PYRIMIDINE-DERIVED COMPOUNDS THAT MODULATE ROR-GAMMA RECEPTOR ACTIVITY AND THEIR USE IN TREATING INFLAMMATORY, METABOLIC, ONCOLOGICAL, AND AUTOIMMUNE DISEASES

Abstract

Active compounds against nuclear receptors, pharmaceutical compositions containing the compounds, and the use of the compounds in therapy are disclosed.

Description

COMPOUNDS ACTIVE AGAINST NUCLEAR RECEPTORS FIELD The aspects and embodiments described herein relate to compounds active against nuclear receptors, pharmaceutical compositions comprising the compounds and methods of treating inflammatory, metabolic, oncological and autoimmune diseases or disorders using the compounds. BACKGROUND Nuclear receptors are a family of transcription factors that participate 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. Some examples of nuclear receptors include retinoic acid receptor-related orphan nuclear receptors (ROR). RORs contain four main domains: an N-terminal A / B domain, a DNA-binding domain, a hinge domain, and a ligand-binding domain. Binding of ligands to the ligand-binding domain is believed to cause conformational changes in the domain that result in actions at downstream sites. There are different isoforms and these isoforms differ only in their N-terminal A / B domain (Jetten, 2009, Nuclear Receptor Signaling). RORs consist of three members, namely ROR alpha (RORa or RORa), ROR beta (RORP or RORb) and ROR gamma (RORy or RORc). RORa is expressed in many tissues such as Purkinje cells of the cerebellum, liver, thymus, skeletal muscle, skin, lung, adipose tissue and kidney. RORa regulates neuronal cell development, bone metabolism and arteriosclerosis (Jetten, 2009, Nuclear Receptor Signaling). Additionally, RORa plays a role in immune responses such as regulating interleukin (IL) 17A expression in T helper (Th) 17 cells and regulatory T cell (Treg) function (Castro PLOS 2017; Malhotra 2018). RORp exhibits a pattern of restricted expression that is limited to certain regions of the brain (cerebral cortex, thalamus, hypothalamus, and pineal gland) as well as the retina (Jetten, 2009, Nuclear Receptor Signaling). RORp has been linked to epilepsy and, together with RORa, also to bipolar disease (Rudolf 2016; Lai 2015). RORy has a broad expression pattern and has been the most recently discovered of the three members. To date, two different protein forms have been reported: RORyl and RORy2 (RORy2 is also known as RORyt). Typically, RORy is used to describe RORyl and / or RORyt. RORyl is expressed in many tissues and is expressed ΜΛ / t / ZUZZ / UOO 14 1 mainly in the kidneys, liver and skeletal muscle. In contrast, RORyt expression is restricted to some cell types of the immune system and to lymphoid organs such as the thymus and secondary lymphoid tissues (Hirose 1994; Jetten, 2009, Nuclear Receptor Signaling). RORyt has been identified as a key regulator of Th17 cell differentiation and IL-17 production by γδ T cells, Th17 cells, cytotoxic T cells (Te)17, and innate lymphoid cells type 3 (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 PLOS2017). T cells lacking RORyt could not differentiate into Th17 cells even under Th17-polarizing culture conditions, whereas overexpression of RORyt in untreated CD4+ T cells was sufficient to accelerate the expression of Th17-related chemokines and cytokines (Gaffen 2014, Nat Rev Immunol', Yang 2014, Trend Pharmacol Sel). IL-23 is a vital checkpoint in the generation, maintenance and activation of pathogenic Th17 lymphocytes. In response to IL23 signals, RORyt cooperates with a network of transcription factors (STAT3, IRF4 and BATF) to initiate the complete differentiation program of Th17 lymphocytes (Gaffen 2014, Nat Rev Immunol). Th17 lymphocytes and the IL-17 immune response have been shown to be associated with the pathology of many human autoimmune and inflammatory disorders. Therapeutic strategies targeting the IL-23—IL-17 axis are being developed in many autoimmune diseases and some of them have already been shown to provide clinical efficacy in certain diseases (Patel 2015; Krueger 2018 Exp Dermatol). Therefore, there is evidence that RORa, RORp, and RORy play a role in the pathogenesis of many diseases. It would be desirable to provide compounds that modulate the activity of RORa and / or RORy for use in the treatment of inflammatory, metabolic and autoimmune diseases. Documents WO2016020288 and WO2016020295 describe compounds that modulate the activity of RORgamma receptors. However, there remains a need for potent RORgamma modulators with improved physicochemical properties. SUMMARY In one aspect, compounds of Formula (I) are provided herein. ΜΛ / t / ZUZZ / UOO 14 1 a stereoisomer thereof, or a pharmaceutically acceptable salt of the 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, C1-6 alkyl and Ci-4 hydroxyalkyl; A is fluorine and Y is hydrogen; either Y and A are taken together with the atoms to which they are attached to form a 5-membered heteroaryl or heteroalicyclyl ring system optionally substituted with 1 or 2 substituents selected from halogen, cyano or Ci-4 alkyl; Roa and Rob are independently selected from the group consisting of hydrogen, C1-4alkyl, hydroxyCi-4alkyl, and haloCi-4alkyl; Ría and Rw are independently selected from the group consisting of hydrogen, hydroxyl, amino, halogen, Ci-4 alkyl, hydroxy Ci-4 alkyl, and halo Ci-4 alkyl; R2 is selected from the group consisting of hydrogen, hydroxyl, amino, cyano, halogen, C1-4 alkyl, Ci-4 haloalkyl, C1-4 hydroxyalkyl, C(=O)OH, C(=O)NH2, C(=O) O-(Cy-4 alkyl) and substituted or unsubstituted heteroaryl; Rsse is selected from the group consisting of Ci-4 alkyl, Ci-4 alkenyl, Ci-4 haloalkyl, Ci-4 hydroxyalkyl, C3-7 cycloalkyl. and C3-7 cycloalkenyl; either Rs and R4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted 4- to 6-membered heteroalicyclic ring system; R4 is hydrogen or Ci-4 alkyl, provided that R3 and R4 are not taken together with the atoms to which they are attached to form a substituted or unsubstituted 4- to 6-membered heteroalicyclic ring system; or R4 and R5 are taken together with the carbon atom to which they are attached to form a C3.4 cycloalkyl; R is absent; or is selected from the group consisting of hydrogen and Ci-4 alkyl, provided that R4 and R5 are not taken together with the carbon atom to which they are attached to form a C8-4 cycloalkyl; Rhea and Reb are independently selected from the group consisting of hydrogen, cyano, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 hydroxyhaloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and substituted heteroaryl. or unsubstituted, and whenever n is 0 then at least one of Rea and Reb is selected from the group consisting of cyano, halogen, Ci-4 alkyl, C1-4 haloalkyl, Cm hydroxyhaloalkyl, C1-4 hydroxyalkyl, C1-alkoxy 4, Ci-4 haloalkoxy, and substituted or unsubstituted heteroaryl; either Rhea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 6-membered heteroalicyclic or 3- to 6-membered alicyclic ring system comprising 1 to 3 heteroatoms selected from S, O, or N, optionally substituted with one to three halogen atoms; and R7 is selected from the group consisting of hydroxyl, cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, Ci-4 hydroxyalkyl, C1-4 alkoxy, and Ci-4 haloalkoxy. In one aspect, provided herein are pharmaceutical compositions 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. In one aspect, provided herein are compounds of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer, or pharmaceutical compositions thereof for use in the treatment and / or prevention of a disease or disorder or a symptom thereof that is selected from the group consisting of asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uveitis, celiac disease and food allergy, atopic dermatitis, lichen planus, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, steatosis, steatohepatitis , nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NAFLD), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (ILD), irritable bowel syndrome (IBS), Sjógren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barre syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, diabetes type II and cancer. Furthermore, favorable features of various embodiments are defined in the dependent claims and within the following detailed description. Detailed description of preferred embodiments Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as customarily interpreted by one skilled in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those found in this section shall prevail unless otherwise indicated. As used herein, any R group(s) such as, without limitation, R, Ri, R2, Rs, R4, Rs, Rs, R9, and R10, represent substituents that can be attached to the indicated atom. Examples of R groups include, but are not limited to, hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heteroalicyclyl. If two R groups are covalently bonded to the same or adjacent atoms, then they may be considered together or combined as defined herein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group. For example, without limitation, if it is stated that Ray Rb of an NRaRb group are considered together or combined, this means that they are covalently bonded to each other at their terminal atoms to form a ring that includes the nitrogen: . Ra—Nf \ Rb As the skilled person will readily recognize, any group given and disclosed herein may comprise one or more additional hydrogens in addition to that provided by a group R, which is hydrogen, attached to the group. Whenever a group is described as substituted or unsubstituted, if substituted, the substituent(s) (which may be present one or more times such as 1,2, 3 or 4 times) are independently selected from alkyl, alkenyl, alkynyl. , cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroal¡c¡cl¡l)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and di-substituted amino groups and protected derivatives thereof. When a substituent in a group is considered to be substituted, the substituent itself is substituted with one or more of the indicated substituents. When the referenced substituent is substituted, this means that one or more hydrogen atoms in the referenced substituent may be replaced by one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, ΜΛ / t / ZUZZ / UOO 14 Ί alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N- sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, and protected derivatives thereof. The protective groups that can form the protected derivatives of the above substituents are known to those skilled in the art and can be consulted in the references of Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, NY, 1999, which are incorporated herein by reference in their entirety. As used herein, Cma Cn, Cm-Cno Cm-n, where m and n" are integers, refers to the number of carbon atoms in the relevant group. That is, the group can contain from m to n, inclusive, carbon atoms. Therefore, for example, a Ci to Ce 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-. If neither m nor n is designated with respect to a group, the broader range described in these definitions should be assumed. As used herein, alkyl refers to a straight or branched hydrocarbon chain group that is fully saturated (no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (wherever it appears herein, a numerical range such as 1 to 20 refers to each integer in the given range; e.g., 1 to 20 atoms of carbon 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, although the present definition also covers the case of the term alkyl in which no numerical interval is designated). The alkyl group may also be an alkyl having 1 to 10 carbon atoms, such as Οι-θ. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compounds may be designated as C1-C4 alkyl, C1-4 alkyl or similar designations. By way of example only, Ci-C4 alkyl or Ci-4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl , n-butyl, isobutyl, sec-butyl and t-butyl. Common alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. When substituted, the one or more substituent groups are one or more groups individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo , alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, Nsulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, ΜΛ / t / ZUZZ / UOO 14 1 trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, and protected derivatives thereof. As used herein, alkenyl refers to an alkyl group containing in the straight or branched hydrocarbon chain one or more double bonds. If more than one double bond is present, the double bonds may be conjugated or unconjugated. The alkenyl group may have 2 to 20 carbon atoms (wherever it appears herein, a numerical range such as 2 to 20 refers to each integer in the given range; e.g., 2 to 20 atoms of carbon 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, although the present definition also covers the case of the term alkenyl in which no numerical interval is designated). When substituted, the substituent group(s) are one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy and amino, including mono- and disubstituted amino groups, and protected derivatives thereof. As used herein, alkynyl refers to an alkyl group containing in the straight or branched hydrocarbon chain one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms (wherever it appears herein, a numerical range such as 2 to 20 refers to each integer in the given range; e.g., 2 to 20 atoms of carbon 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, although the present definition also covers the case of the term alkynyl in which no numerical interval is designated). An alkynyl group may be substituted or unsubstituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with respect to substitution of the alkenyl group. As used herein, hetero may be attached to a group and refers to one or more carbon atoms and the associated hydrogen atom(s) in the attached group having been independently replaced by the same or different heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur. As used herein, heteroalkyl, alone or combined with another term, refers to a linear or branched alkyl group consisting of the aforementioned number of carbon atoms, where one or more carbon atoms, such as 1 ,2, 3 or 4 carbon atoms, and the associated hydrogen atom(s) have been independently replaced by equal or different heteroatoms selected from nitrogen, oxygen and sulfur. The carbon atom(s) being replaced can be found in the middle or at the end of the alkyl group. Some examples of heteroalkyl include C1-6 heteroalkyl wherein one or more of ΜΛ / Ε / ΖυΖΖ / υοΟΊ4Ί carbon atoms have been replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; Examples are -S-alkyl, -O-alkyl, -NH-alkyl, alkylene-O-alkyl, etc. A heteroalkyl may be substituted. As used herein, aryl refers to a carbocyclic ring (all carbon) or two or more fused rings (rings sharing two adjacent carbon atoms) that have a fully delocalized pi electron system. In some embodiments described herein, the aryl group is a Cmo aryl, which may be substituted or unsubstituted. Some examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. An aryl group may be substituted. When substituted, the hydrogen atoms are replaced by one or more substituent groups which are one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl) alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro , silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, and protected derivatives thereof. When substituted, substituents on an aryl group can form a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl. As used herein, heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with a fully delocalized pi electron system), wherein at least one of the atoms in the ring system is a heteroatom, that is, an element other than carbon, which includes, but is not limited to, nitrogen, oxygen and sulfur. In some embodiments described herein, heteroaryl includes, but is not limited to, Ce-w heteroaryl, wherein one to four carbon atoms are replaced by one to four 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. Some examples of multicyclic heteroaryl include, but are not limited to, quinoline, isoquinoline, quinazoline, quinoxaline, indole, purines, benzofuran, benzothiophene, benzopyranones (e.g., coumarin, chromone, and isocoumarin). A heteroaryl may be substituted. When substituted, the hydrogen atoms are replaced by one or more substituent groups which are one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroallcyclyl) alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, SIVIA / t / ZUZZ / UOO 14 I sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, hydroxyhaloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, and protected derivatives thereof. When substituted, substituents on a heteroaryl group can form a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl. An aralkyl or arylalkyl is an aryl group connected, as a substituent, by an alkylene group. The alkylene group and the aryl of an aralkyl may be substituted. Some 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. A heteroaralkyl or heteroarylalkyl is a heteroaryl group connected, as a substituent, by an alkylene group. The alkylene group and the heteroaryl of a heteroaralkyl may be substituted. Some examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl and imidazolylalkyl, and their substituted as well as benzofused analogues. In some cases, the alkylene group is a lower alkylene group. An alkylene is a straight chain linking group, which forms bonds to connect molecular fragments via their terminal carbon atoms. Alkylene can have from 1 to 20 carbon atoms. The alkylene may also be an alkylene having 1 to 10 carbon atoms, such as Ci-g. Alkylene could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene may be designated as C1-C4 alkylene, C1-4 alkylene or similar designations. Some non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-(CH2)4-) groups. In the case of methylene, the two connected fragments connect to the same carbon atom. A lower alkylene group may be substituted. As used herein, heteroalkylene, alone or combined with another term, refers to an alkylene group consisting of the aforementioned number of carbon atoms, in which one or more of the carbon atoms, such as 1,2, 3 or 4 carbon atoms are independently replaced by equal or different heteroatoms selected from oxygen, sulfur and nitrogen. Some 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-CH2NH-, -CH2-CH2- NH-CH2-, -O-CH2-CH2-O-CH2-CH2-O-, -O-CH2-CH2-O-CH2-CH2- and the like. As used herein, alkylidene refers to a divalent group, such as =CR'R, that is bonded to a carbon of another group, forming a double bond. Alkylidene groups include, but are not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, arylalkylidene refers to an alkylidene group wherein R' or R is an aryl group. An alkylidene group may be substituted. ΜΛ / t / ZUZZ / UOO 14 1 As used herein, alkoxy refers to the group -OR where R is an alkyl, e.g. e.g., methoxy, ethoxy, n-propoxy, cyclopropoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like. An alkoxy may be substituted. As used herein, alkylthio refers to the formula -SR where R is an alkyl defined as above, e.g. e.g., methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, isobutylmercapto, sec-butylmercapto, fe / T-butylmercapto and the like. An alkylthio may be substituted. As used herein, aryloxy and arylthio refer to RO- and RS-, where R is an aryl as defined above, e.g. e.g., phenoxy, naphthalenyloxy, azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio and the like. An aryloxy and an arylthio may both be substituted. As used herein, alkenyloxy refers to the formula -OR wherein R is an alkenyl as defined above, e.g. e.g., vinyloxy, propenyloxy, n-butenyloxy, isobutenyloxy, sec-pentenyloxy, tert-pentenyloxy and the like. The alkenyloxy may be substituted. As used herein, acyl refers to a hydrogen, alkyl, alkenyl, alkynyl or aryl connected, as a substituent, by a carbonite group. Some examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted. As used herein, cycloalkyl refers to a fully saturated mono- or multicyclic hydrocarbon ring system (without double bonds). When it is composed of two or more rings, these rings can be joined together in a condensed manner, with bridges or spiranically connected. Cycloalkyl groups can vary from C3a Cio, such as C3a Ce. A cycloalkyl group can be substituted or unsubstituted. Common cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. If substituted, the substituent(s) may be an alkyl or may be selected from those indicated above with respect to substitution of an alkyl group, unless otherwise indicated. When substituted, substituents on a cycloalkyl group can form an aromatic ring fused to the cycloalkyl group, which includes an aryl and a heteroaryl. As used herein, cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there are more than one, they cannot form a fully delocalized pi electron system in the ring (if not , the group would be an aryl, as defined herein). When it is composed of two or more rings, the rings can be connected to each other in a condensed manner, with bridges or spiranically connected. Cycloalkenyl groups can vary from C3 to Cw, such as from C3 to C8, or from Cs to C10. For example, C3.8cycloalkenyl includes C+e cycloalkenyl. C5-8 cycloalkenyl or Cs-s cycloalkenyl. A cycloalkenyl group may be substituted or unsubstituted. When substituted, the substituent(s) may be an alkyl or may be selected from the groups ΜΛ / t / ZUZZ / UOO 14 1 disclosed above with respect to substitution of the alkyl group unless otherwise indicated. When substituted, substituents on a cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, which includes an aryl and a heteroaryl. As used herein, cycloalkynyl refers to a cycloalkyl group containing one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a condensed manner, with bridges, or spiranically connected. Cycloalkynyl groups can vary from Cs to C12. A cycloalkynyl group may be substituted or unsubstituted. When substituted, the substituent(s) may be an alkyl