CCR4 antagonists

Abstract

To provide CCR4 antagonists.SOLUTION: Compounds are provided having formula (I), wherein the groups / letters R1a, R1b, m, R2, R3, R4, X, Y, A, B, n, q, L and Q have the meanings provided herein. The compounds are useful as CCR4 antagonists and are useful for treating diseases and conditions modulated by CCR4 activity. Also provided are compositions that contain the compounds of formula (I), and methods for treating diseases and conditions modulated by CCR4 activity. Still further, the compounds provided herein are useful in methods of screening for additional CCR4-modulatory compounds.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 332,331, filed April 19, 2022, and U.S. Provisional Patent Application No. 63 / 380,126, filed October 19, 2022, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT Not applicable

[0003] Reference to a "Sequence Listing," table, or computer program listing appendix submitted on a compact disc Not applicable [Background technology]

[0004] Chemokines are chemotactic cytokines released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils, and neutrophils to sites of inflammation (reviewed in (Non-Patent Document 1), (Non-Patent Document 2), and (Non-Patent Document 3)). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responding cells, including changes in cell shape, transient increases in intracellular free calcium ion ([Ca2+]) concentrations, granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes), and the respiratory burst associated with leukocyte activation. Thus, chemokines are early triggers of the inflammatory response, causing the release, chemotaxis, and extravasation of inflammatory mediators to sites of infection or inflammation.

[0005] Chemokines are classified into two major classes, CXC (alpha) and CC (beta), depending on whether the first two cysteines are separated by a single amino acid (CXC) or adjacent (CC). Alpha-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2), and melanoma growth stimulating activity protein (MGSA), are primarily chemotactic for neutrophils, whereas beta-chemokines, such as RANTES, MIP-1a, MIP-1b, monocyte chemoattractant protein-1 (MCP-1), MCP-2, MCP-3, and eotaxin, are chemotactic for macrophages, T cells, eosinophils, and basophils (Non-Patent Document 4). Chemokines bind to specific cell surface receptors, termed "chemokine receptors," which belong to a family of G protein-coupled seven-transmembrane domain proteins (reviewed in Non-Patent Document 5).

[0006] Upon binding to their cognate ligands, chemokine receptors transmit intracellular signals via associated trimeric G proteins, resulting in a rapid increase in intracellular calcium concentration. There are at least 11 human chemokine receptors that bind to or respond to beta-chemokines, and at least seven that bind to alpha-chemokines. Furthermore, CX3CR1 (fractalkine receptor) can bind fractalkine chemokines, which are distinguished by a sequence of three amino acids between the first two cysteines. Chemokine receptors have been implicated as important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune conditions such as rheumatoid arthritis and atherosclerosis.

[0007] CC chemokine receptor 4 (CCR4), first identified by Power et al. (Non-Patent Document 6), is a G protein-coupled receptor that binds to chemokines, including CCL22, also known as macrophage-derived chemokine (MDC; a CC chemokine that has been reported to be a chemoattractant for peripheral blood T cells, dendritic cells, and the Th2 subset of natural killer (NK) cells), and CCL17, also known as TARC (thymus- and activation-regulated chemokine), which is also produced by monocytes and dendritic cells.

[0008] The full-length human CCR4 protein (GenBank accession number X85740; SWISS-PROT accession number P51679) has been described (see, for example, (Non-Patent Document 7)) and has the sequence shown in SEQ ID NO: 1.

[0009] Although the overall distribution of CCR4 is unknown, the receptor is primarily expressed on peripheral blood T lymphocytes and is found on approximately 20% of adult peripheral blood effector / memory CD4+ T cells. CCR4 is involved in T lymphocyte homing to the skin and lungs (see, for example, (Non-Patent Document 8), (Non-Patent Document 9), (Non-Patent Document 10), and (Non-Patent Document 11)) and is found on almost all T cells with a skin-homing phenotype (CTLA+ T cells). In fact, CCR4 is highly expressed in cutaneous T-cell lymphoma, and targeting such cells with anti-CCR4 monoclonal antibodies has proven effective in killing these cancer cells (references).

[0010] More recently, CCR4 has been shown to play a key role in the interaction between cancer cells and the immune system. CCR4 is expressed by many regulatory T cells (Tregs), and its dysfunction prevents effector T cells from destroying cancer cells (ref). Furthermore, CCR4 likely plays a role in the entry of Treg cells into tumors, and blocking its function allows effector cells to destroy tumors.

[0011] Therefore, CCR4 may play an important role in leukocyte-mediated skin pathologies. Its role in Treg trafficking suggests that it may play an important role in immuno-oncology. It is also likely that CCR4 is expressed on several other cell types, possibly monocytes / macrophages and dendritic cells. Given the clinical importance of CCR4, identifying compounds that modulate CCR4 function is an attractive avenue for developing new therapeutic agents. Such compounds and methods for their use are provided herein. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Schall, Cytokine, 3:165-183 (1991) [Non-patent document 2] Schall, et al., Curr. Opin. Immunol. 6:865-873 (1994) [Non-patent document 3] Murphy, Rev. Immun., 12:593-633(1994)) [Non-patent document 4] Deng,et al.,Nature,381:661-666(1996) [Non-Patent Document 5] Horuk,Trends Pharm.Sci.,15:159-165(1994) [Non-patent document 6] Power et al. (1995) J. Biol. Chem. 270:19495-19500 [Non-Patent Document 7] Imai et al. (1998) J. Biol. Chem. 273:1764-1768 [Non-patent document 8] Campbell et al. (1999) Nature 400:776-780 [Non-Patent Document 9] Gonzalo et al. (1999) J. Immunol. 163:403-5 411 [Non-Patent Document 10] Lloyd et al.(2000)J.Exp.Med.191:265-273 [Non-Patent Document 11] Kawasaki et al.(2001)J.Immunol.166:2055-2062 [Non-Patent Document 12] Berge, SM, et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19. Summary of the Invention [Means for solving the problem]

[0013] In the present disclosure, compounds having formula (I) are provided: [ka] (In the formula, the group / letter R 1a , R 1b , m, R 2 , R 3 , R 4 , X, Y, A, B, n, q, L, and Q have the meanings provided in the detailed description. Compositions containing compounds of formula (I) and methods for treating diseases and conditions modulated by CCR4 activity are provided. Additionally, the compounds provided herein are useful in methods of screening for additional CCR4-modulating compounds. Disclosure Summary Formula (I): [ka] (wherein the group / letter R 1a , R 1b , m, R 2 , R 3 , R 4, X, Y, A, B, n, q, L and Q have the meanings provided herein. The compounds are useful as CCR4 antagonists and are useful in the treatment of diseases and conditions modulated by CCR4 activity. The present invention provides, for example, the following items. (Item 1) Compounds having formula (I): [ka] or a pharmaceutically acceptable salt thereof [wherein: R 1a is hydrogen, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -CN, C 1~4 Alkoxy, and C 1~4 haloalkoxy; m is an integer from 0 to 4; Each R 1b are independently halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -CN, C 1~4 Alkoxy, and C 1~4 haloalkoxy; R 2 H, -OR a , -N(R a )2, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl; R 3 is hydrogen, C 1~4 Alkyl, halogen, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 3~8 Cycloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Alkoxy-C 1~4 selected from the group consisting of alkyl, -C(O)NH, hydroxy, -NH, and CN; Each R 4is hydrogen, halogen, hydroxy, -CN, C 1~4 Alkoxy, C 1~4 Haloalkoxy, -NH2, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 3~8 selected from the group consisting of cycloalkyl, -SOMe, and -C(O)NH; n is an integer from 0 to 2; X and Y each independently represent N or C(R 4 ) and at least one of X and Y is N; [ka] is a single or double bond; A is C, N or C(R 5a ) (However, if A is N, [ka] is a single bond); B is N or C(R 5b ) and at least one of A and B is N; q is an integer from 0 to 4; Each R 5 independently, C 1~4 Alkyl, C 1~4 Alkoxy, -C(O)OH, halogen, hydroxy, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl, or two R 5 combine to form one or two carbon bridges between non-adjacent ring vertices; R 5a is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl; R 5b is hydrogen, C 1~4 Alkyl, and C 1~4 hydroxyalkyl; L is a bond, -O-, -C(O)-C 0~4 Alkylene-, -C 1~4 Alkylene -C(O)-, -C(O)N(R a )-C 0~4 Alkylene-, -S(O)2-C 0~4 Alkylene, and -N(R a )C(O)-C 0~4 alkylene-; Q is i) a ring having 1 to 3 heteroatom ring vertices selected from N, O, and S; and 0 to 4 R b 4- to 7-membered heterocyclyl substituted with; ii) 0 to 3 R b is replaced by C 1~8 alkyl; iii) A ring having 0 to 3 heteroatom ring vertices selected from N, O, and S, and 0 to 4 R b 7- to 11-membered spirocyclyl substituted with; and iv) a ring having 1 to 3 heteroatom ring vertices selected from N, O, and S, and 0 to 4 R b 5-6 membered heterocyclyl substituted with is a member selected from the group consisting of: Each R a are independently H, and C optionally substituted by OH or —C(O)OH. 1~4 selected from the group consisting of alkyl; Each R b are independently hydroxy, halogen, oxo, -C 0~4 Alkylene-N(R a )2, -CO2R a , C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, -C 1~4 Alkylene-CO2R a , -C 0~4alkylene-heteroaryl, wherein said heteroaryl has 5-6 ring members and 1-4 heteroatom ring vertices selected from N, O, and S, and said heteroaryl optionally contains 1-3 R c , optionally 1 to 3 R c C replaced by 0~4 Alkylene-C 3~8 Cycloalkyl, -C(O)-C 1~4 Alkyl, and -C 0~4 Alkylene-C(O)N(R a )2 is replaced); Each R c are independently halogen, C 1~4 Alkyl, C 1~4 haloalkyl, and —C(O)OH. (Item 2) Compounds having formula (I): [ka] or a pharmaceutically acceptable salt thereof [wherein: R 1a is hydrogen, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -CN, C 1~4 Alkoxy, and C 1~4 haloalkoxy; m is an integer from 0 to 4; Each R 1b are independently halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -CN, C 1~4 Alkoxy, and C 1~4 haloalkoxy; R 2 H, -OR a , -N(R a )2, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl; R 3 is C 1~4selected from the group consisting of alkyl, halogen, -CN, and CF3; Each R 4 is hydrogen, halogen, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 3~8 selected from the group consisting of cycloalkyl, -SOMe, and -C(O)NH; n is 0, 1 or 2; X and Y each independently represent N or C(R 4 ) and at least one of X and Y is N; [ka] is a single or double bond; A is C, N or C(R 5a ) and; B is N or C(R 5b ) and at least one of A and B is N; q is an integer from 0 to 4; Each R 5 independently, C 1~4 Alkyl, hydroxy, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl, or two R 5 combine to form one or two carbon bridges between non-adjacent ring vertices; R 5a is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl; R 5b is hydrogen or C 1~4 is alkyl; L is a bond, -C(O)-, -CH2C(O)-, -C(O)CH2-, -C(O)N(R a )- and -N(R a )C(O)—; Q is i) a ring having 1 to 3 heteroatom ring vertices selected from N, O, and S; and 0 to 4 R b 4- to 7-membered heterocyclyl substituted with; ii) 0 to 3 R b is replaced by C 1~8 Alkyl is a member selected from the group consisting of: Each R a are independently H and C 1~4 selected from the group consisting of alkyl; Each R b are independently hydroxy, oxo, -N(R a )2, -CO2R a , C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkylene-CO2R a , and C 1~4 Alkylene-N(R a )2]. (Item 3) The compound of any of the preceding items, wherein the first-recited portion of the L group is attached to the ring containing the B variable. (Item 4) The compound according to any of the preceding items, wherein the compound is optically enriched or optically pure. (Item 5) The compound of any of the preceding items, wherein n is 1. (Item 6) R 1a and each R 1b is a halogen. (Item 7) R 2 is H or CH3. (Item 8) R 4 is hydrogen. (Item 9) Q is 0 to 2 R bThe compound according to any of the preceding items, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl, substituted with (Item 10) Formula (Ia) [ka] or a pharmaceutically acceptable salt thereof. (Item 11) Q is 0 to 2 R b The compound according to any of the preceding items, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl, substituted with (Item 12) Q is 0 to 3 R b C is replaced by 1~8 The compound according to any of the preceding items, wherein the aryl group is alkyl. (Item 13) The compound of any of the preceding items, wherein L is selected from the group consisting of a bond, —C(O)—, —CHC(O)—, —C(O)CH—, —C(O)NH—, —NHC(O)—, —C(O)N(CH)—, and —N(CH)C(O)—. (Item 14) Formula (Ib) [ka] or a pharmaceutically acceptable salt thereof. (Item 15) Q is 0 to 2 R b The compound according to any of the preceding items, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl, substituted with (Item 16) Q is 0 to 3 R b C is replaced by 1~8 The compound according to any of the preceding items, wherein the aryl group is alkyl. (Item 17) Formula (Ic1), (Ic2) or (Ic3): [ka] or a pharmaceutically acceptable salt thereof. (Item 18) Q is 0 to 2 R b The compound according to any of the preceding items, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl, substituted with (Item 19) Q is 0 to 3 R b C is replaced by 1~8 The compound according to any of the preceding items, wherein the aryl group is alkyl. (Item 20) Formula (Id1), (Id2) or (Id3) [ka] or a pharmaceutically acceptable salt thereof. (Item 21) Q is 0 to 2 R b The compound according to any of the preceding items, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl, substituted with (Item 22) Q is 0 to 3 R b C is replaced by 1~8 The compound according to any of the preceding items, wherein the aryl group is alkyl. (Item 23) The compound of any of the preceding items, wherein L is selected from the group consisting of a bond, —C(O)—, —CHC(O)—, —C(O)CH—, —C(O)NH—, —NHC(O)—, —C(O)N(CH)—, and —N(CH)C(O)—. (Item 24) One of the following formulas: [ka] or a pharmaceutically acceptable salt thereof (wherein Each R b are independently selected from the group consisting of H, Cl, or F, provided that at least one R b is H) The compound of any of the preceding items, having (Item 25) Q is [ka] (In the formula, Each R b independently, C 1~4 selected from the group consisting of alkyl, F, Cl, OH, and —N(H)CH3; and R b1 is H, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~4 Haloalkyl, -C(O)-C 1~3 Alkyl, -C(O)-OC 1~3 Alkyl, -C 1~3 alkylene, selected from the group consisting of -C(O)OH, and -C(O)NH The compound according to any of the preceding items, selected from the group consisting of: (Item 26) One of the following formulas: [ka] or a pharmaceutically acceptable salt thereof (wherein Each R b independently, C 1~4 selected from the group consisting of alkyl, F, Cl, OH, and —N(H)CH3; and R b1 is H, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~4 Haloalkyl, -C(O)-C 1~3 Alkyl, -C(O)-OC 1~3 Alkyl, -C 1~3 alkylene, selected from the group consisting of -C(O)OH, and -C(O)NH The compound of any of the preceding items, having (Item 27) One of the following formulas: [ka] [ka] or a pharmaceutically acceptable salt thereof (wherein Each R b independently, C 1~4 selected from the group consisting of alkyl, F, Cl, and OH; and R 5 is selected from the group consisting of OH, F, and —OCH The compound of any of the preceding items, having (Item 28) R 3 is C 1~4 Alkyl, Cl, F, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, cyclopropyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~3 Alkylene-OC 1~3 The compound according to any of the preceding items, wherein the group is selected from the group consisting of alkyl, hydroxy, -NH2, and -CN. (Item 29) R 3 is selected from the group consisting of Cl, F, —OCH3, —OCH2CH3, OCH(CH3)2, OCF3, OCHF2, —C(CH2)2OH, and hydroxy. (Item 30) R 3 is selected from the group consisting of halogen, —CH3, —OCH3, —CH2OCH3, —OCH2CH3, —OC(H)(CH3)2, CN, —NH2, CF3, —OCF3, and —OCHF2. (Item 31) R 3 The compound according to any of the preceding items, wherein is Cl. (Item 32) A compound according to any of the preceding items selected from Table 1, or a pharmaceutically acceptable salt thereof. (Item 33) A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any of the preceding paragraphs. (Item 34) A composition for treating a disease or condition selected from the group consisting of (1) allergic diseases, (2) inflammatory bowel disease, (3) vaginitis, (4) psoriasis and inflammatory skin diseases, (5) vasculitis, (6) spondyloarthropathy, (7) scleroderma, (8) asthma and respiratory allergic diseases, (9) autoimmune diseases, (10) transplant rejection, (11) other diseases in which unwanted inflammatory responses need to be inhibited, and cancer, in a patient in need of such treatment, the composition comprising a compound according to any of the preceding paragraphs. (Item 35) The composition of any of the preceding items, wherein the disease or condition is selected from the group consisting of allergic diseases, psoriasis, atopic dermatitis, and asthma. (Item 36) A pharmaceutical composition comprising a compound according to any of the preceding paragraphs, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable excipient. (Item 34A) A method for treating a disease or condition selected from the group consisting of: (1) allergic diseases, (2) inflammatory bowel disease, (3) vaginitis, (4) psoriasis and inflammatory skin diseases, (5) vasculitis, (6) spondyloarthropathy, (7) scleroderma, (8) asthma and respiratory allergic diseases, (9) autoimmune diseases, (10) transplant rejection, (11) other diseases in which unwanted inflammatory responses need to be inhibited, and cancer, comprising administering to a patient in need of treatment a compound described in any of the preceding paragraphs. (Item 35A) The method according to any of the preceding items, wherein the disease or condition is selected from the group consisting of allergic diseases, psoriasis, atopic dermatitis, and asthma. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Not applicable DETAILED DESCRIPTION OF THE INVENTION

[0015] While various embodiments and aspects of the present disclosure are shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It will be understood that various alternatives to the embodiments of the present disclosure described herein may be used in practicing the present disclosure.

[0016] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including, but not limited to, patents, patent applications, papers, books, instruction manuals, and journal articles, are expressly incorporated herein by reference in their entirety for all purposes.

[0017] As used herein, the terms "a" or "an" mean one or more.

[0018] The terms "comprise," "include," and "have," and their derivatives, are used interchangeably herein as inclusive, open-ended terms. For example, the use of "comprising," "including," or "having" means not just the elements encompassed by the subject of the clause containing the verb, regardless of what elements are included, having, or comprising.

[0019] Unless otherwise stated, the term "alkyl," by itself or as part of another substituent, means a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms (i.e., C1-8 means 1 to 8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers to unsaturated alkyl groups having one or more double bonds. Similarly, the term "alkynyl" refers to unsaturated alkyl groups having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[0020] The term "cycloalkyl" refers to a group having the indicated number of ring atoms (e.g., C 3~6 "Cycloalkyl" refers to a hydrocarbon ring that is fully saturated or has only one double bond between the ring vertices. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0021] The term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated monocyclic ring (wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized) having the indicated number of ring vertices (e.g., 3- to 7-membered ring) and having from 1 to 5 heteroatoms selected from N, O, and S as ring vertices. Heterocycloalkyls can be monocyclic, bicyclic, or polycyclic ring systems, and can also be bridged, spiro, or fused ring systems. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. Heterocycloalkyl groups can be attached to the remainder of the molecule through a ring carbon or heteroatom. Partially unsaturated heterocycloalkyl groups have one or more double bonds in the ring, but the heterocycloalkyl group is not aromatic.

[0022] The term "alkylene" by itself or as part of another substituent means a divalent group derived from an alkane, as exemplified by -CHCHCHCH-. Typically, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, although in other embodiments of this disclosure, these groups have 10 or fewer carbon atoms. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having four or fewer carbon atoms. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having a double or triple bond, respectively.

[0023] As used herein, in any chemical structure depicted herein, a wavy line "" crossing a single bond, double bond, or triple bond is [ka] " represents a point attachment of a single, double, or triple bond to the rest of the molecule. [ka] A bond represented by is meant to indicate an optional double bond. Thus, the symbol refers to a single bond or a double bond.

[0024] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Furthermore, for dialkylamino groups, the alkyl portions may be the same or different and may be combined with the nitrogen atom to which each is attached to form a 3- to 7-membered ring. Thus, dialkylamino, i.e., -NR a R b A group represented as: is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, and the like.

[0025] "The-(C 1~4 Alkyl)amino-C 1~4 The term "alkyl" refers to C 1~4 Two C's attached to the rest of the molecule via an alkyl group (a 1-4 carbon alkylene linking group) 1~4 It refers to an amino group having an alkyl group (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl). 1~4 Alkyl)amino-C 1~4 Examples of alkyl groups include dimethylaminomethyl, 2-(ethyl(methyl)amino)ethyl, 3-(dimethylamino)butyl, and the like.

[0026] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, "C 1~4 The term "haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Similarly, the term "haloalkoxy" is meant to include monohaloalkoxy and polyhaloalkoxy. For example, "C 1~4 The term "haloalkoxy" is meant to include trifluoromethoxy, 2,2,2-trifluoroethoxy, 4-chlorobutoxy, and the like.

[0027] The term "hydroxyalkyl" is meant to refer to an alkyl group, as defined above, having one or two hydroxyl groups as substituents. For example, "C 1~6 The term "hydroxyalkyl" is meant to include 2-hydroxyethyl and 2,4-dihydroxybutyl.

[0028] The term "acid isostere," unless otherwise specified, refers to a group that can replace a carboxylic acid, having acidic functionality and steric and electronic properties that provide a similar level of activity (or other compound property, such as solubility) to the carboxylic acid. Representative acid isosteres include hydroxamic acids, sulfonic acids, sulfinic acids, sulfonamides, acylsulfonamides, phosphonic acids, phosphinic acids, phosphoric acids, tetrazoles, and oxo-oxadiazoles.

