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] The aspects and embodiments described herein relate to compounds that are active against nuclear receptors, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat inflammatory, metabolic, tumor, and autoimmune diseases or disorders.

Background Art

[0002] 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.

[0003] Examples of nuclear receptors include the nuclear retinoic acid receptor-related orphan receptor (ROR). ROR contains the following 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 cause a conformational change in the domain that results in downstream effects. There are various isoforms, and these isoforms differ only in the N-terminal A / B domain (Jetten, 2009, Nuclear Receptor Signaling).

[0004] ROR consists of three members, namely ROR alpha (RORα or RORa), ROR beta (RORβ or RORb), and ROR gamma (RORγ or RORc).

[0005] RORα is expressed in many tissues such as cerebellar Purkinje cells, liver, thymus, skeletal muscle, skin, lung, adipose tissue, and kidney. RORα controls neuronal development, bone metabolism, and arteriosclerosis (Jetten, 2009, Nuclear Receptor Signaling). Furthermore, RORα is involved in immune responses such as interleukin (IL)-17A expression in T helper (Th) 17 cells and regulation of the function of regulatory T (Treg) cells (Castro PLOS 2017; Malhotra 2018).

[0006] RORβ shows a restricted expression pattern limited to specific regions of the brain (cerebral cortex, thalamus, hypothalamus, and pineal gland) and the retina (Jetten, 2009, Nuclear Receptor Signaling). RORβ is associated with epilepsy and is also associated with bipolar disorder together with RORa (Rudolf 2016; Lai 2015).

[0007] RORγ shows a broad expression pattern and was the last to be discovered among the three members. To date, the following two different 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 and is mainly expressed in the kidney, liver, and skeletal muscle. In contrast, the expression of RORγt is limited to some cell types of the immune system and lymphoid organs such as the thymus and secondary lymphoid tissues (Hirose 1994; Jetten, 2009, Nuclear Receptor Signaling).

[0008] RORγt has been identified as an important regulator of Th17 cell differentiation and IL-17 production by γδ T cells, Th17 cells, T cytotoxic (Tc)17 cells, and type 3 innate lymphoid (ILC3) cells (Gaffen 2014). Th17 cells are a subset of T helper cells that preferentially produce the cytokines IL-17A, IL-17F, IL-21, and IL-22 (Castro PLOS 2017). T cells lacking RORγt are unable to 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-related cytokines and chemokines (Gaffen 2014, Nat Rev Immunol; Yang 2014 Trend Pharmacol Sci). IL-23 is a crucial checkpoint in the generation, maintenance, and activation of pathogenic Th17 cells. In response to the IL-23 signal, RORγt, in concert with a network of transcription factors (STAT3, IRF4, and BATF), initiates the complete differentiation program of Th17 cells (Gaffen 2014, Nat Rev Immunol).

[0009] Th17 cells and the IL-17 immune response have been shown to be associated with the pathology of many human inflammatory and autoimmune disorders. Therapeutic strategies targeting the IL-23-IL-17 axis have been developed in many autoimmune diseases, and some of them have already demonstrated clinical efficacy in some diseases (Patel 2015; Krueger 2018 Exp Dermatol).

[0010] Thus, there is evidence that RORα, RORβ, and RORγ are involved in the pathogenesis of many diseases.

[0011] It would be desirable to provide compounds that modulate the activity of RORα and / or RORγ for use in the treatment of inflammatory, metabolic, and autoimmune diseases. International Publication No. WO 2016 / 020288 pamphlet and International Publication No. WO 2016 / 020295 pamphlet describe compounds that modulate the activity of active or RORγ receptor. However, there is still a need for potent RORγ modulators with improved physicochemical properties.

Prior Art Documents

Patent Documents

[0012]

Patent Document 1

Patent Document 2

Summary of the Invention

Means for Solving the Problems

[0013] In one aspect, a compound of formula (I)

Chemical Formula

[0014] In one aspect, 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, and at least one pharmaceutically acceptable excipient is provided herein.

[0015] In one aspect, a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt of a compound of formula (I) or a stereoisomer, or a pharmaceutical composition thereof, for use in the treatment and / or prevention of a disease or disorder selected from the group consisting of 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 disease, hidradenitis suppurativa, steatosis, fatty hepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ophthalmic diseases, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, episcleritis, obesity, insulin resistance induced by obesity, type II diabetes, and cancer, or symptoms thereof, are provided herein.

[0016] Furthermore, the advantageous features of the various embodiments are set forth in the dependent claims and the description detailed below.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other documents referred to herein are incorporated by reference in their entirety. When there are multiple definitions of terms in this specification, the definitions in this section shall prevail unless otherwise stated.

[0018] As used herein, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10Any "R" group, such as (but not limited to) these, represents a substituent that can be bonded to a specified atom. Examples of R groups include, but are not limited to, hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroaricyclic. When two "R" groups are covalently bonded to the same atom or adjacent atoms, they "come together" or "combine" as defined herein to form a cycloalkyl, aryl, heteroaryl, or heteroaricyclic group. For example, but not limited to, NR a R b group R a and R b are shown to be "together" or "combined", it means that they are covalently bonded to each other at their terminal atoms to form a ring containing the following nitrogen.

Chemical formula

[0019] As will be readily appreciated by those skilled in the art, any given group disclosed herein may contain more hydrogen than provided by an R group that is hydrogen bonded to that group.

[0020] When the base is described as "unsubstituted or substituted", then always, when substituted, the substituents (one or more may be present, such as 1, 2, 3 or 4) are selected independently from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and amino including mono- and di-substituted amino groups, and protected derivatives thereof. When a substituent in a group is considered to be "substituted", the substituent itself is substituted with one or more of the designated substituents. When the referenced substituent is substituted, it means that one or more hydrogen atoms on the referenced substituent may be substituted with a group selected individually and independently from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and amino including mono- and di-substituted amino groups, and protected derivatives thereof. Protecting groups capable of forming the protected derivatives of the above substituents are known to those skilled in the art, see Greene and Wuts, Protective Groups in Organic Synthesis, 3 rdIt can be found in Ed., John Wiley & Sons, New York, NY, 1999. This document is hereby incorporated by reference in its entirety into this specification

[0021] As used herein, "C m ~C n (Cm to Cn)", "C m ~C n " or "C m~n " (where "m" and "n" are integers) refers to the number of carbon atoms in the corresponding group. That is, the group may contain from "m" to "n" carbon atoms. Thus, for example, the "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 in these definitions is assumed to apply

[0022] As used herein, "alkyl" refers to a fully saturated (no double or triple bonds) straight-chain or branched hydrocarbon chain group. An alkyl group may have 1 to 20 carbon atoms (when it appears herein, a numerical range such as "1-20" always refers to each integer within the given range, e.g., "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 20 (including 20) carbon atoms, but this definition also encompasses the presence of the term "alkyl" where no numerical range is specified). An alkyl group can also be an alkyl having 1 to 10 carbon atoms such as "C 1~6 ". An alkyl group can also potentially be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of a compound can be designated as "C1-C4 alkyl", "C 1~4 alkyl" or a similar name. For illustrative purposes only, "C1-C4 alkyl" or "C 1~4"Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, etc. When substituted, the substituent is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and amino including mono- and di-substituted amino groups, and one or more groups individually and independently selected from their protected derivatives.

[0023] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight-chain or branched hydrocarbon chain. When two or more double bonds are present, the double bonds may or may not be conjugated. An alkenyl group can have from 2 to 20 carbon atoms (and whenever it appears herein, a numerical range such as "2 to 20" refers to each integer within the given range; for example, "from 2 to 20 carbon atoms" means that the alkenyl 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 occurrence of the term "alkenyl" without a specified numerical range). When substituted, the substituent is one or more groups independently selected individually from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, oxo, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, and amino including mono- and di-substituted amino groups, and their protected derivatives.

[0024] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight-chain or branched hydrocarbon chain. An alkynyl group can have from 2 to 20 carbon atoms (and whenever it appears herein, a numerical range such as "2 to 20" refers to each integer within the given range; for example, "from 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 occurrence of the term "alkynyl" without a specified numerical range). The alkynyl group may or may not be substituted. When substituted, the substituent can be selected from the same groups disclosed above with respect to alkenyl group substitution.

[0025] As used herein, "hetero" when attached to a radical may refer to one or more carbon atoms, and the relevant hydrogen atoms in the attached radical are independently replaced by the same or different heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur.

[0026] As used herein, "heteroalkyl" alone or in combination with another term refers to a straight-chain or branched alkyl group consisting of a specified number of carbon atoms, wherein one or more carbon atoms, such as 1, 2, 3, or 4 carbon atoms, and the relevant hydrogen atoms are independently replaced by the same or different heteroatoms selected from nitrogen, oxygen, and sulfur. The carbon atoms that are replaced may be in the middle or at the end of the alkyl group. Examples of heteroalkyl include C 1~6 heteroalkyl, wherein one or more of the carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, and nitrogen, and examples are -S-alkyl, -O-alkyl, -NH-alkyl, -alkylene-O-alkyl, etc. Heteroalkyl may be optionally substituted.

[0027] As used herein, "aryl" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings sharing two adjacent carbon atoms) having a fully delocalized π-electron system. In some embodiments described herein, the aryl group is C 1~10Aryl, which may or may not be substituted. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted. When substituted, the hydrogen atom is replaced by one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and amino including mono- and disubstituted amino groups, and protected derivatives thereof. When substituted, the substituents on the aryl group may form a non-aromatic ring fused to the aryl group, such as cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0028] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized π-electron system), wherein 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, as heteroaryl, C 6~10Heteroaryl (wherein 1 to 4 carbon atoms are replaced by 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur) is exemplified, but not limited thereto. Examples of monocyclic "heteroaryl" include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, oxadiazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazole and triazine. Examples of polycyclic "heteroaryl" include, but are not limited to, quinoline, isoquinoline, quinazoline, quinoxaline, indole, purine, benzofuran, benzothiophene, benzopyranone (e.g., coumarin, chromone and isocoumarin). Heteroaryl may be substituted. When substituted, the hydrogen atom is replaced by a substituent which is one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and amino including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, the substituent on the heteroaryl group may form a non-aromatic ring condensed to the aryl group, such as cycloalkyl, cycloalkenyl, cycloalkynyl and heterocyclyl.

[0029] "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 examples, the alkylene group is a lower alkylene group.

[0030] "Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group linked as a substituent via an alkylene. The alkylene and heteroaryl groups of the heteroaralkyl may be substituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl, and imidazolylalkyl, and their substituted and benzocondensed analogs. In some examples, the alkylene group is a lower alkylene group.

[0031] "Alkylene" is a straight-chain linking group that forms a bond connecting molecular fragments via terminal carbon atoms. Alkylene can have 1 to 20 carbon atoms. Alkylene can also be alkylene having 1 to 10 carbon atoms such as "C 1~6 ". Alkylene can also potentially be lower alkylene having 1 to 4 carbon atoms. Alkylene can be designated as "C1-C4 alkylene", "C 1~4 alkylene" or similar names. Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-(CH2)4-) groups. In the case of methylene, the two linked fragments are linked to the same carbon atom. Lower alkylene may be substituted.

[0032] As used herein, "heteroalkylene", alone or in combination with another term, refers to an alkylene group consisting of a specified number of carbon atoms, wherein one or more carbon atoms, such as 1, 2, 3, or 4 carbon atoms, are independently replaced by 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-NH-CH2-, -O-CH2-CH2-O-CH2-CH2-O-, -O-CH2-CH2-O-CH2-CH2-.

[0033] As used herein, "alkylidene" refers to a divalent group such as =CR’R’’, which is bonded to one carbon of another group to form a double bond. Examples of alkylidene groups include, but are not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, "arylalkylidene" refers to an alkylidene group in which R’ or R’’ is an aryl group. The alkylidene group may be substituted.

[0034] As used herein, "alkoxy" refers to the group -OR, where R is alkyl, for example, methoxy, ethoxy, n-propoxy, cyclopropoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amyloxy, tert-amyloxy, etc. The alkoxy may be substituted.

[0035] 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. The alkylthio may be substituted.

[0036] As used herein, "aryloxy" and "arylthio" refer to RO- and RS- (wherein R is aryl as defined above), for example, phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio, and the like. Aryloxy and arylthio may each be substituted.

[0037] As used herein, "alkenyloxy" refers to the formula -OR (wherein R is alkenyl as defined above), for example, vinyloxy, propenyloxy, n-butenyloxy, iso-butenyloxy, sec-pentenyloxy, tert-pentenyloxy, and the like. Alkenyloxy may be substituted.

[0038] As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, or aryl linked as a substituent via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acrylyl. Acyl may be substituted.

[0039] As used herein, "cycloalkyl" refers to a fully saturated (no double bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be linked in a fused, bridged, or spiro fashion. The cycloalkyl group can range from C3 to C6, such as C3 to C 10 and the like. The cycloalkyl group may or may not be substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. When substituted, the substituent can be alkyl or selected from those shown above for substitution of alkyl groups, unless otherwise indicated. When substituted, the substituent on the cycloalkyl group can form an aromatic ring fused to the cycloalkyl group, such as aryl and heteroaryl.

[0040] As used herein, "cycloalkenyl" refers to a cycloalkyl group that contains one or more double bonds in the ring, but if there are two or more, they cannot form a completely delocalized π-electron system in the ring (otherwise, the group would be "aryl" as defined herein). When composed of two or more rings, the rings can be joined in a fused, bridged, or spiro-bonded fashion. The cycloalkenyl group can range from C3-C8 or C5-C 10 such as C3-C 10 and can be in the range of. For example, C 3~8 Examples of cycloalkenyl include C 4~8 cycloalkenyl, C 5~8 cycloalkenyl or C 6~8 cycloalkenyl. The cycloalkenyl group may or may not be substituted. When substituted, the substituent can be alkyl or selected from the groups disclosed above for substitution of alkyl groups, unless otherwise indicated. When substituted, the substituents on the cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, such as aryl and heteroaryl.

[0041] As used herein, "cycloalkynyl" refers to a cycloalkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings can be joined in a fused, bridged, or spiro-bonded fashion. The cycloalkynyl group can range from C8-C 12 and can be in the range of. The cycloalkynyl group may or may not be substituted. When substituted, the substituent can be alkyl or selected from the groups disclosed above for substitution of alkyl groups, unless otherwise indicated. When substituted, the substituents on the cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, such as aryl and heteroaryl.

[0042] As used herein, "heteroalicyclic" or "heteroaricyclic" refers to a 3- to 18-membered ring consisting of carbon atoms and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heteroalicyclic group or heteroaricyclic group can range from C2-C 10It can be in the range of, and in some embodiments, it can be in the range of C2 - C9, and in other embodiments, it can be in the range of C2 - C8. In some embodiments, "heteroalicyclic" or "heteroaricyclic" can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can be bonded in a fused, bridged or spiro-bonded manner, and the nitrogen, carbon and sulfur atoms in "heteroalicyclic" or "heteroaricyclic" may be oxidized, the nitrogen may be quaternized, and the ring may also contain one or more double bonds on the condition that it does not form a completely delocalized π-electron system across all rings. Examples are 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-dihydrobenz[d]oxazole, 2,3-dihydro-1H-benz[d]imidazole, indoline, and 1,3-dihydro-2H-benz[d]imidazol-2-one, and benz[d]oxazol-2(3H)-one. The heteroaricyclic group may or may not be substituted. When substituted, the substituents are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, C-amide, N-amide, S-sulfonamide, N-sulfonamide, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and amino including mono- and disubstituted amino groups, and their protected derivatives, and can be one or more groups.Examples of such "heteroalicyclic" or "heteroaricyclic" 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, thiomorpholinyl, thiomorpholinyl sulfoxide, and thiomorpholinyl sulfone. When substituted, the substituents on the heteroaricyclic group can form an aromatic ring condensed to the heteroaricyclic group, such as aryl and heteroaryl.