or may be selected from the groups disclosed above with respect to substitution of the alkyl group unless otherwise indicated. When substituted, substituents on a cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, which includes an aryl and a heteroaryl. As used herein, heteroalicyclic or heteroalicyclyl refers to a 3 to 18 membered ring consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The heteroalicyclic or heteroalicyclyl groups may range from C2 to C10, in some embodiments they may range from C2 to C9, and in other embodiments they may range from C2 to Ce. In some embodiments, the heteroalicyclic or heteroalicyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. , which can be joined together in a condensed manner, with bridges or connected spiranically; and the nitrogen, carbon and sulfur atoms in the heteroalicyclic or heteroalicyclyl group may be oxidized; the nitrogen may be quaternized; and the rings may also contain one or more double bonds, as long as they do not form a completely delocalized pi electron system throughout all the rings, examples are 2 / 7-benzo[b][1,4]oxazin-3( 4 / - / )-one, 3,4-dihydroquinol¡n-2(1 H)-one, 1,2,3,4tetrahydroquinoline, 3,4-dihydro-2 / - / -benzo[b][1, 4]oxazine, 2,3-dihydrobenzo[d]oxazole, 2,3dihydro-1 / - / -benzo[c / |¡mídazole, indoline and 1,3-dihydro-2 / - / -benzo[d] ¡m¡dazol-2-one and benzo[d|oxazol-2(3H)-one. The heteroalicyclyl groups may be substituted or unsubstituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acllo, ester, O-carboxy, mercapto, alkylthio, arylthio, clane, halogen, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanate, thiocyanate, isothiocyanate, nitro, silyl , haloalkyl, hydroxyalkyl, haloalcoxl, trihalomethanesulfonyl, trihalomethanesulfonamido and amino, including mono- and disubstituted amino groups, and protected derivatives thereof. Some examples of such heteroalicyclic or heteroalicyclyl groups include, but are not limited to, azepinyl, dioxolanyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, piperidinyl ΛΖ-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydrofuranyl , tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinylsulfone. When substituted, substituents on a heteroalicyclyl group can form an aromatic ring fused to the heteroalicyclyl group, which includes an aryl and a heteroaryl. A (cycloalkyl)alkyl is a cycloalkyl group connected, as a substituent, by an alkylene group. The alkylene and cycloalkyl of a (cycloalkyl)alkyl may be substituted. Some examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl and the like. In some cases, the alkylene group is a lower alkylene group. A (cycloalkenyl)alkyl is a cycloalkenyl group connected, as a substituent, by an alkylene group. The alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group. A (cycloalkynyl)alkyl is a cycloalkynyl group connected, as a substituent, by an alkylene group. The alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group. As used herein, halo or halogen refers to F (fluoro), OI (chlorine), Br (bromine) or I (iodine). As used herein, haloalkyl refers to an alkyl group in which one or more of the 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. A haloalkyl may be substituted or unsubstituted and some embodiments relate to a haloalkyl having 1 to 10 carbon atoms such as a C1-6 haloalkyl. As used herein, hydroxyhaloalkyl refers to a halohalkyl group in which one or more of the hydrogen atoms are replaced by hydroxyl. Such substituted hydroxyhaloalkyl groups include, but are not limited to, 1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl and 1,1-difluoro-2-hydroxyethyl. Some embodiments relate to a hydroxyhaloalkyl having 1 to 10 carbon atoms, such as C1-6 hydroxyhaloalkyl. Other embodiments relate to C1.4 hydroxyhaloalkyl. As used herein, haloalkoxy refers to an RO- group wherein R is a haloalkyl group. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. A haloalkoxy may be substituted. As used herein, the term “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxyl group. Such MA / t / ZUZZ / UOO 14 1 groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and hydroxyethyl. A hydroxyalkyl group may be substituted or unsubstituted, and some embodiments refer to a hydroxyalkyl having 1 to 10 carbon atoms, such as Ci-θ hydroxyalkyl or C1-4 hydroxyalkyl. An O-carboxy group refers to a group RC(=O)O- in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl or (heteroalicyclyl )alkyl, as defined herein. An Ocarboxy may be substituted. A C-carboxí group refers to a group -C(=O)OR in which R can be the same as that defined with respect to O-carboxí. A C-carboxy may be substituted. A trihalomethanesulfonyl group refers to a group X3CSO2- where X is a halogen. A dashed bond, ξξζζξ, represents optional unsaturation between the atoms forming the bond. This bond can be unsaturated (e.g., C=C, C=N, C=O) or saturated (e.g., C-C, C-N, C-O). When a dashed bond is present in a ring system, it may be part of an aromatic ring system. As used herein, a linear, bold or dashed (non-wedged) bond refers to the relative stereochemistry that includes all possible stereoisomers at that position. As used herein, and unless otherwise indicated, a wedge bond (bold, dashed or otherwise), —, or......, refers to the absolute stereochemistry relating to the this particular prisoner and summary as represented in that position. A nitro group refers to a -NO2 group. A cyano group refers to a -CN group. A cyanate group refers to an -OCN group. An isocyanate group refers to a -NCO group. A thiocyanate group refers to a -SCN group. A carbonyl group refers to a -C(=O)- group. A thiocarbonyl group refers to a ”-C(=S)- group. An oxo group refers to an =O group. A hydroxy group or hydroxyl group refers to an -OH group. An isothiocyanate group refers to a -NCS group. A sulfinyl group refers to a group -S(=O)-R in which R may be the same as that defined with respect to O-carboxy. A sulfinyl may be substituted. A sulfonyl group refers to a SO2R group in which R may be the same as defined with respect to O-carboxy. A sulfonyl may be substituted. ΜΛ / t / ZUZZ / UOO 14 Ί An S-sulfonamido group refers to a -SO2NRaRb group in which Ra and Rb can be, independently of each other, the same as those defined with respect to the R group that has been defined for O-carboxy, or they can be combined to form a ring system selected from the group consisting of substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted heteroalicyclyl unsubstituted, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. An S-sulfonamide may be substituted. An N-sulfonamido group refers to a group RSO2N(Ra)- in which R and Ra can be, independently of each other, the same as those defined with respect to the group R that has been defined for O-carboxy. An N-sulfonamide may be substituted. A trihalomethanesulfonamido group refers to a group "X3CSO2N(R)- with X as halogen and R may be the same as that defined with respect to O-carboxy. A trihalomethanesulfonamide may be substituted. A C-amido group refers to a group -C(=O)NRaRb in which Ra and Rb can be, independently of each other, the same as those defined with respect to the R group that has been defined for O-carboxy , or they may combine to form a ring system selected from the group consisting of substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, substituted or unsubstituted C3-8 cycloalkynyl, substituted or unsubstituted C3-8 cycloalkenyl , substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. A C-amido may be substituted. An N-amido group refers to a group RC(=O)NRa- in which R and Ra can be, independently of each other, the same as those defined with respect to the R group that has been defined for O-carboxy . An N-amido may be substituted. An ester refers to a group -C(=O)OR in which R can be the same as that defined with respect to O-carboxy. An ester may be substituted. A lower alkoxyalkyl refers to an alkoxy group connected through a lower alkylene group. A lower alkoxyalkyl may be substituted. An amine or amino group refers to RNH2 (a primary amine), R2NH (a secondary amine), R3N (a tertiary amine). An amino group may be substituted. A lower aminoalkyl refers to an amino group connected through a lower alkylene group. A lower aminoalkyl may be substituted. Any monosubstituted or unsubstituted amino group in a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester, and any carboxyl group can be converted to an amide or an ester using techniques well known to those skilled in the art. the technique (refer, for example, to Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999). As used herein, the abbreviations for any protecting groups, amino acids and other compounds are in accordance, unless otherwise indicated, with their common use, recognized abbreviations or the IUPAC Commission on Biochemical Nomenclature. IUB (see Biochem. 11:942-944 (1972)). List of abbreviations ΜΛ / t / ZUZZ / UOO 14 1 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 HPLC prep. h preparative high-performance liquid chromatography hour min minutes EA ethyl acetate EDC-HCI 3-((ethylamino)methlenaamino)- / \ / , / \ / -dimethylpropan-1-amino chloride DIEA diisopropylethylamine TEA triethylamine TFA trifluoroacetic acid HCI hydrochloric acid, hydrogen chloride HOBt 1-hydroxybenzotriazole hydrate HOAt 1-hydroxy-7-azabenzotriazole HATU 1-[bis(dimethylamino)methylene]-1 H-3-oxide hexafluorophosphate 1,2,3-triazolo[4,5-¿>]pyridinium DMAP 4-(dimethylamino)pyridma DAST (diethylamino)sulfur trifluoride DMP Dess-Martin periodinan, 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1 H) -one TBAF tetrabutylammonium fluoride trihydrate TBDMSCI tert-butyldimethylsilyl chloride MsCI methanesulfonyl chloride TsCI 4-toluenesulfonyl chloride SNA nucleophilic aromatic substitution nBuLi n-butyllithium 16 ¡Pr isopropyl DIAD diisopropyl azodicarboxylate Boc tert-butyloxycarbonyl CC flash flash column chromatography tn overnight at room temperature ac. aqueous ND not determined Cbz carboxybenzyl Hex hexane Hept heptane DEA diethylamine PE petroleum ether DAD Diode array detector TOF time of flight IPA ¡sopropanol Pg protecting group LG leaving group atm atmosphere ΜΛ / t / ZUZZ / UOO 14 1 enantiomerically enriched (in certain chemical structures it indicates enantiomerically enriched) (the symbol * is used in the experimental part indicating a mixture of isomers, it is believed that it should be changed to another symbol to avoid confusion with the * mentioned in names). It is understood that, in any compound disclosed herein that has one or more chiral centers, if the absolute stereochemistry is not expressly stated, then each center may independently have an R configuration or an S configuration or a mixture thereof. Therefore, the compounds provided herein may be enantiomerically pure or may be stereoisomeric mixtures. Furthermore, the compounds provided herein may be non-racemic mixtures. Furthermore, it is understood that, in any compound that has one or more double bonds that generate geometric isomers that can be defined as E or Z, each double bond may independently be E or Z or a mixture thereof. Similarly, it is also intended to include all tautomeric forms. As used herein, the term rae refers to racemic, racemate, etc., as interpreted by one skilled in the art. For example, a racemate comprises a mixture of enantiomers of a chiral molecule in equivalent amounts. Typically, a racemate does not exhibit optical activity. As used herein, the term reí refers to the relative, but not absolute, configuration of a stereogenic center with respect to any other stereogenic center within the same compound, as interpreted by one skilled in the art. As used herein, tautomeric and tautomeric refer to alternative forms of a compound disclosed herein that differ in the position of a proton. Some non-limiting examples include keto-enolic and enamino-imine tautomers, or tautomeric forms of heteroaryl groups containing a ring atom bonded to both an -NH- ring moiety and an =N- ring moiety such as pyrazoles, imidazoles. , benzimidazoles, triazoles and tetrazoles. It is understood that there may be isotopes present in the compounds described herein. Each chemical element as represented in the structure of a compound can include any isotope of that element. For example, in a compound described herein, a hydrogen atom can be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, reference herein to a compound encompasses all possible isotopic forms unless the context clearly indicates otherwise. As used herein, reference to an element, whether by description or chemical structure, encompasses all isotopes of that element unless otherwise described. By way of example, it is understood that the term hydrogen or H in a chemical structure, as used herein, encompasses, for example, not only 1H, but also deuterium (2H), tritium (3H) and mixtures thereof unless otherwise indicated by use of a specific isotope. Other specific non-limiting examples of elements for which isotopes are encompassed include carbon, phosphorus, iodine and fluorine. As used herein, a "pharmaceutically acceptable salt" refers to a salt of a compound that does not modify the biological activity or properties of the compound. Pharmaceutical salts can be obtained by reacting a compound disclosed herein with an acid or a base. Salts formed with a base include, but are not limited to, an ammonium salt (NH4+); alkali metal salts such as, but not limited to, sodium or potassium; alkaline earth metal salts such as, but not limited to, calcium or magnesium; salts of organic bases such as, but not limited to, dicyclohexylamine, piperidine, piperazine, methylpiperazine / V-methyl-D-glucamine, dimethylamine, ethylenediamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, but not limited to, arginine and lysine. Useful acid-based salts include, but are not limited to, acetates, adipates, aspartates, ascorbates, benzoates, butyrates, caparate, caproate, caprylate, camsylates, citrates, decanoates, formates, fumarates, gluconates, ΜΛ / t / ZUZZ / UOO 14 1 glutarate, glycolates, hexanoates, laurates, lactates, maleals, nitrates, oleates, oxalates, octanoates, propanoates, palmitates, phosphates, sebacates, succinates, stearates, sulfates, sulfonates, such as methanesulfonates, ethanesulfonates , p-toluenesulfonates, salicylates, tartrates and tosylates. As used herein, modulating the activity of a receptor means either activating it, that is, increasing its cellular function relative to the basal level that is measured in the particular environment in which it is found, or deactivating it, that is, reducing its cellular function below the basal level measured in the environment in which it is found and / or render it unable to carry out its cellular function at all, even in the presence of its natural binding partner. A natural binding partner is an endogenous molecule that is an agonist for the receptor. An agonist is defined as a compound that increases the basal activity of a receptor (i.e., receptor-mediated signal transduction). As used herein, a partial agonist refers to a compound that has affinity for a receptor but, unlike an agonist, when bound to the receptor elicits only a fractional degree of the pharmacological response normally associated with the receptor, including if the compound occupies a large number of receptors. An inverse agonist is defined as a compound that reduces or suppresses the basal activity of a receptor, so that the compound is not technically an antagonist but, instead, is an agonist with negative intrinsic activity. As used herein, an antagonist refers to a compound that binds to a receptor to form a complex that does not result in any response, as if the receptor were unoccupied. An antagonist attenuates the action of an agonist at a receptor. An antagonist can bind reversibly or irreversibly, and effectively eliminates the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise eliminated by a physical or biological process. As used herein, a subject refers to an animal that is the object of treatment, observation or experimentation. An animal includes cold- and warm-blooded vertebrates and invertebrates such as birds, fish, crustaceans, reptiles and, in particular, mammals. A mammal includes, but is not limited to, mice; rats; rabbits; Guinea pigs; dogs; cats; sheep; goats; cows; horses; primates such as monkeys, chimpanzees and apes and, in particular, humans. As used herein, a patient refers to a subject who is being treated by a medical professional such as a medical doctor or a veterinary doctor to attempt to cure, or at least ameliorate the effects of, a disease or disorder. particular or to prevent the disease or disorder from appearing in the first place. As used herein, a carrier refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, the ΜΛ / t / ZUZZ / UOO 141 dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject. As used herein, a diluent refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be necessary or desirable from a pharmaceutical point of view. For example, a diluent can be used to increase the volume of a potent drug whose mass is too small for manufacture or administration. It can also be a liquid to dissolve a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, but not limited to, a phosphate-buffered saline solution that mimics the composition of human blood. As used herein, an excipient refers to an inert substance that is added to a pharmaceutical composition to provide, but is not limited to, volume, consistency, stability, binding capacity, lubrication, disintegrating capacity, etc. to the composition. A diluent is a type of excipient. A receptor is intended to include any molecule present within or on the surface of a cell that can affect cellular physiology when inhibited or stimulated with a ligand. Typically, a receptor comprises an extracellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor to the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding (signal transduction). A receptor also includes any intracellular molecule that, in response to ligation, generates a signal. A receptor also includes any molecule that has the characteristic structure of a receptor, but does not have any identifiable ligand. Additionally, a receptor includes a truncated, modified, mutated receptor or any molecule comprising partial or all sequences of a receptor. A ligand is intended to include any substance that interacts with a receptor. Selective or selectivity is defined as the ability of a compound to generate a desired response from a particular type, subtype, class or subclass of receptor while generating a minor or small response from other types of receptors. The term selective or selectivity as applied to one or more particular subtypes of a compound means the ability of a compound to increase the activity of the subtypes while causing a minor, small or no increase in the activity of other subtypes. As used herein, coadministration of pharmacologically active compounds refers to the delivery of two or more different chemical entities, either in vivo or in vitro. Coadministration refers to the simultaneous delivery of different agents; to the simultaneous delivery of a mixture of agents; as well as the supply of one agent followed by the supply of a second agent or additional agents. ΜΛ / t / ZUZZ / UOO 141 Usually it is intended that the agents that are co-managed act jointly with each other. The term an effective amount, as used herein, means an amount of an active compound or pharmaceutical agent that exerts the biological or medical response in a tissue, system, animal or human that is sought by a researcher, veterinarian, doctor. in medicine or other medicine, which includes the relief or palliation of the symptoms of the disease being treated. When used herein, prevent / prevent should not be construed to mean that a condition and / or disease will never recur after the use of a compound or pharmaceutical composition according to the embodiments disclosed herein to achieve the prevention. Furthermore, the term should also not be interpreted to mean that a condition does not appear, at least to some degree, after such use to prevent said condition. Instead, prevent / prevents is intended to mean that the condition to be prevented, if it appears despite such use, will be less serious than without such use. Compounds In some embodiments, the present disclosure relates to compounds, stereoisomers, and salts of compounds and stereoisomers of Formula (I); ΜΛ / t / ZUZZ / UOO 14 Ί a stereoisomer thereof, or a pharmaceutically acceptable salt of the 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, C1-6 alkyl and C1-4 hydroxyalkyl; A is fluorine and Y is hydrogen; either Y and A are taken together with the atoms to which they are attached to form a 5-membered heteroaryl or heteroalicyclyl ring system optionally substituted with 1 or 2 substituents selected from halogen, cyano or Ci-4 alkyl; Roa and Rob are independently selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; Ria and Rib are independently selected from the group consisting of hydrogen, hydroxyl, amino, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 haloalkyl; R2 is selected from the group consisting of hydrogen, hydroxyl, amino, cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C(=O)OH, C(=O)NH2, C(=O )O-(C1-4 alkyl) and substituted or unsubstituted heteroaryl; R3 is selected from the group consisting of C1-4 alkyl, C1-4 alkenyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, and C3-7 cycloalkenyl; either R3 and R4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted 4- to 6-membered heteroalicyclic ring system; R4 is hydrogen or C1-4 alkyl, provided that R3 and R4 are not taken together with the atoms to which they are attached to form a substituted or unsubstituted 4- to 6-membered heteroalicyclic ring system; or R4 and R5 are taken together with the carbon atom to which they are attached to form a C3-4 cycloalkyl; R is absent; or is selected from the group consisting of hydrogen and C1-4 alkyl, provided that R4 and Rs are not taken together with the carbon atom to which they are attached