Compounds active against nuclear receptors

Abstract

Compounds active against nuclear receptors, pharmaceutical compositions containing the compounds and uses of the compounds in therapy are disclosed.

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. 62 / 951,221, filed December 20, 2019, and U.S. Provisional Patent Application No. 63 / 064,502, filed August 12, 2020, the disclosures of which are incorporated herein by reference in their entireties.

[0002] Aspects and embodiments described herein relate to compounds active against nuclear receptors, pharmaceutical compositions containing the compounds, and methods of using the compounds to treat inflammatory, metabolic, oncology, and autoimmune diseases or disorders. [Background technology]

[0003] Nuclear receptors are a family of transcription factors involved in the regulation of physiological functions such as cell differentiation, embryonic development, and organ physiology. Nuclear receptors have also been identified as important pathological regulators in diseases such as cancer, diabetes, and autoimmune disorders.

[0004] Examples of nuclear receptors include nuclear retinoic acid receptor-related orphan receptors (RORs). RORs contain four major domains: an N-terminal A / B domain, a DNA-binding domain, a hinge domain, and a ligand-binding domain. Binding of a ligand to the ligand-binding domain is thought to induce a conformational change in the domain that results in downstream effects. Various isoforms exist, and these isoforms differ only in the N-terminal A / B domain (Non-Patent Document 1).

[0005] ROR consists of three members, called ROR alpha (RORa or RORa), ROR beta (RORβ or RORb) and ROR gamma (RORγ or RORc).

[0006] RORα is expressed in many tissues, including cerebellar Purkinje cells, liver, thymus, skeletal muscle, skin, lung, adipose tissue, and kidney. RORα regulates neuronal development, bone metabolism, and arteriosclerosis (Non-Patent Document 1). Furthermore, RORα plays a role in immune responses, such as regulating interleukin (IL) 17A expression in T helper (Th) 17 cells and the function of regulatory T (Treg) cells (Non-Patent Document 2; Non-Patent Document 3).

[0007] RORβ exhibits a restricted expression pattern, restricted to specific brain regions (cerebral cortex, thalamus, hypothalamus, and pineal gland) and the retina (Non-Patent Document 1). RORβ is associated with epilepsy and, together with RORa, with bipolar disorder (Non-Patent Document 4; Non-Patent Document 5).

[0008] RORγ shows a widespread expression pattern and was the last of the three members to be discovered. To date, two distinct protein isoforms have been documented: RORγ1 and RORγ2 (RORγ2 is also known as RORγt). Generally, RORγ is used to describe RORγ1 and / or RORγt. RORγ1 is expressed in many tissues, primarily in the kidney, liver, and skeletal muscle. In contrast, RORγt expression is restricted to some cell types of the immune system and lymphoid organs such as the thymus and secondary lymphoid tissues (Non-Patent Document 6; Non-Patent Document 1).

[0009] RORγt has been identified as a key regulator of Th17 cell differentiation and IL-17 production by γδT cells, Th17 cells, T cytotoxic (Tc)17 cells, and innate lymphoid cell type 3 (ILC3) cells (Non-Patent Document 7). Th17 cells are a subset of T helper cells that preferentially produce the cytokines IL-17A, IL-17F, IL-21, and IL-22 (Non-Patent Document 2). T cells lacking RORγt cannot differentiate into Th17 cells even under Th17-polarizing culture conditions, whereas overexpression of RORγt in naive CD4+ T cells was sufficient to promote the expression of Th17-associated cytokines and chemokines (Non-Patent Document 8; Non-Patent Document 9). IL-23 is a crucial checkpoint in the generation, maintenance, and activation of pathogenic Th17 cells. In response to IL-23 signaling, RORγt cooperates with a network of transcription factors (STAT3, IRF4, and BATF) to initiate the complete differentiation program of Th17 cells (Non-Patent Document 8).

[0010] Th17 cells and IL-17 immune responses have been shown to be associated with the pathology of many human inflammatory and autoimmune disorders. Therapeutic strategies targeting the IL-23-IL-17 system have been developed for many autoimmune diseases, and some of them have already been demonstrated to provide clinical efficacy in some diseases (Non-Patent Document 10; Non-Patent Document 11).

[0011] Thus, there is evidence that RORα, RORβ and RORγ play a role in the pathogenesis of many diseases.

[0012] It would be desirable to provide compounds that modulate the activity of RORα and / or RORγ for use in treating inflammatory, metabolic, and autoimmune diseases.

[0013] Patent Documents 1 and 2 describe compounds that activate or modulate the ROR gamma receptor. However, there remains a need for potent ROR gamma modulators with improved physicochemical properties. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] International Publication No. 2016 / 020288 [Patent Document 2] International Publication No. 2016 / 020295 [Non-patent literature]

[0015] [Non-Patent Document 1] Jetten, 2009, Nuclear Receptor Signaling [Non-patent document 2] Castro PLOS 2017 [Non-patent document 3] Malhotra 2018 [Non-patent document 4] Rudolf 2016 [Non-Patent Document 5] Lai 2015 [Non-patent document 6] Hirose 1994 [Non-Patent Document 7] Gaffen 2014 [Non-patent document 8] Gaffen 2014, Nat Rev Immunol [Non-Patent Document 9] Yang 2014, Trend Pharmacol Sci [Non-Patent Document 10] Patel 2015 [Non-Patent Document 11] Krueger 2018 Exp Dermatol Summary of the Invention [Means for solving the problem]

[0016] In one aspect, provided herein is a compound of formula (I) [ka] , a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer, Y1, Y2, and Y3 are independently N or CR8; R is hydrogen, C 1~6 Alkyl, and C 1~4 hydroxyalkyl; R 0a and R 0b are independently hydrogen, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~4 selected from the group consisting of haloalkyl, CN, substituted or unsubstituted heteroalicyclyl, and substituted or unsubstituted heteroaryl; R 1a and R 1b are independently hydrogen, hydroxyl, halogen, amino, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 haloalkyl; R2 is hydrogen, hydroxyl, amino, cyano, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C(=O)OH, C(=O)NH2, C(=O)OC 1~4 selected from the group consisting of alkyl, and substituted or unsubstituted heteroaryl; R3 is C 1~4 Alkyl, C 2~4 Alkenyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~6 Hydroxyhaloalkyl, C 1~4 Alkylene-C 1~4 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, and substituted or unsubstituted C 3~7 cycloalkenyl; R4 and R5 are each independently hydrogen or C 1~4alkyl, or R4 and R5 together with the carbon atom to which they are attached are C 3~4 Forming a cycloalkyl; R6 is hydrogen, CN, halogen, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~6 Hydroxyhaloalkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 selected from the group consisting of haloalkoxy, and substituted or unsubstituted heteroaryl; R7 is hydrogen, hydroxyl, CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkoxy, C 1~4 selected from the group consisting of haloalkoxy, and substituted or unsubstituted heteroaryl; Each R8 is independently hydrogen, hydroxyl, CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 selected from the group consisting of haloalkoxy, and substituted or unsubstituted heteroaryl; and Whenever R7 is hydrogen and each R8 present is hydrogen, R6 may be CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~6 Hydroxyhaloalkyl, C 1~4 Alkoxy, C 1~4 selected from the group consisting of haloalkoxy, and substituted or unsubstituted heteroaryl; and When substituted, heteroalicyclyl is C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~6 Hydroxyhaloalkyl, Hydroxy, C 1~4 substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, and halogen; and When substituted, heteroaryl is C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, Hydroxy, C 1~4 Alkoxy, cyano, halogen, C 1~4 Haloalkyl, C 1~4 Haloalkoxy and C 1~6 hydroxyhaloalkyl; and When substituted, cycloalkyl or cycloalkenyl may be C 1~4 substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and halogen) are provided.

[0017] In one aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt of a compound of formula (I) or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0018] In one aspect, the present invention relates to a method for treating asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases such as allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergies, atopic dermatitis, lichen planus, cystic fibrosis, lung transplant rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus. , Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type II diabetes, and cancer, or a symptom thereof.

[0019] Further advantageous features of various embodiments are defined in the dependent claims and the detailed description below. DETAILED DESCRIPTION OF THE INVENTION

[0020] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other documents referenced herein are incorporated by reference in their entirety. In the event that there are multiple definitions of a term herein, those in this section prevail unless otherwise stated.

[0021] As used herein, R, R 0a , R 0b , R 1a , R 1b, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 Any "R" group, such as, but not limited to, represents a substituent that may be attached to the specified atom. Examples of R groups include, but are not limited to, hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl. When two "R" groups are covalently bonded to the same atom or adjacent atoms, they "together" or "combined," as defined herein, to form a cycloalkyl, aryl, heteroaryl, or heteroalicyclyl group. For example, but not limited to, NR a R b Group R a and R b When referred to as "together" or "in combination," it means that they are covalently bonded to each other at their terminal atoms to form a ring that includes the nitrogen: [ka]

[0022] As will be readily recognized by one of ordinary skill in the art, any given group disclosed herein may contain more hydrogens than those provided by the R groups that are hydrogens attached to that group.

[0023] Whenever a group is described as being "unsubstituted or substituted," when substituted, the substituents (which can be one or more, such as one, two, three, or four) are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When a substituent on a group is deemed to be "substituted," the substituent itself is substituted with one or more of the specified substituents. When a referenced substituent is substituted, it means that one or more hydrogen atoms on the referenced substituent can be replaced with a group individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof.The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in (Non-Patent Document 12), incorporated herein by reference in its entirety.

[0024] As used herein, "C m ~C n (C m to C n )," "C m ~C n (C m -C n )" or "C m~n (where "m" and "n" are integers) refer to the number of carbon atoms in the group in question; that is, a group can contain from "m" to "n" carbon atoms. Thus, for example, a "C1-C6 alkyl" group refers to all alkyl groups having 1 to 6 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, CH3CH(CH)3CH2-, CH3CH(CH)3CH2-, and (CH3)3C-. When "m" and "n" are not specified for a group, the broadest range described by those definitions is intended.

[0025] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain group that is fully saturated (no double or triple bonds). An alkyl group can have 1 to 20 carbon atoms (wherever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" where no numerical range is specified). An alkyl group can also be defined as "C 1~6 The alkyl group can be a medium size alkyl having 1 to 10 carbon atoms, such as "C1-C4 alkyl," "C 1~4For illustrative purposes only, "C1-C4 alkyl" or "C 1~4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like. When substituted, the substituents are one or more groups individually and independently selected from alkenyl, alkynyl, cycloalkyl including but not limited to cyclopropyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy including but not limited to methoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen including but not limited to fluoro, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino including mono- and di-substituted amino groups, and protected derivatives thereof.

[0026] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. When two or more double bonds are present, the double bonds may or may not be conjugated. An alkenyl group may have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as "2 to 20" refers to each integer in the given range; for example, "2 to 20 carbon atoms" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also encompasses the occurrence of the term "alkenyl" where no numerical range is specified). When substituted, the substituents are one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, hydroxyalkyl, haloalkoxy, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof.

[0027] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. The alkynyl group can have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as "2 to 20" refers to each integer in the given range; for example, "2 to 20 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also encompasses the existence of the term "alkynyl" without a specified numerical range). The alkynyl group can be unsubstituted or substituted. If substituted, the substituents can be selected from the same groups disclosed above for alkenyl group substitution.

[0028] As used herein, "hetero" refers to one or more carbon atoms that may be attached to a group, and associated hydrogen atoms in the attached group are independently replaced with the same or different heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur.

[0029] As used herein, "heteroalkyl," alone or in combination with another term, refers to a linear or branched alkyl group of the specified number of carbon atoms, in which one or more carbon atoms, such as 1, 2, 3, or 4 carbon atoms, and associated hydrogen atoms, are independently replaced with the same or different heteroatoms selected from nitrogen, oxygen, and sulfur. The replaced carbon atoms may be located in the middle or at the terminal end of the alkyl group. Examples of heteroalkyl include C 1~6 Included are heteroalkyls, in which one or more of the carbon atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen, and nitrogen, examples being -S-alkyl, -O-alkyl, -NH-alkyl, -alkylene-O-alkyl, etc. Heteroalkyls may be substituted.

[0030] As used herein, "aryl" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) having a completely delocalized π-electron system. In some embodiments described herein, an aryl group is a C 1~10Aryl, which may be substituted or unsubstituted. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups may be substituted. When substituted, the hydrogen atom is replaced by one or more substituents independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, the substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0031] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized π-electron system) in which at least one of the atoms in the ring system is a heteroatom, i.e., an element other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. In some embodiments described herein, heteroaryl includes C 6~10Examples of heteroaryl include, but are not limited to, heteroaryls, in which 1 to 4 carbon atoms are replaced by 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of monocyclic "heteroaryls" include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, oxadiazole, including but not limited to 1,2,4-oxadiazole and 1,3,4-oxadiazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, including but not limited to 1,2,4-triazole and 1,2,3-triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazole, and triazine. Examples of polycyclic "heteroaryls" include, but are not limited to, quinoline, isoquinoline, quinazoline, quinoxaline, indole, purine, benzofuran, benzothiophene, and benzopyranone (e.g., coumarin, chromone, and isocoumarin). Heteroaryls may be substituted. When substituted, the hydrogen atom is replaced by one or more substituents independently selected from alkyl, including but not limited to methyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, including but not limited to 2-hydroxyethyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, the substituents on a heteroaryl group may form a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0032] An "aralkyl" or "arylalkyl" is an aryl group linked as a substituent via an alkylene group. The alkylene and aryl groups of the aralkyl may be substituted. Examples include, but are not limited to, benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group.

[0033] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group linked as a substituent via an alkylene group. The alkylene and heteroaryl groups of a heteroaralkyl may be substituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl, and imidazolylalkyl, as well as substituted and benzo-fused analogs thereof. In some cases, the alkylene group is a lower alkylene group.

[0034] An "alkylene" is a straight-chain tethering group that forms a bond connecting molecular fragments through terminal carbon atoms. Alkylene can have 1 to 20 carbon atoms. Alkylene is also referred to as "C 1~6 Alkylene may also be a medium size alkylene having 1 to 10 carbon atoms, such as "C1-C4 alkylene," "C 1~4 A lower alkylene may be designated as "alkylene" or similar designation. Non-limiting examples include methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-(CH)-) groups. In the case of methylene, the two linked fragments are attached to the same carbon atom. Lower alkylenes may be substituted.

[0035] As used herein, "heteroalkylene," alone or in combination with another term, refers to an alkylene group of the specified number of carbon atoms, wherein one or more of the carbon atoms, such as 1, 2, 3, or 4 carbon atoms, are independently replaced with the same or different heteroatoms selected from oxygen, sulfur, and nitrogen. Examples of heteroalkylene include, but are not limited to, -CH2-O-, -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-NH-, -CH2-CH2-NH-, -CH2-CH2-CH2-NH-CH2-, -CH2-CH2-NH-CH2-, -O-CH2-CH2-O-CH2-CH2-O-, -O-CH2-CH2-O-CH2-CH2-, and the like.

[0036] As used herein, "alkylidene" refers to a divalent group such as =CR'R" that is attached to one carbon of another group, forming a double bond. Alkylidene groups include, but are not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, "arylalkylidene" refers to an alkylidene group where either R' or R" is an aryl group. Alkylidene groups may be optionally substituted.

[0037] As used herein, "alkoxy" refers to the group -OR where R is alkyl, e.g., methoxy, ethoxy, n-propoxy, cyclopropoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy, etc. Alkoxy may be substituted.

[0038] As used herein, "alkylthio" refers to the formula -SR where R is alkyl as defined above, for example, methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methylethyl mercapto (isopropyl mercapto), n-butyl mercapto, iso-butyl mercapto, sec-butyl mercapto, tert-butyl mercapto, etc. Alkylthio may be optionally substituted.

[0039] As used herein, "aryloxy" and "arylthio" refer to RO- and RS- where R is aryl as defined above, e.g., phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio, etc. Both aryloxy and arylthio may be substituted.

[0040] As used herein, "alkenyloxy" refers to the formula -OR where R is alkenyl as defined above, e.g., vinyloxy, propenyloxy, n-butenyloxy, iso-butenyloxy, sec-pentenyloxy, tert-pentenyloxy, etc. Alkenyloxy may be substituted.

[0041] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected as a substituent through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. Acyl may be substituted.

[0042] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double bonds). When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro-connected manner. Cycloalkyl groups include C3-C6 rings, such as C3-C6. 10 The cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. When substituted, the substituents may be independently selected from alkyl, including but not limited to, methyl, or halogen, including but not limited to, fluoro, or may be selected from those set forth above with respect to alkyl group substitution, unless otherwise specified. When substituted, substitution on the cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including aryl and heteroaryl.

[0043] As used herein, "cycloalkenyl" refers to a cycloalkyl group containing one or more double bonds in the ring, provided that if there are more than one, they cannot form a completely delocalized π-electron system in the ring (otherwise the group would be "aryl" as defined herein). When composed of more than one ring, the rings can be linked together in a fused, bridged, or spiro-bonded manner. Cycloalkenyl groups are C3-C8 or C5-C6 10 C3 to C 10 For example, C 3~8 Cycloalkenyl includes C 4~8 Cycloalkenyl, C 5~8 Cycloalkenyl or C 6~8 Cycloalkenyl groups include cycloalkenyl. Cycloalkenyl groups can be unsubstituted or substituted. When substituted, the substituents can be alkyl or, unless otherwise specified, can be selected from the groups disclosed above for alkyl group substitution. When substituted, the substitution on the cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, including aryl and heteroaryl.

[0044] As used herein, "cycloalkynyl" refers to a cycloalkyl group containing one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro-bonded manner. Cycloalkynyl groups include C8 to C6 12 The cycloalkynyl group can be unsubstituted or substituted. If substituted, the substituents can be alkyl or, unless otherwise specified, can be selected from the groups disclosed above for alkyl group substitution. If substituted, substitution on the cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, including aryl and heteroaryl.

[0045] As used herein, "heteroalicyclyl" or "heteroalicyclyl" refers to a 3- to 18-membered ring consisting of carbon atoms and 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A heteroalicyclyl or heteroalicyclyl group is a C2-C 10and in some embodiments, it may range from C2 to C9, and in other embodiments, it may range from C2 to C8. In some embodiments, a "heteroalicyclyl" or "heteroalicyclyl" may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged, or spiro-connected fashion; and the nitrogen, carbon, and sulfur atoms in a "heteroalicyclyl" or "heteroalicyclyl" may be oxidized; the nitrogen may be quaternized; and the rings may also be substituted, provided that they do not form a fully delocalized pi-electron system throughout the entire ring. and may contain one or more double bonds, examples being 2H-benzo[b][1,4]oxazin-3(4H)-one, 3,4-dihydroquinolin-2(1H)-one, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydro-1H-benzo[d]imidazole, indoline, and 1,3-dihydro-2H-benzo[d]imidazol-2-one, and benzo[d]oxazol-2(3H)-one. Heteroalicyclyl groups can be unsubstituted or substituted. If substituted, the substituents can be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof.Examples of such "heteroalicyclyl" or "heteroalicyclyl" include, but are not limited to, azepinyl, dioxolanyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. When substituted, substitutions on a heteroalicyclyl group can form an aromatic ring fused to the heteroalicyclyl group, including aryl and heteroaryl.

[0046] "(Cycloalkyl)alkyl" is a cycloalkyl group linked as a substituent via an alkylene group. The alkylene and cycloalkyl of the (cycloalkyl)alkyl may be substituted. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.

[0047] A "(cycloalkenyl)alkyl" is a cycloalkenyl group linked as a substituent via an alkylene group. The alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group.

[0048] A "(cycloalkynyl)alkyl" is a cycloalkynyl group linked as a substituent via an alkylene group. The alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group.

[0049] As used herein, "halo" or "halogen" refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).

[0050] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen. Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2-fluoroethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl may be substituted or unsubstituted, and in some embodiments, C 1~6 It relates to medium size haloalkyls such as haloalkyls having 1-10 carbon atoms.