[0043] "(Cycloalkyl)alkyl" is a cycloalkyl group linked as a substituent via an alkylene group. The alkylene and cycloalkyl of (cycloalkyl)alkyl may be substituted. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc. In some examples, the alkylene group is a lower alkylene group.

[0044] "(Cycloalkenyl)alkyl" is a cycloalkenyl group linked as a substituent via an alkylene group. The alkylene and cycloalkenyl of (cycloalkenyl)alkyl may be substituted. In some examples, the alkylene group is a lower alkylene group.

[0045] "(Cycloalkynyl)alkyl" is a cycloalkynyl group linked as a substituent via an alkylene group. The alkylene and cycloalkynyl of (cycloalkynyl)alkyl may be substituted. In some examples, the alkylene group is a lower alkylene group.

[0046] As used herein, "halo" or "halogen" refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).

[0047] As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoromethyl, 1,1,1,3,3,3 - hexafluoropropan - 2 - yl, 1 - chloro - 2 - fluoromethyl and 2 - fluoroisobutyl. Haloalkyl may or may not be substituted, and some embodiments relate to haloalkyl having 1 to 10 carbon atoms such as haloalkyl. 1~6 Relate to haloalkyl having 1 to 10 carbon atoms such as haloalkyl.

[0048] As used herein, "hydroxyhaloalkyl" refers to a haloalkyl group in which one or more hydrogen atoms are replaced by hydroxyl. Such hydroxyhaloalkyl groups include, but are not limited to, 1,1,1,3,3,3 - hexafluoro - 2 - hydroxypropan - 2 - yl and 1,1 - difluoro - 2 - hydroxyethyl. Hydroxyhaloalkyl can have 1 to 10 carbon atoms such as hydroxyhaloalkyl or C 1~6 Hydroxyhaloalkyl or C 1~4 Hydroxyhaloalkyl etc. can have 1 to 10 carbon atoms.

[0049] As used herein, "haloalkoxy" refers to an RO - group 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 substituted.

[0050] As used herein, the term "hydroxyalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a hydroxyl group. Such groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyhexyl. The hydroxyalkyl group may or may not be substituted, and in some embodiments, C 1~6 hydroxyalkyl or C 1~4 relates to medium-sized hydroxyalkyls having 1 to 10 carbon atoms such as hydroxyalkyl or hydroxyalkyl.

[0051] The "O-carboxy" group refers to an "RC(=O)O-" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl or (heteroaricyclic)alkyl as defined herein. O-carboxy may be substituted.

[0052] The "C-carboxy" group refers to a "-C(=O)OR" group in which R can be the same as that defined for O-carboxy. C-carboxy may be substituted.

[0053] The "trihalomethanesulfonyl" group refers to an "X3CSO2-" group in which X is halogen.

[0054] A dashed bond

Chemical formula

[0055] As used herein, a bold straight (not wedge-shaped) bond or a hashed bond [Chem.] refers to the relative stereochemistry including all possible stereoisomers at that position.

[0056] As used herein, unless otherwise indicated, a wedge-shaped bond (bold, hashed, or otherwise) [Chem.] refers to the absolute stereochemistry indicating the specific stereoisomer shown at that position.

[0057] The "nitro" group refers to the "-NO2" group.

[0058] The "cyano" group refers to the "-CN" group.

[0059] The "cyanato" group refers to the "-OCN" group.

[0060] The "isocyanato" group refers to the "-NCO" group.

[0061] The "thiocyanato" group refers to the "-SCN" group.

[0062] The "carbonyl" group refers to the "-C(=O)-" group.

[0063] The "thiocarbonyl" group refers to the "-C(=S)-" group.

[0064] The "oxo" group refers to the "=O" group.

[0065] The "hydroxy" group or "hydroxyl" group refers to the "-OH" group.

[0066] The "isothiocyanato" group refers to the "-NCS" group.

[0067] The "sulfinyl" group refers to the "-S(=O)-R" group where R can be the same as defined with respect to O-carboxy. Sulfinyl may be substituted.

[0068] The "sulfonyl" group refers to a "-SO2R-" group where R can be the same as that defined for O-carboxy. Sulfonyl may be substituted.

[0069] The "S-sulfonamide" group is R A and R B are each independently the same as that defined for the R group as defined for O-carboxy, or are combined to form a ring system selected from the group consisting of 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 cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and refers to a "-SO2NR A R B " group. S-sulfonamide may be substituted.

[0070] The "N-sulfonamide" group is R and R A are each independently the same as that defined for the R group as defined for O-carboxy, and may refer to "RSO2N(R A )-". N-sulfonamide may be substituted.

[0071] The "trihalomethanesulfonamide" group refers to an "X3CSO2N(R)-" group having X as halogen, and R can be the same as that defined for O-carboxy. Trihalomethanesulfonamide may be substituted.

[0072] The "C-amide" group is R A and R B are each independently the same as that defined for the R group as defined for O-carboxy, or are combined to form substituted or unsubstituted C 3~8 cycloalkyl, substituted or unsubstituted C3~8 Cycloalkenyl, substituted or unsubstituted C 3~8 Cycloalkyl, substituted or unsubstituted C 3~8 A ring system selected from the group consisting of cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl that can form a “-C(=O)NR A R B ” group. The C-amide may be substituted.

[0073] The “N-amide” group refers to an “RC(=O)NR A -” group in which R and R A can be the same as those defined for the R group as defined for O-carboxy. The N-amide may be substituted.

[0074] “Ester” refers to a “-C(=O)OR” group in which R can be the same as that defined for O-carboxy. The ester may be substituted.

[0075] Lower alkoxyalkyl refers to an alkoxy group linked via a lower alkylene group. Lower alkoxyalkyl may be substituted.

[0076] “Amine” or “amino” refers to “RNHRNH2” (primary amine), “R2NH” (secondary amine), “RR3N” (tertiary amine). The amino group may be substituted.

[0077] Lower aminoalkyl refers to an amino group linked via a lower alkene group. Lower aminoalkyl may be substituted.

[0078] The unsubstituted or mono-substituted amine groups in the compounds of this specification may be converted to amides using techniques well known to those skilled in the art, the hydroxyl groups may be converted to esters, and the carboxyl groups may be converted to amides or esters (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999).

[0079] As used herein, abbreviations for any protecting groups, amino acids, and other compounds, unless otherwise indicated, follow their common usage, recognized abbreviations, or those of the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11:942-944 (1972)).

[0080] 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-performance liquid chromatography Prep-HPLC Preparative high-performance liquid chromatography h Hour min Minute EA Ethyl acetate EDC·HCl 3-((Ethylimino)methylenamino)-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 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 TsCl 4-Toluenesulfonyl chloride NAS Nucleophilic aromatic substitution nBuLi n-Butyllithium iPr Isopropyl DIAD Diisopropyl azodicarboxylate Boc tert-Butyloxycarbonyl Flash CC Flash column chromatography on Overnight rt Room temperature aq Aqueous ND Not determined Cbz Carboxybenzyl Hex Hexane Hept Heptane DEA Diethylamine PE Petroleum ether DAD Diode array detector TOF Time of flight IPA Isopropanol Pg Protecting group lg Leaving group atm Atmosphere ” Enantiomerically enriched (in a specific chemical structure,” (indicating that it is enantiomerically enriched)

[0081] In any compound having one or more chiral centers disclosed herein, where the absolute stereochemistry is not explicitly indicated, it is understood that each center may independently be in the R configuration, the S configuration, or a mixture thereof. Thus, the compounds provided herein can be enantiomerically pure or a mixture of stereoisomers. Further, the compounds provided herein may be a scalemic mixture. In addition, in any compound having one or more double bonds that can be defined as E or Z, it is understood that each double bond may independently be E, Z, or a mixture thereof. Similarly, all tautomeric forms are also intended to be included.

[0082] As used herein, the term "rac" refers to "racemic", "racemate", etc., as understood by those skilled in the art. For example, a racemate contains a mixture of enantiomers of chiral molecules in equal amounts. Usually, a racemate does not exhibit optical activity.

[0083] As used herein, the term "rel" refers to the configuration of an asymmetric center that is relative to any other asymmetric center within the same compound and not absolute, as understood by those skilled in the art.

[0084] As used herein, "tautomer" and "tautomeric" refer to alternative forms of the compounds disclosed herein in which the position of a proton is different. Non-limiting examples include enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to both ring-NH- and ring=N- moieties such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0085] It is understood that isotopes can be present in the compounds described herein. Each chemical element as represented in the compound structure can include any isotope of said element. For example, in the compounds described herein, a hydrogen atom can be any isotope of hydrogen, such as, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references to a compound herein include all possible isotopic forms unless otherwise indicated clearly from the context.

[0086] As used herein, references to an element include all isotopes of that element unless otherwise specified, whether by description or chemical structure. As an example, the term "hydrogen" or "H" in a chemical structure as used herein includes, unless otherwise indicated by the use of a specific isotope, for example, 1 not only H but also deuterium ( 2 H), tritium ( 3 H) and mixtures thereof. Other specific non-limiting examples of elements that include isotopes are carbon, phosphorus, iodine and fluorine.

[0087] As used herein, "pharmaceutically acceptable salts" refer to salts of a compound that do not inhibit the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting the compounds disclosed herein with an acid or a base. Examples of salts formed with a base 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, but not limited thereto. Salts based on useful acids 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, propionate, palmitate, phosphate, sebacate, succinate, stearate, sulfate, methanesulfonate, ethanesulfonate, sulfonates such as p-toluenesulfonate, salicylate, tartrate and tosylate.

[0088] As used herein, "modulating" the activity of a receptor means 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 its natural binding partner. The natural binding partner is an endogenous molecule that is an agonist of the receptor.

[0089] An "agonist" is defined as a compound that increases the basal activity of a receptor (i.e., signal transduction mediated by the receptor).

[0090] As used herein, a "partial agonist" refers to a compound that has affinity for a receptor but, unlike an agonist, typically elicits only a weak pharmacological response associated with the receptor even when the majority of receptors are occupied by the compound when it binds to the receptor.

[0091] An "inverse agonist" is defined as a compound that reduces or suppresses the basal activity of a receptor such that, technically, it is not an antagonist but rather an agonist with negative intrinsic activity.

[0092] As used herein, an "antagonist" refers to a compound that forms a complex that does not cause any reaction upon binding to a receptor as if the receptor were unoccupied. An antagonist attenuates the action of an agonist on the receptor. An antagonist can bind reversibly or irreversibly and effectively abolish the activity of the receptor until the antagonist is metabolized or dissociates, or is removed by a physical or biological process, permanently or at least until then.

[0093] As used herein, a "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include 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.

[0094] As used herein, a "patient" refers to a subject being treated by a medical practitioner such as an M.D. or D.V.M. in order to cure a particular disease or disorder or at least improve its effects, or to prevent the disease or disorder from occurring in the first place.

[0095] As used herein, "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 the cells or tissues of interest.

[0096] As used herein, "diluent" refers to a component in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent can be used to increase the bulk of a potent drug that is too small in mass for manufacture or administration. It can 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 phosphate buffered saline, which mimics the composition of human blood.

[0097] As used herein, "excipient" refers to an inert substance that is added to a pharmaceutical composition to impart to the composition, among other things, bulk, consistency, stability, binding ability, lubricity, disintegrating ability, etc. A "diluent" is a type of excipient.

[0098] "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 includes an extracellular domain having ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and an intracellular domain that generates a cellular signal ( "signal transduction") in response to ligand binding. A receptor also includes any intracellular molecule that generates a signal in response to binding. A receptor also includes any molecule that has the characteristic structure of a receptor but does not have an identifiable ligand. In addition, a receptor includes any molecule that includes a cleaved, modified, mutated receptor, or a partial or all of the sequence of a receptor.

[0099] "Ligand" is intended to include any substance that interacts with a receptor.

[0100] "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 little or no response from other receptor types. "Selective" or "selectivity" for one or more particular subtypes of a compound means the ability of the compound to increase the activity of that subtype while producing little, hardly any or no increase in the activity of other subtypes.

[0101] 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 means the simultaneous delivery of separate agents, the simultaneous delivery of a mixture of agents, and the delivery of a second or additional agent after the delivery of one agent. The agents to be co-administered are usually intended to act in relation to each other.

[0102] As used herein, the term "effective amount" means the amount of an active compound or pharmaceutical that elicits a biological or medical response (including reduction or alleviation of symptoms of the disease being treated) in a tissue, system, animal or human, as determined by a researcher, veterinarian, medical doctor or other clinician.

[0103] As used herein, "prevent / preventing" should not be construed to mean that a condition and / or disease will never occur again after use of a compound or pharmaceutical composition according to the embodiments disclosed herein to achieve prevention. Further, this term should not be construed to mean that the condition will not occur at least to some extent after such use for preventing the condition. Rather, "prevent / preventing" is intended to mean that, if it occurs despite such use, the condition to be prevented will be less severe than if such use had not been made.

[0104] Compound In one embodiment, the compound of formula (I) of the present disclosure

Chemical formula

[0105] In some embodiments disclosed herein, R is hydrogen. In some embodiments disclosed herein, R is C 1~6 alkyl. In some embodiments disclosed herein, R is C 1~4 hydroxyalkyl.

[0106] In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F and -CHF2; and R 0b is selected from the group consisting of hydrogen, C 1~4 alkyl, C 1~4 hydroxyalkyl and C 1~4 haloalkyl. In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl, -CH2OH and -CH2CH2OH. In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl and -CH2OH. In some embodiments disclosed herein, R 0a is hydrogen. In some embodiments disclosed herein, R 0a is methyl. In some embodiments disclosed herein, R 0a is -CH2OH. In some embodiments disclosed herein, R 0b is hydrogen. In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, and R 0b is hydrogen.

[0107] In some embodiments disclosed herein, R 1a R 1bAnd at least one of R2 is not hydrogen. In some embodiments disclosed herein, R 1a is hydrogen. In some embodiments disclosed herein, R 1a is hydroxyl, halogen or C 1~4 haloalkyl. In some embodiments disclosed herein, R 1a is hydroxyl or halogen. In some embodiments disclosed herein, R 1a is hydroxyl. In some embodiments disclosed herein, R 1a is halogen. In some embodiments disclosed herein, R 1a is fluoro. In some embodiments disclosed herein, R 1a is C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments disclosed herein, R 1a is C 1~4 alkyl. In some embodiments disclosed herein, R 1a is C 1~4 haloalkyl. In some embodiments disclosed herein, R 1a is -CF3. In some embodiments disclosed herein, R 1b is selected from the group consisting of hydrogen, halogen and C 1~4 alkyl. In some embodiments disclosed herein, R 1b is selected from the group consisting of hydrogen, fluoro and methyl. In some embodiments disclosed herein, R 1b is hydrogen. In some embodiments disclosed herein, R 1b is fluoro. In some embodiments disclosed herein, R 1b is methyl. In some embodiments disclosed herein, R 1a is selected from the group consisting of hydroxyl, fluoro and -CF3, and R 1b is selected from the group consisting of hydrogen, fluoro and methyl.

[0108] In some embodiments disclosed herein, R2 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, methyl, ethyl, -CH2OH, -CH2CH2OH, and -C(=O)O-C 1~2 alkyl. In some embodiments disclosed herein, R2 is selected from the group consisting of hydrogen, fluoro, and hydroxyl. In some embodiments disclosed herein, R2 is hydroxyl or fluoro. In some embodiments disclosed herein, R2 is hydrogen. In some embodiments disclosed herein, R2 is hydroxyl. In some embodiments disclosed herein, R2 is cyano.

[0109] In some embodiments disclosed herein, R3 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, and cyclobutyl. In some embodiments disclosed herein, R3 is methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments disclosed herein, R3 is ethyl or cyclopropyl. In some embodiments disclosed herein, R3 is methyl. In some embodiments disclosed herein, R3 is ethyl. In some embodiments disclosed herein, R3 is isopropyl. In some embodiments disclosed herein, R3 is cyclopropyl.