to form a C3.4 cycloalkyl; Rhea and Reb are independently selected from the group consisting of hydrogen, cyano, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 hydroxyhaloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and substituted heteroaryl or unsubstituted, and whenever n is 0 then at least one of Rea and Reb is selected from the group consisting of cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, Ci-4 hydroxyhaloalkyl, C1-4 hydroxyalkyl, alkoxy C1-4, Ci-4 haloalkoxy, and substituted or unsubstituted heteroaryl; either Rhea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 6-membered heteroalicyclic or 3- to 6-membered alicyclic ring system comprising 1 to 3 heteroatoms selected from S, O, or N, optionally substituted with one to three halogen atoms; and R7 is selected from the group consisting of hydroxyl, cyano, halogen, C1-4 alkyl, Cu haloalkyl, C1-4 hydroxyalkyl, C1.4 alkoxy, and C1-4 haloalkoxy. In some embodiments disclosed herein, A is fluorine and Y is hydrogen. In some embodiments disclosed herein, Y and A are taken together with the atoms to which they are attached to form a 5-membered heteroaryl or heteroalicyclyl ring system optionally substituted with 1 or 2 substituents selected from halogen, cyano or C1-4 alkyl. In some embodiments, the present disclosure relates to compounds, stereoisomers, and salts of compounds and stereoisomers of Formula (II): ΜΛ / Ε / ΖυΖΖ / υοΟΊ4Ί ΜΛ / t / ZUZZ / UOO 14 Ί X is -CRs- or -N-, and Rs is selected from the group consisting of hydrogen, halogen, cyano, and Ci-4 alkyl. In some embodiments disclosed herein, X is N. In some embodiments disclosed herein, X is -CRs. In some embodiments disclosed herein, Rs is selected from the group consisting of hydrogen, cyano and fluorine. In some embodiments disclosed herein, Rs is hydrogen. In some embodiments disclosed herein, R8 is cyano. In some embodiments disclosed herein, Rs is fluorine. In some embodiments disclosed herein, X is —CH-. In some embodiments disclosed herein, Roa is selected from the group consisting of hydrogen, Cm alkyl, Cm hydroxyalkyl, and Ci-4 haloalkyl. In some embodiments described herein, Roa is hydrogen. In some embodiments disclosed herein, Roa is C1-4 alkyl. In some embodiments disclosed herein, Roa is Ci-4 hydroxyalkyl. In some embodiments disclosed herein, Roa is Ci-4 haloalkyl. In some embodiments disclosed herein, Roa is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F and -CHF2. In some embodiments disclosed herein, Rob is selected from the group consisting of hydrogen, Cm alkyl, Ci-4 hydroxyalkyl, and Ci-4 haloalkyl. In some embodiments described herein, Rob is hydrogen. In some embodiments disclosed herein, Rob is C14 alkyl. In some embodiments disclosed herein, Rob is C1-4 hydroxyalkyl. In some embodiments disclosed herein, Rob is Ci-4 haloalkyl. In some embodiments disclosed herein, Rob is selected from the group consisting of hydrogen, Cm alkyl, Ci-4 hydroxyalkyl, and Ci-4 haloalkyl. In some embodiments disclosed herein, Roa is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F and -CHF2, and Rob is selected from the group consisting of hydrogen, C1-4 alkyl , C1-4 hydroxyalkyl and C14 haloalkyl. In some embodiments disclosed herein, Roa and Rob are both hydrogen. In some embodiments described herein, at least one of Ria, Rw and R2 is not hydrogen. In some embodiments disclosed herein, Ría is selected from the group consisting of hydrogen, hydroxyl, amino, halogen, C1-4 alkyl, C14 hydroxyalkyl, and C1-4 haloalkyl. In some embodiments described herein, Ria is hydrogen. In some embodiments disclosed herein, Ria is hydroxyl. In some embodiments disclosed herein, Ria is amino. In some embodiments disclosed herein, Ria is halogen. In some embodiments disclosed herein, Ria is C1-4 alkyl. In some embodiments disclosed herein, Ria is C1-4 hydroxyalkyl. In some embodiments disclosed herein, Ria is G1-4 haloalkyl. In some embodiments, Ria is hydroxyl or hydrogen. In some embodiments disclosed herein, Riase is selected from the group consisting of hydroxyl, halogen, and C1-4 haloalkyl. In some embodiments disclosed herein, Riase is selected from the group consisting of hydroxyl, fluorine and -CF3. In some embodiments disclosed herein, Rw is selected from the group consisting of hydrogen, hydroxyl, amino, halogen, C1-4 alkyl, Ci4 hydroxyalkyl, and C1-4 haloalkyl. In some embodiments described herein, Rw is hydrogen. In some embodiments disclosed herein, Rw is hydroxyl. In some embodiments disclosed herein, Rw is amino. In some embodiments disclosed herein, Rw is halogen. In some embodiments disclosed herein, Rw is C1-4 alkyl. In some embodiments disclosed herein, Rw is C1-4 hydroxyalkyl. In some embodiments disclosed herein, Rw is C1-4 haloalkyl. In some embodiments disclosed herein, Rw is selected from the group consisting of hydrogen, halogen, and C1-4 alkyl. In some embodiments, Rw is selected from the group consisting of hydrogen, fluorine, and methyl. In some embodiments disclosed herein, Riase selects from the group consisting of hydroxyl, halogen, and C1-4 haloalkyl and Rwse selects from the group consisting of hydrogen, halogen, and C1-4 alkyl. In some embodiments described herein, Riase is selected from the group consisting of hydroxyl, fluorine and CF3, and Rwse is selected from the group consisting of hydrogen, fluorine and methyl. In some embodiments disclosed herein, Ria is hydrogen or hydroxyl and Rw is hydrogen. MA / t / ZUZZ / UOO 14 1 In some embodiments disclosed herein, R2 is selected from the group consisting of hydrogen, hydroxyl, amino, cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C(=O)OH, C (=O)NH2, C(=O)O-(C1-4 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 cyan. In some embodiments disclosed herein, R2 is halogen. In some embodiments disclosed herein, R2 is C14 alkyl. In some embodiments disclosed herein, R2 is C1-4 haloalkyl. In some embodiments disclosed herein, R2 is C1-4 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-C1-4alkyl. 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. In some embodiments disclosed herein, R2 is hydrogen, halogen, hydroxyl, cyano, C1-4 alkyl, Ci^ hydroxyalkyl, or -C(=O)O-C1-4 alkyl. In some embodiments disclosed herein, R2 is hydrogen, halogen, hydroxyl, cyano, methyl, ethyl, -CH2OH, -CH2CH2OH, or -C(=O)O-Ci-2 alkyl. In some embodiments disclosed herein, R2 is hydrogen, halogen, hydroxyl, or C1-4 hydroxyalkyl. In some embodiments disclosed herein, R2 is hydrogen, fluorine, 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. In some embodiments disclosed herein, R2 is hydrogen and Ria is hydroxyl. In some embodiments disclosed herein, R2 is hydroxyl and Ria is hydroxyl. In some embodiments disclosed herein, R3 is selected from the group consisting of C1-4 alkyl, C1-4 alkenyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C3-7 cycloalkyl, and C3-7 cycloalkenyl. In some embodiments disclosed herein, R3 is Ci-4 alkyl. In some embodiments disclosed herein, R3 is Ci-4 alkenyl. In some embodiments disclosed herein, R is C1-4 haloalkyl. In some embodiments disclosed herein, R is C1.4 hydroxyalkyl. In some embodiments disclosed herein ΜΛ / Ε / ^υ^^ / υοΟΊ4Ί document, R3is C3-7 cycloalkyl. In some embodiments disclosed herein, R3 is C3-7 cycloalkenyl In some embodiments disclosed herein, R3 is Cm alkyl or C3-7 cycloalkyl. In some embodiments disclosed herein, R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tere-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. In some embodiments disclosed herein, R4 is hydrogen or Ci-4 alkyl. In some embodiments disclosed herein, R4 is hydrogen. In some embodiments disclosed herein, R4 is Ci-4 alkyl. In some embodiments disclosed herein, R4 is methyl. In some embodiments disclosed herein, Rs is absent. In some embodiments disclosed herein, R is hydrogen or Ci-4 alkyl. In some embodiments disclosed herein, Rs is hydrogen. In some embodiments disclosed herein, Rs is C1-4 alkyl. In some embodiments disclosed herein, Rses methyl. In some embodiments disclosed herein, R4 and Rs are taken together with the carbon atom to which they are attached to form a C3.4 cycloalkyl. In some embodiments disclosed herein, R4 and Rs are taken together with the carbon atom to which they are attached to form a cyclopropyl. In some embodiments disclosed herein, R4 and Rs are taken together with the carbon atom to which they are attached to form a cyclobutyl. In some embodiments disclosed herein, each of R4 and Rs independently is hydrogen or Ci-4 alkyl, or R4 and Rs are taken together with the carbon atom to which they are attached to form a C3.4 cycloalkyl. In some embodiments disclosed herein, each of R4 and Rs independently is hydrogen or methyl, or R4 and Rs are taken together with the carbon atom to which they are attached to form a cyclopropyl. In some embodiments disclosed herein, R4 and Rs are hydrogen. In some embodiments disclosed herein, R3 and R4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted 4- to 6-membered heteroalicyclic ring system. In some embodiments disclosed herein, the heteroalicyclic ring system comprising R3 and R4 is a 4-membered heteroalicyclyl. In some embodiments disclosed herein ΜΛ / Ε / ^υ^^ / υοΟΊ4Ί document, the heteroalicyclic ring system comprising R3 and R4 is a 5-membered heteroalicyclyl. In some embodiments disclosed herein, the heteroalicyclic ring system comprising R3 and R4 is a 6-membered heteroalicyclyl. In some embodiments disclosed herein, the heteroalicyclic ring system comprising R3 and R4 is unsubstituted. In some embodiments disclosed herein, the heteroalicyclic ring system comprising R3 and R4 is substituted with one or two substituents selected from halogen, hydroxyl, and Ci-4 alkyl. In some embodiments disclosed herein, R3 and R4, taken together with the atoms to which they are attached, form a 4- to 6-membered heteroalicyclic ring comprising a double bond, and R5 is absent. In some embodiments disclosed herein, the heteroalicyclic ring system comprising R3 and R4 is azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, 2-azabicyclo[3.1.0]hexanyl, or 3-azabicyclo[3.1.Ojhexanyl; wherein the heteroalicyclic ring system is optionally substituted with one or two substituents selected from halogen and methyl, and whenever the heteroalicyclic ring system is 2azabicyclo[3.1.Ojhexanyl substituted or unsubstituted then R is absent. In some embodiments disclosed herein, the heteroalicyclic ring system comprising R3 and R4 is unsubstituted azetidinyl, unsubstituted pyrrolidinyl, unsubstituted morpholinyl, unsubstituted piperidinyl, 2-azabicyclo[3.1.Ojhexanyl, or 3-azabicyclo[3.1 .Ojhexanyl not substituted. In some embodiments disclosed herein, the heteroalicyclic ring system comprising R3 and R4 is azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, 2-azabicyclo[3.1.Ojhexanyl, or 3-azabicyclo[3.1.Ojhexanyl; wherein 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.Ojhexanyl and R is absent. In some embodiments disclosed herein, the heteroalicyclic ring system is 2azabicyclo[3.1.Ojhexanyl substituted and R is absent. In some embodiments disclosed herein, the heteroalicyclic ring system is unsubstituted 2-azabicyclo[3.1.Ojhexanyl and R is absent. In some embodiments disclosed herein, the heteroalicyclic ring system comprising R3 and R4 is morpholinyl optionally substituted with one or two substituents selected from halogen and methyl, and Rs is hydrogen. In some embodiments disclosed herein, the heteroalicyclic ring system comprising R3 and R4 is unsubstituted morpholinyl, and Rs is hydrogen. In some embodiments disclosed herein, Rhea is selected from the group consisting of hydrogen, cyano, halogen, Ci-4 alkyl, Ci-4 hydroxyalkyl, Ci-4 haloalkyl, Ci-4 hydroxyhaloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxyl, and substituted or unsubstituted heteroaryl ΜΛ / t / ZUZZ / UOO 141 replaced. In some embodiments described herein, Rhea is hydrogen. In some embodiments disclosed herein, Rhea is cyano. In some embodiments disclosed herein, Rhea is halogen. In some embodiments disclosed herein, Rhea is C1-4 alkyl. In some embodiments disclosed herein, Rhea is C1-4 hydroxyalkyl. In some embodiments disclosed herein, Rhea is Ci-4 haloalkyl. In some embodiments disclosed herein, Rhea is C1-4 hydroxyhaloalkyl. In some embodiments disclosed herein, Rhea is C1-4 alkoxyl. In some embodiments disclosed herein, Rhea is C1-4 haloalkoxy. In some embodiments disclosed herein, Rhea is substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, Rhea is substituted heteroaryl. In some embodiments disclosed herein, Rhea is unsubstituted heteroaryl. In some embodiments disclosed herein, Rhea is hydrogen, halogen, C1-4 haloalkyl, or C1-4 haloalkoxy. In some embodiments disclosed herein, Rhea is hydrogen, C1-4 haloalkyl, or C1-4 haloalkoxy. In some embodiments disclosed herein, Rhea is hydrogen, -CF3, CH2F, -CCH3F2, -OCF3, or -ochf2. In some embodiments disclosed herein, Rebse is selected from the group consisting of hydrogen, cyano, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 hydroxyhaloalkyl, C1-4 alkoxy, haloalkoxy C1-4, and substituted or unsubstituted heteroaryl. In some embodiments described herein, Reb is hydrogen. In some embodiments disclosed herein, Reb is cyano. In some embodiments disclosed herein, Rebes halogen. In some embodiments disclosed herein, Reb is C1.4 alkyl. In some embodiments disclosed herein, Rebes C1-4 hydroxyalkyl. In some embodiments disclosed herein, Reb is C1-4 haloalkyl. In some embodiments disclosed herein, Reb is C1-4 hydroxyhaloalkyl. In some embodiments disclosed herein, Rebes C1-4 alkoxyl. In some embodiments disclosed herein, Rebes C1-4 haloalkoxyl. In some embodiments disclosed herein, Rebes substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, Reb is substituted heteroaryl. In some embodiments disclosed herein, Reb is unsubstituted heteroaryl. In some embodiments disclosed herein, Reb is hydrogen, halogen, C1-4 haloalkyl, or C1-4 haloalkoxy. In some embodiments disclosed herein, Rhea is hydrogen, -CF3, -CH2F, -CCH3F2, -OCF3, or -OCHF2, and R6bes hydrogen. In some embodiments disclosed herein, Rhea is -CF3, and R6bes hydrogen. In some embodiments ΜΛ / t / ZUZZ / UOO 141 disclosed herein, n is 0 and at least one of Rea and Reb is selected from the group consisting of cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, C1 hydroxyhaloalkyl -4, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, substituted or unsubstituted heteroaryl; o Rhea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 6-membered heteroalicyclic or 3- to 6-membered alicyclic ring system comprising 1 to 3 heteroatoms selected from S, O, or N , optionally substituted with one to three halogen atoms. In some embodiments disclosed herein, whenever n is 0 then at least one of Rea and Reb is selected from the group consisting of cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyhaloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, Rea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 6-membered heteroalicyclic or 3- to 6-membered alicyclic ring system comprising 1 to 3 heteroatoms selected from S, O, or N, optionally substituted with one to three halogen atoms. In some embodiments disclosed herein, Rea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 6-membered alicyclic ring system, optionally substituted with one to three halogen atoms. In some embodiments disclosed herein, Rea and Reb are taken together with the carbon atom to which they are attached to form a 3 to 6 membered heteroalicyclic ring system comprising 1 to 3 heteroatoms selected from S, O , or N, optionally substituted with one to three halogen atoms. In some embodiments disclosed herein, Rea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 4-membered alicyclic ring system, optionally substituted by one to three fluorine, or a 4- to 5-membered heteroalicyclic ring system, comprising one, two, or three heteroatoms selected from O and N. In some embodiments disclosed herein, Rea and Reb are taken together with the carbon atom to which they are attached. joined together to form a 3- to 4-membered alicyclic ring system, optionally substituted by one to three fluorines. In some embodiments disclosed herein, Rea and Reb are taken together with the carbon atom to which they are attached to form an unsubstituted 3- to 4-membered alicyclic ring system. In some embodiments disclosed herein, Rhea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 4-membered alicyclic ring system substituted by one to three fluorine. In some embodiments disclosed herein, Rea and Reb are taken together with the carbon atom to which they are attached to form a 4- to 5-membered heteroalicyclic ring system, comprising one, two, or three heteroatoms selected from O and N. In some embodiments disclosed herein, Rea and Reb are IVIA / t / ZUZZ / UOO 14 I take together with the carbon atom to which they are attached to form an oxetanyl or a cyclopropyl optionally substituted with one or two fluorines. In some embodiments disclosed herein, Rea and Reb are each independently hydrogen, halogen, C1-4 haloalkyl, or C1-4 haloalkoxy, or Rea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 6-membered alicyclic or 3- to 6-membered heteroalicyclic ring system, optionally substituted by one to three halogen atoms. In some embodiments disclosed herein, Rhea is hydrogen, -CF3, -CH2F, -CCH3F2, -OCF3, or -OCHF2, and Rebes is hydrogen; or Rhea and Reb are taken together with the carbon atom to which they are joined to form a 3- to 4-membered alicyclic ring system, optionally substituted by one to three fluorine, or a 4- to 5-membered heteroalicyclic ring system, comprising one, two, or three heteroatoms selected from O and N. In some embodiments disclosed herein, Rhea is -CF3, and Rebes is hydrogen; o Rea and Reb are taken together with the carbon atom to which they are attached to form an oxetanyl or a cyclopropyl optionally substituted with one or two fluorines. In some embodiments disclosed herein, at least one of Rhea and Reb is substituted or unsubstituted heteroaryl. In some embodiments disclosed herein, at least one of Rea and Reb is heteroaryl substituted with C1-4 alkyl. 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. In some embodiments disclosed herein, R7 is selected from the group consisting of hydroxyl, cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and C1.4 haloalkoxy. . In some embodiments disclosed herein, R? It is hydroxyl. In some embodiments disclosed herein, R / is cyano. In some embodiments disclosed herein, R7 is halogen. In some embodiments disclosed herein, R7 is C1-4 alkyl. In some embodiments disclosed herein, R7 is C1-4 haloalkyl. In some embodiments disclosed herein, R7 is C1-4 hydroxyalkyl. In some embodiments disclosed herein, R7 is C1.4 alkoxy. In some embodiments disclosed herein, R7 is C1-4 haloalkoxy. In some embodiments disclosed herein, R7 is hydroxyl, cyano, halogen, C1-4 haloalkyl, or C1-4 haloalkoxy. In some embodiments disclosed herein, R7 is halogen, hydroxyl, cyano, -CF3, -OCHF2, -CHF2, or OCF3. The compound, stereoisomer or salt according to claim 1, wherein the compound has the structure MA / t / ZUZZ / UOO 141 MA / t / ZUZZ / UOO141 Ría is hydrogen, fluorine or hydroxyl; Rw is hydrogen or fluorine; R2is hydrogen or hydroxyl R3 is methyl, ethyl, cyclopropyl or cyclobutyl; Rhea is -CF3; and as long as at least one of Ria, Rib and R2 is not hydrogen. In some embodiments disclosed herein, Roa and Rob are both hydrogen; Riay Ribson independently hydrogen or hydroxyl; R2 is selected from the group consisting of hydrogen and hydroxyl; R is hydrogen; Y is hydrogen and A is fluorine; o Y and A are taken together with the atoms to which they are attached and the pyrimidine ring of formula (I) to form an unsubstituted pyrrolo[2,3-d]pyramidane; R3 is selected from the group consisting of methyl, ethyl, cyclopropyl and cyclobutyl, and R4 and R5 are hydrogen; or R3 and R4 are taken together with the atoms to which they are attached to form an unsubstituted morpholinyl, and R5 is hydrogen; n is 0; or n is 1 and R7 is a fluorine; R6a is -CF3, and R6b is hydrogen; o Rhea and Reb are taken together with the carbon atom to which they are attached to form an oxetanyl or a two-fluorine substituted cyclopropyl. In one embodiment, the compound, salt, stereoisomer, or stereoisomer salt of Formula (I) is selected from the group consisting of: rel-2-((3R,4Rj -4-(((6-(((1,1-Difluorospiro[2.5]octan-6-¡l)methyl)(ethyl)amino)-5fluorop ¡r¡m¡din-4-¡l)amino)methyl)-3-hydroxypiperidin-1 -yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-(methyl(((1 r,4R)-4(trifluoromethyl)cyclohexyl)methyl)amino)pyrimid ¡n-4-¡l)am¡no)methyl)-3-hydroxy¡p¡per¡din-1 -yl)acetamide, 2-((3R*,4R*)-4-(((6-( et¡l(((1r,4R)-4-(trifluoromethyl)cyclohex¡l)met¡l)amino)-5fluorop¡r¡mjdin-4-yl)amino)met¡l)-3- hydroxypiperidn-1-l)acetamide, 2-((3R*,4R*)-4-(((6-(cyclopropyl(((1 r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino) -5fluorop¡r¡m¡d¡n-4-yl)amino)methyl)-3-hydroxypiperid¡n-1 -yl)acetamide, 2-((3RS,4RS)-4-(((6-(cyclobutyl(((1 r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5fluorop ¡r¡m¡din-4-¡l)am¡no)met¡l)-3-hydroxy¡p¡per¡d¡n-1 -yl)acetamide, re / -2-((3R, 4R)-4-(((6-(((2-oxaespiro[3.5]nonan-7-¡l)met¡l)(ethyl)amino)-5-fluorop¡r¡m¡d¡ n-4yl)amino)methyl)-3-hydroxy¡p¡perídin-1-yl)acetamide, re / -2-((3R,4R)-4-(((6-(ethyl ((1-fluoro-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5fluorop¡r¡m¡d¡n-4-¡l)amino)methyl)-3-h¡ droxi¡p¡períd¡n-1-¡l)acetam¡de, 2-(4-(((5-fluoro-6-((3S)-3-(4-(trifluoromethyl)cyclohexyl)morpholino)pyrmidin -4¡l)amino)met¡l)p¡perídin-1-¡l)acetam¡de, 2-((3RS,4RS)-4-((4-(Ethyl(((1 r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H- pyrrolo[2,3c / |pyrimidín-7-yl)methyl)-3-hydroxypyridin-1 -yl)acetamide, 2-((3R*,4R*)-4-((4-(Ethyl(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2 ,3o(|pyrimidín-7-yl)methyl)-3-hydroxyp¡peridin-1 -yl)acetamide, 2-((3RS,4RS)-4-((4-(cyclobutyl(((1 r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7Rpyrrole[ 2,3-d]pyrimidin-7-yl)methyl)-3-hydroxypiperidín-1 -yl)acetamide, 2-((3R*,4R*)-4-(((6-(ethyl(((1 r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5fluorop ¡r¡midin-4-¡l)amino)methyl)-3,4-di¡hydroxypiper¡n-1-yl)acetamide, and 2-((3R*,4R*)-4-((4-(ethyl(((1 r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7H-pyrrolo[2, 3o(|pyrimidín-7-yl)methyl)-3,4-dihydroxypiperidin-1 -yl)acetamide. In one embodiment, the compound, salt, stereoisomer, or salt of the stereoisomer of Formula (I) is selected from the group consisting of: ΜΛ / t / ZUZZ / UOO 141 F IVIA / t / ZUZZ / UOD 14 I In one embodiment, the compound, salt, stereoisomer, or stereoisomer salt of Formula (I) is selected from the group consisting of: 2-(4-(((6-(((1,1-Difluorospiro[2.5]octan-6-¡l)methyl)(ethyl)amino)-5-fluorop¡r¡ m¡d¡n-4 il)amino)methyl)-3-hydroxy¡piperidin-1 -yl)acetamide, 2-(4-(((5-fluoro-6-(methyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)pyrimidin-4yl)amino)methyl)-3-hydroxyl p¡per¡d¡n-1 -yl)acetamide, 2-(4-(((6-(ethyl¡l((4-(trifluoromethyl)cyclohex¡l)methyl)amino)-5-fluorop¡r¡m¡d¡n-4-yl)amino) methyl)3-hydroxypyridin-1-yl)acetamide, 2-(4-(((6-(cycloprop¡l((4-(trifluoromethyl)cyclohex¡l)methyl)amino)-5-fluoropyrimidín-4yl)amino)methyl)-3-hydroxy¡p¡per Din-1-yl)acetamide, 2-(4-((((6-(cyclobut¡l((4-(trifluoromethyl)cyclohex¡l)methyl)amino)-5-fluorop¡r¡m¡d¡ n-4¡l)am¡no)met¡l)-3-hydroxy¡p¡perídin-1-¡l)acetam¡de, 2-(4-(((6-(((2-oxaespiro[3.5]nonan-7-íl)methyl)(ethyl)amino)-5-fluorop¡rímid¡ n-4¡l)am¡no)met¡l)-3-hydroxy¡piper¡din-1-¡l)acetam¡de, 2-(4-(((6-(ethyl((1-fluoro-4-(trifluoromethyl)cyclohex¡l)methyl)amino)-5-fluorop¡r¡m¡d¡ n-4yl)amino)methyl)-3-hydroxy¡p¡perídin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromet¡l)cyclohex¡l)morphol¡no)p¡r¡m¡d¡n-4¡l)amino )met¡l)p¡perídin-1-¡l)acetam¡de, 2-(4-((4-(Ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7 / - / -pyrrolo[2,3-c / |pyrimidin-7yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, 2-(4-((4-(Ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7 / 7-pyrrolo[2,3-c(|pyrimi) d¡n-7yl)methyl)-3-hydroxy¡p¡peridin-1 -yl)acetamide, 2-(4-((4-(cyclobutyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7 / - / -pyrrolo[2,3- d]p¡r¡m¡d¡n-7¡l)met¡l)-3-hydroxy¡piper¡d¡n-1-¡l)acetam¡de, 2-(4-((((6-(eth¡l((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyr¡m¡d¡n-4-¡l )amino)methyl)3,4-dihydroxypiperidin-l -yl)acetamide, and 2-(4-((4-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7 / - / -pyrrolo[2,3-c / ]pyrimidin-7yl)methyl)-3,4- dihydroxypiperidín-1 -yl)acetamide. In one embodiment, the compound, salt, stereoisomer, or salt of the stereoisomer of ΜΛ / t / ZUZZ / UOO 141 Formula (I) is selected from the group consisting of: Μ Λ / t / ¿U¿¿ / UOO 141 2-(4-(((6-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluoropyrimidin-4-(l)amino)methyl )3,4-dihydroxypiperidin-1 -yl)acetamide, and 2-(4-((4-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7 / - / -pyrrolo[2,3-c / ]pyrimidin-7yl)methyl)-3,4- dihydroxypiperidín-1 -yl)acetamide. In one embodiment, the compound, salt, stereoisomer, or stereoisomer salt of Formula (I) is selected from the group consisting of: In one embodiment, the compound, salt, stereoisomer, or salt of the stereoisomer of Formula (I) is selected from the group consisting of: ΜΛ / t / ZUZZ / UOO 14 Ί In some embodiments, whenever a halogen is specified as a substituent, the halogen will be selected from fluorine or chlorine. The particular embodiments and disclosures used herein are to illustrate different alternatives to the disclosure and the embodiments may be combined with other applicable embodiments. Specific examples of the compounds are disclosed in Table 1 below. Table 1. Illustrative compounds according to their structure and name. Example Structure Name A6-1-11 0 i / F ja 0 HO í N r WJ H F k re / -2-((3fí,4ñ)-4-(((6-(((1,1 - Difluorospiro[ 2.5]octan-6yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4¡l)amino)methyl)-3-hydroxy¡p¡perídin-1 iljacetamide 1st isomer to elute Α6-1-1- 2 re / -2-((3fi,4ñ)-4-(((6-(((1,1- Difluorospiro[2.5]octan-6yl)methyl)(et¡l) amino)-5-fluorop¡r¡m¡d¡n-4¡l)amino)methyl)-3-hydroxy¡p¡perídin-1 il)acetamide 2nd isomer to elute Α6-1-2- 1 0 A / f NH2 vAf ,¿: Q HO ψ N H F k re / -2-((3fí,4ñ)-4-(((6-(((1,1- Difluorospiro[2.5 ]octane-6- ¡l)met¡l)(ethyl)amino)-5-fluorop¡r¡m¡d¡n-4¡l)amino)met¡l)-3-hydrox ¡per¡din¡n-1 il)acetamide 1,er eluting isomer Α6-1-22 re / -2-((3fí,4ñ)-4-(((6-(((1,1- Difluorospiro[2.5]octan-6yl)methyl)(ethyl)amino)-5-fluoropyrimidin-4¡l)amino)methyl)-3-hydroxy¡p¡peridín-1 il) acetamide 2 / eluting isomer Α6-2-1 0 h2nx^ cf3 ,0 , ó HO Y N N oí L λα > n n H i । 2-((3fi*,4fi*)-4-(((5-fluoro-6- (methyl(((1 r,4ñ)-4- (trifluoromethyl)cyclohex¡l)methyl) am¡no)pyrim¡d ¡n-4-¡l)amino)methyl)-3-hydroxy¡p¡per¡din-1 il)acetamide 1st isomer to elute Α6-2- 2 2-((3 / -r,4R*)-4-(((5-fluoro-6(methyl(((1r,4fi)-4(trifluoromethyl)cyclohex¡l)methyl) am¡no)pyrimid ¡n-4-yl)amino)methyl)-3-hydroxy¡p¡perídin-1 il)acetamide 2.s eluting isomer Α6-3-1 O CF3 ώ ό ΗΟ Ν 01 Η 1 1 F 2-((3fi*,4fi*)-4-(((6-(ethyl(((1r,4fi)-4(trifluoromethyl)) cyclohexyl)methyl)amino)-5fluoropírimídin-4-yl)amino)methyl)-3hydroxypiperidin-1 -yl)acetamide 1st isomer to elute Α6-3-2 2- ((3fí*,4ñ*)-4-(((6-(ethyl(((1r,4fí)-4(trifluoromethyl)cyclohex¡l)methyl)amino)-5fluoropyrám¡d ¡n-4-yl)amino)methyl)-3hydroxypiperidin-1 -yl)acetamide 2nd eluting isomer Α6-4-1 Ο cf3 ,ώ ό ΗΟ' Ν Η τ Λ 2-((3fl*, 4fí*)-4-(((6- (cyclopropyl(((1 r,4R))-4- (trifluoromethyl)cyclohex¡l)methyl)amino)-5fluoropyrám¡d¡n- 4-yl)amino)methyl)-3-hydroxypiperidin-1 -yl)acetamide 1,er eluting isomer Α6-4-2 2-((3fi*,4fi*)-4-(((6- ( cyclopropyl(((1 r,4F?)-4- (trifluoromet¡l)cyclohexyl)met¡l)amino)-5fluoropyr¡m¡d¡n-4-yl)amino)met¡l)- 3hydroxypiperidin-1 -yl)acetamide 2 / eluting isomer Α6-5 I r? Ο Ζ 1 / —, \=ο / —Λ. ζ— ς,ζ '— / / ζ \ / —ζ / —\ V V- / ΥίΟ \ / Π \___ / ω 2-((3HS,4fíS)-4-(((6- (cyclobutyl((( 1r,4F?)-4- (trifluoromet¡l)cyclohexyl)met¡l)amino)-5fluoropyrám¡d¡n-4-yl)amino)met¡l)-3- hydroxypiperidin-1 -yl)acetamide Α6-6-1 O U Λ h2n η / \ ..0 Q oí L nonan-7-yl)met¡l)(ethyl)amino)5-fluorop¡rim¡din-4-¡l)amino)methyl)-3hydroxypiperidin-1 -yl)acetamide 1st isomer to elute Α6-6-2 re / -2-((3fí,4ñ)-4-(((6-(((2-oxaspiro[3.5]nonan-7-¡l)methyl) (eth¡l)am¡no)5-fluorop¡r¡m¡d¡n-4-yl)am¡no)methyl)-3hydroxypiperidin-1 -yl)acetamide 2nd isomer to elute Α6-7 -1 0 H2N । CF3 .0 ¿ HO' N oí l ΑΛ J n n Η 1 1 F ^ / -2-((3 / 3,4 / 3)-4-(((6-(6111((1-fluoro4-(trifluoromet) l)cyclohexyl)met¡l)amino)-5fluoropyrám¡d¡n-4-¡l)amino)methyl)-3hydroxypiperidin-1 -yl)acetamide 1,er eluting isomer Α6- 7-2 re / -2-((3fi,4F?)-4-(((6-(ethyl((1 -fluoro4-(trifluoromethyl)cyclohexyl)methyl)amino)-5fluoropyrimid ¡n-4-yl)amino)methyl)-3hydroxypiperidin-1 -yl)acetamide 2nd isomer to elute Α6-8-1 C0 f----< / ---0 LL / \ / \ O \ / \ / 71- z \ / —\ HI ^Z / -Z oA — z CM I 2-(4-(((5-fluoro-6-((3S)-3-(4(trifluoromethyl)c¡ clohex¡l)morphol¡no)p¡r¡m¡d¡n4-¡l)amino)met¡l)p¡períd¡n-1-¡l)acetam¡de 1st eluting isomer Α6 -8-2 2-(4-(((5-fluoro-6-((3S)-3-(4- (trifluoromethyl)cyclohexyl)morpholino)pyramida ¡n4-¡l)amino)met¡l)p¡perid¡n-1-¡l)acetam¡de 2nd isomer to elute Β6-1 0 Υνη2 cf3 Κ - 0 Vyi / Ν^Ν Η0' \_ u2 / 2-((3RS,4fiS)-4-((4-(Ethyl(((1 r,4R)-4(trifluoromet) l)cyclohexyl)met¡l)amino)-7 / - / pyrrolo[2,3-d]pyr¡m¡din-7-¡l)met¡l)-3hydroxypiperidin-1 -yl)acetamide Β6-1-1 zt οΖ / / Υ ζΑγ / ζ / ζ / —\ \ / m 2-((3R*,4fí*)-4-((4-(Etil(((1r,4fí )-4(trifluoromet¡l)cyclohex¡l)methyl)amino)-7 / - / pyrrolo[2,3-d]pyr¡m¡d¡n-7-¡l)met¡ l)-3hydroxypiperidin-1 -yl)acetamide 1,er eluting isomer Β6-1-2 2-((3fí*,4fí*)-4-((4-(Etil(((1r,4fí)-4( trifluoromethyl)cyclohexyl)methyl)amino)-7 / - / pyrrolo[2,3-d]pyrimidin-7-l)methyl)-3hydroxypiperidin -1 -yl)acetamide 2nd isomer to elute Β6-2 CO / ----\ Ο / / \ / \ .. Τ ζ ζ ''ο Τ 2-((3RS,4RS)-4-(( 4- (cyclobutyl(((1 r,4S)-4- (trifluoromethyl)cyclohexyl)methyl)amino)-7 / - / pyrrolo[2,3-d]pyr ¡mid¡n-7-¡l)met¡l)-3- hydroxypiperidin-1 -yl)acetamide AD-6-1 Ο <ΉΗ2 CF3 Λ ά Jxodh 0 J HCWT ΐ Y J Η F 2-((3fí*, 4R*)-4-(((6-(ethyl(((1r,4R)-4(trifluoromethyl)cyclohexyl)methyl)amino)-5fluoropyr¡m¡d¡n-4- ¡l)amino)methyl)-3,4dihydroxypiperidin-1 -yl)acetamide 1st isomer to elute MA / t / ZUZZ / UOO141 AD-6-2 2-((3fí*,4fí*)-4-(((6-(ethyl(((1r,4R)-4(trifluoromethyl)cyclohex¡l)methyl)amino )-5fluoropyrimidin-4-yl)amino)methyl)-3,4dihydroxypiperidin-1 -yl)acetamide 2nd isomer in elution BD-5- 1-1 0 ,^NH2 QF3 X or / Ν Ν γ c\oi II -7 / - / pyrrolo[2,3-c(|p¡r¡m¡din-7-¡l)met¡l)-3,4dihydroxypiperidin-1 -yl)acetamide 1st isomer to elute BD-5 - 1-2 2-((3fi*,4FT)-4-((4-(et¡l(((1 r,4F?)-4(trifluoromet¡l)cyclohex¡l)met¡l) amino)-7 / - / pyrrolo[2,3-c(]pyrimidin-7-yl)methyl)-3,4dihydroxypiperidin-1 -yl)acetamide 2nd isomer to elute In a related aspect, a prodrug of a compound of Formula (I) is provided as described herein. IVIA / t / ZUZZ / UOO 14 I The compounds of the present disclosure are active, for example, having RORy Gal4 < 1000 nM, such as < 500 nM, such as < 100 nM. According to one embodiment, compounds are disclosed herein having IC50 values ​​<1000 nM in the Gal4 assay. According to another preferred embodiment, compounds are disclosed herein having IC50 values ​​<500 nM in the Gal4 assay. According to another more preferred embodiment, compounds are disclosed herein having IC50 values ​​<100 nM in the Gal4 assay. Pharmaceutical compositions In another aspect, the present disclosure relates to a pharmaceutical composition comprising physiologically acceptable surfactants, carriers, diluents, excipients, softening agents, suspending agents, film-forming substances and coating assistants, or a combination thereof; and a compound as described herein, e.g. e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), and (Vil) as described herein, or a salt, stereoisomer or salt of a stereoisomer of this. The compound of Formula (I), (II), (III), (IV), (V), (VI), and (Vil) included in the pharmaceutical composition may also be any compound of the preferred embodiments described above. In another aspect, the present disclosure relates to a pharmaceutical composition comprising physiologically acceptable surfactants, carriers, diluents, excipients, softening agents, suspending agents, film-forming substances and coating assistants, or a combination thereof; and a compound of any of Formulas (I), (II), (III), (IV), (V), (VI), and (Vil) as disclosed herein. Acceptable carriers or diluents, as well as other additives that are to be combined with one or more compounds of Formula (I), (II), (III), (IV), (V), (VI), and (Vil ) as described herein to provide a pharmaceutical composition for therapeutic use are well known in the pharmaceutical field 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. In the pharmaceutical composition, preservatives, stabilizers, colorants, sweeteners, fragrances, flavoring agents, flavor masking agents and the like may be provided. For example, sodium benzoate, ascorbic acid and p-hydroxybenzoic acid esters can be added as preservatives. Additionally, antioxidants and suspending agents can be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols and the like may be used as surfactants; Sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium aluminate and metasilicate, synthetic aluminum silicate, calcium carbonate, sodium hydrogen carbonate, calcium hydrogen phosphate, can be used as excipients. calcium carboxymethylcellulose and the like; magnesium stearate, talc, hardened oil and the like can be used as softening agents; coconut oil, olive oil, sesame oil, peanut oil, soybean oil can be used as suspending agents or lubricants; cellulose acetate and phthalate as a derivative of a carbohydrate such as cellulose or sugar, or a methyl acetate-methacrylate copolymer as a polyvinyl derivative can be used as suspending agents; and plasticizers such as phthalate-type esters and the like can be used as suspending agents. The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. In the art there are multiple techniques for administering a compound including, but not limited to, oral, injection, aerosol, parenteral and topical administration. Pharmaceutical compositions can also be obtained by reacting the compounds with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Similarly, pharmaceutical compositions can also be obtained by reacting the compounds with organic or inorganic bases such as ammonia, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide and the like. MA / t / ZUZZ / UOO 141 The term carrier defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier since it facilitates the uptake of many organic compounds in the cells or tissues of an organism. The term diluent defines chemical compounds diluted in water that will dissolve the compound of interest while stabilizing the biologically active form of the compound. In the art, salts dissolved in buffered solutions are used as diluents. A commonly used buffer solution is phosphate-buffered saline, as it mimics the saline conditions of human blood. Because buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound. The term physiologically acceptable defines a carrier or diluent that does not modify the biological activity or properties of the compound. The pharmaceutical compositions described herein can be administered to a human patient per se or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in a combination therapy, or carriers or one or more suitable excipients. Techniques for the formulation and administration of the compounds of the present application can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition, 1990. Suitable routes of administration may include, for example, oral, rectal, transmucosal, topical or intestinal administration; parenteral delivery, which includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections. The compounds may also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, tablets, transdermal patches (including electrotransport) and the like, for pulsed, timed and / or prolonged administration at a predetermined rate. . The pharmaceutical compositions can be prepared in a manner known per se, e.g. e.g., through conventional processes of mixing, dissolving, granulation, drageing, levigating, emulsification, encapsulation, trapping or tableting. Pharmaceutical compositions for use as described herein may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate the processing of the active compounds into pharmaceutically usable preparations. The appropriate formulation depends on the chosen route of administration. Any of the techniques, carriers and excipients known in the art may be used appropriately and as interpreted in the art, e.g. e.g., at Remington's Pharmaceutical Sciences, which has been mentioned above. Injectable products can be prepared in conventional forms, whether liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid before injection, or as emulsions. Some suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride and the like. Furthermore, if desired, the injectable pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances such as wetting agents, pH buffering agents and the like. Some physiologically compatible buffers include, but are not limited to, Hanks' solution, Ringer's solution, or physiological saline buffer. If desired, absorption enhancing preparations (eg liposomes) can be used. For transmucosal administration, suitable penetrating agents to penetrate the barrier can be used in the formulation. Pharmaceutical formulations for parenteral administration, e.g. For example, by bolus injection or continuous infusion, they include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as suitable oily injection suspensions. Suitable lipophilic carriers or solvents 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 compounds to make possible the preparation of highly concentrated solutions. Formulations for injection may be presented in a unit dosage form, e.g. e.g., in blisters or multi-dose containers, with an added preservative. The compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. e.g., sterile pyrogen-free water, before use. For oral administration, the compounds can be easily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, dense suspensions, suspensions and the like, for oral intake by a patient who is to be ΜΛ / Ε / ΖυΖΖ / υοΟΊ4Ί try. Pharmaceutical preparations for oral use can be obtained by combining the active compounds with a solid excipient, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Some suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added. The tablet cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, enamel solutions and suitable organic solvents or mixtures of solvents. Dyes or pigments can be added to the coatings of dragees or tablets for identification or to characterize different dose combinations of the active compounds. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, enamel solutions and suitable organic solvents or mixtures of solvents. Dyes or pigments can be added to the coatings of dragees or tablets for identification or to characterize different dose combinations of the active compounds. Pharmaceutical preparations that can be used orally include hard capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The hard capsules may contain the active ingredients mixed with a filler such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycols. Additionally, stabilizers can be added. All formulations for oral administration must be in dosages appropriate for such administration. For buccal administration, the compositions may take the form of tablets or dragees that are formulated in a conventional manner. For administration by inhalation, the compounds for use as described herein are conveniently supplied in the form of an aerosol spray presentation from pressurized containers or a nebulizer, with the use of a suitable propellant, e.g. e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, ΜΛ / t / ZUZZ / UOO 141 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 measured amount. Capsules and cartridges of e.g. For example, gelatin, for use in an inhaler or insufflator may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. Also described herein are various pharmaceutical compositions well known in the pharmaceutical art for uses including intraocular, intranasal and intraauricular delivery. Penetrating agents suitable for these uses are generally known in the art. Topical ophthalmic compositions can be formulated as a solution in buffered water at a pH of 5.0 to 8.0. Other ingredients that may be desirable for use in ophthalmic preparations include preservatives (such as benzalkonium chloride, stabilized oxychlorine complex, marketed as Purite™, or stabilized chlorine dioxide), cosolvents (such as polysorbate 20, 60 and 80, Pluronic® F-68, F-84 and P103, cyclodextrin or Solutol) and viscosity enhancing agents (such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose or hydroxypropylcellulose). The compounds disclosed herein may also be used in an intraocular implant as described in US Patent 7,931,909, which is incorporated herein by reference. Pharmaceutical compositions for infraocular delivery include aqueous ophthalmic solutions of the active compounds in water-soluble form, such as eye drops, or in gellan gum (Shedden et al., Clin. Ther., 23(3):440-50 (2001)). or hydrogels (Mayer et al, Ophthalmologica, 210(2):101-3 (1996)); ophthalmic ointments; ophthalmic suspensions, such as microparticles, small polymeric particles containing drugs that are suspended in a liquid carrier medium (Joshi, A., J. Ocul. Pharmacol., 10(1):29-45 (1994)), fat-soluble formulations ( Alm et al., Prog. Clin. Biol. Res., 312:447-58 (1989)) and microspheres (Mordenti, Toxicol. Sci., 52(1):101 6 (1999)); and eye inserts. All references mentioned above are incorporated herein by reference in their entirety. Such pharmaceutical formulations suitable for intraocular delivery are in most cases and preferably formulated to be sterile, isotonic and buffered for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays which are typically prepared to stimulate nasal secretions in various ways to ensure maintenance of normal ciliary action. As described in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety, and as is well known to those skilled in the art, the formulations suitable are in most cases and preferably isotonic, are lightly buffered to maintain a pH of 5.5 to 6.5 and in most cases and preferably include antimicrobial preservatives and MA / t / ZUZZ / UOO 141 suitable pharmacological stabilizers. Pharmaceutical formulations for intra-auricular delivery include suspensions and ointments for topical application to the ear. Common solvents for such auricular formulations include glycerin and water. The compounds disclosed herein may also be formulated into rectal compositions such as suppositories or retention enemas, e.g. e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described above, the compounds can also be formulated as a depot preparation. Such long-acting formulations can be administered by implant (for example, subcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins or as poorly soluble derivatives, for example, as a poorly soluble salt. For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer and an aqueous phase. A common cosolvent system used is the VPD cosolvent system, which is a solution of 3% w / v benzyl alcohol, 8% w / v nonpolar surfactant Polysorbate 80™, and 65% w / v polyethylene glycol. 300, completing the volume in absolute ethanol. Obviously, the proportions of a cosolvent system can vary considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components may vary: for example, other low toxicity non-polar surfactants may be used instead of POLYSORBATE 80™; the size of the polyethylene glycol fraction may vary; Other biocompatible polymers can replace polyethylene glycol, e.g. e.g., polyvinylpyrrolidone; and other sugars or polysaccharides can replace dextrose. Alternatively, other delivery systems can be employed for hydrophobic pharmaceutical compounds. Liposomes and emulsions are well-known examples of carriers or delivery vehicles for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide can also be used. Additionally, the compounds can be delivered using a sustained release system such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been established and are well known to those skilled in the art. Depending on their chemical nature, sustained-release capsules can release the compounds for a few weeks and up to more than 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies can be employed for protein stabilization. MA / t / ZUZZ / UOO 141 Agents designed to be administered intracellularly can be administered using techniques well known to those skilled in the art. For example, such agents can be encapsulated in liposomes. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are protected from the external microenvironment and, because liposomes fuse with cell membranes, are simultaneously efficiently delivered into the cell cytoplasm. The liposome can be coated with a tissue-specific antibody. The liposomes will be directed towards the desired organ and will be selectively captured by it. Alternatively, low molecular weight hydrophobic organic molecules can be administered directly intracellularly. Additional therapeutic or diagnostic agents may be incorporated into the pharmaceutical compositions. Alternatively or additionally, the pharmaceutical compositions may be combined with other compositions containing other therapeutic or diagnostic agents. Combinations The compounds disclosed herein may also be combined with other compounds active in the treatment and / or prevention of inflammatory, metabolic, oncological and autoimmune diseases or disorders, or a symptom thereof. The combinations provided herein comprise 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) Esters of fumaric acid such as dimethyl fumarate; d) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide; e) Retinoids such as acitretin or isotretinoin; f) Anti-inflammatories 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) Antineoplastic agents such as lenalidomide, pomalidomide, pembrolizumab, nivolumab, daratumumab, bortezomib, carfilzomib, ixazomib, bendamustine or ventoclast; ΜΛ / t / ZUZZ / UOO 141 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; I) Interleukin 12 / 23 blockers such as ustekinumab; m) IL-23 blockers such as tristenkizumab, guselkumab or tildrakizumab; n) Anti-IL4 / IL13 antagonist such as dupilumab, lebrikizumab or tralokinumab; o) IL-1β blockers such as canakinumab; p) IL-alpha blockers such as bermekimab; q) CD6 blockers such as itolizumab; r) IL-36R blockers such as BI-655130 or bimekizumab; s) IL-6 antagonist such as tocilizumab; t) Calcineurin inhibitors such as pimecrolimus, tacrolimus or cyclosporine; u) Phototherapy agents commonly used in phototherapy such as psoralen, methoxypsoralen or 5-methoxypsoralen + UVA (PUVA) or UVB treatment (with or without tar); v) Fixed combinations of corticosteroids and vitamin D derivatives; w) Fixed combinations of corticosteroids and retinoids; x) Corticosteroid tapes e y) one or more agents selected from the group consisting of BMS986165, PF-06700841, PF-06826647, piclidenosone, tepilamide fumarate, LYC-30937, LEO-32731, BI-730357, PRCL-02, LNP-1955, GSK-2982772 , CBP-307, KD-025, MP-1032, petesicatib, JTE451, Hemay-005, SM-04755, EDP-1815, BI-730460, SFA-002 ER, JNJ-3534, SAR-441169, BOS-172767, SCD-044, ABBV-157, BAY-1834845, AUR-101, R-835, PBF-1650, RTA-1701, AZD-0284, mirikizumab, CD20 antagonist, salicylic acid, coal tar, Mical-1, DUR928 , AM-001, BMX-010, TA-102, SNA-125, Brepocitinib Tosylate, Pegcantratinib, ESR-114, NP-000888, SM-04755, BOS-475, SB-414, LEO-134310, CBS-3595 , PF-06763809, XCUR-17 and BTX-1308. The active compounds in the combination, that is, the compounds described herein, and the other optional active compounds can be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by means of same route or through a different route. Applications The compounds or pharmaceutical compositions disclosed herein as described above can be used to modulate the activity of a receptor. MA / t / ZUZZ / UOO 141 orphan related to retinoic acid receptors (ROR) such as a RORo, RORp and / or RORy receptor. RORy modulators were 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 reviewed. incorporated by reference in their entirety. Some examples of RORy receptors are RORyl and RORyt receptors. Compounds or pharmaceutical compositions as described above may also exhibit selective modulation of a particular ROR receptor with respect to a different ROR receptor. For example, according to some embodiments disclosed herein, some compounds or pharmaceutical compositions modulate the activity of a RORy receptor to a greater degree than the activity of RORa and / or RORp receptors. The compounds or pharmaceutical compositions disclosed herein can also be used to modulate the activity of cells that produce IL-17A in a RORyt-dependent manner, for example, γδΤ cells, Th17 cells, Tc17 cells and ILC3 cells. The compounds or pharmaceutical compositions disclosed herein can also be used to inhibit the function of RORyt upon stimulation of IL-23, which in turn exerts a negative effect on the differentiation and expansion of pathogenic Tc17 and Th17 cells. Some publications that provide useful background information are Arthritis & Rheumatism, 2014, 66, 579-588; Curr Top Microbial Immun, 2014, 378, 171-182; Drug Disc. Today, May 2014; Nature Rev. Drug Disc. 2012,11,763-776 and Nature Rev. Drug Disc., 2014, 13, 197-216, all of which are Incorporated herein by reference in their entirety. The pharmaceutical compounds or compositions as described herein and above may also be used in therapy or may be used to treat inflammatory, metabolic, oncological and autoimmune diseases or disorders, or a symptom thereof. Some examples of such diseases or disorders are inflammatory, metabolic, oncological and autoimmune diseases or disorders mediated or affected by IL-17A and / or RORy. The role of RORy in the pathogenesis of autoimmune or inflammatory diseases has been revealed in Immunity 2007, 26(5), 643654; Nat. Rev. Immunol. 2006, 6, 205-217; J. Immunol. 2009, 183, 7169-7177; Brain Pathol. 2004, 14, 164-174; Brain 2007, 130, 1089-1104; and Nat Rev. Immunol. 2008, 8, 183-192, all of which are incorporated herein by reference in their entirety. Some more specific examples of diseases or disorders, or a symptom thereof, include asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uveitis, celiac disease and food allergy, atopic dermatitis, lichen planus, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ΜΛ / t / ZUZZ / UOO 141 ichthyosis, bullous diseases, hidradenitis suppurativa, steatosis, steatohepatitis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, disease autoimmune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (Eli), irritable bowel syndrome (Sil), Sjógren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barre syndrome , Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type II diabetes and cancer. More preferably, the diseases or disorders, or a symptom thereof, include acne, atopic dermatitis, lichen planus, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (Eli) and lupus erythematosus. An example of a symptom is a physical or mental characteristic that is considered to indicate a disease condition, particularly such a characteristic that is obvious to the patient, e.g. For example, treating or preventing a symptom is not considered to modify the disease but rather to prevent or alleviate one or more symptoms commonly experienced in connection with that disease. More specifically, compounds or pharmaceutical compositions that have an antagonistic or inverse agonist effect on RORy can be used to reduce the levels of IL-17A and / or other gene products, such as interleukin and cytokines, regulated by RORy. This may occur, for example, in subjects suffering from, for example, asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uveitis, celiac disease. and food allergy, atopic dermatitis, lichen planus, cystic fibrosis, pulmonary allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, osteoarthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (ILD), syndrome irritable bowel syndrome (SIL), Sjógren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barre syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, and diabetes type II. On the contrary, compounds or pharmaceutical compositions that have an agonist effect on RORy can be used to increase IL-17A levels. Increasing IL-17A levels may be particularly useful in conditions of ΜΛ / t / ZUZZ / UOO 14 Ί immunosuppression or to enhance the response of the immune system, for example during infections and in cancer. The compounds described herein can be used in the preparation of a medicament for the treatment and / or prevention of inflammatory, metabolic, oncological and autoimmune diseases or disorders, or a symptom thereof. Administration methods The pharmaceutical compounds or compositions may be administered to the patient by any suitable means. Some non-limiting examples of methods of administration include, but are not limited to, (a) administration via oral routes, wherein said administration includes administration in a capsule, tablet, granule, spray, syrup or other such forms; (b) administration through non-oral routes such as rectal, vaginal, intraurethral, ​​intraocular, intranasal or intraauricular, where said administration includes administration as an aqueous suspension, an oil preparation or the like, or as a drip, spray, suppository , balm, ointment or similar; (c) administration by injection, subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intracapsular, intraspinal, sternum or the like, including delivery with an infusion pump; (d) local administration such as by injection directly into the renal or cardiac area, e.g. e.g., through a depot implant, through an intratumoral injection or through an injection into the intralymphatic nodes; (e) topical administration; as well as (f) administration to ex vivo cells followed by insertion of said cells into the patient; as deemed appropriate by those skilled in the art to bring the compound disclosed herein into contact with living tissue. Pharmaceutical compositions suitable for administration include compositions in which the active ingredients are contained in an amount effective to achieve their desired objective. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, which includes a mammal, e.g. e.g., a human being, what is being treated and the physical characteristics of the specific animal under consideration. The dosage can be tailored to achieve a desired effect, but will depend on factors such as weight, diet, concurrent medication, and other factors that will be recognized by experts in the field of medicine. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or improve the symptoms of a disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the purview of those skilled in the art, especially in light of the detailed disclosure provided herein. As will be very obvious to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending on age, ΜΛ / t / ZUZZ / UOO 141 weight and the species of mammal being treated, the particular compounds used and the specific use for which these compounds are used. Determination of effective dosage levels, which correspond to the dosage levels necessary to achieve the desired result, can be carried out by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are started at lower dosage levels and the dosage level is increased until the desired effect is achieved. Alternatively, acceptable in vitro studies may be used to establish useful doses and routes of administration of the compositions identified by the methods herein using established pharmacological methods. In non-human animal studies, applications of potential products are started at higher dosage levels and the dosage is reduced until the desired effect is no longer achieved or adverse side effects disappear. The dosage can vary widely, depending on the desired effects and the therapeutic indication. Typically, dosages may be between about 10 micrograms / kg and 100 mg / kg body weight, preferably between about 100 micrograms / kg and 10 mg / kg body weight. Alternatively, dosages may be based on and calculated based on the patient's surface area, as interpreted by those skilled in the art. The exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be selected by the physician based on the patient's condition. (See, for example, Fingí etai. 1975, in The Pharmacological Basis of Therapeutics, which is incorporated herein by reference in its entirety, with particular reference to Chapter 1, p. 1). Typically, the dose range of the composition administered to the patient may be about 0.5 to 1000 mg / kg of the patient's body weight. The dosage may be a single dosage or may be a series of two or more, administered over the course of one or more days, as needed by the patient. In cases where human dosages for the compounds have been established for at least some condition, those same dosages, or dosages between about 0.1% and 500%, more preferably between about 25% and 250%, can be used. % of established human dosage. When no human dosage has been established, as will be the case for newly discovered pharmaceutical compounds, a suitable human dosage can be inferred from ED5o or Dl5o values, or other suitable values ​​derived from in vivo or in vitro studies, which They are qualified by toxicity studies and efficacy studies in animals. It should be noted that the responsible physician will know how and when to determine, interrupt or adjust administration due to toxicity or organ dysfunction. On the other hand, the responsible doctor will also know how to adjust the treatment with higher doses if the clinical response is not adequate (excluding toxicity). The magnitude of a dose administered in the management of the disorder of interest will vary depending on the severity of the condition to be treated and the route of administration. The severity of the condition, for example, can be assessed, in part, using standard prognostic assessment methods. Additionally, the dosage and perhaps dosing frequency will also vary according to the age, body weight, and response of the individual patient. In veterinary medicine, a program comparable to that discussed above can be used. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations can be made regarding dosage. The daily dosage regimen for an adult human patient may be, for example, an oral dose between 0.1 mg and 2000 mg of each active ingredient, preferably between 1 mg and 500 mg, e.g. e.g., from 5 to 200 mg. The concentration of an eye drop can be between 0.005 and 5 percent. In one embodiment, an eye drop may vary between 0.01 and 1 percent, or between 0.01 and 0.3 percent in another embodiment. In other embodiments, an intravenous, subcutaneous or intramuscular dose of each active ingredient of between 0.01 mg and 100 mg is used, preferably between 0.1 mg and 60 mg, e.g. e.g., from 1 to 40 mg. In cases of administration of a pharmaceutically acceptable salt, dosages can be calculated in free base form. In some embodiments, the composition is administered 1 to 4 times a day. Alternatively, the compositions disclosed herein can be administered by continuous intravenous infusion, preferably with a dose of each active ingredient of up to 1000 mg per day. As those skilled in the art will understand, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even greatly exceed, the frequency or preferred dosage range mentioned above in order to effectively treat and aggressive infections or particularly aggressive diseases. In some embodiments, the compounds will be administered over a period of continuous therapy, for example, for a week or more, or for months or years. The amount and interval of dosages can be individually adjusted to provide tissue or plasma levels of the active moiety that are sufficient to maintain the modulatory effects, or a minimum effective concentration (MEC). The CME will vary for each compound but can be estimated from in vitro data. The dosages necessary to achieve CME will depend on individual characteristics and the route of administration. Despite this, HPLC assays or biological assays can be used to determine plasma concentrations. Dosing intervals can also be determined using the CME value. The compositions should be administered using a regimen that maintains levels at ΜΛ / Ε / ΖυΖΖ / υοΟΊ4Ί plasma above the CME for 10-90% of the time, preferably 30-90% and most preferably 50-90%. In cases of local or ex vivo administration or selective uptake, it may happen that the effective local concentration of the drug does not correlate with the plasma concentration. The amount of composition administered may depend on the subject being treated, the weight of the subject, the severity of the affliction, the mode of administration, and the judgment of the prescribing physician. The compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or a subset of compounds, sharing certain chemical moieties, can be established by determining the in vitro toxicity against a cell line such as a mammalian and preferably a human cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically in humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using various recognized methods such as in vitro methods, animal models or human clinical trials. There are recognized in vitro models for almost every class of condition, including, but not limited to, cancer, cardiovascular disease, and various immune dysfunctions. Similarly, acceptable animal models can be used to establish the efficacy of chemicals to treat such conditions. When selecting a model to determine efficacy, the expert can be guided by the state of the art to choose a suitable model, dose, route of administration and regimen. Obviously, human clinical trials can also be used to determine the effectiveness of a compound in humans. The compositions may be presented, if desired, in a container or dispensing device that may contain one or more unit dosage forms containing the active ingredient. The packaging may comprise, for example, a plastic or metal foil such as a blister pack. The container or dispensing device may be accompanied by instructions for administration. The container or device may also be accompanied by a note associated with the container in a form prescribed by a government agency regulating the manufacture, use or sale of pharmaceutical products, where such note reflects the agency's approval of the form of the drug for veterinary or human administration. Such a note may be, for example, the U.S. Food and Drug Administration-approved label for prescription drugs or the approved product package insert. Compositions that comprise a compound can also be prepared MA / t / ZUZZ / UOO 141 disclosed herein formulated in a compatible pharmaceutical carrier, placed in a suitable container and labeled for the treatment of an indicated condition. General clarifications As described above with reference to specific illustrative embodiments, they are not intended to be limited to the specific form set forth herein. It should be appreciated that any combination of the above-mentioned embodiments is within the scope of the disclosure. Furthermore, the disclosure is limited only by the appended claims and other embodiments other than the specific ones above are equally possible within the scope of these appended claims. In the claims, the expression comprises / comprehend does not exclude the presence of other species or steps. Furthermore, although individual features may be included in different claims, these may possibly be combined favorably and inclusion in different claims does not imply that a combination of features is not possible and / or favorable. Furthermore, references in the singular do not exclude a plurality. The terms a / a, first / a, second / a, etc. they do not exclude a plurality. The expressions at least one or one or more refer to 1 or a number greater than 1 such as 1,2, 3, 4, 5, 6, 7, 8, 9 or 10. Wherever a chemical name or structure is given, it has been generated by conventional means or by means of suitable software. Compound names were generated with ChemDraw Professional, version 17.1.0.105 (19). In the present disclosure, in the drawings of the structures, the labels o 1, o 2, & 1 or & 2 on each stereogenic center specify the stereochemical group to which the center belongs. In the case of o groups, the meaning is a structure representing a stereoisomer having either the stereochemical group as drawn ((R,S), for example) or the stereoisomer in which the stereogenic centers of the group they have the opposite configuration (S, R). In the case of & groups in combination with the given number (e.g. & 1) indicates a mixture of the marked asymmetrically substituted atoms. When the numbering groups several asymmetrically substituted atoms together, it shows their configuration relative to each other. If displayed as (R,S) the opposite configuration (S,R) is also present for the specified clustered group. In the present disclosure, the symbol ” specifies that it is enantiomerically enriched. Any compound or intermediate synthesized in an enantiomerically enriched manner and where no chiral separation has been carried out is identified with MA / t / ZUZZ / UOO 141 EXPERIMENTAL PART The following examples are merely examples and should not be construed in any way to limit the scope of the disclosure. Instead, disclosure is limited only by the accompanying claims. General chemical procedures GENERAL Unless otherwise indicated, starting materials were obtained from commercial suppliers such as (but not limited to) AbBchem, ABCR, Alfa Aesar, Anaspec, Anichem, Apollo Scientific, ASDI-Inter, Asiba Pharmatech, Astetech, ArkPharm, Bachem, Chem-lmpex, ChemCollect, Chembridge, Combi-Blocks, Enamine, FCH, Fluka, Fluorochem, Frontier Scientific, HDH Pharma, InFarmatik, InterBioScreen, Life Chemicals, Manchester organics, Matrix, MercaChem, NetChem, Oakwood Chemical, PepTech , Pharmcore, PrincetonBio, Sigma-Aldrich, TRC, Tyger Scientific, and Ukrorgsyn, and were used without further purification. Solvents such as