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 active against nuclear receptors, pharmaceutical compositions comprising 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 four major domains: the N-terminal A / B domain, the DNA-binding domain, the hinge domain, and the 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 atherosclerosis (Jetten, 2009, Nuclear Receptor Signaling). Furthermore, RORα plays a role in immune responses such as the expression of interleukin (IL)-17A in T helper (Th) 17 cells and the regulation of the function of T regulatory (Treg) cells (Castro PLOS 2017; Malhotra 2018).

[0006] RORβ exhibits a restricted pattern of expression limited to specific regions of the brain (cerebral cortex, thalamus, hypothalamus, and pineal gland) as well as 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, two different protein isoforms: RORγ1 and RORγ2 (RORγ2 is also known as RORγt) have been documented. 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 restricted 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 cells (ILC3) (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 cannot differentiate into Th17 cells even under Th17 polarization culture conditions, but 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 initiates the complete differentiation program of Th17 cells in cooperation with a network of transcription factors (STAT3, IRF4, and BATF) (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 been demonstrated to have clinical efficacy in some diseases (Patel 2015; Krueger 2018 Exp Dermatol).

[0010] Therefore, there is evidence that RORα, RORβ, and RORγ play roles in the pathogenesis of many diseases.

[0011] It is desirable to provide compounds that modulate the activity of RORα and / or RORγ for use in treating inflammatory, metabolic, and autoimmune diseases. International Publication No. 2016 / 020288 pamphlet and International Publication No. 2016 / 020295 pamphlet describe compounds that modulate the active or ROR gamma receptor. However, there remains a need for potent ROR gamma 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, herein, a compound of formula (I)

Chemical Formula

[0014] In one aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer, and at least one pharmaceutically acceptable excipient.

[0015] In one aspect, provided herein are compounds of formula (I) or stereoisomers thereof, or pharmaceutically acceptable salts of the compounds or stereoisomers, or pharmaceutical compositions 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 allergy, 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, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), systemic 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, episcleritis, obesity, insulin resistance due to obesity, type II diabetes, and cancer, or symptoms thereof.

[0016] Furthermore, the advantageous features of the various embodiments are defined 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 a term herein, the definitions in this section shall control unless otherwise stated.

[0018] As used herein, R, R1, R2, R3, R4, R5, R8, R9, and R 10Any "R" group, such as, but not limited to, these, represents a substituent that can be attached to the designated 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, as defined herein, they "together" or "in combination" form a cycloalkyl, aryl, heteroaryl, or heteroaricyclic group. For example, without limitation, NR a R b of the R group a and R b are shown to be "together" or "in combination", it means that they are covalently bonded to each other at their terminal atoms to form a ring containing nitrogen.

Chemical Structure

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

[0020] When the base is described as "unsubstituted or substituted", always when substituted, the substituents (which may be present one or more times, such as 1, 2, 3 or 4 times) are 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 are independently selected from these protected derivatives. When a substituent on a group is considered to be "substituted", the substituent itself is substituted with one or more of the specified substituents. When the mentioned substituent is substituted, one or more hydrogen atoms on the mentioned substituent can be replaced by a group individually and 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 di-substituted amino groups, and their protected derivatives. Protecting groups capable of forming the above-mentioned protected derivatives of substituents are known to those skilled in the art and are incorporated herein by reference in its entirety by the literature, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd It can be found in Ed., John Wiley & Sons, New York, NY, 1999.

[0021] As used herein, "C m ~C n (C m to C n )", "C m ~C n (C m -C n )" or "C m~n " (where "m" and "n" are integers) refers to the number of carbon atoms in the corresponding group. That is, the group may contain "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 should be assumed.

[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 can have 1 to 20 carbon atoms (whenever it appears in this specification, numerical ranges such as "1~20" refer to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but the definition in the present invention also includes the presence of the term "alkyl" for which 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 may be represented as "C1~C4 alkyl", "C 1~4 alkyl" or similar notations. By way of example only, "C1~C4 alkyl" or "C 1~4"Alkyl" indicates the presence of 1 to 4 carbon atoms in the alkyl chain, i.e., 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 by no means 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 the protected derivatives thereof.

[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 may have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as "2 to 20" refers to each integer within the given range; for example, "2 to 20 carbon atoms" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, but the definition in the present invention also encompasses the presence 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 protected derivatives thereof.

[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 may have 2 to 20 carbon atoms (whenever it appears herein, a numerical range such as "2 to 20" refers to each integer within the given range; for example, "2 to 20 carbon atoms" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 20 carbon atoms, but the definition in the present invention also encompasses the presence of the term "alkynyl" without a specified numerical range). An alkynyl group may or may not be substituted. When substituted, the substituent may be selected from the same groups disclosed above for alkenyl group substitution.

[0025] As used herein, "hetero" may be attached to a radical and refers to one or more carbon atoms, and the associated 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, one or more carbon atoms such as 1, 2, 3, or 4 carbon atoms, and the associated hydrogen atoms are independently replaced by the same or different heteroatoms selected from nitrogen, oxygen, and sulfur. The carbon atoms to be replaced may be present in the middle or at the end of the alkyl group. Examples of heteroalkyl include C where one or more of the carbon atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen, and nitrogen 1~6 heteroalkyl is included, and examples include -S-alkyl, -O-alkyl, -NH-alkyl, -alkylene-O-alkyl, etc. Heteroalkyl may be 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 1~10It is aryl, 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 substituents 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, a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl, may be formed by the substituents on the aryl group.

[0028] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized π-electron system), and 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 is exemplified but not limited to those in which 1 to 4 carbon atoms are replaced by 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. Examples of monocyclic "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 that is 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, a non-aromatic ring condensed with an aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl, may be formed by the substituent on the heteroaryl group.

[0029] "Aralkyl" or "arylalkyl" is an aryl group linked as a substituent via an alkylene group. The alkylene and aryl groups of aralkyl may be substituted. Examples include, but are not limited to, benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group.

[0030] "Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group linked as a substituent via an alkylene group. The alkylene and heteroaryl groups of 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 cases, the alkylene group is a lower alkylene group.

[0031] "Alkylene" is a straight-chain tethering group that forms a bond connecting molecular fragments via terminal carbon atoms. Alkylene can have 1 to 20 carbon atoms. Alkylene can also be an alkylene having 1 to 10 carbon atoms such as " 1~6 C". Alkylene can also be a lower alkyl having 1 to 4 carbon atoms. Alkylene may be represented as "C1-C4 alkylene", " 1~4 alkylene" or similar notations. 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 of the 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 attached to one carbon of another group that forms 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 either R’ or R’’ is an aryl group. The alkylidene group may be substituted.

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

[0035] As used herein, "alkylthio" refers to a 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- where R is aryl as defined above, for example, phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio, and the like. Both aryloxy and arylthio may be substituted.

[0037] As used herein, "alkenyloxy" refers to the formula -OR where 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 through a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acrylyl. Acyl may be substituted.

[0039] As used herein, "cycloalkyl" refers to a completely saturated (no double bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro-bonded manner. 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, unless otherwise indicated, can be selected from those shown above for alkyl group substitution. When substituted, a substituted cycloalkyl group can form an aromatic ring fused to a cycloalkyl group containing aryl and heteroaryl.

[0040] As used herein, "cycloalkenyl" refers to a cycloalkyl group containing one or more double bonds in the ring, provided that when 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 linked together in a fused, bridged, or spiro - bonded manner. The cycloalkenyl group can range from C3 to C 10 , for example, from C3 to C8 or from C5 to C 10 . 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, unless otherwise indicated, can be selected from the groups disclosed above for alkyl group substitution. When substituted, a substituted cycloalkenyl group can form an aromatic ring fused to a cycloalkenyl group containing aryl and heteroaryl through the substituent on the cycloalkenyl group.

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

[0042] As used herein, "heterocycloaliphatic" 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 heterocycloaliphatic or heteroaricyclic group can range from C2 to C10It may be in the range of, in some embodiments, it may be in the range of C2 - C9, and in other embodiments, it may be in the range of C2 - C8. In some embodiments, the "heteroalicyclic" or "heteroaricyclic" may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, and may be bonded together in a manner of condensation, bridging or spiro linkage; the nitrogen, carbon and sulfur atoms in the "heteroalicyclic" or "heteroaricyclic" may be oxidized; the nitrogen may be quaternized; the ring may also contain one or more double bonds on the condition that it does not form a completely delocalized π - electron system throughout the entire ring. Examples include 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 - dihydrobenzoxazole, 2,3 - dihydro - 1H - benzimidazole, indoline, and 1,3 - dihydro - 2H - benzimidazol - 2 - one, and benzoxazol - 2(3H) - one. The heteroaricyclic group may be unsubstituted or substituted. When substituted, the substituent may be 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 di - substituted amino groups, and protected derivatives thereof.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 substituent on the heteroaricyclic group can form an aromatic ring condensed with a heteroaricyclic group including 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 cases, 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 cases, 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 cases, 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 1~6 haloalkyl.

[0048] As used herein, "hydroxyhaloalkyl" refers to a haloalkyl group in which one or more hydrogen atoms are replaced by hydroxyl. Such substituted "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. Some embodiments relate to hydroxyhaloalkyl having 1 to 10 carbon atoms such as 1~6 hydroxyhaloalkyl. Other embodiments relate to 1~4 hydroxyhaloalkyl.

[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 group 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 hydroxyalkyls having 1 to 10 carbon atoms such as hydroxyalkyl.

[0051] The "O-carboxy" group refers to the "RC(=O)O-" group, where 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] "C-carboxy" refers to the "-C(=O)OR" group, where R can be the same as defined for O-carboxy. C-carboxy may be substituted.

[0053] The "trihalomethanesulfonyl" group refers to the "X3CSO2-" group, where X is halogen.

[0054] A dashed bond

Chem.

[0055] As used herein, a straight (not wedge-shaped) bold bond or a dashed bond, i.e.,

Chem.

[0056] As used herein, unless otherwise indicated, a wedge bond (bold, dashed, or otherwise) [Chem.] refers to the absolute stereochemistry of a specific stereoisomer as 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 for O-carboxy. Sulfinyl may be substituted.

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

[0069] The "S-sulfonamide" group refers to the "-SO2NR A R B " group, where R A and R B can each independently be the same as defined for the R group as defined for O-carboxy, or can be 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. S-sulfonamide may be substituted.

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

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

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

[0073] The "N-amide" group refers to the "-RC(=O)NR A -" group, and R and R A can each independently be the same as defined for the R group as defined for O-carboxy. The N-amide may be substituted.

[0074] "Ester" refers to the "-C(=O)OR" group, and R can be the same as 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 "RNH2" (primary amine), "R2NH" (secondary amine), "R3N" (tertiary amine). The amino group may be substituted.

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

[0078] Using techniques well known to those skilled in the art, the unsubstituted or mono-substituted amine groups of the compounds herein may be converted to amides, any hydroxyl groups may be converted to esters, and any carboxyl groups may be converted to either amides or esters (e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 3 rdSee 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 Atmospheric pressure ’’ Enantiomerically enriched (within a specific chemical structure, ’’ indicates enantiomerically enriched) (In some experiments showing a mixture of isomers, the symbol * is used, but it should be changed to another symbol to avoid confusion with * listed in the name).

[0081] In any compound having one or more chiral centers disclosed herein, if the absolute stereochemistry is not explicitly indicated, 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 give rise to geometric isomers that can be defined as E or Z, each double bond may independently be E, Z, or a mixture thereof. Similarly, all tautomeric forms are intended to be included.