[0029] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0030] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom of a parent molecule. Non-limiting examples of substituents in the present disclosure include R 1 and R2 These substituents can be monovalent or divalent. A monovalent substituent is attached to the parent moiety by replacing one hydrogen atom of the parent moiety through a single bond. The hydrogen atom that the monovalent substituent replaces can be an available hydrogen atom from a carbon or nitrogen atom of the parent moiety. A divalent substituent is attached to the parent moiety by replacing two available hydrogen atoms of the parent moiety through a double bond. It is understood that the substituents described in this disclosure cannot be attached to the parent moiety in a way that results in an unstable molecule.

[0031] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound, neat or in a suitable inert solvent, with a sufficient amount of the desired acid. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, or methanesulfonic acid.Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Non-Patent Document 12). Certain specific compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0032] The neutral forms of these compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for the purposes of this disclosure.

[0033] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Furthermore, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0034] Certain compounds of the present disclosure can exist in unsolvated forms and solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0035] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; all stereoisomers, tautomers, racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., individual enantiomers) are intended to be encompassed within the scope of the present invention. Compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of isotopes may be defined as a range from the amount found in nature of the atom in question to the amount consisting of 100%. For example, compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13 Non-radioactive isotopes such as C) may be incorporated. Such isotopic variations may provide additional utilities to those described elsewhere in this application. For example, isotopic variants of the disclosed compounds may find additional utility, including, but not limited to, as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the disclosed compounds may have altered pharmacokinetic and pharmacodynamic characteristics that can contribute to increased safety, tolerability, or efficacy during treatment. All isotopic variations of the disclosed compounds, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0036] A "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In other embodiments, the subject is a human.

[0037] As used herein, the phrase "CCR4-mediated pathology or disease" and related phrases and terms refer to a pathology or disease characterized by inappropriate, e.g., subnormal or supranormal, CCR4 functional activity. Inappropriate CCR4 functional activity can result from CCR4 expression in cells that do not normally express CCR4, increased CCR4 expression (e.g., resulting in inflammatory and immunoregulatory disorders and diseases), or decreased CCR4 expression. Inappropriate CCR4 functional activity can also result from TARC and / or MDC secretion by cells that do not normally secrete TARC and / or MDC, increased TARC and / or MDC expression (e.g., resulting in inflammatory and immunoregulatory disorders and diseases), or decreased TARC and / or MDC expression. A CCR4-mediated pathology or disease can be mediated completely or partially by inappropriate CCR4 functional activity. However, a CCR4-mediated condition or disease is one in which modulation of CCR4 has some effect on the underlying condition or disease (eg, a CCR4 antagonist brings about some improvement in the health of at least some patients).

[0038] The term "therapeutically effective amount" refers to that amount of a subject compound that elicits the biological or medical response in a tissue, system, animal or human that is desired by a researcher, veterinarian, physician or other clinician.

[0039] I. Overview The compounds of the present disclosure are capable of modulating CCR4 function and are useful in the treatment of a variety of inflammatory and immunoregulatory disorders and diseases.

[0040] II. Embodiment A. Compound In one aspect, provided herein is a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof [wherein: R 1a is hydrogen, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -CN, C 1~4Hydroxyalkoxy, and C 1~4 haloalkoxy; m is an integer from 0 to 4; Each R 1b are independently halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -CN, C 1~4 Alkoxy, and C 1~4 haloalkoxy; R 2 H, -OR a , -N(R a )2, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl; R 3 is hydrogen, C 1~4 Alkyl, halogen, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 3~8 Cycloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Alkoxy-C 1~4 selected from the group consisting of alkyl, -C(O)NH, hydroxy, -NH, and -CN; Each R 4 is hydrogen, halogen, hydroxy, -CN, C 1~4 Alkoxy, C 1~4 Haloalkoxy, -NH2, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 3~8 selected from the group consisting of cycloalkyl, -SOMe, and -C(O)NH; n is an integer from 0 to 2; X and Y each independently represent N or C(R 4 ) and at least one of X and Y is N; [ka] is a single or double bond; A is C, N or C(R 5a ) (However, if A is N, [ka] is a single bond); B is N or C(R 5b ) and at least one of A and B is N; q is an integer from 0 to 4; Each R 5 independently, C 1~4 Alkyl, C 1~4 Alkoxy, -C(O)OH, halogen, hydroxy, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl, or two R 5 combine to form one or two carbon bridges between non-adjacent ring vertices; R 5a is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl; R 5b is hydrogen, C 1~4 Alkyl, and C 1~4 hydroxyalkyl; L is a bond, -O-, -C(O)-C 0~4 Alkylene-, -C 1~4 Alkylene -C(O)-, -C(O)N(R a )-C 0~4 Alkylene-, -S(O)2-C 0~4 Alkylene, and -N(R a )C(O)-C 0~4 alkylene-; Q is i) a ring having 1 to 3 heteroatom ring vertices selected from N, O, and S; and 0 to 4 R b 4- to 7-membered heterocyclyl substituted with; ii) 0 to 3 R b is replaced by C 1~8 alkyl; iii) A ring having 0 to 3 heteroatom ring vertices selected from N, O, and S, and 0 to 4 R b 7- to 11-membered spirocyclyl substituted with; and iv) a ring having 1 to 3 heteroatom ring vertices selected from N, O, and S, and 0 to 4 R b 5-6 membered heterocyclyl substituted with is a member selected from the group consisting of: Each R a are independently H, and C optionally substituted by OH or —C(O)OH. 1~4 selected from the group consisting of alkyl; Each R b are independently hydroxy, halogen, oxo, -C 0~4 Alkylene-N(R a )2, -CO2R a , C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, -C 1~4 Alkylene-CO2R a , -C 0~4 alkylene-heteroaryl, where the heteroaryl has 5-6 ring members and 1-4 heteroatom ring vertices selected from N, O, and S, and the heteroaryl optionally has 1-3 R c , optionally -1 to 3 R c C replaced by 0~4 Alkylene-C 3~8 Cycloalkyl, -C(O)-C 1~4 Alkyl, and -C 0~4 Alkylene-C(O)N(R a )2 is replaced); Each R c are independently halogen, C 1~4 Alkyl, C 1~4 haloalkyl, and —C(O)OH. is provided.

[0041] In another aspect, provided herein is a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof [wherein: R 1a is hydrogen, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -CN, C 1~4 Alkoxy, and C 1~4 haloalkoxy; m is an integer from 0 to 4; Each R 1b are independently halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -CN, C 1~4 Alkoxy, and C 1~4 haloalkoxy; R 2 H, -OR a , -N(R a )2, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl; R 3 is a halogen, C 1~4 Alkyl, -CN, and CF3 selected from the group consisting of: Each R 4 is hydrogen, halogen, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 3~8 selected from the group consisting of cycloalkyl, -SOMe, and -C(O)NH; n is 0, 1 or 2; X and Y each independently represent N or C(R 4 ) and at least one of X and Y is N; [ka] is a single or double bond; A is C, N or C(R 5a ) and; B is N or C(R 5b ) and at least one of A and B is N; q is an integer from 0 to 4; Each R 5 independently, C 1~4 Alkyl, hydroxy, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl, or two R 5 combine to form one or two carbon bridges between non-adjacent ring vertices; R 5a is hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 hydroxyalkyl; R 5b is hydrogen or C 1~4 is alkyl; L is a bond, -C(O)-, -CH2C(O)-, -C(O)CH2-, -C(O)N(R a )- and -N(R a )C(O)—; Q is i) a ring having 1 to 3 heteroatom ring vertices selected from N, O, and S; and 0 to 4 R b 4- to 7-membered heterocyclyl substituted with; ii) 0 to 3 R b is replaced by C 1~8 Alkyl is a member selected from the group consisting of: Each R a are independently H and C 1~4 selected from the group consisting of alkyl; Each R b are independently hydroxy, oxo, -N(R a )2, -CO2R a , C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkylene-CO2R a , and C 1~4 Alkylene-N(R a )2] is provided.

[0042] In some embodiments, the first-recited moiety in the L group is attached to the ring that includes the B variable.

[0043] In some embodiments, the compound of formula (I) is optically enriched or optically pure.

[0044] In one group of embodiments, compounds of formula (I) are provided wherein n is 1. In another group of embodiments, R 1a and R 1b In yet another group of embodiments, compounds of formula (I) are provided wherein R 2 In yet another group of embodiments, compounds of formula (I) are provided wherein R is H or CH. 3 In another group of embodiments, compounds of formula (I) are provided wherein each R 4 But hydrogen, halogen, -CN, C 1~4 Alkyl, and C 1~4 In another group of embodiments, compounds of formula (I) are provided wherein R is selected from the group consisting of haloalkyl. 4 In yet another group of embodiments, compounds of formula (I) are provided wherein each Q is selected from 0 to 2 R b The compound of formula (I) is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl, substituted with

[0045] In another group of embodiments, compounds of formula (I) have the sub-formula (Ia): or a pharmaceutically acceptable salt thereof: [ka]

[0046] In some selected embodiments, each Q is 0 to 2 R b In other selected embodiments, compounds of Formula (Ia) are provided wherein Q is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, substituted with 0 to 3 R b C is replaced by 1~8 Also provided are compounds of Formula (Ia), wherein L is a bond, —C(O)—, —CHC(O)—, —C(O)CH—, —C(O)NH—, —NHC(O)—, —C(O)N(CH)—, and The compound is selected from the group consisting of: —N(CH3)C(O)—.

[0047] In another group of embodiments, compounds of formula (I) have the sub-formula (Ib): or a pharmaceutically acceptable salt thereof: [ka]

[0048] In some selected embodiments, each Q is 0 to 2 R b In other selected embodiments, compounds of formula (Ib) are provided wherein Q is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, substituted with 0 to 3 R b C is replaced by 1~8 Also provided are compounds of formula (Ib), wherein L is alkyl. Still further selected embodiments are compounds wherein L is a bond, —C(O)—, —CHC(O)—, —C(O)CH—, —C(O)NH—, —NHC(O)—, —C(O)N(CH)—, and The compound is selected from the group consisting of: —N(CH3)C(O)—.

[0049] In another group of embodiments, compounds of formula (I) have the sub-formula (Ic1), (Ic2) or (Ic3), or a pharmaceutically acceptable salt thereof: [ka]

[0050] In some selected embodiments, each Q is 0 to 2 R b In other selected embodiments, compounds of formula (Ic1), (Ic2), or (Ic3) are provided, wherein Q is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, substituted with 0 to 3 R b C is replaced by 1~8 Also provided are compounds of Formula (Ic1), (Ic2), or (Ic3), wherein L is alkyl. Still further selected embodiments are compounds thereof wherein L is selected from the group consisting of a bond, —C(O)—, —CHC(O)—, —C(O)CH—, —C(O)NH—, —NHC(O)—, —C(O)N(CH)—, and —N(CH)C(O)—.

[0051] In another group of embodiments, compounds of formula (I) have the sub-formula (Id1), (Id2) or (Id3), or a pharmaceutically acceptable salt thereof: [ka]

[0052] In some selected embodiments, each Q is 0 to 2 R b In other selected embodiments, compounds of formula (Id1), (Id2), or (Id3) are provided, wherein Q is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, substituted with 0 to 3 R b C is replaced by 1~8 Also provided are compounds of formula (Id1), (Id2), or (Id3), wherein L is alkyl. Still further selected embodiments are compounds thereof wherein L is selected from the group consisting of a bond, —C(O)—, —CHC(O)—, —C(O)CH—, —C(O)NH—, —NHC(O)—, —C(O)N(CH)—, and —N(CH)C(O)—.

[0053] In some selected embodiments, compounds of formula (Ie1) or a pharmaceutically acceptable salt thereof are provided: [ka] (Wherein Q, L, B, A, q and R 5 has the meaning given above for formula (I).

[0054] In some embodiments, there is provided a compound of formula (If1), (If2), (If3), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, each R b are independently selected from the group consisting of H, Cl, or F, provided that at least one R b is H).

[0055] In some selected embodiments, Q is [ka] (In the formula, Each R b independently, C 1~4 selected from the group consisting of alkyl, F, Cl, OH, and —N(H)CH3; and R b1 is H, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~4 Haloalkyl, -C(O)-C 1~3 Alkyl, -C(O)-OC 1~3 Alkyl, -C 1~3 alkylene selected from the group consisting of -C(O)OH and -C(O)NH The compounds of formula (I), (Ia), (Ib), (Ic1), (Ic2), (Ic3), (Id1), (Id2), (Id3), (Ie1), (If1), (If2), (If3), (Ig1) to (Ig10), and (Ih1) to (Ih12) are provided, which are selected from the group consisting of:

[0056] In some embodiments, compounds of formula (Ig1)-(Ig10), or pharmaceutically acceptable salts thereof, are provided. [ka] (In the formula, each R b independently, C 1~4 selected from the group consisting of alkyl, F, Cl, OH, and —N(H)CH3; and R b1 is H, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~4 Haloalkyl, -C(O)-C 1~3 Alkyl, -C(O)-OC 1~3 Alkyl, -C 1~3 alkylene, selected from the group consisting of -C(O)OH, and -C(O)NH

[0057] In some embodiments, compounds of Formula (Ih1)-(Ih12), or pharmaceutically acceptable salts thereof, are provided: [ka] [ka] (In the formula, each R b independently, C 1~4 selected from the group consisting of alkyl, F, Cl, and OH; and R 5 is selected from the group consisting of OH, F, and —OCH

[0058] In some selected embodiments, R 3 But C 1~4 Alkyl, Cl, F, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, cyclopropyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~3 Alkylene-OC 1~3In some embodiments, compounds of Formula (I), (Ia), (Ib), (Ic1), (Ic2), (Ic3), (Id1), (Id2), (Id3), (Ie1), (If1), (If2), (If3), (Ig1)-(Ig10), and (Ih1)-(Ih12) are provided, wherein R is selected from the group consisting of alkyl, hydroxy, -NH2, and -CN. 3 is selected from the group consisting of Cl, F, —OCH, —OCHCH, —OCH(CH), —OCF, —OCHF, —C(CH)OH, and hydroxy. 3 is selected from the group consisting of halogen, —CH, —OCH, —CHOCH, —OCHCH, —OC(H)(CH), —CN, —NH, —CF, —OCF, and —OCHF. 3 is Cl.

[0059] In some embodiments, the compound of formula (I) is selected from the compounds in Table 1 below that have ++ or +++ activity.

[0060] In some embodiments, the compound of formula (I) is selected from the compounds in Table 1 below that have +++ activity.

[0061] B. Composition In addition to the compounds provided above, compositions for modulating CCR4 activity in humans and animals will typically contain a pharmaceutical carrier or diluent.

[0062] The term "composition," as used herein, is intended to encompass a product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0063] The pharmaceutical composition for administering the compounds of the present disclosure can be conveniently presented in unit dosage form and can be prepared by any method well known in the fields of pharmacy and drug delivery.All methods include the step of bringing the active ingredient into association with a carrier that constitutes one or more accessory ingredients.In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.In this pharmaceutical composition, the active target compound is contained in an amount sufficient to produce the desired effect depending on the process or condition of the disease.

[0064] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying agents as described in U.S. Patent Application Publication No. 2002 / 0012680, hard or soft capsules, syrups, elixirs, liquids, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a medicament with a clean and pleasant taste. Tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated, or they can be enteric- or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by the techniques described in U.S. Pat. Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[0065] The preparation for oral use can also be provided as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.In addition, emulsions can be prepared with non-water-miscible ingredients such as oils, and stabilized with surfactants such as monoglycerides or diglycerides, PEG esters, etc.

[0066] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, and the dispersing or wetting agent can be a natural phosphatide such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long-chain fatty alcohol such as heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride such as polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0067] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions can contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents, such as those described above, can be added to provide chewable oral preparations. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

[0068] Dispersible powders or granules suitable for preparing aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.Additional excipients, such as sweeteners, flavoring agents, and coloring agents, can also be included.

[0069] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion.The oil phase can be vegetable oil such as olive oil or peanut oil, or mineral oil such as liquid paraffin, or a mixture thereof.Suitable emulsifiers can be natural gums such as gum acacia or gum tragacanth, natural phosphatides such as soybean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.Emulsifiers can also contain sweeteners and flavoring agents.

[0070] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations can also contain demulcents, preservatives, flavorings, and coloring agents. Oral liquid preparations can be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

[0071] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated by known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0072] The compounds of the present disclosure can also be administered in the form of suppositories for rectal drug administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. Furthermore, the compounds can be administered by intraocular delivery using solutions or ointments. Furthermore, the subject compounds can be delivered transdermally using iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds of the present disclosure can be used. As used herein, topical application also includes the use of mouthwashes and gargles.

[0073] The compounds of the present disclosure may also be coupled to carriers that are polymers suitable for targetable drug carriers. Examples of such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present disclosure may be coupled to carriers from a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. Polymers and semipermeable polymer matrices can be formed into shaped articles such as valves, stents, tubes, and prostheses.

[0074] In view of the above, provided herein are embodiments of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of any of Formula (I), (Ia), (Ib), (Ic1), (Ic2), (Ic3), (Id1), (Id2), (Id3), (Ie1), (If1), (If2), (If3), (Ig1)-(Ig10), or (Ih1)-(Ih12), as described above, or a pharmaceutically acceptable salt thereof.

[0075] C.How to use In another aspect, the present disclosure provides methods for treating or preventing a CCR4-mediated condition or disease by administering to a subject having the condition or disease a therapeutically effective amount of any compound of Formula I. The compounds used in the methods are those provided in the embodiments herein, as well as those compounds whose particular structures are specifically illustrated in the Examples below, the accompanying drawings, and elsewhere in the specification.

[0076] Diseases and conditions associated with inflammation, infection, and cancer can be treated or prevented with the compounds and compositions of the present invention. In one group of embodiments, diseases or conditions, including chronic diseases in humans or other species, can be treated with inhibitors of CCR4 function. Such diseases or conditions include: (1) allergic diseases, such as systemic anaphylaxis or hypersensitivity reactions, drug allergies, insect sting allergies, and food allergies; (2) inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis, and enteritis; (3) vaginitis; (4) psoriasis and inflammatory skin diseases, such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, dermatomyositis, lichen planus, bullous pemphigoid, urticaria, and pruritus; (5) vasculitis; (6) spondyloarthropathy; (7) scleroderma; (8) asthma and respiratory allergic diseases, such as allergic asthma, exercise-induced asthma, allergic rhinitis, and hypersensitivity pulmonary disease; and (9) arthritis (rheumatoid and psoriatic). (10) autoimmune diseases such as leukemia, lymphoma and other blood-borne cancers, including cutaneous T-cell lymphoma, mycosis fungoides, acute lymphoblastic leukemia, and the like; and (12) other diseases in which an undesirable inflammatory response needs to be inhibited, such as atherosclerosis, myositis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome, and gout.

[0077] In another group of embodiments, diseases or conditions can be treated with agonists of CCR4 function. Examples of diseases that can be treated with CCR4 agonists include cancer, diseases involving angiogenesis or neovascularization (neoplastic diseases, retinopathies, and macular degeneration), infectious diseases (viral infections, e.g., HIV infection and bacterial infection), and immunosuppressive diseases such as organ transplant conditions and skin transplant conditions. The term "organ transplant condition" is meant to include bone marrow transplant conditions and solid organ (e.g., kidney, liver, lung, heart, pancreas, or a combination thereof) transplant conditions.

[0078] Preferably, the present method is directed to the treatment of a disease or condition selected from allergic diseases (including skin allergies and allergic airway disorders), atopic allergic conditions including atopic dermatitis, psoriasis, cancer (including solid tumors and metastatic disease), and asthma. Depending on the disease being treated and the condition being treated, the compounds of the present disclosure can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation, nasally, vaginally, rectally, sublingually, or topically, and can be formulated into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each administration route, either alone or together. The present disclosure also contemplates the administration of the compounds of the present disclosure in a depot formulation.

[0079] Those skilled in the art will understand that agents that modulate CCR4 activity can be combined with other therapeutic agents and / or chemotherapeutic agents or radiation. In some instances, the amount of chemotherapeutic agent or radiation is subtherapeutic when provided without the compositions of the present disclosure. Those skilled in the art will understand that "combination" can include combination in therapy (i.e., two or more drugs administered as a mixture, or at least simultaneously, or at least introduced into a subject at different times, but both in the subject's bloodstream at the same time). Furthermore, the compositions of the present disclosure can be administered before or after a second therapeutic regimen, for example, before or after the administration of chemotherapy or radiation.

[0080] For the treatment or prevention of conditions requiring chemokine receptor modulation, an appropriate dosage level is generally about 0.001 to 100 mg / kg of patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level is about 0.01 to about 25 mg / kg per day, more preferably about 0.05 to about 10 mg / kg per day. Suitable dosage levels can be about 0.01 to 25 mg / kg per day, about 0.05 to 10 mg / kg per day, or about 0.1 to 5 mg / kg per day. Within this range, the dosage can be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of active ingredient, to tailor the dosage to the patient being treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

[0081] It will be understood, however, that the specific dosage level and frequency for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and length of action of that compound, the age, weight, genetic characteristics, general health, sex, and diet of the subject, as well as the mode and time of administration, rate of excretion, drug combination, and the severity of the particular condition of the subject being treated.