[0110] In some embodiments disclosed herein, R4 is hydrogen or C 1~4 alkyl. In some embodiments disclosed herein, R4 is hydrogen. In some embodiments, R4 is C 1~4 alkyl. In some embodiments disclosed herein, R4 is methyl.

[0111] In some embodiments disclosed herein, R5 is absent, hydrogen, or C 1~4is alkyl. In some embodiments disclosed herein, R5 is absent. In some embodiments disclosed herein, R5 is hydrogen. In some embodiments disclosed herein, R5 is C 1~4 is alkyl. In some embodiments disclosed herein, R5 is methyl.

[0112] In some embodiments disclosed herein, R4 and R5 are independently hydrogen or methyl. In some embodiments disclosed herein, R4 and R5 are hydrogen. In some embodiments disclosed herein, R4 and R5 are methyl.

[0113] In some embodiments, R 3 and R 4 together with the atoms to which they are attached form a 4- to 6-membered heteroalicyclic ring. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is selected from the group consisting of 4-membered heteroaricyclic, 5-membered heteroaricyclic and 6-membered heteroaricyclic. In some embodiments disclosed herein, R3 and R4 together with the atoms to which they are attached form a 4-membered heteroaricyclic. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a 5-membered heteroaricyclic. In some embodiments, R3 and R4 together with the carbon atom to which they are attached form a 6-membered heteroaricyclic. In some embodiments disclosed herein, the heteroalicyclic ring system is unsubstituted. In some embodiments disclosed herein, the heteroalicyclic ring system may be substituted with one or two substituents selected from halogen, hydroxyl and C 1~4 alkyl. In some embodiments disclosed herein, the heteroalicyclic ring system is substituted with one or two substituents selected from halogen, hydroxyl and C 1~4 alkyl. In some embodiments disclosed herein, R 3 and R 4 together with the atoms to which they are attached form a 4- to 6-membered heteroalicyclic ring system containing a double bond, and R5 does not exist.

[0114] In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.1.0]hexanyl, where the heteroalicyclic ring system may be substituted with one or two substituents selected from halogen, hydroxyl, and C 1~4 alkyl, and when the heteroalicyclic ring system is 2-azabicyclo[3.1.0]hexanyl, R5 always does not exist. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is morpholinyl which may be substituted with one or two substituents selected from halogen and methyl, and R5 is hydrogen (provided that the heteroalicyclic ring system is not 2-azabicyclo[3.1.0]hexanyl). In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is unsubstituted morpholinyl.

[0115] In some embodiments disclosed herein, R6 is selected from the group consisting of hydrogen, halogen, C 1~4 haloalkyl, C 1~6 hydroxyhaloalkyl, C 1~4 haloalkoxy, C 1~4 hydroxyalkyl, and C 1~4 5-membered heteroaryl optionally substituted with alkyl. In some embodiments disclosed herein, R6 is hydrogen, halogen, -CF3, -CHF 2、-CCH3F2, -OCF3, -OCHF2, -C(CF3)2OH, and a 5-membered heteroaryl optionally substituted with one or two methyl groups. In some embodiments disclosed herein, R6 is -CF3, or a pyrazole optionally substituted with one methyl group. In some embodiments disclosed herein, R6 is -CF3. In some embodiments disclosed herein, R6 is unsubstituted pyrazole. In some embodiments disclosed herein, R6 is a pyrazole substituted with one methyl.

[0116] In some embodiments disclosed herein, R7 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -CF3, -OCHF2, -CHF2, and -OCF3. In some embodiments disclosed herein, R7 is selected from the group consisting of hydrogen, fluoro, -CF3, and hydroxyl. In some embodiments disclosed herein, R7 is hydrogen or fluoro. In some embodiments disclosed herein, R7 is hydrogen.

[0117] In some embodiments disclosed herein, Y1, Y2, and Y3 are -CH-; or Y1 is -N-, and Y2 and Y3 are -CH-; or Y2 is -N-, and Y1 and Y3 are -CH-; or Y3 is -N-, and Y1 and Y2 are -CH-; or Y3 is -CH-, and Y1 and Y2 are -N-. In some embodiments disclosed herein, Y1, Y2, and Y3 are -CH-. In some embodiments disclosed herein, Y1 is -N-, and Y2 and Y3 are -CH-. In some embodiments disclosed herein, Y2 is -N-, and Y1 and Y3 are -CH-. In some embodiments disclosed herein, Y3 is -N-, and Y1 and Y2 are -CH-. In some embodiments, Y3 is -CH-, and Y1 and Y2 are -N-. In some embodiments, Y1 is -CH-, and Y2 and Y3 are -CR8- (wherein each R8 is independently selected from the group consisting of hydrogen, methyl, fluoro, hydroxyl, and -CF3). In some embodiments disclosed herein, each R8 is hydrogen. In some embodiments disclosed herein, each R8 is methyl. In some embodiments disclosed herein, each R8 is -CF3. In some embodiments disclosed herein, Y2 is -N-, and Y1 and Y3 are -CH-, or Y3 is -N-, and Y1 and Y2 are -CH-.

[0118] In some embodiments disclosed herein, X is -CR9-, and R9 is hydrogen, cyano, or fluoro. In some embodiments disclosed herein, R9 is hydrogen. In some embodiments disclosed herein, R9 is fluoro. In some embodiments disclosed herein, R9 is cyano. In some embodiments disclosed herein, X is -CH-. In some embodiments disclosed herein, X is -N-.

[0119] In some embodiments disclosed herein, the compound is of formula (II), (III), (IV), or (V):

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

[0120] In some embodiments disclosed herein, Y2 and Y3 are independently -CH- or -CF-. In some embodiments disclosed herein, Y2 is -CH- and Y3 is -N-. In some embodiments disclosed herein, R 0a and R 0b are independently selected from hydrogen, methyl, and -CH2OH; R1a and R 1b is independently selected from the group consisting of hydrogen, fluoro and hydroxyl; R2 is selected from the group consisting of hydrogen, cyano and hydroxyl; R is hydrogen; X is -CR9- or -N- (wherein R9 is selected from the group consisting of hydrogen, cyano and fluoro); R3 is selected from the group consisting of methyl, ethyl, isopropyl and cyclopropyl, and R4 and R5 are independently hydrogen or R3 and R4 together with the atom to which they are attached form unsubstituted morpholinyl and R5 is H; R6 is selected from the group consisting of hydrogen, -CF3 and pyrazole (wherein pyrazole may be substituted by methyl); R7 is hydrogen; and Y1, Y2 and Y3 are -CH- or Y1 is -CH-, Y2 is -CF-, Y3 is -CH- or Y1 is -CH-, Y2 is -CH-, Y3 is -CF- or Y1 is -CH-, Y2 is -CH-, Y3 is -N- or Y1 is -CH-, Y2 is -N-, and Y3 is -CH- or Y1 is -N-, Y2 is -N-, Y3 is -CH- or Y1 is -CH-, Y2 is -C(CF3)-, Y3 is -CH-.

[0121] Certain embodiments relate to compounds, pharmaceutically acceptable salts, stereoisomers or salts of stereoisomers according to formula (II) or (III), other embodiments relate to compounds, pharmaceutically acceptable salts, stereoisomers or salts of stereoisomers according to formula (IV) or (V), in some of those embodiments, R9 is hydrogen, and in other embodiments, R9 is fluoro.

[0122] In one embodiment, the compound, salt, stereoisomer or salt of a stereoisomer of formula (I) is 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((5-Cyano-4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((5-Fluoro-4-(methyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, rel-(R)-2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoropiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoropiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-((3R*,4R*)-3-Hydroxy-4-((4-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, rel-(R)-2-(4-((4-(3-(4-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, rel-2-((3R,4R)-3-Hydroxy-4-((4-((R)-3-(3-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, rel-2-((3R,4R)-3-Hydroxy-4-((4-((S)-3-(3-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((5-Cyano-4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)propanamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)-2-methylpropanamide, 2-(4-((4-(Cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-Cyano-4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((5-Fluoro-4-(methyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acet amide, rac-2-((3R,4R)-4-((4-(Cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((5-Fluoro-4-( isoPropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((6-(Cyclopropyl(3-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-3-hydroxy-4-((6-( iso Propyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-3-hydroxy-4-((4-( isoPropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, rel-2-((3R,4R)-3-hydroxy-4-((4-( iso Propyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((6-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pi rimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-((4-cyanobenzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(ethyl(3-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-((4-(1H-Pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-((3R*,4R*)-3-Fluoro-4-((4-((S)-3-(5-(trifluoromethyl)pyridin-2-yl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, (S)-2-(4-((4-(3-(5-(trifluoromethyl)pyridin-2-yl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and rel-2-((3R,4R)-4-((4-(ethyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7 -yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide is selected from the group consisting of.

[0123] In some embodiments disclosed herein, the compound, salt, stereoisomer or salt of a stereoisomer of formula (I) is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

[0124] In some embodiments disclosed herein, the compound, salt, stereoisomer or salt of a stereoisomer of formula (I) is 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((5-Cyano-4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((5-Fluoro-4-(methyl(4-(trifluoromethyl)benzyl)a mino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(3-Hydroxy-4-((4-(3-(4-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-(3-(4-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(3-Hydroxy-4-((4-(3-(3-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((5-Cyano-4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)propanamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)-2-methylpropanamide, 2-(4-((4-(Cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-Cyano-4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((5-Fluoro-4-(methyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxy piperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((5-Fluoro-4-( iso propyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(3-(trifluoro methyl )benzyl)amino)-9H-purin-9-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(3-Hydroxy-4-((6-( iso propyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(3-Hydroxy-4-((4-( iso Propyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-((4-Cyanobenzyl)(ethyl)amino)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-((4-(1H-Pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(3-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-((4-(1H-Pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(3-Fluoro-4-((4-(3-(5-(trifluoromethyl)pyridin-2-yl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-(3-(5-(trifluoromethyl)pyridin-2-yl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-((4-(1H-Pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-((4-(1H-Pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and 2-(4-((4-(ethyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide is selected from the group consisting of.

[0125] In some embodiments disclosed herein, the compound, salt, stereoisomer or salt of a stereoisomer of formula (I) is

Chem.

Chem.

Chem.

Chem.

Chem.

[0126] In some embodiments disclosed herein, the compound, salt, stereoisomer or salt of a stereoisomer of formula (I) is 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, rel-(R)-2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoropiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(3-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-((4-(1H-Pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, rac-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, rel-2-((3R,4R)-4-((4-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, rel-2-((3R,4R)-4-((4-(cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and rel-2-((3R,4R)-4-((4-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide selected from the group consisting of.

[0127] In some embodiments disclosed herein, the compound, salt, stereoisomer or salt of a stereoisomer of formula (I) is 2-(4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidin-1-yl)acetamide, 2-(4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(3-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-((4-(1H-Pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(4-((4-((4-(1H-Pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and 2-(4-((4-(Cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide selected from the group consisting of.

[0128] In some embodiments disclosed herein, the compound, salt, stereoisomer or salt of a stereoisomer of formula (I) is

Chem.

Chem.

Chem.

[0129] In some embodiments disclosed herein, the compound, salt, stereoisomer or salt of a stereoisomer of formula (I) is

Chem.

Chem.

[0130] In some embodiments, when a halogen is specified as a substituent, the halogen is always selected from fluoro or chloro.

[0131] The embodiments and specific disclosures used herein are for explaining different options of the present disclosure, and the embodiments can be combined with other applicable embodiments.

[0132] Specific examples of the compound are disclosed in Table 1 below.

[0133] [Table 1]

[0134] [Table 2]

[0135] [Table 3]

[0136] [Table 4]

[0137] [Table 5]

[0138] [Table 6]

[0139] [Table 7]

[0140]

Table 8

[0141]

Table 9

[0142]

Table 10

[0143]

Table 11

[0144]

Table 12

[0145]

Table 13

[0146]

Table 14

[0147]

Table 15

[0148] In related aspects, prodrugs of the compounds of formula (I) as described herein are provided.

[0149] The compounds of the present disclosure are active and have, for example, an RORγ Gal4 < 1000 nM, for example, < 500 nM, for example, < 100 nM, etc., and have a substantially lower logP (a decreased logP of 1.5, for example, 2.0, for example, 2.5 log units, etc.) than the compounds disclosed in International Publication No. WO 2016 / 020288 pamphlet and International Publication No. WO 2016 / 020295 pamphlet. In certain embodiments, LogD and LogP are substantially lower than the compounds in International Publication No. WO 2016 / 020288 pamphlet and International Publication No. WO 2016 / 020295 pamphlet. Accordingly, the compounds disclosed herein have improved lipophilicity at similar potencies. Accordingly, the compounds disclosed herein may be improved regulators of RORγ, for example, attractive interactions (e.g., higher binding ability) to the hydrophobic binding site of the ligand binding domain (LBD) of RORγ and have a low logP and / or a low LogD.

[0150] 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 substance and coating aid, or a combination thereof; and a compound disclosed herein, for example, a compound of formula (I), (II), (III) and (IV) disclosed herein, or a salt, stereoisomer, or salt of a stereoisomer thereof. The compounds of formula (I), (II), (III) and (IV) contained in the pharmaceutical composition may also be any of the compounds of the above 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 substance and coating aid, or a combination thereof; and a compound of any one of formulas I, II, III and IV disclosed herein. Acceptable carriers or diluents, as well as other additives, combined with one or more of the compounds of formulas I, II, III and IV disclosed herein for providing a pharmaceutical composition for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990). This document is hereby incorporated by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavorings, flavor correctors, etc. 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 aliphatic alcohols, etc. may be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium aluminometasilicate, synthetic aluminum silicate, calcium carbonate, sodium bicarbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, etc. may be used as excipients; magnesium stearate, talc, hardened oil, etc. may be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean oil may be used as suspending agents or lubricants; cellulose acetate phthalate as a derivative of carbohydrates such as cellulose or sugar, or methyl methacrylate copolymer as a derivative of polyvinyl may be used as a suspending agent; plasticizers such as phthalic esters may be used as suspending agents.

[0151] The term "pharmaceutical composition" refers to a mixture of the compounds disclosed herein with other chemical components such as diluents or carriers. Pharmaceutical compositions facilitate the administration of the compounds to a living body. Many techniques for administering the compounds exist in the art, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting the compounds with inorganic acids or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Similarly, pharmaceutical compositions can also be obtained by reacting the compounds with inorganic bases or organic bases such as ammonia, sodium carbonate, sodium bicarbonate, sodium hydroxide, etc.

[0152] The term "carrier" defines a chemical substance 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 because it facilitates the uptake of many organic compounds into cells or tissues of a living body.

[0153] The term "diluent" defines a chemical substance diluted in water that dissolves the compound of interest and stabilizes the biologically active form of the compound. Salts dissolved in buffer solutions are utilized as diluents in the art. One commonly used buffer solution is phosphate buffered saline to mimic the salt conditions of human blood. Since the salts of the buffer can control the pH of the solution at low concentrations, buffered diluents rarely modify the biological activity of the compound.

[0154] The term "physiologically acceptable" defines a carrier or diluent that does not inhibit the biological activity and properties of the compound.

[0155] The pharmaceutical compositions described herein can be administered to human patients, either alone or as pharmaceutical compositions mixed with other active ingredients, or suitable carriers or excipients in the case of combination therapy. The techniques of formulation and administration of the compounds of the present application can be found in "Remington’s Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0156] Suitable routes of administration can include, for example, oral, rectal, transmucosal, topical, or enteral administration; parenteral delivery including intramuscular, subcutaneous, intravenous, intramedullary injection, and intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection. The compounds can also be administered in sustained release or controlled release dosage forms for long-term and / or periodic pulsed administration at a predetermined rate, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like.