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

[0083] As used herein, the term "rel" refers to the configuration of a relative chiral center that is not absolute with respect to any other chiral center within the same compound, as understood by one of ordinary skill 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 the -NH- moiety and the =N- moiety of the ring, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

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

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

[0087] As used herein, "pharmaceutically acceptable salts" refers 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. 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 amino groups 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, cantharate, 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 either activating it, i.e., increasing its cellular function above a baseline level measured in a particular context in which it is found, or inactivating it, i.e., reducing its cellular function below a baseline level measured in the context in which it is found and / or preventing its cellular function from occurring at all even in the presence of its natural binding partner. The natural binding partner is an endogenous molecule that is an agonist for the receptor.

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

[0090] As used herein, "partial agonist" refers to a compound that has affinity for a receptor but has a different affinity than an agonist, and that, when binding to the receptor, elicits only a minimal pharmacological response associated with the receptor even when a large number of receptors are occupied by the compound.

[0091] An "inverse agonist" is defined as a compound that reduces or suppresses the constitutive activity of a receptor such that the compound has negative intrinsic activity, although it is not strictly an antagonist.

[0092] As used herein, "antagonist" refers to a compound that forms a complex that does not elicit any response 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 efficiently eliminates the activity of the receptor until the antagonist is metabolized or dissociates, or is removed by other means by physical or biological processes, or at least until the antagonist is metabolized or dissociates.

[0093] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates such as birds, fish, crustaceans, reptiles, particularly mammals. Examples of "mammals" include, but are not limited to, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; female cows; horses; primates such as monkeys, chimpanzees, and apes, and particularly humans.

[0094] As used herein, "patient" refers to a subject who is being treated by a medical professional such as a medical doctor or a veterinarian in order to cure or at least recover from the effects of a particular disease or disorder, or to prevent the occurrence of the disease or disorder 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 a subject.

[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 volume of a potent drug that is too low in mass for manufacture or administration. A diluent can also be a liquid for dissolving a drug administered by injection, oral ingestion, or inhalation. Common forms of diluents in the art are buffered aqueous solutions such as phosphate buffered saline that mimic the composition of human blood, but are not limited thereto.

[0097] As used herein, "excipient" refers to an inert substance that is added to a pharmaceutical composition, but not limited to, to impart volume, viscosity, stability, binding ability, lubricity, disintegration ability, etc. to the composition. "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 inhibited or stimulated by a ligand. Typically, a receptor includes an extracellular domain having ligand-binding properties, a transmembrane domain that anchors the receptor within the cell membrane, and a cytoplasmic 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 has no identifiable ligand. In addition, a receptor includes any molecule that includes a cleaved, modified, mutated receptor, or a partial or all 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 less or little or no response from other receptor types. "Selective" or "selectivity" of one or more specific subtypes of a compound means the ability of the compound to increase the activity of that subtype while increasing less, little or not at all 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 components, whether in vitro or in vivo. Co-administration means simultaneous delivery of separate agents; simultaneous delivery of a mixture of agents; and delivery of a second or additional agent after delivery of one agent. Agents co-administered are usually intended to function in concert with 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 alleviation or mitigation of symptoms of a 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 symptoms and / or disease will never occur again after use of a compound or pharmaceutical composition according to embodiments disclosed herein to achieve prevention. Further, this term should not be construed to mean that after such use to prevent the symptoms, the symptoms are unlikely to occur at least to some extent. Rather, "prevent / preventing" is intended to mean that if the symptoms to be prevented occur notwithstanding such use, they will be less severe than if such use were not made.

[0104] Compound In some embodiments, the present disclosure relates to a compound of formula (I), stereoisomers, and salts of the compound and stereoisomers:

Chemical formula

[0105] In some embodiments disclosed herein, A is fluoro and Y is hydrogen. In some embodiments disclosed herein, Y and A, together with the atom to which they are attached, form a 5-membered heteroaryl or heteroalicyclic ring system optionally substituted with one or two substituents selected from halogen, cyano or C 1~4 alkyl.

[0106] In some embodiments, the disclosure relates to compounds of formula (II), stereoisomers, and salts of the compounds and stereoisomers:

Chemical formula

[0107] In some embodiments disclosed herein, X is N. In some embodiments disclosed herein, X is -CR8. In some embodiments disclosed herein, R8 is selected from the group consisting of hydrogen, cyano and fluoro. In some embodiments disclosed herein, R8 is hydrogen. In some embodiments disclosed herein, R8 is cyano. In some embodiments disclosed herein, R8 is fluoro. In some embodiments disclosed herein, X is -CH-.

[0108] In some embodiments disclosed herein, R 0a is hydrogen, C 1~4 alkyl, C 1~4Hydroxyalkyl, and C 1~4 is selected from the group consisting of haloalkyl. In some embodiments disclosed herein, R 0a is hydrogen. In some embodiments disclosed herein, R 0a is C 1~4 alkyl. In some embodiments disclosed herein, R 0a is C 1~4 hydroxyalkyl. In some embodiments disclosed herein, R 0a is C 1~4 haloalkyl. In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F, and -CHF2.

[0109] In some embodiments disclosed herein, 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 0b is hydrogen. In some embodiments disclosed herein, R 0b is C 1~4 alkyl. In some embodiments disclosed herein, R 0b is C 1~4 hydroxyalkyl. In some embodiments disclosed herein, R 0b is C 1~4 haloalkyl. In some embodiments disclosed herein, R 0b is selected from the group consisting of hydrogen, C 1~4 alkyl, C 1~4 hydroxyalkyl, and C 1~4 haloalkyl.

[0110] In some embodiments disclosed herein, R 0a is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F, and -CHF2; R0b 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 and R 0b are both hydrogen.

[0111] In some embodiments disclosed herein, at least one of R 1a , R 1b , and R2 is not hydrogen.

[0112] In some embodiments disclosed herein, R 1a is selected from the group consisting of hydrogen, hydroxyl, amino, halogen, C 1~4 alkyl, C 1~4 hydroxyalkyl, and C 1~4 haloalkyl. In some embodiments disclosed herein, R 1a is hydrogen. In some embodiments disclosed herein, R 1a is hydroxyl. In some embodiments disclosed herein, R 1a is amino. In some embodiments disclosed herein, R 1a is halogen. In some embodiments disclosed herein, R 1a is C 1~4 alkyl. In some embodiments disclosed herein, R 1a is C 1~4 hydroxyalkyl. In some embodiments disclosed herein, R 1a is C 1~4 haloalkyl. In some embodiments, R 1a is hydroxyl or hydrogen. In some embodiments disclosed herein, R 1a is selected from the group consisting of hydroxyl, halogen, and C 1~4 haloalkyl. In some embodiments disclosed herein, R 1a is selected from the group consisting of hydroxyl, fluoro, and -CF3.

[0113] In some embodiments disclosed herein, R 1b is selected from the group consisting of hydrogen, hydroxyl, amino, halogen, C 1~4 alkyl, C 1~4 hydroxyalkyl, and C 1~4 haloalkyl. In some embodiments disclosed herein, R 1b is hydrogen. In some embodiments disclosed herein, R 1b is hydroxyl. In some embodiments disclosed herein, R 1b is amino. In some embodiments disclosed herein, R 1b is halogen. In some embodiments disclosed herein, R 1b is C 1~4 alkyl. In some embodiments disclosed herein, R 1b is C 1~4 hydroxyalkyl. In some embodiments disclosed herein, R 1b is C 1~4 haloalkyl. In some embodiments disclosed herein, R 1b is selected from the group consisting of hydrogen, halogen, and C 1~4 alkyl. In some embodiments, R 1b is selected from the group consisting of hydrogen, fluoro, and methyl.

[0114] In some embodiments disclosed herein, R 1a is selected from the group consisting of hydroxyl, halogen, and C 1~4 haloalkyl, and R 1b is selected from the group consisting of hydrogen, halogen, and C 1~4 alkyl. 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. In some embodiments disclosed herein, R 1ais hydrogen or hydroxyl, and R 1b is hydrogen.

[0115] In some embodiments disclosed herein, R2 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)OH, -C(=O)NH2, -C(=O)O-C 1~4 alkyl, and substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, R2 is hydrogen. In some embodiments disclosed herein, R2 is hydroxyl. In some embodiments disclosed herein, R2 is amino. In some embodiments disclosed herein, R2 is cyano. In some embodiments disclosed herein, R2 is halogen. In some embodiments disclosed herein, R2 is C 1~4 alkyl. In some embodiments disclosed herein, R2 is C 1~4 haloalkyl. In some embodiments disclosed herein, R2 is C 1~4 hydroxyalkyl. In some embodiments disclosed herein, R2 is -C(=O)OH. In some embodiments disclosed herein, R2 is -C(=O)NH2. In some embodiments disclosed herein, R2 is -C(=O)O-C 1~4 alkyl. In some embodiments disclosed herein, R2 is substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, R2 is substituted heteroaryl. In some embodiments disclosed herein, R2 is unsubstituted heteroaryl.

[0116] In some embodiments disclosed herein, R2 is hydrogen, halogen, hydroxyl, cyano, C 1~4 alkyl, C 1~4 hydroxyalkyl, or -C(=O)O-C 1~4It is alkyl. In some embodiments disclosed herein, R2 is hydrogen, halogen, hydroxyl, cyano, methyl, ethyl, -CH2OH, -CH2CH2OH, or -C(=O)O-C 1~2 It is alkyl. In some embodiments disclosed herein, R2 is hydrogen, halogen, hydroxyl, or C 1~4 It is hydroxyalkyl. In some embodiments disclosed herein, R2 is hydrogen, fluoro, hydroxyl, or -CH2OH. In some embodiments disclosed herein, R2 is hydrogen or hydroxyl. In some embodiments disclosed herein, R2 is hydrogen. In some embodiments disclosed herein, R2 is hydroxyl.

[0117] In some embodiments disclosed herein, R2 is hydrogen and R 1a is hydroxyl. In some embodiments disclosed herein, R2 is hydroxyl and R 1a is hydroxyl.

[0118] In some embodiments disclosed herein, R3 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. In some embodiments disclosed herein, R3 is C 1~4 alkyl. In some embodiments disclosed herein, R3 is C 1~4 alkenyl. In some embodiments disclosed herein, R3 is C 1~4 haloalkyl. In some embodiments disclosed herein, R3 is C 1~4 hydroxyalkyl. In some embodiments disclosed herein, R3 is C 3~7 cycloalkyl. In some embodiments disclosed herein, R3 is C 3~7 cycloalkenyl.

[0119] In some embodiments disclosed herein, R3 is C 1~4 alkyl or C 3~7 cycloalkyl. In some embodiments disclosed herein, R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, cyclopropyl or cyclobutyl. In some embodiments disclosed herein, R3 is methyl, ethyl, cyclopropyl or cyclobutyl. In some embodiments disclosed herein, R3 is ethyl or cyclobutyl. In some embodiments disclosed herein, R3 is ethyl.

[0120] In some embodiments disclosed herein, R4 is hydrogen or C 1~4 alkyl. In some embodiments disclosed herein, R4 is hydrogen. In some embodiments disclosed herein, R4 is C 1~4 alkyl. In some embodiments disclosed herein, R4 is methyl.

[0121] In some embodiments disclosed herein, R5 is absent. In some embodiments disclosed herein, R5 is hydrogen or C 1~4 alkyl. In some embodiments disclosed herein, R5 is hydrogen. In some embodiments disclosed herein, R5 is C 1~4 alkyl. In some embodiments disclosed herein, R5 is methyl.

[0122] In some embodiments disclosed herein, R4 and R5, together with the carbon atom to which they are attached, form a C 3~4 cycloalkyl. In some embodiments disclosed herein, R4 and R5, together with the carbon atom to which they are attached, form cyclopropyl. In some embodiments disclosed herein, R4 and R5, together with the carbon atom to which they are attached, form cyclobutyl.