[0082] In one group of embodiments, the compounds and compositions described herein can be combined with other compounds and compositions that have utility in connection with the prevention and treatment of cancers and diseases or conditions associated with CCR4 signaling. Such other drugs can be administered simultaneously or sequentially with the compounds or compositions of the present disclosure, by routes and in amounts commonly used therefor. When the compounds or compositions of the present disclosure are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds or compositions of the present disclosure can be used. Thus, pharmaceutical compositions of the present disclosure include those that contain one or more other active ingredients or therapeutic agents in addition to the compounds or compositions of the present disclosure. Examples of other therapeutic agents that can be combined with the compounds or compositions of the present disclosure and administered separately or in the same pharmaceutical composition include, but are not limited to, cisplatin, paclitaxel, methotrexate, cyclophosphamide, ifosfamide, chlorambucil, carmustine, carboplatin, vincristine, vinblastine, thiotepa, lomustine, semustine, 5-fluorouracil, corticosteroids, calcineurin inhibitors, NSAIDs, 5-lipoxygenase inhibitors, and cytarabine. The weight ratio of the compound of the present disclosure to the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when the compound of the present disclosure is combined with a second anticancer drug, the weight ratio of the compound of the present disclosure to the second drug generally ranges from about 1000:1 to about 1:1000, preferably from about 200:1 to about 1:200. Combinations of a compound of the present disclosure and other active ingredients will generally also be within the aforementioned range, provided that, in each case, an effective dose of each active ingredient is used.

[0083] How to Treat Inflammation Additionally, the compounds and compositions of the present disclosure are useful for treating inflammation and can be combined with other compounds and compositions having therapeutic utility that may require treatment before, after, or simultaneously with the treatment of cancer or inflammation with the present compounds. Thus, combination methods and compositions are also components of the present disclosure for preventing and treating a condition or disease of interest, such as inflammatory or autoimmune disorders, conditions, and diseases, including psoriasis, dermatomyositis, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, polyarticular arthritis, multiple sclerosis, allergic diseases, atopic dermatitis, and asthma, as well as the above-mentioned conditions.

[0084] For example, in the treatment or prevention of inflammation or autoimmunity, or bone loss associated with, for example, arthritis, the compounds and compositions may be used in combination with anti-inflammatory or analgesic agents such as opiate agonists, lipoxygenase inhibitors such as inhibitors of 5-lipoxygenase, cyclooxygenase inhibitors such as cyclooxygenase-2 inhibitors, interleukin inhibitors such as interleukin-1 inhibitors, NMDA antagonists, inhibitors of nitric oxide or inhibitors of nitric oxide synthesis, nonsteroidal anti-inflammatory agents, or cytokine suppressive anti-inflammatory agents such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, steroidal analgesics, sufentanil, sulindac, tenidap, and the like. Similarly, the compounds and compositions can be administered with analgesics such as those listed above; enhancers such as caffeine, H2 antagonists (e.g., ranitidine), simethicone, aluminum hydroxide, or magnesium hydroxide; decongestants such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levodesoxyephedrine; antitussives such as codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; diuretics; and sedating or non-sedating antihistamines.

[0085] As mentioned above, the compounds and compositions of the present disclosure may be used in combination with other drugs used in the treatment, prevention, suppression, or amelioration of diseases or conditions for which the compounds and compositions of the present disclosure are useful. Such other drugs may be administered simultaneously or sequentially with the compounds or compositions of the present disclosure, by a route and in an amount commonly used therefor. When the compounds or compositions of the present disclosure are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds or compositions of the present disclosure are contemplated. Thus, pharmaceutical compositions of the present disclosure include those that contain one or more other active ingredients or therapeutic agents in addition to the compounds or compositions of the present disclosure. Examples of other therapeutic agents that can be combined with the compounds or compositions of the present disclosure and administered separately or in the same pharmaceutical composition include, but are not limited to: (A) VLA-4 antagonists, (b) corticosteroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone, salmeterol, salbutamol, and formoterol; (c) cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®), other FK-506-type immunosuppressants, and mycophenolate mofetil. (d) immunosuppressants such as brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like;(e) nonsteroidal antiasthmatics (e.g., terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (e.g., zafirlukast, montelukast, pranlukast, iralukast, povilkast, and SKB-106, 203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); f) propionic acid derivatives (such as aluminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (such as indomethacin, acemetacin, alclofenac, clidanac, dioxaprofen, Clofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxipinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam, and (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h) inhibitors of phosphodiesterase type IV (PDE IV); (i) gold compounds such as auranofin and aurothioglucose; (j) TNF-alpha modulators such as etanercept (Enbrel®);(k) antibody therapeutics such as Orthoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®), B cell modulators such as rituximab (Rituxan®) and infliximab (Remicade®); (l) other antagonists of chemokine receptors, particularly CCR1, CCR5, CXCR2, CXCR3, CCR2, CCR3, CCR4, CCR7, CCR9, CX3CR1 and CXCR6; (m) lubricants or skin emollients such as petrolatum and lanolin. (n) keratolytic agents (e.g., tazarotene), (o) vitamin D3 derivatives, such as calcipotriene or calcipotriol (Dovonex®); (p) PUVA; (q) anthralin (Drithrocreme®), (r) etretinate (Tegison®) and isotretinoin; (s) interferon beta-1β (Betaseron®), interferon beta-1α (Avonex®), azathioprine (Imurek®, Imuran®), glutathione acetate (t) multiple sclerosis treatments such as latiramer (Capoxone®), glucocorticoids (e.g., prednisolone) and cyclophosphamide, (t) DMARDS such as methotrexate; (u) T-cell costimulatory modulators such as abatacept (Orencia®); (v) antimetabolites such as 5-aminosalicylic acid and its prodrugs, hydroxychloroquine, D-penicillamine, azathioprine, 6-mercaptopurine and methotrexate, DNA synthesis inhibitors such as hydroxyurea, and microtubule disrupters such as colchicine. Other compounds, such as disintegrating agents. The weight ratio of the compound of the present disclosure to the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when the compound of the present disclosure is combined with an NSAID, the weight ratio of the compound of the present disclosure to the NSAID is generally in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of the compound of the present disclosure with other active ingredients are also generally within the above ranges, but in each case, an effective dose of each active ingredient is used. [Example]

[0086] III. Working Examples The following examples are offered to illustrate, but not to limit, the claimed disclosure.

[0087] Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1 H-NMR spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaks are given relative to TMS and are listed in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and proton number. Mass spectrometry results are reported as the ratio of mass to charge, followed by the relative abundance of each ion (in parentheses). In this example, a single m / e value is reported for the M+H (or, where noted, MH) ion, which contains the most common atomic isotope. The isotopic pattern corresponds to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry was performed on a Hewlett-Packard MSD electrospray mass spectrometer using an HP1100 HPLC for sample delivery. Typically, the analyte was dissolved in methanol at 0.1 mg / mL, and 1 microliter was injected into the mass spectrometer with the delivery solvent, scanning from 100 to 1500 daltons. All compounds could be analyzed in positive ESI mode using acetonitrile / water containing 1% formic acid as the delivery solvent. The compounds provided below could also be analyzed in negative ESI mode using acetonitrile / water containing 2 mM NHOAc as the delivery system.

[0088] The following abbreviations are used in the examples and throughout the present disclosure: rt, room temperature; HPLC, high-pressure liquid chromatography; TFA, trifluoroacetic acid; LC-MSD, liquid chromatography / mass selective detector; LC-MS, liquid chromatography / mass spectrometer; Pd2dba3, tris(dibenzylideneacetone)dipalladium; THF, tetrahydrofuran; DMF, dimethylformamide or N,N-dimethylformamide; DCM, dichloromethane; DMSO, dimethyl sulfoxide; TLC, thin-layer chromatography; KHMDS, potassium hexamethyldisilazane; ES, electrospray; sat., saturated.

[0089] Compounds within the scope of the present disclosure can be synthesized using a variety of reactions known to those skilled in the art, as described below. Those skilled in the art will also recognize that alternative methods may be employed to synthesize target compounds of the present disclosure, and that the approaches described within the body of this document are not exhaustive, but provide broadly applicable and practical routes to compounds of interest.

[0090] Certain molecules claimed in this patent may exist in different tautomeric, enantiomeric and diastereomeric forms, and all such variants of these compounds are claimed.

[0091] Detailed descriptions of the experimental procedures used to synthesize key compounds in this document are linked to molecules described by physical data that identify the compounds and by structural diagrams related to the compounds.

[0092] Those skilled in the art will also recognize that acids and bases are frequently used during standard workup procedures in organic chemistry. Salts of parent compounds are sometimes prepared during the experimental procedures described within this patent, if they have the necessary inherent acidity or basicity.

[0093] Synthesis Examples Example 1: Synthesis of tert-butyl (R)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate [ka] Step a: To a solution of 2,4,5-trichloropyrimidine (5.0 g, 27.3 mmol) and (R)-1-(2,4-dichlorophenyl)ethan-1-amine (5.18 g, 27.3 mmol) in MeCN (100 mL) was added trimethylamine (3.8 mL, 27.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. The contents were concentrated and the solid was filtered off. The filtrate was purified by silica gel column chromatography to give (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine. MS: (ES) m / z C 12 H 10 ClN4O3[M+H] + Calculated value: 336.0, measured value: 336.0.

[0094] Step b: To a solution of (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (1.0 g, 2.97 mmol) and tert-butyl piperazine-1-carboxylate (0.55 g, 2.95 mmol) in DMSO (30 mL) was added N,N-diisopropylethylamine (2.6 mL, 14.9 mmol) and cesium fluoride (0.45 g, 2.96 mmol). The reaction mixture was heated at 100° C. for 3 hours and then diluted with water and ethyl acetate. The organic and aqueous layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (R)-4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carboxylate. MS: (ES) m / z C 21 H 27 Cl3N5O2[M+H] +The calculated value is 486.1 and the measured value is 486.2.

[0095] Step c: To a solution of tert-butyl (R)-4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carboxylate (1.3 g, 2.67 mmol) in dioxane (3 mL) was added a solution of 4.0 M HCl in dioxane (5 mL, 19.3 mmol). The reaction mixture was stirred at room temperature for 16 hours. The contents were concentrated to give (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(piperazin-1-yl)pyrimidin-4-amine. MS: (ES) m / z C 16 H 19 Cl3N5[M+H] + The calculated value is 386.1 and the measured value is 386.0.

[0096] Step d: To a solution of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(piperazin-1-yl)pyrimidin-4-amine (300 mg, 0.709 mmol) and (tert-butoxycarbonyl)-D-proline (168 mg, 0.78 mmol) in DCM (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg, 0.99 mmol) and dimethylaminopyridine (90 mg, 0.74 mmol). The contents were stirred at room temperature for 16 hours. The reaction mixture was concentrated and then diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography followed by preparative HPLC to give tert-butyl (R)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate. 1H NMR (400MHz, CDCl3) (mixture of rotamers) δ 7.85(s,0.5H),7.84(s,0.5H),7.38(s,0.5H),7.37(s,0.5H),7.23(d,J=8.5Hz,1H),7.19(d,J=8.4Hz,1H),5.53 - 5.39(m,2H),4.67(d,J=3.6Hz,0.5H),4.55(dd,J=9.3,3.6Hz,0.5H),3.75 - 3.36(m,9H),2.25 - 2.07(m,1H),2.07 - 1.94(m,1H),1.92 - 1.78(m,2H),1.58(s,1.5H),1.53(m,2.5H),1.46(s,4.5H),1.38(m,4.5H).MS:(ES)m / z C 26 H 34 Cl3N6O3[M+H] + Calculated value: 583.2, measured value: 583.2.

[0097] Example 2: Synthesis of 2-(4-(D-prolyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidine [ka] To a solution of tert-butyl (R)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (190 mg, 0.325 mmol) in dioxane (1 mL) was added 4.0 M HCl in dioxane (1.0 mL, 4.00 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated to dryness. The crude material was purified by preparative HPLC to give 2-(4-(D-prolyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidine. 1H NMR(400MHz,CDCl3)δ 12.05(s,1H),8.35(s,1H),8.02(d,J=1.9Hz,1H),7.43(d,J=2.0Hz,1H),7.26 - 7.20(m,2H),6.25(d,J=6.4Hz,1H),5.61 - 5.39(m,1H),4.88(bs,1H),3.96 - 3.81(m,3H),3.75 - 3.27(m,6H),2.59 - 2.43(m,1H),2.19(ddd,J=13.6,7.2,7.2Hz,1H),2.12 - 1.99(m,1H),1.92(ddd,J=13.1,6.6,6.6Hz,1H),1.61(d,J=7.2Hz,3H).MS:(ES)m / z C 21 H 26 Cl3N6O[M+H] + Calculated value: 483.1, measured value: 483.1.

[0098] Example 3: Synthesis of 5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino))-2-(4-((2-hydroxyethyl)-D-propyl)piperazin-1-yl)pyrimidine [ka] To a solution of 2-(4-(D-prolyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidine (50 mg, 0.084 mmol) in MeCN (1 mL) was added potassium carbonate (35 mg, 0.25 mmol) and 2-iodoethanol (0.01 mL, 0.128 mmol). The reaction mixture was heated at 85° C. for 16 hours and then quenched with water. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography followed by preparative HPLC to give 5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(4-((2-hydroxyethyl)-D-prolyl)piperazin-1-yl)pyrimidine. 1H NMR(400MHz,CD3OD)δ 7.96(s,1H),7.49(s,1H),7.41(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H),5.62(q,J=7.2Hz,1H),4.84 - 4.75(m,2H),4.02 - 3.73(m,6H),3.65 - 3.57(m,3H),3.56 - 3.40(m,2H),3.37 - 3.34(m,1H),3.28 - 3.23(m,1H),2.69 - 2.50(m,1H),2.28 - 2.13(m,1H),2.09 - 1.90(m,2H),1.59(d,J=7.2Hz,3H).MS:(ES)m / z C 23 H 30 Cl3N6O2[M+H] + 527.1, actual value 527.2.

[0099] Example 4 Synthesis of 3-((R)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)propanoic acid [ka] To a solution of 2-(4-(D-prolyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidine (50 mg, 0.084 mmol) in toluene (1 mL) was added N,N-diisopropylethylamine (0.03 mL, 0.167 mmol) and acrylic acid (0.01 mL, 0.146 mmol). The reaction mixture was heated at 85° C. for 16 hours and then concentrated to dryness. The crude material was purified by preparative HPLC to give 3-((R)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)propanoic acid. 1H NMR(400MHz,CD3OD)δ 7.95(s,1H),7.48(s,1H),7.41(d,J=8.8Hz,1H),7.31(d,J=8.4,1H),5.61(q,J=6.8Hz,1H),4.82 - 4.68(m,1H),3.96 - 3.75(m,5H),3.75 - 3.62(m,1H),3.62 - 3.53(m,2H),3.53 - 3.39(m,3H),3.28 - 3.19(m,1H),2.82(dd,J=6.6,6.6Hz,2H),2.68 - 2.55(m,1H),2.26 - 2.16(m,1H),2.06 - 1.93(m,2H),1.58(d,J=6.8Hz,3H).MS:(ES)m / z C 24 H 30 Cl3N6O3[M+H] + The calculated value is 555.1 and the measured value is 555.2.

[0100] Example 5: Synthesis of tert-butyl (S)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate [ka] To a solution of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(piperazin-1-yl)pyrimidin-4-amine (300 mg, 0.709 mmol) and (tert-butoxycarbonyl)-D-proline (168 mg, 0.78 mmol) in DCM (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg, 0.99 mmol) and dimethylaminopyridine (90 mg, 0.74 mmol). The contents were stirred at room temperature for 16 hours. The reaction mixture was concentrated and then diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography followed by preparative HPLC to give tert-butyl (S)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate. 1 H NMR (400MHz, CDCl3) (mixture of rotamers) δ 7.85(s,0.5H),7.84(s,0.5H),7.39(s,0.5H),7.37(s,0.5H),7.24(d,J=8.8Hz,1H),7.19(d,J=8.7Hz,1H),5.54 - 5.37(m,2H),4.67(d,J=7.6Hz,0.5H),4.54(dd,J=8.8,4.0Hz,0.5H),3.75 - 3.40(m,9H),3.32 - 3.22(m,1H),2.25 - 2.08(m,1H),2.07 - 1.94(m,1H),1.92 - 1.76(m,2H),1.57(s,-2.5H),1.54(s,1.5H),1.46(s,4.5H),1.39(s,4.5H).MS:(ES)m / z C 26 H 34 Cl3N6O3[M+H] + Calculated value: 583.2, measured value: 583.2.

[0101] Example 6: Synthesis of 2-(4-(L-prolyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidine [ka] To a solution of tert-butyl (S)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (377 mg, 10.34 mmol) in dioxane (2 mL) was added 4.0 M HCl in dioxane (2.6 mL, 10.3 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated to dryness. The crude material was purified by preparative HPLC to give 2-(4-(L-prolyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidine. 1 H NMR(400MHz,CDCl3)δ 12.09(s,1H),8.03(s,1H),7.43(s,1H),7.25 - 7.20(m,2H),6.23(m,1H),5.52 - 5.44(m,1H),4.90(s,1H),3.97 - 3.83(m,3H),3.73 - 3.64(m,1H),3.63 - 3.40(m,5H),3.37 - 3.27(m,1H),2.58 - 2.46(m,1H),2.20(ddd,J=14.0,7.1,7.1Hz,1H),2.07(ddd,J=7.4,6.7,6.7Hz,1H),1.95 - 1.85(m,1H),1.62(d,J=6.9,3H).MS:(ES)m / z C 21 H 26 Cl3N6O[M+H] + Calculated value: 483.1, measured value: 483.1.

[0102] Example 7: Synthesis of 1-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-((R)-pyrrolidin-2-yl)ethan-1-one [ka] Step a: To a mixture of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(piperazin-1-yl)pyrimidin-4-amine hydrochloride (40 mg, 0.090 mmol), (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (30 mg, 0.13 mmol), and HATU (80 mg, 0.21 mmol) in DMF (2 mL) was added triethylamine (0.080 mL, 0.57 mmol). The mixture was stirred at room temperature for 1 h, quenched with saturated NaHCO3, and extracted with EtOAc. The organic phase was separated and filtered over MgSO4. The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography to give tert-butyl (R)-2-(2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-1-carboxylate. MS: (ES) m / z C 27 H 36 Cl3N6O3[M+H] + The calculated value was 597.2 and the measured value was 597.3.

[0103] Step b: (R)-tert-butyl 2-(2-(4-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (50 mg, 0.080 mmol) was added to a 4.0 M solution of HCl in dioxane (2 mL, 8 mmol). The resulting solution was stirred at room temperature for 0.5 hours, evaporated to dryness, and purified by preparative HPLC to give 1-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-((R)-pyrrolidin-2-yl)ethan-1-one. 1H NMR(400MHz,CD3OD)δ 7.99(s,1H),7.49(s,1H),7.41(d,J=8.4Hz,1H),7.33(d,J=8.4Hz,1H),5.63(q,J=7.2Hz,1H),3.85 - 3.95(m,1H),3.50 - 3.82(m,9H),3.22 - 3.33(m,1H),3.00 - 3.08(m,1H),2.80 - 2.87(m,1H),2.20 - 2.30(m,1H),2.03 - 2.15(m,1H),1.92 - 2.02(m,1H),1.71 - 1.82(m,1H),1.60(d,J=7.2Hz,3H).MS:(ES)m / z C 22 H 28 Cl3N6O[M+H] + The calculated value was 497.1, and the measured value was 497.2.

[0104] Example 8 Synthesis of ((R)-azetidin-2-yl)(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)methanone [ka] Step a: To a mixture of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(piperazin-1-yl)pyrimidin-4-amine hydrochloride (40 mg, 0.090 mmol), (R)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (30 mg, 0.15 mmol), and HATU (80 mg, 0.21 mmol) in DMF (2 mL) was added triethylamine (0.080 mL, 0.57 mmol). The mixture was stirred at room temperature for 1 hour, quenched with saturated NaHCO3, and extracted with EtOAc. The organic phase was separated and filtered over MgSO4. The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography to give tert-butyl (R)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate. MS: (ES) m / z C 25 H32 Cl3N6O3[M+H] + Calculated value: 569.2, measured value: 569.2.

[0105] Step b: (R)-tert-butyl 2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (40 mg, 0.070 mmol) was added to a solution of 4.0 M HCl in dioxane (2 mL, 8 mmol). The resulting solution was stirred at room temperature for 0.5 h, evaporated to dryness, and purified by reverse-phase HPLC to give ((R)-azetidin-2-yl)(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)methanone. 1 H NMR(400MHz,CD3OD)δ 7.99(s,1H),7.50(s,1H),7.42(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H),5.59 - 5.66(m,1H),5.51 - 5.50(m,1H),4.10 - 4.19(m,1H),3.88 - 3.98(m,1H),3.74 - 3.84(m,3H),3.61 - 3.70(m,2H),3.46 - 3.56(m,1H),3.34 - 3.45(m,2H),2.86 - 2.97(m,1H),2.52 - 2.67(m,1H),1.60(d,J=7.2Hz,3H). MS: (ES) m / z C 20 H 24 Cl3N6O[M+H] + Calculated value: 469.1, measured value: 469.1.

[0106] Example 9: (R)-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)(3-methylazetidin-3-yl)methanone [ka] Step a: To a mixture of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(piperazin-1-yl)pyrimidin-4-amine hydrochloride (50 mg, 0.12 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (38 mg, 0.19 mmol), and HATU (100 mg, 0.26 mmol) in DMF (2 mL) was added triethylamine (0.10 mL, 0.72 mmol). The mixture was stirred at room temperature for 1 hour, quenched with saturated NaHCO3, and extracted with EtOAc. The organic phase was separated and filtered over MgSO4. The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography to give tert-butyl (R)-3-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)-3-methylazetidine-1-carboxylate. MS: (ES) m / z C 26 H 34 Cl3N6O3[M+H] + The calculated value was 583.2 and the measured value was 583.3.