[0051] As used herein, "haloalkoxy" refers to the group RO-, where R is a haloalkyl group. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. Haloalkoxy may be optionally substituted.

[0052] As used herein, the term "hydroxyalkyl" refers to an alkyl in which one or more of the hydrogen atoms have been replaced by a hydroxyl group. Such groups include, but are not limited to, hydroxymethyl, hydroxyethyl, including but not limited to 2-hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, and hydroxyhexyl. Hydroxyalkyl groups can be substituted or unsubstituted, and some embodiments include C 1~6

[0033] With respect to medium size hydroxyalkyls, such as hydroxyalkyl having 1 to 10 carbon atoms; if substituted, the substituents may be one or more groups independently selected from the group consisting of halogen, including but not limited to fluoro, and haloalkyl, including but not limited to trifluoromethyl; such substituted "hydroxyalkyl" groups include, but are not limited to, 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl and 1,1-difluoro-2-hydroxyethyl.

[0053] An "O-carboxy" group refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. O-carboxy is optionally substituted.

[0054] A "C-carboxy" group refers to a "-C(=O)OR" group where R can be the same as defined for O-carboxy. C-carboxy can be optionally substituted.

[0055] A "trihalomethanesulfonyl" group refers to an "X3CSO2" group where X is a halogen.

[0056] Dashed join [ka] represents optional unsaturation between the atoms forming the bond. This bond can be unsaturated (e.g., C=C, C=N, C=O) or saturated (e.g., CC, CN, CO). The dashed bond is present in a ring system that may form part of an aromatic ring system.

[0057] As used herein, a straight (not wedge) bold or dashed bond [ka] refers to the relative stereochemistry at that position, including all possible stereoisomers.

[0058] As used herein, and unless otherwise indicated, a wedge bond (bold, dashed, or otherwise) [ka] refers to the absolute stereochemistry, referring to the specific stereoisomer as drawn at that position.

[0059] A "nitro" group refers to a "-NO2" group.

[0060] A "cyano" group refers to a "-CN" group.

[0061] A "cyanato" group refers to an "-OCN" group.

[0062] An "isocyanato" group refers to a "-NCO" group.

[0063] A "thiocyanato" group refers to a "-SCN" group.

[0064] A "carbonyl" group refers to a "-C(=O)-" group.

[0065] A "thiocarbonyl" group refers to a "-C(=S)-" group.

[0066] An "oxo" group refers to a "=O" group.

[0067] A "hydroxy" or "hydroxyl" group refers to an "-OH" group.

[0068] An "isothiocyanato" group refers to a "-NCS" group.

[0069] A "sulfinyl" group refers to a "-S(=O)-R" group where R can be the same as defined for O-carboxy. Sulfinyl may be substituted.

[0070] A "sulfonyl" group refers to a "SO2R" group where R can be the same as defined for O-carboxy. Sulfonyl may be substituted.

[0071] An "S-sulfonamide" group is R A and R B each independently can be the same as defined for the R group as defined for O-carboxy, or a substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 Cycloalkenyl, substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 "-SO2NR" which may be combined to form a ring system selected from the group consisting of cycloalkenyl, substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; A R B " group. The S-sulfonamide may be substituted.

[0072] An "N-sulfonamido" group is one in which R and R A each of which may independently be the same as defined for the R group as defined for O-carboxy. A )-". N-sulfonamides may be substituted.

[0073] A "trihalomethanesulfonamido" group refers to an "X3CSO2N(R)-" group with X as the halogen and R can be the same as defined for O-carboxy. Trihalomethanesulfonamido may be substituted.

[0074] A "C-amide" group is R A and R B each independently can be the same as defined for the R group as defined for O-carboxy, or a substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8Cycloalkenyl, substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 "-C(=O)NR" which may be combined to form a ring system selected from the group consisting of cycloalkenyl, substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; A R B " group. The C-amide may be substituted.

[0075] An "N-amido" group is one in which R and R A each independently may be the same as defined for the R group as defined for O-carboxy. A -" group. N-amides may be substituted.

[0076] "Ester" refers to the group "-C(=O)OR" where R can be the same as defined for O-carboxy. Esters may be substituted.

[0077] Lower alkoxyalkyl refers to an alkoxy group linked via a lower alkylene group. Lower alkoxyalkyl may be substituted.

[0078] "Amine" or "amino" refers to "RNH2" (primary amine), "R2NH" (secondary amine), or "RN" (tertiary amine). The amino group may be substituted.

[0079] A lower aminoalkyl refers to an amino group linked through a lower alkene group. A lower aminoalkyl may be substituted.

[0080] Any unsubstituted or monosubstituted amine group in the compounds herein may be converted to an amide, any hydroxyl group may be converted to an ester, and any carboxyl group may be converted to either an amide or an ester, using techniques well known to those skilled in the art (see, for example, Non-Patent Document 12).

[0081] As used herein, abbreviations for any protecting groups, amino acids, and other compounds follow their common usage, accepted abbreviations, or the IUPAC-IUB Biochemical Nomenclature Commission, unless otherwise indicated (see Non-Patent Document 13).

[0082] List of abbreviations DMF Dimethylformamide DMSO dimethyl sulfoxide MeOH Methanol EtOH ethanol THF tetrahydrofuran DCM dichloromethane, methylene chloride DCE 1,2-dichloroethane LRMS low resolution mass spectrometry HPLC High Pressure Liquid Chromatography Prep-HPLC Preparative High-Pressure Liquid Chromatography h time min EA Ethyl acetate EDC·HCl 3-((ethylimino)methyleneamino)-N,N-dimethylpropan-1-aminium chloride DIEA Diisopropylethylamine TEA Triethylamine TFA trifluoroacetic acid HCl Hydrochloric acid, hydrogen chloride HOBt 1-Hydroxybenzotriazole Hydrate HOAt 1-hydroxy-7-azabenzotriazole HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate DMAP 4-(dimethylamino)pyridine DAST (Diethylamino)sulfur trifluoride DIAD Diisopropyl azodicarboxylate DMP Dess-Martin Periodinane, 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one TBAF Tetrabutylammonium fluoride trihydrate TBDMSCl tert-butyldimethylsilyl chloride MsCl methanesulfonyl chloride NAS Nucleophilic Aromatic Substitution nBuLi n-butyllithium iPr Isopropyl Boc tert-butyloxycarbonyl Flash CC Flash column chromatography on overnight rt room temperature aq water-based ND Not decided Cbz Carboxybenzyl Hex Hept Heptane DEA Diethylamine PE Petroleum Ether DAD Diode Array Detector TOF Time of Flight IPA Isopropanol Pg protecting group " Enriched in one enantiomer

[0083] In any compound disclosed herein having one or more chiral centers, where the absolute stereochemistry is not explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure or stereoisomeric mixtures. Furthermore, the compounds provided herein may be scalenic mixtures. Additionally, in any compound having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Likewise, all tautomeric forms are also intended to be included.

[0084] As used herein, the term "rac" refers to "racemic," "racemate," and the like, as understood by those skilled in the art. For example, a racemate contains a mixture of equal amounts of enantiomers of a chiral molecule. Typically, a racemate exhibits no optical activity.

[0085] As used herein, the term "rel" refers to the relative, not absolute, configuration of an asymmetric center with respect to any other asymmetric centers within the same compound, as would be understood by one of ordinary skill in the art.

[0086] As used herein, "tautomer" and "tautomeric" refer to alternating forms of the compounds disclosed herein that differ in the location of a proton. Non-limiting examples include enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to both the ring -NH- and ring =N- moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0087] It is understood that isotopes may exist in the compounds described herein. Each chemical element as represented in the compound structure may include any isotope of said element. For example, in the compounds described herein, hydrogen atoms may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, in this specification, reference to a compound includes all possible isotopic forms, unless the context clearly indicates otherwise.

[0088] As used herein, a reference to an element, regardless of description or chemical structure, includes all isotopes of that element unless otherwise specified. As an example, the term "hydrogen" or "H" in a chemical structure as used herein refers to all isotopes of that element unless otherwise indicated by the use of a specific isotope, e.g., 1 Not only H but also deuterium ( 2 H), tritium ( 3It is understood that isotopes also include elements such as carbon, phosphorus, iodine, and fluorine, as well as mixtures thereof.

[0089] As used herein, "pharmaceutically acceptable salts" refers to salts of compounds that do not abrogate the biological activity and properties of the compounds. Pharmaceutical salts can be obtained by reacting the compounds disclosed herein with an acid or a base. Salts formed with bases include ammonium salts (NH4 + ); alkali metal salts such as, but not limited to, sodium or potassium; alkaline earth salts such as, but not limited to, calcium or magnesium; salts of organic bases such as, but not limited to, dicyclohexylamine, piperidine, piperazine, methylpiperazine, N-methyl-D-glucamine, diethylamine, ethylenediamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, but not limited to, arginine and lysine. Useful acid-based salts include, but are not limited to, acetate, adipate, aspartate, ascorbate, benzoate, butyrate, caprate, caproate, caprylate, camsylate, citrate, decanoate, formate, fumarate, gluconate, glutarate, glycolate, hexanoate, laurate, lactate, maleate, nitrate, oleate, oxalate, octanoate, propanoate, palmitate, phosphate, sebacate, succinate, stearate, sulfate, sulfonates such as methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate, tartrate, and tosylate.

[0090] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvents, or 1 to about 100, or 1 to about 10, or 1 to about 2, 3, or 4 solvents or water molecules.

[0091] As used herein, a "prodrug" refers to a compound that may not be pharmaceutically active but is converted into an active drug upon in vivo administration. Prodrugs may be designed to alter the metabolic stability or transport properties of a drug, mask side effects or toxicity, improve the flavor of a drug, or alter other properties or characteristics of a drug. Prodrugs are often useful because they can be administered more easily than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. A prodrug may also have better solubility in pharmaceutical compositions than the active parent drug. A non-limiting example of a prodrug is a compound disclosed herein, which is administered as an ester ("prodrug") to facilitate absorption across cell membranes, where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to a carboxylic acid (the active entity) inside the cell, where water solubility is advantageous. A further example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized in vivo to release the active parent compound. Knowledge of pharmacodynamic processes and in vivo drug metabolism allows one skilled in the art to design prodrugs of a pharmaceutically active compound once that compound is known (see, for example, (Non-Patent Document 14)).

[0092] As used herein, "modulating" the activity of a receptor means either activating it, i.e., increasing its cellular function above the basal level measured in the particular environment in which it is found, or inactivating it, i.e., reducing its cellular function below the basal level measured in the cellular environment in which it is found and / or preventing it from performing its cellular function at all, even in the presence of a natural binding partner. A natural binding partner is an endogenous molecule that is an agonist for the receptor.

[0093] An "agonist" is defined as a compound that increases the basal activity of a receptor (ie, signal transduction mediated by the receptor).

[0094] As used herein, "partial agonist" refers to a compound that has affinity for a receptor, but is not agonist-like, and when bound to a receptor, it elicits to a small extent the pharmacological response normally associated with the receptor, even when the majority of the receptor is occupied by the compound.

[0095] An "inverse agonist" is defined as a compound that reduces or inhibits the basal activity of a receptor, such that the compound is not technically an antagonist, but rather an agonist with negative intrinsic activity.

[0096] As used herein, "antagonist" refers to a compound that binds to a receptor to form a complex that does not elicit any response, as if the receptor were unoccupied. Antagonists attenuate the action of an agonist on a receptor. Antagonists may bind reversibly or irreversibly and effectively eliminate the activity of the receptor, either persistently or at least until the antagonist is metabolized, dissociated, or otherwise removed by physical or biological processes.

[0097] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as birds, fish, crustaceans, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and especially humans.

[0098] As used herein, "patient" refers to a subject being treated by a medical professional, such as an MD or DVM, to attempt to cure or at least ameliorate the effects of a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.

[0099] As used herein, a "carrier" refers to a compound that facilitates the uptake of a compound into cells or tissues. For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0100] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the mass of a potent drug substance that is too small to manufacture or administer. It may also be a liquid for dissolving a drug to be administered by injection, oral ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate-buffered saline, which mimics the composition of human blood.

[0101] As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, integrity, consistency, stability, binding ability, lubrication, disintegration ability, etc. A "diluent" is a type of excipient.

[0102] "Receptor" is intended to include any molecule present inside or on the surface of a cell that can affect the physiological function of the cell when it is inhibited or stimulated by a ligand. Typically, a receptor contains an extracellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and an intracytoplasmic domain that generates a cellular signal in response to ligand binding ("signal transduction"). Receptors also include any intracellular molecule that generates a signal in response to binding. Receptors also include any molecule that has the characteristic structure of a receptor but does not have an identifiable ligand. In addition, receptors include truncated, modified, or mutated receptors, or any molecule containing partial or all of the sequence of a receptor.

[0103] "Ligand" is intended to include any substance that interacts with a receptor.

[0104] "Selective" or "selectivity" is defined as the ability of a compound to produce a desired response from a particular receptor type, subtype, class, or subclass while producing a lesser or no response from other receptor types. "Selective" or "selectivity" for one or more particular subtypes of a compound refers to the ability of the compound to increase the activity of that subtype while producing a lesser, lesser, or no increase in the activity of other subtypes.

[0105] As used herein, "co-administration" of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Co-administration refers to the simultaneous delivery of separate agents; the simultaneous delivery of a mixture of agents; and the delivery of one agent followed by a second or additional agent. Co-administered agents are usually intended to work in combination with each other.

[0106] As used herein, the term "effective amount" means the amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal or human that is desired by a researcher, veterinarian, medical doctor or other clinician, including reduction or alleviation of the symptoms of the disease being treated.

[0107] As used herein, "prevent / preventing" should not be interpreted to mean that following use of a compound or pharmaceutical composition according to an embodiment disclosed herein to achieve prevention, a condition and / or disease may never occur again. Moreover, the term should not be interpreted to mean that a condition is not likely to occur, at least to some extent, following such use to prevent said condition. Rather, "prevent / preventing" is intended to mean that the condition to be prevented, if it occurs despite such use, will be less severe than it would be in the absence of such use.

[0108] compound In one embodiment, the present disclosure provides a compound of formula (I) [ka] , a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer, Y1, Y2, and Y3 are independently N or CR8; R is hydrogen, C 1~6 Alkyl, and C 1~4 hydroxyalkyl; R 0a and R 0b are independently hydrogen, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~4 selected from the group consisting of haloalkyl, CN, substituted or unsubstituted heteroalicyclyl, and substituted or unsubstituted heteroaryl; R 1a and R 1b are independently hydrogen, hydroxyl, halogen, amino, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 haloalkyl; R2 is hydrogen, hydroxyl, amino, cyano, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C(=O)OH, C(=O)NH2, C(=O)OC 1~4 selected from the group consisting of alkyl, and substituted or unsubstituted heteroaryl; R3 is C 1~4 Alkyl, C 2~4 Alkenyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~6 Hydroxyhaloalkyl, C 1~4 Alkylene-C 1~4 Alkoxy, substituted or unsubstituted C 3~7 Cycloalkyl, and substituted or unsubstituted C 3~7 cycloalkenyl; R4 and R5 are each independently hydrogen or C 1~4alkyl, or R4 and R5 together with the carbon atom to which they are attached are C 3~4 Forming a cycloalkyl; R6 is hydrogen, CN, halogen, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~6 Hydroxyhaloalkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 selected from the group consisting of haloalkoxy, and substituted or unsubstituted heteroaryl; R7 is hydrogen, hydroxyl, CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkoxy, C 1~4 selected from the group consisting of haloalkoxy, and substituted or unsubstituted heteroaryl; Each R8 is independently hydrogen, hydroxyl, CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 selected from the group consisting of haloalkoxy, and substituted or unsubstituted heteroaryl; and Whenever R7 is hydrogen and each R8 present is hydrogen, R6 may be CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~6 Hydroxyhaloalkyl, C 1~4 Alkoxy, C 1~4 selected from the group consisting of haloalkoxy, and substituted or unsubstituted heteroaryl; and When substituted, heteroalicyclyl is C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~6 Hydroxyhaloalkyl, Hydroxy, C 1~4 substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, and halogen; and When substituted, heteroaryl is C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, Hydroxy, C 1~4 Alkoxy, cyano, halogen, C 1~4 Haloalkyl, C 1~4 Haloalkoxy and C 1~6 hydroxyhaloalkyl; and When substituted, cycloalkyl or cycloalkenyl may be C 1~4 substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and halogen).

[0109] In some embodiments disclosed herein, R is hydrogen.

[0110] In some embodiments disclosed herein, R6 is hydrogen, CN, halogen, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Hydroxyalkyl, C 1~6hydroxyhaloalkyl; 5-membered heteroaryl, and 5-membered heteroaryl substituted with one or two substituents independently selected from methyl or hydroxyethyl, and whenever R7 is hydrogen and each R8 present is hydrogen, R6 cannot be hydrogen. In other embodiments, R6 is selected from the group consisting of hydrogen, CN, chloro, CF3, CHF2, CCH3F2, OCF3, and OCHF2, OCH2F, C(CF3)2OH, CF2CH2OH, pyrazolyl, and pyrazolyl substituted with one substituent selected from methyl or 2-hydroxyethyl, and whenever R7 is hydrogen and each R8 present is hydrogen, R6 cannot be hydrogen. In other embodiments, R6 is selected from the group consisting of hydrogen, CF3, CCH3F2, OCHF2, C(CF3)2OH, pyrazolyl, and methyl-pyrazolyl, and whenever R7 is hydrogen and each R8 present is hydrogen, R6 cannot be hydrogen. In other embodiments, R6 is selected from the group consisting of CF3, C(CF3)2OH, 1-methyl-1H-pyrazol-4-yl, and 1H-pyrazol-1-yl. In other embodiments, R6 is CF3.

[0111] In some embodiments disclosed herein, R7 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, CH3, OCH3, CF3, CHF2, OCF3, and OCHF2. In other embodiments, R7 is hydrogen or fluoro.

[0112] In some embodiments disclosed herein, Y1, Y2, and Y3 are each CH. In some embodiments, Y1 is N, and Y2 and Y3 are each CH. In some embodiments, Y2 is N, and Y1 and Y3 are each CH. In some embodiments, Y3 is N, and Y1 and Y2 are each CH. In some embodiments, Y3 is CH-, and Y1 and Y2 are each N.

[0113] In some embodiments disclosed herein, Y1 and Y2 are each CH- and Y3 is CR8, wherein R8 is selected from the group consisting of hydrogen, hydroxyl, methyl, OCH3, fluoro, chloro, and CF3.

[0114] In some embodiments disclosed herein, R8 is hydrogen or fluoro.

[0115] In some embodiments disclosed herein, Y2 is N, and Y1 and Y3 are independently CH. In some embodiments, Y3 is N, and Y1 and Y2 are each independently CH.

[0116] In some embodiments disclosed herein, R6 is hydrogen, at least one of Y2 or Y3 is CR8, and R8 is CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 haloalkoxy. In some embodiments, R6 is hydrogen and Y2 is C(OCF3).

[0117] In some embodiments disclosed herein, R and R are independently hydrogen or methyl. In some embodiments, R and R, together with the carbon atom to which they are attached, form a cyclopropyl.

[0118] In some embodiments disclosed herein, R4 is hydrogen or methyl and R5 is hydrogen.

[0119] In some embodiments disclosed herein, R4 and R5 are each hydrogen.

[0120] In some embodiments disclosed herein, R3 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, CH2CH2F, CH2CHOCH3, cyclopropyl-CH2-, cyclopropyl, methylcyclopropyl, cyclobutyl, and fluorocyclobutyl. In some embodiments, R3 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, and 3-fluorocyclobutyl. In some embodiments, R3 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, (1r,3S)-3-fluorocyclobutyl, and (1s,3R)-3-fluorocyclobutyl. In some embodiments, R3 is selected from the group consisting of methyl, ethyl, and cyclopropyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is cyclopropyl.