[0123] In some embodiments disclosed herein, each of R4 and R5 is independently hydrogen or C 1~4 alkyl, or R4 and R5, together with the carbon atom to which they are attached, form a C 3~4 cycloalkyl. In some embodiments disclosed herein, each of R4 and R5 is independently hydrogen or methyl, or R4 and R5, together with the carbon atom to which they are attached, form a cyclopropyl.

[0124] In some embodiments disclosed herein, R4 and R5 are hydrogen.

[0125] In some embodiments disclosed herein, R3 and R4, together with the atoms to which they are attached, form a substituted or unsubstituted 4- to 6-membered heteroalicyclic ring system. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is a 4-membered heteroarysilyl. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is a 5-membered heteroarysilyl. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is a 6-membered heteroarysilyl. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is unsubstituted. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is substituted with one or two substituents selected from halogen, hydroxyl, and C 1~4 alkyl. In some embodiments disclosed herein, R3 and R4, together with the atoms to which they are attached, form a 4- to 6-membered heteroalicyclic ring containing a double bond, and R5 is absent.

[0126] In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, 2-azabicyclo[3.1.0]hexanyl, or 3-azabicyclo[3.1.0]hexanyl; the heteroalicyclic ring system is optionally substituted with one or two substituents selected from halogen and methyl, and when the heteroalicyclic ring system is substituted or unsubstituted 2-azabicyclo[3.1.0]hexanyl, R5 is always absent. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is unsubstituted azetidinyl, unsubstituted pyrrolidinyl, unsubstituted morpholinyl, unsubstituted piperidinyl, 2-azabicyclo[3.1.0]hexanyl, or unsubstituted 3-azabicyclo[3.1.0]hexanyl. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, 2-azabicyclo[3.1.0]hexanyl, or 3-azabicyclo[3.1.0]hexanyl; the heteroalicyclic ring system is substituted with one or two substituents selected from halogen and methyl. In some embodiments disclosed herein, the heteroalicyclic ring system is substituted or unsubstituted 2-azabicyclo[3.1.0]hexanyl and R5 is absent. In some embodiments disclosed herein, the heteroalicyclic ring system is substituted 2-azabicyclo[3.1.0]hexanyl and R5 is absent. In some embodiments disclosed herein, the heteroalicyclic ring system is unsubstituted 2-azabicyclo[3.1.0]hexanyl and R5 is absent.

[0127] In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is morpholinyl optionally substituted with one or two substituents selected from halogen and methyl, and R5 is hydrogen. In some embodiments disclosed herein, the heteroalicyclic ring system containing R3 and R4 is unsubstituted morpholinyl, and R5 is hydrogen.

[0128] In some embodiments disclosed herein, R 6ais selected from the group consisting of hydrogen, cyano, halogen, C 1~4 alkyl, C 1~4 hydroxyalkyl, C 1~4 haloalkyl, C 1~4 hydroxyhaloalkyl, C 1~4 alkoxy, C 1~4 haloalkoxy, and substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, R 6a is hydrogen. In some embodiments disclosed herein, R 6a is cyano. In some embodiments disclosed herein, R 6a is halogen. In some embodiments disclosed herein, R 6a is C 1~4 alkyl. In some embodiments disclosed herein, R 6a is C 1~4 hydroxyalkyl. In some embodiments disclosed herein, R 6a is C 1~4 haloalkyl. In some embodiments disclosed herein, R 6a is C 1~4 hydroxyhaloalkyl. In some embodiments disclosed herein, R 6a is C 1~4 alkoxy. In some embodiments disclosed herein, R 6a is C 1~4 haloalkoxy. In some embodiments disclosed herein, R 6a is substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, R 6a is substituted heteroaryl. In some embodiments disclosed herein, R 6a is unsubstituted heteroaryl. In some embodiments disclosed herein, R 6a is hydrogen, halogen, C 1~4 haloalkyl, or C 1~4 haloalkoxy. In some embodiments disclosed herein, R 6a is hydrogen, C 1~4 haloalkyl, or C1~4 is a haloalkoxy. In some embodiments disclosed herein, R 6a is hydrogen, -CF3, -CH2F, -CCH3F2, -OCF3, or -OCHF2.

[0129] In some embodiments disclosed herein, R 6b is hydrogen, cyano, halogen, C 1~4 alkyl, C 1~4 hydroxyalkyl, C 1~4 haloalkyl, C 1~4 hydroxyhaloalkyl, C 1~4 alkoxy, C 1~4 haloalkoxy, and selected from the group consisting of substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, R 6b is hydrogen. In some embodiments disclosed herein, R 6b is cyano. In some embodiments disclosed herein, R 6b is halogen. In some embodiments disclosed herein, R 6b is C 1~4 alkyl. In some embodiments disclosed herein, R 6b is C 1~4 hydroxyalkyl. In some embodiments disclosed herein, R 6b is C 1~4 haloalkyl. In some embodiments disclosed herein, R 6b is C 1~4 hydroxyhaloalkyl. In some embodiments disclosed herein, R 6b is C 1~4 alkoxy. In some embodiments disclosed herein, R 6b is C 1~4 haloalkoxy. In some embodiments disclosed herein, R 6b is substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, R 6b is substituted heteroaryl. In some embodiments disclosed herein, R 6bis an unsubstituted heteroaryl. In some embodiments disclosed herein, R 6b is hydrogen, halogen, C 1~4 haloalkyl, or C 1~4 haloalkoxy.

[0130] In some embodiments disclosed herein, R 6a is hydrogen, -CF3, -CH2F, -CCH3F2, -OCF3, or -OCHF2, and R 6b is hydrogen. In some embodiments disclosed herein, R 6a is -CF3 and R 6b is hydrogen. In some embodiments disclosed herein, n is 0, and at least one of R 6a and R 6b is selected from the group consisting of cyano, halogen, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 hydroxyhaloalkyl, C 1~4 hydroxyalkyl, C 1~4 alkoxy, C 1~4 haloalkoxy, substituted or unsubstituted heteroaryl; or R 6a and R 6b together with the carbon atom to which they are attached, contain 1 to 3 heteroatoms selected from S, O, or N, and form a 3- to 6-membered cycloaliphatic ring system or a 3- to 6-membered heteroalicyclic ring system optionally substituted with 1 to 3 halogen atoms. In some embodiments disclosed herein, when n is 0, it is always the case that at least one of R 6a and R 6b is selected from the group consisting of cyano, halogen, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 hydroxyhaloalkyl, C 1~4 hydroxyalkyl, C 1~4 alkoxy, C 1~4 haloalkoxy, substituted or unsubstituted heteroaryl.

[0131] In some embodiments disclosed herein, R6a and R 6b together with the carbon atom to which they are attached, contain 1 to 3 heteroatoms selected from S, O, or N, and form a 3- to 6-membered cycloaliphatic ring system or a 3- to 6-membered heteroalicyclic ring system optionally substituted with 1 to 3 halogen atoms. In some embodiments disclosed herein, R 6a and R 6b together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring system optionally substituted with 1 to 3 halogen atoms. In some embodiments disclosed herein, R 6a and R 6b together with the carbon atom to which they are attached, contain 1 to 3 heteroatoms selected from S, O, or N, and form a 3- to 6-membered heteroalicyclic ring system optionally substituted with 1 to 3 halogen atoms. In some embodiments disclosed herein, R 6a and R 6b together with the carbon atom to which they are attached, form a 3- to 4-membered cycloaliphatic ring system optionally substituted with 1 to 3 fluorines, or a 4- to 5-membered heteroalicyclic ring system containing 1, 2, or 3 heteroatoms selected from O and N. In some embodiments disclosed herein, R 6a and R 6b together with the carbon atom to which they are attached, form a 3- to 4-membered cycloaliphatic ring system optionally substituted with 1 to 3 fluorines. In some embodiments disclosed herein, R 6a and R 6b together with the carbon atom to which they are attached, form an unsubstituted 3- to 4-membered cycloaliphatic ring system. In some embodiments disclosed herein, R 6a and R 6b together with the carbon atom to which they are attached, form a 3- to 4-membered cycloaliphatic ring system substituted with 1 to 3 fluorines. In some embodiments disclosed herein, R 6a and R 6b together with the carbon atom to which they are attached, form a 4- to 5-membered heteroalicyclic ring system containing 1, 2, or 3 heteroatoms selected from O and N. In some embodiments disclosed herein, R 6a and R6b Together with the carbon atom to which they are attached, form an oxetanyl or cyclopropyl optionally substituted with one or two fluorines.

[0132] In some embodiments disclosed herein, R 6a and R 6b are each independently hydrogen, halogen, C 1~4 haloalkyl, or C 1~4 haloalkoxy, or R 6a and R 6b together with the carbon atom to which they are attached, form a 3- to 6-membered heteroalicyclic ring system or a 3- to 6-membered alicyclic ring system optionally substituted with 1 to 3 halogen atoms.

[0133] In some embodiments disclosed herein, R 6a is hydrogen, -CF3, -CH2F, -CCH3F2, -OCF3, or -OCHF2, R 6b is hydrogen; or R 6a and R 6b together with the carbon atom to which they are attached, form a 3- to 4-membered alicyclic ring system optionally substituted with 1 to 3 fluorines, or a 4- to 5-membered heteroalicyclic ring system containing 1, 2, or 3 heteroatoms selected from O and N. In some embodiments disclosed herein, R 6a is -CF3, R 6b is hydrogen; or R 6a and R 6b together with the carbon atom to which they are attached, form an oxetanyl or cyclopropyl optionally substituted with one or two fluorines. In some embodiments disclosed herein, at least one of R 6a and R 6b is substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, at least one of R 6a and R 6b is heteroaryl substituted with C 1~4 alkyl.

[0134] In some embodiments disclosed herein, n is 0 or 1. In some embodiments disclosed herein, n is 0. In some embodiments disclosed herein, n is 1.

[0135] In some embodiments disclosed herein, R7 is selected from the group consisting of hydroxyl, cyano, halogen, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 hydroxyalkyl, C 1~4 alkoxy, and C 1~4 haloalkoxy. In some embodiments disclosed herein, R7 is hydroxyl. In some embodiments disclosed herein, R7 is cyano. In some embodiments disclosed herein, R7 is halogen. In some embodiments disclosed herein, R7 is C 1~4 alkyl. In some embodiments disclosed herein, R7 is C 1~4 haloalkyl. In some embodiments disclosed herein, R7 is C 1~4 hydroxyalkyl. In some embodiments disclosed herein, R7 is C 1~4 alkoxy. In some embodiments disclosed herein, R7 is C 1~4 haloalkoxy. In some embodiments disclosed herein, R7 is hydroxyl, cyano, halogen, C 1~4 haloalkyl, or C 1~4 haloalkoxy. In some embodiments disclosed herein, R7 is halogen, hydroxyl, cyano, -CF3, -OCHF2, -CHF2 or -OCF3.

[0136] The compound, stereoisomer, or salt according to claim 1, wherein the compound has the following structure [Chemical formula] [Chemical formula] (wherein, R 1a is hydrogen, fluoro or hydroxyl; R 1b is hydrogen or fluoro; R2 is hydrogen or hydroxyl R3 is methyl, ethyl, cyclopropyl or cyclobutyl; R 6a is -CF3; provided that at least one of R 1a , R 1b and R2 is not hydrogen).