[0107] Step b: (R)-tert-Butyl 3-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)-3-methylazetidine-1-carboxylate (65 mg, 0.11 mmol) was added to a solution of 4.0 M HCl in dioxane (2 mL, 8 mmol). The resulting solution was stirred at room temperature for 0.5 h, evaporated to dryness, and purified by preparative HPLC to give (R)-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)(3-methylazetidin-3-yl)methanone. 1H NMR(400MHz,CD3OD)δ 7.97(s,1H),7.50(s,1H),7.41(d,J=8.4Hz,1H),7.31(d,J=8.4Hz,1H),5.56 - 5.64(m,1H),5.49(s,1H),4.48(d,J=10.8Hz,2H),3.92(d,J=10.8Hz,2H),3.45 - 3.70(m,5H),3.16 - 3.40(m,2H),1.66(s,3H),1.59(d,J=7.2Hz,3H).MS:(ES)m / z C 21 H 26 Cl3N6O[M+H] + Calculated value: 483.1, measured value: 483.1.

[0108] Example 10: Synthesis of (R)-2-amino-1-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-methylpropan-1-one [ka] Step a: To a mixture of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(piperazin-1-yl)pyrimidin-4-amine hydrochloride (40 mg, 0.090 mmol), 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (39 mg, 0.19 mmol), and HATU (54 mg, 0.14 mmol) in DMF (2 mL) was added triethylamine (0.040 mL, 0.29 mmol). The mixture was stirred at room temperature for 1 h, quenched with saturated NaHCO3, and extracted with EtOAc. The organic phase was separated and filtered over MgSO4. The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography to give tert-butyl (R)-(1-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate. MS: (ES) m / z C 25 H 34 Cl3N6O3[M+H] + Calculated value: 571.2, measured value: 571.2.

[0109] Step b: (R)-(1-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)tert-butylcarbamate (37 mg, 0.064 mmol) was added to a 4.0 M solution of HCl in dioxane (2 mL, 8 mmol). The mixture was stirred at room temperature for 0.5 h, evaporated to dryness under high vacuum, and purified by preparative HPLC to give (R)-2-amino-1-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-methylpropan-1-one. 1 H NMR(400MHz,CD3OD)δ 7.99(s,1H),7.50(s,1H),7.42(d,J=8.4Hz,1H),7.30 - 7.35(m,1H),5.63(q,J=7.2Hz,1H),3.62 - 3.78(m,8H),1.68(s,6H),1.60(d,J=7.2Hz,3H).MS:(ES)m / z C 20 H 26 Cl3N6O[M+H] + Calculated value: 471.1, measured value: 471.1.

[0110] Example 11: Synthesis of (R)-1-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one [ka] To a mixture of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(piperazin-1-yl)pyrimidin-4-amine hydrochloride (35 mg, 0.080 mmol), dimethylglycine (15 mg, 0.15 mmol), and HATU (50 mg, 0.13 mmol) in DMF (2 mL) was added triethylamine (0.050 mL, 0.36 mmol). The mixture was stirred at room temperature for 1 hour, quenched with saturated NaHCO3, and extracted with EtOAc. The organic phase was separated and filtered over MgSO4. The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography to give (R)-1-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)-2-(dimethylamino)ethan-1-one. 1 H NMR(400MHz,CDCl3)δ 7.84(s,1H),7.38(s,1H),7.17 - 7.27(m,2H),5.38 - 5.51(m,2H),3.37 - 3.68(m,8H),3.12(s,2H),2.29(s,6H),1.53(d,J=6.4Hz,3H).MS:(ES)m / z C 20 H 26 Cl3N6O[M+H] + Calculated value: 471.1, measured value: 471.1.

[0111] Example 12: Synthesis of (4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)((R)-piperazin-2-yl)methanone [ka] To a solution of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(piperazin-1-yl)pyrimidin-4-amine (200 mg, 0.47 mmol) and (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (112 mg, 0.49 mmol) in DCM (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (127 mg, 0.82 mmol) and dimethylaminopyridine (58 mg, 0.48 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated to dryness. The material was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by preparative HPLC to give (4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazin-1-yl)((R)-piperidin-2-yl)methanone. 1 H NMR(400MHz,CD3OD)δ 7.93(s,1H),7.48(s,1H),7.40(d,J=8.4Hz,1H),7.31(d,J=8.4,1H),5.60(q,J=7.2Hz,1H),4.34(d,J=11.2Hz,1H),3.92 - 3.81(m,1H),3.81 - 3.70(m,2H),3.64 - 3.48(m,5H),3.46 - 3.34(m,2H),3.05(dd,J=13.6,10.0Hz,1H),2.12(d,J=14.4Hz,1H),2.00 - 1.84(m,2H),1.80 - 1.68(m,2H),1.67 - 1.61(m,1H),1.58(d,J=7.2Hz,3H).MS:(ES)m / z C 22 H 28 Cl3N6O[M+H] + The calculated value was 497.1 and the measured value was 497.2.

[0112] Example 13: Synthesis of 2-(4-(D-prolyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidine [ka] Step a: To a solution of 2,4,5-trichloro-6-methyl-pyrimidine (3.00 g, 15.2 mmol) and triethylamine (3.2 mL, 22.8 mmol) in MeCN (60 mL) was added (1R)-1-(2,4-dichlorophenyl)ethanamine (2.89 g, 15.2 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated and purified by silica gel column chromatography to give 2,5-dichloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-methyl-pyrimidin-4-amine. MS: (ES) m / z C 13 H 12 Cl4N3[M+H] + The calculated value is 350.0 and the measured value is 350.0.

[0113] Step b: A mixture of 2,5-dichloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-methyl-pyrimidin-4-amine (400 mg, 1.14 mmol), tert-butyl piperazine-1-carboxylate (212 mg, 1.14 mmol), CsF (173 mg, 1.14 mmol), and N,N-diisopropylethylamine (0.61 mL, 3.42 mmol) in DMSO (3 mL) was heated at 100 °C overnight. The contents were diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl 4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-6-methyl-pyrimidin-2-yl]piperazine-1-carboxylate. MS: (ES) m / z C 22 H 29 Cl3N5O2[M+H] + Calculated value: 500.1, measured value: 500.1.

[0114] Step c: To a solution of tert-butyl 4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-6-methyl-pyrimidin-2-yl]piperazine-1-carboxylate (560 mg, 1.12 mmol) in DCM (0.5 mL) was added 4.0 M HCl in dioxane (3.0 mL, 12 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-methyl-2-piperazin-1-yl-pyrimidin-4-amine hydrochloride (480 mg, 1.10 mmol). MS: (ES) m / z C 17 H 21 Cl3N5[M+H] + The calculated value is 400.1 and the measured value is 400.0.

[0115] Step d: To a solution of 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-methyl-2-piperazin-1-yl-pyrimidin-4-amine (50 mg, 0.125 mmol) and (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (27 mg, 0.125 mmol) in DMF (1 mL) was added DIPEA (0.065 mL, 0.374 mmol) and HATU (47 mg, 0.125 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and then washed with HO and brine. The organic layer was dried over NaSO, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (2R)-2-[4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-6-methyl-pyrimidin-2-yl]piperazine-1-carbonyl]pyrrolidine-1-carboxylate. MS: (ES) m / z C 27 H 36 Cl3N6O3[M+H] + The calculated value is 597.2 and the measured value is 597.1.

[0116] Step e: A solution of tert-butyl (2R)-2-[4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-6-methyl-pyrimidin-2-yl]piperazine-1-carbonyl]pyrrolidine-1-carboxylate (70 mg, 0.117 mmol) and a 4.0 M solution of HCl in dioxane (1.0 mL, 4.00 mmol) was stirred at room temperature for 2 hours. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC to give 2-(4-(D-prolyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidine. 1 H NMR(400MHz,CD3OD)δ 7.48(s,1H),7.40(d,J=8.4Hz,1H),7.31(d,J=8.4Hz,1H),5.59(q,J=8.4Hz,1H),4.71(t,J=8.4Hz,1H),3.92 - 3.30(m,12H),2.57 - 2.45(m,1H),2.43(s,3H),2.16 - 1.88(m,3H),1.58(d,J=8.4Hz,3H).MS:(ES)m / z C 22 H 28 Cl3N6O[M+H] + Calculated value: 497.1, measured value: 497.1.

[0117] Example 14: Synthesis of 2-((S)-4-(D-prolyl)-3-(hydroxymethyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidine [ka] The title compound was prepared from a similar procedure by using (S)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate as one of the starting materials. 1H NMR(400MHz,CD3OD)δ 7.47(s,1H),7.39(d,J=8.4Hz,1H),7.30(d,J=8.4Hz,1H),5.56 - 5.52(m,1H),4.80 - 4.36(m,4H),4.25 - 4.00(m,1H),3.81 - 3.55(m,3H),3.52 - 3.30(m,4H),3.22 - 2.80(m,2H),2.57 - 2.45(m,5H),2.43-2.38(m,3H),2.16 - 1.92(m,3H),1.57(d,J=8.4Hz,3H).MS:(ES)m / z C 23 H 29 Cl3N6O2[M+H] + 527.1, actual value 527.2.

[0118] Example 15: Synthesis of (R)—N-(1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperidin-4-yl)pyrrolidine-2-carboxamide [ka] The title compound was prepared from a similar procedure by using tert-butyl piperidin-4-ylcarbamate and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine as starting materials. 1 H NMR(400MHz,CD3OD)δ 7.93(s,1H),7.47(s,1H),7.39(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H),5.59(q,J=8.4Hz,1H),4.30 - 4.10(m,3H),4.03 - 3.92(m,1H),3.45 - 3.30(m,5H),3.19(t,J=13.0Hz,2H),2.47 - 2.36(m,1H),2.11 - 1.86(m,5H),1.57(d,J=8.4Hz,3H),1.55 - 1.41(m,1H),1.31 -1.15(m,1H).MS:(ES)m / z C 22 H 28 Cl3N6O[M+H] +Calculated value: 497.1, measured value: 497.1.

[0119] Example 16: Synthesis of 2-((R)-4-(D-prolyl)-2-methylpiperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidine [ka] The title compound was prepared from a similar procedure by using (R)-tert-butyl 3-methylpiperazine-1-carboxylate and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine as starting materials. 1 H NMR(400MHz,CD3OD)δ 7.93(s,1H),7.48(d,J=4.0Hz,1H),7.38(d,J=8.4Hz,1H),7.30(d,J=8.4Hz,1H),5.60 - 5.51(m,1H),4.71 - 4.61(m,2H),4.35 - 4.05(m,2H),3.88 - 3.72(m,1H),3.58 - 3.22(m,6H),3.20 - 2.88(m,1H),2.68 - 2.42(m,1H),2.17 - 1.83(m,3H),1.58(d,J=7.1Hz,3H),1.02 - 0.79(m,3H).MS:(ES)m / z C 22 H 28 Cl3N6O[M+H] + Calculated value: 497.1, measured value: 497.1.

[0120] Example 17: Synthesis of 2-(D-prolyl)-5-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane [ka] The title compound was prepared from a similar procedure by using tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine as starting materials. 1 H NMR(400MHz,CD3OD)δ 7.94(s,1H),7.62 - 7.46(m,1H),7.41 - 7.28(m,2H),5.70 - 5.50(m,1H),5.12 - 4.60(m,4H),4.05 - 3.25(m,6H),2.90 - 2.65(m,1H),2.57 - 2.38(m,1H),2.16 - 1.86(m,5H),1.60(s,3H).MS:(ES)m / z C 22 H 25 Cl3N6O[M+H] + Calculated value: 495.1, measured value: 495.1.

[0121] Example 18: Synthesis of [(2R)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-[(2R)-pyrrolidin-2-yl]methanone [ka] Step a: To a mixture of 2,5-dichloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]pyrimidin-4-amine (150 mg, 0.45 mmol) and N,N-diisopropylethylamine (0.093 mL, 0.53 mmol) in DMF (1 mL) was added tert-butyl (2R)-2-methylpiperazine-1-carboxylate (89 mg, 0.45 mmol). The mixture was stirred at 80 °C for 15 hours, diluted with ethyl acetate (100 mL), and washed with HO and brine. The organic layer was dried over MgSO, filtered, and the filtrate was concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (2R)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2-methyl-piperazine-1-carboxylate. MS: (ES) m / z C 22 H 29 Cl3N5O2[M+H] + Calculated value: 500.1, measured value: 500.1.

[0122] Step b: A mixture of tert-butyl (2R)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2-methyl-piperazine-1-carboxylate (170 mg, 0.34 mmol) in 4N HCl solution in dioxane (2 mL, 8 mmol) was stirred at room temperature for 30 minutes. The mixture was diluted with diethyl ether, the solid product was filtered, washed with diethyl ether, and the residual solvent was removed in vacuo to give 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-amine. MS: (ES) m / z C 17 H 21 Cl3N5[M+H] + Calculated value: 400.1, measured value: 400.1.

[0123] Step c: To a mixture of 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-amine (62 mg, 0.14 mmol), (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (31 mg, 0.14 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.20 mmol) in DCM (1 mL) was added 4-(dimethylamino)pyridine (18 mg, 0.15 mmol). The mixture was stirred at room temperature for 48 hours. The reaction was quenched with saturated NH4Cl(aq), and the aqueous mixture was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated. The organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (2R)-2-[(2R)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2-methyl-piperazine-1-carbonyl]pyrrolidine-1-carboxylate. MS: (ES) m / z C 27 H 36 Cl3N6O3[M+H] + Calculated value: 597.2, measured value: 597.2.

[0124] Step d: A mixture of tert-butyl (2R)-2-[(2R)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2-methyl-piperazine-1-carbonyl]pyrrolidine-1-carboxylate (47 mg, 0.079 mmol) in a solution of 4N HCl in dioxane (1 mL, 4 mmol) was stirred at room temperature for 30 minutes. The mixture was diluted with diethyl ether, the solid was filtered, washed with diethyl ether, and the residual solvent was removed in vacuo to give [(2R)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-[(2R)-pyrrolidin-2-yl]methanone. 1H NMR(400MHz,CD3OD)δ 8.92(s,1H),8.03(s,1H),7.99(s,1H),7.51(s,1H),7.41(d,J=7.9Hz,1H),7.34(d,J=9.4Hz,1H),5.70 - 5.56(m,1H),4.69 - 4.48(m,1H),4.36 - 4.11(m,1H),4.09 - 3.73(m,2H),3.64 - 3.32(m,5H),2.61 - 2.46(m,1H),2.17 - 1.84(m,3H),1.67 - 1.55(m,3H),1.40 - 1.10(m,4H).MS:(ES)m / z C 22 H 28 Cl3N6O [M+H] + Calculated value: 497.1, measured value: 497.1.

[0125] Example 19: Synthesis of [(2R)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-piperazin-1-yl-methanone [ka] Step a: To a mixture of 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-4-amine dihydrochloride (80 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.088 mL, 0.51 mmol) in DCM (1 mL) was added tert-butyl 4-chlorocarbonylpiperazine-1-carboxylate (75 mg, 0.30 mmol). The contents were stirred at room temperature for 9 hours. The mixture was diluted with DCM and washed with HO and brine. The organic layer was concentrated and purified by silica gel column chromatography to give tert-butyl 4-((R)-4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-2-methylpiperazine-1-carbonyl)piperazine-1-carboxylate. MS: (ES) m / z C 27 H 37 Cl3N7O3[M+H] +Calculated value: 612.2, measured value: 612.2.

[0126] Step b: A mixture of tert-butyl 4-((R)-4-(5-chloro-4-(((1R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-2-methylpiperazine-1-carbonyl]piperazine-1-carboxylate (30 mg, 0.049 mmol) in a solution of 4 N HCl in dioxane (1 mL, 4 mmol) was stirred at room temperature for 30 minutes. The mixture was diluted with diethyl ether, the solid was filtered and washed with diethyl ether, and the residual solvent was removed in vacuo to give [(2R)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2-methyl-piperazin-1-yl]-piperazin-1-yl-methanone. 1 H NMR(400MHz,CD3OD)δ 8.06(s,1H),7.95(s,1H),7.51(s,1H),7.42 - 7.38(m,1H),7.36 - 7.31(m,1H),5.60(q,J=7.0Hz,1H),4.08 - 3.92(m,3H),3.56 - 3.34(m,7H),3.28 - 3.18(m,5H),3.13(s,1H),1.60(d,J=6.9Hz,3H),1.18(d,J=6.6Hz,3H).MS:(ES)m / z C 22 H 29 Cl3N7O[M+H] + Calculated value: 512.1, measured value: 512.1.

[0127] Example 20: Synthesis of [(2R,5S)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2,5-dimethyl-piperazin-1-yl]-[(2R)-pyrrolidin-2-yl]methanone [ka] Step a: To a mixture of 2,5-dichloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]pyrimidin-4-amine (300 mg, 0.89 mmol) and N,N-diisopropylethylamine (140 mg, 1.1 mmol) in DMF (5 mL) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (190 mg, 0.89 mmol). The contents were stirred at 100° C. for 18 h. The mixture was diluted with ethyl acetate and washed with HO and brine. The organic layer was dried over MgSO, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (2R,5S)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2,5-dimethyl-piperazine-1-carboxylate. MS: (ES) m / z C 23 H 31 Cl3N5O2[M+H] + Calculated value: 514.1, measured value: 514.1.

[0128] Step b: A mixture of tert-butyl (2R,5S)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2,5-dimethyl-piperazine-1-carboxylate (216 mg, 0.42 mmol) in a solution of 4N HCl in 1,4-dioxane (2 mL, 8 mmol) was stirred at room temperature for 1 hour. The mixture was diluted with diethyl ether, the solid product was filtered and washed with diethyl ether, and the residual solvent was removed in vacuo to give 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrimidin-4-amine. MS: (ES) m / z C 18 H 23 ClN3O5[M+H] + Calculated value: 414.1, measured value: 414.1.

[0129] Step c: To a mixture of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-((2S,5R)-2,5-dimethylpiperazin-1-yl)pyrimidin-4-amine (100 mg, 0.21 mmol), (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (68 mg, 0.32 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) in DCM (1 mL) was added 4-(dimethylamino)pyridine (26 mg, 0.21 mmol). The mixture was stirred at room temperature for 48 h. The reaction was quenched with saturated NH4Cl(aq), and the aqueous mixture was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (2R)-2-[(2R,5S)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2,5-dimethyl-piperazine-1-carbonyl]pyrrolidine-1-carboxylate. MS: (ES) m / z C 28 H 38 Cl3N6O3[M+H] + Calculated value: 611.2, measured value: 611.2.

[0130] Step d: A mixture of tert-butyl (2R)-2-[(2R,5S)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2,5-dimethyl-piperazine-1-carbonyl]pyrrolidine-1-carboxylate (64 mg, 0.11 mmol) in a solution of 4N HCl in dioxane (1 mL, 4 mmol) was stirred at room temperature for 30 minutes. The mixture was diluted with diethyl ether, the solid product was filtered, washed with diethyl ether, and the residual solvent was removed in vacuo to give [(2R,5S)-4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]-2,5-dimethyl-piperazin-1-yl]-[(2R)-pyrrolidin-2-yl]methanone. 1H NMR(400MHz,DMSO-d6)δ 8.78 - 8.41(m,1H),7.95(s,1H),7.59(s,1H),7.53(d,J=8.5,1H),7.43(d,J=8.5Hz,1H),5.55 - 5.36(m,1H),4.86 - 3.95(m,7H),3.30 - 3.11(m,3H),2.47 - 2.19(m,2H),2.04 - 1.83(m,3H),1.85 - 1.64(m,1H),1.48(d,J=6.9Hz,3H),1.28 - 0.92(m,4H).MS:(ES)m / z C 23 H 30 Cl3N6O[M+H] + The calculated value is 511.2 and the measured value is 511.1.

[0131] Example 21: Synthesis of 2-(3-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)ethan-1-ol [ka] Step a: To a mixture of pyridinium chlorochromate (30 g, 140 mmol) in DCM (300 mL) was added tert-butyl (3S)-3-(4-hydroxy-1-piperidyl)piperidine-1-carboxylate (10 g, 35 mmol). The contents were stirred at room temperature for 72 hours, and 2 M aqueous KCO was added. This biphasic mixture was stirred for 2 hours, filtered through celite, and the layers were separated. The aqueous layer was extracted with DCM, and the organic layers were combined, dried over MgSO, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel column chromatography to give tert-butyl (3S)-3-(4-oxo-1-piperidyl)piperidine-1-carboxylate. MS: (ES) m / z C 15 H 30 N2O4[M+H3O] + Calculated value: 301.2, measured value: 301.2.

[0132] Step b: To a mixture of tert-butyl (3S)-3-(4-oxo-1-piperidyl)piperidine-1-carboxylate (6.3 g, 22 mmol) in THF (100 mL) under a N atmosphere at −78° C., a solution of 1 M lithium bis(trimethylsilyl)amide in THF (27 mL, 27 mmol) was added dropwise over 10 minutes. The mixture was stirred at −20° C. for 2 hours and then cooled to −78° C. A solution of N,N-bis(trifluoromethanesulfonyl)aniline (10 g, 29 mmol) in 40 mL of THF was added dropwise, and the mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated NH4Cl(aq), and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to give tert-butyl (3S)-3-[4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridin-1-yl]piperidine-1-carboxylate. MS: (ES) m / z C 16 H 26 F3N2O5S[M+H] + The calculated value is 415.1 and the measured value is 415.2.