[0157] The pharmaceutical compositions can be manufactured in a manner known per se, for example, by conventional mixing, dissolving, granulating, sugar coating, micronizing, emulsifying, encapsulating, entrapping, or tablet-forming processes.

[0158] The pharmaceutical compositions for use described herein can be formulated in conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries that facilitate the processing of the active compound into a pharmaceutical formulation that can be used pharmaceutically. Suitable formulations depend on the chosen route of administration. Any well-known techniques, carriers, and excipients can be used as appropriate and as understood in the art, for example, as in Remington’s Pharmaceutical Sciences above.

[0159] Injections can be prepared in conventional forms as either a liquid solution or suspension, a solid form suitable for solution or suspension in a liquid prior to injection, or an emulsion. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, etc. In addition, if necessary, the pharmaceutical composition for injection 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 saline buffer. If necessary, absorption-promoting formulations (e.g., liposomes) may be utilized.

[0160] For transmucosal administration, suitable penetration enhancers for permeating the barrier can be used in the formulation.

[0161] For example, pharmaceutical formulations for parenteral administration by bolus injection or continuous infusion include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active compound can be prepared as suitable 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 may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions. Injectable formulations can be provided in unit dosage forms (for example, ampoules or multi-dose containers) with added preservatives. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form before use, for compositions with a suitable vehicle, for example, sterile pyrogen-free water.

[0162] For oral administration, the compounds can be readily formulated by combining the active compound with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by a 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 mixture of granules, after adding suitable auxiliaries if necessary, to obtain tablets or dragee cores. Suitable excipients include, in particular, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate can be added if required. 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 solvents, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings to characterize the identity or different combinations of the active compound dosage. 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 solvents, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings to characterize the identity or different combinations of the active compound dosage.

[0163] Examples of pharmaceutical preparations for oral use 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 may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer may be added. All formulations for oral administration should be in dosage amounts suitable for such administration.

[0164] For buccal administration, the composition can be in the form of tablets or dragees formulated in a conventional manner.

[0165] For administration by inhalation, the compounds for use as described herein are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0166] Furthermore, various pharmaceutical compositions well known in the pharmaceutical art for use including intraocular, intranasal, and auricular delivery are disclosed herein. Suitable penetration enhancers for these uses are generally known in the art. Topical ophthalmic compositions can be formulated as aqueous solutions buffered at a pH of 5.0 to 8.0. Other components that may be desirable for use in ophthalmic preparations include preservatives (benzalkonium chloride, stabilized oxychloro complex sold as Purite™, or stabilized chlorine dioxide), co-solvents (polysorbates 20, 60, and 80, Pluronic® F-68, F-84, and P-103, cyclodextrin, or Solutol, etc.) and viscosity increasing agents (polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, or hydroxypropyl cellulose). The compounds disclosed herein can also be used in intraocular implants as described in U.S. Patent No. 7,931,909, which is 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 (Shedden et al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayer et al., Ophthalmologica, 210(2):101-3 (1996)); ophthalmic ointments; microparticles, small polymeric particles containing drugs suspended in a liquid carrier medium (Joshi, A., J. Ocul. Pharmacol., 10(1):29-45 (1994)), lipophilic formulations (Alm et al., Prog. Clin. Biol. Res., 312:447-58 (1989)), and ophthalmic suspensions such as microspheres (Mordenti, Toxicol. Sci., 52(1):101-6 (1999)); as well as ocular 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 to be sterile and isotonic, and buffered for stability and comfort.Pharmaceutical compositions for nasal delivery may also include droplets and sprays, often formulated to simulate nasal secretions in many respects to ensure maintenance of normal ciliary action. As disclosed in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990) (which is incorporated herein by reference in its entirety) and well known 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 an antibacterial preservative and a suitable drug stabilizer. Pharmaceutical formulations for auricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such otic formulations include glycerin and water.

[0167] The compounds disclosed herein may also be formulated into rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

[0168] In addition to the formulations described above, the compounds may also be formulated as depot formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin or may be formulated as a poorly soluble derivative, e.g., a poorly soluble salt.

[0169] For hydrophobic compounds, suitable pharmaceutical carriers can be cosolvent systems comprising benzyl alcohol, nonpolar surfactants, water-miscible organic polymers, 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% nonpolar surfactant polysorbate 80(trademark), and 65 w / v% polyethylene glycol 300 made up to volume with absolute ethanol. Of course, the proportions of the cosolvent system can be varied significantly without destroying its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components can be changed: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80(trademark); the fraction size of the polyethylene glycol may be varied; other biocompatible polymers may replace the polyethylene glycol, for example, polyvinylpyrrolidone; and other sugars or polysaccharides may replace the dextrose.

[0170] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be utilized. Liposomes and emulsions are well-known examples of delivery media or carriers for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide can also be utilized. Furthermore, the compounds can be delivered using sustained release systems such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. A variety of sustained release materials have been established and are well-known to those skilled in the art. Sustained release capsules can release the compound for periods of 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 utilized.

[0171] Agents intended to be administered intracellularly can be administered using techniques well known to those skilled in the art. For example, such agents can be encapsulated in liposomes. All molecules present in an aqueous solution during liposome formation are incorporated into the aqueous interior. The contents of the liposomes are protected from the external microenvironment and efficiently delivered to the cytoplasm as the liposomes fuse with the cell membrane. 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 into the cell.

[0172] Additional therapeutic or diagnostic agents can be incorporated into a pharmaceutical composition. Alternatively or in addition, the pharmaceutical composition can be combined with other compositions containing other therapeutic or diagnostic agents.

[0173] Combination The compounds disclosed herein may also be combined with other active compounds in the treatment and / or prevention of inflammatory, metabolic, tumor and autoimmune diseases or disorders or symptoms thereof.

[0174] The combinations provided herein are the compounds disclosed herein, as well as a) corticosteroids, such as prednisone, methylprednisolone or betamethasone; b) immunosuppressants, such as cyclosporine, tacrolimus methotrexate, hydroxyurea, mycophenolate mofetil, mycophenolic acid, sulfasalazine, 6-thioguanine or azathioprine; c) fumaric acid esters, such as 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 agents, such as lenalidomide, pomalidomide, pembrolizumab, nivolumab, daratumumab, bortezomib, carfilzomib, ixazomib, bendamustine or ventoclast; j) T cell blockers, 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, such as 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, such as canakinumab; p) IL-alpha blockers, such as belmekizumab; q) CD6 blockers, such as itolizumab; r) IL-36 blockers, such as BI-655130 or bimekizumab; s) IL-6 antagonists, such as tocilizumab; t) Calcineurin inhibitors, such as pimecrolimus, tacrolimus or cyclosporine; u) Phototherapy agents commonly used in phototherapy, such as psoralen, methoxypsoralen or 5-methoxypsoralen + UVA (PUVA), or treatment with UVB (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) one or more additional active substances such as one or more agents selected from the group consisting of BMS986165, PF-06700841, PF-06826647, picridinosone, tepiramide 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, milikizumab, CD20 antagonist, salicylic acid, coal tar, Mical-1, DUR-928, AM-001, BMX-010, TA-102, SNA-125, brepositnib tosylate, pegcanratinib, ESR-114, NP-000888, SM-04755, BOS-475, SB-414, LEO-134310, CBS-3595, PF-06763809, XCUR-17 and BTX-1308, etc.

[0175] The active compounds in the combination, namely, the compounds disclosed herein, and other optional active compounds may be administered together in the same pharmaceutical composition, or in separate, simultaneous, combined or sequential administrations by the same or different routes, in different compositions intended for such administrations.

[0176] Use The compounds or pharmaceutical compositions disclosed in the present specification 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 in B. Fauber and S. Magnuson, J. Med. Chem., February 6, 2014, and (Pandya et al, J. Med. Chem. 2018, 61, 24, 10976 - 10995), and these documents are hereby incorporated by reference in their entirety. Examples of RORγ receptors are the RORγ1 and RORγt receptors. The compounds or pharmaceutical compositions as described above can also exhibit selective modulation of specific ROR receptors with respect to different ROR receptors. For example, according to some embodiments disclosed herein, some compounds or pharmaceutical compositions modulate the activity of the RORγ receptor to a greater extent than they modulate the activity of the RORα and / or RORβ receptors.

[0177] The compounds or pharmaceutical compositions disclosed in the present specification can also be used to modulate 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 in the present specification can also be used to inhibit RORγt function upon IL-23 stimulation and then negatively affect the differentiation and proliferation of pathogenic Tc17 and Th17.

[0178] Papers providing useful background technical information are Arthritis & Rheumatism, 2014, 66, 579 - 588; Curr Top Microbial Immun, 2014, 378, 171 - 182; Drug Disc. Today, 2014, May; Nature Rev. Drug Disc. 2012, 11, 763 - 776, and Nature Rev. Drug Disc., 2014, 13, 197 - 216, and all of these documents are hereby incorporated by reference in their entirety.

[0179] This specification and the compounds or pharmaceutical compositions as described above may also be used in therapy, or may be used to treat inflammatory, metabolic, tumor and autoimmune diseases or disorders or symptoms thereof. Examples of such diseases or disorders are inflammatory, metabolic, tumor 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 Immunity 2007, 26(5), 643-654; Nat. Rev. Immunol. 2006, 6, 205-217; J. Immunol. 2009, 183, 7169-7177; Brain Pathol. 2004, 14, 164-174; Brain 2007, 130, 1089-1104; and Nat Rev. Immunol. 2008, 8, 183-192, all of which are incorporated herein by reference in their entirety.

[0180] More specific examples of the disease or disorder, 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, pemphigus, hidradenitis suppurativa, adiposis, fatty hepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ophthalmic diseases, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, insulin resistance induced by obesity, type II diabetes, and cancer.

[0181] More preferably, the disease or disorder, or its symptoms, include 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.

[0182] Examples of symptoms are physical or mental characteristics that are considered to indicate the state of a disease, particularly such characteristics that are apparent to the patient; for example, treating or preventing a symptom is not considered to modulate the disease, but rather to prevent or alleviate one or more symptoms commonly experienced in connection with such a disease.

[0183] More specifically, compounds or pharmaceutical compositions having an antagonist or inverse agonist effect against RORγ may be used to reduce the levels of IL-17A and / or other gene products such as interleukins and cytokines, and to control RORγ. For example, this may be in subjects suffering from, 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 disease, hidradenitis suppurativa, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ophthalmic diseases, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, insulin resistance induced by obesity and type II diabetes.

[0184] Conversely, a compound or pharmaceutical composition having an agonist effect on RORγ may be used to increase the level of IL-17A. Increasing the level of IL-17A may be particularly useful for boosting the immune response in a state of reduced immune function or, for example, during infection and cancer.

[0185] The compounds described herein can be used in the manufacture of medicaments for the treatment and / or prevention of inflammatory, metabolic, tumor and autoimmune diseases or disorders or symptoms thereof.

[0186] Route of administration The compound or pharmaceutical composition can be administered to a patient by any suitable means. Non-limiting examples of methods of administration include, inter alia, (a) administration via the oral route (this administration includes administration in capsules, tablets, granules, sprays, syrups, or other such forms), as considered appropriate by those skilled in the art for contacting the compounds disclosed herein with living tissue; (b) administration by parenteral routes such as rectal, vaginal, intraurethral, intraocular, intranasal, or intratympanic (this administration includes administration as aqueous suspensions, oily preparations, etc., or as drops, sprays, suppositories, medicated dressings, ointments, etc.); (c) administration by subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intra-articular, intraspinal, intrasternal injection, etc. (including infusion pump delivery); (d) local administration such as direct injection in the kidney or heart area, for example depot implantation, intratumoral injection or intranodal injection; (e) topical administration; and (f) administration to cells ex vivo followed by insertion of said cells into the patient.

[0187] A pharmaceutical composition suitable for administration includes a composition in which the active ingredient is contained in an amount effective to achieve its intended purpose. The therapeutically effective amount of the compounds disclosed herein required as a dosage will depend on the route of administration, the type of animal being treated (including mammals such as humans), and the physical characteristics of the particular animal under consideration. The dosage can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concurrent drug therapy and other factors that will be recognized by those skilled in the medical art. More specifically, a therapeutically effective amount means an amount of the compound effective to prevent, alleviate or reverse the symptoms of the disease in the subject being treated or to extend survival. Determination of a therapeutically effective amount is well within the ability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0188] As will be readily apparent to those skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending on the age, body weight and mammalian species being treated, the particular compound utilized, and the particular use for which these compounds are utilized. Determination of an effective dosage level, i.e., the dosage level required to achieve the desired result, can be accomplished by those skilled in the art using conventional pharmacological methods. Usually, human clinical application of a product is initiated at a relatively low dosage level and the dosage level is increased until the desired effect is achieved. Alternatively, acceptable in vitro tests can be used to establish the useful dosages and routes of administration of the compositions identified by the methods herein using established pharmacological methods.

[0189] In non-human animal testing, the application of a promising product is initiated at a relatively high dosage level and the dosage is decreased until the desired effect is no longer obtained or adverse side effects disappear. The dosage can range widely depending on the desired effect and therapeutic index.

[0190] Typically, the dosage 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, the dosage can be calculated based on and according to the surface area of the patient, as understood by those skilled in the art.

[0191] The exact formulation, route of administration and dosage of the pharmaceutical compositions disclosed herein can be selected by the individual physician in view of the patient's condition (see, for example, Fingl et al. 1975, “The Pharmacological Basis of Therapeutics”, especially, see p. 1 of Ch. 1. This document is hereby incorporated by reference in its entirety). Typically, the dosage range of the composition administered to the patient can be about 0.5 to 1000 mg / kg of the patient's body weight. The dosage can be a single dose, as required by the patient, or a series of two or more doses administered over one or more days. When the human dosage of the compound has been established for at least some conditions, the same dosage, or a dosage between about 0.1% and about 500% of the established human dosage, more preferably between about 25% and about 250% can be used. In the case of newly discovered pharmaceutical compounds, when the human dosage has not been established, as determined by toxicity and efficacy tests in animals, the ED 50 or ID 50 value, or a suitable human dosage can be inferred from other appropriate values obtained from in vitro or in vivo tests.

[0192] It should be noted that attending physicians will likely know the methods and timing for suspending, interrupting, or adjusting administration due to toxicity or organ damage. Conversely, attending physicians will also likely know to adjust treatment to a higher level if the clinical response is insufficient (excluding toxicity). The dosage scale administered in the management of the target disorder will vary depending on the severity of the condition being treated and the route of administration. The severity of the condition can be partially evaluated, for example, by standard prognostic assessment methods. Additionally, the dosage and perhaps the dosing frequency will also vary depending on the age, weight, and response of the individual patient. A program equivalent to the above may be used in veterinary medicine.

[0193] The exact dosage will be determined for each drug, but in most cases, some generalizations regarding dosage can be made. A daily dosing schedule for adult human patients can be, for example, an oral dose between 0.1 mg and 2000 mg, preferably between 1 mg and 500 mg, for example, between 5 and 200 mg of each active ingredient. The eye drops can be in a concentration range between 0.005% and 5%. In one embodiment, the eye drops can be in the range between 0.01% and 1%, or in another embodiment, between 0.01% and 0.3%. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, for example, between 1 and 40 mg of each active ingredient is used. In the case of administration of a pharmaceutically acceptable salt, the dosage can be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times a day. Alternatively, the compositions disclosed herein may preferably be administered by continuous intravenous infusion at a dosage of up to 1000 mg of each active ingredient per day. As will be understood by those skilled in the art, in certain situations, particularly for effectively and aggressively treating aggressive diseases or infections, it may be necessary to administer the compounds disclosed herein in amounts exceeding the above preferred dosage ranges or frequencies, or far exceeding them. In some embodiments, the compounds will be administered for a period of continuous therapy, for example, for more than one week, or for one month or one year.