[0137] In some embodiments disclosed herein, R 0a and R 0b are both hydrogen; R 1a and R 1b are independently hydrogen or hydroxy; R2 is selected from the group consisting of hydrogen and hydroxyl; R is hydrogen; Y is hydrogen, A is fluoro; or, Y and A together with the atom to which they are attached and the pyrimidine ring of formula (I) form an unsubstituted pyrrolo[2,3-d]pyrimidine; R3 is selected from the group consisting of methyl, ethyl, cyclopropyl and cyclobutyl, R4 and R5 are hydrogen; or, R3 and R4 together with the atom to which they are attached form an unsubstituted morpholinyl, R5 is hydrogen; n is 0; or, n is 1 and R7 is fluoro; R 6a is -CF3, R 6b is hydrogen; or, R 6a and R 6b together with the carbon atom to which they are attached form an oxetanyl or cyclopropyl substituted with two fluoros.

[0138] In one embodiment, the compound, salt, stereoisomer, or salt of a stereoisomer of formula (I) is the following: rel-2-((3R,4R)-4-(((6-(((1,1-difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-Fluoro-6-((methyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide 2-((3R*,4R*)-4-(((6-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide 2-((3R*,4R*)-4-(((6-(Cyclopropyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide 2-((3RS,4RS)-4-(((6-(Cyclobutyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide rel-2-((3R,4R)-4-(((6-(((2-Oxaspiro[3.5]nonan-7-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide rel-2-((3R,4R)-4-(((6-(Ethyl((1-fluoro-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide 2-(4-(((5-Fluoro-6-((3S)-3-(4-(trifluoromethyl)cyclohexyl)morpholino)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide 2-((3RS,4RS)-4-((4-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide 2-((3R*,4R*)-4-((4-(ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-((3RS,4RS)-4-((4-(cyclobutyl(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-(ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and 2-((3R*,4R*)-4-((4-(ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, is selected from the group consisting of.

[0139] In one embodiment, the compound, salt, stereoisomer, or salt of a stereoisomer of formula (I) is as follows:

Chemical formula

Chemical formula

Chemical formula

[0140] In one embodiment, the compound, salt, stereoisomer, or salt of a stereoisomer of formula (I) is as follows: 2-(4-(((6-(((1,1-Difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-Fluoro-6-(methyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclopropyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(cyclobutyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(((2-oxaspiro[3.5]nonan-7-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(ethyl((1-fluoro-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((5-Fluoro-6-(3-(4-(trifluoromethyl)cyclohexyl)morpholino)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-((4-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Cyclobutyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(Ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and It is selected from the group consisting of 2-(4-((4-(Ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide.

[0141] In one embodiment, the compound, salt, stereoisomer, or salt of a stereoisomer of formula (I) is as follows:

Chemical formula

Chemical formula

Chemical formula

[0142] In one embodiment, the compound, salt, stereoisomer, or salt of a stereoisomer of formula (I) is as follows: 2-((3R*,4R*)-4-(((6-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-((3RS,4RS)-4-(((6-(Cyclobutyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and 2-((3R*,4R*)-4-((4-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide selected from the group consisting of.

[0143] In one embodiment, the compound, salt, stereoisomer, or salt of a stereoisomer of formula (I) is as follows: 2-(4-(((6-(Ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(Cyclobutyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-(((6-(Ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and 2-(4-((4-(Ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide selected from the group consisting of.

[0144] In one embodiment, the compound, salt, stereoisomer, or salt of a stereoisomer of formula (I) is as follows:

Chemical formula

[0145] In one embodiment, the compound, salt, stereoisomer, or salt of a stereoisomer of formula (I) is as follows:

Chemical formula

[0146] In some embodiments, whenever halogen is specified as a substituent, the halogen is always selected from fluoro or chloro.

[0147] The embodiments and specific disclosures used herein are for explaining different alternative forms of the present disclosure, and the embodiments may be combined with other applicable embodiments.

[0148] Specific examples of the compounds are disclosed in Table 1 below.

[0149]

Table 1

[0150]

Table 2

[0151]

Table 3

[0152]

Table 4

[0153]

Table 5

[0154] In related aspects, prodrugs of the compounds of formula (I) as described herein are provided.

[0155] The compounds of the present disclosure are active and have, for example, a Gal4 of RORγ of <1000 nM, such as <500 nM, such as <100 nM.

[0156] According to one embodiment, compounds having a value of IC 50 <1000 nM in the Gal4 assay are disclosed herein.

[0157] According to another preferred embodiment, compounds having a value of IC 50 <500 nM in the Gal4 assay are disclosed herein.

[0158] According to another more preferred embodiment, compounds having a value of IC 50 <100 nM in the Gal4 assay are disclosed herein.

[0159] Pharmaceutical composition In another aspect, the present disclosure relates to a pharmaceutical composition comprising a physiologically acceptable surfactant, carrier, diluent, excipient, emollient, suspending agent, film-forming substance, and coating aid, or a combination thereof; and a compound as disclosed herein, for example, a compound of formula (I), (II), (III), (IV), (V), (VI), and (VII) as disclosed herein, or a salt, stereoisomer, or salt of a stereoisomer thereof. The compounds of formula (I), (II), (III), (IV), (V), (VI), and (VII) included 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, emollient, suspending agent, film-forming substance, and coating aid, or a combination thereof; and a compound of any one of formula (I), (II), (III), (IV), (V), (VI), and (VII) as disclosed herein. To provide a pharmaceutical composition for therapeutic use, acceptable carriers or diluents, as well as other additives, combined with one or more of the compounds of formula (I), (II), (III), (IV), (V), (VI), and (VII) as disclosed herein, 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), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavorings, taste modifiers, etc. may be provided in the pharmaceutical composition. For example, as preservatives, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid may be added. In addition, antioxidants and suspending agents may be used.In various embodiments, as the surfactant, alcohols, esters, sulfated aliphatic alcohols, etc. may be used; as the excipient, 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 the lubricant, magnesium stearate, talc, hardened oil, etc. may be used; as the suspending agent or lubricant, coconut oil, olive oil, sesame oil, peanut oil, soybean oil may be used; as the suspending agent, 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 the suspending agent, plasticizers such as phthalic acid esters may be used.

[0160] 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 an organism. There are multiple techniques in the art for administering the compounds, including, but not limited to, oral, injection, aerosol, parenteral administration, 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.

[0161] 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 for facilitating the uptake of many organic compounds into cells or tissues of an organism.

[0162] The term "diluent" defines a chemically diluted substance 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, which is for mimicking 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.

[0163] The term "physiologically acceptable" defines a carrier or diluent that does not inhibit the biological activity and properties of the compound.

[0164] The pharmaceutical compositions described herein can be administered to a human patient per se or, in the case of combination therapy, in a pharmaceutical composition mixed with other active ingredients or with a suitable carrier or excipient. Techniques for formulating and administering the compounds of the present application can be found in "Remington’s Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0165] 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 pulsed administration at a given rate over a long period of time and / or periodically, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, etc.

[0166] The pharmaceutical compositions can be manufactured in a manner known per se, for example, by conventional mixing, dissolving, granulating, sugar coating tablet making, levigating, emulsifying, encapsulating, entrapping, or tablet forming processes.

[0167] Pharmaceutical compositions for use as described herein can be formulated in conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate processing the active compound into a pharmaceutically usable preparation. Suitable formulations depend on the chosen route of administration. Any well-known techniques, carriers, and excipients may be used as appropriate, for example, as understood in the art in Remington’s Pharmaceutical Sciences mentioned above.

[0168] Injections can be prepared in conventional form as 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, pharmaceutical compositions for injection may contain small amounts of non-toxic auxiliary substances such as wetting agents, pH buffering agents, etc., if necessary. Physiologically compatible buffers include, but are not limited to, Hank's solution, Ringer's solution, or saline buffer. Absorption-promoting formulations (e.g., liposomes) may be utilized if necessary.

[0169] For transmucosal administration, suitable penetration enhancers may be used in the formulation to permeate the barrier.

[0170] For example, pharmaceutical preparations for parenteral administration by bolus injection or continuous infusion include aqueous solutions of the active compound in water-soluble form. Further, 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 carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound so that a high-concentration solution can be prepared. Injectable preparations can be provided in unit dosage forms with added preservatives, for example, in ampoules or multi-dose containers. 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 for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0171] In the case of oral administration, the active compound can be easily formulated by combining it 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 the patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules to obtain tablets or dragee cores after adding suitable auxiliaries if necessary. 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, alginic acid or its salts such as sodium alginate may be added if necessary. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used and 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 may be added to the tablets or dragee coatings for identification purposes or to characterize different combinations of doses of the active compound. For this purpose, concentrated sugar solutions may be used and 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 may be added to the tablets or dragee coatings for identification purposes or to characterize different combinations of doses of the active compound.

[0172] Examples of pharmaceutical preparations for oral use include push-fit capsules made of gelatin, as well as 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. The active compound may be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin, or liquid polyethylene glycol in the soft capsule. Further, a stabilizer may be added. All formulations for oral administration must be in a dosage suitable for such administration.

[0173] For buccal administration, the composition can take the form of tablets or troches formulated in a conventional manner.

[0174] For administration by inhalation, the compounds for use as described herein are conveniently delivered in the form of an aerosol spray presentation by means of a pressurized pack or a nebulizer using a suitable propellant, for example 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.

[0175] 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 from 5.0 to 8.0. Other ingredients that may be desirable for use in ophthalmic formulations include preservatives (benzalkonium chloride, Purite (商標)Stabilized oxychloro complexes sold as such, 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, etc.). The compounds disclosed herein may also be used as 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 gels (Shedden et al., Clin. Ther., 23(3):440-50(2001)) or hydrogels (Mayer et al., Ophthalmologica, 210(2):101-3(1996)); ophthalmic ointments; ophthalmic suspensions, for example, microparticles, small polymeric particles containing a drug 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 microspheres (Mordenti, Toxicol. Sci., 52(1):101-6(1999)); and intraocular 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 mimic nasal mucus in many respects to ensure normal ciliary action.Disclosed in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is hereby incorporated by reference in its entirety, and as is well known to those skilled in the art, suitable formulations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 - 6.5, and most often and preferably contain an antibacterial preservative and a suitable drug stabilizer. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such ear preparations include glycerin and water.

[0176] The compounds disclosed herein may also be formulated in rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

[0177] In addition to the formulations described above, the compounds may also be formulated as depot formulations. Such long - acting formulations can be administered by injection (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.

[0178] In the case of hydrophobic compounds, suitable pharmaceutical carriers can be a co - solvent system comprising benzyl alcohol, a non - polar surfactant, a water - miscible organic polymer, and an aqueous phase. A common co - solvent system used is the VPD co - solvent system, which is a solution of 3 w / v% benzyl alcohol, 8 w / v% non - polar surfactant polysorbate 80 (商標) constituted by volume in absolute ethanol, and 65 w / v% polyethylene glycol 300. Of course, the proportions of the co - solvent system may be varied significantly without impairing its solubility and toxicity characteristics. Furthermore, the identity of the co - solvent components may be varied: for example, polysorbate 80 (商標)Other low-toxic non-polar surfactants may be used instead; the fraction size of polyethylene glycol may be varied; polyethylene glycol may be replaced with other biocompatible polymers such as polyvinylpyrrolidone; and dextrose may be replaced with other sugars or polysaccharides.

[0179] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be utilized. Liposomes and emulsions are well-known examples of delivery media or carriers for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide may also be utilized. Further, the compounds may 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 over periods ranging from a few weeks to up to 100 days depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for stabilizing the protein may be used.

[0180] Agents intended to be administered intracellularly can be administered using techniques well-known to those skilled in the art. For example, such agents may be encapsulated in liposomes. All molecules present in the aqueous solution during liposome formation are incorporated into the aqueous interior. The contents of the liposome are protected from the external microenvironment and, since the liposome fuses with the cell membrane, are efficiently delivered to the cytoplasm. Liposomes can be coated with tissue-specific antibodies. Liposomes are targeted to and selectively taken up by the desired organ. Alternatively, low-molecular-weight hydrophobic organic molecules may be administered directly into the cell.