DMF, DMSO and DCM, etc. They were used directly or anhydrized with molecular sieves. EQUIPMENT NMR 1H NMR spectra were recorded on the following instruments: Bruker Avance 300 spectrometer (at 300 MHz), Bruker Avance III 400 spectrometer (at 400 MHz), Bruker Avance Neo (400 MHz), Bruker Avance III 600 (at 600 MHz), VNMR spectrometer (at 400 MHz) using the solvents CD3OD, CDCI3 or DMSO-cfe. Chemical shifts are indicated in ppm (δ) using the residual solvent as an internal standard; CDCI3: 7.26 ppm; CD3OD: 3.31; DMSO-cfe: 2.50 ppm. Coupling constants (J) are indicated in Hz. U / HPLC ANALYTICAL For analytical U / HPLC, the following equipment was used: Waters Acquity system equipped with Acquity BEH C18 (1.7 pm, 2.1 x 50 mm) with a linear gradient of a binary solvent system using a flow rate of 0.5 ml / min and DAD at room temperature, combined with type MS detection SQD I. Agilent Infinity l / ll -TOF6230B / CLND Antek 8060 equipped with Acquity BEH C18 (1.7 pm, 2.1 x 50 mm) with a linear gradient of a binary solvent system using a flow rate of 0.75 ml / min combined with DAD. Agilent 1200-1260 Infinity series equipped with Waters nm, combined with MS detection (Agilent). Shimadzu Nexera equipped with Waters from MS (Shimadzu). ΜΛ / t / ZUZZ / UOO 141 Waters Acquity system using Acquity BEH C18 (1.7 pm, 2.1 x 50 mm) with a linear gradient of a binary solvent system using a flow rate of 0.65 ml / min and DAD at room temperature, combined with a Waters detection spectrometer of MS. PREPARATIVE HPLC For prep. HPLC, the following equipment was used: Waters Acquity system using Supelco DISCOVERY C18 (5 pm, 25 cm x 21.2 mm), with a linear gradient of a binary solvent system using a flow rate of 45 ml / min and UV detection at 254 nm, combined with detection of MS on a Waters Micromass ZQ single quadrupole mass spectrometer. Shimadzu Nexera , combined with MS detection on a Shimadzu LCMS-2020. Waters Masslynx system equipped with a Waters combined with MS detection (Waters). Gilson GX-281 TRILUTION fitted with a Phenomenex Gemini NX-C18 column (5 pm, 21.2 x 150 mm) with a linear gradient of a binary solvent system using a flow rate of 15 ml / min and UV detection at 214 nm or 254 nm, combined with MS detection (Waters). The following linear gradients have been used: HCO2H - (H2O / CH3CN / HCO2H (100 / 0 / 0.1% to 0 / 100 / 0.1%)) NH4OAc - (H2O / CH3CN / NH4OAc (100 / 0 / 0.02% to 0 / 100 / 0.02%)) TFA - (H2O / CH3CN / TFA (100 / 0 / 0.1% to 0 / 100 / 0.1%)) NH4HCO3-(H2O / CH3CN / NH4HCO3(100 / 0 / 0.1% to 0 / 100 / 0.1%)) NH4OH - (H2O / CH3CN / NH4OH (100 / 0 / 0.1% to 0 / 100 / 0.1%)) HCO2 NH4- (H2O / 50% MeOH + 50% CH3CN / HCO2H / NH3(95 / 5 / 0.05% / 0.01% to 5 / 95 / 0.05% / 0.01%)) Ultrafast QC was carried out in most cases on Isolera® automated systems. The ultra-fast CC and TLC prep. were carried out using SÍO2, if not mentioned otherwise. Despite this, C18 columns have also been used (using a gradient of water-acetonitrile / MeOH (1:1), with or without 0.1% v / v of ammonium formate in both phases, from 0% to a 100% acetonitrile / MeOH (1:1)). ANALYTICAL CHIRAL CHROMATOGRAPHY It was carried out in a Waters UPC2 system coupled to a DAD detector with a Waters QDa type MS detector, equipped with a chiral column with a gradient elution. ΜΛ / t / ZUZZ / UOO 141 using a flow rate of 1 ml / min. The chiral columns available were CHIRALPAK (3 pm, 4.6 x 100 mm) IA, IB, IC and ID and Trefoil AMY1 (2.5 pm, 2.1 x 150 mm). The following linear gradients have been used for the analytical UPC2: CO2 / MeOH / DEA (99 / 1 / 0.2% to 60 / 40 / 0.2%)) CO2 / EtOH / DEA (99 / 1 / 0.2% to 60 / 40 / 0.2%) CO2 / IPA / DEA (from 99 / 1 / 0.2% to 60 / 40 / 0.2%) PREPARATIVE CHIRAL CHROMATOGRAPHY Before chiral separation, compounds were purified by standard methods described previously using appropriate solvents. Preparative chiral separations were carried out on a Gilson system (306, GX-281 trilution, 156-UV / Vis, Waters 3100 MSD) or a Waters SFC-80 system, fitted with a chiral column with the specified solvents using rates of flow between 10-50 ml / min (only 50 g / min for SCF) and detection at 214 or 230 nm. The chiral columns available were Reprosil AMS (5 pm, 20 mm x 250 mm), Lux C2 (5 pm, 21.2 mm x 250 mm), Lux C4 (5 pm, 21.2 mm x 250 mm), Chiralpak® IA, IB column , IC, ID, IF or IG (5 pm, 20 mm x 250 mm) or Chiralcel® OJ-H or OD-H. The exact elution and column conditions used for each compound are described in the experimental part. SYNTHESIS METHODS The compounds described herein can be synthesized by one of the following methods General Method A - Synthesis from Boc-protected piperidines MA / t / ZUZZ / UOO 141 Re The secondary amine A1 was reacted with 4,5,6-thfluoropyrimidine (at room temperature or slightly above, 30 °C) together with a suitable base (such as; DIEA, TEA or K2CO3) at rt. After the reaction was completed, intermediate A2 was treated and purified by chromatography (flash CC or HPLC) or used as crude oil. The intermediate A2, a base (such as DIEA, TEA or CS2CO3) and the primary amine A3 were then dissolved in a solvent (such as DMSO or DMSO-water, water, water-ethanol mixtures) and the temperature was increased. at 70-100 °C in, or until the reaction was considered complete. Treatment and purification then provided intermediate A4, which was subjected to deprotection. The intermediate product of the following deprotection with Boc A5 was most often used directly, as the corresponding pyridinium salt (HCl or TFA), in the alkylation with 2-bromoacetamide and a suitable base, such as DIEA or K2CO3. First, A6 products were purified by chromatographic methods (to ensure pure products and to isolate possible diastereoisomers). In cases where the products (or intermediates) were stereoisomers, they were often (but not always) subjected to chiral chromatography to obtain the individual stereoisomers as final products. All the compounds in Table A have been synthesized using this methodology, in ranges from 2 pmol to a scale of approximately 1 mol. Example A6-1 Synthesis and isolation of the 4 stereoisomers of re / -2-((3F?,4ñ)-4-(((6-(((1,1difluorospiro[2.5]octan-6-¡l)methyl)(et ¡l)amino)-5-fluorop¡r¡m¡d¡n-4-l)amino)met¡l)-3hydroxypiperidin-1 -yljacetamide, A6-1 -1 -1, A6-1 - 1 -2, A6-1 -2-1 and A6-1 -2-2. ΜΛ / t / ZUZZ / UOO 141 Α2-1-1 and A2-1-2 ΜΛ / t / ZUZZ / UOO 14 1 Synthesis of Λ / -((1,1 -difluorospiro[2.5]octan-6-¡l)methyl)-A / -ethyl-5,6-difluoropirimidín-4amine, A2-1, and separation of the stereoisomers A2-1-1 and A2-1-2. F A2-1 4,5,6-Trifluoropinmidine (673 mg, 5.0 mmol) and DIEA (1.8 g, 14.1 mmol) were added to a solution of A1 -1 (1.1 g, crude) in DMSO (10 mL). The reaction was stirred at room temperature, poured into water (20 mL) and extracted with EA (3 x 20 mL). The combined EA phase was washed with brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by ultrafast CC (PE:EA=15:1) yielding the desired product A2-1. After HPLC prep. (CHIRALPAK IC, Hex:IPA= 98:2) two stereoisomers A2-1 -1 and A2-1 -2 were obtained. EM Cale, (calculated): 317; Experimental MS: 318 ([M+H]+). Synthesis of (3 / 7,4 / 7)-4-(((6-(((1,1 -difluorospiro[2.5]octan-6-¡l)methyl)(ethyl)amino) rac-iert-butyl -5fluoroprímjdin-4-yl)amino)methyl)-3-hydroxypiperidín-1-carboxylate, A4-1-1 and A41-2. MA / t / ZUZZ / UOO 141 A3-1 (243 mg, 1.1 mmol) and DIEA (275 mg, 2.1 mmol) were added in turn to a solution of A2-1 -1 (223 mg, 0.7 mmol) and the reaction was stirred at 95° C for 3 hours. After that, Η2Ο (20 mL) was added and the mixture was extracted with EA (3 × 20 mL). The EA phase was washed with brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo yielding crude A4-1 -1, which was used without further purification. MS caled.: 527; Experimental MS: 528 ([M+H]+). A2-1-2 (525 mg, 1.7 mmol) was treated as described for A2-1-1 to produce A4-1-2. MS caled.: 527; Experimental MS: 528 ([M+H]+). Synthesis of rao(3fí,4fí)-4-(((6-(((1,1 -difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5fluoropyrimidin-4-yl)amino)methyl )piperidin-3-ol, A5-1-1 and A5-1-2. A4-1-1 (461 mg) was dissolved in HCl / EA (10 mL). The reaction was stirred at room temperature for 2 h and then concentrated in vacuo yielding crude A5-1-1, which was used without further purification. MS caled.: 427; Experimental MS: 428 ([M+H]+). A4-1-2 (920 mg) was treated as described for A4-1-1 yielding crude A5-1-2. MS caled.: 427; Experimental MS: 428 ([M+H]+). Synthesis of rac-2-((3R,4fi)-4-(((6-(((1,1 -difluorospiro[2.5]octan-6-yl)methyl)(ethyl)amino)-5fluoropyrimidin-4-yl )amino)methyl)-3-hydroxypiperidin-1 -yl)acetamide, A6-1-1 and A6-1-2. ΝΗ2 Λ ΗΟ Ν Η MA / t / ZUZZ / UOO 141 2-Bromoacetamide (195 mg, 1.4 mmol) and K2CO3 (485 mg, 3.5 mmol) were added to a solution of A5-1-1 (440 mg, crude) in DMF (12 mL). The reaction was stirred at 35° C for 3 h. The mixture was poured into H2O (20 mL), extracted with EA (3 x 20 mL). The combined organic phase was washed with brine (20 mL), and dried (Na2SO4), filtered and concentrated in vacuo. The residue was subjected to ultrafast CC (DCM:MeOH=20:1) producing A6-1-1. 2-bromoacetamide (457 mg, 3.3 mmol), and K2CO3 (1.1 g, 8.3 mmol) were added. to a solution of A5-1 -2 (910 mg, crude) in DMF (12 mL) and the reaction was stirred at 35 ° C for 3 h. Then, it was poured into H2O (20 mL), extracted with EA (3 x 20 mL). The combined organic phase was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by ultrafast CC (DCM:MeOH=20:1) producing A6-1-2. re / -2-((3R,4F?)-4-(((6-(((1,1-D¡fluorospiro[2.5]octan-6-yl)methyl)(et¡l)am¡ no)-5f luoropi r¡ m ¡di η-4-i l)am i no) metí I)-3-hydroxypiperid i n -1 -yl)acetamide, A6-1 -1 -1, A6-1 -1 -2 , A6-1 -2-1 and A6-1-2-2. A6-1-1-1 A6-1-1-2 A6-1-2-1 A6-1-2-2 A6-1-1 (160 mg, 0.33 mmol) was subjected to chiral HPLC (CHIRALPAK ID, Hex:EtCH:DEA=70:30:0.3) yielding A6-1-1-1 (eluted 1eryisomer) and A6-1 -1-2 (28isomer in elution). A6-1-2 (346 mg, 0.72 mmol) was subjected to chiral HPLC (CHIRALPAK ID, Hex:EtOH:DEA=60:40:0.3) yielding A6-1-2-1 (eluted 1eryisomer) and A6-1 -2-2 (2nd isomer to elute). The following compounds in Table A were prepared according to General Method A. Table A: Α1 A3 A6 Α1-2 A3-1 A6-2-1 cf3 Boc 0 9 ώ HO yiy CF3 .0 . ñ HIT I NH2 {3R,4R)-4- I O o 9 -z^ A / -methyl-1 - (aminomethyl)-3- F 1 ((1r,4r)-4- hydroxypiperidin-1- rac-tert-(methyl(((1r,4R)-4- exyl)methanamine butyl 2-((3ñ*,4FT)-4-(((5-fluoro-6- (trifluoromethyl)cycloh carboxylate) trifluoromethyl)cyclohexyl)methyl)amino)pyrimidin -4-l)amino)methyl)-3-hydroxypiperidin-1 il )acetamide 1st isomer to elute A1-2 A3-1 A6-2-2 2-((3R*,4R*)-4-(((5-fluoro-6- (methyl(((1r, 4F?)-4- (tnfluoromet¡l)cyclohex¡l)met¡l)amino)p¡r¡m¡d¡n -4-¡l)amino)met¡l)-3-hydrox piperidin-1 yl)acetamide 2.8 isomer in elution A1-3 cf3 9 HN N-(((1r,4r)- 4- (trifluoromethyl)cyclohexyl)methyl)ethanam¡n a A3-1 A6 -3-1 0 F^N^^i CF3 ,0 „ o HO QT N N O1 l AJk J n n Η I I F 2-((3fí*,4fí*)-4-(((6-(ethyl(((1r ,4R)-4(trifluoromethyl)cyclohexyl)methyl)amino)-5fluoropyrimidin-4-yl)amino)methyl)-3hyd roxypiperidin-1 -yl)acetamide 1st isomer in elution A1-3 A3-1 A6-3-2 2-((3fí*,4fí*)-4-(((6-(ethyl(((1r,4R)-4(trifluoromethyl)cyclohex¡l)methyl)amino)-5fluorop¡rim¡din-4-yl )amino)methyl)-3hydroxypiperidin-1 -yl)acetamide 2.' eluting isomer Α1-4 cf3 9 ΗΝ N-(((1r,4r)- 4- (trifluoromethyl)cycloh exyl)methyl)c ¡cloprop anamine A3-1 A6-4-1 0 H2N^ CF3 ,0 Q HO N H τ Λ 2-((3fí*,4fí*)-4-(((6(cyclopropyl(((1 r,4ñ)- 4- (trifluoromethyl)cyclohexyl)methyl)amino)-5fluoropyrámidín-4-l)amino)methyl)-3hydroxy¡p¡per¡ d¡n-1 -yl)acetamide 1,er eluting isomer A1-4 A3-1 A6-4-2 2-((3fí*,4fí*)-4-(((6- (cyclopropyl(((1 r,4R)-4- (trifluoromethyl)cyclohexyl)methyl)amino)-5fluoropyrámidin-4-l)amino)methyl)-3- hydroxypiperidin -1 -yl)acetamide 2nd isomer to elute A1-5 cf3 9 N-(((1r,4r)- 4- (trifluoromethyl)cycloh A3-1 T T > Q \ 5 1 y—\ γο z— ΊΖ '--7 Y2 \ / —z / —\ V ( \ίΟ \___ / ω exyl)methyl)cyclobute namine 6! 9 2-((3fiS,4fiS)-4-(((6- (cyclobutyl(((1 r,4R)-4- (trifluoromethyl)cyclohexyl)methyl)amino)-5fluoropyrimidin-4-yl)amino)methyl) -3- hydroxy¡p¡perídin-1 -yl)acetamide A1-6 0 ΗΓΓ N-((2oxaespiro[3.5]nonone n-7yl)methyl)ethanamide A3-1 A6-6- 1 O Z°\ n o HO' ητ N N oí l ΛΛ J n n Η 1 1 F re / -2-((3fí,4F?)-4-(((6-(((2- oxaspiro[3.5]nonan-7 -yl)methyl)(ethyl)am¡no)-5fluoropyr¡m¡d¡n-4-¡l)am¡no)methyl)-3hyd roxypiperidin-1 -yl)acetamide 1,er isomer in eluate A1 -6 A3-1 A6-6-2 re / -2-((3F?,4R)-4-(((6-(((2- oxaspiro[3.5]nonan-7-yl)methyl)(et¡ l)amino)-5fluoropyrámidín-4-l)amino)methyl)-3- hydroxypiperidin-1 -yl)acetamide 2.' isomer in elution A1-7 cf3 r f j HIT N -((1fluoro-4(trifluoromethyl)cyclohexyl)methyl)ethanamín a A3-1 A6-7-1 0 H2N j cf3 . 0,. Φ HO' N oí l ) N Y^ N Η I | F re / -2-((3F?,4F?)-4-(((6-(ethyl((1-fluoro-4(trifluoromethyl)cyclohexyl)methyl)amino) -5fluoropyrimidin-4-yl)amino)methyl)-3hyd roxypiperidin-1 -yl)acetamide 1,er eluting isomer Α1-7 A3-1 A6-7-2 re / -2-((3fi,4F?)-4-(((6-(ethyl((1 -fluoro-4(trifluoromethyl)cyclohex ¡l)methyl)amino)-5fluorop¡rim¡din-4-¡l)amino)met¡l)-3hyd roxypiperidin-1 -yl)acetamide 2.8 eluting isomer Α1-8 A3-2 A6-8-1 cf3 Boc 9 0 H2N'^ j cf3 99 Λ ήη2 4- k^A (3S)-3-(4- (Am¡nomet¡l)p¡perídin- H F (trifluoromet¡l) cycloh 1-carboxylate ether- 2-(4-(((5-fluoro-6-((3S)-3-(4- exyl)morpholine butyl (trifluoromethyl)cyclohexyl)morphol) no)p¡r¡m¡d¡n4-¡l)amino)met¡l)p¡períd¡n-1-¡l)acetam¡de 1,er eluting isomer A1-8 A3-2 A6 -8-2 2-(4-(((5-fluoro-6-((3S)-3-(4- (trifluoromethyl)cyclohexyl)morpholino)pyrmidin - 4-¡l)amino)methyl)p¡perídin-1-¡l)acetam¡de 2.8 eluting isomer General method B - Synthesis from piperidines protected with Boc. ΜΛ / t / ZUZZ / UOO 141 The secondary amine, A1 with B1, was reacted in a suitable solvent (such as DMF, DMSO, EtOH, BuOH, water) together with a suitable base (such as; DIEA, TEA or K2CO3) at an elevated temperature (80- 130°C) in a sealed container and often (but not always) with an additive (such as Kl). After the reaction was considered complete, intermediate product B2 was isolated. When B1 was protected, the tosyl group was subsequently removed using K2CO3 or NaOH at a slightly elevated temperature (typically 50°C). B2 was then reacted together with Boc-protected piperidine B3, in a suitable solvent (such as DMF, DMSO, EtOH, BuOH, water) together with a suitable base (such as; CS2CO3, DIEA, TEA or K2CO3). B4 was then deprotected using an acid (such as HCl or TFA) in a suitable solvent at room temperature. B5 was most often used directly, as the corresponding pyridinium salt (HCl or TFA), in alkylation with the corresponding 2haloacetamides and a suitable base, such as DIEA, TEA, Cs2CO3 or K2CO3. First, the B6 products were purified by chromatographic methods (to ensure pure products and to isolate possible diastereoisomers). In cases where the B6 products were racemic (or diastereomeric) these were often (but not always) subjected to chiral resolution (by chromatography) to obtain the individual stereoisomers as the final products. Example B6-1-1 and B6-1-2 ΜΛ / t / ZUZZ / UOO 141 a) NaH, THF. b) TFA, DCM. c) 2-Bromoacetamide, K2CO3, DMF. d) CHIRALPAK IC (Hex:EtOH:DEA=40:60:0.3). Scheme B6-1 (3fiS,4fiS)-4-((4-(ethyl(((1r,4ñ)-4-(tnfluoromethyl)cyclohexyl)methyl)amino)-7 / - / -pyrrolo[2,3d|p¡r¡m¡d¡n-7-¡l)met¡l)-3-hydroxy¡p¡períd¡n-1-tere-butyl carboxylate , B4-1. CF3 CS2CO3 (757 mg, 0.23 mmol) and B2-1 (250 mg, 0.77 mmol) were added to a solution of B3-1 (356 mg, 0.92 mmol) in DMF (10 mL) and the reaction was heated to 40°C. for 5 hours. Then, H2O (100 mL) was added and the mixture was extracted with EA (3 x 80 ml). The combined organic fraction was washed with H2O (60 mL), brine (60 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash CC (MeOH:DCM =1:10) yielding B4-1. LCMS: MS caled.: 539; Experimental MS: 540 ([M+H]+). (3RS,4ñS)-4-((4-(Ethyl(((1 r,4R)-4-(tñfluoromethyl)cyclohex¡l)methyl)amino)-7 / - / -p¡ rrolo[2,3cdpyrim¡din-7-yl)methyl)piperid¡η-3-ol, B5-1. TFA (3 mL) was added to a solution of B4-1 (240 mg, 0.45 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 1 h. The solution was concentrated in vacuo yielding crude B5-1 which was used without further purification. LCMS: MS cal.: 439; Experimental MS: 440 ([M+H]+). 2-((3F?S,4ñS)-4-((4-(Ethyl(((1 r,4ñ)-4-(tñfluoromethyl)cyclohexíl)methyl)amino)-7H- pyrrolo[2,3cdpyrimidin-7-yl)methyl)-3-hydroxypiperidin-1-yl)acetamide, B6-1. MA / t / ZUZZ / UOO 141 A mixture of crude B5-1 (290 mg, 0.45 mmol), K2CO3 (184 mg, 1.34 mmol), and 2-bromoacetamide (74 mg, 0.53 mmol) in DMF (5 mL) was stirred at 25°C for 16 h. . H2O (40 mL) was then added and the resulting mixture was extracted with EA (3 x 40 mL). The combined organic fraction was washed with H2O (30 mL), brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by ultrafast CC (MeOH:DCM =1:10) obtaining B6-1. 2-((3 / T,4F?*)-4-((4-(Ethyl(((1 r,4fl)-4-(trifluoromethyl)cyclohex¡l)methyl)amino )-7H-pyrrolo[2,3c / |pyrimidín-7-¡l)methyl)-3-hydroxyp¡perídin-1 -yl)acetamide, B6-1-1 and B6-1-2. B6-1-1 and B6-1-2 Chiral chromatography (CHIRALPAK IC (Hex:EtCH:DEA=40:60:0.3) of B6-1 provided B6-1 -1 (, 1eisomer eluted) and B6-1 -2 (2eisomer eluted). The following compounds in Table B were synthesized following general method B using the starting materials disclosed. Table B: A1 B2 B3 B6 A1-5 B2-1 N^N Ts B3-1 B6-2 CF3 / 7-(((1 r,4 / j4(trifluoromethyl) cyclohexyl)methyl) cyclobutanamine 4-chloro-7-tosyl7H-pyrrolo[2,3d]pyrimídina 2-((3F?S,4F?S)-4-((4(cyclobutyl(((1 r,4S)-4(trifluoromethyl)cyclohexyl)methyl)amino)7H-pyrrole [2,3-d]p¡r¡m¡din-7-yl)met¡l)3-hydroxy¡p¡perid¡n-1-¡l)acetamide ΜΛ / t / ZUZZ / UOO 141 B3-1 synthesis B3-1-1 B3-1-2 B3-1-3 B3-1 a) NaBH4, EtOH. b) Pd / C, (Boc)2O, MeOH. c) TsCI, Et3N, DCM. Scheme B3-1 rac-(3F?,4F?)-1 -Benzyl-4-(hydroxy¡met¡l)p¡perid¡n-3-ol, ¡B3-1 -2. Bn i B3-1-2 NaBH4 (1.3 g, 33.6 mmol) was added portionwise to a 0°C suspension of methyl 1-benzyl3-oxopiperidin-4-carboxylate (5 g, 16.8 mmol) in MeOH (50 mL). The reaction was then slowly warmed to rt and stirred for 6 h. The reaction was then quenched with NH4CI (aq, sat, 30 ml) and H2O (70 ml). The mixture was extracted with EA (2 x 100 ml) and the combined organic fraction was washed with H2O (100 ml), brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep HPLC obtaining ¡B3-1-2. LCMS: MS cal.: 221; Experimental MS: 222 ([M+H]+). (3fi,4F?)-3-hydroxy¡-4-(hydroxy¡methyl)pyridin-1-rac-tert-butylcarboxylate, ¡B3-1-3. Boc ώ ho HCJ ¡B3-1-3 Pd / C (150 mg, 10%) and BOC2O (946 mg, 4.3 mmol) were added to a suspension of B2 (800 mg, 3.62 mmol) in MeOH (20 mL) and the reaction was stirred at rt for 18 h under H2 (1 atm). The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash CC (MeOH:DCM=1:20) yielding ¡B3-1 -3. LCMS: MS cal.: 231; Experimental MS: 176 ([M-56+H]+). rae-tere-butyl (3ñ,4 / z?)-3-hydroxy-4-((tosyloxy)methyl)piper¡din-1-carboxylate), B3-1. boc ...either Today TsCT B3-1 A solution of TsCl (717 mg, 3.8 mmol) in DCM (2 ml) was added to a 0°C solution of ¡B3-1 -3 (790 mg, 3.42 mmol) and Et3N (1 g, 10.3 mmol) in DCM (10 mi). The reaction was then slowly warmed to rt and stirred for 20 h. The reaction was quenched with H2O (40 mL), and the mixture was extracted with EA (3 x 50 mL). The combined organic phase was washed with H2O (40 mL), brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by ultrafast CC (EA:PE=1:10) obtaining B3-1. LCMS: MS cal.: 385; Experimental MS: 286 ([M-101 +H]+). Diol ligands have also been synthesized, via route A or B. Diol-A route: Synthesis of 2-((3 / 7*,4 / T*)-4-(((6-(ethyl(((1 r,4R))-4-(trifluoromethyl)cyclohexyl)methyl)am no)-5fluoropyrimidín-4-yl)amino)methyl)-3,4-d¡hydroxy¡piperidin-1 -yl)acetamide, AD-6-1 and AD-6-2 ΜΛ / t / ZUZZ / UOO 141 a) DMSO, DIEA. b) Sharpless dihydroxylation. c) Pd / C, H2MeOH. d) 2Bromoacetamide, K2CO3, DMF, chiral separation (CHIRALPAK IG, Hex:EtOH:DEA=60:40:0.3). AD-6 Scheme A / -Ethyl-5,6-difluoro- / V-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)methyl)pyrimidín-4-amine, A2-3 C.F. A2-3 A2-3 was synthesized as described in General Method A, using 4,5,6trif luoropi rimidine and A1 -3. / ^-((1 -Benzyl-1,2,3,6-tetrahydropyridin-4-i I) metí I)-Δ / θ-θΐΙΙ-δ-ΐ looro-A / 3-(((1 r,4r )-4(trifluoromethyl)cyclohex¡l)methyl)pyrim¡dine-4,6-d¡amine) AD-3 A solution of (1-benzyl-1,2,3,6-tetrahydropyridin-4-¡l)methanamine- / V-ethyl5,6-difluoro-A / -(((1 r) was heated ,4 / )-4-(trifluoromethyl)cyclohex¡l)methyl)pyrimidin-4-amine AD-1 (800 mg, 2.91 mmol), N- ethyl-5,6-difluoro-N-(((1 r,4r)-4-(trifluoromethyl)cyclohex¡l)methyl)p¡r¡m¡d¡n-4-am¡ na AD-2 (940 mg, 2.91 mmol) and DIEA (1.9 g, 14.6 mmol) in DMSO (20 mL) up to 90° in a microwave reactor. After that, H2O (50 mL) was added and the mixture was extracted with EA (3 x 20 mL). The combined organic phase was washed with brine (3 x 20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash CC (EA:PE=1:2 to MeOH:DCM=1:30) yielding AD-3. LCMS: MS cal.: 505; Experimental MS: 506 ([M+H]+). (3ñS,4ñS)-1-Benzyl-4-(((6-(ethyl(((1 r,4ñ)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5fluoropyramídin- 4-yl)amino)methyl)piperidin-3,4-diol, AD-4 ΜΛ / t / ZUZZ / UOO 141 AD-3 (700 mg, 1.4 mmol) was dissolved in t-BuOH / H2O (10 ml_ / 10 mL) cooled to 0°C and then K3Fe(CN)e (1.4 g, 4.16 mmol), K2CO3(574 mg, 4.16 mmol), (DHQ)2PHAL (33 mg, 0.04mmol), K2OsO2(OH)4 (16 mg, 0.04 mmol) and MeSO2NH2 (132 mg, 1.39 mmol). The reaction was stirred at rt for tn. Sodium nitrite (10 g) and H2O (20 mL) were then added and the mixture was stirred for an additional 1 h. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic phase was washed with brine and concentrated in vacuo. The residue was purified by flash DC (EA:PE=1:2 to 1:1) yielding AD-4. LCMS: MS caled.: 539; Experimental MS: 540 ([M+H]+). (3ñS,4ñS)-4-(((6-(Ethyl(((1 r,4F?))-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5 -fluorop¡ñmid¡n4-yl)amino)methyl)p¡per¡din-3,4-diol, AD-5 Pd / C (300 mg, 10%) was added to a solution of AD-4 (560 mg, 1.0 mmol) in MeOH (10 mL) and the reaction was stirred at rt. under H2(1 atm). The mixture was filtered and concentrated in vacuo yielding AD-5. LCMS: MS caled.: 449; Experimental MS: 450 ([M+H]+). 