[0194] The dosage and dosing interval can be adjusted individually to provide a plasma or tissue level 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 the individual characteristics and route of administration. However, plasma concentrations may be determined using an HPLC assay or a bioassay.

[0195] The dosing interval can also be determined using the MEC value. The composition should be administered using a regimen that maintains plasma levels above the MEC for between 10% and 90% of that time, preferably between 30% and 90%, and most preferably between 50% and 90%.

[0196] In the case of topical or ex vivo administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0197] The amount of the composition to be administered can depend on the subject being treated, the subject's weight, the severity of the pain, the mode of administration, and the judgment of the prescribing physician.

[0198] The compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicity of certain compounds sharing certain chemical moieties, or a subset of compounds, can be established by determining in vitro toxicity against mammalian, preferably human cell lines such as cell lines. The results of such tests are often predictive of toxicity in mammals, or more specifically animals such as 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. For almost all classes of conditions including, but not limited to, cancer, cardiovascular disease, and various immune dysfunctions, there are recognized in vitro models. Similarly, acceptable animal models can be used to establish the efficacy of a chemical substance for treating such conditions. When selecting a model for determining efficacy, one of ordinary skill in the art can be guided by state-of-the-art techniques for selecting an appropriate model, dose, and route of administration, as well as regulatory regimens. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0199] The composition may, if necessary, be provided in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. The pack may include, for example, a 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 a container in a form determined by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by the agency of the form of the drug for human or veterinary administration. Such notice may be, for example, a label approved by the U.S. Food and Drug Administration for a prescription drug, or an approved product insert. A composition comprising a compound disclosed herein formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0200] General Introduction As described above with respect to specific illustrative embodiments, it is not intended to 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 other than the above specific embodiments are equally possible within the scope of these appended claims.

[0201] In the claims, the term "comprising" does not exclude the presence of other species or steps. Further, individual features may be included in different claims, but these may, in some cases, be advantageously combined, and the inclusion in different claims does not mean that a combination of features is not feasible and / or not advantageous. In addition, a reference to the singular does not exclude the plural. Terms such as "a", "an", "first", "second", etc. do not exclude a plurality. The phrase "at least one" or "one or more" refers to one or a number greater than one, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0202] When a chemical name or structure is given, it has always been generated using conventional means or suitable software means. The names for the compounds were generated by ChemDraw Professional, version 17.1.0.105(19).

[0203] In the present disclosure, in the diagrams of structures, the labels "or1", "or2", "&1" or "&2" for each stereocenter specify the "stereochemical group" to which the center belongs.

[0204] In the case of the "or" group, its meaning is a structure representing one stereoisomer having the "stereochemical group" (e.g., (R, S)) as depicted or a stereoisomer having the opposite configuration (S, R) at the asymmetric center of the group.

[0205] In the case of the "ampersand" (&) radical, the & combined with a given number (e.g., &1) represents a mixture of marked asymmetrically substituted atoms. When numbering brings together several asymmetrically substituted atoms, this indicates their configurations relative to one another. When they are designated as (R,S), the opposite configuration (S,R) also exists with respect to the specified paired radicals.

[0206] In the present disclosure, the symbol " indicates that it is enantiomerically enriched. A compound or intermediate synthesized by a method that does not perform chiral separation and is enantiomerically enriched is ” indicated by.

Examples

[0207] Experiment The following examples are merely illustrative and should in no way be construed as limiting the scope of the present disclosure. Rather, the present disclosure is limited only by the appended claims.

[0208] General chemical procedures Overview Unless otherwise specified, starting materials were obtained from commercial manufacturers such as (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 used without further purification. Solvents such as DMF, DMSO and DCM were used directly or dried over molecular sieves.

[0209] Equipment NMR 1 1H 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), Varian VNMR spectrometer (400 MHz) using CD3OD, CDCl3 or DMSO-d6 solvents. Chemical shifts are reported in ppm (δ) using the residual solvent as an internal standard; CDCl3: 7.26 ppm; CD3OD: 3.31; DMSO-d6: 2.50 ppm. Coupling constants (J) are given in Hz.

[0210] Analytical U / HPLC The following equipment was used for analytical U / HPLC. A Waters Acquity system equipped with Acquity BEH C18 (1.7 μm, 2.1×50 mm) with a linear gradient of a two-component solvent system using DAD at a flow rate of 0.5 mL / min and ambient temperature, combined with MS detection SQD I. An Agilent Infinity I / II -TOF6230B / CLND Antek 8060 equipped with Acquity BEH C18 (1.7 μm, 2.1×50 mm) with a linear gradient of a two-component solvent system using a flow rate of 0.75 mL / min in combination with DAD. An Agilent 1200 series - 1260 Infinity equipped with Waters XBridge C18 (5 μm, 4.6×50 mm) with a linear gradient of a two-component solvent system using a flow rate of 1.5 mL / min and UV detection at 214 nm or 254 nm in combination with MS detection (Agilent). A Shimadzu Nexera equipped with Waters Xbridge C18 (5 μm, 4.6×50 mm) with a linear gradient of a two-component solvent system using a flow rate of 1.5 mL / min and UV detection at 214 nm or 254 nm in combination with MS detection (Shimadzu). A Waters Acquity system equipped with Acquity BEH C18 (1.7 μm, 2.1×50 mm) with a linear gradient of a two-component solvent system using DAD at a flow rate of 0.65 mL / min and ambient temperature, combined with MS detection using a Waters detector.

[0211] Preparative HPLC The following equipment was used for Prep-HPLC. A Waters Acquity system equipped with Supelco Discovery C18 (5 μm, 25 cm×21.2 mm) with a linear gradient of a two-component solvent system using a flow rate of 45 mL / min and UV detection at 254 nm in combination with MS detection on a Waters Micromass ZQ Quadrupole MS. Shimadzu Nexera X2 equipped with a Merck Chromolith SpeedROD RP-18E (5 μm, 10×100 mm) using a linear gradient of a two-component solvent system with a flow rate of 4 - 7 mL / min and UV detection at 254 nm, combined with MS detection on a Shimadzu LCMS-2020. Waters Masslynx system equipped with a Waters XBridge C18 column (5 μm, 19x150 mm) using a linear gradient of a two-component solvent system with a flow rate of 15 mL / min and UV detection at 214 nm or 254 nm, combined with MS detection (Waters). Gilson GX-281 TRILUTION equipped with a Phenomenex Gemini NX-C18 column (5 μm, 21.2x150 mm) using a linear gradient of a two-component solvent system with a flow rate of 15 mL / min and UV detection at 214 nm or 254 nm, combined with MS detection (Waters).

[0212] 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%))

[0213] Flash CC was performed most frequently on the Isolera® automated system. Flash CC and Prep-TLC were performed using SiO2, unless otherwise stated. However, C18 columns were also used (gradient of water-acetonitrile / MeOH (1:1), containing or not containing 0.1 v / v% ammonium formate in both phases, using 0–100% acetonitrile / MeOH (1:1)).

[0214] Analytical chiral chromatography Performed on a Waters UPC2 system connected to a DAD detector and a Waters QDa MS detector equipped with a chiral column with gradient elution using a flow rate of 1 mL / min. 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). The following linear gradients were 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%)

[0215] Preparative chiral chromatography Before chiral separation, the compounds were purified by standard methods previously described using an appropriate solvent.

[0216] Fractional chiral separation was carried out using Gilson (306, GX-281 trilution, 156-UV / Vis, Waters 3100 MSD) equipped with a chiral column with a solvent specified using a flow rate of 10 - 50 mL / min (50 g / min only for SCF) and detection at 214 or 230 nm, or Waters SFC-80; available chiral columns were Reprosil AMS (5 μm, 20 mm × 250 mm), Lux C2 (5 μm, 21.2 mm × 250 mm), Lux C4 (5 μm, 21.2 mm × 250 mm), Chiralpak® column IA, IB, IC, ID, IF or IG (5 μm, 20 mm × 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.

[0217] Synthesis method The compounds disclosed herein can be synthesized by one of the following nine general methods: General method K, General method L, General method P, General methods 2P-4P, General method R, General methods 2R, and General method Q.

[0218] General method K - Mitsunobu alkylation

Chemical formula

[0219] General scheme K In the Mitsunobu reaction, pyrrolopyrimidine K1 was alkylated with primary alcohol K2 using PPh3 and DIAD to form K3. Subsequently, K3 was subjected to a NAS reaction with a primary alkylamine such as DIEA or TEA (often without additional base) to generate K4. Then, K4 was alkylated with benzyl halide K5 using NaH in DMF to produce K6. Deprotection of the following Boc (HCl in dioxane or TFA) yielded K7. Then, in most cases, K7 was directly used as the corresponding pyridinium salt (HCl of TFA) in the subsequent alkylation with the corresponding 2-haloacetamide A1 and an appropriate base such as K2CO3 or DIEA to obtain K8. When K8 was a racemic mixture or a mixture of diastereomers, it was often (but not always) subjected to chiral chromatography to obtain a single stereoisomer.

[0220] Example K8-1 Synthesis of 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidin-1-yl)acetamide and chiral separation into its stereoisomers K8-1-1 and K8-1-2.

Chemical Structure

[0221] Scheme K8-1 tert-Butyl 4-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidine-1-carboxylate, K3-1.

Chemical Structure

[0222] tert-Butyl 4-((4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidine-1-carboxylate, K4-1.

Chemical Structure

[0223] tert-Butyl 4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidine-1-carboxylate, K6-1.

Chemical Structure

[0224] N-Cyclopropyl-7-((3,3-difluoropiperidin-4-yl)methyl)-N-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine HCl, K7-1. [ka] K6-1 (240 mg, 0.43 mmol) was dissolved in EA / HCl (15 mL) and then stirred at room temperature for 30 min. Concentration in vacuo gave crude K7-1, which was used without further purification. LCMS: MS calculated: 465; MS found: 466 ([M+H] + ).

[0225] 2-(4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidin-1-yl)acetamide, K8-1. [ka] K2CO3 (590 mg, 4.24 mmol) was then added to a solution of K7-1 (213 mg, 0.424 mmol) in dry DMF (20 mL), followed by 2-bromoacetamide (59 mg, 0.424 mmol). The reaction mixture was stirred at 50 °C and then quenched with H2O (30 mL). The mixture was extracted with EA (3 × 20 mL), and the combined organic phases were concentrated in vacuo. The residue was purified by flash CC (PE:EA = 1:3) to afford K8-1.

[0226] Isolation of two stereoisomers, rel-(R)-2-(4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidin-1-yl)acetamide, K8-1-1 and K8-1-2.

Chemical formula

[0227] The following compounds were synthesized according to General Method K.

[0228]

Table 16

[0229]

Table 17

[0230] General Method P:

Chemical formula

[0231] General Scheme P The aromatic nucleophilic substitution (NAS) reaction between P1 and A2 was carried out in a sealed container, often (but not always) using an additive (such as KI), at a high temperature (80 - 130 °C), in a suitable solvent (such as DMF, DMSO, EtOH, BuOH, water, etc.) and an appropriate base (such as DIEA, TEA or K2CO3, etc.) to obtain P2, or P3 (when N-Ts was N-H). Then, the Ts group was removed by using K2CO3 or NaOH at a slightly higher temperature (usually 50 °C) to obtain P3.

[0232] Subsequently, P3 was reacted with piperidine X protected with Boc, and then the Boc of P4 (used as HCl in dioxane or TFA) was deprotected to obtain P5 as a salt. P5 was usually directly used as the corresponding pyridinium salt (HCl or TFA) in the alkylation with the following A1 and a suitable base (for example, DIEA, TEA, Cs2CO3 or K2CO3) to obtain P6.

[0233] When P6 was a mixture of stereoisomers, they were often (but not always) subjected to chiral chromatography to obtain a single stereoisomer as the final product.

[0234] The A2 component was synthesized by a general method described in WO 2016 / 020288 pamphlet (pages 167 - 176) or as outlined below.

[0235] Example P6 - 1 Synthesis of rac - 2 - ((3R,4R) - 3 - hydroxy - 4 - ((4 - ((S) - 3 - (4 - (trifluoromethyl)phenyl)morpholino) - 7H - pyrrolo[2,3 - d]pyrimidin - 7 - yl)methyl)piperidin - 1 - yl)acetamide, P8 - 1, and separation of stereoisomers, P6 - 1 - 1 and P6 - 1 - 2.

Chemical formula

[0236] Scheme P6-1 (S)-4-(7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-(4-(trifluoromethyl)phenyl)morpholine, P2-1

Chemical formula

[0237] A vial was charged with (S)-3-(4-(trifluoromethyl)phenyl)morpholine, A2-4 (680 mg, 2.5 mmol), 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (0.84 mg, 2.75 mmol), KI (210 mg, 1.8 mmol), TEA (760 mg, 7.5 mmol) and H2O (10 mL). The vial was sealed and then stirred at 130 °C overnight. After cooling to room temperature, the vial was opened and extracted with EA (3 × 15 mL). The combined organic phases were then concentrated in vacuo to give crude P2-1, which was used without further purification. LCMS: MS calculated value: 502; MS measured value: 503 ([M+H] + )

[0238] (S)-4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-3-(4-(trifluoromethyl)phenyl)morpholine, P3-1.

Chemical formula

[0239] tert-Butyl (3RS,4RS)-3-hydroxy-4-((4-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1-carboxylate, P4-1.

Chemical formula

[0240] (3RS,4RS)-4-((4-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-3-ol, P5-1.

Chemical formula

[0241] 2-((3RS,4RS)-3-Hydroxy-4-((4-((S)-3-(4-(Trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, P6-1.

Chemical formula

[0242] Under N2 atmosphere, K2CO3 (88 mg, 0.64 mmol), then 1-bromoacetamide (27 mg, 0.19 mmol) were added to a suspension of crude P5-1 (110 mg) in dry DMF (4 mL). Then the reaction mixture was stirred and then quenched with H2O (40 mL). The resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were washed with H2O (40 mL) and brine (40 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Then the crude product was purified by flash CC (MeOH:DCM = 1:10) to obtain P6-1.

[0243] Isolation of two stereoisomers 2-((3R*,4R*)-3-Hydroxy-4-((4-((S)-3-(4-(Trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, P6-1-1 and P6-1-2.

Chemical formula

[0244] The following compounds were synthesized according to the general method P.

[0245]

Table 18

[0246]

Table 19

[0247]

Table 20

[0248]

Table 21

[0249]

Table 22

[0250]

Table 23

[0251]

Table 24

[0252]

Table 25

[0253]

Table 26

[0254]

Table 27

[0255]

Table 28

[0256]

Table 29

[0257]

Table 30

[0258]

Table 31

[0259]

Table 32

[0260]

Table 33

[0261]

Table 34

[0262]

Table 35

[0263]

Table 36

[0264]

Table 37

[0265]

Table 38

[0266]

Table 39

[0267] Synthesis of 4-chloro-5-fluoro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, P1-5.

Chem.

[0268] Scheme P1-5 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine, P1-2.

Chem.

[0269] 4-chloro-5-fluoro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, P1-5.

Chem.

[0270] A solution of 4-methylbenzene-1-sulfonyl chloride (840 mg, 4.41 mmol) in DCM (20 mL) was added to a suspension of 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine, P1-2 (504 mg, 2.94 mmol), and TEA (615 μL, 4.41 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature for 2 hours and then further stirred at 40 °C for 2 hours. The solvent was then removed under vacuum, and the residue was partitioned between H2O and EA. The organic layer was separated, washed with water (×2) and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was then purified by flash CC (Hex:EA = 10:0~6:4) to afford 4-chloro-5-fluoro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, P1-5. LCMS: calculated MS value: 325; measured MS value: 326 ([M - 56 + H] + )。

[0271] Synthesis of rac-tert-butyl (3R,4R)-3-hydroxy-4-((tosyloxy)methyl)piperidine-1-carboxylate, X-1.