[0181] Additional therapeutic or diagnostic agents may be incorporated into the pharmaceutical composition. Alternatively or in addition, the pharmaceutical composition may be combined with other compositions containing other therapeutic or diagnostic agents.

[0182] 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.

[0183] The combinations provided herein are the compounds disclosed herein and one or more additional active substances, such 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) anti-cancer 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-36R 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 treatment with 5-methoxypsoralen + UVA (PUVA) or UVB (regardless of the presence or absence of tar); v) Fixed combinations of corticosteroids and vitamin D derivatives; w) Fixed combinations of corticosteroids and retinoids; x) Corticosteroid tapes; and y) Comprising one or more agents selected from the group consisting of BMS986165, PF-06700841, PF-06826647, picrilidone, 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, mirikizumab, CD20 antagonists, salicylic acid, coal tar, Mical-1, DUR-928, AM-001, BMX-010, TA-102, SNA-125, brepositiniib tosylate, pegcanratinib, ESR-114, NP-000888, SM-04755, BOS-475, SB-414, LEO-134310, CBS-3595, PF-06763809, XCUR-17 or BTX-1308.

[0184] The active compounds in the combination, namely the compounds disclosed herein, and any other optional active compounds may be co-administered in the same pharmaceutical composition by the same or different routes, or may be administered in separate compositions intended for separate, simultaneous, combined or sequential administration.

[0185] Use The compounds or pharmaceutical compositions disclosed herein as described above can be used to modulate the activity of retinoic acid receptor-related orphan receptors (ROR), such as RORα, RORβ and / or RORγ receptors. Modulators of RORγ have been reviewed by B. Fauber and S. Magnuson in J. Med. Chem., February 6, 2014, and Pandya et al in J. Med. Chem. 2018, 61, 24, 10976 - 10995, which are hereby incorporated by reference in their entirety. Examples of RORγ receptors are the RORγ1 or RORγt receptors. Compounds or pharmaceutical compositions as described above may also exhibit selective modulation of a particular ROR receptor over 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.

[0186] The compounds or pharmaceutical compositions disclosed herein can also be used to modulate the activity of cells that produce IL-17A in an RORγt-dependent manner, such as γδT cells, Th17 cells, Tc17 cells and ILC3 cells. The compounds or pharmaceutical compositions disclosed herein can also be used to inhibit RORγt function upon stimulation with IL-23, which in turn adversely affects the differentiation and proliferation of pathogenic Tc17 and Th17.

[0187] 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, all of which are hereby incorporated by reference in their entirety.

[0188] The compounds or pharmaceutical compositions as described herein and above may also be used in therapy or for treating 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 hereby incorporated by reference in their entirety.

[0189] 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, bullous disease, hidradenitis suppurativa, 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, episcleritis, obesity, insulin resistance due to obesity, type II diabetes, and cancer.

[0190] More preferably, the disease or disorder, or symptoms thereof, 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.

[0191] Examples of symptoms are physical or mental characteristics that are considered to indicate the symptoms of a disease, particularly such characteristics that are apparent to the patient, and for example, treating or preventing the symptoms is not considered disease-modifying, but preventing or reducing one or more symptoms commonly experienced in connection with such a disease.

[0192] 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 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 diseases, 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, episcleritis, obesity, insulin resistance due to obesity and type II diabetes.

[0193] Conversely, compounds or pharmaceutical compositions having an agonist effect against RORγ may be used to increase the IL-17A level. Increasing the IL-17A level may be particularly useful, for example, in states where the immune function is reduced during infection and in cancer, or to boost the response of the immune system.

[0194] The compounds described herein may be used in the manufacture of a medicament for the treatment and / or prevention of inflammatory, metabolic, tumor and autoimmune diseases or disorders or symptoms thereof.

[0195] Method 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, including administration in the form of capsules, tablets, granules, sprays, syrups, or other such forms, as would be considered appropriate by one of ordinary skill in the art for contacting the disclosed compounds with living tissue; (b) administration via parenteral routes, such as in the form of aqueous suspensions, oily preparations, etc., or by administration as drops, sprays, suppositories, plasters, ointments, etc., including rectal, vaginal, intraurethral, intraocular, intranasal, or intratympanic administration; (c) administration via subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intra-articular, intraspinal, intrasternal injection, etc., including infusion pump delivery; (d) local administration by direct injection in the kidney or heart area, such as depot injection, intratumoral injection, or intranodal injection; (e) topical administration; and (f) administration of cells ex vivo followed by insertion of the cells into the patient.

[0196] Pharmaceutical compositions suitable for administration include compositions containing the active ingredient in an amount effective to achieve the 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 assumed. The dosage can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, co-medication, and other factors recognized by those of ordinary skill in the medical arts. 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 prolong survival. Determination of a therapeutically effective amount is well within the ability of one of ordinary skill in the art, particularly in view of the detailed disclosure provided herein.

[0197] As will be readily apparent to those skilled in the art, the useful in vivo dosage administered and the specific method of administration will vary depending on the age, weight and mammalian species being treated, the particular compound utilized, and the specific use for which these compounds are utilized. Determination of effective dosage levels, i.e., the dosage levels necessary to achieve the desired result, can be accomplished by those skilled in the art using conventional pharmacological methods. Typically, human clinical applications of the product are initiated at relatively low dosage levels and the dosage level is increased until the desired effect is achieved. Alternatively, acceptable in vitro tests can be used to establish useful dosages and routes of administration of the compositions specified by the methods herein using established pharmacological methods.

[0198] In non-human animal testing, the application of promising products is initiated at relatively high dosage levels and the dosage is decreased until the desired effect can no longer be obtained or adverse side effects disappear. Dosages can range widely depending on the desired effect and therapeutic index.

[0199] Typically, the dosage can be about 10 micrograms / kg to 100 mg / kg body weight, preferably about 100 micrograms / kg to 10 mg / kg body weight. Alternatively, the dosage may be calculated based on the patient's body surface area as is understood by those skilled in the art.

[0200] The exact formulation, route of administration and dosage of the pharmaceutical compositions disclosed herein may be selected by the individual physician, taking into account the patient's condition. (See, for example, Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”, incorporated herein by reference in its entirety, particularly Ch. 1, p. 1). Generally, the dosage range of the composition administered to a patient can be from about 0.5 to 1000 mg per kg of the patient's body weight. The dosage may be a single dose, if required by the patient, or a series of two or more doses given over one or more days. If the human dosage of the compound has been established in at least some indications, the same dosages may be used, or dosages from about 0.1% to about 500%, more preferably from about 25% to about 250% of the established human dosage may be used. In cases where the human dosage of a newly discovered pharmaceutical compound has not been established, a suitable human dosage can be extrapolated from the ED 50 or ID 50 value, or other appropriate values obtained from in vitro or in vivo tests.

[0201] It should be noted that the attending physician will know the methods and timing for discontinuing, interrupting, or adjusting administration due to toxicity or organ failure. Conversely, the attending physician will also know to adjust the treatment to a higher level if the clinical response is inadequate (excluding toxicity). The magnitude of the dosage administered in the management of the disorder of interest will vary depending on the severity of the symptoms being treated and the route of administration. The severity of the symptoms can be partially evaluated, for example, by standard prognostic assessment methods. Further, the dosage, and perhaps the frequency of administration, will also vary depending on the age, weight, and response of the individual patient. Programs corresponding to those described above may be used in veterinary medicine.

[0202] The correct dosage will be determined for each agent, but in most cases some generalizations can be made regarding dosage. The daily dosing schedule for adult human patients can be, for example, an oral dose of 0.1 mg to 2000 mg, preferably 1 mg to 500 mg, for example 5 to 200 mg, of each active ingredient. The eye drops can be in the range of a concentration of 0.005 to 5%. In one embodiment, the eye drops can be in the range of 0.01 to 1%, or in another embodiment, 0.01 to 0.3%. In other embodiments, intravenous, subcutaneous, or intramuscular dosages of 0.01 mg to 100 mg, preferably 0.1 mg to 60 mg, for example 1 to 40 mg, of each active ingredient are used. When administering a pharmaceutically acceptable salt, the dosage can be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times per 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 circumstances, particularly for the effective and aggressive treatment of invasive diseases or infections, the compounds disclosed herein may need to be administered in amounts exceeding the preferred dosage ranges or frequencies described above, or in amounts far exceeding them. In some embodiments, the compound will be administered for a period of continuous therapy, for example, for more than one week, or for one month or one year.

[0203] The dosage and dosing interval may be adjusted individually to provide a plasma or tissue level of the active moiety or a minimum effective concentration (MEC) sufficient to maintain the modulating effect. The MEC varies for each compound but can be estimated from in vitro data. The dosage required to achieve the MEC will depend on the characteristics of the individual and the route of administration. However, HPLC assays or bioassays may be used to determine plasma concentrations.

[0204] The dosing interval can also be determined using the MEC value. The composition should be administered using a dosing schedule that maintains plasma levels above the MEC for 10 to 90%, preferably 30 to 90%, most preferably 50 to 90% of that period.

[0205] In the case of topical administration, ex vivo administration, or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0206] The amount of the composition to be administered may 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.

[0207] The compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicity of certain compounds sharing a particular chemical moiety, or a subset of compounds, can be established by determining the in vitro toxicity against mammalian, preferably human cell lines such as human 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, recognized in vitro models exist. 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 the state-of-the-art for selecting an appropriate model, dosage, and route of administration, as well as the regulatory regime. Naturally, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0208] The composition may be provided in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient, if necessary. The pack may comprise a metal or plastic foil such as, for example, 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 governmental agency regulating 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, the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. Also, a composition comprising a compound disclosed herein formulated in a suitable pharmaceutical carrier may be prepared, placed in an appropriate container, and labeled for the treatment of the indicated condition.

[0209] General As described above with respect to specific exemplary embodiments, it is not intended to be limited to the specific forms described herein. Any combination of the embodiments referred to above 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 specific embodiments described above are equally possible within the scope of these appended claims.

[0210] In the claims, the terms "comprising" or "comprises" do not exclude the presence of other species or steps. Further, although individual features may be included in different claims, 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, 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, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0211] When a chemical name or structure is provided, it is always generated by conventional means or suitable software. The names for the compounds were generated by ChemDraw Professional, version 17.1.0.105(19).

[0212] In the present disclosure, the notations “or1”, “or2”, “&1”, or “&2” at each chiral center in the structure diagrams specify the “stereochemical group” to which the center belongs.

[0213] In the case of an “or” group, it means a structure representing one stereoisomer having either the “stereochemical group” as depicted (e.g., (R,S)) or a stereoisomer having the opposite configuration (S,R) of the asymmetric center of the group.

[0214] In the case of an “&” group, an & combined with a given number (e.g., &1) indicates that the marked asymmetrically substituted atoms are a mixture. When numbering encounters several asymmetrically substituted atoms together, this indicates their configurations relative to each other. If they are represented as (R,S), the opposite configuration (S,R) also exists for the specified encountered groups.

[0215] In the present disclosure, the symbol ’’ specifies being rich in enantiomers. Any compound or intermediate synthesized in an enantiomer-rich manner without chiral separation is specified by ’’.

Examples

[0216] Experiment The following examples are merely examples 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.

[0217] 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.

[0218] 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 were 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 shown in Hz.

[0219] Analytical U / HPLC For analytical U / HPLC, the following equipment was used: 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 Corporation). 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 Waters detector.

[0220] Preparative HPLC For preparative HPLC, the following equipment was used: 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, 19 × 150 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, 21.2 × 150 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).