2-((3ñS,4fíS)-4-(((6-(eth¡l(((1r,4ñ)-4-(trifluoromethyl)cyclohex¡l)methyl)amino)-5fluorop¡ r¡mid¡n-4-¡l)amino)methyl)-3,4-d¡hydroxy¡piper¡din-1 -yl)acetamide, AD-6. EITHER K2CO3 (1.1 g, 8.00 mmol) and 2-bromoacetamide (221 mg, 1.60 mmol) were added to a solution of AD-5 (360 mg, 0.8 mmol) in DMF (10 mL) and the reaction was stirred at 25°C. for 2 hours. After that, H2O (50 mL) was added and the mixture was extracted with EA (3 x 20 mL). The combined organic phase was washed with brine (3x15 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep TLC (MeOH:DCM=1:10) yielding AD-6. LCMS: MS cal.: 506; Experimental MS: 507 ([M+H]+). Isolation of the two stereoisomers 2-((3 / ^,4 / ^)-4-(((6-(6^1(((1 / 14 / 7)-4(trifluoromethyl)cyclohexyl) )met¡l)am¡no)-5-fluoropy¡m¡m¡n-4-yl)am¡no)met¡l)-3,4-di¡hydroxy¡piper¡d¡n-1 l)acetamide, AD-6-1 and AD-6-2 Chiral separation (CHIRALPAK IG (Hex:EtOH:DEA=40:60:0.3) of AD-6 provided AD-6-1 (, 1Eisomer eluted) and AD-6-2 (2Sisomer eluted). Diol B Route: Synthesis of 2-((3 / 7,4fi*)-4-((4-(ethyl(((1 r,4fi)-4-(trifluoromethyl)cyclohexyl)methyl)am no)-7 / - / pyrrolo[2,3-c / ]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin-1-yl)acetamide, BD-5-1-1 and BD-5-1 -2 DOC L4 CF3 f | CF3 • π BOC - HN N / HOL / V N \ v on \___ / BD’1 BD-2 O cf3 \\ η X AnH2 c X 0.9 ~ Q. r? 9 ~ BD-4 ___ , CF3 Boc - X χ9 BD-3 O ^~~NH2 QF3 O, ry9 houav ho N y N BD-5-1-1 and BD-5-1-2 a) NaH, DMF. b) Pd / C, NH4CO2H, MeOH. c) TFA, DCM. d) 2-Bromoacetamide, K2CO3, DMF. e) Chiral chromatography, IC (Hex:EtOH:DEA=40:60:0.3). Scheme BD-5-1 (3 / 3S,4ñS)-3-(benzyloxy)-4-((4-(ethyl(((1 r,4 / 3)-4-(trifluoromethyl)cyclohexyl)methyl) tere-butyl amino)-7 / - / pyrrolo[2,3-d|pyrimidin-7-yl)methyl)-4-hydroxypiperidin-1-carboxylate ΜΛ / t / ZUZZ / UOO 141 Under a N2 atmosphere, NaH (75 mg, 1.86 mmol) was added to a solution of AD-2 (300 mg, 0.93 mmol) in dry DMF (20mL), after 30 min a solution of BD1 (443 mg, 1.39 mmol) in dry DMF (4 mL) and the reaction was stirred at 60°. The reaction was quenched with NH4CI (aq, sat, 40 mL) and extracted with EA (3 x 20 mL). The combined organic fraction was washed with brine (3x15 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash DC (EA:PE=1:5 to 1:4) yielding BD-2. LCMS: MS cal.: 645; Experimental MS: 646 ([M+H]+). (3ñS,4ñS)-4-((4-(ethyl(((1 r,4ñ)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-7 / - / -pyrrolo[2,3cdpyrimídin- Tere-butyl 7-yl)methyl)-3,4-dihydroxypiperidine-1-carboxylate CF3 boc BD-3 A mixture of BD-2 (750 mg, 0.93mmol) in MeOH (20 mL), NH4CO2H (1.4 g, 22.32 mmol) and Pd / C (500 mg, 10%) was refluxed. The mixture was then filtered and concentrated in vacuo to provide crude BD-3. LCMS: MS cal.: 555; Experimental MS: 556 ([M+H]+). (3F?S,4F?S)-4-((4-(Ethyl(((1 r,4F?)-4-(trifluoromet¡l)cyclohex¡l)met¡l)amino )-7 / - / -pyrrolo[2,3c(|pyrimidín-7-yl)methyl)pyridine-3,4-diol, BD-4. CF3 BD-3 (413 mg, 0.74 mmol) was stirred at rt for 1 h in a mixture of TFA (4 mL) and DCM (10 mL). The mixture was then concentrated in vacuo providing the crude product BD4, which was used without further purification. LCMS: MS cal.: 455; Experimental MS: 456 ([M+H]+). 2-((3F?S,4 / :?S)-4-((4-(Ethyl(((1 r,4ñ)-4-(trifluoromethyl)cyclohex¡l)methyl)amino)- 7 / 7-pyrrolo[2,3c / |pyrimidin-7-¡l)met¡l)-3,4-dih¡droxy¡p¡perídin-1 -yl)acetamide ), BD-5 BD-5-1 K2CO3 (1.0 g, 7.40 mmol) and 2-bromoacetamide (205 mg, 1.48 mmol) were added to a solution of crude BD-4 (785 mg) in DMF (10 mL). The reaction was stirred at rt for 2 h. After that, H2O (50 mL) was added and the mixture was extracted with EA (3 x 30 mL). The combined organic phase was washed with brine (3 x 20mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep TLC. (MeOH:DCM=1:10) providing two stereo isomers BD-5-1 and BD-5-2. Separation and isolation of 2-((3 / ^,47^)-4-((4-(6^1(((1 / 34 / 7)-4(trifluoromethyl)cyclohexyl)methyl)amino)-7 stereoisomers / 7-pyrrolo[2,3-c / ]pyrimidin-7-yl)methyl)-3,4-dihydroxypiperidin1-yl)acetamide, BD-5-1-1 and BD-5-1-2 and BD-5-1-2 BD-5-1 was separated by chiral HPLC (CHIRALPAK IG, Hex:EtGH:DEA=40:60:0.3) providing the stereoisomers BD-5-1-1 (eluting 1eryisomer,) and BD-5-1-2 (2Sisomer in Synthesis of N-((1,1-difluorospiro[2.5]octan-6-¡l)methyl)ethanamine, A1 -1 a) EtNH2, DIEA, HATU. b) BH3THF. Scheme A1-1 Synthesis of / V-ethyl-1,1 -difluorospiro[2.5]octan-6-carboxamide, iA1 -1 -2 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 was stirred at 30°C for 30 min, followed by ethylamine (2 M in THF, 7 mL). The reaction was stirred at 30°C, diluted with water (20 mL), extracted with EA (3 x 20 mL), washed with brine, and dried over Na2SO4. The organic solution was concentrated in vacuo yielding crude IA1 -1 -2 which was used without further purification. MS caled.: 217; Experimental MS: 218 ([M+H]+). Synthesis of N-((1,1-difluorospiro[2.5]octan-6-l)methyl)ethanamine, A1 -1 F A1-1 ΜΛ / t / ZUZZ / UOO 141 Under a N2 atmosphere, BH3THF (1 M, 18 mL) was added portionwise to a solution of crude ¡A1 -1 -2 (1.5 g) in THF (15 mL). The reaction was refluxed overnight, cooled using an ice bath, and quenched by adding MeOH (4 mL), followed by 1 N HCl (4 mL), and then the mixture was stirred at 50°C for 30 min and after that, it was concentrated in vacuo. The residue was taken as K2CO3sat. (20 mL), extracted with DCM (3 x 20 mL), washed with brine (20 mL) and dried over Na2SO4. The organic solution was filtered and concentrated in vacuo yielding crude A1-1, which was used without further purification. MS caled.: 203; Experimental MS: 204 ([M+H]+). Synthesis of / V-methyl-1-((1r,4r)-4-(trifluoromethyl)cyclohex¡l)methanamine (A1-2), A / -(((1r,4 / j4- (trifluoromet¡l)cyclohexyl)met¡l)ethanam¡ne (A1 -3) and A / -(((1 r,4r)-4(trifluoromet¡l)cyclohex¡l)met¡l) cyclopropanamine (A1-4). CF3Qf3 A1-2 A1-3 A1-4 These intermediate products were synthesized according to the synthesis of A1 -1 but using 2-((1 r,4r)-4-(trifluoromethyl)cyclohexyl)acetic acid instead of ¡A-1-1 together with either; methylamine hydrochloride, ethylamine or cyclopropylamine, respectively. Synthesis of A / -((2-oxaspiro[3.5]nonan-7-¡l)met¡l)ethanam¡ne, A1-6. HO ¡A1-6-1 ¡A1-6-2 A1-6 MA / t / ZUZZ / UOO 141 a) Dess-Martin oxidation. b) EtNH2, MgSO4, NaBH4, MeOH. Scheme A1 -6 2-Oxaspiro[3.5]nonan-7-carbaldehyde, ¡A1 -6-2. Dess-Martin periodinan (956 mg, 2.25 mmol) was added to an ice-cold solution of (2-oxaespiro[3.5]nonan-7-yl)methanol (320 mg, 2.05 mmol) in DCM (10 ml) and stirred the reaction at rt for 2.5 hours. The mixture was adjusted with NaHCO3(aq.) to pH= 7 - 8, extracted with DCM (2 x 50 mL), dried (Na2SO4) and concentrated in vacuo producing ¡A1-6-2.1H-NMR (400MHz , CDCI3): δ 9.61 (d, J = 0.8 Hz, 1H), 4.37 (d, J = 5.2 Hz, 4H), 2.20 (m, 1 H), 2.13-2.03 (m, 2H), 1.88-1.84 ( m, 2H), 1.59-1.52 (m, 2H), 1.40-1.36 (m, 2H). A / -(2-Oxaspiro[3.5]nonan-7-ylmethyl)ethanam, A1 -6. A1-6 A mixture of ¡A1-6-2 (310 mg, 2 mmol), MeOH (10 mL), MgSO4 (1 g) and ethanamine (2 mL, 2 mol / L) was stirred at rt overnight. Then, NaBH4 (133 mg, 3.5 mmol) was added and the reaction was stirred for another 2 h at rt. After that, H2O was added, and the mixture was extracted with EA (3 x 50 mL), dried (Na2SO4) and concentrated in vacuo yielding A1-6.1HRMN (400 MHz, CDCI3): 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= 3.6Hz, 1H), 1.10 (t, J = 7.2Hz, 3H). Synthesis of Λ / -(((1 r,4r)-4-(trifluoromethyl)cyclohexyl)methyl)cyclobutanamine, A1-5. ΜΛ / t / ZUZZ / UOO 141 A1 -5 was synthesized according to the synthesis of A1 -6 but using DMSO / oxalyl chloride oxidation (Swern) instead of Dess-Martin oxidation, followed by reductive amination with cyclobutylamine. LCMS: MS cal.: 235; Experimental MS: 236 ([M+H]+). Synthesis of / \ / -((1-fluoro-4-(trifluoromethyl)cyclohex¡l)methyl)ethanam¡ne, A1-7. a) SOCI2, MeOH. b) LDA, N-Fluorobenzenesulfonimide. c) KOH, EtOH. d) N-(4methoxybenzyl)ethanamina, HATU, DIEA, DMF. e) BH3THF. f) H2, Pd / C, MeOH. Scheme A1-7 4-Trifluoromethyl-cyclohexanecarboxylic acid methyl ester, ¡A1-7-2. Under a N2 atmosphere, SOCl2 (12.2 g, 102 mmol) was added dropwise to a 0°C solution of (1r,4r)-4-(tnfluoromethyl)cyclohexan-1-carboxylic acid (10 g , 51 mmol) in MeOH (200 mL). The reaction was stirred at rt for tn. The reaction was then concentrated in vacuo and water (200 mL) was added. The mixture was extracted with DCM (2 x 200 mL) and the combined organic phase was washed with NaHCOs sat (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo yielding 7-2 which was used without further purification. 1-Fluoro-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester, ¡A1-7-3. CF3 LJU ¡A1-7-3 O^OMe Under a N2 atmosphere, LDA (2.0 M, 5.5 ml) was added dropwise to a solution of IA1-7-2 (2.1 g, 10 mmol) in THF (30 mL) at -70°C and the mixture was stirred. reaction at this temperature for 1 h. After that, a solution of Nfluorobenzenesulfonimide (3.2 g, 10 mmol) in THF (5 mL) was added dropwise. The resulting mixture was slowly warmed to rt and stirred for a further 16 h. The reaction was quenched with sat NH4Cl (20 mL). Water (60 mL) was added and the mixture was extracted with DCM (2 x 50 mL). The combined organic phase was washed with water (40 mL), brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by ultrafast CC (EA:PE=1:10) yielding iA1 -7-3. 1 -fluoro-4-trifluoromethyl-cyclohexanecarboxylic acid, i A1 -7-4. MA / t / ZUZZ / UOO 141 O^O H KOH (164 mg, 2.9 mmol) was added to a solution of ¡A1 -7-2 (500 mg, 2.19 mmol) in EtOH (9 mL) and H2O (3 mL) at rt and the reaction was stirred at rt for 18 h. Water (50 mL) was added and the mixture was washed with EA (2 x 50 mL). The aqueous phase was acidified with HCl (1 M) to pH=2 and extracted with DCM (2 x 50 mL), the combined organic phase was washed with H2O (40 mL), brine (40 mL), dried over Na2SO4 and it leaked. Concentration in vacuo gave crude A1 -7-4 which was used without further purification. -Fluoro-4-trifluoromethyl-cyclohexanecarboxylic acidethyl-(4-methoxy-benzyl)-amide ¡A1 -7-5. DIEA (541 mg, 4.2 mmol), ethyl-(4-methoxy-benzyl)-amine (416 mg, 2.52 mmol) and HATU (960 mg, 2.52 mmol) were in turn added to a solution of ¡A1- 7-4 (450 mg, 2.1 mmol) in DMF (10 mL). The reaction was then stirred at room temperature for 5 h and then water (50 mL) was added. The mixture was extracted with EA (2 x 50 mL). The combined organic phase was washed with H2O (30 mL), brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by ultrafast CC (EA:PE=1:1) yielding ¡A1-7-5. LCMS: MS cal.: 361; Experimental MS: 362 ([M+H]+). Ethyl-(1-fluoro-4-trifluoromethyl-cyclohexylmethyl)-(4-methoxy-benzyl)-amine, iA1 -7-6 CF3ó A1-7-6 X ,PMB N MA / t / ZUZZ / UOO 141 A solution of BH3THF (2.0 M in THF, 3.5 ml) was added to a 0°C solution of ¡A1-7-5 (510 mg, 1.41 mmol) (10 mL) and the reaction was heated to 65°C for 6 p.m. The reaction was quenched with MeOH (5 mL) and extracted with DCM (2 x 50 mL). The combined organic phase was washed with water (40 mL) and brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by ultrafast CC (EA:PE=1:10) yielding ¡A1-7-6. LCMS: MS caled.: 347; Experimental MS: 348 ([M+H]+). Ethyl-(1-fluoro-4-trifluoromethyl-cyclohexylmethyl)-amine, A1 -7. cf3 Φ 'NH Pd / C (100 mg, 10%) was added to a solution of ¡A1 -6-1 (350 mg, 0.99 mmol) in MeOH (5 mL) and stirred at 25°C under H2 (1 atm) for 20 h. After that, the mixture was filtered and concentrated in vacuo. The residue was purified using ultrafast CC (EA:PE=1:2) obtaining A1-7. LCMS: MS cal.: 227; Experimental MS: 228 ([M+H]+). Synthesis of (3S)-3-(4-(trifluoromethyl)cyclohexyl)morpholine, A1-8. A mixture of (S)-3-(4-(trifluoromethyl)phenyl)morpholine (1.5 g, 5.6 mmol), RUCI3 H2O (635 mg, 2.8 mmol) and trioctylamine (0.49 mL, 1.1 mmol) to H2 under pressure (700 psi) at 60°C for 140 h. After that, the reaction mixture was filtered through celite, concentrated in vacuo, 2 M NaOH was added, and the resulting mixture was extracted with EA (2 x 30 mL). The combined EA phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash CC (MeOH:DCM=1:10) yielding A1-8. LCMS: MS cal.: 237; Experimental MS: 238 ([M+H]+). / V-Et¡l- / V-(((1r,4ó-4-(trifluoromethyl)cyclohexyl)methyl)-7H-pyrrolo[2,3-a(|prírim¡d¡ n-4-amine, BD-1 cf3 a) TEA, A1 -1, Kl, H2O. b) K2CO3, MeOH. Scheme BD-1 / V-Ethyl-7-tosyl- / \ / -(((1 r,4Y4-(trifluoromethyl)cyclohex¡l)methyl)-7 / - / -pyrrolo[ 2,3-c(|p¡r¡m¡d¡n-4amine, ¡BD-1. CF3 4-chloro-7-tosyl-7 / - / -pyrrolo[2,3-c / |pyrimidine (1.2 g, 3.9 mmol), A1 -3 (810 mg, 3.9 mmol), H2O (5 mL), TEA (5mL) and Kl (650 mg, 1.9 mmol) in a sealed vial at 130°C. The reaction was allowed to cool and then extracted with EA (3 x 15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash CC (PE:EA= 10:1 to 5:1) yielding ¡BD-1. A / -Ethyl-A / -(((1 r,4ó-4-(trifluoromethyl)cyclohex¡l)methyl)-7 / - / -pyrrolo[2,3-a(|p¡ rimidín-4-amine, BD-1. CF3 K2CO3 (3.4 g, 18.3 mmol) was added to a solution of ¡BD-1 (1.1 g, 2.2 mmol) in MeOH (10 mL). The reaction was then stirred at 50°C for 4 h. After cooling to room temperature, the reaction was extracted with EA (3 x 15 mL). The combined EA phase was dried (Na2SO4), filtered and concentrated in vacuo yielding crude BD-1 which was used without further purification. LCMS: MS cal.: 326; Experimental MS: 327 ([M+H]+). Synthesis of tere-butyl 4-(benzyloxy¡)-1-oxa-6-azaspiro[2.5]octan-6-carboxylate, L4 MA / t / ZUZZ / UOO 141 boc Yo boc Yo a) NaH, Me3SI, DMF. L4 scheme Under a N2 atmosphere, NaH (283 mg, 7.1 mmol, 60%) was added to a 0°C solution of trimethylsulfonium iodide (1.44 g, 7.1 mmol) in dry DMF (20 mL) and allowed to settle. shake for 30 min. After that, a solution of tere-butyl (3-(benzyloxy¡)4-oxopiperidin-1-carboxylate) (1.8 g, 5.9 mmol) in dry DMF (5 mL) was slowly added and then stirred at ta. The reaction was quenched with NH4Cl (sat ac 50 mL) and the mixture was extracted with EA (3 x 15 mL). The combined organic phase was washed with brine (2x10 mL), dried (Na2SCU), filtered, concentrated in vacuo yielding crude L4 which was used without further purification. LCMS: MS caled.: 319; Experimental MS: 342 ([M+Na]+). Analytical table 1: H-NMR Patent Example Prep HPLC Method Analytical HPLC Method 0 M S Calc. / MS Observed: Chiral HPLC Method A 6-1-1-1 1H-NMR (400 MHz, CDCI3):ó7.89 (d, J=1.6 Hz, 1H), 6.94 (s, 1H), 5.91 (s, 1H), 5.38-2.42 (m, 1H), 4,874.92 (m, 1H), 4.09-4.17 (m, 1H) ), 3.50-3.61 (m,2H), 3.313.45 (m, 3H), 3.02-3.12 (m, 4H), 2.85-2.89 (m, 1H), 2.102.24 (m, 2H), 1.76-1.79 (m, 3H), 1.54-1.66 (m, 6H), 1.401.43 (m, 1H), 1.15-1.19 (t, J = 7.2 Hz, 3H), 1.06-1.14 (m, Ultrafast C C (DCM: MeOH= 20:1) N H4Ac 4 85 ID (Hex:EtOH:D EA 70:30:0.3) 2H), 1.00-1.04 (t, J = 8.4 Hz, 2H). A 6-1-1-2 1H-NMR (400 MHz, CDCI3):5 7.89 (d, J=1.6 Hz, 1H), 6.94 (s, 1H), 5.91 (s, 1Η), 5.39-5.40 (m , 1Η), 4.874.92 (m, 1H), 4.09-4.17 (m, 1H), 3.49-3.61 (m, 2H), 3.31 3.45 (m, 3H), 3.02-3.12 (m, 4H), 2.85- 2.89 (m, 1H), 2.102.24 (m, 2H), 1.76-1.79 (m, 3H), 1.54-1.66 (m, 6H), 1.371.43 (m, 1H), 1.15-1.19 (t, J = 7.2 Hz, 3H), 1.06-1.14 (m, 2H), 1.00-1.04 (t, J = 8.8 Hz, 2H). C Ultrafast C (DCM: MeOH= 20:1) N H4Ac 4 85 ID (Hex:EtOH:D EA 70:30:0.3) A 6-1-2-1 1H-NMR (400 MHz, CDCI3):ó7. 89 (d, J=2.0 Hz, 1Η), 6.93 (s, 1Η), 5.89 (s, 1Η), 5.48-5.50 (m, 1Η), 4.904.93 (m, 1H), 4.09-4.15 (m, 1H), 3.33-3.60 (m,5H),3.023.13 (m, 4H), 2.85-2.88 (m, 1H), 2.10-2.24 (m,2H), 1.751.79 (m, 3H), 1.53- 1.68 (m, 4H), 1.38-1.42 (m,3H), 1.001.22 (m, 5H), 0.95-1.00 (t, J = 8.4 Hz, 2H). C Ultrafast C (DCM: MeOH= 20:1) N H4Ac 4 85 ID (Hex:EtOH:D EA 60:40:0.3) Μ Λ / t / ZUZZ / UOO 141 A 6-1-2-2 1H-NMR (400 MHz, CDCI3):ó7.89 (d, J=1.6 Hz, 1H), 6.93 (s, 1H), 5.89 (s, 1H), 5.46-5.47 ( m, 1H), 4,884.93 (m, 1H), 4.09-4.16 (m, 1H), 3.31-3.61 (m,5H), 3,023.13 (m, 4H), 2.85-2.88 (m, 1H), 2.09-2.24 (m,2H), 1.751.81 (m, 3H), 1.53-1.68 (m, 4H), 1.38-1.42 (m,3H), 1.081.22 (m, 5H), 0.95-1.00 (t , J = 8.4 Hz, 2H). C Ultrafast C (DCM: MeOH= 20:1) N H4Ac 4 85 ID (Hex:EtOH:D EA 60:40:0.3) A 6-2-1 1HNMR (400 MHz, MeOH-d4) δ 7.68 (d, J = 1.2 Hz, 1 H), 3.55-3.50 (m, 1H), 3.38-3.29 (m, 4 H), 3.05 (d, J = 3.6 Hz, 3 H), 2.95-2.88 (m, 3 H) , 2.76-2.73 (m, 1 H), 2.06-1.95 (m, 3 H), 1.94-1.84 (m, 2 H) 1.73-1.63 (m, 4 H), 1.42-1.37 (m, 2 H), 1.25-1.15 (m, 2 H), 0.99-0.93 (m, 2 H) N H4HCO 3 MS caled.: 490; Experimental MS: 491 OJ (Hex: EtOH=85:15) A 6-2-2 1HNMR (400 MHz, MeOH-d4) δ 7.68 (d, J = 1.2 Hz, 1 H), 3.55-3.50 (m , 1H), 3.39-3.29 (m,4H), 3.05 (d, J = 3.2 Hz, 3 H), 2.97-2.89 (m, 3 H), 2.77-2.74 (m, 1 H), 2.07-1.95 ( m, 3 H), 1.94-1.84 (m, 2 H) 1.73-1.64 (m, 4 H), 1.43-1.36 (m, 2 H), 1.25-1.15 (m, 2 H), 0.80-0.78 (m , 2 H) N H4HCO 3 MS caled.: 490; Experimental MS: 491 OJ (Hex: EtOH=85:15) A 6-3-1 1HNMR (400 MHz MeOH-d4) δ 7.68 (d, J=4 Hz, 1H), 3.44-3.57 (m,3H ), 3.253.39 (m, 4H), 2.86-2.95(m, N H4HCO 3 H N4HOA c M S caled.: 490; MS 3H), 2.74 (d, J=12 Hz, 1H), 1.84-2.06 (m, 5H), 1.73-1.76 (m, 2H), 1.60-1.65 (m, 2H), 1.37-1.42 (m, 2H) , 1.13-1.24 (m, 3H), 1.04-1.08 (t, J=8 Hz 3H),0.90-0.98 (m, 2H). experimental: 491 A 6-3-2 1HNMR (400 MHz MeOH-d4) δ 7.67 (d, J=4 Hz, 1H), 3.44-3.56 (m,3H), 3.293.39 (m, 4H), 2.87 -2.97(m, 3H), 2.74 (d, J=12 Hz, 1H), 1.95-2.05 (m, 3H), 1.84-1.87 (m, 2H), 1.73-1.76 (m, 2H), 1.60-1.66 (m, 2H), 1.37-1.43 (m, 2H), 1.13-1.24 (m, 3H), 1.04-1.08 (t, J=8 Hz 3H),0.90-0.98 (m, 2H). N H4HCO 3 H N4HOA C M S caled.: 490; Experimental MS: 491 A 6-4-1 1HNMR (400 MHz CDCI3) δ 7.92 (d, J = 1.2 Hz, 1H), 6.94 (s, 1H), 5.85 (s, 1H), 5.48-5.49 (m, 1H), 5.955.05 (m, 1H), 4.09-4.17 (m, 1H), 3.43-3.49 (m,2H), 3.323.37 (m, 1H), 3.03-3.15 (m, 4H), 2.86- 2.95 (m,2H), 2,112.24 (m, 2H), 1.94-1.98 (m, 3H), 1.82-1.86 (m,2H), 1,531.69 (m, 5H), 1.40-1.46 (m, 1H ), 1.25-1.34 (m,3H), 0.921.02 (m, 2H), 0.79-0.85 (m, 2H), 0.64-0.66 (m, 2H). N H4HCO 3 H N4HOA c M S caled.: 502; Experimental MS: 503 ID (Hex:EtOH:D EA 80:20:0.3) ΜΛ / Ε / ΖυΖΖ / υοΟΊ4Ί A 6-4-2 1HNMR (400 MHz CDCI3)5 7.92 (d, J = 1.2 Hz, 1H), 6.94 (s, 1H), 5.85 (s, 1H), 5.41-5.43 (m, 1H), 5.955. 05 (m, 1H), 4.10-4.17 (m, 1H), 3.43-3.50 (m, 2H), 3.333.37 (m, 1H), 3.03-3.15 (m, 4H), 2.86-2.95 (m,2H) ), 2,112.24 (m, 2H), 1.94-1.97 (m, 3H), 1.76-1.86 (m,2H), 1,531.65 (m, 5H), 1.39-1.46 (m, 1H), 1.25-1.34 (m,3H), 0.921.02 (m, 2H), 0.79-0.86 (m, 2H), 0.64-0.66 (m, 2H). N H4HCO 3 H N4HOA c M S caled.: 502; Experimental MS: 503 ID (Hex:EtOH:D EA 80:20:0.3) A 6-5 1H NMR (400 MHz, Chloroform-d) δ 0.75 - 0.94 (m, 2H), 1.14-1.23 (m, 3H), 1.32 - 1.36 (m, 2H), 1.55 1.67 (m, 3H), 1.72 (d, J = 12.3 Hz, 2H), 1.82-2.26 (m, 10H), 2.80 (d, J = 11.3 Hz, 1H), 2.92 - 3.10 (m, 3H), 3.27 (dd, J = 10.0, 5.5 Hz, 1H), 3.34 (d, J = 7.2 Hz, 1H), 4.06 (ddd, J = 15.1, 7.8, 3.2 Hz , 1H), 4.35-4.46 (m, 1H), 4.86 (s, 1H), 5.27 (s, 1H), 6.85 (s, 1H), 7.85 (d, J = 1.5 Hz, 1H). 517.0 A 6-6-1 1HNMR (400MHz, CDCI3) δ 7.88 (d, J= 1.6 Hz, 1H),6.93 (s, 1H), 5.65 (d, J= 2.8 Hz, 1H), 4.88 (s, 1H) , 4.41 (s, 2H), 4.33-4.14 (m, 2H), 4.15-4.09 (m, 1H), 3.583.47 (m, 2H), 3.37-3.30 (m, 3H), 3.11-3.03 (m, 4H), 2.86 (d, J = 12.0 Hz, 1H), 2.212.11 (m, 4H), 1.72-1.51 (m, 4H), 1.4-1.35 (m, 4H), 1.201.14 (m, 3H) , 0.98-0.93 (m, 3H). N H4HCO 3 MS caled.: 464; Experimental MS: 465 IG (Hex:EtOH:D EA 50:50:0.5) A 6-6-2 1HNMR (400MHz, CDCI3) δ 7.87 (d,J= 1.6 Hz, 1H), 6.92 (s, 1H) ), 5.41 (d, J = 2.8 Hz, 1H), 4.88 (s, 1H), 4.41 (s, 2H), 4.33 (s, 2H), 4.19-4.05 (m, 1H), 3.58-3.47 (m, 5H), 3.11-3.02 (m, 3H), 2.87-2.85 (m, 1H), 2.23-2.10 (m, 4H), 1.65-1.53(m, 4H), 1.41-1.35 (m, 3H), 1.25 ( s, 1H), 1.16 (t, J= 12 Hz, 3H), 0.98-0.89(m, 2H). N H4HCO 3 MS caled.: 464; Experimental MS: 465 IG (Hex:EtOH:D EA 50:50:0.5) A 6-7-1 1H NMR (400 MHz, MeOH-d4) δ 8.16 (s, 1H), 7.49 (d, J = 10.0 Hz, 1H), 7.40-7.37 (m, 2H), 7.19 (d, J= 3.6 Hz, 1H), 6.49 (d, J = 3.6 Hz, 1H), 5.13 (s, 2H), 4.44 (d, J = 14.4 Hz, 1H), 4.20 (d, J = 14.4 Hz, 1H), 3.90 (c, J = 7.2 Hz, 2H), 3.55 (dd, J=10.0 Hz, 4.4 Hz, 1H), 2.96 (s , 2H), 2.74-2.70 (m, T LC prep (MeOH: DCM=1:20) N H4HOA c Caled. MS: 508; Experimental MS: 509 IG (Hex:EtOH:D EA 60:40:0.3 ) Μ Λ / t / ZUZZ / UOO 141 1H), 2.53 - 2.51 (m, 1H), 2.44 - 2.35 (m, 2H), 1.68 1.60 (m, 1H), 1.43-1.40 (m, 1H), 1.35 (t, J=7.2 Hz, 3H). A 6-7-2 1H NMR (400 MHz, MeOH-d4) δ 8.16 (s, 1H), 7.49 (d, J = 10.4Hz, 1H), 7.40-7.37 (m, 2H), 7.19 (d, J = 3.6 Hz, 1H), 6.49 (d, J = 3.6 Hz, 1H), 5.13 (s, 2H), 4.44 (d, J = 14.4 Hz, 1H), 4.20 (d, J = 14.4 Hz, 1H), 3.90 (c, J = 7.2 Hz, 2H), 3.55 (dd, J = 10.4Hz, 4.8Hz, 1H), 2.96 (s, 2H), 2.74-2.70 (m, 1H), 2.53 - 2.51 (m, 1H ), 2.44 - 2.35 (m, 2H), 1.68 1.60 (m, 1H), 1.43-1.40 (m, 1H), 1.35 (t, J=7.2 Hz, 3H). T LC prep (MeOH: DCM=1:20) N H4HOA c MS caled.: 508; Experimental MS: 509 IG (Hex:EtOH:D EA 60:40:0.3) A 6-8-1 1H NMR (400 MHz, CDCI3): δ7.93 (s, 1H), 7.07 (s, 1H) , 5.50 (s, 1H), 4.74 (s, 1H), 4.13-4.10 (m, 1H), 4.023.99 (m, 2H), 3.88-3.85 (m, 1H), 3.61-3.55 (m,2H) , 3.373.29 (m, 3H), 2.98 (s, 2H), 2.92-2.89 (m, 2H), 2.19-2.13 (m, 3H), 2.02-1.93 (m, 4H), 1.80-1.74 (m, 2H), 1.62-1.57 (m, 1H), 1.38-1.26 (m, 5H), 1.06-0.89 (m, 2H). NH4HC 03 T FA M S caled.: 502; MS expe rime ntal: 503 A 6-8-2 1Η NMR (400 MHz, CDCI3): δ7.93 (s, 1H), 7.07 (s, 1H), 5.50 (s, 1H), 4.74 (s, 1H), 4.13-4.10 (m , 1H), 4,023.99 (m, 2H), 3.88-3.85 (m, 1H), 3.61-3.55 (m, 2H), 3,373.29 (m, 3H), 2.98 (s, 2H), 2.92-2.89 (m, 2H), 2.19-2.13 (m, 3H), 2.02-1.93 (m, 4H), 1.80-1.74 (m, 2H), 1.62-1.57 (m, 1H), 1.38-1.26 (m, 5H) , 1.06-0.89 (m, 2H). N H4HCO 3 T FA MS caled.: 502; Experimental MS: 503 Β 6-1-1 1H NMR (400 MHz, CD3OD-cW) δ 8.02 (s, 1H), 7.01 (d,J = 3.6 Hz, 1H), 6.45 (d, J = 3.6 Hz , 1H), 4.29 4.18 (m, 2H), 3.74 (c, J = 7.2 Hz, 2H), 3.53 (d, J = 7.2 Hz, 2H), 3.32 - 3.26 (m, 1H), 2.95-2.90 (m , 1H), 2.88 (s, 2H), 2.68 (d, J = 11.2 Hz, 1H), 2.04 - 1.91 (m, 3H), 1.87 - 1.77 (m, 5H), 1.66 1.59 (m, 1H), 1.43 -1.39 (m, 1H), 1.31 - 1.27 (m, 2H), 1.25 - 1.14 (m, 4H), 1.10 1.01 (m, 2H). C Ultrafast C (MeOH: DCM =1:10) N H4Ac 4 97 IC (Hex:EtOH:D EA=40:60:0.3) Β 6-1-2 1H NMR (400 MHz, CD3OD-c / 4) δ 8.04 (s, 1H), 7.02 (d, <7 = 3.6 Hz, 1H), 6.47 (d, J = 3.6 Hz, 1H), 4.30 4.19 (m, 2H), 3.75 (c, J = 6.8 Hz, 2H ), 3.55 (d, J= 6.8 Hz, 2H), 3.34 - 3.28 (m, 1H), 2.98-2.91 (m, 3H), 2.71 (d, J = 11.2 Hz, 1H), 2.06-1.95 Ultrafast C C (MeOH: DCM =1:10) N H4Ac 4 97 IC (Hex:EtOH:D EA=40:60:0.3) Μ Λ / t / ZUZZ / UOO 141 (m, 3Η), 1.89-1.79 (m, 5Η), 1.68 - 1.61 (m, 1Η), 1.45 1.41 (m, 1Η), 1.33-1.29 (m, 2Η), 1.27 - 1.15 (m, 4Η) ), 1.12-1.03 (m, 2H). Β 6-2 1H NMR (400 MHz, Chloroform-d) δ 1.04 (m, 2H), 1.25 (m, 2H), 1.43 (ddd, J = 20.9, 10.6, 6.7 Hz, 2H), 1.57 (m,4H ), 1.68-1.88 (m, 6H), 1.95 (d, J = 11.4 Hz, 2H), 2.08 - 2.27 (m, 4H), 2.28-2.48 (m, 2H), 2.83 (d, J = 11.1 Hz, 1H), 2.90-3.12 (m, 3H), 3.68 (t, J = 7.3 Hz, 1H), 3.77 (dd, J = 14.7, 2.1 Hz, 1H), 4.87 (ddd, J = 13.5, 10.6, 2.8 Hz , 2H), 5.26 (s a, 1H), 6.48 (d, J = 3.6 Hz, 1H), 6.75 (s a, 1H), 6.84 (d, J = 3.6 Hz, 1H), 8.26 (s, 1H). 