[0133] Step c: A mixture of tert-butyl (3S)-3-[4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridin-1-yl]piperidine-1-carboxylate (1.0 g, 2.4 mmol), potassium phenoxide (480 mg, 3.6 mmol), triphenylphosphine (38 mg, 0.14 mmol), and bis(pinacolato)diboron (670 mg, 2.7 mmol) in toluene (6 mL) was sparged with N gas for 5 minutes. Pd(PPh)Cl (51 mg, 0.072 mmol) was added and stirred at 50 °C for 3 hours. The contents were diluted with H0 and extracted with ethyl acetate. The organic layer was dried over MgSO, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel column chromatography to give tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]piperidine-1-carboxylate. MS: (ES) m / z C 21 H 38 BN2O4[M+H]+ Calculated value: 393.3, measured value: 393.3.

[0134] Step d: A mixture of 2,5-dichloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]pyrimidin-4-amine (260 mg, 0.76 mmol), tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]piperidine-1-carboxylate (300 mg, 0.76 mmol), and potassium carbonate (320 mg, 2.3 mmol) in a 1:1 solution of 1,4-dioxane / HO (4 mL) was sparged with N gas for 5 minutes. Pd(dppf)Cl-DCM complex (31 mg, 0.038 mmol) was added, and the mixture was stirred at 80 °C for 15 hours. The contents were diluted with HO and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel column chromatography to give tert-butyl 3-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate. MS: (ES) m / z C 27 H 35 Cl3N5O2[M+H] + Calculated value: 566.2, measured value: 566.2.

[0135] Step e: A mixture of tert-butyl 3-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate in a solution of 4N HCl in dioxane (1 mL, 4 mmol) was stirred at room temperature for 30 minutes. The mixture was diluted with diethyl ether, the solid product was filtered, washed with diethyl ether, and residual solvent was removed in vacuo to give 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(1-(piperidin-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amine dihydrochloride. MS: (ES) m / z C 22H 27 Cl3N5[M+H] + Calculated value: 466.1, measured value: 466.1.

[0136] Step f: To a mixture of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(1-(piperidin-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amine dihydrochloride (45 mg, 0.097 mmol) and potassium carbonate (41 mg, 0.3 mmol) in acetonitrile (0.5 mL) was added 2-iodoethanol (17 mg, 0.1 mmol). The mixture was stirred at 80° C. for 5 hours. The crude mixture was purified by preparative HPLC to give 2-(3-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)ethan-1-ol. 1 H NMR(400MHz,CD3OD)δ 8.21(s,1H),7.69 - 7.63(m,1H),7.43(s,1H),7.42 - 7.35(m,1H),7.26(d,J=8.6Hz,1H),6.95(s,1H),5.63(q,J=7.0Hz,1H),4.01 - 3.81(m,5H),3.81 - 3.70(m,1H),3.68 - 3.51(m,2H),3.51 - 3.33(m,4H),3.13(s,1H),3.09 - 2.96(m,1H),2.95 - 2.82(m,1H),2.79 - 2.64(m,1H),2.35 - 2.08(m,2H),1.97 - 1.78(m,2H),1.56(d,J=7.2Hz,3H).MS:(ES)m / z C 24 H 31 Cl3NO[M+H] + Calculated value: 510.2, measured value: 510.2.

[0137] Example 22: Synthesis of 3-(3-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)propanoic acid [ka] To a mixture of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(1-(piperidin-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amine dihydrochloride (45 mg, 0.097 mmol) and N,N-diisopropylethylamine (52 mg, 0.40 mmol) in toluene (1 mL) was added acrylic acid (50 mg, 0.70 mmol). The mixture was stirred at 85° C. for 18 hours. The mixture was concentrated in vacuo and purified by preparative HPLC to give 3-(3-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)propanoic acid. 1 H NMR(400MHz,CD3OD)δ 8.20(s,1H),7.65 - 7.60(m,1H),7.44(s,1H),7.39(d,J=8.6Hz,1H),7.26(d,J=8.6Hz,1H),6.99 - 6.89(m,1H),5.62(q,J=7.9,7.0Hz,1H),3.89(s,2H),3.65 - 3.53(m,1H),3.53 - 3.33(m,6H),3.19 - 3.08(m,1H),2.93 - 2.75(m,4H),2.74 - 2.60(m,1H),2.22 - 2.03(m,2H),1.90 - 1.74(m,2H),1.56(d,J=7.5Hz,3H).MS:(ES)m / z C 25 H 31 Cl3N5O2[M+H] + Calculated value: 538.2, measured value: 538.2.

[0138] Example 23: Synthesis of 3-(3-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)propanamide [ka] To a mixture of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(1-(piperidin-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amine dihydrochloride (45 mg, 0.097 mmol) and potassium carbonate (54 mg, 0.4 mmol) in acetonitrile (0.5 mL) was added 3-bromopropanamide (18 mg, 0.12 mmol). The mixture was stirred at 80° C. for 5 hours. The crude mixture was purified by preparative HPLC to give 3-(3-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)propanamide. 1 H NMR(400MHz,CD3OD)δ 8.21(s,1H),7.68 - 7.59(m,3H),7.44(s,1H),7.39(d,J=8.7Hz,1H),7.26(d,J=8.3Hz,1H),6.95(d,J=2.0Hz,1H),5.69 - 5.57(m,1H),4.02 - 3.87(m,2H),3.81 - 3.67(m,1H),3.65 - 3.53(m,1H),3.52 - 3.32(m,6H),3.28 - 3.17(m,1H),3.06 - 2.81(m,2H),2.79 - 2.62(m,2H),2.35 - 2.05(m,2H),1.94 - 1.79(m,2H),1.57(d,J=7.3Hz,3H).MS:(ES)m / z C 25 H 32 Cl3N6O[M+H] + Calculated value: 537.2, measured value: 537.2.

[0139] Example 24: Synthesis of 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-[4-(3-piperidyl)piperazin-1-yl]pyrimidin-4-amine [ka] Step a: To a mixture of 2,5-dichloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]pyrimidin-4-amine (500 mg, 1.5 mmol) and N,N-diisopropylethylamine (210 mg, 1.6 mmol) in DMF (5 mL) was added tert-butyl piperazine-1-carboxylate. The mixture was stirred at 80 °C for 3 hours. The contents were cooled to room temperature, diluted with ethyl acetate, and then washed with HO and brine. The organic layer was dried over MgSO, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl 4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]piperazine-1-carboxylate. MS: (ES) m / z C 21 H 27 Cl3N5O2[M+H] + Calculated value: 486.1, measured value: 486.1.

[0140] Step b: To a mixture of tert-butyl 4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]piperazine-1-carboxylate (540 mg, 1.1 mmol) in DCM (4 mL) was added trifluoroacetic acid (1.5 g, 13 mmol). The contents were stirred at room temperature for 18 hours. The mixture was quenched with saturated K2CO3 (aq) and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated to give 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-piperazin-1-yl-pyrimidin-4-amine. MS: (ES) m / z C 16 H 19 Cl3N5[M+H] + Calculated value: 386.1, measured value: 386.1.

[0141] Step c: To a solution of 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-piperazin-1-yl-pyrimidin-4-amine (340 mg, 0.88 mmol), tert-butyl 3-oxopiperidine-1-carboxylate (180 mg, 0.89 mmol), triethylamine (180 mg, 1.8 mmol), and acetic acid (110 mg, 1.8 mmol) was added sodium cyanoborohydride (220 mg, 3.6 mmol). The mixture was stirred at room temperature for 24 hours and then heated at 50° C. for 18 hours. The crude reaction mixture was concentrated and purified by silica gel column chromatography to give tert-butyl 3-[4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]piperazin-1-yl]piperidine-1-carboxylate. MS: (ES) m / z C 26 H 36 Cl3N6O2[M+H] + Calculated value: 569.2, measured value: 569.2.

[0142] Step d: A mixture of tert-butyl 3-[4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]piperazin-1-yl]piperidine-1-carboxylate (140 mg, 0.24 mmol) in a solution of 4 N HCl in dioxane (5 mL, 20 mmol) was stirred at room temperature for 18 hours. The mixture was concentrated to dryness to give 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-[4-(3-piperidyl)piperazin-1-yl]pyrimidin-4-amine. 1 H NMR(400MHz,CD3OD)δ 8.04(s,1H),7.67 - 7.61(m,1H),7.52(s,1H),7.43(dd,J=49.0,8.5Hz,1H),7.35(d,J=9.2Hz,1H),5.65(q,J=7.1Hz,1H),4.19 - 3.33(m,11H),3.24 - 2.90(m,3H),2.37 - 2.24(m,1H),2.19 - 2.07(m,1H),1.94 - 1.81(m,2H),1.61(d,J=7.1Hz,3H).MS:(ES)m / z C21 H 28 Cl3N6[M+H] + Calculated value: 469.1, measured value: 469.1.

[0143] Example 25: Synthesis of 3-[3-[4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]piperazin-1-yl]-1-piperidyl]propanoic acid [ka] To a mixture of 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-[4-(3-piperidyl)piperazin-1-yl]pyrimidin-4-amine dihydrochloride (48 mg, 0.088 mmol) and N,N-diisopropylethylamine (46 mg, 0.35 mmol) in toluene (1 mL) was added acrylic acid (45 mg, 0.62 mmol). The mixture was stirred at 85 °C for 18 h. The reaction was quenched with saturated NaHCO (aq) and extracted with DCM. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give 3-[3-[4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]piperazin-1-yl]-1-piperidyl]propanoic acid. 1 H NMR(400MHz,CD3OD)δ 8.35 - 8.28(m,1H),7.90(s,1H),7.51 - 7.44(m,1H),7.42 - 7.36(m,1H),7.35 - 7.28(m,1H),5.57(q,J=7.0Hz,1H),3.76 - 3.60(m,4H),3.49 - 3.34(m,4H),3.25 - 3.00(m,2H),2.93 - 2.81(m,3H),2.79 - 2.59(m,4H),2.12 - 1.99(m,1H),1.99 - 1.87(m,1H),1.84 - 1.66(m,2H),1.58(d,J=7.1Hz,3H).MS:(ES)m / z C 24 H 32 Cl3N6O2[M+H] +Calculated value: 541.2, measured value: 541.2.

[0144] Example 26: Synthesis of 2-([3,4'-bipiperidin]-1'-yl)-5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine [ka] Step a: To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 1.29 mmol) and 4-iodopyridine (265 mg, 1.29 mmol) in ethanol (2 mL) and toluene (4 mL) was added 2 M aqueous KCO (2 mL, 3.88 mmol). The mixture was degassed with N for 10 minutes, and tetrakis(triphenylphosphine)palladium(0) (74 mg, 0.065 mmol) was added. The reaction was heated at 100 °C for 3 hours, and then the contents were filtered through Celite. The filtrate was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl 5,6-dihydro-[3,4'-bipyridine]-1(2H)-carboxylate. MS: (ES) m / z C 15 H 21 N2O2[M+H] + The calculated value is 261.2, and the measured value is 261.2.

[0145] Step b: To a solution of tert-butyl 5,6-dihydro-[3,4'-bipyridine]-1(2H)-carboxylate (136 mg, 0.52 mmol) in MeOH (2 mL) was added PtO (54 mg, 0.24 mmol) and acetic acid (0.15 mL, 2.61 mmol). The reaction mixture was placed on a Parr shaker under H at 50 psi for 3 days. The contents were filtered and the filtrate was concentrated to give tert-butyl [3,4'-bipiperidine]-1-carboxylate. MS: (ES) m / z C 15 H 29 N2O2[M+H] +The calculated value is 269.2, and the measured value is 269.2.

[0146] Step c: To a solution of tert-butyl [3,4'-bipiperidine]-1-carboxylate (140 mg, 0.52 mmol) and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (176 mg, 0.52 mmol) in DMSO (1 mL) was added N,N-diisopropylamine (0.45 mL, 2.61 mmol), followed by cesium fluoride (79.2 mg, 0.52 mmol). The mixture was heated at 100°C for 16 hours. The reaction was quenched with water, and the contents were extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl 1'-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-[3,4'-bipiperidine]-1-carboxylate. MS: (ES) m / z C 27 H 37 Cl3N5O2[M+H] + Calculated value: 568.2, measured value: 568.2.

[0147] Step d: To a solution of tert-butyl 1'-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-[3,4'-bipiperidine]-1-carboxylate (140 mg, 0.52 mmol) in dioxane (2 mL) was added a solution of 4.0 M HCl in dioxane (2 mL, 8.0 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The crude material was purified by preparative HPLC to give 2-([3,4'-bipiperidin]-1'-yl)-5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine. 1H NMR(400MHz,CD3OD)δ 7.90(s,1H),7.50(s,1H),7.38(d,J=8.4,1H),7.32(d,J=8.4Hz,1H),5.56(q,J=6.8Hz,1H),4.35(d,J=10.8Hz,1H),4.25(d,J=11.6Hz,1H),3.37 - 3.32(m,2H),3.05 - 2.78(m,3H),2.75 - 2.64(m,1H),2.00 - 1.84(m,2H),1.84 - 1.64(m,3H),1.59(d,J=7.2Hz,3H),1.57 - 1.49(m,2H),1.32 - 1.17(m,2H),0.91(s,1H).MS:(ES)m / z C 22 H 29 Cl3N5[M+H] + The calculated value was 468.1 and the measured value was 486.2.

[0148] Example 27: Synthesis of 2-(1'-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-[3,4'-bipiperidin]-1-yl)ethan-1-ol [ka] To a solution of 2-([3,4'-bipiperidin]-1'-yl)-5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (75 mg, 0.15 mmol) in MeCN (1 mL) was added KCO (62 mg, 0.45 mmol) and 2-iodoethanol (44 mg, 0.26 mmol). The reaction was stirred at 80 °C for 4 hours and then quenched with water. The contents were extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography followed by preparative HPLC to give 2-(1'-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-[3,4'-bipiperidin]-1-yl)ethan-1-ol. 1H NMR(400MHz,CD3OD)δ 7.86(s,1H),7.48(s,1H),7.37(d,J=8.8Hz,1H),7.31(d,J=8.4Hz,1H),5.67 - 5.46(m,1H),4.46 - 4.26(m,2H),3.89(dd,J=5.3,5.3Hz,2H),3.59(dd,J=14.0,14.0Hz,2H),3.28 - 3.16(m,2H),2.96 - 2.82(m,3H),2.74(dd,J=12.3Hz,1H),2.01(d,J=15.2Hz,1H),1.92 - 1.81(m,1H),1.80 - 1.63(m,5H),1.57(d,J=6.8Hz,3H),1.30 - 1.17(m,2H),1.04 - 0.80(m,1H).MS:(ES)m / z C 24 H 33 Cl3NO[M+H] + The calculated value is 512.2, and the measured value is 512.3.

[0149] Example 28: Synthesis of 3-(1'-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-[3,4'-bipiperidin]-1-yl)propanoic acid [ka] To a solution of 2-([3,4'-bipiperidin]-1'-yl)-5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (75 mg, 0.15 mmol) in toluene (1 mL) was added N,N-diisopropylethylamine (0.05 mL, 0.74 mmol) and acrylic acid (0.02 mL, 0.26 mmol). The reaction was stirred at 85°C for 16 hours. The contents were concentrated and the crude material was purified by preparative HPLC to give 3-(1'-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-[3,4'-bipiperidin]-1-yl)propanoic acid. 1H NMR(400MHz,CD3OD)δ 7.89(s,1H),7.50(s,1H),7.37(d,J=8.8Hz,1H),7.32(d,J=8.4Hz,1H),5.61 - 5.53(m,1H),4.36(d,J=12.0Hz,1H),4.31 - 4.23(m,1H),3.60 - 3.46(m,3H),3.45 - 3.37(m,2H),2.99 - 2.89(m,3H),2.89 - 2.81(m,2H),2.80 - 2.70(m,1H),2.07 - 1.98(m,1H),1.91 - 1.66(m,5H),1.59(d,J=7.2,Hz,3H),1.32 - 1.15(m,2H),1.06 - 0.85(m,1H).MS:(ES)m / z C 25 H 33 Cl3N5O2[M+H] + Calculated value: 540.2, measured value: 540.2.

[0150] Example 29: Synthesis of (R)—N-((3R,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)-3-hydroxypiperidin-4-yl)pyrrolidine-2-carboxamide [ka] Step a: To a solution of 2,4-dichloro-5-fluoropyrimidine (350 mg, 2.1 mmol) and (R)-1-(2,4-dichlorophenyl)ethan-1-amine (400 mg, 2.1 mmol) in DMSO (2 mL) was added DIPEA (1.8 mL, 10.5 mmol). The reaction mixture was stirred at 90° C. for 3 hours. Water was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-fluoropyrimidin-4-amine. MS: (ES) m / z C 12 H 10 Cl3FN3[M+H] + The calculated value is 320.0, and the measured value is 320.0.

[0151] Step b: To a solution of (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-fluoropyrimidin-4-amine (100 mg, 0.31 mmol) and tert-butyl ((3R,4S)-3-hydroxypiperidin-4-yl)carbamate (77 mg, 0.35 mmol) in DMSO (1 mL) was added DIPEA (0.1 mL, 0.58 mmol). The reaction mixture was stirred at 100° C. for 16 hours. Water was added and the mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl ((3R,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamate. MS: (ES) m / z C 22 H 29 Cl2FN5O3[M+H] + Calculated value: 500.2, measured value: 500.2.

[0152] Step c: To a solution containing tert-butyl ((3R,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamate (110 mg, 0.22 mmol) in dioxane (1 mL) was added 4.0 M HCl in dioxane (1 mL, 4.0 mmol). The contents were stirred at room temperature for 3 hours and then concentrated to give (3R,4S)-4-amino-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)piperidin-3-ol. MS: (ES) m / z C 17 H 21 Cl2FNO[M+H] + Calculated value: 400.1, measured value: 400.1.

[0153] Step d: To a solution containing (3R,4S)-4-amino-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)piperidin-3-ol (85 mg, 0.19 mmol) and (tert-butoxycarbonyl)-D-proline (50 mg, 0.23 mmol) in DMF (1 mL) was added HATU (148 mg, 0.39 mmol) followed by EtN (0.11 mL, 0.79 mmol). The reaction was stirred at room temperature for 16 h and then quenched with water. The mixture was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (R)-2-(((3R,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamoyl)pyrrolidine-1-carboxylate. MS: (ES) m / z C 27 H 36 Cl2FN6O4[M+H] + The calculated value was 597.2 and the measured value was 597.3.

[0154] Step e: To a solution containing tert-butyl (R)-2-(((3R,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamoyl)pyrrolidine-1-carboxylate (102 mg, 0.17 mmol) in dioxane (1 mL) was added 4.0 M HCl in dioxane (1 mL, 4.0 mmol). The contents were stirred at room temperature for 5 hours, then concentrated and purified by preparative HPLC to give (R)—N-((3R,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)pyrrolidine-2-carboxamide. 1H NMR(400MHz,CD3OD)δ 7.82(dd,J=5.3,0.7Hz,1H),7.49(d,J=2.1Hz,1H),7.41(d,J=8.4Hz,1H),7.34(dd,J=8.4,2.1Hz,1H),5.75 - 5.52(m,1H),4.87 - 4.83(m,1H),4.41(s,1H),4.24(dd,J=8.5,6.6Hz,1H),4.06 - 3.98(m,2H),3.53 - 3.36(m,1H),3.36 - 3.32(m,3H),3.22 - 2.95(m,1H),2.43(ddd,J=12.7,8.4,6.2Hz,1H),2.12 - 1.88(m,4H),1.58(d,J=7.1Hz,3H).MS:(ES)m / z C 22 H 28 Cl2FN6O2[M+H] + The calculated value was 497.2, and the measured value was 497.2.

[0155] Example 30: Synthesis of (R)-5-(4-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-2-one [ka] Step a: To a solution of 2,4-dichloro-5-fluoropyrimidine (350 mg, 2.1 mmol) and (R)-1-(2,4-dichlorophenyl)ethan-1-amine (400 mg, 2.1 mmol) in DMSO (2 mL) was added DIPEA (1.8 mL, 10.5 mmol). The reaction mixture was stirred at 90° C. for 3 hours. Water was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-fluoropyrimidin-4-amine. MS: (ES) m / z C 12 H 10 Cl3FN3[M+H] + The calculated value is 320.0, and the measured value is 320.0.

[0156] Step b: To a mixture of (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-fluoropyrimidin-4-amine (624 mg, 0.91 mmol) and tert-butyl piperazine-1-carboxylate (400 mg, 2.15 mmol) was added DIPEA (1.7 mL, 9.8 mmol). The reaction mixture was stirred at 115° C. for 3 hours. An additional amount of tert-butyl piperazine-1-carboxylate (400 mg, 2.15 mmol) was added, and the contents were stirred for an additional 16 hours at 115° C. Water was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (R)-4-(4-((1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate. MS: (ES) m / z C 21 H 27 Cl2FN5O2[M+H] + Calculated value: 470.1, measured value: 470.1.

[0157] Step c: To a solution containing tert-butyl (R)-4-(4-((1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (150 mg, 0.32 mmol) in dioxane (1 mL) was added 4.0 M HCl in dioxane (1 mL, 4.0 mmol). The contents were stirred at room temperature for 3 hours and then concentrated to give (R)-N-(1-(2,4-dichlorophenyl)ethyl)-5-fluoro-2-(piperazin-1-yl)pyrimidin-4-amine hydrochloride. MS: (ES) m / z C 16 H 19 Cl2FN5[M+H] + The calculated value is 370.1, and the measured value is 370.1.