[0121] In some embodiments disclosed herein, R2 is hydrogen, hydroxyl, amino, CN, halogen, methyl, ethyl, CH2OH, CH2CH2OH, C(=O)OC 1~2In some embodiments, R2 is selected from the group consisting of alkyl, C(=O)NH2, and unsubstituted or substituted 5-membered heteroaryl. In some embodiments, R2 is selected from the group consisting of hydrogen, hydroxyl, CN, fluoro, methyl, CH2OH, C(=O)OCH3, C(=O)NH2, oxadiazolyl, and triazolyl. In some embodiments, R2 is selected from the group consisting of hydrogen, hydroxyl, CN, methyl, CH2OH, C(=O)OCH3, C(=O)NH2, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1H-1,2,4-triazol-3-yl, and 1H-1,2,3-triazol-5-yl. In some embodiments, R2 is selected from the group consisting of hydrogen, CN, methyl, CH2OH, and hydroxyl. In some embodiments, R2 is hydrogen or hydroxyl. In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl.

[0122] In some embodiments disclosed herein, R 1a is selected from the group consisting of hydrogen, hydroxyl, fluoro, and CF3; R 1b is selected from the group consisting of hydrogen, fluoro, and methyl.

[0123] In some embodiments disclosed herein, R 1a is selected from the group consisting of hydroxyl, fluoro, and CF3; R 1b is selected from the group consisting of hydrogen, fluoro, and methyl.

[0124] In some embodiments disclosed herein, R 1a is hydroxyl or fluoro. In some embodiments, R 1a is a hydroxyl.

[0125] In some embodiments disclosed herein, R 1b , is hydrogen. In some embodiments, R 1b is methyl.

[0126] In some embodiments disclosed herein, R 1a , R 1b and at least one of R2 is not hydrogen.

[0127] In some embodiments disclosed herein, R 1a is selected from the group consisting of hydrogen, hydroxyl, and fluoro; R 1b is selected from the group consisting of hydrogen, fluoro, and methyl; and R is selected from the group consisting of hydrogen, hydroxyl, methyl, CN, CHOH, and CHCHOH. In some embodiments, R 1a is selected from the group consisting of hydroxyl and hydrogen. 1a is hydroxyl or R is selected from the group consisting of hydroxyl, CHOH, and CHCHOH; 1b is hydrogen, and R2 is selected from the group consisting of hydrogen, hydroxyl, CH2OH, and CH2CH2OH.

[0128] In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl, CHOH, CHCHOH, CHF, and CHF; and R 0b is hydrogen, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 haloalkyl.

[0129] In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl, CHOH, and CHCHOH. In some embodiments, R 0a is hydrogen. In some embodiments, R 0b is hydrogen.

[0130] In some embodiments, provided herein are compounds having the structure of Formula (II) or Formula (III): [ka] , a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer, R 1a is fluoro or hydroxyl, and R 1b is hydrogen or fluoro, R is hydrogen or hydroxyl, R is CF, Y and Y are independently N or CR, and R is hydrogen or fluoro. In some embodiments, Y and Y are each CH, or Y is CH and Y is CF. In some embodiments, R 1a is hydroxyl and R 1b is hydrogen. In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl.

[0131] In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl, CHOH, and CHCHOH; R 0b is selected from the group consisting of hydrogen and methyl; R 1a is selected from the group consisting of hydrogen, hydroxyl, fluoro, and CF; R 1bis selected from the group consisting of hydrogen, fluoro, and methyl; R2 is selected from the group consisting of hydrogen, hydroxyl, amino, CN, fluoro, methyl, CH2-OH, C(=O)-NH2, C(=O)O-CH3, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1H-imidazol-2-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-3-yl, and 4-methyl-4H-1,2,4-triazol-3-yl; R is selected from the group consisting of hydrogen and CH2OH. R3 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, CH2CH2F, CH2CH2OCH3, cyclopropyl-CH2-, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, and 3-fluorocyclobutyl; R4 is hydrogen or methyl; R5 is hydrogen; R6 is hydrogen, chloro, CN, CF3, CHF2, CCH3F2, OCH3, OCF3, OCH2F, OCHF2, C(CF3)2OH, CF2CH2OH, 1H-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl, and 1-(2-hydroxyethyl)-1H-pyrazol-4-yl; R7 is hydrogen or chloro; Y1, Y2, and Y3 are each CH; or Y1 is CH, Y2 is CH, and Y3 is selected from the group consisting of N, C(F), C(OCH3), C(CH3), C(Cl), and C(CF3); or Y1 is CH and Y2 is selected from the group consisting of N, C(CN), C(1H-1,2,4-triazol-1-yl), C(OCF3), C(OCH3), C(F), C(OCHF2), and C(Cl). and Y3 is CH; or Y1 is CH, Y2 is C(Cl), and Y3 is C(Cl); or Y1 is C(CH3), Y2 is CH, and Y3 is C(CH3); or Y1 is C(CH3), Y2 is C(CH3), and Y3 is CH; or Y1 is C(CF3), Y2 is C(CF3), and Y3 is CH; or Y1 is C(Cl), Y2 is C(Cl), and Y3 is CH; or Y1 is N, Y2 is N, and Y3 is CH.In some cases, when R7 is H and Y1, Y2, and Y3 are CH, R6 is selected from the group consisting of chloro, CN, CF3, C(CH3)F2, OCF3, OCH2F, OCHF2, C(CF3)2OH, CF2CH2OH, 1H-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl, and 1-(2-hydroxyethyl)-1H-pyrazol-4-yl.

[0132] In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl, CHOH, and CHCHOH; R 0b is hydrogen or methyl; R 1a is selected from the group consisting of hydrogen, hydroxyl, CF3, and fluoro; R 1bis selected from the group consisting of hydrogen, fluoro, and methyl; R2 is selected from the group consisting of hydrogen, hydroxyl, CN, CH2OH, methyl, CO2Me, CONH2, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1H-1,2,3-triazol-5-yl, and 1H-1,2,4-triazol-3-yl; R is hydrogen; R3 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl-CH2-, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, (1r,3S)-3-fluorocyclobutyl, and (1s,3R)-3-fluorocyclobutyl; R4 is hydrogen R5 is hydrogen; R6 is selected from the group consisting of hydrogen, CF3, CF2CH3, OCHF2, C(CF3)2OH, 1H-pyrazol-1-yl, and 1-methyl-1H-pyrazol-4-yl; R7 is hydrogen; Y1, Y2, and Y3 are each CH; or Y1 is CH, Y2 is CH, and Y3 is C(F); or Y1 is CH, Y2 is C(OCF3) or C(OCH3), and Y3 is CH; or Y1 is CH, Y2 is CH, and Y3 is N; or Y1 is CH, Y2 is N, and Y3 is CH; or Y1 is N, Y2 is N, and Y3 is CH. In some cases, when R7 is H and Y1, Y2, and Y3 are each CH, R6 is selected from the group consisting of CF3, CF2CH3, OCHF2, C(CF3)2OH, 1H-pyrazol-1-yl, and 1-methyl-1H-pyrazol-4-yl.

[0133] In some embodiments, R 0a is selected from the group consisting of hydrogen, methyl, and CHOH; R 0b is hydrogen or methyl; R 1a is selected from the group consisting of hydrogen, hydroxyl, and fluoro; R 1bis selected from the group consisting of hydrogen, fluoro, and methyl; R2 is selected from the group consisting of hydrogen, hydroxyl, CN, CH2OH, methyl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, and 1H-1,2,3-triazol-5-yl; R is hydrogen; R3 is ethyl or cyclopropyl; R4 is hydrogen; R5 is hydrogen; R6 is selected from the group consisting of hydrogen, CF3, CF2CH3, OCHF2, C(CF3)2OH, 1H-pyrazol-1-yl, and 1-methyl-1H-pyrazol-4-yl; R7 is hydrogen; Y1, Y2, and Y3 are each CH; or Y1 is CH, Y2 is CH, and Y3 is C(F); or Y1 is CH, Y2 is C(OCF3), and Y3 is CH. In some cases, when R7 is H and Y1, Y2, and Y3 are each CH, R6 is selected from the group consisting of CF3, CF2CH3, OCHF2, C(CF3)2OH, 1H-pyrazol-1-yl, and 1-methyl-1H-pyrazol-4-yl.

[0134] In some embodiments disclosed herein, R 0a is selected from the group consisting of CN, substituted or unsubstituted heteroalicyclyl, and substituted or unsubstituted heteroaryl; and R 0b is hydrogen or C 1~4 In some embodiments, R 0a is unsubstituted or substituted heteroaryl. In some embodiments, R 0a is substituted or unsubstituted pyridinyl.

[0135] In some embodiments disclosed herein, R 0b is hydrogen.

[0136] In one embodiment disclosed herein, the compound, stereoisomer, or salt of formula (I) is A7-1 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-1-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-2 2-(4-(((6-(cyclopropyl(2-methyl-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-3-1 rel-(R)-2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-3-2 rel-(R)-2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the second-eluting isomer, A7-4-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-4-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the second eluting isomer, A7-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-5-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the second-eluting isomer, A7-6-1 rel-(R)-2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-6-2 rel-(R)-2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the second-eluting isomer, A7-7-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, the first-eluting isomer, A7-7-2 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, the second eluting isomer, A7-7-3 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, the third eluting isomer, A7-7-4 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, the fourth eluting isomer, A7-8 methyl 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxylate, A7-9 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-10 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-11 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-14 rac-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-14-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-14-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-15 rac-2-((3R,4R)-4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-15-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-15-2 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, second eluting isomer, A7-16 rac-2-((3R,4R)-4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-16-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-16-2 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-17 rac-2-((3R,4R)-4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-17-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-17-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-18 rac-2-((3R,4R)-4-(((6-(cyclobutyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-18-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-18-2 rel-2-((3R,4R)-4-(((6-(cyclobutyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-19 rac-2-((3R,4R)-4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-19-1 rel-2-((3R,4R)-4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-19-2 rel-2-((3R,4R)-4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-20 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-20-1 rel-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-20-2 rel-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-21 rac-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-21-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-21-2 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-22 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-22-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-22-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-23 rac-2-((3R,4R)-4-(((6-(cyclobutyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-23-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-23-2 rel-2-((3R,4R)-4-(((6-(cyclobutyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-24 rac-2-((3R,4R)-4-(((6-(cyclobutyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-24-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-24-2 rel-2-((3R,4R)-4-(((6-(cyclobutyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-25 rac-2-((3R,4R)-4-(((6-(cyclopropyl((6-(difluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-25-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(difluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-26 rac-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-26-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-26-2 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-27 rac-2-((3R,4R)-4-(((6-(ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-27-1 rel-2-((3R,4R)-4-(((6-(ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-27-2 rel-2-((3R,4R)-4-(((6-(ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-28 rac-2-((3R,4R)-4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-28-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-28-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-29 rac-2-((3R,4R)-4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-29-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-29-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-30 rac-2-((3R,4R)-4-(((5-fluoro-6-((2-fluoroethyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-31 rac-2-((3R,4R)-4-(((5-fluoro-6-(((1r,3S)-3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-32 rac-2-((3R,4R)-4-(((5-fluoro-6-(((1s,3R)-3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-33 2-(4-(((6-(cyclopropyl(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-34 2-(4-(((6-(cyclopropyl(1-(4-(trifluoromethyl)phenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-35 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-36 2-(4-(((6-((3-cyanobenzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-38 2-(4-(((6-((3-(1H-1,2,4-triazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-39 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-40 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1-difluoroethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-41 rac-2-((3R,4R)-4-(((5-fluoro-6-((1-methylcyclopropyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-42 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-43 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-44 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxamide, A7-45 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-46 2-(4-(((6-((4-chloro-2,5-dimethylbenzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-47 2-(4-(((6-(cyclopropyl(2,5-dimethylbenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-49 rac-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-50 2-(4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-51 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-52 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-53 2-(4-(((6-((4-chloro-3,5-dimethylbenzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-54 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-54-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-54-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-55” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, enriched in one enantiomer, A7-56 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-(trifluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-57” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, enriched in one enantiomer, A7-58 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-methoxy-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-60 rac-2-((3R,4R)-4-(((5-fluoro-6-((methyl-d3)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-61 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-methoxy-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-64 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-hydroxypropanamide, A7-65 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-66-1 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, The first eluting major isomer, A7-66-2 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, The second eluting major isomer, A7-67” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-hydroxybutanamide, enriched in one enantiomer, A7-68 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-69” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide-2,2-d2, enriched in one enantiomer, A7-70 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)-3-hydroxypropanamide, A7-72 rac-2-((3R,4R)-4-(((6-(ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-73 rac-2-((3R,4R)-4-(((6-(ethyl(4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-74 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-75 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-76 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-77 rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-78 rac-2-((3R,4R)-4-(((6-((4-cyanobenzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-79 rac-2-((3R,4R)-4-(((6-((4-(1,1-difluoro-2-hydroxyethyl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-80 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-81 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, A7-82 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, A7-83 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-84 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-imidazol-2-yl)piperidin-1-yl)acetamide, A7-85 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, A7-86 rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-87 2-(4-(1-((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)-2-hydroxyethyl)piperidin-1-yl)acetamide, B4-1-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the first-eluting isomer, B4-1-1-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the second-eluting isomer, B4-1-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the first-eluting isomer, B4-1-2-2 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the second-eluting isomer, B4-2-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, first eluting isomer B4-2-1-2 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, the second eluting isomer, C4-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, the first-eluting isomer, C4-1-2 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, the second-eluting isomer, C4-2-1 2-(4-(((6-((3,5-bis(trifluoromethyl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, the first-eluting isomer, D5-1-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-1-1-2 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second eluting isomer, D5-1-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-1-2-2 rel-2-((3R,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second eluting isomer, D5-2-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-2-1-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second-eluting isomer, D5-2-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-2-2-2 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second-eluting isomer, D5-3-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-3-1-2 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second-eluting isomer, D5-3-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-3-2-2 rel-2-((3R,4S)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second-eluting isomer, D5-4” rel-2-((3R,4R)-4-(((6-(ethyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enriched in one enantiomer, D5-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, major isomer, D5-5-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, minor isomers, D5-6” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enriched in one enantiomer, D5-9” rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enriched in one enantiomer, D5-10” rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enriched in one enantiomer, E6-1 2-(4-amino-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, F2-1 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(2-methylbenzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-2 rac-2-((3R,4R)-4-(((6-((2,6-dichlorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-3 rac-2-((3R,4R)-4-(((6-((2,3-dichlorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-4 rac-2-((3R,4R)-4-(((6-((2,6-dichlorobenzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-5 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(1-(o-tolyl)ethyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-6 rac-2-((3R,4R)-4-(((6-((1-(2-chlorophenyl)ethyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-7 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(3-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-8 rac-2-((3R,4R)-4-(((6-((3-cyanobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-9 rac-2-((3R,4R)-4-(((5-fluoro-6-(isobutyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-10 rac-2-((3R,4R)-4-(((6-((cyclopropylmethyl)(2-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-11 rac-2-((3R,4R)-4-(((6-((4-cyanobenzyl)(isobutyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-12 rac-2-((3R,4R)-4-(((6-((4-chloro-3-fluorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-13 rac-2-((3R,4R)-4-(((6-((4-(difluoromethoxy)benzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-14 rac-2-((3R,4R)-4-(((6-((4-(difluoromethoxy)-3-methoxybenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-15 rac-2-((3R,4R)-4-(((6-((4-chlorobenzyl)(isopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-16 rac-2-((3R,4R)-4-(((5-fluoro-6-((2-methoxyethyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-17 rac-2-((3R,4R)-4-(((6-((2,4-dichlorobenzyl)(isobutyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-18 rac-2-((3R,4R)-4-(((6-((4-cyanobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-19 rac-2-((3R,4R)-4-(((5-fluoro-6-(((6-methoxypyridin-3-yl)methyl)(methyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-20 rac-2-((3R,4R)-4-(((6-((3-(difluoromethoxy)benzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-21 rac-2-((3R,4R)-4-(((6-((3,5-dichlorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-22 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-23 rac-2-((3R,4R)-4-(((6-((3-chlorobenzyl)(isopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide is selected from the group consisting of:

[0137] In some cases, a compound, stereoisomer, or salt having the structure of formula (I) 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-methyl-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, methyl 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxylate, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclobutyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclobutyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclobutyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((6-(difluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-((((5-fluoro-6-((2-fluoroethyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-((3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(1-(4-(trifluoromethyl)phenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-((3-cyanobenzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-((3-(1H-1,2,4-triazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1,1-difluoroethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-((1-methylcyclopropyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(difluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxamide, 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-((4-chloro-2,5-dimethylbenzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2,5-dimethylbenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-((4-chloro-3,5-dimethylbenzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, 2-(4-(((6-(cyclopropyl(3-(trifluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, 2-(4-(((6-(cyclopropyl(3-methoxy-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-((methyl-d3)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-methoxy-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-hydroxybutanamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide-2,2-d2, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((4-cyanobenzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((4-(1,1-difluoro-2-hydroxyethyl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-imidazol-2-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, 2-(4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(1-((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)-2-hydroxyethyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-((3,5-bis(trifluoromethyl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-((3R,4R)-4-(((6-(cyclopropyl(2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-amino-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(methyl(2-methylbenzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((2,6-dichlorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((2,3-dichlorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((2,6-dichlorobenzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(methyl(1-(o-tolyl)ethyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((1-(2-chlorophenyl)ethyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(methyl(3-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((3-cyanobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(isobutyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((cyclopropylmethyl)(2-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((4-cyanobenzyl)(isobutyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((4-chloro-3-fluorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((4-(difluoromethoxy)benzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((4-(difluoromethoxy)-3-methoxybenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((4-chlorobenzyl)(isopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-((2-methoxyethyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((2,4-dichlorobenzyl)(isobutyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((4-cyanobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(((6-methoxypyridin-3-yl)methyl)(methyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((3-(difluoromethoxy)benzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-((3,5-dichlorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(methyl(4-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, and 2-(4-(((6-((3-chlorobenzyl)(isopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide is selected from the group consisting of:

[0138] In some cases, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is A7-1 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-2 2-(4-(((6-(cyclopropyl(2-methyl-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-3-1 rel-(R)-2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, A7-4-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, A7-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, A7-6-1 rel-(R)-2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, A7-7-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, A7-8 methyl 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxylate, A7-9 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-10 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-11 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-14 rac-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-14-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-15 rac-2-((3R,4R)-4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-15-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-16 rac-2-((3R,4R)-4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-16-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-17 rac-2-((3R,4R)-4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-17-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-18 rac-2-((3R,4R)-4-(((6-(cyclobutyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-18-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-19 rac-2-((3R,4R)-4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-19-1 rel-2-((3R,4R)-4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-20 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-20-1 rel-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-21 rac-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-21-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-22 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-22-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-23 rac-2-((3R,4R)-4-(((6-(cyclobutyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-23-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-24 rac-2-((3R,4R)-4-(((6-(cyclobutyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-24-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-25 rac-2-((3R,4R)-4-(((6-(cyclopropyl((6-(difluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-25-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(difluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-26 rac-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-26-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-27 rac-2-((3R,4R)-4-(((6-(ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-27-1 rel-2-((3R,4R)-4-(((6-(ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-28 rac-2-((3R,4R)-4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-28-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-29 rac-2-((3R,4R)-4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-29-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-30 rac-2-((3R,4R)-4-(((5-fluoro-6-((2-fluoroethyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-31 rac-2-((3R,4R)-4-(((5-fluoro-6-(((1r,3S)-3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-32 rac-2-((3R,4R)-4-(((5-fluoro-6-(((1s,3R)-3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-33 2-(4-(((6-(cyclopropyl(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-34 2-(4-(((6-(cyclopropyl(1-(4-(trifluoromethyl)phenyl)ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-35 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-36 2-(4-(((6-((3-cyanobenzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-38 2-(4-(((6-((3-(1H-1,2,4-triazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-39 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-40 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1-difluoroethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-41 rac-2-((3R,4R)-4-(((5-fluoro-6-((1-methylcyclopropyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-42 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-43 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-44 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxamide, A7-45 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-46 2-(4-(((6-((4-chloro-2,5-dimethylbenzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-47 2-(4-(((6-(cyclopropyl(2,5-dimethylbenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-49 rac-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-50 2-(4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-51 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-52 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-53 2-(4-(((6-((4-chloro-3,5-dimethylbenzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-54 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-54-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-55” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, A7-56 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-(trifluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-57” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, A7-58 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-methoxy-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-60 rac-2-((3R,4R)-4-(((5-fluoro-6-((methyl-d3)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-61 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-methoxy-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-64 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-hydroxypropanamide, A7-65 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-66-1 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-67” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-hydroxybutanamide, A7-68 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-69” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide-2,2-d2, A7-70 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)-3-hydroxypropanamide, A7-72 rac-2-((3R,4R)-4-(((6-(ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-73 rac-2-((3R,4R)-4-(((6-(ethyl(4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-74 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-75 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-76 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-77 rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-78 rac-2-((3R,4R)-4-(((6-((4-cyanobenzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-79 rac-2-((3R,4R)-4-(((6-((4-(1,1-difluoro-2-hydroxyethyl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-80 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-81 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, A7-82 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, A7-83 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-84 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-imidazol-2-yl)piperidin-1-yl)acetamide, A7-85 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, A7-86 rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-87 2-(4-(1-((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)-2-hydroxyethyl)piperidin-1-yl)acetamide, B4-1-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, B4-1-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, B4-2-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, C4-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, C4-2-1 2-(4-(((6-((3,5-bis(trifluoromethyl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, D5-1-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-1-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-2-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-2-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-3-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-3-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-4” rel-2-((3R,4R)-4-(((6-(ethyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-6” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-9” rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-10” rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, E6-1 2-(4-amino-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, F2-1 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(2-methylbenzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-2 rac-2-((3R,4R)-4-(((6-((2,6-dichlorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-3 rac-2-((3R,4R)-4-(((6-((2,3-dichlorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-4 rac-2-((3R,4R)-4-(((6-((2,6-dichlorobenzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-5 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(1-(o-tolyl)ethyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-6 rac-2-((3R,4R)-4-(((6-((1-(2-chlorophenyl)ethyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-7 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(3-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-8 rac-2-((3R,4R)-4-(((6-((3-cyanobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-9 rac-2-((3R,4R)-4-(((5-fluoro-6-(isobutyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-10 rac-2-((3R,4R)-4-(((6-((cyclopropylmethyl)(2-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-11 rac-2-((3R,4R)-4-(((6-((4-cyanobenzyl)(isobutyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-12 rac-2-((3R,4R)-4-(((6-((4-chloro-3-fluorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-13 rac-2-((3R,4R)-4-(((6-((4-(difluoromethoxy)benzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-14 rac-2-((3R,4R)-4-(((6-((4-(difluoromethoxy)-3-methoxybenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-15 rac-2-((3R,4R)-4-(((6-((4-chlorobenzyl)(isopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-16 rac-2-((3R,4R)-4-(((5-fluoro-6-((2-methoxyethyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-17 rac-2-((3R,4R)-4-(((6-((2,4-dichlorobenzyl)(isobutyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-18 rac-2-((3R,4R)-4-(((6-((4-cyanobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-19 rac-2-((3R,4R)-4-(((5-fluoro-6-(((6-methoxypyridin-3-yl)methyl)(methyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-20 rac-2-((3R,4R)-4-(((6-((3-(difluoromethoxy)benzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-21 rac-2-((3R,4R)-4-(((6-((3,5-dichlorobenzyl)(methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-22 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, F2-23 rac-2-((3R,4R)-4-(((6-((3-chlorobenzyl)(isopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide is selected from the group consisting of:

[0139] In other preferred embodiments disclosed herein, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is A7-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-1-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-3-1 rel-(R)-2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-3-2 rel-(R)-2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the second-eluting isomer, A7-4-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-4-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the second eluting isomer, A7-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-5-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the second-eluting isomer, A7-6-1 rel-(R)-2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-6-2 rel-(R)-2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the second-eluting isomer, A7-7-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, the first-eluting isomer, A7-7-2 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, the second eluting isomer, A7-7-3 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, the third eluting isomer, A7-7-4 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, the fourth eluting isomer, A7-8 methyl 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxylate, A7-9 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-10 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-14-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-14-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-15-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-15-2 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, second eluting isomer, A7-16-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-16-2 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-17-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-17-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-19-1 rel-2-((3R,4R)-4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-19-2 rel-2-((3R,4R)-4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-20-1 rel-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-20-2 rel-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-21-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-21-2 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-22-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-22-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-26-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-26-2 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-28-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-28-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-29-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-29-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-31 rac-2-((3R,4R)-4-(((5-fluoro-6-(((1r,3S)-3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-32 rac-2-((3R,4R)-4-(((5-fluoro-6-(((1s,3R)-3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-39 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-40 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1-difluoroethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-41 rac-2-((3R,4R)-4-(((5-fluoro-6-((1-methylcyclopropyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-42 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-43 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-44 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxamide, A7-45 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-50 2-(4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-51 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-52 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-54-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-54-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-55” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, enriched in one enantiomer, A7-56 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-(trifluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-57” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, enriched in one enantiomer, A7-58 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-methoxy-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-60 rac-2-((3R,4R)-4-(((5-fluoro-6-((methyl-d3)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-65 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-66-1 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, The first eluting major isomer, A7-66-2 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, The second eluting major isomer, A7-67” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-hydroxybutanamide, enriched in one enantiomer, A7-68 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-69” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide-2,2-d2, enriched in one enantiomer, A7-70 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)-3-hydroxypropanamide, A7-72 rac-2-((3R,4R)-4-(((6-(ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-74 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-75 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-76 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-80 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-81 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, A7-82 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, A7-85 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, A7-86 rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, B4-1-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the first-eluting isomer, B4-1-1-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the second-eluting isomer, B4-1-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the first-eluting isomer, B4-1-2-2 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the second-eluting isomer, B4-2-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, the first-eluting isomer, B4-2-1-2 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, the second eluting isomer, C4-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, the first-eluting isomer, C4-1-2 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, the second-eluting isomer, D5-1-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-1-1-2 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second eluting isomer, D5-1-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-1-2-2 rel-2-((3R,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second eluting isomer, D5-2-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-2-1-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second-eluting isomer, D5-2-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-2-2-2 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, D5-3-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-3-1-2 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second-eluting isomer, D5-3-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-3-2-2 rel-2-((3R,4S)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second-eluting isomer, D5-4” rel-2-((3R,4R)-4-(((6-(ethyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enriched in one enantiomer, D5-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, major isomer, D5-5-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, minor isomers, D5-6” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enriched in one enantiomer, D5-9” rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enriched in one enantiomer, F2-7 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(3-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide is selected from the group consisting of:

[0140] In some cases, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is A7-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-3-1 rel-(R)-2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, A7-4-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, A7-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, A7-6-1 rel-(R)-2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, A7-7-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, A7-8 methyl 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxylate, A7-9 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-10 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-14-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-15-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-16-1 rel-2-((3R,4R)-4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-17-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-19-1 rel-2-((3R,4R)-4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-20-1 rel-2-((3R,4R)-4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-21-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-22-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-26-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-28-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-29-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-31 rac-2-((3R,4R)-4-(((5-fluoro-6-(((1r,3S)-3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-32 rac-2-((3R,4R)-4-(((5-fluoro-6-(((1s,3R)-3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-39 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-40 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1-difluoroethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-41 rac-2-((3R,4R)-4-(((5-fluoro-6-((1-methylcyclopropyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-42 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-43 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-44 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxamide, A7-45 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-50 2-(4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-51 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-52 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-54-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-55” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, A7-56 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-(trifluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-57” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, A7-58 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-methoxy-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-60 rac-2-((3R,4R)-4-(((5-fluoro-6-((methyl-d3)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-65 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-66-1 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-67” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-hydroxybutanamide, A7-68 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-69” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide-2,2-d2, A7-70 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)-3-hydroxypropanamide, A7-72 rac-2-((3R,4R)-4-(((6-(ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-74 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-75 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-76 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-80 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-81 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, A7-82 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, A7-85 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, A7-86 rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, B4-1-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, B4-1-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, B4-2-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, C4-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, D5-1-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-1-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-2-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-2-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-3-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-3-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-4” rel-2-((3R,4R)-4-(((6-(ethyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-6” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-9” rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, F2-7 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(3-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide is selected from the group consisting of:

[0141] In some cases, the compound, salt, or salt of a stereoisomer is 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-(trifluoromethyl)piperidin-1-yl)acetamide, methyl 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxylate, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclobutyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclobutyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(isopropyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(methyl(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-fluorocyclobutyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1,1-difluoroethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-((1-methylcyclopropyl)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(difluoromethoxy)-2-fluorobenzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(difluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 1-(2-amino-2-oxoethyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxamide, 2-(4-(((6-(cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, 2-(4-(((6-(cyclopropyl(3-(trifluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, 2-(4-(((6-(cyclopropyl(3-methoxy-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-((methyl-d3)(4-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-hydroxybutanamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide-2,2-d2, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, 2-(4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and 2-(4-(((5-fluoro-6-(methyl(3-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide is selected from the group consisting of:

[0142] In some cases, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is A7-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-1-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-5-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, the second-eluting isomer, A7-6-1 rel-(R)-2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the first-eluting isomer, A7-6-2 rel-(R)-2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, the second-eluting isomer, A7-10 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-21-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-21-2 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-22-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-22-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-26-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, A7-26-2 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-40 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1-difluoroethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-43 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-50 2-(4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-51 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-54-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, A7-54-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second-eluting isomer, A7-55” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, enriched in one enantiomer, A7-56 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-(trifluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-57” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, enriched in one enantiomer, A7-65 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-69” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide-2,2-d2, enriched in one enantiomer, A7-70 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)-3-hydroxypropanamide, A7-74 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-75 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-76 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-81 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, A7-82 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, A7-85 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, A7-86 rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, B4-1-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the first-eluting isomer, B4-1-1-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, the second-eluting isomer, B4-2-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, the first-eluting isomer, B4-2-1-2 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, the second eluting isomer, C4-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, the first-eluting isomer, C4-1-2 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, the second-eluting isomer, D5-1-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-1-1-2 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second eluting isomer, D5-2-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-2-1-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second-eluting isomer, D5-2-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-2-2-2 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the second eluting isomer, D5-3-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the first-eluting isomer, D5-3-1-2 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, the second-eluting isomer, D5-4” rel-2-((3R,4R)-4-(((6-(ethyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enriched in one enantiomer, D5-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, major isomer, D5-5-2 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, minor isomers, D5-6” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enriched in one enantiomer, D5-9” rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, enantiomerically enriched is selected from the group consisting of:

[0143] In some cases, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is A7-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, A7-6-1 rel-(R)-2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, A7-10 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, A7-21-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-22-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-26-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-40 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1-difluoroethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-43 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(difluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-50 2-(4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, A7-51 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, A7-54-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-55” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, A7-56 rac-2-((3R,4R)-4-(((6-(cyclopropyl(3-(trifluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-57” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, A7-65 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, A7-69” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide-2,2-d2, A7-70 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)-3-hydroxypropanamide, A7-74 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-75 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-76 rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-81 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, A7-82 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, A7-85 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, A7-86 rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, B4-1-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, B4-1-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, B4-2-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, C4-1-1 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, D5-1-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-1-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide D5-2-1-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-2-2-1 rel-2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-3-1-1 rel-2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-3-2-1 rel-2-((3R,4S)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-4” rel-2-((3R,4R)-4-(((6-(ethyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-5-1 rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-6” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, D5-9” rel-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and F2-7 rac-2-((3R,4R)-4-(((5-fluoro-6-(methyl(3-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide is selected from the group consisting of:

[0144] In some cases, the compounds, stereoisomers, or salts of the present disclosure may be 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,3-difluoropiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1,1-difluoroethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(difluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, 2-(4-(((6-(cyclopropyl(3-(trifluoromethoxy)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-methylpropanamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide-2,2-d2, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydroxymethyl)piperidin-1-yl)-3-hydroxypropanamide, 2-(4-(((6-(cyclopropyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, 2-(4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-methylpiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and 2-(4-(((5-fluoro-6-(methyl(3-(trifluoromethoxy)benzyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide is selected from the group consisting of:

[0145] In certain embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a stereoisomer or salt thereof or a salt of a stereoisomer thereof.

[0146] In certain embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a stereoisomer or salt thereof or a salt of a stereoisomer thereof.

[0147] In a preferred embodiment, the compound of the present invention is 2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide.

[0148] In a preferred embodiment, the compound of the present invention is 2-((3S,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide.

[0149] In a preferred embodiment, the compound of the present invention is 2-((3R,4S)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide.

[0150] In a preferred embodiment, the compound of the present invention is 2-((3S,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxy-3-methylpiperidin-1-yl)acetamide.

[0151] In a preferred embodiment, the compound of the present invention is 2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide.

[0152] In a preferred embodiment, the compound of the present invention is 2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide.

[0153] In a preferred embodiment, the compound of the present invention is 2-((3R,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide.

[0154] In a preferred embodiment, the compound of the present invention is 2-((3S,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide.

[0155] In a preferred embodiment, the compound of the present invention is 2-((3R,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide.

[0156] In a preferred embodiment, the compound of the present invention is 2-((3S,4S)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide.

[0157] In a preferred embodiment, the compound of the present invention is 2-((3R,4S)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide.

[0158] In a preferred embodiment, the compound of the present invention is 2-((3S,4R)-4-(((6-(ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide.

[0159] In other particular embodiments, the present disclosure relates to compounds of formula (I) or a salt, stereoisomer, or salt of a stereoisomer thereof, wherein R 0a is selected from the group consisting of -CN, substituted or unsubstituted heteroalicyclyl, and substituted or unsubstituted heteroaryl; and R 0b is hydrogen or C 1~4 In some preferred embodiments, R 0a is substituted or unsubstituted heteroaryl. In another more preferred embodiment, R 0a is substituted or unsubstituted pyridinyl. In an even more preferred embodiment, R 0b is hydrogen.

[0160] In some embodiments disclosed herein, the compound, stereoisomer, or salt has the structure of formula (IV): [ka] (In the formula, R 0a is substituted or unsubstituted pyridinyl; R 0b is hydrogen; R 1a is hydroxyl; R 1b is hydrogen; R2 is hydrogen or hydroxyl; R3 is ethyl or cyclopropyl; R6 is CF3; and Y3 is CR8, where R8 is hydrogen or fluoro.

[0161] In some embodiments disclosed herein, R 0ais selected from the group consisting of CN, pyridinyl, and tetrahydropyranyl; R 0b is hydrogen; R 1a is hydroxyl; R 1b is hydrogen; R2 is hydrogen or hydroxyl; R is hydrogen; R3 is ethyl or cyclopropyl; R4 is hydrogen; R5 is hydrogen; R6 is CF3; R7 is hydrogen; and Y1, Y2, and Y3 are each CH.

[0162] In some embodiments disclosed herein, R 0a is pyridinyl; R 0b is hydrogen; R 1a is hydroxyl; R 1b is hydrogen; R2 is hydrogen or hydroxyl; R is hydrogen; R3 is ethyl or cyclopropyl; R4 is hydrogen; R5 is hydrogen; R6 is CF3; R7 is hydrogen; and Y1, Y2, and Y3 are each CH.

[0163] In other embodiments, the present disclosure relates to a compound of formula (I) or a salt, stereoisomer, or salt of a stereoisomer thereof, wherein R 0a is selected from the group consisting of —CN, pyridinyl, and tetrahydropyranyl; R 0b is hydrogen; R 1a is hydroxyl; R 1b is hydrogen; R2 is hydrogen or hydroxyl; R is hydrogen; R3 is ethyl or cyclopropyl; R4 is hydrogen; R5 is hydrogen; R6 is -CF3; R7 is hydrogen; and Y1, Y2, and Y3 are each -CH-.

[0164] In another more preferred embodiment, the present disclosure relates to a compound of formula (I) or a salt, stereoisomer, or salt of a stereoisomer thereof, wherein R 0a is pyridinyl; R 0b is hydrogen; R 1a is hydroxyl; R 1bis hydrogen; R2 is hydrogen or hydroxyl; R is hydrogen; R3 is ethyl or cyclopropyl; R4 is hydrogen; R5 is hydrogen; R6 is -CF3; R7 is hydrogen; and Y1, Y2, and Y3 are each -CH-.

[0165] In other embodiments disclosed herein, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is A7-59 rac-2-cyano-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-62 rac-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, A7-63 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, A7-71 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide, D5-7” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, enriched in one enantiomer, D5-7-1 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, The first eluting major isomer, D5-7-2 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, the second-eluting major isomer, and D5-8” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, enriched in one enantiomer is selected from the group consisting of:

[0166] In some cases, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is A7-59 rac-2-cyano-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-62 rac-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, A7-63 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, A7-71 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide, D5-7” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, D5-7-1 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, and D5-8” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide is selected from the group consisting of:

[0167] In some cases, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is 2-cyano-2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide, 2-(4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, and 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide is selected from the group consisting of:

[0168] In some cases, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is A7-62 rac-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, A7-63 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, D5-7” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, enriched in one enantiomer, D5-7-1 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, the major isomer eluting first, D5-7-2 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide or rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, the second-eluting major isomer, and D5-8” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, enriched in one enantiomer is selected from the group consisting of:

[0169] In some cases, the compound, salt, stereoisomer, or salt of a stereoisomer according to formula (I) is A7-62 rac-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, A7-63 rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, D5-7” rel-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, D5-7-1 rel-(R)-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, rel-(R)-2-((3S,4S)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, and D5-8” rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide is selected from the group consisting of:

[0170] In some embodiments, whenever halogen is specified as a substituent, the halogen is selected from fluoro or chloro.

[0171] The embodiments and specific disclosures used herein are intended to illustrate different options of the present disclosure, and the embodiments may be combined with other applicable embodiments.

[0172] Specific examples of compounds are disclosed in Table 1 below.

[0173] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

[0174] In a related embodiment, there are provided prodrugs of compounds of formula (I) as described herein.

[0175] The compounds of the present disclosure are active, e.g., have RORy Gal4 <1000 nM, e.g., <500 nM, e.g., <100 nM, and have a substantially lower log P (reduced log P of 1.5, e.g., 2.0, e.g., 2.5 log units) than the compounds disclosed in (Patent Document 1) and (Patent Document 2). In certain embodiments, the Log D and Log P are substantially lower than the compounds in (Patent Document 1) and (Patent Document 2). Thus, the compounds disclosed herein have improved lipophilicity with similar potency. Thus, the compounds disclosed herein may be improved modulators of RORy, e.g., have attractive interactions (e.g., higher binding affinity) with the hydrophobic binding site of the ligand binding domain (LBD) of RORy, and a lower log P and / or a lower log D.

[0176] Pharmaceutical Composition In another aspect, the present disclosure relates to a pharmaceutical composition comprising a physiologically acceptable surfactant, carrier, diluent, excipient, lubricant, suspending agent, film-forming material, and coating aid, or a combination thereof; and a compound as disclosed herein, for example, a compound of Formula (I), (II), (III), and (IV) as disclosed herein, or a salt, stereoisomer, or salt of a stereoisomer thereof. The compound of Formula (I), (II), (III), and (IV) included in the pharmaceutical composition may also be any of the compounds in the above-described preferred embodiments. In another aspect, the present disclosure relates to a pharmaceutical composition comprising a physiologically acceptable surfactant, carrier, diluent, excipient, lubricant, suspending agent, film-forming material, and coating aid, or a combination thereof; and a compound of any one of Formulas I, II, or III disclosed herein. Acceptable carriers or diluents and other additives to be combined with one or more compounds of Formulae (I), (II), (III), and (IV) as disclosed herein to provide a pharmaceutical composition for therapeutic use are well known in the pharmaceutical arts and are described, for example, in (Non-Patent Document 15), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavorings, taste-masking agents, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used.In various embodiments, alcohols, esters, sulfated fatty alcohols, etc. may be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminometasilicate, synthetic aluminum silicate, calcium carbonate, sodium bicarbonate, calcium hydrogen phosphate, calcium carboxymethylcellulose, etc. may be used as excipients; magnesium stearate, talc, hydrogenated oils, etc. may be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soy sauce may be used as suspending agents or lubricants; cellulose acetate phthalate as a derivative of carbohydrates such as cellulose or sugar, and methyl acetate-methacrylate copolymer as a derivative of polyvinyl may be used as suspending agents; and plasticizers such as phthalate esters may be used as suspending agents.