[0221] 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%)).

[0222] Flash CC was most often performed on an Isolera® automated system. Flash CC and preparative TLC were performed using SiO2, unless otherwise stated. However, C18 columns were also used (using a gradient of water-acetonitrile / MeOH (1:1) with 0.1 v / v% ammonium formate in both phases, with or without, 0–100% acetonitrile / MeOH (1:1)).

[0223] Analytical chiral chromatography Performed on a Waters UPC2 system connected to a Waters QDa MS detector equipped with a chiral column with gradient elution using a DAD detector and a flow rate of 1 mL / min. Available chiral columns were CHIRALPAK IA, IB, IC and ID (3 μm, 4.6×100 mm), and Trefoil AMY1 (2.5 μm, 2.1×150 mm).

[0224] For analytical UPC2, the following linear gradients were used: 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%).

[0225] Preparative chiral chromatography Before chiral separation, the compounds were purified by standard methods described previously using an appropriate solvent.

[0226] Fractional chiral separation was carried out using either a Gilson (306, GX-281 trilution, 156-UV / Vis, Waters 3100 MSD) equipped with a chiral column with a specified solvent or Waters SFC-80, with a flow rate of 10-50 mL / min (simply 50 g / min in the case of SCF) and detection at either 214 nm or 230 nm; 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 columns and elution conditions used for each compound are described in the Experimental section.

[0227] Synthesis method The compounds disclosed herein can be synthesized by one of the following methods.

[0228] General method A - Synthesis from Boc-protected piperidine

Chemical formula

[0229] The product A6 was first purified by chromatography (to ensure a pure product and isolate possible diastereomers).

[0230] When the product (or intermediate) was a stereoisomer, they were often (but not always) subjected to chiral chromatography in order to obtain a single stereoisomer as the final product.

[0231] All compounds in Table A were synthesized using this methodology in the range of 2 μmol to a maximum of about 1 mol scale.

[0232] Example A6-1 Synthesis and isolation of the four stereoisomers, A6-1-1-1, A6-1-1-2, A6-1-2-1 and A6-1-2-2 of rel-2-((3R,4R)-4-(((6-(((1,1-difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide.

Chemical Structure

[0233] N-((1,1-Difluorospiro[2.5]octan-6-yl)methyl)-N-ethyl-5,6-difluoropyrimidin-4-amine, synthesis of A2-1, and separation of stereoisomers A2-1-1 and A2-1-2.

Chem.

[0234] rac-tert-Butyl (3R,4R)-4-((((6-(((1,1-difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate, synthesis of A4-1-1 and A4-1-2.

Chem.

[0235] Synthesis of rac-(3R,4R)-4-(((6-(((1,1-difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-3-ol, A5-1-1 and A5-1-2.

Chem.

[0236] Synthesis of rac-2-((3R,4R)-4-(((6-(((1,1-difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A6-1-1 and A6-1-2.

Chem.

[0237] rel-2-((3R,4R)-4-(((6-(((1,1-Difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, A6-1-1-1, A6-1-1-2, A6-1-2-1 and A6-1-2-2.

Chemical formula

[0238] The compounds in Table A below were prepared according to general method A.

[0239]

Table 6

[0240]

Table 7

[0241]

Table 8

[0242]

Table 9

[0243] General method B - Synthesis from B - Boc - protected piperidine.

Chemical formula

[0244] Examples B6 - 1 - 1 and B6 - 1 - 2

Chemical Structure

[0245] Scheme B6 - 1 tert - butyl (3RS,4RS) - 4 - ((4 - (ethyl(((1r,4R) - 4 - (trifluoromethyl)cyclohexyl)methyl)amino) - 7H - pyrrolo[2,3 - d]pyrimidin - 7 - yl)methyl) - 3 - hydroxypiperidine - 1 - carboxylate, B4 - 1.

Chem.

[0246] (3RS,4RS)-4-((4-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-3-ol, B5-1.

Chem.

[0247] 2-((3RS,4RS)-4-((4-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, B6-1.

Chem.

[0248] 2-((3R*,4R*)-4-((4-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, B6-1-1 and B6-1-2.

Chemical formula

[0249] The following compounds in Table B were synthesized according to the general method B using the disclosed starting materials.

[0250]

Table 10

[0251] Synthesis of B3-1

Chemical formula

[0252] Scheme B3-1 rac-(3R,4R)-1-Benzyl-4-(hydroxymethyl)piperidin-3-ol, iB3-1-2.

Chem.

[0253] rac-tert-Butyl (3R,4R)-3-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate, iB3-1-3.

Chem.

[0254] rac-tert-Butyl (3R,4R)-3-hydroxy-4-((tosyloxy)methyl)piperidine-1-carboxylate), B3-1.

Chem.

[0255] The diol ligands were also synthesized via Route A or B.

[0256] Diol Route - A: Synthesis of 2 - ((3R*,4R*)-4 - ((((6 - (ethyl(((1r,4R)-4 - (trifluoromethyl)cyclohexyl)methyl)amino)-5 - fluoropyrimidin - 4 - yl)amino)methyl)-3,4 - dihydroxypiperidin - 1 - yl)acetamide, AD - 6 - 1 and AD - 6 - 2 [Chemical formula] a) DMSO, DIEA. b) Sharpless dihydroxylation. c) Pd / C, H2 MeOH. d) 2 - bromoacetamide, K2CO3, DMF, chiral separation (CHIRALPAK IG, Hex:EtOH:DEA = 60:40:0.3).

[0257] Scheme AD - 6 N - ethyl - 5,6 - difluoro - N - ((((1r,4r)-4 - (trifluoromethyl)cyclohexyl)methyl)pyrimidin - 4 - amine, A2 - 3 [Chemical formula] A2 - 3 was synthesized using 4,5,6 - trifluoropyrimidine and A1 - 3 as outlined in the general method A.

[0258] N 4 -((1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)methyl)-N 6 -ethyl-5-fluoro-N 6 -(((1r,4r)-4-(Trifluoromethyl)cyclohexyl)methyl)pyrimidine-4,6-diamine) AD-3

Chemical Structure

[0259] (3RS,4RS)-1-Benzyl-4-(((6-(ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-3,4-diol, AD-4

Chemical Structure

[0260] (3RS,4RS)-4-(((6-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)piperidine-3,4-diol, AD-5

Chemical formula

[0261] 2-((3RS,4RS)-4-(((6-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, AD-6.

Chemical formula

[0262] Isolation of two stereoisomers of 2-((3R*,4R*)-4-(((6-(ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, AD-6-1 and AD-6-2

Chemical Structure

[0263] Diol Route - B: Synthesis of 2-((3R*,4R*)-4-((4-(ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, BD-5-1-1 and BD-5-1-2

Chemical Structure

[0264] Scheme BD-5-1 tert-Butyl (3RS,4RS)-3-(benzyloxy)-4-((4-(ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-hydroxypiperidine-1-carboxylate [Chemical formula] Under N2 atmosphere, NaH (75 mg, 1.86 mmol) was added to a solution of AD-2 (300 mg, 0.93 mmol) in anhydrous DMF (20 mL). After 30 minutes, a solution of BD-1 (443 mg, 1.39 mmol) in anhydrous DMF (4 mL) was added dropwise, and the reaction mixture was stirred at 60 °C. The reaction was quenched with NH4Cl (saturated aqueous solution, 40 mL) and extracted with EA (3 × 20 mL). The combined organic fractions were washed with brine (3 × 15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash CC (EA:PE = 1:5~1:4) to obtain BD-2. LCMS: Calculated MS value: 645; Observed MS value: 646 ([M+H] + )

[0265] tert-Butyl (3RS,4RS)-4-((4-(ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidine-1-carboxylate [Chemical formula] A mixture of BD-2 (750 mg, 0.93 mmol), MeOH (20 mL), NH4CO2H (1.4 g, 22.32 mmol), and Pd / C (500 mg, 10%) was refluxed overnight. Next, the reaction mixture was filtered and concentrated in vacuo to obtain crude BD-3. LCMS: Calculated MS value: 555; Observed MS value: 556 ([M+H] + )

[0266] (3RS,4RS)-4-((4-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-3,4-diol, BD-4.

Chem.

[0267] 2-((3RS,4RS)-4-((4-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide), BD-5

Chem.

[0268] Separation and isolation of stereoisomers of 2-((3R*,4R*)-4-((4-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, BD-5-1-1 and BD-5-1-2 [Chemical] BD-5-1 was separated by chiral HPLC (CHIRALPAK IG, Hex:EtOH:DEA = 40:60:0.3) to obtain stereoisomers BD-5-1-1 (the first eluted isomer) and BD-5-1-2 (the second eluted isomer).

[0269] Synthesis of A1 building block: [Chemical]

[0270] Synthesis of N-((1,1-difluorospiro[2.5]octan-6-yl)methyl)ethanamine, A1-1 [Chemical] a) EtNH2, DIEA, HATU. b) BH3.THF.

[0271] Scheme A1-1 Synthesis of N-ethyl-1,1-difluorospiro[2.5]octane-6-carboxamide, iA1-1-2 [Chemical] DIEA (1.8 g, 14.1 mmol) and HATU (2.1 g, 5.6 mmol) were added to a solution of 1,1-difluorospiro[2.5]octane-6-carboxylic acid (890 mg, 4.7 mmol) in DMF (10 mL). The reaction mixture was stirred at 30 °C for 30 minutes, then ethylamine (2 M in THF, 7 mL) was added. The reaction mixture was stirred at 30 °C overnight, diluted with water (20 mL), extracted with EA (3 × 20 mL), washed with brine and dried over Na2SO4. The organic solution was concentrated in vacuo to give crude iA1-1-2, which was used without further purification. MS calculated: 217; MS found: 218 ([M+H] + )

[0272] Synthesis of N-((1,1-difluorospiro[2.5]octan-6-yl)methyl)ethanamine, A1-1 [Chemical formula] Under N2 atmosphere, BH3·THF (1 M, 18 mL) was added portionwise to a solution of crude iA1-1-2 (1.5 g) in THF (15 mL). The reaction mixture was refluxed overnight, cooled in an ice bath, quenched by adding MeOH (4 mL) and then 1 N HCl (4 mL), then the mixture was stirred at 50 °C for 30 minutes and then concentrated in vacuo. The residue was taken up in saturated K2CO3 (20 mL), extracted with DCM (3 × 20 mL), washed with brine (20 mL) and dried over Na2SO4. The organic solution was filtered and concentrated in vacuo to give crude A1-1, which was used without further purification. MS calculated value: 203; MS measured value: 204 ([M + H] + ).

[0273] Synthesis of N-methyl-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)methanamine (A1-2), N-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)methyl)ethanamine (A1-3) and N-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)methyl)cyclopropanamine (A1-4). [Chemical formula] These intermediates were synthesized according to the synthesis of A1-1, using 2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)acetic acid instead of iA-1-1, together with either methylamine hydrochloride, ethylamine or cyclopropylamine respectively.

[0274] Synthesis of N-((2-oxaspiro[3.5]nonan-7-yl)methyl)ethanamine, A1-6 [Chemical formula] a) Dess-Martin oxidation. b) EtNH2, MgSO4, NaBH4, MeOH.

[0275] Scheme A1-6 2-Oxaspiro[3.5]nonane-7-carbaldehyde, iA1-6-2. [Chemical formula] Dess-Martin periodinane (956 mg, 2.25 mmol) was added to a solution of (2-oxaspiro[3.5]nonan-7-yl)methanol (320 mg, 2.05 mmol) in DCM (10 mL) cooled with ice, and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was adjusted to pH = 7 - 8 with NaHCO3 (aqueous solution), extracted with DCM (2 × 50 mL), dried (Na2SO4), and concentrated in vacuo to give iA1-6-2. 1 1H-NMR (400 MHz, CDCl3): δ 9.61 (d, J = 0.8 Hz, 1H), 4.37 (d, J = 5.2 Hz, 4H), 2.20 (m, 1H), 2.13 - 2.03 (m, 2H), 1.88 - 1.84 (m, 2H), 1.59 - 1.52 (m, 2H), 1.40 - 1.36 (m, 2H).