[0158] Step d: To a solution containing (R)-N-(1-(2,4-dichlorophenyl)ethyl)-5-fluoro-2-(piperazin-1-yl)pyrimidin-4-amine hydrochloride (130 mg, 0.32 mmol) and (R)-5-oxopyrrolidine-2-carboxylic acid (51 mg, 0.40 mmol) in DMF (0.5 mL) was added HATU (242 mg, 0.64 mmol) followed by EtN (0.15 mL, 1.1 mmol). The reaction was stirred at room temperature for 16 hours and then quenched with water. The mixture was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (R)-5-(4-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-2-one. 1 H NMR(400MHz,CD3OD)δ 7.99 - 7.87(m,1H),7.52(s,1H),7.42(d J=8.6Hz,1H),7.34(d,J=8.4Hz,1H),5.73 - 5.55(m,1H),4.74(dt,J=8.0,3.4Hz,1H),3.94 - 3.48(m,8H),2.57 - 2.46(m,1H),2.40 - 2.34(m,2H),2.09 - 1.99(m,1H),1.59(d,J=7.0Hz,3H).MS:(ES)m / z C 21 H 24 Cl2FN6O2[M+H] + Calculated value: 481.1, measured value: 481.1.

[0159] Example 31: Synthesis of (5R)-5-(4-(5-chloro-4-((1-(2,4-dichloro-5-fluorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-2-one [ka] Step a: To a vial was added 2,4,5-trichloropyrimidine (91 mg, 0.50 mmol), DMF (4 mL), 1-(2,4-dichloro-5-fluoro-phenyl)ethanamine (208 mg, 1.00 mmol), and DIPEA (0.35 mL, 2.00 mmol). The mixture was stirred at 100 °C for 1.5 hours, cooled to room temperature, diluted with water and saturated NaHCO, and extracted with EtOAc. The organic layer was separated, filtered over NaSO, concentrated, and purified by silica gel column chromatography to give 2,5-dichloro-N-[1-(2,4-dichloro-5-fluoro-phenyl)ethyl]pyrimidin-4-amine. MS: (ES) m / z C 12 H9Cl4FN3[M+H] + Calculated value: 354.0, measured value: 354.0.

[0160] Step b: To a vial of 2,5-dichloro-N-[1-(2,4-dichloro-5-fluoro-phenyl)ethyl]pyrimidin-4-amine (100 mg, 0.28 mmol) was added tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol). The mixture was stirred at 125° C. for 1 hour, cooled to room temperature, and purified by silica gel column chromatography to give tert-butyl 4-[5-chloro-4-[1-(2,4-dichloro-5-fluoro-phenyl)ethylamino]pyrimidin-2-yl]piperazine-1-carboxylate. MS: (ES) m / z C 21 H 26 Cl3FN5O2[M+H] + Calculated value: 504.1, measured value: 504.1.

[0161] Step c: To a flask containing tert-butyl 4-[5-chloro-4-[1-(2,4-dichloro-5-fluoro-phenyl)ethylamino]pyrimidin-2-yl]piperazine-1-carboxylate (120 mg, 0.24 mmol), 4.0 M HCl in dioxane (3.0 mL, 12.0 mmol) was added. The mixture was stirred for 0.5 hours and then concentrated to dryness to give 5-chloro-N-[1-(2,4-dichloro-5-fluoro-phenyl)ethyl]-2-piperazin-1-yl-pyrimidin-4-amine hydrochloride. MS: (ES) m / z C 16 H 18 Cl3FN5[M+H] + The calculated value is 404.1 and the measured value is 404.0.

[0162] Step d: To a vial of 5-chloro-N-[1-(2,4-dichloro-5-fluoro-phenyl)ethyl]-2-piperazin-1-yl-pyrimidin-4-amine hydrochloride (35 mg, 0.079 mmol) in DMF (1 mL) was added (2R)-5-oxopyrrolidine-2-carboxylic acid (25 mg, 0.19 mmol), HATU (70 mg, 0.18 mmol), and EtN (0.10 mL, 0.72 mmol). The mixture was stirred for 0.5 hours, quenched with water, and purified by preparative HPLC to give (5R)-5-[4-[5-chloro-4-[1-(2,4-dichloro-5-fluoro-phenyl)ethylamino]pyrimidin-2-yl]piperazine-1-carbonyl]pyrrolidin-2-one. 1 H NMR(400MHz,CD3OD)δ 7.98(s,1H),7.67 - 7.62(m,1H),7.32(dd,J=10,1.2Hz,1H),5.63 - 5.55(m,1H),4.73 - 4.67(m,1H),3.80 - 3.59(m,7H),3.57 - 3.47(m,1H),2.57 - 2.45(m,1H),2.42 - 2.31(m,2H),2.07 - 1.94(m,1H),1.60(d,J=7.2Hz,3H).MS:(ES)m / z C 21 H 23 Cl3FN6O2[M+H] + Calculated value: 515.1, measured value: 515.1.

[0163] Example 32: Synthesis of 3-(1'-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-[3,4'-bipiperidin]-1-yl)propanamide [ka] To a vial of 3-(1'-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-[3,4'-bipiperidin]-1-yl)propanoic acid (32 mg, 0.058 mmol) in DCM (4 mL) was added oxalyl dichloride (50 mg, 0.39 mmol) and DMF (0.05 mL). The mixture was stirred for 15 hours and then concentrated to dryness. The resulting residue was redissolved in DCM and a saturated solution of NH in DCM (0.3 mL) was added. The mixture was stirred for 0.5 hours and purified by silica gel column chromatography to give 3-(1'-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-[3,4'-bipiperidin]-1-yl)propanamide. 1 H NMR(400MHz,CD3OD)δ 7.86(s,1H),7.75(s,1H),7.74(s,1H),7.36(m,1H),7.27(m,1H),5.47 - 5.40(m,1H),4.45(d,J=12.8Hz,2H),3.76 - 3.69(m,1H),3.55 - 3.20(m,5H),2.97 - 2.60(m,6H),2.02 - 1.92(m,1H),1.85 - 1.74(m,2H),1.65 - 1.57(m,1H),1.57 - 1.45(m,4H),1.39(d,J=6.4Hz,3H),1.30 - 1.05(m,2H);(ES) m / z C 25 H 34 Cl3N6O[M+H] + Calculated value: 539.2, measured value: 539.2.

[0164] Example 33: Synthesis of 2-(4-(D-prolyl)piperazin-1-yl)-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-hydroxypyrimidine [ka] To a vial of [4-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]piperazin-1-yl]-[(2R)-pyrrolidin-2-yl]methanone hydrochloride (50 mg, 0.10 mmol) was added BBr3 (0.13 mL, 1.37 mmol). The mixture was stirred for 3 hours, then cooled to 0 °C, and water and MeOH were added. The contents were concentrated to dryness and purified by preparative HPLC to give 2-(4-(D-prolyl)piperazin-1-yl)-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-hydroxypyrimidine. 1 H NMR(400MHz,CD3OD)δ 7.49(s,1H),7.42(d,J=8.4Hz,1H),7.31(d,J=8.0Hz,1H),7.12(s,1H),5.63(q,J=7.2Hz,1H),5.49(s,1H),4.71(t,J=7.6Hz,1H),3.83 - 3.32(m,10H),2.56 - 2.46(m,1H),2.14 - 1.90(m,3H),1.57(d,J=6.8Hz,3H).MS:(ES)m / z C 21 H 27 Cl2N6O2[M+H] + Calculated value: 465.1, measured value: 465.1.

[0165] Example 34: Synthesis of (R)—N-((3S,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-methoxypyrimidin-2-yl)-3-hydroxypiperidin-4-yl)pyrrolidine-2-carboxamide [ka] Step a: To a vial of 2-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-methoxy-pyrimidin-4-amine (250 mg, 0.75 mmol), tert-butyl N-[(3S,4S)-3-hydroxy-4-piperidyl]carbamate (325 mg, 1.50 mmol) was added. The mixture was stirred at 125° C. for 3 hours, cooled to room temperature, and purified by silica gel column chromatography to give tert-butyl N-[(3S,4S)-1-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]-3-hydroxy-4-piperidyl]carbamate. MS: (ES) m / z C 23 H 32 Cl2N5O4[M+H] + The calculated value is 512.2, and the measured value is 512.3.

[0166] Step b: To a vial was added tert-butyl N-[(3S,4S)-1-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]-3-hydroxy-4-piperidyl]carbamate (380 mg, 0.74 mmol) and 4.0 M HCl in dioxane (3.0 mL, 12.0 mmol). The mixture was stirred for 0.5 hours and concentrated to dryness to give (3S,4S)-4-amino-1-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]piperidin-3-ol hydrochloride. MS: (ES) m / z C 18 H 24 Cl2N5O2[M+H] + Calculated value: 412.1, measured value: 412.1.

[0167] Step c: To a vial of (3S,4S)-4-amino-1-[4-[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]piperidin-3-ol hydrochloride (40 mg, 0.089 mmol) in DMF (2 mL) was added (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (28 mg, 0.130 mmol), HATU (70 mg, 0.18 mmol), and EtN (0.10 mL, 0.72 mmol). The mixture was stirred for 0.5 h, quenched with water and saturated NaHCO, and extracted with EtOAc. The organic layer was collected, filtered through NaSO, and purified by silica gel column chromatography to give tert-butyl (2R)-2-[[(3S,4S)-1-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]-3-hydroxy-4-piperidyl]carbamoyl]pyrrolidine-1-carboxylate. MS: (ES) m / z C 28 H 39 Cl2N6O5[M+H] + The calculated value is 609.2 and the measured value is 609.3.

[0168] Step d: To a vial containing tert-butyl (2R)-2-[[(3S,4S)-1-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]-3-hydroxy-4-piperidyl]carbamoyl]pyrrolidine-1-carboxylate (50 mg, 0.084 mmol), 4N HCl in dioxane (2.0 mL, 8.19 mmol) was added. The mixture was stirred for 0.5 hours, concentrated to dryness, and purified by preparative HPLC to give the desired product, (R)-N-((3S,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-methoxypyrimidin-2-yl)-3-hydroxypiperidin-4-yl)pyrrolidine-2-carboxamide. 1H NMR(400MHz,CD3OD)δ 8.92(d,J=6.0Hz,1H),8.46(d,J=7.6Hz,1H),7.46(s,1H),7.38(d,J=8.8Hz,1H),7.30(d,J=8.0Hz,1H),7.24(s,1H),5.64 - 5.54(m,1H),4.26 - 4.16(m,3H),3.89(s,3H),3.87 - 3.80(m,1H),3.50 - 3.32(m,3H),3.17(dd,J=11.4,11.4Hz,1H),3.00(dd,J=11.8,11.8Hz,1H),2.47 - 2.37(m,1H),2.10 - 1.90(m,4H),1.56(d,J=7.2Hz,3H),1.30 - 1.18(m,1H).MS:(ES)m / z C 23 H 31 Cl2N6O3[M+H] + Calculated value: 509.2, measured value: 509.2.

[0169] Example 35: Synthesis of (R)-5-(4-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-methoxypyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-2-one [ka] To a vial of N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-methoxy-2-piperazin-1-yl-pyrimidin-4-amine hydrochloride (35 mg, 0.084 mmol) in DMF (1.5 mL) was added (2R)-5-oxopyrrolidine-2-carboxylic acid (25 mg, 0.19 mmol), HATU (85 mg, 0.22 mmol), and EtN (0.10 mL, 0.72 mmol). The mixture was stirred for 0.5 h, quenched with water, and purified by preparative HPLC to give (R)-5-(4-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-methoxypyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-2-one. 1H NMR(400MHz,CD3OD)δ 8.98(d,J=7.2Hz,1H),7.50(s,1H),7.39(d,J=8.4Hz,1H),7.31(d,J=8.4Hz,1H),7.28(s,1H),5.67 - 5.59(m,1H),4.74 - 4.68(m,1H),3.91(s,3H),3.80 - 3.51(m,8H),2.55 - 2.45(m,1H),2.45 - 2.25(m,2H),2.07 - 1.97(m,1H),1.57(d,J=6.4Hz,3H).MS:(ES)m / z C 22 H 27 Cl2N6O3[M+H] + Calculated value: 493.1, measured value: 493.1.

[0170] Example 36: Synthesis of 2-(4-(D-prolyl)piperazin-1-yl)-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-methoxypyrimidine [ka] Step a: To a vial of 2,4-dichloro-5-methoxy-pyrimidine (754 mg, 4.21 mmol) in DMF (12 mL) was added (1R)-1-(2,4-dichlorophenyl)ethanamine (800 mg, 4.21 mmol) and DIPEA (0.77 mL, 4.42 mmol). The mixture was stirred at 90 °C for 5 hours, cooled to room temperature, diluted with water and saturated NaHCO and extracted with EtOAc. The organic layer was separated, filtered over NaSO, concentrated to dryness and purified by silica gel column chromatography to give 2-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-methoxy-pyrimidin-4-amine. MS: (ES) m / z C 13 H 13 Cl3N3O[M+H] + Calculated value: 332.0, measured value: 332.0.

[0171] Step b: To a vial was added 2-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-methoxy-pyrimidin-4-amine (200 mg, 0.60 mmol) and tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol). The mixture was stirred at 125° C. for 5 hours, cooled to room temperature, and purified by silica gel column chromatography to give tert-butyl 4-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]piperazine-1-carboxylate. MS: (ES) m / z C 22 H 30 Cl2N5O3[M+H] + The calculated value is 482.2 and the measured value is 482.1.

[0172] Step c: To a flask containing tert-butyl 4-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]piperazine-1-carboxylate (280 mg, 0.58 mmol), 4.0 M HCl in dioxane (4.0 mL, 16.0 mmol) was added. The mixture was stirred for 0.5 hours and then concentrated to dryness to give N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-methoxy-2-piperazin-1-yl-pyrimidin-4-amine hydrochloride. MS: (ES) m / z C 17 H 22 Cl2NO[M+H] + The calculated value is 382.1, and the measured value is 382.1.

[0173] Step d: To a vial of N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-methoxy-2-piperazin-1-yl-pyrimidin-4-amine (170 mg, 0.44 mmol) in DMF (2 mL) was added (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (110 mg, 0.51 mmol), HATU (200 mg, 0.53 mmol), and EtN (0.30 mL, 2.15 mmol). The mixture was stirred for 0.5 h, quenched with water and saturated NaHCO, and extracted with EtOAc. The organic layers were collected, filtered through Na2SO4, and purified by silica gel column chromatography to give tert-butyl (2R)-2-[4-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]piperazine-1-carbonyl]pyrrolidine-1-carboxylate. MS: (ES) m / z C 27 H 37 Cl2N6O4[M+H] + The calculated value was 579.2 and the measured value was 579.3.

[0174] Step e: To a vial of tert-butyl (2R)-2-[4-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]piperazine-1-carbonyl]pyrrolidine-1-carboxylate (160 mg, 0.28 mmol) was added 4.0 M HCl in dioxane (4.0 mL, 16.0 mmol). The mixture was stirred for 0.5 h, evaporated to dryness, basified with saturated NaHCO and extracted with EtOAc. The organic layer was separated, filtered through NaSO, concentrated and purified by silica gel column chromatography to give [4-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-methoxy-pyrimidin-2-yl]piperidin-1-yl]-[(2R)-pyrrolidin-2-yl]methanone. 1H NMR(400MHz,CD3OD)δ 9.01(d,J=6.8Hz,1H),7.50(s,1H),7.40(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H),7.29(s,1H),5.67 - 5.59(m,1H),4.73(dd,J=8.6Hz,1H),3.92(s,3H),3.86 - 3.33(m,10H),2.55 - 2.43(m,1H),2.05 - 1.90(m,3H),1.57(d,J=6.8Hz,3H).MS:(ES)m / z C 22 H 29 Cl2N6O2[M+H] + The calculated value was 479.2 and the measured value was 479.3.

[0175] Example 37: Synthesis of 2-(4-(D-prolyl)piperazin-1-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(2,2,2-trifluoroethoxy)pyrimidine [ka] Step a: To a solution of 2,4-dichloropyrimidin-5-ol (1.00 g, 6.06 mmol) and cesium carbonate (2.57 g, 7.88 mmol) in DMF (6 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.69 g, 7.27 mmol). The reaction mixture was stirred at room temperature for 4 hours and then diluted with water and ethyl acetate. The organic and aqueous layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give 2,4-dichloro-5-(2,2,2-trifluoroethoxy)pyrimidine. MS: (ES) m / z C6H4Cl2F3N2O[M+H] + The calculated value was 247.0 and the measured value was 246.9.

[0176] Step b: To a solution of 2,4-dichloro-5-(2,2,2-trifluoroethoxy)pyrimidine (590 mg, 2.39 mmol) and (R)-1-(2,4-dichlorophenyl)ethan-1-amine (450 mg, 2.39 mmol) in DMF (8 mL) was added DIPEA (1.2 mL, 7.2 mmol). The reaction mixture was heated at 100° C. for 4 hours and then diluted with water and ethyl acetate. The organic and aqueous layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine. MS: (ES) m / z C 14 H 12 Cl3F3N3O[M+H] + The calculated value is 400.0 and the measured value is 400.0.

[0177] Step c: To a solution of (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine (500 mg, 1.25 mmol) in DMSO (3 mL) was added tert-butyl piperazine-1-carboxylate (2.10 g, 11.2 mmol). The reaction mixture was heated at 120° C. for 16 hours and then diluted with water and ethyl acetate. The organic and aqueous layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (R)-4-(4-((1-(2,4-dichlorophenyl)ethyl)amino)-5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)piperazine-1-carboxylate. MS: (ES) m / z C 23 H 29 Cl2F3N5O3[M+H] + Calculated value: 550.2, measured value: 550.2.

[0178] Step d: To a solution of tert-butyl (R)-4-(4-((1-(2,4-dichlorophenyl)ethyl)amino)-5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)piperazine-1-carboxylate (0.53 g, 0.96 mmol) in DCM (1.6 mL) was added 4.0 M HCl in dioxane (2.4 mL, 9.6 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-piperazin-1-yl-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine. MS: (ES) m / z C 18 H 21 Cl2F3N5O[M+H] + Calculated value: 450.1, measured value: 450.1.

[0179] Step e: To a solution of N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-piperazin-1-yl-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine (100 mg, 0.191 mmol) and (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (49 mg, 0.23 mmol) in DMF (0.8 mL) was added HATU (94 mg, 0.25 mmol) and DIPEA (0.2 mL, 1.1 mmol). The contents were stirred at room temperature for 4 hours. The reaction mixture was concentrated and then diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (R)-2-(4-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate. MS: (ES) m / z C 28 H 36 Cl2F3N6O4[M+H] + The calculated value was 647.2, and the measured value was 647.3.

[0180] Step f: To a solution of tert-butyl (R)-2-(4-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (100 mg, 0.154 mmol) in DCM (0.2 mL) was added 4.0 M HCl in dioxane (0.4 mL, 1.6 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give 2-(4-(D-prolyl)piperazin-1-yl)-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(2,2,2-trifluoroethoxy)pyrimidine. 1 H NMR(400MHz,CD3OD)δ 7.57(s,1H),7.50(s,1H),7.42(d,J=8.8Hz,1H),7.33(d,J=8.0Hz,1H),5.70 - 5.50(m,1H),4.76 - 4.68(m,3H),3.90 - 3.72(m,3H),3.70 - 3.57(m,4H),3.56 - 3.32(m,3H),2.55 - 2.50(m,1H),2.13 - 2.00(m,2H),1.99 - 1.93(m,1H),1.60(d,J=6.8Hz,3H).MS:(ES)m / z C 23 H 28 Cl2F3N6O2[M+H] + Calculated value: 547.2, measured value: 547.2.

[0181] Example 38: Synthesis of (R)-5-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)pyrrolidin-2-one [ka] Step a: A mixture of (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (702 mg, 2.08 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (810 mg, 2.62 mmol), and potassium carbonate (1.40 g, 4.87 mmol) in a 10:3 solution of toluene / HO (13 mL) was sparged with N gas for 5 minutes. Pd(dppf)Cl-DCM complex (120 mg, 0.0705 mmol) was added, and the mixture was stirred at 120 °C for 2 hours. The contents were diluted with HO and extracted with ethyl acetate. The organic layer was dried over MgSO, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel column chromatography to give tert-butyl (R)-(4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate. MS: (ES) m / z C 22 H 26 Cl3N4O2[M+H] + Calculated value: 483.1, measured value: 483.1.

[0182] Step b: To a solution of tert-butyl (R)-4-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (900 mg, 1.86 mmol) in DCM (4 mL) was added 4.0 M HCl in dioxane (3.0 mL, 12 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated to dryness to give (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amine. MS: (ES) m / z C 17 H 18 Cl3N4[M+H] + The calculated value is 383.1, and the measured value is 383.1.

[0183] Step c: To a solution of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amine (200 mg, 0.438 mmol) and (2R)-5-oxopyrrolidine-2-carboxylic acid (68 mg, 0.53 mmol) in DMF (1.8 mL) was added HATU (250 mg, 0.657 mmol) and DIPEA (0.5 mL, 2.6 mmol). The contents were stirred at room temperature for 2 hours. The reaction mixture was concentrated and then diluted with ethyl acetate and water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (R)-5-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)pyrrolidin-2-one. 1 H NMR(400MHz,CD3OD)δ 8.39(s,1H),7.51(s,1H),7.44(d,J=8.8Hz,1H),7.33(d,J=8.0Hz,1H),7.02(s,1H),5.90 - 5.70(m,1H),4.80 - 4.60(m,1H),4.50 - 4.20(m,2H),3.80 - 3.65(m,2H),2.80 - 2.30(m,5H),2.10 - 1.90(m,1H),1.64(d,J=6.8Hz,3H).MS:(ES)m / z C 22 H 23 Cl3N5O2[M+H] + Calculated value: 494.1, measured value: 494.1.