[0177] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. Pharmaceutical compositions facilitate the administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid. Similarly, pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic base, such as ammonia, sodium carbonate, sodium bicarbonate, or sodium hydroxide.

[0178] The term "carrier" defines a chemical that facilitates the incorporation of a compound into cells or tissues. For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier to facilitate the uptake of many organic compounds into cells or tissues of living organisms.

[0179] The term "diluent" defines a chemical substance diluted in water that dissolves a compound of interest and stabilizes the compound's biologically active form. Salts dissolved in buffer solutions are utilized as diluents in the art. One commonly used buffer solution is phosphate buffered saline, which mimics the salt conditions of human blood. Because the buffer salts can control the pH of the solution at low concentrations, buffered diluents rarely alter the biological activity of the compound.

[0180] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0181] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions in which they are mixed with other active ingredients, in the case of combination therapy, or with suitable carriers or excipients. Techniques for formulation and administration of the compounds of the present application can be found in (Non-Patent Document 15).

[0182] Suitable routes of administration may include, for example, oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, and intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection. The compounds may also be administered in sustained- or controlled-release dosage forms for prolonged and / or periodic pulse administration at a predetermined rate, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like.

[0183] The pharmaceutical compositions may be manufactured in a manner that is itself known, for example by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

[0184] Pharmaceutical compositions for use as described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any of the well-known techniques, carriers, and excipients can be used as suitable and as understood in the art, for example, in the above (Non-Patent Document 15).

[0185] Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride, and the like. In addition, if necessary, the injectable pharmaceutical composition may contain minor amounts of non-toxic auxiliary substances such as wetting agents, pH buffering agents, and the like. Physiologically compatible buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If necessary, absorption-enhancing preparations (e.g., liposomes) may be utilized.

[0186] For transmucosal administration, penetrants appropriate to the barrier to be permeated can be used in the formulation.

[0187] Pharmaceutical formulations for parenteral administration, for example, by bolus injection or continuous infusion, include aqueous solutions of the active compound in water-soluble form. Furthermore, suspensions of the active compound can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit, or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Injectable formulations can be provided in unit dosage form (e.g., ampoules or multi-dose containers) with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0188] For oral administration, the compound can be easily formulated by combining the active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers allow the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture, after adding suitable excipients as needed, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or cellulose preparations such as polyvinylpyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solvent, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solvent, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0189] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

[0190] For buccal administration, the compositions may take the form of tablets or dragees formulated in conventional manner.

[0191] For administration by inhalation, the compound for use as described herein is conveniently delivered in the form of aerosol spray from a pressurized pack or nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.In the case of pressurized aerosol, dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges, for example, gelatin, for use in inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, for example, lactose or starch.

[0192] Additionally, various pharmaceutical compositions well known in the pharmaceutical arts are disclosed herein for uses including intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art. Topical eye drop compositions can be formulated as aqueous solutions buffered at a pH of 5.0 to 8.0. Other ingredients that may be desirable for use in eye drop preparations include preservatives (benzalkonium chloride, stabilized oxychloro complexes sold as Purite™, or stabilized chlorine dioxide), cosolvents (such as polysorbates 20, 60, and 80, Pluronic® F-68, F-84, and P-103, cyclodextrins, or Solutol), and viscosity-enhancing agents (polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, or hydroxypropylcellulose). The compounds disclosed herein can also be used in intraocular implants as described in U.S. Patent No. 5,999,499, incorporated herein by reference. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compound in water-soluble form, such as eye drops, or gellan gum (Non-Patent Document 16) or hydrogels (Non-Patent Document 17); ophthalmic ointments; ophthalmic suspensions, such as microparticles, small polymeric particles containing a drug suspended in a liquid carrier medium (Non-Patent Document 18), lipid-soluble formulations (Non-Patent Document 19), and microspheres (Non-Patent Document 20); and ophthalmic inserts. All of the above references are incorporated herein by reference in their entirety. Such suitable pharmaceutical formulations for intraocular delivery are most often and preferably formulated sterile, isotonic, and buffered for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays, which are often prepared to simulate nasal secretions in many respects to ensure maintenance of normal ciliary action.As disclosed in (Non-Patent Document 15), which is incorporated herein by reference in its entirety, and as will be familiar to those skilled in the art, suitable formulations are most often and preferably isotonic and slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably contain antimicrobial preservatives and appropriate drug stabilizers. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such otic formulations include glycerin and water.

[0193] The compounds disclosed herein may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0194] In addition to the formulations described above, the compound can also be formulated as a depot preparation.Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.Thus, for example, the compound can be formulated with suitable polymers or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or can be formulated as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0195] For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD cosolvent system, which is a solution of 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant Polysorbate 80™, and 65% w / v polyethylene glycol 300 made up to volume with absolute ethanol. Naturally, the proportions of the cosolvent system may be varied significantly without destroying its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used in place of Polysorbate 80™; the fraction size of the polyethylene glycol may be changed; other biocompatible polymers may replace polyethylene glycol, such as polyvinylpyrrolidone; and other sugars or polysaccharides may replace dextrose.

[0196] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be used. Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide, can also be used. Furthermore, compounds can be delivered using sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing a therapeutic agent. Various sustained-release materials have been established and are well known to those skilled in the art. Sustained-release capsules can release compounds for several weeks, up to 100 days, depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization can be used.

[0197] Drugs intended for intracellular administration can be administered using techniques well known to those skilled in the art. For example, such drugs can be encapsulated in liposomes. All molecules present in aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The contents of the liposomes are protected from the external microenvironment because the liposomes fuse with the cell membrane and are efficiently delivered to the cytoplasm. Liposomes can be coated with tissue-specific antibodies. The liposomes will be targeted to and selectively taken up by the desired organ. Alternatively, small hydrophobic organic molecules can be administered directly intracellularly.

[0198] Additional therapeutic or diagnostic agents may be incorporated into the pharmaceutical composition. Alternatively, or in addition, the pharmaceutical composition may be combined with another composition containing other therapeutic or diagnostic agents.

[0199] combination The compounds disclosed herein may also be combined with other active compounds in the treatment and / or prevention of inflammatory, metabolic, oncology and autoimmune diseases or disorders or symptoms thereof.

[0200] The combinations provided herein comprise a compound disclosed herein, and a) Corticosteroids, such as prednisone, methylprednisolone or beta-methasone; b) immunosuppressants, such as cyclosporine, tacrolimus methotrexate, hydroxyurea, mycophenolate mofetil, mycophenolic acid, sulfasalazine, 6-thioguanine or azathioprine; c) fumaric acid esters, for example, dimethyl fumarate; d) dihydroorotate dehydrogenase (DHODH) inhibitors, such as leflunomide; e) retinoids, such as acitretin or isotretinoin; f) anti-inflammatory drugs, such as apremilast, crisaborole, celecoxib, diclofenac, aceclofenac, aspirin or naproxen; g) JAK inhibitors, such as tofacitinib, baricitinib, upadacitinib, ruxolitinib or delgocitinib; h) antibiotics, such as gentamicin; i) anticancer drugs, such as lenalidomide, pomalidomide, pembrolizumab, nivolumab, daratumumab, bortezomib, carfilzomib, ixazomib, bendamustine or ventoclast; j) T-cell blocking agents, such as alefacept or efalizumab; k) Tumor necrosis factor-alpha (TNF-alpha) blockers, such as etanercept, adalimumab, infliximab, golimumab, certolizumab pegol; l) Interleukin 12 / 23 blockers, e.g., ustekinumab; m) IL-23 blockers, such as risankizumab, guselkumab or tildrakizumab; n) anti-IL4 / IL13 antagonists, such as dupilumab, lebrikizumab or tralokinumab; o) IL-1β blockers, e.g., canakinumab; p) IL-alpha blockers, e.g., bermekimab; q) CD6 blocking agents, e.g., itolizumab; r) IL-36R blockers, such as BI-655130 or bimekizumab; s) IL-6 antagonists, for example, tocilizumab; t) calcineurin inhibitors, such as pimecrolimus, tacrolimus or cyclosporine; u) phototherapeutic agents commonly used in phototherapy, such as psoralen, methoxypsoralen, or 5-methoxypsoralen plus UVA (PUVA) or UVB treatment (with or without tar); v) fixed combinations of corticosteroids and vitamin D derivatives; w) fixed combinations of corticosteroids and retinoids; x) corticosteroid tapes; and y)BMS986165, PF-06700841, PF-06826647, piclidenoson, tepiramid fumarate, LYC-30937, LEO-32731, BI-730357, PRCL-02, LNP-1955, GSK-2982772, CBP-307, KD-025, MP-1032, petesicatib, JTE-451, Hemay-005, SM-04755, EDP-1815, BI-730460, SFA-002 ER, JNJ-3534, SAR-441169, BOS-172767, SCD-044, ABBV-157, BAY-1834845, AUR-101, R-835, PBF-1650, RTA-1701, AZD-0284, mirikizumab, CD20 antagonist, salicylic acid, coal tar, Mical-1, DUR-928, AM-001, BMX-010, and one or more additional active agents, such as one or more agents selected from the group consisting of TA-102, SNA-125, brepositinib tosylate, pegcantratinib, ESR-114, NP-000888, SM-04755, BOS-475, SB-414, LEO-134310, CBS-3595, PF-06763809, XCUR-17, and BTX-1308.

[0201] The active compounds in a combination, i.e., a compound disclosed herein and other optional active compounds, may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, combined or sequential administration by the same or different routes.

[0202] use The compounds or pharmaceutical compositions disclosed herein as described above can be used to modulate the activity of retinoic acid receptor-related orphan receptors (RORs), such as RORα, RORβ, and / or RORγ receptors. Modulators of RORγ are reviewed by (Non-Patent Document 21) and (Non-Patent Document 22), which are incorporated herein by reference in their entireties. Examples of RORγ receptors are RORγl and RORγt receptors. The compounds or pharmaceutical compositions as described above may also exhibit selective modulation of specific ROR receptors relative to different ROR receptors. For example, according to some embodiments disclosed herein, some compounds or pharmaceutical compositions modulate the activity of RORγ receptors to a greater extent than they modulate the activity of RORα and / or RORβ receptors.

[0203] The compounds or pharmaceutical compositions disclosed herein can also be used to regulate the activity of cells that produce IL-17A in a RORγt-dependent manner, such as γδT cells, Th17 cells, Tc17 cells, and ILC3 cells. The compounds or pharmaceutical compositions disclosed herein can also be used to inhibit RORγt function upon IL-23 stimulation and subsequently negatively affect the differentiation and proliferation of pathological Tc17 and Th17 cells.

[0204] Articles providing useful background information are (Non-Patent Document 23); (Non-Patent Document 24); (Non-Patent Document 25); (Non-Patent Document 26), and (Non-Patent Document 27), all of which are incorporated herein by reference in their entirety.

[0205] The compounds or pharmaceutical compositions as described herein and above may also be used in therapy or to treat inflammatory, metabolic, oncology, and autoimmune diseases or disorders or symptoms thereof. Examples of such diseases or disorders are inflammatory, metabolic, oncology, and autoimmune diseases or disorders mediated or affected by IL-17A and / or RORγ. The role of RORγ in the pathogenesis of autoimmune or inflammatory diseases is disclosed in (Non-Patent Document 28); (Non-Patent Document 29); (Non-Patent Document 30); (Non-Patent Document 31); (Non-Patent Document 32); and (Non-Patent Document 33), all of which are incorporated herein by reference in their entireties.

[0206] More specific examples of diseases or disorders, or symptoms thereof, include asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases such as allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergies, atopic dermatitis, lichen planus, cystic fibrosis, lung transplant rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, hidradenitis suppurativa, and hidradenitis suppurativa. These include inflammation, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, type 1 diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type 2 diabetes, and cancer.

[0207] More preferably, the disease or disorder, or symptom thereof, includes acne, atopic dermatitis, lichen planus, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous disease, hidradenitis suppurativa, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), and lupus erythematosus.

[0208] An example of a symptom is a physical or mental characteristic that is considered to be indicative of a disease state, particularly one that is evident to the patient; for example, treating or preventing a symptom is not considered to control the disease, but prevents or alleviates one or more symptoms commonly experienced in association with such a disease.

[0209] More specifically, compounds or pharmaceutical compositions having an antagonistic or inverse agonistic effect on RORγ may be used to reduce the levels of IL-17A and / or other gene products, such as interleukins and cytokines, to regulate RORγ, including, for example, asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases, such as allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergies, atopic dermatitis, lichen planus, cystic fibrosis, lung transplant rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-atopic dermatitis, and the like. The present invention may be in subjects suffering from: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, and type II diabetes.

[0210] Conversely, compounds or pharmaceutical compositions that have an agonistic effect on RORy may be used to increase IL-17A levels, which may be particularly useful in boosting immune system responses in immune-compromised states or during infection and cancer, for example.

[0211] The compounds described herein may be used in the manufacture of a medicament for the treatment and / or prevention of inflammatory, metabolic, oncology and autoimmune diseases or disorders or symptoms thereof.

[0212] Administration method The compound or pharmaceutical composition may be administered to the patient by any suitable means. Non-limiting examples of methods of administration include, among others, as deemed appropriate by one of skill in the art for contacting the compounds disclosed herein with biological tissues: (a) administration via the oral route (which includes administration in capsules, tablets, granules, sprays, syrups, or other such forms); (b) administration via parenteral routes such as rectal, vaginal, intraurethral, ​​intraocular, intranasal, or intraauricular (which includes administration as aqueous suspensions, oily preparations, and the like, or as drops, sprays, suppositories, liniments, ointments, and the like); (c) administration via subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intraarticular, intraspinal, intrasternal injection, and the like (including infusion pump delivery); (d) local administration such as direct injection in the kidney or cardiac region, e.g., depot placement, intratumoral injection, or intralymph node injection; (e) topical administration; and (f) administration of cells ex vivo followed by insertion of the cells into a patient.

[0213] Pharmaceutical compositions suitable for administration include compositions containing the active ingredient in an amount effective to achieve its intended purpose. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal being treated (including mammals, e.g., humans), and the physical characteristics of the particular animal under consideration. Dosages can be adjusted to achieve the desired effect and will depend on factors such as body weight, diet, concurrent medications, and other factors that will be recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of compound effective to prevent, alleviate, or ameliorate symptoms of disease or prolong survival of the subject being treated. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0214] As will be readily apparent to those skilled in the art, the useful in vivo dosage and specific mode of administration to be administered will vary depending on the age, weight, and mammalian species being treated, the specific compound being used, and the specific application for which these compounds are being used. The determination of effective dosage levels, i.e., the dosage levels required to achieve the desired result, can be achieved by those skilled in the art using conventional pharmacological methods. Typically, human clinical applications of a product begin at a relatively low dosage level, with the dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro tests can be used to establish useful doses and routes of administration for the compositions identified by the methods herein using established pharmacological methods.

[0215] In non-human animal studies, applications of promising products are initiated at relatively high dosage levels, with the dosage being reduced until the desired effect is no longer achieved or adverse side effects disappear. Dosages can range widely depending on the desired effect and therapeutic indication.

[0216] Typically, dosages can be between about 10 micrograms / kg and 100 mg / kg body weight, preferably between about 100 micrograms / kg and 10 mg / kg body weight. Alternatively, dosages can be based on and calculated based on the patient's surface area, as will be understood by those skilled in the art.

[0217] The exact formulation, route of administration, and dosage of the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition (see, e.g., (Non-Patent Document 34), incorporated herein by reference in its entirety, in particular, Ch. 1, p. 1). Typically, the dosage range of the composition administered to a patient can be about 0.5 to 1000 mg / kg of the patient's body weight. The dosage can be a single dose or a series of two or more doses administered over one or more days, as needed by the patient. In cases where human dosages of a compound have been established for at least some conditions, those same dosages, or dosages between about 0.1% and about 500%, more preferably between about 25% and about 250%, of the established human dosage, can be used. In cases where a human dosage has not been established, such as in the case of a newly discovered pharmaceutical compound, it is possible to use a dosage that is within the ED (European Standards for Clinical Trials and Clinical Trials) as qualified by animal toxicity and efficacy studies. 50 or ID 50 Suitable dosages for humans can be extrapolated from these values, or other appropriate values ​​obtained from in vitro or in vivo tests.

[0218] It should be noted that the attending physician would know how and when to discontinue, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is inadequate (excluding toxicity). The magnitude of the dose administered in the management of the disorder of interest will vary with the severity of the condition being treated and the route of administration. The severity of the condition may be assessed, for example, in part, by standard prognostic evaluation methods. Furthermore, the dosage and perhaps frequency of administration will also vary with the age, weight, and response of the individual patient. A program equivalent to that described above may be used in veterinary medicine.

[0219] While the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding dosage can be made. A daily dosage regimen for an adult human patient can be, for example, between 0.1 mg and 2000 mg of each active ingredient, preferably between 1 mg and 500 mg, e.g., a 5-200 mg oral dose. Eye drops can range in concentration between 0.005 and 5%. In one embodiment, eye drops can range between 0.01 and 1%, or in another embodiment, between 0.01 and 0.3%. In other embodiments, intravenous, subcutaneous, or intramuscular doses of each active ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g., 1 to 40 mg, are used. When administering a pharmaceutically acceptable salt, the dosage can be calculated as the free base. In some embodiments, the composition is administered one to four times daily. Alternatively, the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of up to 1000 mg of each active ingredient per day. As will be appreciated by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed or far exceed the preferred dosage ranges or frequencies set forth above to effectively and aggressively treat, particularly aggressive diseases or infections. In some embodiments, the compounds will be administered for a period of continuous therapy, for example, for a week or more, or for a month or a year.

[0220] Dosage and administration intervals can be individually adjusted to provide plasma or tissue levels of the active moiety sufficient to maintain the modulating effect, or the minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and the route of administration. However, HPLC assays or bioassays may be used to determine plasma concentrations.

[0221] Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0222] In cases of local or ex vivo administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0223] The amount of composition administered will be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0224] The compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicity of a particular compound, or a subset of compounds, sharing certain chemical moieties can be established by determining their in vitro toxicity on cell lines, such as mammalian, preferably human, cell lines. The results of such tests are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit, or monkey, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition, including, but not limited to, cancer, cardiovascular disease, and various immune dysfunctions. Similarly, accepted animal models can be used to establish the efficacy of chemicals for treating such conditions. When selecting a model for determining efficacy, one skilled in the art can be guided by the state of the art to select the appropriate model, dose, and route of administration, as well as the administration regime. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0225] The compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or veterinary administration. Such notice may, for example, be labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions comprising the compounds disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a designated condition.

[0226] Overview As described above with respect to certain illustrative embodiments, it is not intended that the present disclosure be limited to the specific forms described herein. Any combination of the above embodiments should be understood to be within the scope of the present disclosure. Rather, the present disclosure is limited only by the appended claims, and other embodiments than the specific embodiments described above are equally possible within the scope of these appended claims.

[0227] In the claims, the term "comprises / comprising" does not exclude the presence of other species or steps. Furthermore, although individual features may be included in different claims, these may sometimes be advantageously combined, and inclusion in different claims does not imply that a combination of features is not feasible and / or advantageous. In addition, reference to the singular does not exclude a plurality. The terms "a," "an," "first," "second," etc. do not exclude a plurality. The phrases "at least one" or "one or more" refer to one or more than one, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0228] Wherever chemical names or structures are given, they have been generated using conventional or suitable software means. Names for compounds were generated with ChemDraw Professional, version 17.1.0.105(19).