Chemical Structure

[0272] Scheme X-1 rac-tert-butyl (3R,4R)-3-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate, iX-1-2.

Chemical Structure

[0273] rac-tert-butyl (3R,4R)-3-hydroxy-4-((tosyloxy)methyl)piperidine-1-carboxylate, X-1.

Chemical Structure

[0274] Alternatively, X-1 was synthesized as follows:

Chemical Structure

[0275] Scheme X-1b TEA (520 mg, 5.1 mmol) was added to a solution of iX-1-2 (590 mg, 2.55 mmol) in DCM (10 mL). The solution was cooled to 0 °C, and then a solution of TsCl (530 mg, 2.8 mmol) in DCM (1 mL) was added. The reaction mixture was then stirred at room temperature for 18 h, quenched with H2O (50 mL), and the resulting mixture was extracted with DCM (2 × 70 mL). The combined organic layers were washed with H2O (50 mL), brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was then purified by flash CC (EA:PE = 1:1~MeOH:DCM = 1:10) to give X-1. LCMS: MS calcd: 385; MS found: 330 ([M - 56 + H] + )。

[0276] Enantiomerically enriched rel-tert-butyl (3R,4R)-3-hydroxy-4-((tosyloxy)methyl)piperidine-1-carboxylate, X-1 ” Synthesis

Chem.

[0277] Scheme X-1 ” rel-(3R,4R)-1-benzyl-4-(hydroxymethyl)piperidin-3-ol, iX-1~4 ” :

Chem.

[0278] HPLC analysis (Chiralpak ID, gradient: 1 - 45% isopropanol (+0.2% DEA) / CO2 for 17 minutes) showed an ee of 76%.

[0279] Enantiomerically enriched rel-(3R,4R)-4-(hydroxymethyl)piperidin-3-ol, iX1-1 ” 。

Chem.

[0280] Enantiomerically enriched rel-tert-butyl (3R,4R)-3-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate, iX-1-2”

Chem.

[0281] A solution of Boc2O (7.82 g, 35.8 mmol) in DCM (20 mL) was added dropwise to a stirred and cooled (ice bath) solution of iX-1-1” (4.70 g, 35.8 mmol) in a mixture of DCM (30 mL) and MeOH (12 mL). After stirring, the mixture was evaporated and the residue was purified by flash CC (MeOH:DCM = 0~5%) to obtain iX-1-2”. MS calculated value: 231; MS measured value: 232 ([M+H]+). 1 H NMR (400 MHz, CDCl3) 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).

[0282] Enantiomerically enriched rel-tert-butyl (3R,4R)-3-hydroxy-4-((tosyloxy)methyl)piperidine-1-carboxylate, X-1”.

Chemical formula

[0283] A solution of iX-1-2” (7.96 g, 34.4 mmol) in dry pyridine (17 mL) was stirred, cooled in an ice bath, and TsCl (7.22 g, 37.9 mmol) was added portionwise over 10 minutes. The mixture was warmed to room temperature over 3 hours. Then, the mixture was diluted with DCM, washed with 1M aqueous HCl, NaHCO3 (4% aqueous solution), and brine, dried, and evaporated to give a thick yellow oil. This residue was purified by flash CC (EA:Hex = 0~60%) to obtain X-1”. MS calculated value: 385; MS measured value: 386 ([M+H]+). 11H NMR (400 MHz, CDCl3) 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 - 3.52 (m, 1H), 3.93 - 4.14 (m, 2H), 4.15 - 4.32 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.76 - 7.81 (d, J = 8.0 Hz, 2H).

[0284] tert-Butyl 4-cyano-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate, Synthesis of X-3

Chemical Structure

[0285] Scheme X-3 TEA (726 μL, 5 mmol) and MsCl (193 μL, 2.5 mmol) were sequentially added to a solution of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate, iX-3-1 (500 mg, 2 mmol) in dry DCM (20 mL), and the reaction mixture was stirred at room temperature for 2 hours. Then, additional DCM (20 mL) was added, and the organic phase was washed with H2O (30 mL) and brine (30 mL), dried (MgSO4), and concentrated in vacuo to obtain X-3. LCMS: Calculated MS value: 318; Observed MS value: 363 ([M + H] + )、263([M - 101 + H] + ).

[0286] rac-tert-Butyl (3R,4R)-3-hydroxy-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate, Synthesis of X-4

Chemical Structure

[0287] Scheme X-4 To a solution of iX-1-2 (300 mg, 1.30 mmol) and TEA (0.272 mL, 1.94 mmol) in DCM (15 mL) was added MsCl (0.110 mL, 1.42 mmol). The reaction mixture was then stirred overnight. The reaction mixture was diluted with chloroform, washed with water (×3), brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash CC (Hex:EA = 0% - 100%) to give X-4. LCMS: calculated MS value: 309; measured MS value: 310 ([M+H] + ), 210 ([M-101+H] + ).

[0288] General method 2P When R6 is a heterocyclic ring, general method 2P was also used.

Chemical formula

[0289] General scheme 2P When R6 was a heterocyclic ring, the iodo intermediate 2P6 was synthesized from the corresponding iodo-benzylamine as described in general method P, and P6 was obtained via Suzuki coupling (with Pd and boronic acid, or ester) or standard backward coupling (with Cu and nitrogen-containing heterocyclic ring).

[0290] Example P6-34” Synthesis of enantiomerically enriched rel-2-((3R,4R)-4-((4-(ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide

Chemical formula

[0291] Under an N2 atmosphere, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (43 mg, 0.21 mmol), 2 M Cs2CO3 (205 μL, 0.41 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (11 mg, 13.5 μmol) were added to a solution of 2P6-1” (75 mg, 0.14 mmol) in dioxane (2 mL). The reaction mixture was stirred at 100 °C for 4 h. Water was added, and the product was extracted with EA (×3). The combined organic layers were washed with H2O, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was then purified by flash CC (MeOH:DCM = 15:85) to give P6-34”. LCMS: Calculated MS value: 502.6; Measured MS value: 503 ([M+H] + )。

[0292] The following compounds were synthesized according to General Method 2P.

[0293]

Table 40

[0294] Example P6-36” Synthesis of enantiomerically enriched rel-2-((3R,4R)-4-((4-(ethyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide

Chemical Structure

[0295] Under an N2 atmosphere, 1H-pyrazole (18 mg, 0.26 mmol), K2CO3 (36.5 mg, 0.26 mmol), trans-1,2-cyclohexane-1,2-diamine (6.5 μL, 54 μmol), and CuI (2.5 mg, 13 μmol) were added to a solution of 2P6-2” in NMP (2 mL). The reaction mixture was stirred at 120 °C. H2O was added, and the resulting mixture was extracted with EA (×3). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was first purified by flash CC (MeOH:DCM = 15:85) and then by a C18 column (H2O:MeOH = 100:0~0:100) to obtain P6-36”. LCMS: Calculated MS value: 506.6; Measured MS value: 507 ([M+H] + )。

[0296] General method for the synthesis of alcohol from 3P-epoxide

Chemical formula

[0297] General scheme 3P In these examples, P3 was alkylated with tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate and a suitable base (such as K2CO3, TEA, DIEA, or NaH) to produce the intermediate 3P4. Then, it was deprotected with an acid (such as HCl or TFA) at room temperature in a suitable solvent to obtain 3P5, which was mostly used as the corresponding pyridinium salt (HCl or TFA) or free amine in the alkylation with the corresponding 2-bromoacetamide (A1) and a suitable base (such as TEA, DIEA, or K2CO3) to produce 3P6.

[0298] Synthesis of 2-(4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 3P6-1

Chemical formula

[0299] Scheme 3P6-1 Synthesis of tert-butyl 4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidine-1-carboxylate, 3P4-1

Chemical formula

[0300] To a solution of P3-1 (55 mg, 0.157 mmol) in dry DMF (2 mL) was added tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (38 mg, 0.178 mmol). The resulting mixture was stirred at 70 °C and then water was added to quench the reaction. The mixture was extracted with EA, and the combined organic phases were washed with water (×3), brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash CC (Hex:EA = 1:0~1:1) to give 3P4-1. LCMS: Calculated MS value: 563; Observed MS value: 564 ([M+H] + )

[0301] 4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-4-ol, 3P5-1

Chemical formula

[0302] 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 3P6-1.

Chemical formula

[0303] To a solution of 3P5-1 (45 mg, 0.097 mmol) in DCM (2 mL) were added trimethylamine (0.032 mL) and 2-bromoacetamide (16 mg). The resulting mixture was stirred at room temperature and then diluted with DCM. This diluted solution was washed with water (×3) and brine, dried (MgSO4), filtered, and concentrated in vacuo. The remaining residue was purified by flash CC (DCM:MeOH = 1:0 to 9:1) to give 3P6-1. LCMS: Calculated MS value: 520; Observed MS value: 521 ([M+H] + )。

[0304] The following compounds were synthesized according to General Method 3P.

[0305]

Table 41

[0306]

Table 42

[0307] General method: Alkylation with 4P-acetate.

Chemical formula

[0308] General scheme 4P When the R0 group is not H, the alkylation of P5 was carried out using the corresponding substituted 2-bromoacetate and a suitable base (as described above) to obtain 4P6. Subsequently, P6 was obtained by subsequent aminolysis (NH3 in MeOH).

[0309] Synthesis of rac-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, P6-37

[0310] Example P6-37

Chemical formula

[0311] Scheme P6-37 rac-Methyl 2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanoate, 4P6-1.

Chemical formula

[0312] To a solution of P5-1 (102 mg, 0.229 mmol) in dry DMF (3 mL) were added DIEA (120 μL, 0.689 mmol) and methyl 2-bromo-3-hydroxypropanoate (84 mg, 0.459 mmol). The reaction mixture was stirred overnight at room temperature. Excess DIEA (1.5 equiv) and methyl 2-bromo-3-hydroxypropanoate (1 equiv) were added and the mixture was stirred for an additional 4 h. The reaction mixture was then diluted with water and the product was extracted with EA (×3). The combined organic solutions were washed with water (×3), brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 4P6-1. LCMS: Calculated for MS: 547; Found: 548 ([M+H] + )。

[0313] rac-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, P6-37

Chem.

[0314] General method for the synthesis of diols from L-epoxides

Chem.

[0315] General Scheme L P1 was substituted with secondary amine A2 using a base suitable in water (i.e., TEA) to obtain P2. Subsequently, the tosyl group was removed by heating P2 in MeOH with K2CO3 at a slightly elevated temperature. Then, P3 was deprotonated with NaH and alkylated with epoxide L1 in DMF to produce L2. The benzyl deprotection of L2 to L3 was achieved using Pd / C and NH4HCO2 in MeOH. Subsequent Boc deprotection (HCl in dioxane or TFA) gave L4. Then, in most cases, L4 was directly used as the corresponding pyridinium salt (HCl of TFA) in the alkylation with the subsequent corresponding 2-bromoacetamide A1 and a suitable base such as K2CO3 or DIEA to obtain L5. When L5 was a mixture of stereoisomers, in many cases (but not always), they were subjected to chiral chromatography to obtain a single stereoisomer.

[0316] Example L5-1 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, synthesis of L5-1, and separation and isolation of two stereoisomers L5-1-1-1 and L5-1-1-2 are included.

Chemical formula

[0317] Scheme L5-1 N-Cyclopropyl-7-tosyl-N-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, P2-2.

Chemical formula

[0318] A vial was charged with P1-1 (4.0 g, 13.3 mmol), A2-1 (N-(4-(trifluoromethyl)benzyl)cyclopropanamine) (3.1 g, 14.3 mmol), TEA (4.0 g, 39 mmol), KI (1.1 g, 6.5 mmol) and H2O (30 mL). The vial was sealed and heated at 130 °C overnight. The reaction mixture was extracted with EA (3 × 50 mL), and the pooled organic phases were concentrated in vacuo. The residue was purified by flash CC (PE:EA = 8:1 to 5:1) to give P2-2. LCMS: calculated for MS: 486; found for MS: 487 ([M+H] + )。

[0319] N-Cyclopropyl-N-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, P3-2.

Chem.

[0320] tert-Butyl 3-(benzyloxy)-4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidine-1-carboxylate, L2-1.

Chem.

[0321] tert-Butyl 4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidine-1-carboxylate, L3-1.

Chemical Structure

[0322] Pd / C (500 mg, 10%) was added to a solution of L2-1 (680 mg, 1.0 mmol) and NH4HCO2 (1.6 g, 25.1 mmol) in MeOH. The reaction mixture was refluxed overnight. After cooling to ambient temperature, the mixture was filtered and concentrated in vacuo. The residue was purified by Prep-TLC (EA:PE = 1:1) to give L3-1. LCMS: Calculated MS value: 561; Observed MS value: 562 ([M+H] + )。

[0323] 4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-3,4-diol, L4-1.

Chemical Structure

[0324] A solution of L3-1 (320 mg, 0.57 mmol) in a mixture of TFA (0.5 mL) and DCM (8 mL) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give crude L4-1, which was used without further purification. LCMS: Calculated MS value: 461; Measured MS value: 462 ([M+H] + )

[0325] 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, synthesis of L5-1, and separation of diastereomers rac-2-((3R,4R)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, L5-1-1 and rac-2-((3R,4S)-4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, L5-1-2.

Chemical Structure

[0326] Separation of the enantiomers of L5-1-1 into rel-2-((3R,4R)-4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, L5-1-1-1 and L5-1-1-2

Chem.

[0327] L5-1-1-1, the first eluted enantiomer, and L5-1-1-2, the second eluted enantiomer.

[0328] The following compounds were synthesized according to the general method L.

[0329]

Table 43

[0330]

Table 44

[0331] Synthesis of tert-butyl 4-(benzyloxy)-1-oxa-6-azaspiro[2.5]octane-6-carboxylate, L4

Chem.

[0332] Under a N2 atmosphere, NaH (283 mg, 7.1 mmol, 60%) was added to a 0 °C solution of trimethylsulfonium iodide (1.44 g, 7.1 mmol) in dry DMF (20 mL), and the reaction mixture was stirred for 30 minutes. Then, a solution of iL4 (tert-butyl 3-(benzyloxy)-4-oxopiperidine-1-carboxylate) (1.8 g, 5.9 mmol) in dry DMF (5 mL) was slowly added, and the mixture was then stirred overnight at room temperature. The reaction was quenched with NH4Cl (50 mL of saturated aqueous solution), and the mixture was extracted with EA (3 × 15 mL). The combined organic layers were washed with brine (2 × 10 mL), dried (Na2SO4), filtered, and concentrated in vacuo to obtain crude L4, which was used without further purification. LCMS: Calculated MS value: 319; Observed MS value: 342 (M+Na) + 。

[0333] General method R. Synthesis of diols by Sharpless dihydroxylation Enantiomerically enriched R5 diols were also synthesized using Sharpless dihydroxylation.

Chemical formula

[0334] General scheme R The intermediate P3 was alkylated with a benzyl-protected piperidine R1 and the base outlined above. Then, Sharpless dihydroxylation was performed on R2 to obtain the diol R3”. These were then deprotected with hydrogen and Pd / C at room temperature in a suitable solvent. The resulting R4” was then alkylated with the corresponding 2-haloacetamide and a suitable base such as DIEA, TEA, Cs2CO3 or K2CO3 to obtain R5”. (To ensure pure products and isolate possible diastereomers) R5” was first purified by chromatography. Furthermore, the enantiomerically enriched R5” product was often (but not always) subjected to chiral resolution (by chromatography) to obtain the pure stereoisomer as the final product.