[0184] Example 39: Synthesis of (R)-5-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-2-one [ka] To a solution of 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-piperazin-1-yl-pyrimidin-4-amine (50 mg, 0.11 mmol) in DMF (1 mL) was added (2R)-5-oxopyrrolidine-2-carboxylic acid (21 mg, 0.16 mmol), EDCI (31 mg, 0.16 mmol), and 4-(N,N-dimethylamino)pyridine (13 mg, 0.11). The reaction was stirred at 25° C. for 24 hours and then quenched with water. The contents were extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (R)-5-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-2-one. 1 H NMR(400MHz,CD3OD)δ 7.81(s,1H),7.46(s,1H),7.37(dd,J=8.5,1.9Hz,1H),7.29 - 7.24(m,1H),7.07(d,J=6.2Hz,1H),5.57 - 5.40(m,1H),4.69(dd,J=9.7,4.5Hz,1H),3.76 - 3.35(m,8H),2.56 - 2.42(m,1H),2.39 - 2.29(m,2H),2.07 - 1.95(m,1H),1.52(dd,J=6.9,2.0Hz,3H).MS:(ES)m / z C 21 H 24 Cl3N6O2[M+H] + Calculated value: 497.1, measured value: 497.1.

[0185] Example 40: Synthesis of (R)-4-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)-1-methylimidazolidin-2-one [ka] Step a: To a solution of benzyl (4R)-1-methyl-2-oxo-imidazolidine-4-carboxylate (250 mg, 1.1 mmol) in 4:1 THF / HO (5 mL) was added lithium hydroxide monohydrate (49 mg, 1.2 mmol). The reaction was stirred at 55 °C for 3 h and then concentrated. The residue was diluted with MeCN (5 mL), and the solid was washed with EtO and dried in vacuo to give lithium (4R)-1-methyl-2-oxo-imidazolidine-4-carboxylate. MS: (ES) m / z C5H7N2O3[MH] - The calculated value is 143.0 and the measured value is 143.0.

[0186] Step b: To a solution of 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-piperazin-1-yl-pyrimidin-4-amine (205 mg, 0.11 mmol) in DMF (1 mL) was added lithium (4R)-1-methyl-2-oxo-imidazolidine-4-carboxylate (18 mg, 0.12 mmol), EDCI (26 mg, 0.16 mmol), and 4-(N,N-dimethylamino)pyridine (13 mg, 0.11 mmol). The reaction was stirred at 25° C. for 24 hours and then quenched with water. The contents were extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (R)-4-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperazine-1-carbonyl)-1-methylimidazolin-2-one. 1 H NMR(400MHz,CD3OD)δ 7.80(s,1H),7.48 - 7.44(m,1H),7.40 - 7.35(m,1H),7.29 - 7.24(m,1H),7.06(d,J=6.0Hz,1H),5.55 - 5.44(m,1H),4.68 - 4.59(m,1H),3.79 - 3.67(m,2H),3.58(q,J=8.0,6.7Hz,4H),3.52 - 3.38(m,4H),2.80 - 2.70(m,3H),1.52(d,J=7.9Hz,3H).MS:(ES)m / z C 21 H 25Cl3N7O2[M+H] + Calculated value: 512.1, measured value: 512.1.

[0187] Example 41: Synthesis of (R)-5-((S)-4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3-methylpiperazine-1-carbonyl)pyrrolidin-2-one [ka] Step a: To a solution of 2,5-dichloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]pyrimidin-4-amine (100 mg, 0.28 mmol) in DMSO (1 mL) was added tert-butyl (3S)-3-methylpiperazine-1-carboxylate (57 mg, 0.28 mmol) and DIPEA (0.055 mL, 0.31 mmol). The reaction was stirred at 90° C. for 24 hours and then quenched with water. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (S)-4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate. MS: (ES) m / z C 22 H 29 Cl3N5O2[M+H] + Calculated value: 500.1, measured value: 500.1.

[0188] Step b: A solution of tert-butyl (S)-4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3-methylpiperazine-1-carboxylate (50 mg, 0.090 mmol) in 4 N HCl in dioxane (2 mL) was stirred at 25° C. for 30 min. The mixture was then diluted with EtO to precipitate a solid. The suspension was filtered and the solid was dried under vacuum to give 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-((S)-2-methylpiperazin-1-yl)pyrimidin-4-amine. MS: (ES) m / z C17 H 21 Cl3N5[M+H] + Calculated value: 400.1, measured value: 400.1.

[0189] Step c: To a solution of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-((S)-2-methylpiperazin-1-yl)pyrimidin-4-amine (44 mg, 0.10 mmol) in DCM (1 mL) was added (2R)-5-oxopyrrolidine-2-carboxylic acid (14 mg, 0.11 mmol), HATU (42 mg, 0.16 mmol), and DIPEA (0.052 mL, 0.30 mmol). The reaction was stirred at 25° C. for 30 min and then quenched with water. The contents were extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (R)-5-((S)-4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3-methylpiperazine-1-carbonyl)pyrrolidin-2-one. 1 H NMR(400MHz,CD3OD)δ 7.80(s,1H),7.48 - 7.43(m,1H),7.40 - 7.35(m,1H),7.31 - 7.21(m,1H),7.04 - 6.95(m,1H),5.47(q,J=7.0Hz,1H),4.81 - 4.62(m,1H),4.61 - 4.51(m,1H),4.34 - 4.13(m,2H),3.94 - 3.64(m,1H),3.20 - 2.69(m,3H),2.57 - 2.23(m,3H),2.14 - 1.88(m,1H),1.52(d,J=7.0Hz,3H),1.19 - 1.00 (m, 3H). MS: (ES) m / z C 22 H 26 Cl3N6O2[M+H] + Calculated value: 511.1, measured value: 511.1.

[0190] Example 42: Synthesis of (2R,5S)—N-((3S,4S)-1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-yl)-5-methylpyrrolidine-2-carboxamide [ka] Step a: To a mixture of tert-butyl (3S,4S)-4-amino-3-fluoro-piperidine-1-carboxylate (250 mg, 1.1 mmol), isobenzofuran-1,3-dione (170 mg, 1.1 mmol), and zinc(II) bromide (260 mg, 1.1 mmol) in toluene (6 mL) was added trimethyl(trimethylsilyloxy)silane (280 mg, 1.7 mmol). The reaction was stirred at 120 °C for 18 hours and then quenched with water. The mixture was extracted with 9:1 methanol / ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give 2-[(3S,4S)-3-fluoro-4-piperidyl]isoindoline-1,3-dione. MS: (ES) m / z C 13 H 14 FN2O2[M+H] + Calculated value: 249.1, measured value: 249.1.

[0191] Step b: To a solution of 2,5-dichloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]pyrimidin-4-amine (102 mg, 0.30 mmol) in DMF (2 mL) was added 2-[(3S,4S)-3-fluoro-4-piperidyl]isoindoline-1,3-dione (75 mg, 0.30 mmol). The reaction was stirred at 90° C. for 24 hours and then concentrated. The crude material was dissolved in methanol (1 mL) and hydrazine (0.095 mL, 3.0 mmol) was added. The resulting mixture was stirred for 2 hours and then filtered. The filtrate was concentrated, and the crude material was purified by silica gel column chromatography to give 2-[(3S,4S)-4-amino-3-fluoro-1-piperidyl]-5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]pyrimidin-4-amine. MS: (ES) m / z C 17 H 20 Cl3FN5[M+H] + Calculated value: 418.1, measured value: 418.1.

[0192] Step c: To a solution of 2-[(3S,4S)-4-amino-3-fluoro-1-piperidyl]-5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]pyrimidin-4-amine (23 mg, 0.050 mmol) in DCM (1 mL) was added (2R,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (13 mg, 0.055 mmol), HATU (21 mg, 0.55 mmol), and DIEA (0.026 mL, 0.15 mmol). The reaction was stirred at 23 °C for 16 hours and then quenched with water. The contents were extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (2R,5S)-2-((((3S,4S)-1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate. MS: (ES) m / z C 28 H 37 Cl3FN6O3[M+H] +Calculated value: 629.2, measured value: 629.2.

[0193] Step d: A solution of tert-butyl (2R,5S)-2-(((3S,4S)-1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate (30 mg, 0.011 mmol) in 4 N HCl in 1,4-dioxane (1 mL) was stirred at 25° C. for 30 minutes. The mixture was then diluted with 20 mL of EtO, causing a solid to precipitate. The suspension was filtered and the solid was dried under vacuum to give (2R,5S)—N-((3S,4S)-1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-yl)-5-methylpyrrolidine-2-carboxamide. 1 H NMR(400MHz,DMSO-d6)δ 9.08 - 8.93(m,1H),8.79 - 8.66(m,1H),8.51(d,J=8.1Hz,1H),7.85(s,1H),7.49(d,J=2.1Hz,1H),7.4 0(d,J=8.4Hz,1H),7.32(dd,J=8.4,2.1Hz,1H),5.34(p,J=7.0Hz,1H),4.46 - 3.86(m,7H),3.10 - 2.89(m,2H),2.35 - 2.24(m,1H),2.10 - 1.98(m,1H),1.80 - 1.58(m,2H),1.57 - 1.44(m,1H),1.40(d,J=7.1Hz,3H),1.24(d,J=6.5Hz,3H).MS:(ES)m / z C 23 H 29 Cl3FN6O[M+H] + Calculated value: 529.1, measured value: 529.1.

[0194] Example 43: Synthesis of (2R,5S)—N-((3S,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-5-methylpyrrolidine-2-carboxamide [ka] Step a: A mixture of formic acid (2.3 mL, 60.0 mmol) and acetic anhydride (3.4 mL, 36.4 mmol) was stirred at 60 °C for 1 h. The reaction was cooled to 25 °C, and then 2,4-dichloropyrimidin-5-ol (1.0 g, 6.1 mmol) and sodium acetate (250 mg, 3.0 mmol) were added. The reaction was stirred at 25 °C for 2 h and then quenched with saturated NaHCO (aq). The biphasic mixture was shaken with toluene, and the resulting layers were separated. The organic layer was washed with HO and brine, then dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give 2,4-dichloropyrimidin-5-yl formate. MS: (ES) m / z C5H3Cl2N2O2 [M+H] + The calculated value is 193.0 and the measured value is 193.0.

[0195] Step b: To a solution of 2,4-dichloropyrimidin-5-yl formate (460 mg, 2.4 mmol) in DCM (2.5 mL) was added N-ethyl-N-(trifluoro-λ-sulfanyl)ethanamine (1.2 g, 7.2 mmol) dropwise at 25° C. The reaction was stirred at 25° C. for 48 h and then quenched with saturated NaHCO (aq). The biphasic mixture was extracted with DCM, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give 2,4-dichloro-5-(difluoromethoxy)pyrimidine. MS: (ES) m / z C5H3Cl2F2N2O [M+H] + Calculated value: 215.0, measured value: 215.0.

[0196] Step c: To a solution of 2,4-dichloro-5-(difluoromethoxy)pyrimidine (170 mg, 0.79 mmol) and DIPEA (0.55 mL, 3.1 mmol) in DMF (3 mL) was added (1R)-1-(2,4-dichlorophenyl)ethanamine (150 mg, 0.79 mmol). The reaction was stirred at 90° C. for 16 hours and then quenched with water. The contents were extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give 2-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-(difluoromethoxy)pyrimidin-4-amine. MS: (ES) m / z C 13 H 11 Cl3F2N3O[M+H] + The calculated value is 368.0, and the measured value is 368.0.

[0197] Step d: To a solution of 2-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-(difluoromethoxy)pyrimidin-4-amine (200 mg, 0.54 mmol) and DIPEA (0.19 mL, 1.1 mmol) in DMF (1.1 mL) was added tert-butyl N-[(3S,4S)-3-hydroxy-4-piperidyl]carbamate (120 mg, 0.55 mmol). The reaction was stirred at 90° C. for 1 hour and then quenched with water. The contents were extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl ((3S,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamate. MS: (ES) m / z C 23 H 30 Cl2F2N5O4[M+H] + Calculated value: 548.2, measured value: 548.2.

[0198] Step e: A solution of tert-butyl ((3S,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamate (85 mg, 0.15 mmol) in 4 N HCl in dioxane was stirred at 25 °C for 30 min. The mixture was then diluted with EtO to precipitate a solid. The suspension was filtered and the solid was dried under vacuum to give (3S,4S)-4-amino-1-[4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-(difluoromethoxy)pyrimidin-2-yl]piperidin-3-ol. MS: (ES) m / z C 18 H 22 Cl2F2N5O2[M+H] + Calculated value: 448.1, measured value: 448.1.

[0199] Step f: To a solution of (3S,4S)-4-amino-1-[4-[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]-5-(difluoromethoxy)pyrimidin-2-yl]piperidin-3-ol (40 mg, 0.077 mmol) in DCM (1 mL) was added (2R,5S)-5-methylpyrrolidine-2-carboxylic acid (19 mg, 0.084 mmol), HATU (32 mg, 0.084 mmol), and DIPEA (0.051 mL, 0.31 mmol). The reaction was stirred at 23 °C for 16 hours and then quenched with water. The mixture was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (2R,5S)-2-(((3S,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate. MS: (ES) m / z C 29 H 39 Cl2F2N6O5[M+H] + Calculated value: 659.2, measured value: 659.2.

[0200] Step g: A solution of tert-butyl (2R,5S)-2-(((3S,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate (24 mg, 0.033 mmol) in 4 N HCl in 1,4-dioxane (1 mL) was stirred at 25° C. for 30 minutes. The mixture was then diluted with EtO, causing a solid to precipitate. The suspension was filtered and the solid was dried under vacuum to give (2R,5S)—N-((3S,4S)-1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)-5-methylpyrrolidine-2-carboxamide. 1 H NMR(400MHz,DMSO-d6)δ 8.83 - 8.68(m,1H),8.51 - 8.28(m,1H),7.86 - 7.71(m,1H),7.57(s,1H),7.50 - 7.35(m,2H),7.29 - 6.79(m,1H),5.43(d,J=10.8Hz,1H),4.69 - 3.81(m,8H),3.74 - 3.59(m,2H),3.38 - 3.18(m,1H),2.43 - 2.30(m,1H),2.17 - 2.03(m,1H),1.87 - 1.63(m,2H),1.63 - 1.51(m,1H),1.46(d,J=6.7Hz,3H),1.32(d,J=4.5Hz,3H).MS:(ES)m / z C 24 H 31 Cl2F2N6O3[M+H] + Calculated value: 559.2, measured value: 559.2.

[0201] Example 44: Synthesis of 2-(4-(D-prolyl)piperazin-1-yl)-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidine [ka] Step a: A mixture of 2-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-(difluoromethoxy)pyrimidin-4-amine (170 mmol, 0.45 mmol) and tert-butyl piperazine-1-carboxylate (1.3 g, 7.2 mmol). The reaction was stirred at 125° C. for 7 hours and then cooled to 25° C. The crude material was purified by silica gel column chromatography to give tert-butyl (R)-4-(4-((1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)piperazine-1-carboxylate. MS: (ES) m / z C 22 H 28 Cl2F2N5O3[M+H] + Calculated value: 518.2, measured value: 518.2.

[0202] Step b: A solution of tert-butyl (R)-4-(4-((1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)piperazine-1-carboxylate (130 mg, 0.25 mmol) in 4 N HCl in dioxane was stirred at 25° C. for 30 min. The mixture was then diluted with EtO to precipitate a solid. The suspension was filtered and the solid was dried under vacuum to give N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-(difluoromethoxy)-2-piperazin-1-yl-pyrimidin-4-amine. MS: (ES) m / z C 17 H 20 Cl2F2N5O[M+H] + Calculated value: 418.1, measured value: 418.1.

[0203] Step c: To a solution of N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-5-(difluoromethoxy)-2-piperazin-1-yl-pyrimidin-4-amine (40 mg, 0.081 mmol) in DCM (1 mL) was added (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (19 mg, 0.090 mmol), HATU (34 mg, 0.090 mmol), and DIPEA (0.055 mL, 0.33 mmol). The reaction was stirred for 25 min. The mixture was stirred at °C for 30 minutes and then quenched with water. The contents were extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (R)-2-(4-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate. MS: (ES) m / z C 27 H 35 Cl2F2N6O4[M+H] + Calculated value: 615.2, measured value: 615.2.

[0204] Step d: A solution of tert-butyl (R)-2-(4-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (40 mg, 0.061 mmol) in 4 N HCl in 1,4-dioxane (1 mL) was stirred at 25° C. for 30 minutes. The mixture was then diluted with EtO to precipitate a solid. The suspension was filtered, and the solid was dried under vacuum to give 2-(4-(D-prolyl)piperazin-1-yl)-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(difluoromethoxy)pyrimidine. 1H NMR(400MHz,CD3OD)δ 9.34(d,J=6.5Hz,1H),7.76(s,1H),7.51(s,1H),7.41 - 7.35(m,1H),7.35 - 7.28(m,1H),6.89(t,J=72.2,70.5Hz,1H),5.71 - 5.58(m,1H),4.73(t,J=7.5Hz,1H),3.96 - 3.35(m,11H),2.59 - 2.45(m,1H),2.19 - 1.88(m,3H),1.59(d,J=7.2Hz,3H).MS:(ES)m / z C 22 H 27 Cl2F2N6O2[M+H] + Calculated value: 515.2, measured value: 515.2.

[0205] Example 45: Synthesis of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(4-(((S)-pyrrolidin-3-yl)oxy)piperidin-1-yl)pyrimidin-4-amine [ka] Step a: To a mixture of pyridin-4-ol (500 mg, 5.3 mmol), (3R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (980 mg, 5.3 mmol), and triphenylphosphine (1.4 g, 5.3 mmol) in THF (18 mL) was added DIAD (1.1 g, 5.3 mmol). The reaction was stirred at 55° C. for 24 hours and then concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (3R)-3-(4-pyridyloxy)pyrrolidine-1-carboxylate. MS: (ES) m / z C 14 H 21 N2O3[M+H] + Calculated value: 265.2, measured value: 265.2.

[0206] Step b: To a solution of tert-butyl (3R)-3-(4-pyridyloxy)pyrrolidine-1-carboxylate (580 mg, 2.2 mmol) in MeOH (2 mL) was added platinum(IV) oxide (50 mg, 0.22 mmol) and concentrated HCl (0.36 mL, 4.4 mmol). The reaction was shaken in a Parr reactor under H (50 psi) at 20° C. for 24 h. The mixture was filtered through Celite, and the filtrate was concentrated to give tert-butyl (3S)-3-(4-piperidyloxy)pyrrolidine-1-carboxylate. MS: (ES) m / z C 14 H 27 N2O3[M+H] + The calculated value is 271.2, and the measured value is 271.2.

[0207] Step c: To a solution of 2,5-dichloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]pyrimidin-4-amine (200 mg, 0.59 mmol) in DMF (2 mL) was added tert-butyl (3S)-3-(4-piperidyloxy)pyrrolidine-1-carboxylate hydrochloride (180 mg, 0.59 mmol) and DIPEA (0.21 mL, 1.2 mmol). The reaction was stirred at 80° C. for 24 hours and then quenched with water. The contents were extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (S)-3-((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylate. MS: (ES) m / z C 26 H 35 Cl3N5O3[M+H] + Calculated value: 570.2, measured value: 570.2.

[0208] Step d: A solution of tert-butyl (S)-3-((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylate (30 mg, 0.053 mmol) in 4 N HCl in 1,4-dioxane (2 mL) was stirred at 25° C. for 30 minutes. The mixture was then diluted with EtO to precipitate a solid. The suspension was filtered and the solid was dried under vacuum to give 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(4-(((S)pyrrolidin-3-yl)oxy)piperidin-1-yl)pyrimidin-4-amine. 1 H NMR(400MHz,CDCl3)δ 8.80(d,J=4.0Hz,1H),7.91(s,1H),7.48(s,1H),7.41 - 7.36(m,1H),7.36 - 7.30(m,1H),5.66 - 5.52(m,1H),4.51 - 4.42(m,1H),3.94 - 3.69(m,4H),3.63 - 3.43(m,2H),3.42 - 3.32(m,3H),2.27 - 2.01(m,2H),1.96 - 1.75(m,2H),1.70 - 1.40(m,5H),1.35 - 1.19(m,1H).MS:(ES)m / z C 21 H 27 Cl3NO[M+H] + Calculated value: 470.1, measured value: 470.1.

[0209] Example 46: Synthesis of 2-((S)-3-((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperidin-4-yl)oxy)pyrrolidin-1-yl)ethan-1-ol [ka] To a solution of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(4-(((S)-pyrrolidin-3-yl)oxy)piperidin-1-yl)pyrimidin-4-amine (16 mg, 0.030 mmol) in MeCN (1 mL) was added 2-iodoethanol (5.2 mg, 0.030 mmol) and potassium carbonate (24 mg, 1.1 mmol). The reaction was stirred at 80° C. for 18 hours and then concentrated. The crude material was purified by preparative HPLC to give 2-((S)-3-((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperidin-4-yl)oxy)pyrrolidin-1-yl)ethan-1-ol. 1 H NMR(400MHz,CD3OD)δ 7.77 - 7.73(m,1H),7.43 - 7.40(m,1H),7.38 - 7.33(m,1H),7.29 - 7.23(m,1H),6.97(d,J=5.2Hz,1H),5.49 - 5.39(m,1H),4.51 - 4.41(m,1H),4.08 - 3.97(m,2H),3.86 - 3.80(m,2H),3.67 - 3.57(m,2H),3.43 - 3.34(m,4H),3.21 - 3.07(m,3H),2.22 - 2.10(m,1H),1.78 - 1.65(m,2H),1.51(d,J=8.1Hz,3H),1.37 - 1.26(m,1H),1.20 - 1.06(m,1H).MS:(ES) m / z C 23 H 31 Cl3N5O2[M+H] + Calculated value: 514.2, measured value: 514.2.