[0229] In the present disclosure, in the structural drawings, the label "or1", "or2", "&1", or "&2" of each stereocenter designates the "stereochemical group" to which that center belongs.

[0230] In the case of an "or" group, the meaning is a structure representing one stereoisomer having either the "stereochemical group" as depicted (e.g., (R,S)) or a stereoisomer in which the asymmetric center of the group has the opposite configuration (S,R).

[0231] In the case of an "&" group, the & in combination with a given number (e.g., &1) indicates a mixture of the marked asymmetrically substituted atoms. When the numbering groups several asymmetrically substituted atoms together, this indicates their configuration relative to each other. When they are designated as (R,S), the opposite configuration (S,R) also exists with respect to the designated group.

[0232] In this disclosure, the symbol "" designates enriched in one enantiomer. Any compound or intermediate that has not undergone chiral separation and has been synthesized in a manner that is enriched in one enantiomer is identified by ". [Example]

[0233] experiment The following examples are illustrative only and should not be construed as limiting the scope of the present disclosure in any way. Rather, the present disclosure is limited only by the appended claims.

[0234] General Chemical Procedures overview Unless otherwise noted, starting materials were obtained from commercial manufacturers, including (but not limited to) AbBchem, ABCR, Alfa Aesar, Anaspec, Anichem, Apollo Scientific, ASDI-Inter, Asiba Pharmatech, Astatech, ArkPharm, Bachem, Chem-Impex, ChemCollect, Chembridge, Combi-Blocks, Enamine, FCH, Fluka, Fluorochem, Frontier Scientific, HDH Pharma, InFarmatik, InterBioScreen, Life Chemicals, Manchester organics, Matrix, MercaChem, NetChem, Oakwood Chemical, PepTech, Pharmcore, PrincetonBio, Sigma-Aldrich, TRC, Tyger Scientific, and Ukrorgsyn, and were used without further purification. Solvents, such as DMF, DMSO, and DCM, were used directly or dried over molecular sieves.

[0235] device NMR 1 H NMR spectra were recorded on the following Bruker Avance 300 spectrometer (300 MHz), Bruker Avance III 400 spectrometer (400 MHz), Bruker Avance Neo (400 MHz), Bruker Avance III 600 (600 MHz), and Varian V NMR spectrometer (400 MHz) using CD3OD, CDCl3, or DMSO-d6 solvents. Chemical shifts are reported in ppm (δ) using residual solvent as the internal standard: CDCl3: 7.26 ppm; CD3OD: 3.31 ppm; DMSO-d6: 2.50 ppm. Coupling constants (J) are given in Hz.

[0236] Analytical U / HPLC The following equipment was used for analytical U / HPLC: Waters Acquity system equipped with an Acquity BEH C18 (1.7 μm, 2.1×50 mm) coupled with MS detection SQD I with a linear gradient of the binary solvent system using DAD at a flow rate of 0.5 mL / min and ambient temperature. Agilent Infinity I / II -TOF6230B / CLND Antek 8060 equipped with an Acquity BEH C18 (1.7 μm, 2.1×50 mm) with a linear gradient of a binary solvent system using a flow rate of 0.75 mL / min coupled with a DAD. Agilent 1200 Series-1260 Infinity equipped with a Waters XBridge C18 (5 μm, 4.6×50 mm) with a linear gradient of the binary solvent system using a flow rate of 1.5 mL / min and UV detection at 214 nm or 254 nm coupled with MS detection (Agilent). Shimadzu Nexera equipped with a Waters Xbridge C18 (5 μm, 4.6×50 mm) with a linear gradient of the binary solvent system using a flow rate of 1.5 mL / min and UV detection at 214 nm or 254 nm, coupled with MS detection (Shimadzu). MS detection Waters Acquity system equipped with an Acquity BEH C18 (1.7 μm, 2.1×50 mm) coupled with a Waters detector with a linear gradient of the binary solvent system using a DAD at a flow rate of 0.65 mL / min and ambient temperature.

[0237] Preparative HPLC The following equipment was used for preparative HPLC: Waters Acquity system equipped with a Supelco Discovery C18 (5 μm, 25 cm x 21.2 mm) with a linear gradient of the binary solvent system using a flow rate of 45 mL / min and UV detection at 254 nm, coupled with MS detection on a Waters Micromass ZQ Quadrupole MS. A Shimadzu Nexera X2 equipped with a Merck Chromolith SpeedROD RP-18E (5 μm, 10 × 100 mm) with a linear gradient of a binary solvent system using a flow rate between 4 and 7 mL / min and UV detection at 254 nm, coupled with MS detection on a Shimadzu LCMS-2020. A Waters Masslynx system equipped with a Waters Xbridge C18 column (5 μm, 19×150 mm) with a linear gradient of the binary solvent system using a flow rate of 15 mL / min and UV detection at 214 nm or 254 nm, coupled with MS detection (Waters). Gilson GX-281 TRILUTION equipped with a Phenomenex Gemini NX-C18 column (5 μm, 21.2×150 mm) with a linear gradient of a binary solvent system using a flow rate of 15 mL / min and UV detection at 214 nm or 254 nm, coupled with MS detection SQD (Waters).

[0238] The following linear gradients were used: HCO2H-(H2O / CH3CN / HCO2H(100 / 0 / 0.1%~0 / 100 / 0.1%)) NH4OAc-(H2O / CH3CN / NH4OAc(100 / 0 / 0.02%~0 / 100 / 0.02%)) TFA-(H2O / CH3CN / TFA(100 / 0 / 0.1%~0 / 100 / 0.1%)) NH4HCO3-(H2O / CH3CN / NH4HCO3(100 / 0 / 0.1%~0 / 100 / 0.1%)) NH4OH-(H2O / CH3CN / NH4OH(100 / 0 / 0.1%~0 / 100 / 0.1%)) HCO2NH4-(H2O / 50%MeOH+50%CH3CN / HCO2H / NH3(95 / 5 / 0.05% / 0.01%~5 / 95 / 0.05% / 0.01%))

[0239] Flash CC was most often performed on an Isolera® automated system. Flash CC and preparative TLC were performed on SiO2 unless otherwise noted. However, C18 columns were also used (water-acetonitrile / MeOH (1:1) gradient, 0-100% acetonitrile / MeOH (1:1) with or without 0.1% v / v ammonium formate in both phases).

[0240] Analytical Chiral Chromatography The analysis was carried out on a Waters UPC2 system connected to a DAD detector and a Waters QDa MS detector equipped with chiral columns by gradient elution using a flow rate of 1 mL / min. The available chiral columns were CHIRALPAK (3 μm, 4.6 × 100 mm) IA, IB, IC, and ID, and Trefoil AMY1 (2.5 μm, 2.1 × 150 mm).

[0241] The following linear gradient was used for analytical UPC2: CO2 / MeOH / DEA(99 / 1 / 0.2%~60 / 40 / 0.2%)) CO2 / EtOH / DEA(99 / 1 / 0.2%~60 / 40 / 0.2%) CO2 / IPA / DEA(99 / 1 / 0.2%~60 / 40 / 0.2%)

[0242] Preparative chiral chromatography Prior to chiral separation, the compounds were purified by standard methods previously described using appropriate solvents.

[0243] Preparative chiral separations were performed on either a Gilson (306, GX-281 trilution, 156-UV / Vis, Waters 3100 MSD) or a Waters SFC-80 equipped with a chiral column with the solvent specified, using flow rates between 10 and 50 mL / min (only 50 g / min for SCF) and detection at either 214 or 230 nm; available chiral columns were Reprosil AMS (5 μm, 20 mm x 250 mm), Lux C2 (5 μm, 21.2 mm x 250 mm), Lux C4 (5 μm, 21.2 mm x 250 mm), Chiralpak® columns IA, IB, IC, ID, IF, or IG (5 μm, 20 mm x 250 mm), or Chiralcel® OJ-H or OD-H. The exact column and elution conditions used for each compound are described in the experimental section.

[0244] Synthesis method The compounds disclosed herein may be synthesized by one of the following general methods: General Method A, General Method 2A, General Method 3A, General Method 4A, General Method 5A, General Method 6A, General Method B, General Method C, General Method 1D, General Method 2D, General Method 2D', General Method 3D, General Method E and General Method F.

[0245] General Method A - Synthesis from Boc protected piperidine. [ka] Secondary amine A1 was reacted with A2 (ambient or slightly elevated temperature, 30 °C) with a suitable base (such as DIEA, TEA, or K2CO3) at room temperature. After the reaction was deemed complete, intermediate A3 was either worked up and purified by chromatography (flash CC or HPLC) or used crude. Intermediate A3, a base (such as DIEA, TEA, or Cs2CO3), and primary amine A4 were then dissolved in a solvent (DMSO or DMSO-HO, HO, or HO-EtOH mixture) and the temperature was raised to 70-100 °C overnight or until the reaction was deemed complete. Workup and purification then provided intermediate A5, which underwent deprotection. The intermediate formed after boc-deprotection A6 was most often used directly as the corresponding piperidinium salt (HCl or TFA) in alkylation with 2-bromoacetamide A8 and a suitable base such as DIEA, Na2CO3, or K2CO3 at room temperature or heated to 100 °C. The product A7 was first purified by standard chromatographic methods.

[0246] When the A7 products were mixtures of stereoisomers, they were often (but not always) subjected to chiral resolution (chromatography) to obtain a single stereoisomer as the final product.

[0247] All compounds in Table A were synthesized using this methodology on scales ranging from 2 μmol up to approximately 1 mol.

[0248] Example A7-1 Synthesis of rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide A7-1 and chiral separation of A7-1-1 and A7-1-2 [ka] a) DIEA, DMSO, room temperature, overnight. b) DIEA, DMSO, 80°C, overnight. c) i) HCl, dioxane, 60 min. ii) DIEA, 2-bromoacetamide. d) Chiral chromatography.

[0249] Scheme A7-1 Synthesis of rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-1 N-cyclopropyl-5,6-difluoro-N-(4-(trifluoromethyl)benzyl)pyrimidin-4-amine, A3-1 [ka] To dry DMSO (7 mL) were added A2-1 (375 mg, 2.8 mmol), A1-1 (737 mg, 3.1 mmol), and DIEA (1.5 mL), and the reaction was stirred overnight. The reaction mixture was then poured into aq LiCl (40 mL, 5%) and extracted three times with EA. The combined EA phase was then washed twice with aq LiCl (5%) and once with brine, followed by drying (Na2SO4). After filtration, concentration under reduced pressure gave the crude product, which was then purified by flash CC (EA:Hept) to give A3-1 (832 mg). LCMS: MS calculated: 329; MS found: 330 ([M+1] + ).

[0250] (3R,4R)-rac-tert-butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate, A5-1 [ka] Compound A3-1 (828 mg, 2.5 mmol) was dissolved in dry DMSO (8 mL), and then A4-1 (750 mg, 3.26 mmol) and DIEA (2.2 mL) were added. The reaction mixture was heated to 80 °C overnight. The reaction mixture was cooled and then poured into aq LiCl (40 mL, 5%) and extracted three times with EA. The combined EA phase was then washed twice with aq LiCl (5%), brine, and dried (Na SO ). Filtration and concentration under reduced pressure gave the crude product, which was subsequently purified by flash CC (EA:Hept) to give A5-1 (1.28 g). LCMS: MS calculated: 539; MS found: 540 ([M+1] + ).

[0251] rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-1 [ka] Compound A5-1 (1.27 g, 2.35 mmol) was added to HCl in dioxane (2 M, 10 mL) and stirred at ambient temperature for 60 minutes, then concentrated under reduced pressure. The resulting residue was dissolved in a solution of DIEA (3.3 mL) in DCM (30 mL) on an ice bath. 2-Bromoacetamide (0.39 g, 2.8 mmol) was then added, and the reaction was allowed to reach room temperature and then stirred overnight. The reaction was concentrated under reduced pressure. Aq NaHCO3 (saturated) was then added to the resulting slurry, and the resulting mixture was then extracted three times with EA. The combined EA phase was washed with brine, dried (Na2SO4), filtered, concentrated, and purified by flash CC (MeOH:DCM) to give A7-1 (1.0 g, 2.0 mmol, 71% over four steps).

[0252] rel-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-1-1 and A7-1-2 [ka] Compound A7-1 (0.95 g) was then subjected to chiral chromatography to obtain optically pure compounds: A7-1-1 (380 mg) as the first eluting isomer and A7-1-2 (365 mg) as the second eluting isomer.

[0253] General Method A was used to prepare the following Example Numbers using the starting materials indicated (Table A).

[0254] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48] Table 49

Table 50

[0255] Synthesis via general method 2A-substituted bromoacetamides. [ka] A7 was also obtained by alkylation of A6 with A9 to give A10, followed by subsequent aminolysis (NH in MeOH) to give A7. However, in addition to the alkylation procedure described above, alkylation can require high temperatures (up to 100 °C).

[0256] When A7 was a mixture of stereoisomers, they were often (but not always) subjected to chiral resolution (chromatography) to obtain a single stereoisomer as the final product.

[0257] Example A7-62 Synthesis of rac-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, A7-62 [ka] a) DIEA, DMF. b) NH3, MeOH.

[0258] Scheme A7-62 2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetate rac-ethyl, A10-1. [ka] DIEA (0.89 ml, 5.1 mmol) and ethyl 2-bromo-2-(4-pyridyl)acetate (229 mg, 0.94 mmol) were added sequentially to a solution of A6-1 (425 mg, 0.85 mmol) in DMF (11 mL), and the reaction was stirred overnight at room temperature. The reaction was quenched with HO (60 mL) and subsequently extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 15 mL), dried (NaSO), filtered, and concentrated in vacuo. The residue was then purified by flash CC (DCM:MeOH = 100:0 to 93:7) to give A10-1 (218 mg, 0.37 mmol).

[0259] rac-2-((3R,4R)-4-(((6-(ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(pyridin-4-yl)acetamide, A7-62. [ka] A10-1 (218 mg, 0.37 mmol) was dissolved in 7N ammonia in MeOH (10 mL), and the resulting solution was stirred in a closed flask at 80 °C for 45 h. The solution was concentrated in vacuo, and the residue was purified by chromatography on a first C18 column (HO:MeOH = 100:0 to 0:100), followed by flash CC (DCM:MeOH = 10:0 to 9:1) to give A7-62 (18 mg, 32 μmol).

[0260] The following examples were synthesized according to general procedure 2A.

[0261] [Table 72] [Table 73] [Table 74] [Table 75] [Table 76]

[0262] Synthesis via general method 3A-substituted bromoacetamides. [ka] A7 can also be synthesized from A10 by ester hydrolysis (with a suitable base such as LiOH or NaOH) to give A11 (or the corresponding metal salt), followed by coupling with NH3 (using standard coupling reagents such as HATU).

[0263] Example A7-71 Synthesis of rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide, A7-71. [ka] a) DIEA, DMF. b) LiOH, THF / MeOH (1 / 1). c) NH3, TEA, HATU, THF.

[0264] Scheme A7-71 2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)acetic acid rac-methyl, A10-2. [ka] DIEA (0.82 ml, 4.7 mmol) and methyl 2-bromo-2-tetrahydropyran-4-ylacetate (383 mg, 1.61 mmol) were added sequentially to a solution of intermediate A6-2 (400 mg, 0.78 mmol) in DMF (8.5 mL), and the reaction was stirred at 60 °C for 24 h. The reaction was quenched with HO (60 mL) and subsequently extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3 × 15 mL), dried (NaSO), filtered, and concentrated in vacuo. The residue was then purified by flash CC (DCM:MeOH = 100:0 to 95:5) to give A10-2 (131 mg, 0.22 mmol).

[0265] rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)acetic acid, A11-1 [ka] A10-2 (131 mg, 0.22 mmol) was dissolved in THF (1 mL) and MeOH (1 mL), a solution of LiOH monohydrate (33 mg, 0.79 mmol) was added, and the mixture was stirred at 60 °C overnight. The solvent was evaporated to give 125 mg of crude product. This crude product was purified using a C18 column (HO:MeOH = 100:0 to 0:100) to give A11-1 (34 mg, 0.058 mmol).

[0266] rac-2-((3R,4R)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide, A7-71 [ka] A11-1 (34 mg, 0.058 mmol) was dissolved in DMF (0.5 mL), and 0.4 M ammonia solution in THF (22 μL, 0.18 mmol), HATU (33 mg, 0.09 mmol), and triethylamine (40 μL, 0.29 mmol) were added. The mixture was stirred at room temperature overnight. H2O was added and extracted with EA (3 × 20 mL). The organic phase was washed with 1 N NaOH aq. and brine to give 7 mg of crude product. The crude product was purified by flash CC (DCM:MeOH = 100:0 to 90:10) to give A7-71 (2.8 mg, 0.005 mmol).

[0267] General Method 4A [ka] When R6 was a heterocyclic ring, the iodo intermediate A12 was synthesized from the corresponding iodo-benzylamine as outlined in general method A, and then underwent either a Suzuki coupling (with Pd and a boronic acid or ester) or a standard Buchwald coupling (with Cu and a nitrogen-containing heterocyclic ring) to give A7.

[0268] Example A7-72 Synthesis of rac-2-((3R,4R)-4-(((6-(ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-72 [ka] a) Standard Suzuki coupling

[0269] Scheme A7-72 Under a N atmosphere, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A13-1 (17 mg, 82 μmol), 2M CsCO (111 μL, 0.22 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), DCM complex (6 mg, 7 μmol) were added to a solution of A12-1 (40 mg, 74 μmol) in dioxane (1 mL). The reaction mixture was stirred at 100 °C for 4 h. HO was added, and the product was extracted with EA (×3). The combined organic layers were washed with HO, brine, dried (MgSO), filtered, and concentrated in vacuo. The residue was first purified by flash CC (MeOH:DCM=1:9) followed by C18 column (H2O:MeOH=100:0 to 0:100) to give A7-72 (8 mg, 16 μmol) as a white solid. LCMS: MS calculated: 496.6; MS found: 497 ([M+H] + ).

[0270] The following compounds were synthesized according to Method 4A as in Examples A7-72 using the starting materials indicated (Table 4A).

[0271] [Table 77] [Table 78]

[0272] Example A7-76 Synthesis of rac-2-((3R,4R)-4-(((6-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-76 [ka] a) Standard Buchwald coupling

[0273] Scheme A7-76 Under a N2 atmosphere, 1H-pyrazole (30 mg, 0.44 mmol), K2CO3 (38 mg, 0.27 mmol), trans-1,2-cyclohexane-1,2-diamine (6.6 μL, 55 μmol), and CuI (2.6 mg, 14 μmol) were added to a solution of A12-3 in NMP (2 mL). The reaction mixture was stirred to reflux overnight. An additional amount of all reagents was added, and the mixture was heated to reflux for another day. HO was added, and the product was extracted with EA (x3). The combined organic layers were washed with HO, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was then purified first by flash CC (MeOH:DCM = 15:85), followed by a C18 column (HO:MeOH = 100:0 to 0:100) to give A7-76 (35 mg, 68 μmol) as a white solid. LCMS: MS calculated: 512.6; MS found: 513 ([M+H] + ).

[0274] Common Method 5A: Left to Right [ka] Primary amine A4 was reacted with A2 (ambient or slightly elevated temperature, i.e., 30 °C) with a suitable base (such as DIEA, TEA, or K2CO3). After the reaction was deemed complete, intermediate A14 was either worked up and purified by chromatography (flash CC or HPLC) or used crude. Deprotection of intermediate A14 in an acidic medium (TFA or HCl) at room temperature gave intermediate A15, which was used directly in the subsequent alkylation step with 2-bromoacetamide and a suitable base (such as DIEA, TEA, or Cs2CO3). The resulting intermediate A16 was then stirred with secondary amine A1 in a solvent (DMSO or DMSO-HO, HO, or HO-ethanol mixture) at temperatures between 70 and 150 °C overnight or until the reaction was deemed complete. Workup and purification then afforded the desired final compound A7.