[0335] Example R5-1 Synthesis of enantiomerically enriched rel-2-((3R,4R)-4-((4-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, R5-1

Chemical formula

[0336] Scheme R5-1 1-benzyl-4-(chloromethyl)-1,2,3,6-tetrahydropyridine hydrochloride, R1

Chemical formula

[0337] N-(4-(1H-pyrazol-1-yl)benzyl)-7-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methyl)-N-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine, R2-1

Chemical formula

[0338] Enantiomerically enriched rel-(3R,4R)-4-((4-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-1-benzylpiperidine-3,4-diol, R3-1”

Chemical Structure

[0339] R2-1 (1.2 mg, 2.38 mmol) was mixed with tBuOH (20 mL) / H2O (20 mL) at 0 °C, and then the following reagents were added: potassium hexacyanoferrate(III) (2.4 g, 7.29 mmol), potassium carbonate (990 mg, 7.16 mmol), (DHQ)2PHAL (186 mg, 0.24 mmol), potassium osmate(VI) dihydrate (88 mg, 0.24 mmol), and methanesulfonamide (272 mg, 2.86 mmol). The reaction mixture was then stirred at room temperature for 2 days. Subsequently, the reaction was quenched by the addition of NaNO2 (1.64 g) and water (3 mL), and the mixture was stirred at room temperature for 1 hour. Further water was added, and the mixture was extracted with DCM (×3). The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated in vacuo. The residue was then purified by flash CC (MeOH:DCM = 1:9) to afford R3-1”. LCMS: Calculated MS value: 537.7; Measured MS value: 538 ([M+H] + ).

[0340] Enantiomerically enriched rel-(3R,4R)-4-((4-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-3,4-diol, R4-1 ”

Chemical Structure

[0341] Pd / C (10%, 30 mg) was added to a solution of R3-1” (288 mg, 0.54 mmol) in MeOH (10 mL), and the reaction mixture was stirred under H2 (18 psi) in a Parr reactor. An additional 10% Pd / C (30 mg, 0.28 mmol) was added, and the reaction mixture was stirred again under H2 (18 psi) for an additional 2 days. The mixture was filtered through Celite, and the solvent was removed in vacuo. The remaining solid R4-2” was used without further purification. LCMS: Calculated MS value: 447.5; Observed MS value: 448 ([M+H] + )。

[0342] Enantiomerically enriched rel-2-((3R,4R)-4-((4-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, R5-1 ”

Chemical Structure

[0343] K2CO3 (372 mg, 2.69 mmol) and 2-bromoacetamide (136 mg, 0.99 mmol) were sequentially added to a solution of R4-1 ” (402 mg, 0.90 mmol) in DMF (6 mL), and the reaction mixture was stirred at room temperature overnight. Then, H2O was added, and the mixture was extracted with AcOEt (×3). The combined organic layers were washed with H2O, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash CC (MeOH:DCM = 1:9) to obtain R5-1 ” to give. LCMS: Calculated MS value: 504.6; Observed MS value: 505 ([M+H] + )。

[0344] The following compounds were synthesized according to method R.

[0345]

Table 45

[0346]

Table 46

[0347] General method 2R In some cases where R6 is a heterocyclic ring, general method 2R was used.

Chemical formula

[0348] General scheme 2R 2P3 was obtained from the corresponding iodophenyl derivative as described above and then reacted with benzyl-protected piperidine R1 to obtain 2R2. Sharpless dihydroxylation was carried out to obtain enantiomerically enriched diol 2R3 ” was obtained. Then, standard backward coupling (with Cu and a nitrogen-containing heterocyclic ring) was carried out on 2R3” to obtain R3 ” was obtained. Then, as described above, R3” was converted to R5 ” by deprotection to R4 and subsequent alkylation with 2-bromoacetamide. ” was converted.

[0349] Example R5-4” Enantiomerically enriched rel-2-((3R,4R)-4-((4-(Cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, R5-4 ” Synthesis

Chemical formula

[0350] Scheme R5-4” 7-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methyl)-N-cyclopropyl-N-(2-fluoro-4-iodobenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 2R2-4

Chem.

[0351] Under N2 atmosphere, 2P3-1 (437 mg, 1.69 mmol) was added to a solution of R1 (628 mg, 1.54 mmol) and Cs2CO3 (1.5 g, 4.6 mmol) in dry DMF (15 mL). The reaction mixture was heated at 60 °C for 2 days. Water was added and the resulting mixture was extracted with EA (×3). The combined organic layers were washed with H2O, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was then purified by flash CC (MeOH:DCM = 1:9) to give 2R2-4. LCMS: MS calculated value: 593.5; MS measured value: 594 ([M+H] + )。

[0352] Enantiomerically enriched rel-(3R,4R)-1-benzyl-4-((4-(cyclopropyl(2-fluoro-4-iodobenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-3,4-diol, 2R3-4”

Chem.

[0353] 2R2-4 (430 mg, 0.72 mmol) was mixed with tBuOH (8 mL) and water (8 mL) at 0 °C. Then the following reagents were added: potassium hexacyanoferrate(III) (715 mg, 2.17 mmol), K2CO3 (300 mg, 2.17 mmol), (DHQ)2PHAL (56 mg, 0.072 mmol), potassium osmate(VI) dihydrate (27 mg, 0.073 mmol) and methanesulfonamide (83 mg, 0.87 mmol). The reaction mixture was then stirred at room temperature for 2 days. Then the reaction was quenched by the addition of NaNO2 (500 mg) and H2O (1 mL), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water, extracted with DCM (×3), and the combined organic layers were washed with water and brine, dried (MgSO4), and concentrated in vacuo. The residue was then purified by flash CC (MeOH:DCM = 1:9) to give 2R3-4”. LCMS: calculated for MS: 627.5; found for MS: 628 ([M+H] + )

[0354] Enantiomerically enriched rel-(3R,4R)-1-benzyl-4-((4-(cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-3,4-diol, R3-4”

Chemical Structure

[0355] Under an N2 atmosphere, 1H-pyrazole (47 mg, 0.70 mmol), K2CO3 (96 mg, 0.69 mmol), (1R,2R)-cyclohexane-1,2-diamine (17 mg, 0.15 mmol), and CuI (6.6 mg, 0.035 mmol) were added to a solution of 2R3-4” in NMP (5 mL). The reaction mixture was stirred at 120 °C overnight. Water was added, and the product was extracted with AcOEt (×3). The combined organic layers were washed with H2O, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was then purified by flash CC (MeOH:DCM = 1:9) to obtain R3-4”. LCMS: Calculated MS value: 567.7; Measured MS value: 568 ([M+H] + )。

[0356] Enantiomerically enriched rel-(3R,4R)-4-((4-(Cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-3,4-diol, R4-4”

Chemical formula

[0357] Enantiomerically enriched rel-2-((3R,4R)-4-((4-(Cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, R5-4” [Chemistry]

[0358] R4-4” (103 mg, 0.21 mmol) was dissolved in DMF (3 mL), and K2CO3 (90 mg, 0.65 mmol) and 2-bromoacetamide (36 mg, 0.26 mmol) were added. The reaction mixture was stirred at room temperature overnight. Then, water was added and the mixture was extracted with EA (×3). The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash CC (MeOH:DCM = 1:9) to obtain R5-4”. LCMS: calculated for MS: 534.6; found MS: 535 ([M+H] + )

[0359] The following compounds were synthesized according to Method 2R.

[0360] [Table 47]

[0361] General method Q - from left to right [Chemistry]

[0362] General scheme Q K1 was alkylated with primary halide X and Cs2CO3 or by hydroxy K2 (in Mitsunobu reaction with PPh3 and DIAD) to form Q1. Then, Q1 was subjected to NAS reaction with A2 using DIEA or TEA to generate Q2. As described above, the intermediate Q2 was then subjected to Boc deprotection to obtain Q3, followed by alkylation with 2-bromoacetamide to obtain Q4. When Q4 contains a mixture of stereoisomers, they were often (but not always) subjected to chiral chromatography to obtain a single stereoisomer.

[0363] Synthesis and isolation of 2-((3R*,4R*)-3-fluoro-4-((4-((S)-3-(5-(trifluoromethyl)pyridin-2-yl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, Q4-1-1 and Q4-1-2. [Chemical formula] a) DIAD, PPh3, DCM. b) Pd2(dba)3, Ruphos, Cs2CO3. c) Chiral separation. d) TFA, DCM. e) 2-bromoacetamide. f) K2CO3, DMF.

[0364] Scheme Q4-1 rac-tert-butyl (3R,4R)-4-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoropiperidine-1-carboxylate, Q1-1 [Chemical formula]

[0365] Under a nitrogen atmosphere, DIAD (528 mg, 2.6 mmol) was added to an ice-cooled mixture of K1-1 (370 mg, 1.6 mmol), K2-2 (200 mg, 1.30 mmol) and PPh3 (85 mg, 2.6 mmol) in DCM (15 mL). The reaction mixture was allowed to reach room temperature and then stirred at room temperature for 16 hours. H2O (100 mL) was added and the mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash CC (EA:PE = 1:5) to give Q1-1. LCMS: Calculated MS value: 368; Observed MS value: 369 ([M+H] + )

[0366] rac-tert-butyl (3R,4R)-3-fluoro-4-((4-((S)-3-(5-(trifluoromethyl)pyridin-2-yl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1-carboxylate, Q2-1

Chemical Structure

[0367] Subsequently, the following were obtained by chiral separation: Q2-1-1, the first eluting isomer, Q2-1-2, the second eluting isomer.

[0368] Synthesis of Stereoisomers 2-((3R*,4R*)-3-fluoro-4-((4-((S)-3-(5-(trifluoromethyl)pyridin-2-yl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, Q4-1-1 and Q4-1-2

Chemical Structure

[0369] Example Q4-1-1 Q2-1-1 (6 mg, 11 μmol) was dissolved in DCM (3 mL), and then TFA (0.5 mL) was added. After stirring at room temperature for 2 hours, the solution was concentrated in vacuo to afford a brown oil. This oil was added to a mixture of 2-bromoacetamide (1.5 mg, 16 μmol) and K2CO3 in DMF (3 mL), and the reaction mixture was stirred at 50 °C for 16 hours. Purification by preparative HPLC gave Q4-1-1.

[0370] Example Q4-1-2 Q2-1-2 (6 mg, 11 μmol) was dissolved in DCM (3 mL), and then TFA (0.5 mL) was added. After stirring at room temperature for 2 hours, the solution was concentrated in vacuo to afford a brown oil. This oil was added to a mixture of 2-bromoacetamide (1.5 mg, 16 μmol) and K2CO3 in DMF (3 mL), and the reaction mixture was stirred at 50 °C for 16 hours. Purification by preparative HPLC gave Q4-1-2.

[0371] The following compounds were synthesized according to Method Q.

[0372] [Table 48]

[0373] Analysis data.

[0374] [Table 49]

[0375] [Table 50]

[0376] [Table 51]

[0377] [Table 52]

[0378]

Table 53

[0379]

Table 54

[0380]

Table 55

[0381]

Table 56

[0382]

Table 57

[0383]

Table 58

[0384]

Table 59

[0385]

Table 60

[0386]

Table 61

[0387]

Table 62

[0388]

Table 63

[0389]

Table 64

[0390] Biological evaluation The activity of the compounds was evaluated using the RORγ reporter assay (also called the Gal4 assay). Both the Gal4 assay and the Th17 assay (another suitable assay) are cell-based assays that monitor the functional activity of the compounds being assayed.

[0391] The activity of the disclosed compounds was also evaluated using IL-17A secretion in the activated PBMC assay.

[0392] The compounds disclosed herein were also evaluated in an in vivo pharmacodynamic model in mice (anti-CD3-induced plasma IL-17A).

[0393] In addition, the compounds disclosed herein can be evaluated in various mouse disease models, such as the collagen-induced arthritis (CIA) model (an animal model for rheumatoid arthritis) and the experimental autoimmune encephalomyelitis (EAE) model (an animal model for multiple sclerosis).

[0394] RORγ reporter assay (Gal4) The HEK293 cell line is transiently co-transfected with two plasmids, one having the RORγ ligand-binding domain fused to the galactose-responsive transcription factor (Gal4) and the other having the luciferase reporter gene and the Gal binding site (UAS). This configuration allows for the determination of RORγ activity in the cell line through the measurement of luminescence.

[0395] A suspension of RORγ reporter cells was dispensed into plates and cultured at 37 °C and 5% CO2 for 2 hours. The culture medium formulation consisted of DMEM / F-12 medium (Gibco) supplemented with 10% heat-inactivated FBS (Sigma-Aldrich), non-essential amino acids (Sigma-Aldrich), 2 mM Glutamax (Gibco), and 100 U / mL penicillin (Sigma-Aldrich). Dose-response curves for the compounds were prepared in 100% DMSO and further diluted 100-fold in the culture medium. The compound solutions were added to the plates containing the cells (final DMSO concentration of 0.1%) and incubated at 37 °C and 5% CO2 for 24 hours. Luciferase detection reagent was added to each well, and relative light units (RLU) were quantified from each assay well using a plate-reading luminometer.

[0396] After calculating the values of mean RLU ± S.D. for all treatment sets, the percent decrease in RORγ activity in response to the corresponding test compound was calculated. The following formula was used: Activity = 100 * [1 - [x test compound / mean vehicle]]. The theoretical minimum decrease (0% decrease). For all experiments, the activity values were plotted against the compound concentration in one plot and adjusted to a four-parameter logistic curve to obtain the absolute IC50 value along with the 95% confidence interval. These calculations were performed in excel-fit software using the X-204 model curve.

[0397] The results of the RORγ reporter (Gal4) assay are shown in Table 2 below.

[0398]

Table 65

[0399] As can be seen from Table 2 above, the compounds of the present disclosure were found to exhibit favorable activity across the RORγ reporter (Gal4) assay.

[0400] According to one embodiment, an IC of <500 nM in the RORγ reporter assay (Gal4)50 Compounds having a value are disclosed herein.

[0401] According to another preferred embodiment, a compound having an IC value of < 100 nM in the RORγ reporter assay (Gal4) 50 Compounds having a value are disclosed herein.

[0402] Th17 assay (another suitable assay) PBMCs were isolated from buffy coats of healthy human volunteers using the Ficoll paque PLUS kit (GE Healthcare, catalog number 17-1440-02) according to the manufacturer's instructions. Naïve CD4+ T cells were isolated using the Naïve CD4+ T cell kit, human (Milteny Biotec, catalog number 130-094-131). The following modifications were made to the manufacturer's protocol: 1) the incubation of the biotin-antibody cocktail and anti-biotin microbeads was extended up to 30 minutes, and 2) the cells were washed with 40 mL of Miltenyi buffer. Th17 cell differentiation by the test compound (or solvent for control, 0.1% DMSO) during overall differentiation was performed in 96-well plates (400,000 cells / well, 160 μl RPMI 1640 + 10% fetal bovine serum) coated with anti-CD3 (BD Pharmingen, 5 μg / ml) containing 5 μg / ml anti-CD28 (BD Pharmingen), 10 ng / ml IL-2 (R&D Systems), 2.5 ng / ml TGFβ-1 (R&D Systems), 20 ng / ml IL-1β (R&D Systems), 20 ng / ml IL-6 (R&D Systems), 30 ng / ml IL-23 (R&D Systems), 2.5 μg / ml anti-IL-4 (R&D Systems) and 1 μg / ml anti-IFNγ (R&D Systems). The test compounds were tested in triplicate diluted 1000-fold in the medium (final DMSO concentration is 0.1%). Incubation was carried out at 37 °C, 5% CO2, 95% humidity for 7 days, and 2-fluoro-4'-[[4-(4-pyridinylmethyl)-1-piperazinyl]methyl]-α,α-bis(trifluoromethyl)-[1,1'-biphenyl]-4-methanol (SR2211 Calbiochem, catalog number 557353) was used as a positive control. As a negative control, the cells were differentiated into Th0 using 5 μg / ml anti-CD28 (BD Pharmingen), 10 ng / ml IL-2 (R&D Systems), 2 μg / ml anti-IL4 (R&D Systems) and 2 μg / ml anti-IFNγ (R&D Systems).The IL-17 levels in the supernatant were measured by ELISA (R&D Systems).

