,9-Diaza-bicyclo[4.2.1]-non-3-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 6-amino-2-(3-aminoazetidin-1-yl)-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; 6-amino-2-[(1R,5S,6R)-6-(aminomethyl)-3-azabicyclo-[3.1.0]hexan-3-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 6-amino-2-[2-(aminomethyl)-azetidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 2-((3aR,4R,6aS)-4-amino-hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-((3aS,6aS)-4-amino-hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-((3aS,4S,6aR)-4-amino-hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-((3aS,4R,6aR)-4-amino-hexahydro-cyclopenta[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-((3aR,6aR)-4-amino-hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-((3aR,4S,6aS)-4-Amino-hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; (4M)-2-(4-amino-4-methylpiperidin-1-yl)-6-chloro-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (4P)-2-(4-amino-4-methylpiperidin-1-yl)-6-chloro-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; 2-((3R,4S)-3-Amino-4-hydroxy-pyrrolidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-pyridin-4-yl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-4-methyl-piperidin-1-yl)-5-(2-chloro-4-fluoro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-4-methyl-piperidin-1-yl)-5-(4-chloro-pyridin-3-yl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-((3S,4S)-3-Amino-4-hydroxy-pyrrolidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; 2-(4-Amino-4-methyl-piperidin-1-yl)-6-methyl-5-pyridin-4-yl-pyrimidine-4-carboxylic acid amide; (4M)-2-{[(1S,3R)-3-aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (4M)-2-{[(1R,3S)-3-aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (4P)-2-{[(1R,3S)-3-aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (4P)-2-{[(1S,3R)-3-aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; 6-amino-2-(4-amino-4-methyl-azepan-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-4-methyl-piperidin-1-yl)-5-(1H-indol-3-yl)-6-methyl-pyrimidine-4-carboxylic acid amide; 2-(4-Amino-cyclohexyl-amino)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; (5M)-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichloro-phenyl)-6-methylpyrimidine-4-carboxamide; (5P)-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichloro-phenyl)-6-methylpyrimidine-4-carboxamide; (5M)-2-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]-decane-8-yl]-5-(2,3-dichloro-phenyl)-6-methylpyrimidine-4-carboxamide; (5P)-2-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]-decane-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (5P)-2-[(3aR,6aS)-3a-(Aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5M)-2-[(3aR,6aS)-3a-(Aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5P)-2-[(3aR,7aS)-3a-(Aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (5P)-2-[(3aS,7aR)-3a-(Aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (5M)-2-[(3aR,7aS)-3a-(Aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (5M)-2-[(3aS,7aR)-3a-(Aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (5P)-2-[(3aS,6aR)-3a-(Aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5M)-2-[(3aS,6aR)-3a-(Aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5P)-6-amino-2-[4-amino-4-(difluoromethyl)piperidin-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5M)-6-amino-2-[4-amino-4-(difluoromethyl)piperidin-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5P)-6-amino-2-[(4S)-4-amino-4-methylazepan-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5P)-6-amino-2-[(4R)-4-amino-4-methylazepan-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; (5M)-6-amino-2-[(4S)-4-amino-4-methylazepan-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamide; 2-(4-Amino-4-methyl-piperidin-1-yl)-5-(2-chloro-3-trifluoromethyl-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide; 6-Amino-2-[(4-amino-cyclohexyl)-methyl-amino]-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide; (5M)-2-[(1R)-1-amino-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (5P)-2-[(1R)-1-amino-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (4M)-2-(4-amino-4-methylpiperidin-1-yl)-5-(2-chloro-4-fluoro-3-methoxyphenyl)-6-methylpyrimidine-4-carboxamide; (4P)-2-(4-amino-4-methylpiperidin-1-yl)-5-(2-chloro-4-fluoro-3-methoxyphenyl)-6-methylpyrimidine-4-carboxamide; (5P)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidinyl]-1'-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (5M)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (5M)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (5P)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; 6-amino-2-[(4S)-4-amino-4,6-dihydrospiro[cyclopenta[d][1,3]thiazol-5,4'-piperidin]-1'-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; 2-[(3R)-3-amino-3H-spiro[1-benzofuran-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; 6-amino-2-[(3R)-3-amino-3H-spiro[1-benzofuran-2,4′-piperidinyl]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (4M)-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (4M)-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (4P)-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (4P)-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide; (4P)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (4P)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; (4M)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidin]-1'-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; and (4M)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable adjuvant.

13. A pharmaceutical composition comprising the compound according to claim 1, and a pharmaceutically acceptable carrier and / or excipient.

Images