[0275] Example A7-77 Synthesis of rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide [ka] a) DIEA, DMSO. b) TFA, DCM. c) DIEA, DMF, 2-bromoacetamide. d) DIEA, DMSO

[0276] Scheme A7-77 (3R,4R)-4-(((5,6-difluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate rac-tert-butyl ester, A14-1 [ka] A2 (367 μL, 4.0 mmol) was dissolved in DMSO (17 mL) and DIEA (2.09 mL, 12.0 mmol), and A4-1 (970 mg, 4.0 mmol) was added. The reaction mixture was stirred at room temperature overnight. The crude was poured into H2O and extracted with EA (2x). The organic phase was washed with H2O (2x) and brine. The organic phase was then dried over MgSO4, filtered, and concentrated to give A14-1 (1.38 g, 4.0 mmol). LCMS: MS calculated: 344; MS found: 345 ([M+H] + ).

[0277] rac-(3R,4R)-4-(((5,6-difluoropyrimidin-4-yl)amino)methyl)piperidin-3-ol, A15-1 [ka] A14-1 (1.47 g, 4.27 mmol) was dissolved in DCM (8.5 mL) and TFA (3.3 mL, 43.1 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. Cyclohexane was added twice and evaporated. A15-1 (1.04 g, 4.27 mmol) was used without further purification. LCMS: MS calculated: 244; MS found: 245 ([M+H] + ).

[0278] rac-2-((3R,4R)-4-(((5,6-difluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A16-1 [ka] A15-1 (1.04 g, 4.27 mmol) was dissolved in DMF (56 mL), DIEA (4.5 mL, 25.77 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Next, 2-bromoacetamide (650 mg, 4.71 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in MeOH (10 mL) and passed through a 15 g ion-exchange SCX column. An additional 50 mL of MeOH was passed through the column, followed by 40 mL of a 3.5 M solution of NH3 in MeOH to release the product from the column. After evaporation of the solvent, A16-1 (981 mg, 3.2 mmol) was obtained. LCMS: MS calculated: 301; MS found: 302 ([M+H] + ).

[0279] rac-2-((3R,4R)-4-(((6-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A7-77 [ka] A16-1 (90 mg, 0.30 mmol) was dissolved in DMSO (0.8 mL) and DIEA (160 μL, 0.92 mmol), and N-[(4-pyrazol-1-ylphenyl)methyl]ethanamine A1-64 (63 mg, 0.31 mmol) was added. The reaction mixture was heated at 140 °C for 3 h. The crude material was poured into HO and extracted with EA (2x). The organic phase was washed with HO (2x) and brine, dried, and concentrated in vacuo to give 115 mg of crude material. The crude residue was purified by flash CC (DCM:MeOH = 100:0 to 90:10) to give A7-77 (53 mg, 0.11 mmol). LCMS: MS calculated: 482; MS found: 483 ([M+H] + ).

[0280] The following compounds were synthesized according to general procedure 5A using the starting materials indicated (Table 5A).

[0281] [Table 79]

[0282] General Method 6A-Conversion of R2 to a 5-membered heterocyclic ring. [ka] When the R2 group in A5 was either a carboxamide, cyano, or ester, the R2 group was converted to a five-membered heterocyclic ring in the examples below. The compounds were then converted to the A5' to A7 final products using a deprotection-alkylation procedure as described in General Method A.

[0283] Example A7-80 Synthesis of 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-80 [ka] a) i) DMF-DMA ii) NH2NH2.2HCl, NaOH, dioxane iii) AcOH. b) i) HCl, dioxane. ii) 2-Bromoacetamide, DIEA.

[0284] Scheme A7-80 N 4 -((4-(1H-1,2,4-triazol-3-yl)piperidin-4-yl)methyl)-N 6 -cyclopropyl-5-fluoro-N 6 -(4-(trifluoromethyl)benzyl)pyrimidine-4,6-diamine, A6-8. [ka] DMF-DMA (0.35 mL, 2.5 mmol) was added to tert-butyl 4-carbamoyl-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate A5-2 (61 mg, 0.11 mmol), and the mixture was refluxed at 110 °C for about 2 h. The volatiles were evaporated under reduced pressure to give the corresponding amidine intermediate. Hydrazine dihydrochloride (57 mg, 0.54 mmol) in 5 M aqueous NaOH (0.15 ml, 0.75 mmol) was added to a solution of this amidine intermediate in 1,4-dioxane (0.3 mL). Glacial AcOH (1.6 mL) was added, and the reaction mixture was stirred at room temperature for about 30 min, followed by stirring at 90 °C for 5 h. Next, 0.8 ml of 4 M HCl in dioxane was added to completely deprotect the Boc group, and the mixture was stirred at room temperature for 1 h. Workup was carried out by adding HO (20 mL) and washing with EA (20 mL). The aqueous phase was basified with 2 N NaOH and extracted with DCM (2 x 20 mL). The organic phase was washed with brine (20 mL), dried (NaSO), and concentrated to give A6-8 (36 mg, 0.07 mmol). LCMS: MS calculated: 490.5; MS found: 491 ([M+H] + ).

[0285] 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-80. [ka] This compound was prepared by alkylation of A6-8 with 2-bromoacetamide following the procedure previously described for the synthesis of Example A7-1. LCMS: MS calculated: 547.6; MS found: 548 ([M+H] + ).

[0286] Example A7-81 Synthesis of 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide [ka] a) Hydroxylamine hydrochloride, NaHCO3, MeOH. b) i) CH(OEt)3, BF3·Et2O, ii) HCl / dioxane. c) 2-Bromoacetamide, DIEA.

[0287] Scheme A7-81 (Z)-tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(N'-hydroxycarbamimidoyl)piperidine-1-carboxylate, A5-4. [ka] A suspension of tert-butyl 4-cyano-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate A5-3 (50 mg, 0.09 mmol), hydroxylamine hydrochloride (26 mg, 0.37 mmol), and NaHCO (38 mg, 0.45 mmol) in MeOH (0.5 mL) was heated to 75 °C overnight to form the corresponding amidoxime intermediate. The reaction was worked up by filtration with DCM, followed by washing the filtrate with HO (20 mL) and brine (20 mL). The organic phase was dried (NaSO) and concentrated to give A5-4 (37 mg, 0.06 mmol). LCMS: MS calculated: 581.6; MS found: 582 ([M+H] + ).

[0288] N 4 -((4-(1,2,4-oxadiazol-3-yl)piperidin-4-yl)methyl)-N 6 -cyclopropyl-5-fluoro-N 6 -(4-(trifluoromethyl)benzyl)pyrimidine-4,6-diamine, A6-9 [ka] To a solution of A5-4 (37 mg, 0.06 mmol) in triethyl orthoformate (100 μL, 0.6 mmol) under N was added BF EtO (5 μL, 0.04 mmol), and the mixture was heated to 100 °C for 90 min. The reaction was then concentrated to dryness, to which 4 N HCl in dioxane (0.5 mL) was added, and the mixture was stirred at room temperature for 1 h. After this period, the reaction was again concentrated, and the corresponding oxadiazole intermediate was used directly in the next synthetic step. LCMS: MS calculated: 491.5; MS found: 492 ([M+H] + ).

[0289] 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)acetamide, A7-81 [ka] This compound was prepared by alkylation of A6-9 with 2-bromoacetamide following the procedure previously described for the synthesis of Example A7-1. LCMS: MS calculated: 548.5; MS found: 549 ([M+H] + ).

[0290] Example A7-82 Synthesis of 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, A7-82 [ka] a) Hydrazine hydrate, EtOH. b) CH(OMe)3. c) TFA, DCM. d) DIEA, 2-bromoacetamide.

[0291] Scheme A7-82 tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(hydrazinecarbonyl)piperidine-1-carboxylate, A5-6 [ka] A mixture of 1-(tert-butyl)4-ethyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-1,4-dicarboxylate A5-5 (356 mg, 0.60 mmol) and hydrazine hydrate (0.6 mL, 10 mmol) in EtOH (1 mL) was heated to 120 °C in a microwave for 18 h. The solvent was evaporated, EtO (30 mL) was added, and washed with aq 2N NaOH (30 mL) and brine (30 mL). The organic phase was dried (NaSO) and concentrated to give A5-6 (258 mg, 0.11 mmol). LCMS: MS calculated: 581.6; MS found: 582 ([M+H] + ).

[0292] tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate, A5-7 [ka] A mixture of A5-6 (258 mg, 0.11 mmol) and CH(OMe) (0.24 mL, 2.2 mmol) was heated to 125 °C overnight in a sealed tube. EA (30 mL) was then added, and the organic phase was washed with saturated aqueous NaHCO (30 mL), HO (30 mL), and brine (30 mL). After drying (NaSO) and evaporation, 217 mg of crude product was obtained. This crude product was purified by flash CC (Hex:EA = 100:0 to 50:50). Collection of the product-containing fractions afforded A5-7 (9 mg, 0.015 mmol). LCMS: MS calculated: 591.6; MS found: 592 ([M+H] + ).

[0293] N 4 -((4-(1,3,4-oxadiazol-2-yl)piperidin-4-yl)methyl)-N 6 -cyclopropyl-5-fluoro-N6 -(4-(trifluoromethyl)benzyl)pyrimidine-4,6-diamine, A6-10 [ka] A5-7 (9 mg, 0.015 mmol) was dissolved in DCM (50 μL), TFA (12 μL) was added, and the mixture was stirred at room temperature for 3 h. The reaction was then concentrated to dryness to give A6-10. LCMS: MS calculated: 491.5; MS found: 492 ([M+H] + ).

[0294] 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide, A7-82 [ka] This compound was prepared by alkylation of the above intermediate with 2-bromoacetamide following the procedure previously described for the synthesis of Example A7-1. LCMS: MS calculated: 548.5; MS found: 549 ([M+H] + ).

[0295] Example A7-83 Synthesis of 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-83 [ka] a) i) NaOH, EtOH. ii) EDC, HCl, HOBt, N-methylhydrazinecarbothioamide, DCM. iii) NaOH, EtOH. iv) H2O2, DCM. b) i) TFA, DCM. ii) DIEA, 2-bromoacetamide.

[0296] Scheme A7-83 1-(tert-butoxycarbonyl)-4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-4-carboxylic acid, A5-8 [ka] 2N NaOH (1.6 mL, 3.2 mmol) was added to a solution of A5-5 (181 mg, 0.30 mmol) in EtOH (3 mL). The reaction mixture was stirred at room temperature for 3 h. The organic solvent was removed, HO was added, and the solution was acidified with 2N HCl to pH 3. The product was extracted with DCM (x3). The combined organic layers were washed with HO, dried (phase separation cartridge), and concentrated in vacuo. A5-8 was obtained as a white solid (168 mg, 0.29 mmol). LCMS: MS calculated: 567.6; MS found: 568 ([M+H] + ).

[0297] tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(2-(methylcarbamothioyl)hydrazine-1-carbonyl)piperidine-1-carboxylate, A5-9 [ka] EDC.HCl (85 mg, 0.44 mmol), HOBt (60 mg, 0.44 mmol), and N-methylhydrazinecarbothioamide (47 mg, 0.45 mmol) were added to a solution of A5-8 (168 mg, 0.29 mmol) in DCM (5 mL), and the reaction mixture was stirred at room temperature for 4 h. Additional N-methylhydrazinecarbothioamide (47 mg, 0.45 mmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with DCM, and the organic layer was washed with HO, dried (phase separation cartridge), and the solvent was removed in vacuo. The residue was then purified by flash CC (MeOH:DCM = 1:9) to give A5-9 (121 mg, 0.18 mmol) as a solid. LCMS: MS calculated: 654.7; MS found: 655 ([M+H] + ).

[0298] tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(4-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate, A5-10 [ka] A5-9 (114 mg, 0.17 mmol) was dissolved in EtOH (1.8 mL) and 8 N NaOH (0.55 mL, 4.4 mmol) was added. The reaction mixture was stirred at 80 °C overnight. HO was added to the reaction mixture, and 2 N HCl was added until the pH reached 4. The product was extracted with DCM (x3), and the combined organic layers were washed with HO and brine, dried (phase separation cartridge), and the solvent was removed in vacuo. The product A5-10 (98 mg, 0.15 mmol) was used for the next reaction without further purification. LCMS: MS calculated: 636.7; MS found: 637 ([M+H] + ).

[0299] tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate, A5-11 [ka] A 35% solution of HO (50 μL, 64 μmol) in AcOH (280 μL) was added to an ice-cold solution of A5-10 in DCM (1.5 mL), and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, the crude was diluted with HO, and 2N NaOH was added until pH 12. The product was extracted with DCM (×3), and the combined organic layers were washed with HO, dried (phase separation cartridge), and the solvent was removed in vacuo. The residue was then purified by flash CC (MeOH:DCM = 1:9) to give A5-11 (39 mg, 64 μmol) as a solid. LCMS: MS calculated: 604.6; MS found: 605 ([M+H] + ).

[0300] 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)acetamide, A7-83 [ka] This compound was prepared following the procedure previously described for the synthesis of Example A7-1 by first Boc deprotection followed by alkylation with 2-bromoacetamide. LCMS: MS calculated: 561.6; MS found: 562 ([M+H] + ).

[0301] Example A7-84 Synthesis of 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-imidazol-2-yl)piperidin-1-yl)acetamide, A7-84 [ka] a) LiAlH4, THF. b) Glyoxal, NH4OH, MeOH. c) i) TFA, DCM, ii) DIEA, 2-bromoacetamide

[0302] Scheme A7-84 tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-formylpiperidine-1-carboxylate, A5-12 [ka] 1M LiAlH in THF (1.1 mL, 1.1 mmol) was added dropwise to a suspension of A5-5 (520 mg, 0.87 mmol) in THF (8 mL) at −78 °C. The reaction mixture was stirred at this temperature for 2 h, and then it was quenched by the addition of HO (0.15 mL), 2N NaOH (0.75 mL), and HO (2.25 mL). The suspension was filtered through Celite®, and the solvent was removed in vacuo. The residue was purified by flash CC (Hex:EA = 100:0 to 0:100) to give A5-12 (340 mg, 0.61 mmol) as a solid. LCMS: MS calculated: 551.6; MS found: 552 ([M+H] + ).

[0303] tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-imidazol-2-yl)piperidine-1-carboxylate, A5-13 [ka] Glyoxal monohydrate (213 mg, 2.79 mmol) was added to a solution of A5-12 (141 mg, 0.26 mmol) in MeOH (7.5 mL) and 32% w / w NH4OH (3.75 mL, 63 mmol). The reaction mixture was stirred at room temperature for 3 h. Additional amounts of 32% w / w NH4OH (2 mL, 34 mmol) and glyoxal monohydrate (150 mg, 2 mmol) were added, and the mixture was stirred at room temperature for 2 days. The solvent was removed in vacuo, HO was added, and the product was extracted with EA (x3). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash CC (Hex:EA = 100:0 to 0:100) to give A5-13 (25 mg, 0.04 mmol) as a solid. LCMS: MS calculated: 589.6; MS found: 590 ([M+H] + ).

[0304] 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-imidazol-2-yl)piperidin-1-yl)acetamide, A7-84. [ka] This compound was prepared following the procedure previously described for the synthesis of Example A7-1 by first Boc deprotection followed by alkylation with 2-bromoacetamide. LCMS: MS calculated: 546.6; MS found: 547 ([M+H] + ).

[0305] Example A7-85 Synthesis of 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, A7-85 [ka] a) Dimethyl (1-diazo-2-oxopropyl)phosphonate, K2CO3, MeOH. b) CuI, azidotrimethylsilane, DMF. c) i) TFA, DCM, ii) DIEA, 2-bromoacetamide

[0306] Scheme A7-85 tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-ethynylpiperidine-1-carboxylate, A5-14 [ka] KCO (66 mg, 0.48 mmol) was added to an ice-cold solution of A5-12 (100 mg, 0.18 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (36 μL, 0.239 mmol) in MeOH (2 mL), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with HO, and the product was extracted with EA (×3). The combined organic layers were washed with brine, dried (MgSO), filtered, and concentrated. The residue was purified by flash CC (Hex:EA = 100:0 to 0:100) to give A5-14 (78 mg, 0.14 mmol) as a solid. LCMS: MS calculated: 547.6; MS found: 548 ([M+H] + ).

[0307] tert-Butyl 4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate, A5-15 [ka] Under a N atmosphere, CuI (1.1 mg, 5.8 μmol) was added to a solution of A5-14 (75 mg, 0.14 mmol) in DMF (1 mL) and MeOH (0.11 mL). Then, azidotrimethylsilane (28 μL, 0.21 mmol) was added, and the reaction mixture was stirred at 100 °C overnight. Additional azidotrimethylsilane (15 μL, 0.11 mmol) was added, and the reaction mixture was heated at 100 °C overnight. The mixture was diluted with EA, and the organic layer was washed with HO and brine, dried (MgSO), filtered, and concentrated. The residue was purified by flash CC (MeOH:DCM = 1:9) to give A5-15 (18 mg, 0.03 mmol) as a white solid. LCMS: MS calculated: 590.6; MS found: 591 ([M+H] + ).

[0308] 2-(4-(((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)acetamide, A7-85 [ka] This compound was prepared following the procedure previously described for the synthesis of Example A7-1 by first Boc deprotection followed by alkylation with 2-bromoacetamide. LCMS: MS calculated: 547.6; MS found: 548 ([M+H] + ).

[0309] Synthesis of benzylic amine A1 A1 building blocks were either commercially available or synthesized by reductive amination as outlined below.

[0310] Synthesis of N-(2-fluoro-4-(trifluoromethyl)benzyl)ethanamine, A1-18 [ka] a) EtNH2, MgSO4, NaBH4, DCM

[0311] Scheme A1-18 Dry MgSO (375 mg, 3.12 mmol) was added to a solution of compound 2-fluoro-4-(trifluoromethyl)benzaldehyde iA1-1 (200 mg, 1.04 mmol) and EtNH (0.52 mL, 1.04 mmol) in DCM (8 mL). The mixture was stirred at room temperature for 2 hours, and then NaBH (119 mg, 3.12 mmol) was added to the mixture, and the reaction was stirred overnight. The reaction was filtered, and the filtrate was concentrated in vacuo to give crude A1-18 (267 mg, 1.04 mmol) as a colorless oil. Crude A1-18 was used without further purification. LCMS: MS calculated: 221; MS found: 222 ([M+H] + ).

[0312] A1-34 and A1-65 were prepared by reductive amination from the corresponding alkylamine and 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzaldehyde, which was prepared as described in Michael et al.'s January 2013 publication (Patent Document 4).

[0313] Synthesis of 2-(4-((ethylamino)methyl)phenyl)-2,2-difluoroethan-1-ol, A1-39 [ka] a) EtNH2, NaBH3CN, AcOH, MeOH. b) Boc2O, TEA, MeOH. c) 2-Bromo-2,2-difluoroethyl acetate, Cu, DMSO. d) TFA, DCM. e) LiAlH4, THF.

[0314] Scheme A1-39 N-(4-iodobenzyl)ethanamine, iA1-3 [ka] 4-Iodobenzaldehyde iA1-2 (2 g, 8.6 mmol) was dissolved in MeOH (90 mL) and EtNH (4.8 mL, 2 M in MeOH), AcOH (0.5 mL, 8.7 mmol), and NaBHCN (650 mg, 10.3 mmol) were added. The reaction mixture was stirred at room temperature overnight. HCl (10 mL, 2 M) was then added dropwise, and when bubbling ceased, H2O was added and MeOH was evaporated under reduced pressure. The aqueous residue was extracted with DCM (x2). The pH of the aqueous phase was made basic with 2 N NaOH and extracted with DCM (3x). The organic phase from the basic extraction was dried (MgSO4), filtered, and concentrated to give iA1-3 (980 mg, 3.75 mmol). LCMS: MS calculated: 261; MS found: 262 ([M+H]+).