[0210] Example 47: Synthesis of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(4-(((S)-1-methylpyrrolidin-3-yl)oxy)piperidin-1-yl)pyrimidin-4-amine [ka] To a solution of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(4-(((S)-pyrrolidin-3-yl)oxy)piperidin-1-yl)pyrimidin-4-amine (50 mg, 0.092 mmol) in MeCN (1 mL) was added aqueous formaldehyde (2.9 mg, 0.97 mmol), EtN (0.013 mL, 0.092 mmol), and sodium triacetoxyborohydride (24 mg, 1.1 mmol). The reaction was stirred at 55° C. for 24 hours and then concentrated. The crude material was purified by preparative HPLC to give 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(4-(((S)-1-methylpyrrolidin-3-yl)oxy)piperidin-1-yl)pyrimidin-4-amine. 1 H NMR(400MHz,CD3OD)δ 7.87(s,1H),7.46(s,1H),7.40 - 7.35(m,1H),7.33 - 7.28(m,1H),5.61 - 5.51(m,1H),4.54 - 4.42(m,1H),3.98 - 3.82(m,2H),3.81 - 3.62(m,3H),3.50 - 3.34(m,3H),3.14(d,J=12.5Hz,2H),2.97(s,3H),2.50 - 2.04(m,2H),1.90 - 1.70(m,2H),1.63 - 1.46(m,4H),1.39(s,1H).MS:(ES)m / z C 22 H 29 Cl3NO[M+H] + The calculated value is 484.1, and the measured value is 484.1.

[0211] Example 48: Synthesis of 2-(1-(D-prolyl)piperazin-4-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidine [ka] Step a: To a solution of tert-butyl 4-carbamimidoylpiperidine-1-carboxylate (3.5 g, 15 mmol) in EtOH (70 mL) was added ethyl 2-chloro-3-oxopropanoate (2.3 g, 15 mmol) and potassium carbonate (6.3 g, 45 mmol). The reaction was stirred at 80° C. for 16 hours and then filtered through Celite. The filtrate was concentrated and the crude material was purified by silica gel column chromatography to give tert-butyl 4-(5-chloro-4-hydroxy-pyrimidin-2-yl)piperidine-1-carboxylate. MS: (ES) m / z C 14 H 19 ClN3O3[MH] - Calculated value: 312.1, measured value: 312.1.

[0212] Step b: To a suspension of tert-butyl 4-(5-chloro-4-hydroxy-pyrimidin-2-yl)piperidine-1-carboxylate (1.0 g, 3.3 mmol) in toluene (16 mL) was added DIPEA (1.1 mL, 6.5 mmol) followed by phosphorus(V) oxychloride (0.30 mL, 3.3 mmol). The reaction was stirred at 120° C. for 1 hour and then concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl 4-(4,5-dichloropyrimidin-2-yl)piperidine-1-carboxylate. MS: (ES) m / z C 14 H 20 Cl2N3O2[M+H] + Calculated value: 332.1, measured value: 332.1.

[0213] Step c: To a solution of tert-butyl 4-(4,5-dichloropyrimidin-2-yl)piperidine-1-carboxylate (480 mg, 1.4 mmol) in DMF (5 mL) was added (1R)-1-(2,4-dichlorophenyl)ethanamine (270 mg, 1.4 mmol) and DIPEA (0.50 mL, 2.9 mmol). The reaction was stirred at 90 °C for 1 hour and then quenched with water. The contents were extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl 4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]piperazine-1-carboxylate. MS: (ES) m / z C 22 H 28 Cl3N4O2[M+H] + Calculated value: 485.1, measured value: 485.1.

[0214] Step d: A solution of tert-butyl 4-[5-chloro-4-[[(1R)-1-(2,4-dichlorophenyl)ethyl]amino]pyrimidin-2-yl]piperidine-1-carboxylate (400 mg, 0.82 mmol) in 4N HCl in 1,4-dioxane (2 mL) was stirred at 25° C. for 30 minutes. The mixture was then diluted with EtO to precipitate a solid. The suspension was filtered, and the solid was dried under vacuum to give 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-(4-piperidyl)pyrimidin-4-amine. MS: (ES) m / z C 17 H 20 Cl3N4[M+H] + The calculated value is 385.1, and the measured value is 385.1.

[0215] Step e: To a solution of 5-chloro-N-[(1R)-1-(2,4-dichlorophenyl)ethyl]-2-(4-piperidyl)pyrimidin-4-amine (50 mg, 0.11 mmol) in DMF (1 mL) was added (2R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (26 mg, 0.12 mmol), HATU (46 mg, 0.12 mmol), and DIPEA (0.50 mL, 2.9 mmol). The reaction was stirred at 25° C. for 18 hours and then quenched with water. The contents were extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give tert-butyl (R)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate. MS: (ES) m / z C 27 H 35 Cl3N5O3[M+H] + Calculated value: 582.2, measured value: 582.2.

[0216] Step f: A solution of tert-butyl (R)-2-(4-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate (30 mg, 0.053 mmol) in 4 N HCl in 1,4-dioxane (2 mL) was stirred at 25° C. for 30 minutes. The mixture was then diluted with EttO to precipitate a solid. The suspension was filtered, and the solid was dried under vacuum to give 2-(1-(D-prolyl)piperidin-4-yl)-5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino))pyrimidine. 1H NMR(400MHz,CD3OD)δ 9.38(s,1H),8.53 - 8.44(m,1H),7.55 - 7.47(m,1H),7.44 - 7.37(m,1H),7.37 - 7.29(m,1H),5.80 - 5.64(m,1H),4.72(dt,J=49.3,8.3Hz,1H),4.50(dd,J=38.4,13.3Hz,1H),4.05 - 3.82(m,1H),3.78 - 3.55(m,2H),3.42(dt,J=30.8,9.0Hz,2H),3.11 - 2.97(m,1H),2.97 - 2.83(m,1H),2.61 - 2.47(m,1H),2.26 - 1.86(m,4H),1.86 - 1.68(m,1H),1.68 - 1.59(m,3H),1.53 - 1.25(m,2H).MS:(ES) m / z C 22 H 27 Cl3NO[M+H] + Calculated value: 482.1, measured value: 482.1.

[0217] Biological Examples Endogenous CEM cells express CCR4 Chemotaxis assays can be used to determine the effectiveness of potential receptor antagonists in blocking migration mediated through chemokine receptors such as CCR4. This assay is routinely performed using a ChemoTX® microchamber system equipped with a 5 μm pore size polycarbonate membrane.

[0218] HBSS:CEM cells are harvested by centrifugation at 400 x g at room temperature and then suspended at 5 million cells / ml in Hank's Balanced Salt Solution (HBSS) buffer containing 0.1% BSA. Compounds to be tested are serially diluted from a maximum final concentration of 10 μM (or an equivalent volume of the solvent (DMSO)) and then added to the cell / buffer mixture. Separately, their EC 50A concentration (0.1 nM) of recombinant human CCL22 (MDC) is placed in the lower well of a ChemoTX® plate. A 5 μm (pore size) polycarbonate membrane is placed on the plate, and 20 μL of the cell / compound mixture is transferred onto each well of the membrane. The plate is incubated at 37°C for 60 minutes, after which the polycarbonate membrane is removed and 5 μL of the DNA intercalating dye CyQUANT (Invitrogen, Carlsbad, CA) is added to the lower well. The amount of fluorescence, which corresponds to the number of migrated cells, is measured using a Spectrafluor Plus plate reader (TECAN, San Jose, CA).

[0219] FBS:CEM cells are harvested by centrifugation at 400 x g at room temperature and then suspended at 5 million cells / ml in 100% fetal bovine serum (FBS) containing 1% HEPE. Compounds to be tested are serially diluted from a maximum final concentration of 10 μM (or an equivalent volume of the solvent, DMSO) and then added to the cell / buffer mixture. Separately, the EC 50 A concentration (0.1 nM) of recombinant human CCL22 (MDC) is placed in the lower well of a ChemoTX® plate. A 5 μm (pore size) polycarbonate membrane is placed on the plate, and 20 μL of the cell / compound mixture is transferred onto each well of the membrane. The plate is incubated at 37°C for 60 minutes, after which the polycarbonate membrane is removed and 5 μL of the DNA intercalating dye CyQUANT (Invitrogen, Carlsbad, CA) is added to the lower well. The amount of fluorescence, which corresponds to the number of migrated cells, is measured using a Spectrafluor Plus plate reader (TECAN, San Jose, CA).

[0220] In the table below, activity is indicated as follows: IC50 less than 100nM (+++); 100 nM or more but less than 1000 nM (++); and More than 1000nM.

[0221] [Table 1]

[0222] Table 2

[0223] Table 3

[0224] Table 4

[0225] Table 5

[0226] Table 6

[0227] Table 7

[0228] Table 8

[0229] Table 9

[0230] Table 10

[0231] Table 11

[0232] Table 12

[0233] Table 13

[0234] Table 14

[0235] Table 15

[0236] Table 16

[0237] Table 17

[0238] Table 18

[0239] Table 19

[0240] Table 20

[0241] Table 21

[0242] Table 22

[0243] Table 23

[0244] Table 24

[0245] Table 25

[0246] Table 26

[0247] Table 27

[0248] Table 28

[0249] Table 29

[0250] Table 30

[0251] Table 31

[0252] Table 32

[0253] Table 33

[0254] Table 34

[0255] Table 35

[0256] Table 36

[0257] Table 37

[0258] Table 38

[0259] Table 39

[0260] Table 40

[0261] Table 41

[0262] Table 42

[0263] Table 43

[0264] Table 44

[0265] Table 45

[0266] Table 46

Claims

1. Compounds having formula (I): 【Transformation 67】 or a pharmaceutically acceptable salt thereof [wherein: R １ａ is hydrogen, halogen, C １～４ Alkyl, C １～４ Haloalkyl, -CN, C １～４ Alkoxy, and C １～４ haloalkoxy; m is an integer from 0 to 4; Each R １ｂ are independently halogen, C １～４ Alkyl, C １～４ Haloalkyl, -CN, C １～４ Alkoxy, and C １～４ haloalkoxy; R ２ is H, -OR ａ , -N(R ａ ) ２ , C １～４ Alkyl, C １～４ Haloalkyl, and C １～４ hydroxyalkyl; R ３ is hydrogen, C １～４ Alkyl, halogen, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, C ３～８ Cycloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C １～４ Alkoxy-C １～４ Alkyl, —C(O)NH ２ , hydroxy, -NH ２ and CN; Each R ４ is hydrogen, halogen, hydroxy, -CN, C １～４ Alkoxy, C １～４ Haloalkoxy, —NH ２ , C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, C ３～８ Cycloalkyl, —SO ２ Me, and —C(O)NH ２ selected from the group consisting of: n is an integer from 0 to 2; X and Y are each independently N or C(R ４ ) and at least one of X and Y is N; 【Transformation 68】 is a single or double bond; A is C, N or C(R ５ａ ) (However, if A is N, then 【Transformation 69】 is a single bond); B is N or C(R ５ｂ ) wherein at least one of A and B is N; q is an integer from 0 to 4; Each R ５ are independently １～４ Alkyl, C １～４ Alkoxy, —C(O)OH, halogen, hydroxy, C １～４ Haloalkyl, and C １～４ hydroxyalkyl, or two R ５ are combined to form one or two carbon bridges between non-adjacent ring vertices; R ５ａ is hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, and C １～４ hydroxyalkyl; R ５ｂ is hydrogen, C １～４ Alkyl, and C １～４ hydroxyalkyl; L is a bond, —O—, —C(O)—C ０～４ Alkylene-, -C １～４ Alkylene—C(O)—, —C(O)N(R ａ )-C ０～４ Alkylene-, -S(O) ２ -C ０～４ Alkylene, and —N(R ａ ) C(O)-C ０～４ alkylene-; Q is, i) a ring having 1 to 3 heteroatom ring vertices selected from N, O, and S, and 0 to 4 R ｂ 4- to 7-membered heterocyclyl substituted by ii) 0 to 3 R ｂ C is substituted with １～８ Alkyl; iii) 0 to 3 heteroatom ring vertices selected from N, O, and S; and 0 to 4 R ｂ 7- to 11-membered spirocyclyl substituted with iv) 1 to 3 heteroatom ring vertices selected from N, O, and S; and 0 to 4 R ｂ 5-6 membered heterocyclyl substituted by is a member selected from the group consisting of: Each R ａ are independently H, and C optionally substituted by OH or —C(O)OH. １～４ selected from the group consisting of alkyl; Each R ｂ are independently hydroxy, halogen, oxo, -C ０～４ Alkylene-N(R ａ ) ２ , -CO ２ R ａ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, —C １～４ Alkylene-CO ２ R ａ , -C ０～４ alkylene-heteroaryl, wherein said heteroaryl has 5-6 ring members and 1-4 heteroatom ring vertices selected from N, O and S, and said heteroaryl optionally has 1-3 R ｃ , optionally 1 to 3 R ｃ C substituted by ０～４ Alkylene-C ３～８ Cycloalkyl, —C(O)—C １～４ Alkyl, and -C ０～４ Alkylene -C(O)N(R ａ ) ２ (replaced by); Each R ｃ are independently halogen, C １～４ Alkyl, C １～４ haloalkyl, and —C(O)OH.

2. Compounds having formula (I): 【Transformation 70】 or a pharmaceutically acceptable salt thereof [wherein: R １ａ is hydrogen, halogen, C １～４ Alkyl, C １～４ Haloalkyl, -CN, C １～４ Alkoxy, and C １～４ haloalkoxy; m is an integer from 0 to 4; Each R １ｂ are independently halogen, C １～４ Alkyl, C １～４ Haloalkyl, -CN, C １～４ Alkoxy, and C １～４ haloalkoxy; R ２ is H, -OR ａ , -N(R ａ ) ２ , C １～４ Alkyl, C １～４ Haloalkyl, and C １～４ hydroxyalkyl; R ３ is C １～４ Alkyl, halogen, —CN, and CF ３ selected from the group consisting of: Each R ４ is hydrogen, halogen, -CN, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, C ３～８ Cycloalkyl, —SO ２ Me, and —C(O)NH ２ selected from the group consisting of: n is 0, 1 or 2; X and Y are each independently N or C(R ４ ) and at least one of X and Y is N; 【Chemistry 71】 is a single or double bond; A is C, N or C(R ５ａ ) and B is N or C(R ５ｂ ) and at least one of A and B is N; q is an integer from 0 to 4; Each R ５ are independently １～４ Alkyl, hydroxy, C １～４ Haloalkyl, and C １～４ hydroxyalkyl, or two R ５ are combined to form one or two carbon bridges between non-adjacent ring vertices; R ５ａ is hydrogen, C １～４ Alkyl, C １～４ Haloalkyl, and C １～４ hydroxyalkyl; R ５ｂ is hydrogen or C １～４ is alkyl; L is a bond, —C(O)—, or —CH ２ C(O)-, -C(O)CH ２ -, -C(O)N(R ａ )- and -N(R ａ )C(O)—; Q is, i) a ring having 1 to 3 heteroatom ring vertices selected from N, O, and S, and 0 to 4 R ｂ 4- to 7-membered heterocyclyl substituted with ii) 0 to 3 R ｂ C is substituted with １～８ Alkyl is a member selected from the group consisting of: Each R ａ are independently H and C １～４ selected from the group consisting of alkyl; Each R ｂ are independently hydroxy, oxo, -N(R ａ ) ２ , -CO ２ R ａ , C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, C １～４ Alkylene-CO ２ R ａ , and C １～４ Alkylene-N(R ａ ) ２ selected from the group consisting of:

3. 3. The compound of claim 1 or 2, wherein the first-recited portion of the L group is attached to a ring that includes the B variable.

4. 3. The compound of claim 1 or 2, wherein the compound is optically enriched or optically pure.

5. 3. The compound of claim 1 or 2, wherein n is 1.

6. R １ａ and each R １ｂ The compound according to claim 1 or 2, wherein is a halogen.

7. R ２ is H or CH ３ 3. The compound according to claim 1 or 2, wherein

8. R ４ The compound of claim 1 or 2, wherein is hydrogen.

9. Q is 0 to 2 R ｂ 3. The compound of claim 1 or 2, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl, substituted with:

10. Formula (Ia) 【Chemistry 72】 or a pharmaceutically acceptable salt thereof.

11. Q is 0 to 2 R ｂ 11. The compound of claim 10, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, substituted with:

12. Q is 0 to 3 R ｂ C substituted with １～８ The compound of claim 10, wherein the compound is alkyl.

13. L is a bond, —C(O)—, or —CH ２ C(O)-, -C(O)CH ２ -, -C(O)NH-, -NHC(O)-, -C(O)N(CH ３ )-, and -N(CH ３ 3. The compound of claim 1, wherein the compound is selected from the group consisting of: )C(O)—.

14. Formula (Ib) 【Transformation 73】 or a pharmaceutically acceptable salt thereof.

15. Q is 0 to 2 R ｂ 15. The compound of claim 14, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, substituted with:

16. Q is 0 to 3 R ｂ C substituted with １～８ 15. The compound of claim 14, wherein the compound is alkyl.

17. Formula (Ic1), (Ic2) or (Ic3): 【Chemistry 74】 or a pharmaceutically acceptable salt thereof.

18. Q is 0 to 2 R ｂ 18. The compound of claim 17, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, substituted with:

19. Q is 0 to 3 R ｂ C substituted with １～８ 18. The compound of claim 17, wherein the compound is alkyl.

20. Formula (Id1), (Id2) or (Id3) 【Chemistry 75】 or a pharmaceutically acceptable salt thereof.

21. Q is 0 to 2 R ｂ 21. The compound of claim 20, wherein the compound is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, substituted with:

22. Q is 0 to 3 R ｂ C substituted with １～８ 21. The compound of claim 20, wherein the compound is alkyl.

23. L is a bond, —C(O)—, or —CH ２ C(O)-, -C(O)CH ２ -, -C(O)NH-, -NHC(O)-, -C(O)N(CH ３ )-, and -N(CH ３ 21. The compound of claim 20, wherein the compound is selected from the group consisting of: )C(O)—.

24. One of the following formulas: 【Transformation 76】 or a pharmaceutically acceptable salt thereof, Each R ｂ are independently selected from the group consisting of H, Cl, or F, provided that at least one R ｂ is H) 3. The compound of claim 1 or 2, having the formula:

25. Q is, 【Chemical 77】 (In the formula, Each R ｂ are independently １～４ Alkyl, F, Cl, OH and —N(H)CH ３ selected from the group consisting of: R ｂ１ is H, C １～４ Alkyl, C １～４ Hydroxyalkyl, C １～４ Haloalkyl, —C(O)—C １～３ Alkyl, —C(O)—O—C １～３ Alkyl, —C １～３ Alkylene -C(O)OH and -C(O)NH ２ selected from the group consisting of 3. The compound of claim 1 or 2, selected from the group consisting of:

26. One of the following formulas: 【Transformation 78】 or a pharmaceutically acceptable salt thereof, Each R ｂ are independently １～４ Alkyl, F, Cl, OH, and —N(H)CH ３ selected from the group consisting of: R ｂ１ is H, C １～４ Alkyl, C １～４ Hydroxyalkyl, C １～４ Haloalkyl, —C(O)—C １～３ Alkyl, —C(O)—O—C １～３ Alkyl, —C １～３ Alkylene -C(O)OH and -C(O)NH ２ selected from the group consisting of 2. The compound of claim 1 having the formula:

27. One of the following formulas: 【Chemistry 79】 【Chemistry 80】 or a pharmaceutically acceptable salt thereof, Each R ｂ are independently １～４ selected from the group consisting of alkyl, F, Cl, and OH; and R ５ is OH, F, and -OCH ３ selected from the group consisting of 2. The compound of claim 1 having the formula:

28. R ３ is C １～４ Alkyl, Cl, F, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, cyclopropyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C １～３ Alkylene -O-C １～３ Alkyl, hydroxy, -NH ２ 3. The compound of claim 1, wherein the aryl group is selected from the group consisting of —C, —C, and —CN.

29. R ３ is Cl, F, -OCH ３ , -OCH ２ CH ３ , OCH(CH ３ ) ２ , OCF ３ , OCHF ２ , -C(CH ２ ) ２ 29. The compound of claim 28, wherein the group is selected from the group consisting of OH and hydroxy.

30. R ３ is a halogen, -CH ３ , -OCH ３ , -CH ２ OCH ３ , -OCH ２ CH ３ , -OC(H)(CH ３ ) ２ , CN, -NH ２ , C.F. ３ , -OCF ３ , and -OCHF ２ 29. The compound of claim 28 selected from the group consisting of:

31. R ３ 29. The compound of claim 28, wherein is Cl.

32. 2. The compound of claim 1 selected from Table 1, or a pharmaceutically acceptable salt thereof.

33. 10. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1.

34. A composition for treating a disease or condition selected from the group consisting of (1) allergic diseases, (2) inflammatory bowel disease, (3) vaginitis, (4) psoriasis and inflammatory skin diseases, (5) vasculitis, (6) spondyloarthropathy, (7) scleroderma, (8) asthma and respiratory allergic diseases, (9) autoimmune diseases, (10) transplant rejection, (11) other diseases in which unwanted inflammatory responses need to be inhibited, and cancer, in a patient in need of such treatment, the composition comprising a compound of claim 1.

35. 35. The composition of claim 34, wherein the disease or condition is selected from the group consisting of allergic disease, psoriasis, atopic dermatitis, and asthma.

36. 10. A pharmaceutical composition comprising a compound according to claim 1 or 2, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable excipient.

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