[0276] N-(2-Oxaspiro[3.5]nonan-7-ylmethyl)ethanamine, A1-6. [Chemical formula] A mixture of iA1-6-2 (310 mg, 2 mmol), MeOH (10 mL), MgSO4 (1 g) and ethanamine (2 mL, 2 mol / L) was stirred at room temperature overnight. Next, NaBH4 (133 mg, 3.5 mmol) was added and the reaction mixture was stirred at room temperature for an additional 2 h. Then, H2O was added, the mixture was extracted with EA (3 × 50 mL), dried (Na2SO4), and concentrated in vacuo to give A1-6. 1H-NMR (400 MHz, CDCl3): δ 4.40 (s, 2H), 4.33 (s, 2H), 2.65 - 2.59 (m, 2H), 2.42 (d, J = 6.8 Hz, 2H), 2.13 (d, J = 13.2 Hz, 2H), 1.7 - 1.68 (m, 2H), 1.44 - 1.639 (m, 2H), 1.37 (d, J = 3.6 Hz, 1H), 1.10 (t, J = 7.2 Hz, 3H).

[0277] Synthesis of N-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)methyl)cyclobutanamine, A1-5.

Chemical Structure

[0278] Synthesis of N-((1-fluoro-4-(trifluoromethyl)cyclohexyl)methyl)ethanamine, A1-7.

Chemical Structure

[0279] Scheme A1-7 Methyl 4-trifluoromethyl-cyclohexanecarboxylate, iA1-7-2.

Chemical Structure

[0280] Methyl 1-fluoro-4-trifluoromethyl-cyclohexanecarboxylate, iA1-7-3.

Chemical formula

[0281] 1-Fluoro-4-trifluoromethyl-cyclohexanecarboxylic acid, iA1-7-4.

Chemical formula

[0282] Ethyl 1-fluoro-4-(trifluoromethyl)cyclohexanecarboxylate-(4-methoxybenzyl)-amide, iA1-7-5.

Chemical Structure

[0283] Ethyl (1-fluoro-4-(trifluoromethyl)cyclohexylmethyl)-(4-methoxybenzyl)-amine, iA1-7-6

Chemical Structure

[0284] Ethyl-(1-fluoro-4-trifluoromethyl-cyclohexylmethyl)-amine, A1-7. [Chemical formula] Pd / C (100 mg, 10%) was added to a solution of iA1-6-1 (350 mg, 0.99 mmol) in MeOH (5 mL), and the mixture was stirred at 25 °C for 20 h under H2 (1 atm). The reaction mixture was then filtered and concentrated in vacuo. The residue was purified using flash CC (EA:PE = 1:2) to give A1-7. LCMS: MS calcd: 227; MS found: 228 ([M+H] + ).

[0285] Synthesis of (3S)-3-(4-(trifluoromethyl)cyclohexyl)morpholine, A1-8. [Chemical formula] A mixture of (S)-3-(4-(trifluoromethyl)phenyl)morpholine (1.5 g, 5.6 mmol), RuCl3·H2O (635 mg, 2.8 mmol) and trioctylamine (0.49 mL, 1.1 mmol) was exposed to H2 under pressure (700 psi) at 60 °C for 140 h. The reaction mixture was then filtered through celite, concentrated in vacuo, 2 M NaOH was added and the resulting mixture was extracted with EA (2 × 30 mL). The combined EA phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash CC (MeOH:DCM = 1:10) to give A1-8. LCMS: MS calculated: 237; MS found: 238 ([M+H] + ).

[0286] N-Ethyl-N-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, BD-1

Chemical formula

[0287] Scheme BD-1 N-Ethyl-7-tosyl-N-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, iBD-1.

Chemical formula

[0288] N-Ethyl-N-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, BD-1. [Chemical formula] K2CO3 (3.4 g, 18.3 mmol) was added to a solution of iBD-1 (1.1 g, 2.2 mmol) in MeOH (10 mL). The reaction mixture was then stirred at 50 °C for 4 h. After cooling to ambient temperature, the mixture was extracted with EA (3 × 15 mL). The combined EA phases were dried (Na2SO4), filtered, and concentrated in vacuo to afford crude BD-1, which was used without further purification. LCMS: MS calculated: 326; MS found: 327 ([M+H] + )

[0289] Synthesis of tert-butyl 4-(benzyloxy)-1-oxa-6-azaspiro[2.5]octane-6-carboxylate, L4 [Chemical formula] a) NaH, Me3SI, DMF.

[0290] Scheme L4 Under N2 atmosphere, NaH (283 mg, 7.1 mmol, 60%) was added to a solution of trimethylsulfonium iodide (1.44 g, 7.1 mmol) in anhydrous DMF (20 mL) at 0 °C, and the reaction mixture was stirred for 30 min. Then, a solution of (tert-butyl 3-(benzyloxy)-4-oxopiperidine-1-carboxylate) (1.8 g, 5.9 mmol) in anhydrous DMF (5 mL) was added slowly, and the mixture was then stirred at room temperature overnight. 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 afford crude L4, which was used without further purification. LCMS: MS calculated: 319; MS found: 342 ([M+Na] + )

[0291]

Table 11

[0292]

Table 12

[0293]

Table 13

[0294]

Table 14

[0295]

Table 15

[0296]

Table 16

[0297]

Table 17

[0298]

Table 18

[0299] General method G - cyclic alkoxy - substituted secondary amine

Chemical formula

[0300] These separated stereoisomers, XG3 (denoted as 1G3, 2G3, etc.) were then reacted with the primary amine A4 to obtain XG4. After boc deprotection (XG5), it was then alkylated with bromoacetamide to generate XG6. Next, chiral separation (chromatography) was performed on the stereoisomer mixture XG6 in order to isolate as many stereoisomers as possible.

[0301] Example G6-1 Synthesis and isolation of four stereoisomers of G6-1

Chemical formula

[0302] Scheme G6-1 Synthesis of N-((6,6-dimethyltetrahydro-2H-pyran-3-yl)methyl)-N-ethyl-5,6-difluoropyrimidin-4-amine, G2-1, and separation of the stereoisomers rel-(R)-N-((6,6-dimethyltetrahydro-2H-pyran-3-yl)methyl)-N-ethyl-5,6-difluoropyrimidin-4-amine, 1G2-1 and 2G2-1

Chemical formula

[0303] Separation and isolation of stereoisomers rel-(R)-N-((6,6-dimethyltetrahydro-2H-pyran-3-yl)methyl)-N-ethyl-5,6-difluoropyrimidin-4-amine, 1G2-1 and 2G2-1

Chemical formula

[0304] Synthesis of tert-butyl (3RS,4RS)-4-((((6-((((S*)-6,6-dimethyltetrahydro-2H-pyran-3-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate, 1G4-1 and 2G4-1

Chemical formula

[0305] A mixture of 2G3-1 (97 mg, 0.34 mmol), XYZ (92 mg, 0.40 mmol), DIEA (103 mg, 0.80 mmol) and DMSO (10 mL) was stirred at 80 °C overnight. Then, the reaction mixture was cooled to room temperature, washed with H2O, and extracted with EA (20 mL). The organic phase was washed with brine, dried (Na2SO4), concentrated to obtain 2G4-1. MS calculated value: 495; MS measured value: 496 ([M+H] + )。

[0306] (3RS,4RS)-4-(((6-((((S*)-6,6-Dimethyltetrahydro-2H-pyran-3-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-ium trifluoroacetate, synthesis of 1G5-1 and 2G5-1.

Chemical formula

[0307] A mixture of 2G4-1 (166 mg, 0.33 mmol), DCM (3 mL) and TFA (3 mL) was stirred at room temperature for 2 hours and concentrated to obtain 2G5-1. MS calculated value: 395; MS measured value: 396 ([M+H] + )。

[0308] 2-((3RS,4RS)-4-(((6-((((S*)-6,6-Dimethyltetrahydro-2H-pyran-3-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, synthesis of 1G6-1 and 2G6-1.

Chemical formula

[0309] Isolation of four stereoisomers, rel-2-((3R,4R)-4-(((6-((((S)-6,6-dimethyltetrahydro-2H-pyran-3-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide and rel-2-((3R,4R)-4-(((6-((((R)-6,6-dimethyltetrahydro-2H-pyran-3-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 1G6-1-1, 1G6-1-2, 2G6-1-1 and 2G6-1-2.

Chemical formula

[0310] Subsequent chiral chromatography of 2G6-1 gave two stereoisomers, 2G6-1-1 (the first elution peak) and 2G6-1-2 (the second elution peak).

[0311] The following compounds in Table 3 were synthesized according to the general method G.

[0312]

Table 19

[0313] In the first chiral purification, the first and second eluted isomers were not separated. In the second chiral purification, the second and third eluted isomers were not separated from the mixture of the first and second eluted isomers.

[0314] Synthesis of G1-1 N-((6,6-Dimethyltetrahydro-2H-pyran-3-yl)methyl)ethanamine, synthesis of G1-1.

Chemical formula

[0315] N-((6-(Trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)ethanamine, synthesis of G1-2.

Chemical formula

[0316] iG1-3-1 was prepared according to the pamphlet of International Publication No. WO2017024018 A1 by Claremon, D., et al.

[0317] Scheme G1-3 Synthesis of N-Ethyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide, iG1-2-2 [Chemical formula] TEA (1.2 g, 7.5 mmol) and HATU (2.1 g, 5.6 mmol) were added to a solution of 6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid (740 mg, 3.7 mmol) in THF (10 mL). After stirring the reaction mixture at 30 °C for 30 minutes, ethylamine (2 M in THF, 3.7 mL) was added and the reaction was stirred at 30 °C overnight. H2O (20 mL) was added and the mixture was extracted with EA (3 × 20 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo to afford crude iG1-2-2. MS calculated: 225; MS found: 226 ([M+H] + ).

[0318] Synthesis of N-((6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)ethanamine, G1-2 [Chemical formula] Under N2 atmosphere, BH3.THF (15 mL, 14.9 mmol) was added portionwise to a solution of crude iG1-2-2 (1.5 g) in THF (10 mL) and the reaction was stirred under reflux overnight. Next, the reaction was cooled to 0 °C (ice bath) and then MeOH (2 mL) was added followed by HCl (2 mL, 1 M). After concentration, Na2CO3 (saturated, 20 mL) was added and the residue and mixture were extracted with EA (3 × 20 mL). The combined organic phases were washed with brine (20 mL) and dried (Na2SO4). The organic solution was filtered and concentrated in vacuo to afford crude 2-5 which was used without further purification. MS calculated: 211; MS found: 212 ([M+H] + ).

[0319] [Table 20]

[0320]

Table 21

[0321]

Table 22

[0322]

Table 23

[0323] Biological evaluation The activity of the compounds was evaluated using a RORγ reporter assay (also called the Gal4 assay). Both the Gal4 and Th17 assays (another preferred assay) are cell-based assays that monitor the functional activity of the compound being assayed.

[0324] Also, the compounds disclosed herein were evaluated in a mouse in vivo pharmacodynamic model (anti-CD3-induced plasma IL-17A).