[0315] tert-Butyl ethyl (4-iodobenzyl)carbamate, iA1-4 [ka] iA1-3 (980 mg, 3.75 mmol) was suspended in MeOH (30 mL), and TEA (1.0 mL, 7.2 mmol) was added, followed by BocO (1 g, 4.6 mmol). The mixture was stirred at room temperature for 18 h. The solvent was then evaporated under reduced pressure. The residue was redissolved in DCM, washed with H2O (x3) and brine (x1), dried (MgSO4), and concentrated in vacuo to give iA1-4 (1.16 g, 3.2 mmol). LCMS: MS calculated: 361; MS found: 362 ([M+H]+).

[0316] 2-(4-(((tert-butoxycarbonyl)(ethyl)amino)methyl)phenyl)-2,2-difluoroethyl acetate, iA1-5 [ka] iA1-4 (400 mg, 1.1 mmol), ethyl 2-bromo-2,2-difluoroacetate (0.3 mL, 2.3 mmol), and Cu (250 mg, 3.9 mmol) were suspended in DMSO (8 mL) in a sealed tube and heated to 60 °C overnight. The reaction mixture was poured into a saturated solution of NH4Cl (100 mL), and HO (50 mL) was added. The aqueous phase was extracted with EA (x3), and the combined EA phases were dried (MgSO4) and concentrated in vacuo. The residue (650 mg) was purified by flash CC (Hex:EA = 100:0 to 90:10) to give iA1-5 (365 mg, 1.0 mmol). LCMS: MS calculated: 357; MS found: 358 ([M+H] + ).

[0317] 2-(4-((ethylamino)methyl)phenyl)-2,2-difluoroacetic acid ethyl ester, iA1-6 [ka] iA1-5 (365 mg, 1.0 mmol) was dissolved in DCM (10 mL), followed by the addition of TFA (2 mL, 26.1 mmol). The reaction mixture was stirred at room temperature for several hours and then concentrated in vacuo. The residue was suspended in HO and made basic by the portionwise addition of NaCO, and the aqueous phase was then extracted with EtO (x2). The combined organic phases were washed with HO (x1), dried over MgSO, and concentrated in vacuo to give iA1-6 (136 mg, 0.53 mmol). LCMS: MS calculated: 257; MS found: 258 ([M+H] + ).

[0318] 2-(4-((ethylamino)methyl)phenyl)-2,2-difluoroethan-1-ol, A1-39 [ka] A suspension of LiAlH (80 mg, 2.1 mmol) in THF (4 mL) was cooled in an ice bath, followed by the dropwise addition of a solution of iA1-6 (136 mg, 0.53 mmol) in THF (2 mL). The reaction mixture was allowed to reach room temperature and stirred for an additional 2 h. To this mixture was added dropwise, in order: HO (0.2 mL), NaOH (2N, 0.2 mL), and finally HO (0.6 mL). After filtration through Celite®, the filtrate was dried (MgSO), filtered, and concentrated in vacuo to give A1-39 (92 mg, 0.43 mmol). LCMS: MS calculated: 215; MS found: 216 ([M+H] + ).

[0319] Synthesis of N-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)cyclopropanamine, A1-67: [ka] a) 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, PdCl2dppf, DCM, NaHCO3, dioxane. b) Cyclopropanamine, NaBH4, MeOH.

[0320] Scheme A1-67 2-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzaldehyde, iA1-8 [ka] 2-Fluoro-4-iodobenzaldehyde iA1-7 (1.05 g, 4.20 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.75 g, 8.41 mmol) were dissolved in 1,4-dioxane (12 mL), and NaHCO (6.3 mL, 13 mmol, 2 M) was added. N was bubbled through the solution, followed by the addition of PdCl dppf.DCM. The reaction mixture was heated at 80 °C overnight in a sealed tube. The cooled reaction mixture was filtered through Celite®, washed with EA, and the solvent was removed in vacuo. The residue was purified by flash CC (Hex:EtO) to give iA1-8 (826 mg, 4.05 mmol). LCMS: MS calculated: 204; MS found: 205 ([M+H] + ).

[0321] N-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)cyclopropanamine, A1-67 [ka] Cyclopropanamine (310 μL, 4.47 mmol) was added to a solution of iA1-8 (826 mg, 4.05 mmol) in MeOH (30 mL). The reaction mixture was heated to reflux overnight, cooled to 0 °C, followed by the addition of NaBH (306 mg, 8.09 mmol), followed by stirring at room temperature for 4 h. The solvent was removed in vacuo, HO was added, and the product was extracted with DCM. The combined organic phases were washed with HO, brine, passed through a phase separation cartridge, dried, and concentrated to give A1-67 (806 mg, 3.29 mmol). LCMS: MS calculated: 245; MS found: 256 ([M+H] + ).

[0322] Synthesis of Boc-protected piperidine, A4: A4 building blocks were either commercially available or synthesized as outlined below.

[0323] Synthesis of tert-butyl 4-(aminomethyl)-3-(trifluoromethyl)piperidine-1-carboxylate, A4-5 [ka] a) Phthalimide, DCM, Ph3P, DIAD. b) PtO2, H2, AcOH. c) TEA, DCM, Boc2O. d) Hydrazine, EtOH.

[0324] Scheme A4-5 2-((3-(trifluoromethyl)pyridin-4-yl)methyl)isoindoline-1,3-dione, iA4-2 [ka] DIAD (1.20 g, 5.97 mmol) was added to a solution of (3-(trifluoromethyl)pyridin-4-yl)MeOH (iA4-1) (0.70 g, 3.98 mmol), phthalimide (0.70 g, 4.77 mmol), and PhP (1.56 g, 5.97 mmol) in DCM (50 mL) with stirring at 0 °C. The reaction was then stirred at room temperature for 4 h before being quenched with HO. The resulting mixture was extracted with DCM (2 × 50 mL), the combined organic phases were dried (NaSO), concentrated, and the residue was purified by flash CC (EA:PE = 1:5) to give crude iA4-2 (1.2 g) as a white solid containing phthalimide. This crude material was used without further purification. LCMS: MS calculated: 306; MS found: 307 ([M+1] + ).

[0325] 2-((3-(trifluoromethyl)piperidin-4-yl)methyl)hexahydro-1H-isoindole-1,3(2H)-dione, iA4-3 [ka] PtO (0.2 g) was added to a solution of iA4-2 (1.2 g, 3.9 mmol) in AcOH (5 mL) at room temperature, and the reaction was stirred at 50 °C under H (60 psi) for 2 days. The pH was then adjusted to 8–9 with NHOH at 0 °C. The resulting mixture was extracted with EA (2 × 100 mL), and the combined organic phases were washed with brine (10 mL), dried (NaSO), and finally concentrated to give iA4-3 (1.4 g) as a yellow oil, which was used without further purification. LCMS: MS calculated: 318; MS found: 319 ([M+1] + ).

[0326] tert-Butyl 4-((1,3-dioxooctahydro-2H-isoindol-2-yl)methyl)-3-(trifluoromethyl)piperidine-1-carboxylate (iA4-4) [ka] At room temperature, BocO (1.02 g, 4.68 mmol) was added to a solution of iA4-3 (1.4 g, 3.9 mmol) and TEA (0.78 g, 7.8 mmol) in DCM (20 mL). The reaction was stirred at room temperature for 2 hours, followed by the addition of HO. The resulting mixture was extracted with DCM (2 × 50 mL), and the combined organic phases were dried (NaSO) and concentrated to give iA4-4 (1.7 g) as a yellow oil. This material was used without further purification. LCMS: MS calculated: 418; MS found: 363 ([M+1-56] + ).

[0327] tert-Butyl 4-(aminomethyl)-3-(trifluoromethyl)piperidine-1-carboxylate (A4-5) [ka] At room temperature, hydrazine hydrate (85%, 6 mL) was added to a solution of iA4-4 (crude 1.4 g, 3.9 mmol) in EtOH (10 mL). The reaction was heated to 80 °C for 3 h, followed by the addition of HO (10 mL). EtOH was evaporated, and the resulting mixture was extracted with EA (2 × 50 mL). The combined organic phases were dried (NaSO) and concentrated to give A4-5 (0.9 g) as a brown oil, which was used without further purification. LCMS: MS calculated: 282; MS found: 227 ([M+1-56] + ).

[0328] Synthesis of Enantiomerically Enriched (3R,4R)-rel-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, A4-1 [ka] a) (+)-alpine boramine TMEDA complex, BF3. Et2O, Et2O / THF, followed by H2O2, NaOH. b) Pd / C, HCO2NH4, MeOH. c) Boc2O, DCM / MeOH. d) TsCl, pyridine. e) NH3.

[0329] Scheme A4-1” rel-(3R,4R)-1-benzyl-4-(hydroxymethyl)piperidin-3-ol, iA4-6 [ka] Under an inert atmosphere (Ar) and at room temperature, BF3Et2O (12 mL, 97.2 mmol) was added dropwise to a stirred solution of (+)-alpine boramine TMEDA complex (20.28 g, 48.7 mmol) in a mixture of dry Et2O (150 mL) and dry THF (32 mL). After 2 h 15 min, a solution of iA4-5 (7.6 g, 37.0 mmol) in THF (32 mL) was added dropwise to the white suspension over approximately 15 min, and the reaction was stirred at room temperature for 2.5 h and then at 55 °C overnight. The reaction was cooled on an ice bath, followed by the dropwise addition of HO (7.6 mL), followed by the addition of NaOH (5 M, 12 mL) and aqueous HO (35%, 19.2 mL), and finally aq. NaOH (50%, 48 mL). The mixture was then heated to reflux (oil bath 60 °C) for 4 h and subsequently cooled to room temperature. An aqueous solution of K2CO3 (saturated, 80 mL) was added, and the mixture was extracted with EA (3 x 400 mL). The combined organic phases were dried and concentrated in vacuo to give an oil (26 g). The crude material was dissolved in EA (220 mL) and extracted with HCl (5 M, 2 x 110 mL). The combined acidic aqueous layers were washed with EA (200 mL) and cooled on an ice bath, followed by the addition of solid K2CO3 (ca. 101 g) in small portions until the pH of the aqueous phase remained strongly basic. The basic aqueous phase was then extracted with EA (4 x 200 mL), and the combined EA phases were dried and concentrated in vacuo to give iA4-6" (8.08 g, 36 mmol). MS calculated: 221; MS found: 222 ([M+H] + ). 1 H NMR(400MHz,chloroform-d)δ 1.16-1.31(m,1H),1.42-1.61(m,2H),1.79-1.88(m,1H),1.90-1.99(m,1H),2.79(dd,J=9.4,1.8Hz,1H), 2.91-3.00(m,1H),3.46(d,J=13.0Hz,1H),3.52(d,J=13.0Hz,1H),3.59-3.74(m,3H),7.17-7.34(m,5H).

[0330] HPLC analysis (Chiralpak ID, gradient: 1 to 45% iIPA (+0.2% DEA) over 17 min in CO2) showed an 88:12 mixture of enantiomers (76% ee).

[0331] rel-(3R,4R)-4-(hydroxymethyl)piperidin-3-ol, iA4-7 [ka] Ammonium formate (6.91 g, 109.6 mmol) and Pd / C (10%, 0.711 g, 0.67 mmol) were added to a solution of iA4-6″ (8.08 g, 36.5 mmol) in MeOH (110 mL), and the reaction was stirred and heated to reflux (oil bath temperature 80° C.). Additional portions of Pd / C (10%, 0.711 g, 0.67 mmol) were added after 30 min and again after 60 min. After 3.5 h, the reaction mixture was cooled and filtered through Celite®. The filter cake was washed with MeOH, and the filtrate and washings were combined and concentrated under reduced pressure to provide iA4-7″ (4.70 g, 35.8 mmol). MS calculated: 131; MS found: 132 ([M+H] + ). 1 H NMR(400MHz,DMSO-d6)δ 0.98-1.13(m,1H),1.20-1.33(m,1H),1.59-1.69(m,1H),2.07-2.18(m,1H),2.24-2.36(m,1H),2.80(d,J=12.0Hz, 1H),2.90(dd,J=11.5,4.5Hz,1H),3.11(d,J=4.1Hz,1H),3.25-3.36(m,1H),3.59(dd,J=10.2,4.1Hz,1H),4.32(br s,1H),4.49(br s,1H).

[0332] (3R,4R)-3-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate rel-tert-butyl ester, iA4-8 [ka] A solution of BocO (7.82 g, 35.8 mmol) in DCM (20 mL) was added dropwise to a stirred, cooled (ice bath) solution of iA4-7″ (4.70 g, 35.8 mmol) in a mixture of DCM (30 mL) and MeOH (12 mL). After stirring overnight, the mixture was concentrated, and the residue was purified by flash CC (MeOH:DCM = 0:100 to 5:95) to give iA4-8″ (7.96 g) as a colorless oil. MS calculated: 231; MS found: 232 ([M+H] + ). 1 H NMR (400 MHz, chloroform-d) δ 1.07-1.21 (m, 1H), 1.45 (s, 9H), 1.53-1.62 (m, 2H), 1.64-1.75 (m, 1H), 2.47-2.58 (m, 1H), 2.59-2.73 (m, 1H), 3.49-3.60 (m, 1H), 3.65-3.74 (m, 1H), 3.74-3.83 (m, 1H), 3.98-4.31 (m, 2H).

[0333] (3R,4R)-3-hydroxy-4-((tosyloxy)methyl)piperidine-1-carboxylate rel-tert-butyl ester, iA4-9 [ka] TsCl (7.22 g, 37.9 mmol) was added portionwise (over 10 min) to a stirred solution of iA4-8″ (7.96 g, 34.4 mmol) in dry pyridine (17 mL) on an ice bath. The mixture was allowed to reach room temperature over 3 h. The mixture was then diluted with DCM and washed with aq HCl (1 M), aq NaHCO3 (4%), brine, dried, and concentrated to give a thick yellow oil. The residue was purified by flash CC (EA:Hex=0:100 to 40:60) to give iA4-9″ (8.49 g, 22 mmol) as a white solid. MS calculated: 385; MS found: 386 ([M+H] + ). 1H NMR(400MHz,chloroform-d)δ 1.36-1.42(m,1H),1.45(s,9H),1.62-1.73(m,2H),2.42-2.54(m,4H),2.55-2.71(m,1H),3.40-3.5 2(m,1H),3.93-4.14(m,2H),4.15-4.32(m,2H),7.35(d,J=8.0Hz,2H),7.76-7.81(d,J=8.0Hz,2H...

Claims

1. Compounds according to formula (I): 【158】 , a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or stereoisomer, １ , Y ２ and Y ３ is independently, CR ８ and R is hydrogen; R ０ａ and R ０ｂ are independently hydrogen or C １～４ is alkyl; R １ａ and R １ｂ are independently hydrogen or hydroxyl; R ２ is hydrogen or hydroxyl; R ３ is C １～４ Alkyl, or substituted or unsubstituted C ３～７ is cycloalkyl; R ４ and R ５ are each independently hydrogen or C １～４ is alkyl; R ６ is hydrogen, C １～６ hydroxyhaloalkyl, or C １～４ haloalkyl; R ７ is hydrogen or halogen; Each R ８ are independently hydrogen, halogen, or C １～４ haloalkoxy; and R ７ is hydrogen and each R ８ Whenever is hydrogen, R ６ is C １～４ Haloalkyl or C １～６ hydroxyhaloalkyl; and When substituted, cycloalkyl is C １～４ substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and halogen; However, the compound, stereoisomer, or pharmaceutically acceptable salt thereof is 【Chemical 226】 【Chemical 227】 【Chemical 228】 【Chemical 229】 (It is not a compound having the structure

2. R ６ But CF ３ and C(CF ３ ) ２ 2. The compound, stereoisomer, or salt of claim 1, wherein the compound, stereoisomer, or salt is selected from the group consisting of: OH.

3. R ６ But CF ３ 3. The compound, stereoisomer, or salt of claim 1, wherein:

4. R ７ The compound, stereoisomer, or salt of any one of claims 1 to 3, wherein is hydrogen or fluoro.

5. Y １ , Y ２ and Y ３ The compound, stereoisomer, or salt of any one of claims 1 to 4, wherein each is CH.

6. R ８ The compound, stereoisomer, or salt of any one of claims 1 to 4, wherein is hydrogen or fluoro.

7. R ６ is hydrogen and Y ２ is C(OCF ３ 5. The compound, stereoisomer, or salt of claim 1, wherein

8. R ３ The compound, stereoisomer, or salt of any one of claims 1 to 7, wherein is selected from the group consisting of methyl, ethyl, and cyclopropyl.

9. R ２ The compound, stereoisomer, or salt according to any one of claims 1 to 8, wherein is hydrogen.

10. R ２ The compound, stereoisomer, or salt of any one of claims 1 to 8, wherein is hydroxyl.

11. R １ａ is hydrogen or hydroxyl, and R １ｂ The compound, stereoisomer, or salt of any one of claims 1 to 10, wherein is hydrogen.

12. R １ａ , R １ｂ and R ２ 12. The compound, stereoisomer, or salt of any one of claims 1 to 11, wherein at least one of is not hydrogen.

13. R １ａ is hydrogen or hydroxyl; R １ｂ is hydrogen; and R ２ The compound, stereoisomer, or salt of any one of claims 1 to 12, wherein is hydrogen or hydroxyl.

14. R １ａ is hydroxyl or R ２ is hydroxyl, １ａ is hydroxyl or hydrogen; R １ｂ is hydrogen; and R ２ 14. The compound, stereoisomer, or salt of claim 13, wherein is hydrogen or hydroxyl.

15. 10. The compound, stereoisomer, or salt of claim 1 having the structure of Formula (II) or Formula (III): 【Chemistry 159】 (In the formula, R １ａ is hydroxyl; R １ｂ is hydrogen; R ２ is hydrogen or hydroxyl; R ６ is CF ３ and Y ２ and Y ３ is CR ８ and R ８ is hydrogen or fluoro).

16. Y ２ and Y ３ are each CH, or Y ２ is CH and Y ３ 16. The compound, stereoisomer, or salt of claim 15, wherein is CF.

17. R ０ａ is hydrogen; R ０ｂ is hydrogen or methyl; R １ａ is hydrogen or hydroxyl; R １ｂ is hydrogen; R ２ is hydrogen or hydroxyl; R is hydrogen; R ３ is ethyl or cyclopropyl; R ４ is hydrogen; R ５ is hydrogen; R ６ However, hydrogen, CF ３ , C.F. ２ CH ３ , or C(CF ３ ) ２ OH; R ７ is hydrogen; Y １ , Y ２ and Y ３ are each CH; or Y １ is CH and Y ２ is CH and Y ３ is C(F); or Y １ is CH and Y ２ is C(OCF ３ ) and Y ３ is CH, Here, Y １ , Y ２ and Y ３ are each CH, and R ７ is hydrogen, R ６ But CF ３ , C.F. ２ CH ３ , or C(CF ３ ) ２ OH, 2. The compound, stereoisomer, or salt of claim 1.

18. 【Catalog 230】 【Chemistry 231】 【Chemical 232】 【Chemical 233】 【Chemical 234】 【Chemistry 235】 【Chemical 236】 【Chemical 237】 2. The compound or salt of claim 1, selected from:

19. A pharmaceutical composition comprising a compound, stereoisomer, or salt according to any one of claims 1 to 18 and at least one pharmaceutically acceptable excipient.

20. 20. Use of a compound, stereoisomer or salt according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment of an inflammatory, metabolic, oncological or autoimmune disease.

21. 20. A composition comprising a compound, stereoisomer or salt according to any one of claims 1 to 18 for use in the treatment and / or prevention of inflammatory, metabolic, oncological or autoimmune diseases.

22. The disease may be asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases, atopic dermatitis, cystic fibrosis, lung transplant rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, lichen planus, hidradenitis suppurativa, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease (FAFLD), or steroid hormone-dependent ...

22. The composition of claim 21, wherein the disease is selected from the group consisting of hepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type II diabetes, and cancer.

23. The composition described in claim 22, wherein the allergic disease is selected from allergic rhinitis, allergic conjunctivitis, uveitis, sprue and food allergy.

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