[0403]

Table 66

[0404] IL-17A secretion in activated PBMC Heparinized whole blood from healthy human volunteers was supplied by Hospital de Sant Pau (Barcelona) under the approval of the local ethics review committee for human research (Hospital de Sant Pau, Barcelona, Spain). Human peripheral blood mononuclear cells (PBMCs) were isolated from healthy human volunteers by density gradient centrifugation using Ficoll-Paque (GE healthcare). PBMCs were suspended in a cell culture medium consisting of RPMI 1640 medium (Sigma-Aldrich) containing 10% heat-inactivated fetal bovine serum (Sigma-Aldrich), 2 mM L-glutamine (Gibco), 20 mM Hepes (Gibco) and 100 U / mL penicillin (Sigma-Aldrich). The cells were seeded at 40,000 cells per well in a 384-well plate (DiscoverX) and cultured at 37 °C and 5% CO2 for 2 hours.

[0405] Dose-response curves for the compounds were generated using those serially diluted 5-fold in 100% DMSO (10 concentrations) and further diluted 100-fold in the culture medium. Compound solutions (5 μL) were added to plates containing cells (final DMSO concentration of 0.1%) and incubated for 30 minutes. The cells were then stimulated with CD3 / CD28 Dynabeads (ThermoFIsher, 1:1 bead-to-cell ratio) at 37 °C and 5% CO2 for 48 hours.

[0406] The levels of IL-17A in the supernatant were determined by fluorescence analysis in an immunoassay using hIL17A QBeads (Intellicyt) and an iQue flow cytometer according to the manufacturer's instructions. Inhibition of IL-17A secretion was calculated using the following formula: Inhibition = 100 * [1 - [(x - mean basal condition) / (mean maximum condition - mean basal condition)]]. Activated DMSO-treated cells were used as the maximum condition, and activated GNE09461 (10 μM)-treated cells were used as the basal condition. Inhibition values were plotted against compound concentration and fitted to a four-parameter logistic curve to obtain the absolute IC50 value along with the 95% confidence interval.

[0407]

Table 67

[0408] As can be seen from Table 4 above, the compounds of the present disclosure have been found to exhibit advantageous activity against IL-17A secretion in the activated PBMC assay.

[0409] According to one embodiment, compounds having an IC 50 value of < 500 nM for IL-17A secretion in the activated PBMC assay are disclosed herein.

[0410] According to another preferred embodiment, compounds having an IC 50 value of < 200 nM for IL-17A secretion in the activated PBMC assay are disclosed herein.

[0411] According to another more preferred embodiment, compounds having an IC 50 value of < 100 nM for IL-17A secretion in the activated PBMC assay are disclosed herein.

[0412] According to another even more preferred embodiment, compounds having an IC 50 value of < 50 nM for IL-17A secretion in the activated PBMC assay are disclosed herein.

[0413] In vivo IL-17A induction in a murine anti-CD3 model Male C57BL / 6JRj mice (7 weeks old) were purchased from Janvier Labs and housed in Almirall's animal facilities throughout the study. The animals were conditioned for 5 days in a new environment at 22 °C ± 2 °C, 55% ± 10% relative humidity, and a 12-hour:12-hour light:dark cycle. The animals were housed in polycarbonate cages and had free access to water and non-purified stock diet (2014 Teklad Global 14% Protein Rodent Maintenance Diet, Envigo) throughout the study. Animal care was conducted in accordance with the European Committee Directive 2010 / 63 / EU and the laws of Catalonia and Spain. All procedures were performed in accordance with the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines and with the approval of the Animal Experimentation Ethics Committee of Almirall (Barcelona, Spain). The mice were intraperitoneally injected with 7.5 μg of anti-CD3e (clone 145-2C11, Pharmingen BD) at 0 hours (day 0) and 48 hours (day 3). The non-induced group was injected with PBS instead of anti-CD3e. At the end of the study (4 hours after anti-CD3e injection), the animals were anesthetized with isoflurane (Baxter), and 0.5 - 1 mL of blood samples were collected by intracardiac puncture into heparinized tubes. Plasma samples were stored at -80 °C for subsequent analysis. The test compound was freshly suspended in sterile 0.5% methylcellulose, 0.1% tween®-80 solution (10 mL / kg body weight). The compound was administered by oral gavage according to the selected dosing and body weight, and control animals received the same volume of vehicle. Administration was performed twice daily from day 0 to day 3, and the last administration was performed 1 hour before anti-CD3e injection. Plasma levels of IL-17A were measured by ELISA (R&D Systems) according to the manufacturer's instructions. Results were calculated as the percentage decrease in plasma IL-17A relative to the difference between the non-induced group and the anti-CD3e-induced group using the following formula: Inhibition = 100 * [1 - [(x - mean non-induced) / (mean control vehicle - mean non-induced)]]. IL-17A inhibition for each administration can be represented as the mean of each dosing group ± S.E.M.Statistical analysis of the data was performed using Dunnett's multiple comparison test after one-way ANOVA when appropriate. Differences were considered significant when p ≤ 0.05. Results:

[0414]

Table 68

[0415] In summary, the compounds disclosed herein were found to at least modulate the activity of RORγ. The compounds disclosed herein are active and have, for example, <500 nM, <100 nM, etc., of Gal4 with <1000 nM. Further, in comparative studies of properties, they exhibit improved lipophilicity as revealed by a decrease in LogP and / or LogD as compared to previously described highly potent compounds; see, for example, Tables 5a - b. In these tables, all numbers (except for Gal4 activity) were calculated and the method is indicated in the column headings.

[0416]

Table 69

[0417]

Table 70

[0418] The RORγ Gal4 data used to generate the comparison in Table 5a is based on Gal4 data generated for the listed compounds (data not available in either WO 2016 / 020288 or WO 2016 / 020295), and since the Gal4 data only existed as % inhibition, LipE is not reported in Table 5b.

[0419] In connection with Tables 5a - b above, Tables 6 and 7 show a comparison between the compounds of the present disclosure and known compounds having structural similarity and considered related.

[0420]

Table 71

[0421]

Table 72

[0422] ALOGP and LipE are calculated using Canvas, which is part of the Schrödinger software suite (Release 2019-1).

[0423] As mentioned, therefore, the compounds disclosed herein can be good regulators of RORγ, for example, having attractive interactions (e.g., high binding ability) for the hydrophobic binding site of the ligand binding domain (LBD) of the RORγ receptor, and good physicochemical properties as described above.

[0424] Furthermore, the compounds disclosed herein have utility in vivo and as a result have been found to be useful for treating inflammatory, metabolic and autoimmune diseases or symptoms thereof. The present invention provides, for example, the following items. (Item 1) A compound according to formula (I)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

1. A compound according to formula (I) 【Chemical 104】 , its stereoisomers, or pharmaceutically acceptable salts of said compound or stereoisomers (wherein Y １ , Y ２ and Y ３ are independently, -N- or -CR ８ -; X is -CR ９ - or -N-; R ０ａ and R ０ｂ each independently is selected from the group consisting of hydrogen, C １～４ alkyl, C １～４ hydroxyalkyl, and C １～４ haloalkyl; R is selected from the group consisting of hydrogen, C １～６ alkyl and C １～４ hydroxyalkyl; R １ａ and R １ｂ are, independently, selected from the group consisting of hydrogen, hydroxyl, halogen, amino, C １～４ alkyl, C １～４ hydroxyalkyl and C １～４ haloalkyl; R ２ is selected from the group consisting of hydrogen, hydroxyl, amino, cyano, halogen, C １～４ alkyl, C １～４ haloalkyl, C １～４ hydroxyalkyl, -C(=O)NH ２ , -C(=O)OH, -C(=O)O-C １～４ alkyl, and substituted or unsubstituted heteroaryl; R ３ is selected from the group consisting of C １～４ alkyl, C １～４ alkenyl, C １～４ haloalkyl, C １～４ hydroxyalkyl, C ３～７ cycloalkyl and C ３～７ cycloalkenyl; or R ３ and R ４ together with the atoms to which they are attached, form a 4- to 6-membered heteroalicyclic ring system which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl and C １～４ alkyl; R ４ is hydrogen or C １～４ alkyl (provided that R ３ and R ４ do not together with the atoms to which they are attached form a 4- to 6-membered heteroalicyclic ring system); or R ４ and R ５ together with the carbon atom to which they are attached form C ３～４ cycloalkyl; R ５ is, when present, hydrogen or C １～４ alkyl (provided that R ４ and R ５ do not together with the carbon atom to which they are attached form C ３～４ cycloalkyl); R ６ is selected from the group consisting of hydrogen, -CN, halogen, C １～４ alkyl, C １～４ hydroxyalkyl, C １～４ haloalkyl, C １～６ hydroxyhaloalkyl, C １～４ alkoxy, C １～４ haloalkoxy and 5- to 6-membered heteroaryl (wherein the 5- to 6-membered heteroaryl may be substituted with C １～４ alkyl); R ７ is selected from the group consisting of hydrogen, hydroxyl, -CN, halogen, C １～４ alkyl, C １～４ haloalkyl, C １～４ hydroxyalkyl, C １～４ alkoxy and C １～４ haloalkoxy; Each R ８ is independently selected from the group consisting of hydrogen, hydroxyl, -CN, halogen, C １～４ alkyl, C １～４ haloalkyl, C １～４ alkoxy and C １～４ haloalkoxy; and R ７ is hydrogen, and each R present ８ is always hydrogen, R ６ is selected from the group consisting of -CN, halogen, C １～４ alkyl, C １～４ haloalkyl, C １～６ hydroxyhaloalkyl, C １～４ hydroxyalkyl, C １～４ alkoxy, C １～４ haloalkoxy and 5- to 6-membered heteroaryl (wherein the 5- to 6-membered heteroaryl may be substituted with C １～４ alkyl); R ９ is selected from the group consisting of hydrogen, halogen, cyano and C １～４ alkyl).

2. The compound according to claim 1, wherein R is hydrogen, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or a stereoisomer thereof.

3. R ０ａ is selected from the group consisting of hydrogen, methyl, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ F and -CHF ２ ; and R ０ｂ is selected from the group consisting of hydrogen, C １～４ alkyl, C １～４ hydroxyalkyl and C １～４ haloalkyl, the compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt of said compound or its stereoisomers.

4. R １ａ , R １ｂ and R ２ At least one of which is not hydrogen, the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt of said compound or its stereoisomer.

5. R １ａ is selected from the group consisting of hydroxyl, fluoro and -CF ３ ; and R １ｂ is selected from the group consisting of hydrogen, fluoro and methyl, the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt of said compound or its stereoisomer.

6. R ２ is hydrogen, halogen, hydroxyl, cyano, methyl, ethyl, -CH ２ OH, -CH ２ CH ２ OH and -C(=O)O-C １～２ alkyl, and is the compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or the stereoisomer thereof.

7. R ３ is a compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, cyclopropyl and cyclobutyl.

8. R ４ and R ５ are, independently, hydrogen or methyl, the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt of said compound or its stereoisomer.

9. R ３ and R ４ together with the atoms to which they are attached form a 4- to 6-membered heteroalicyclic ring; and further R ３ and R ４ the heteroalicyclic ring system containing them is selected from the group consisting of 4-membered heteroaryclyl, 5-membered heteroaryclyl and 6-membered heteroaryclyl, and further the heteroalicyclic ring system is optionally substituted with one or two substituents selected from halogen, hydroxyl and C １～４ alkyl, the compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or a stereoisomer thereof.

10. R ６ is selected from the group consisting of hydrogen, halogen, C １～４ haloalkyl, C １～６ hydroxyhaloalkyl, C １～４ haloalkoxy, C １～４ hydroxyalkyl, and C １～４ 5-membered heteroaryl which may be substituted with alkyl, the compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or a stereoisomer thereof.

11. R ７ is a compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -CF ３ , -OCHF ２ , -CHF ２ and -OCF ３ .

12. Y １ , Y ２ and Y ３ is -CH-; or Y １ is -N- and Y ２ and Y ３ is -CH-; or Y ２ is -N-, and Y １ and Y ３ is -CH-; or Y ３ is -N-, and Y １ and Y ２ is -CH-; or Y ３ is -CH-, and Y １ and Y ２ is -N-. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or a stereoisomer thereof.

13. Y １ is -CH-, Y ２ and Y ３ is -CR ８ -(wherein each R ８ is independently selected from the group consisting of hydrogen, methyl, fluoro, hydroxyl and -CF ３ ), the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt of said compound or its stereoisomer.

14. Y ２ is -N-, and Y １ and Y ３ is -CH-; or Y ３ is -N-, and Y １ and Y ２ is -CH-. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or a stereoisomer thereof.

15. X is -CR ９ -, and R ９ is hydrogen, cyano or fluoro, the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt of said compound or its stereoisomer.

16. (i) Y ２ and Y ３ are each independently —CH— or —CF—; or (ii) Y ２ is -CH-, and Y ３ is -N-, the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt of the compound or its stereoisomer.

17. R ０ａ and R ０ｂ are each independently selected from the group consisting of hydrogen, methyl and -CH ２ OH; R １ａ and R １ｂ are each independently selected from the group consisting of hydrogen, fluoro and hydroxyl; R ２ is selected from the group consisting of hydrogen, cyano and hydroxyl; R is hydrogen; X is -CR ９ - or -N- (wherein R ９ is selected from the group consisting of hydrogen, cyano and fluoro); R ３ is selected from the group consisting of methyl, ethyl, isopropyl and cyclopropyl, and R ４ and R ５ are each independently hydrogen or R ３ and R ４ together with the atoms to which they are attached form an unsubstituted morpholinyl, and R ５ is H; R ６ is selected from the group consisting of hydrogen, -CF ３ and pyrazole (wherein the pyrazole may be substituted by methyl); R ７ is hydrogen; and Y １ , Y ２ and Y ３ is -CH-; or Y １ is -CH-, and Y ２ is -CF-, and Y ３ is -CH-; or Y １ is -CH-, and Y ２ is -CH-, and Y ３ is -CF-; or Y １ is -CH-, and Y ２ is -CH-, and Y ３ is -N-; or Y １ is -CH-, Y ２ is -N-, Y ３ is -CH-; or Y １ is -N-, and Y ２ is -N-, and Y ３ is -CH-; or Y １ is -CH-, and Y ２ is -C(CF ３ )-, and Y ３ is -CH-. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or a stereoisomer thereof.

18. 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((5-Cyano-4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((5-Fluoro-4-(methyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,3-difluoropiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoropiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(3-Hydroxy-4-((4-(3-(4-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide 2-(4-((4-(3-(4-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(3-Hydroxy-4-((4-(3-(3-(trifluoromethyl)phenyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((5-Cyano-4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)propanamide, 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)-2-methylpropanamide, 2-(4-((4-(Cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-Cyano-4-((4-(cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((5-Fluoro-4-(methyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((5-Fluoro-4-(isopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((6-(Cyclopropyl(3-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(3-Hydroxy-4-((6-(isopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(3-Hydroxy-4-((4-(isopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide 2-(4-((6-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-9H-purin-9-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(((4-Cyanobenzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(((4-(1H-Pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(3-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(((4-(1H-Pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(4-(trifluoromethyl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)-3-hydroxypropanamide, 2-(3-Fluoro-4-((4-(3-(5-(trifluoromethyl)pyridin-2-yl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-(3-(5-(trifluoromethyl)pyridin-2-yl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1-yl)acetamide, 2-(4-((4-((4-(1H-pyrazol-1-yl)benzyl)(ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-((4-(1H-pyrazol-1-yl)benzyl)(cyclopropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclopropyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and 2-(4-((4-(Ethyl(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or a stereoisomer thereof, selected from the group consisting of

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

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, for treating an inflammatory, metabolic, tumor or autoimmune disease.

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