[0325] RORγ reporter assay (Gal4) The HEK293 cell line is transiently co-transfected with two plasmids, one having a RORγ ligand binding domain fused to the galactose-responsive transcription factor (Gal4) and the other having a luciferase reporter gene and a Gal binding site (UAS). This configuration enables the determination of RORγ activity in the cell line through the measurement of luminescence.

[0326] A suspension of RORγ reporter cells was dispensed into plates and cultured at 37 °C and 5% CO2 for 2 hours. The medium composition 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). The dose-response curves for the compounds were prepared in 100% DMSO and further diluted 100-fold in the culture medium. The compound solution was added to the plates containing the cells (final DMSO concentration of 0.1%), and the plates were 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.

[0327] After calculating the mean RLU ± S.D. values for all treatment sets, the percentage decrease in RORγ activity in response to the corresponding test compound was calculated. The following formula was used: Activity = 100 * [1 - (× test compound / mean vehicle), with a theoretical minimum decrease (0% decrease). For all experiments, the activity values were plotted against the compound concentration in a single 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 using excel-fit software with the X-204 model curve.

[0328] The results of the RORγ reporter (Gal4) assay are shown in Table 2 below.

[0329]

Table 24

[0330] As can be seen from Table 2 above, the compounds of the present disclosure were found to exhibit advantageous activity across the RORγ reporter (Gal4) assay.

[0331] According to one embodiment, in the RORγ reporter assay (Gal4), IC50 Compounds having a <1000 nM value are disclosed herein.

[0332] According to another preferred embodiment, in the RORγ reporter assay (Gal4), IC 50 Compounds having a <500 nM value are disclosed herein.

[0333] According to another more preferred embodiment, in the RORγ reporter assay (Gal4), IC 50 Compounds having a <100 nM value are disclosed herein.

[0334] In vivo induction of IL-17A in a mouse anti-CD3 model Male C57BL / 6JRj mice (7 weeks old) were purchased from Janvier Labs and housed in Almirall's animal facility throughout the study. The animals were conditioned to a new environment at 22 °C ± 2 °C, 55% ± 10% relative humidity, and a 12 h:12 h light–dark cycle for 5 days. The animals were housed in polycarbonate cages and given 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 European Committee Directive 2010 / 63 / EU and Catalan and Spanish laws. All procedures were performed in accordance with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines and with approval from the Almirall (Barcelona, Spain) Animal Experimentation Ethics Committee.

[0335] At 0 hours (day 0) and 48 hours (day 3), mice were intraperitoneally injected with 7.5 μg of anti-CD3e (clone 145-2C11 from Pharmingen BD). The non-induced group was injected with PBS instead of anti-CD3e. At the end of the test (4 hours after anti-CD3e injection), the animals were anesthetized with isoflurane (Baxter), and 0.5 - 1 mL of blood samples were collected into heparinized tubes by intracardiac puncture. Plasma samples were stored at -80 °C for subsequent analysis.

[0336] The test compound was freshly suspended in sterile 0.5% methylcellulose, 0.1% tween (R)-80 solution (10 mL / kg body weight). The compound was orally administered by forced gavage according to the selected dosing and body weight; the control animals were given the same volume of vehicle. Treatment was performed twice a day from day 0 to day 3, and the last dose was given 1 hour before anti-CD3e injection.

[0337] Plasma levels of IL-17A were measured by ELISA (R&D Systems) according to the manufacturer's instructions. The 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 treatment can be expressed as the mean of each treatment group ± S.E.M. Statistical analysis of the data was performed by one-way ANOVA, followed by Dunnett's multiple comparison test if appropriate. Differences were considered significant if p ≤ 0.05.

[0338] Results

[0339]

Table 25

[0340] In summary, the compounds disclosed herein have been found to at least modulate the activity of RORγ. The compounds disclosed herein are active and have, for example, Gal4 < 1000 nM, for example < 500 nM, for example < 100 nM.

[0341] Furthermore, the compounds disclosed herein have been found to have utility in vivo and, as a result, may be useful for treating inflammatory, metabolic and autoimmune diseases or conditions thereof. The present invention provides, for example, the following items. (Item 1) A compound according to formula (I)

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Claims

1. A compound according to formula (I) 【Chemical 81】 its stereoisomers, or a pharmaceutically acceptable salt of said compound or stereoisomer (wherein,[[]] n is selected from the group consisting of 0, 1 and 2; R is selected from the group consisting of hydrogen, C １～６ alkyl and C １～４ hydroxyalkyl; A is fluoro and Y is hydrogen; or Y and A, together with the atoms to which they are attached, form a 5-membered heteroaryl or heteroalicyclic ring system optionally substituted with one or two substituents selected from halogen, cyano or C １～４ alkyl; R ０ａ and R ０ｂ are independently selected from the group consisting of hydrogen, C １～４ alkyl, C １～４ hydroxyalkyl, and C １～４ haloalkyl; R １ａ and R １ｂ are independently selected from the group consisting of hydrogen, hydroxyl, amino, halogen, 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)OH, -C(=O)NH ２ , -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 substituted or unsubstituted 4- to 6-membered heteroalicyclic ring system; 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 substituted or unsubstituted 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 ６ａ and R ６ｂ are each independently selected from the group consisting of hydrogen, cyano, halogen, C １～４ alkyl, C １～４ hydroxyalkyl, C １～４ haloalkyl, C １～４ hydroxyhaloalkyl, C １～４ alkoxy, C １～４ haloalkoxy, and substituted or unsubstituted heteroaryl, provided that when n is 0, at least one of R ６ａ and R ６ｂ is selected from the group consisting of cyano, halogen, C １～４ alkyl, C １～４ haloalkyl, C １～４ hydroxyhaloalkyl, C １～４ hydroxyalkyl, C １～４ alkoxy, C １～４ haloalkoxy, and substituted or unsubstituted heteroaryl; or R ６ａ and R ６ｂ together with the carbon atoms to which they are attached, contain from 1 to 3 heteroatoms selected from S, O, or N and form a 3- to 6-membered cycloaliphatic ring system or a 3- to 6-membered heteroalicyclic ring system optionally substituted with from 1 to 3 halogen atoms; and R ７ is selected from the group consisting of hydroxyl, cyano, halogen, C １～４ alkyl, C １～４ haloalkyl, C １～４ hydroxyalkyl, C １～４ alkoxy, and C １～４ haloalkoxy).

2. The compound, stereoisomer, or salt according to Claim 1, wherein A is fluoro and Y is hydrogen.

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 ; 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, stereoisomer, or salt according to claim 1.

4. R ０ａ and R ０ｂ The compound, stereoisomer, or salt according to claim 1, wherein both are hydrogen.

5. R １ａ , R １ｂ and R ２ The compound, stereoisomer, or salt according to claim 1, wherein at least one of

6. 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, stereoisomer, or salt according to claim 1.

7. R １ａ The compound, stereoisomer, or salt according to claim 1, wherein R is hydroxyl or hydrogen.

8. R １ｂ The compound, stereoisomer, or salt according to claim 1, wherein R is hydrogen.

9. R ２ is hydrogen, halogen, hydroxyl, cyano, methyl, ethyl, -CH ２ OH, -CH ２ CH ２ OH or -C(=O)O-C １～２ alkyl, the compound, stereoisomer, or salt according to claim 1.

10. R ３ The compound, stereoisomer, or salt according to claim 1, wherein R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, or cyclobutyl.

11. R ４ and R ５ each is independently hydrogen or methyl, or R ４ and R ５ forms a cyclopropyl together with the carbon atom to which they are attached, the compound, stereoisomer, or salt according to claim 1.

12. R ３ and R ４ wherein the heteroalicyclic ring system containing R and R is 4-membered heteroaryclyl, 5-membered heteroaryclyl, or 6-membered heteroaryclyl, and the heteroalicyclic ring system is optionally substituted with one or two substituents selected from halogen, hydroxyl, and C １～４ alkyl, the compound, stereoisomer, or salt according to claim 1.

13. R ３ and R ４ wherein the heteroalicyclic ring system containing R and R is azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, 2-azabicyclo[3.1.0]hexanyl, or 3-azabicyclo[3.1.0]hexanyl, the heteroalicyclic ring system is optionally substituted with one or two substituents selected from halogen and methyl, and when the heteroalicyclic ring system is substituted or unsubstituted 2-azabicyclo[3.1.0]hexanyl, R ５ is absent, the compound, stereoisomer, or salt according to claim 12.

14. R ６ａ and R ６ｂ are each independently hydrogen, halogen, C １～４ haloalkyl, or C １～４ haloalkoxy, or R ６ａ and R ６ｂ together with the carbon atom to which they are attached form a 3- to 6-membered heteroalicyclic ring system or a 3- to 6-membered alicyclic ring system optionally substituted with 1 to 3 halogen atoms, the compound, stereoisomer, or salt according to claim 1.

15. R ６ａ is hydrogen, -CF ３ , -CH ２ F, -CCH ３ F ２ , -OCF ３ , or -OCHF ２ , and R ６ｂ is hydrogen; or, R ６ａ and R ６ｂ together with the carbon atom to which they are attached form a 3- to 4-membered alicyclic ring system optionally substituted with 1 to 3 fluorines, or a 4- to 5-membered heteroalicyclic ring system containing 1, 2, or 3 heteroatoms selected from O and N, the compound, stereoisomer, or salt according to claim 1.

16. R ６ａ is -CF ３ and R ６ｂ is hydrogen; or, R ６ａ and R ６ｂ together with the carbon atom to which they are attached form an oxetanyl or cyclopropyl optionally substituted with one or two fluorines, the compound, stereoisomer, or salt according to claim 1.

17. The compound, stereoisomer, or salt according to Claim 1, wherein n is 0 or 1.

18. R ７ is halogen, hydroxyl, cyano, -CF ３ , -OCHF ２ , -CHF ２ or -OCF ３ The compound, stereoisomer, or salt according to claim 1, wherein

19. The compound, stereoisomer, or salt according to Claim 1, wherein R ０ａ and R ０ｂ are both hydrogen; R １ａ and R １ｂ are independently hydrogen or hydroxyl; R ２ is selected from the group consisting of hydrogen and hydroxyl; R is hydrogen; Y is hydrogen and A is fluoro; or Y and A, together with the atom to which they are attached and the pyrimidine ring of formula (I), form an unsubstituted pyrrolo[2,3-d]pyrimidine; R ３ is selected from the group consisting of methyl, ethyl, cyclopropyl and cyclobutyl, R ４ and R ５ are hydrogen; or R ３ and R ４ together with the atoms to which they are attached form an unsubstituted morpholinyl, and R ５ is hydrogen; n is 0; or, n is 1 and R ７ is fluoro; R ６ａ is -CF ３ and R ６ｂ is hydrogen; or, R ６ａ and R ６ｂ together with the carbon atom to which they are attached form an oxetanyl or cyclopropyl group substituted with two fluorines, a compound, stereoisomer, or salt thereof.

20. The compound, stereoisomer, or salt according to Claim 1, wherein 2-(4-((((6-((((1,1-difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((((5-fluoro-6-(methyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((((6-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((((6-(cyclopropyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((((6-(cyclobutyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((((6-(((2-oxaspiro[3.5]nonan-7-yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide 2-(4-((((6-(ethyl((1-fluoro-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide 2-(4-((((5-fluoro-6-(3-(4-(trifluoromethyl)cyclohexyl)morpholino)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide 2-(4-((((4-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide 2-(4-((((4-(cyclobutyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide 2-(4-((((6-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-yl)amino)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, and A compound, stereoisomer, or salt selected from the group consisting of 2-(4-((((4-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20, a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

22. A pharmaceutical composition comprising the compound, stereoisomer, or salt according to any one of claims 1 to 20 for treating inflammatory, metabolic, tumor, or autoimmune diseases.

Images