5 23 523 Α D-6-1 1H NMR (400 MHz, CDCI3): Ó7.87 (s a, 1H), 6.95 (s a, 1H), 5.66 (s a, 1H), 5.41 (s a, 1H), 4.98 ( s a, 1H), 3.74-3.69 (m, 1H), 3.59-3.51 (m, 3H), 3.41-3.36 (m, 3H), 3.16-3.11 (m, 1H), 3.03 (s, 2H), 2.78- 2.74 (m, 1H), 2.592.56 (m,2H), 2.44 (t, J=10.8 Hz, 1H), 2.01-1.96 (m, 3H), 1.86-1.83 (m, 2H), 1.78-1.65 ( m, 3H), 1.34-1.25 (m, 2H), 1.17 (t,J = 6.8 Hz,3H), 1.050.96 (m, 2H) T LC prep (MeOH: DCM=1 :10) H N4HOA c MS caled.: 506; Expe rime ntal MS: 507 IG (Hex:EtOH:D EA 60:40:0.3) Μ Λ / t / ZUZZ / UOO 141 A D-6-2 1H NMR (400 MHz, CDCI3): 67.86 (s a, 1H), 6.94 (sa, 1H), 5.61 (sa, 1H), 5.40 (s a, 1H), 4.96 (s a, 1H), 3.73-3.68 (m, 1H), 3.57-3.50 (m, 3H), 3.40-3.34 (m, 3H), 3.15-3.10 (m, 1H), 3.02 (s, 2H), 2.77-2.73 (m, 1H ), 2.582.55 (m, 2H), 2.43 (t, J= 10.4 Hz, 1H), 2.00-1.95 (m, 3H), 1.85-1.82 (m, 2H), 1.77-1.64 (m, 3H), 1.33-1.24 (m, 2H), 1.16(1, J = 6.8 Hz,3H), 1.040.95 (m, 2H) P repTLC (MeOH: DCM=1 :10) H N4HOA c MS caled.: 506; Experimental MS: 507 IG (Hex:EtOH:D EA 60:40:0.3) B D-5-1-1 1H NMR (400 MHz, CDCI3): 68.22 (s, 1H),6.85 (S, 1H) ,6.79 (S a, 1H), 6.43 (s, 1H), 5.62 (s a, 1H),4.46 (d,J= 14.4 Hz, 1H),3.83-3.71 (m, 3H),3.63-3.56 (m, 2H),3.32-3.28 (m, 1H),2.99 (s, 2H),2.74-2.70 (m, 1H),2.58-2.56 (m, 2H), 2.46 (t, J= 10.8 Hz, 1H),2.03 -1.85 (m, 6H), 1.75-1.63 (m, 3H), 1.34-1.25 (m, 6H), 1.151.06 (m, 2H). P repTLC (MeOH: DCM=1 :10) N H4Ac 5 13 IG (Hex:EtOH:D EA 40:60:0.3) B D-5-1-2 1H NMR (400 MHz, CDCI3): 68.22 (s, 1H),6.85 (s, 1H),6.80 (s a, 1H), 6.43 (s, 1H), 5.65 (s a, 1H),4.46 (d,J= 14.8 Hz, 1H),3.83-3.71 (m, 3H ),3.63-3.57 (m, 2H),3.32-3.28 (m, 1H),2.99 (s, 2H), 2.74-2.71 (m, 1H),2.59-2.57 (m, 2H), 2.46 P repTLC (MeOH : DCM=1 :10) N H4Ac 5 13 IG (Hex:EtOH:D EA 40:60:0.3) Μ Λ / t / ZUZZ / UOO 141 (t, J= 10.8 Hz, 1H),2.04-1.85 (m, 6H), 1.75-1.63 (m, 3H),1.34-1.25 (m, 6H), 1.151.06 (m, 2H). General Method G - Cyclic Alkoxyl Substituted Secondary Amines IVIA / t / ZUZZ / UOD 14 I GENERAL SCHEME G The secondary amine G1 was reacted with A2 (at room temperature or slightly above, 30 °C) together with a suitable base (such as DIEA, TEA or K2CO3) at rt. After the reaction was completed, intermediate G2 was treated and purified by chromatography (flash CC or HPLC). G3 stereoisomers were then isolated, if possible. These separate stereoisomers, XG3 (designated 1G3, 2G3, etc.) were then reacted with the primary amine A4 to provide XG4. After deprotection with boc, XG5 was subsequently subjected to alkylation with 2-bromoacetamide producing XG6. The XG6 stereoisomeric mixtures were then subjected to chiral resolution (chromatography) to isolate as many stereoisomers as possible. Example G6-1 Synthesis and isolation of the four stereoisomers of G6-1 100 1G6-1-1 and 1G6-1-2 ΜΛ / t / ZUZZ / UOO 141 a) DMSO, DIEA, A2-1. b) Chiral separation. c) A4-6, DMSO, DIEA. d) TFA, DCM. e) CS2CO3, DMF. f) Chiral separation. G6-1 Scheme Synthesis of / V-((6,6-dimet¡ltetrah¡dro-2 / 7-pyran-3-¡l)met¡l)- / \ / -ethyl-5,6-difluorop ¡r¡mid¡n-4amine, G2-1. and separation of the rel-(phy)- / V-((6,6-dimethyltetrahdro-2H-pyran-3yl)methyl)- / V-ethyl-5,6-difluorop¡ stereoisomers r¡m¡d¡n-4-amine, 1G2-1 and 2G2-1 A mixture of G1-1 (340 mg, 1.98 mmol), 4,5,6-trifluoropyrimidine (318 mg, 2.38 mmol), DIEA (510 mg, 3.96 mmol), and DMSO (20 mL) was stirred at rt overnight. . H2O (50 mL) was then added and the mixture was extracted with DCM (50 mL x 2). The combined organic phase was washed with H2O, brine, dried (Na2SO4) and concentrated. The residue was purified by flash DC (PE:EA=10:1 to 5:1) to provide G2-1. MS caled.: 285; Experimental MS: 286 ([M+H]+). 101 Separation and isolation of the stereoisomers re / -( / z?)-A / -((6,6-dimethyltetrahydro-2 / - / pyran-3-l)metyl)-A / -et l-5,6-difluoropirimidin-4-amine, 1G2-1 and 2G2-1 1G3-1 and 2G3-1 ΜΛ / t / ZUZZ / UOO 141 G2-1 was subjected to chiral chromatography providing 1G2-1 (240 mg, eluted 1Eisomer) and 2G2-1 (230 mg, eluted 2Sisomer). Synthesis of (3F?S,4F?S)-4-(((6-((((S*)-6,6-dimethyltetrahydro-2H-pyran-3¡l)methyl)( eth¡l)am¡no)-5-fluorop¡r¡m¡din-4-l)am¡no)met¡l)-3-hydroxy¡p¡períd¡n-1 -carboxylate of terebutyl, 1G4-1 and 2G4-1 1G4-1 2G4-1 A mixture of 1G3-1 (110 mg, 0.39 mmol), XYZ (105 mg, 0.46 mmol), DIEA (118 mg, 0.91 mmol), and DMSO (10 mL) was stirred at 80°C. After that, the reaction was cooled to rt, washed with H2O and extracted with EA (20 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated yielding 1G4-1. MS caled.: 495; Experimental MS: 496 ([M+H]+). 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. After that, the reaction was cooled to rt, washed with H2O and extracted with EA (20 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated to yield 2G4-1. MS caled.: 495; Experimental MS: 496 ([M+H]+). Synthesis of (3fiS,4fiS)-4-(((6-((((S*))-6,6-dimethyltetrahydro-2H-p¡ran-3¡l)methyl)(et) trifluoroacetate l)amino)-5-fluorop¡rím¡din-4-yl)amino)methyl)-3-hydroxyp¡peridín-1 -lo, 1G5-1 and 2G5-1. 1G5-1 and 2G5-1 A mixture of 1G4-1 (170 mg, 0.34 mmol), DCM (3 mL), and TFA (3 mL) was stirred at rt for 2 h and then concentrated yielding 1G5-1. MS caled.: 395; Experimental MS: 396 ([M+H]+). 102 A mixture of 2G4-1 (166 mg, 0.33 mmol), DCM (3 mL), and TFA (3 mL) was stirred at rt for 2 hours and concentrated yielding 2G5-1. Calculated MS: 395; Experimental MS: 396 ([M+H]+). Synthesis of 2-((3F?S,4F?S)-4-(((6-((((S*))-6,6-dimethyltetrahydro-2H-p¡ran-3¡l)met¡ I) (eti l)amino) -5-f luoropi rim ¡d¡n-4-yl)am¡no)met¡l)-3-hydroxy¡p¡per¡d¡ n-1 -il) acetamide, 1G6-1 and 2G6-1. MA / t / ZUZZ / UOO 141 A mixture of 1G5-1 (174 mg, 0.34 mmol), DMF (7 mL), K2CO3 (141 mg, 1.02 mmol), and 2-bromoacetamide (56.6 mg, 0.41 mmol) was stirred at rt. Water was added and the EA mixture was extracted. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. After that, the residue was purified by ultrafast CC (DCM:MeOH=30:1 to 10:1) yielding 1G6-1. A mixture of 2G5-1 (170 mg, 0.33 mmol), DMF (7 mL), K2CO3 (136 mg, 0.99 mmol), and 2bromoacetamide (55.3 mg, 0.41 mmol) was stirred at rt. Water was added and the EA mixture was extracted. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. After that, the residue was purified by ultrafast DC (DCM:MeOH=30:1 to 10:1) yielding 2G6-1. Isolation of the 4 rel-2-((3R,4F?)-4-(((6-((((S)-6,6-dimethyltetrahydro2 / 7-p¡ran-3-¡l))met¡ stereoisomers l)(eth¡l)am¡no)-5-fluorop¡r¡m¡din-4-¡l)am¡no)met¡l)-3-hydroxy¡p¡períd¡n- 1 iljacetamide and rel-2-((3fí,4fí)-4-(((6-(((( / ?)-6,6-dimet¡ltettrah¡dro-2 / 7-pyran-3-yl )met¡l)(ethyl¡l)amino)-5fluorop¡r¡m¡d¡n-4-¡l)amino)met¡l)-3-hydroxy¡p¡perid¡n-1 -l)acetamide, 1G6-1-1, 1G6-1-2, 2G6-1-1 and 2G6-1-2. 1G6-1-1 1G6-1-2 and 2G6-1-1 2G6-1-2 Subsequent chiral chromatography 1G6-1 gave 1G6-1 -1 (1erpico eluted) and 1G6-1 2 (2Spico eluted). Subsequent chiral chromatography of 2G6-1 gave two stereoisomers 2G6-1-1 (1st eluting peak,) and 2G6-1-2 (2nd eluting peak,). 103 The following compounds in Table 3 have been synthesized according to General Method G. Table 3: MA / t / ZUZZ / UOO 141 G1 (((3-(ethyl((6-(trifluoromethyl)tetrahydro-(trifluoromethyl)tetrahydro-2H- 2H-pyran-3-¡l)methyl)amino)-2-fluorophenyl )amino)methyl)-3- pyran-3-yl)methyl)ethanamine hydroxypiperid i n -1 -yl)acetamide G1-2 1&2G6-2-2&3* rel-2-((3R, 4R)-4-(((3-(ethyl((6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)amino)-2-fluorophenyl) amino)methyl)-3hydroxypiperidin-1 -yl)acetamide *mixture of two stereoisomers G1-2 1&2G6-2-4 rel-2-((3R,4R)-4-(((3-(ethyl( (6-(trifluoromethyl)tetrahydro-2H-p¡ran-3-¡l)methyl)amino)-2-fluorophen¡l)amino)methyl)-3hydroxypiperid i n -1 - il)acetamide G1-2 3G6-2-1 rel-2-((3R,4R)-4-(((3-(ethyl((6-(trifluoromethyl)tetrahydro- 2H-pyran-3- ¡l)methyl¡l)amino)-2-fluorophen¡l)amino)methyl)-3hydroxypiperid i n -1 -yl)acetamide G1-2 3G6-2-2 rel-2-((3R,4R )-4-(((3-(ethyl((6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)amino)-2-fluorophenyl)am ¡no)methyl)-3hydroxypiperidin-1 -yl)acetamide G1-2 4G6-2-1 rel-2-((3R,4R)-4-(((3-(ethyl((6-(trifluoromethyl)) tetrahydro- 2H-pyran-3-¡l)methyl)amino)-2-fluorophen¡l)amino)methyl)-3hydroxypiperidi n-1 -yl)acetamide G1-2 4G6- 2-2 104 rel-2-((3R,4R)-4-(((3-(ethyl((6-(trifluoromethyl)tetrahydro2H-pyran-3-¡l)methyl)amino )-2-fluorophenyl)amino)methyl)-3hydroxypiperidin-1 -yl)acetamide In the first chiral purification, the eluting 1 and 2S isomers were not separated. In the second chiral purification, the eluted isomers 2Sy 3e, from the mixture of the eluted isomers 1ery and 2S, were not separated. G1-1 synthesis Synthesis of / V-((6,6-dimethyltetrahydro-2 / - / -pyran-3-l)methyl)ethanamine, G1-1. H.N. G1-1 A mixture of 6,6-dimethyltetrahydro-2 / - / -pyran-3-carbaldehyde (360 mg, 2.53 mmol), MeOH (10 mL), MgSÜ4 (1 g) and ethanamine (2 mL, 2 mol / L) at rt. NaBH4 (96 mg, 2.53 mmol) was then added and the reaction was stirred at rt for 2 h. The reaction was quenched with NH4CI and H2O, extracted with EA (2x50 mL). The combined organic phase was washed with H2O and brine, dried (Na2SO4) and finally concentrated in vacuo yielding G1 -1. MS caled.: 171; Experimental MS: 172 ([M+H]+). MA / t / ZUZZ / UOO 141 Synthesis of / V-((6-(trifluoromethyl)tetrahydro-2H-pyran-3-l)methyl)ethanamine, G1-2. a) EtNH, HATU, DIEA. b) BH3 THF. ¡G1-3-1 was prepared according to Claremon, D., et al document WO 2017024018 A1 Scheme G1-3 Synthesis of A / -ethyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide, ¡G1-2-2 G1-2-2 105 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 at 30 °C for 30 min, ethylamine (2 M in THF, 3.7 mL) was added and the reaction was stirred at 30 °C. H2O (20 mL) was added and the mixture was extracted with EA (3 x 20 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo yielding crude IG1 -22. MS caled.: 225; Experimental MS: 226 ([M+H]+). Synthesis of / V-((6-(trifluoromethyl)tetrahydro-2 / - / -pyran-3-l)methyl)ethanamine, G1-2. G1-2 MA / t / ZUZZ / UOO 141 Under a 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 at reflux. The reaction was then cooled to 0 °C (ice bath) and then MeOH (2 mL) was added, followed by HCl (2 mL, 1 M). After concentration, Na2COs (sat, 20 mL) was added to the residue and the mixture was extracted with EA (3 x 20 mL). The combined organic phase was washed with brine (20 mL), dried (Na2SO4). The organic solution was filtered and concentrated in vacuo yielding crude 2-5, which was used without further purification. MS caled.: 211; Experimental MS: 212 ([M+H]+). Analytical table 2. Patent Example 1H-NMR Prep HPLC Method Analytical HPLC Method Observation of chiral separation method 1 G6-1-1 1 H-NMR (400MHz, CDCI3): δ 7.88 (d, J= 2.0 Hz , 1H), 6.96 (S, 1H), 5.88 (s, 1H), 5.34 (d, J = 2.4 Hz, 1H), 4.87 (s, 1H), 4.17-4.10 (m, 1H), 3.70-3.30 ( m, 6H), 3.10-3.02 (m, 3H), 2.86 (d, J = 10.8 Hz, 1H), 2.23-2.10 (m, 2H), 1.961.95 (m, 1H), 1.71-1.67 (m, Ultrafast DC (DCM:MeO H=30:1 to 10:1) NH 4OAC 53 I D (CO2:I PA:DE A=60:4 0:0.3) 106 1Η), 1.58-1.47 (m, 5Η), 1,451.36 (m, 3H), 1.20-1.15 (m, 9H). 1 G6-1-2 1H-NMR (400MHz, CDCI3): δ7.88 (d, J = 2.0 Hz, 1H), 6.95 (s, 1H), 5.88 (s, 1H), 5.34 (d, J = 2.4 Hz, 1H), 4.87 (s, 1H), 4.12-4.10 (m, 1H), 3.69-3.32 (m, 6H), 3.11-3.02 (m, 3H), 2.87 (d, J = 1.6 Hz, 1H) , 2.20-2.10 (m, 2H), 1.701.62 (m, 1H), 1.55-1.51 (m, 5H), 1.46-1.37 (m, 3H), 1.201.15 (m, 9H). Ultrafast DC (DCM:MeO H=30:1 to 10:1) NH 4OAC 53 I D (CO2:I PA:DE A=60:4 0:0.3) 2 G6-1-1 1H-NMR (400MHz, CDCI3) δ 7.88 (d, J= 1.6 Hz, 1H), 6.96 (d, J = 3.2 Hz, 1H), 5.42 (d,J = 2.0Hz, 1H), 4.87 (s, 1H), 4.16-4.11 (m, 1H), 3.703.65 (m, 1H), 3.58-3.48 (m, 2H), 3.42-3.38 (m, 2H), 3.353.30 (m, 1H), 3.10-3.02 (m, 3H), 2.86 ( d, J = 12.0 Hz, 1H), 2.20-2.10 (m, 2H), 1.96 (s, 1H), 1.71-1.58 (m, 6H), 1.451.37 (m, 3H), 1.23-1.15 (m, 9H) Ultrafast DC (DCM:MeO H=30:1 to 10:1) TF A 53 I A (CO2: MeOH: DEA=6 0:40:0. 3) 2 G6-1-2 1H-NMR (400MHz, CDCI3) δ 7.88 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 3.2 Hz, 1H), 5.45(d, J = 2.0 Hz, 1H), 4.89 (t, J = 7.6 Hz, 1H) , 4.15-4.05 (m, 1H), 3.69-3.65 (m, 1H), 3.573.49 (m, 2H), 3.42-3.39 (m, ultrafast DC (DCM:MeO H=30:1 to 10:1) NH 4OAC 53 I A (CO2: MeOH: DEA=6 0:40:0. 3) 107 2Η), 3.36-3.30 (m, 1Η), 3.113.00 (m, 3Η), 2.86 (d, J = 10.8 Hz, 1H), 2.23-2.10 (m, 2H), 1.95 (d, J = 6.4 Hz , 1H), 1.701.58 (m, 6H), 1.45-1.36 (m, 3H), 1.20-1.15 (m, 9H) 1 &2G6-21 1H-NMR (400 MHz, CDCI3): δ 7.88 (d, J = 1.6 Hz, 1H), 6.94 (s, 1H), 5.83 (s, 1H), 5.38-5.42 (m, 1H), 4.90-4.95 (m, 1H), 4.10-4.17 (m, 1H), 3.95- 3.99 (m, 1H), 3.60-3.85 (m, 4H), 3.42-3.50 (m, 2H), 3.29-3.35 (m, 1H), 3.02-3.13 (m, 4H), 2.85-2.89 (m, 1H ), 2.11-2.24 (m, 2H), 2.04-2.08 (m, 1H), 1.82-1.87 (m, 2H), 1.50-1.81 (m, 2H), 1.37-1.44 (m, 1H), 1.26-1.33 (m, 2H), 1.17-1.25 (t, J = 6.8 Hz, 3H) Ultrafast DC (DCM:MeO H=20:1) NH 4OAc 93 I G (Hex:E tOH:D EA = 50:50: 0.3) 1 &2G6-22&3** 1H-NMR (400 MHz, CDCI3): δ 7.88 (d, J = 1.6 Hz, 1H), 6.94 (s, 1H), 5.83 (s, 1H), 5.45-5.50 (m, 1H ), 4.90-4.95 (m, 1H), 4.08-4.14 (m, 1H), 3.95-3.99 (m, 1H), 3.74-3.82 (m, 2H), 3.60-3.68 (m, 2H), 3.45-3.55 (m, 2H), 3.29-3.36 (m, 1H), 3.02-3.13 (m, 4H), 2.85-2.89 (m, 1H), 2.10-2.24 (m, 2H), 2.04-2.08 (m, 1H) , 1.50-1.89 (m, 4H), 1.32-1.44 (m, 1H), 1.26-1.33 (m, 2H), 1.18-1.22 (t, J = 7.2 Hz, 3H) Ultrafast DC (DCM:MeO H=20 :1) NH 4OAc 93 I G (Hex:E tOH:D EA = 50:50: 0.3) Μ Λ / t / ZUZZ / UOO 141 108 1 &2G6-24 1H-NMR (400 MHz, CDCI3): δ 7.88 (d, J = 1.6 Hz, 1H), 6.93 (s, 1H), 5.83 (s, 1H), 5.34-5.38 (m, 1H), 4.90-4.95 (m, 1H), 4.10-4.17 (m, 1H), 3.95-3.99 (m, 1H), 3.60-3.85 (m, 4H), 3.42-3.49 (m, 2H), 3.29-3.35 (m , 1H), 3.02-3.12 (m, 4H), 2.85-2.89 (m, 1H), 2.11-2.24 (m, 2H), 2.04-2.08 (m, 1H), 1.82-1.87 (m, 2H), 1.53 -1.81 (m, 2H), 1.37-1.44 (m, 1H), 1.26-1.33 (m, 2H), 1.17-1.25 (t, J = 6.8 Hz, 3H) Ultrafast DC (DCM:MeO H=20:1 ) NH 4OAc 93 I G (Hex:E tOH:D EA = 50:50: 0.3) 3 G6-2-1 1H-NMR (400 MHz, CDCI3): δ 7.88 (d, J = 1.6 Hz, 1H), 6.94 (s, 1H), 5.77 (s, 1H), 5.34-5.38 (m, 1H), 4.90-4.95 (m, 1H), 4.05-4.17 (m, 2H), 3.64-3.70 (m, 1H), 3.47 -3.56 (m, 2H), 3.23-3.45 (m, 4H), 3.02-3.13 (m, 4H), 2.85-2.89 (m, 1H), 2.08-2.24 (m, 3H), 1.96-2.00 (m, 1H), 1.84-1.89 (m, 1H), 1.54-1.67 (m, 2H), 1.37-1.44 (m, 1H), 1.23-1.33 (m, 2H), 1.16-1.21 (t, J = 6.8 Hz, 3H) Ultrafast DC (DCM:MeO H=20:1) NH 4OAc 93 I D (Hex:l PA:DE A 40:60: 0.3) 3 G6-2-2 1H-NMR (400 MHz, CDCI3): δ 7.88 (d, J = 1.6 Hz, 1H), 6.94 (s, 1H), 5.77 (s, 1H), 5.37-5.41 (m, 1H), 4.90-4.95 (m, 1H), 4.04-4.15 (m, 2H ), 3.64-3.69 (m, 1H), 3.41-3.54 (m, 3H), 3.23-3.34 (m, 3H), 3.02-3.13 (m, 4H), 2.85-2.89 Ultrafast DC (DCM:MeO H=20 :1) NH 4OAc 93 I D (Hex:l PA:DE A 40:60: 0.3) 109 (m, 1 Η), 2.10-2.24 (m, 3H), 1.95-1.99 (m, 1H), 1.84-1.89 (m, 1H), 1.5-1.67 (m, 2H), 1.40-1.43 (m, 1H ), 1.23-1.33 (m, 2H), 1.16-1.21 (t, J = 6.8 Hz, 3H) 4 G6-2-1 1H-NMR (400 MHz, CDCI3): δ 7.88 (d, J = 2.0 Hz, 1H), 6.95 (s, 1H), 5.77 (s, 1H), 5.42-5.44 (m, 1H), 4.90-4.95 (m, 1H), 4.05-4.17 (m, 2H), 3.64-3.70 (m, 1H), 3.47-3.56 (m, 2H), 3.23-3.45 (m, 4H), 3.02-3.13 (m, 4H), 2.85-2.89 (m, 1H), 2.08-2.24 (m, 3H), 1.96- 2.00 (m, 1H), 1.84-1.89 (m, 1H), 1.54-1.67 (m, 2H), 1.37-1.44 (m, 1H), 1.22-1.33 (m, 2H), 1.16-1.21 (t, J = 6.8 Hz, 3H) Ultrafast DC, (DCM:MeO H=20:1) NH 4OAc 93 I A (Hex:E tOH:D EA = 60:40: 0.3) 4 G6-2-2 1H-NMR (400 MHz , CDCI3): δ 7.88 (d, J = 2.0 Hz, 1H), 6.94 (s, 1H), 5.77 (s, 1H), 5.42-5.44 (m, 1H), 4.90-4.95 (m, 1H), 4.05 -4.17 (m, 2H), 3.64-3.70 (m, 1H), 3.41-3.54 (m, 3H), 3.23-3.34 (m, 3H), 3.02-3.13 (m, 4H), 2.85-2.89 (m, 1H), 2.08-2.24 (m, 3H), 1.96-1.99 (m, 1H), 1.84-1.89 (m, 1H), 1.53-1.67 (m, 2H), 1.37-1.44 (m, 1H), 1.22- 1.33 (m, 2H), 1.16-1.21 (t, J = 6.8 Hz, 3H) Ultrafast DC, (DCM:MeO H=20:1) NH 4OAc 93 I A (Hex:E tOH:D EA = 60:40: 0.3) 110 BIOLOGICAL EVALUATION The activity of the compounds was evaluated using a RORy reporter assay (also called Gal4 assay). The Gal4 and Th17 assays (another suitable assay) are both cell-based assays that monitor the functional activity of the compounds tested. The compounds disclosed herein have also been evaluated in an in vivo mouse pharmacodynamic model (plasma CD3-induced anti-IL-17A). RORy indicator assay (Gal4) The HEK293 cell line is transiently cotransfected with two plasmids, one with the RORy ligand-binding domain fused to the galactose-sensitive transcription factor (Gal4) and the other with the luciferase reporter gene and binding sites. to Gal (UAS). This construction allows the determination of RORy activity in a cellular system by measuring luminescence. A suspension of RORy indicator cells was dispensed into plates and cultured for 2 h at 37aC and 5% CO2. The medium formulation consisted of DMEM / F12 medium (Gibco) supplemented with 10% heat-inactivated FBS (Sigma-Aldrich), non-essential amino acids (Sigma-Aldrich), 2 mM Glutamax (Gibco), and 100 U / ml of penicillin (Sigma-Aldrich). Dose-response curves with the compounds were prepared in 100% DMSO and further diluted 100-fold in culture medium. The solutions of the compounds were added to the plate containing the cells (final DMSO concentration of 0.1%) and incubated for 24 h at 37eC and 5% CO2. Luciferase detection reagent was added to each well and relative light units (RLU) were quantified for each assay well using a plate reader luminometer. Mean ULR values ​​± S.D. were counted. for all treatment sets and percentage reductions in RORy activity in response to the respective test compound were then calculated. The following formula was used: activity = 100 * [1 - [x test compound / average vehicle], where the theoretical minimum reduction (0% reduction). For all experiments, activity values ​​were plotted against compound concentrations in a single graph and fitted to a four-parameter logistic curve to obtain the absolute IC50 value along with the 95% confidence interval. These calculations were performed with the excel-fit software using the X-204 model curve. The results of the RORy (Gal4) indicator assay are shown in Table 2 below. ΜΛ / Ε / ΖυΖΖ / υοΟΊ4Ί 111 Table 2: RORy indicator assay (Gal4) Patent Example IC50 (nM) A6-1-1-1 35 A6-1-1-2 44 A6-1-2-1 49 A6-1-2-2 ND A6 -2-1 57 A6-2-2 85 A6-3-1 8.1 A6-3-2 14 A6-4-1 31 A6-4-2 33 A6-5 17 A6-6-1 690 A6-6 -2 980 A6-7-1 43 A6-7-2 69 A6-8-1 ND A6-8-2 480 B6-1-1 ND B6-1-2 ND B6-2 ND AD-6-1 1, 2 AD-6-2 15 BD-5-1-1 3.3 BD-5-1-2 4.3 As can be seen in Table 2 above, the compounds of the present disclosure were found to show beneficial activity through the RORy (Gal4) Indicator Assay. IVIA / t / ZUZZ / UOD 14 I 112 According to one embodiment, compounds having an IC50 value <1000 nM in the RORy (Gal4) indicator assay are disclosed herein. According to another preferred embodiment, compounds having an IC50 value <500 nM in the RORy (Gal4) indicator assay are disclosed herein. According to another more preferred embodiment, compounds having an IC50 value <100 nM in the RORy (Gal4) indicator assay are disclosed herein. Induction of IL-17A in vivo in an anti-CD3 mouse model Male C57BL / 6JRj mice (7 weeks old) were purchased from Janvier Labs and housed in the Almirall animal facility throughout the study. Animals were allowed to condition for 5 days in their new environment at 22°C ± 2°C, with 55% ± 10% relative humidity and 12 h: 12 h light:dark cycles. Animals were housed in polycarbonate cages, with free access to water and a conventional unpurified diet (global rodent maintenance diet with 14% protein 2014 Teklad, Envigo) throughout the course of the studies. The care of the animals was addressed in compliance with the European Committee Directive 2010 / 63 / EU and Catalan and Spanish legislation. All procedures were carried out in accordance with ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines and with the approval of the Animal Experimentation Ethics Committee. of Almirall (Barcelona, ​​Spain). Mice were injected intraperitoneally with 7.5 pg of anti-CD3e (clone 145-2C11 from Pharmingen BD) at the time points of 0 h (day 0) and 48 h (day 3). The uninduced group was injected with PBS instead of anti-CD3e. At the completion of the study (4 h after anti-CD3e injection), animals were anesthetized with isoflurane (Baxter) and 0.5-1 ml blood samples were taken by intracardiac puncture into heparinized tubes. Plasma samples were stored at -80SC for further analysis. Test compounds were freshly suspended in a sterile solution with 0.5% methylcellulose and 0.1% tween-80 (10 ml / kg body weight). The compounds were administered by oral gavage according to body weight and selected dosage; control animals received an equivalent volume of vehicle. Treatments were delivered twice daily from day 0 to day 3, with the last administration occurring 1 h before anti-CD3e injection. 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 reduction of plasma IL-17A versus the difference between the non-induced group and the anti-CD3e induced group using the formula: inhibition =100 * [1 - [(x - group mean uninduced) / (control vehicle mean - uninduced group mean)]]. The inhibition of IL17A for each treatment can be expressed as the mean for each treatment group ± ΜΛ / t / ZUZZ / UOO 141 113 E.E.M. Statistical analysis of data was carried out with a one-way ANOVA followed by Dunnett's multiple comparisons test where appropriate. Differences were considered significant when p < 0.05. Results: Compound IL-17A inhibition (%] at 3 mg / kg AD-6-1 95% In summary, it has been determined that the compounds disclosed herein at least modulate the activity of RORy. The compounds disclosed herein are active, for example, with Gal4 <1000 nM, such as <500 nM, such as <100 nM. Furthermore, it has been determined that the compounds disclosed herein have utility in vivo and, as a consequence, could be useful in the treatment of inflammatory, metabolic and autoimmune diseases or symptoms thereof.

Claims

1. A compound according to Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt of the 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, C1-6 alkyl, and Cm hydroxyalkyl; A is fluorine and Y is hydrogen; or Y and A are taken together with the atoms to which they are attached to form a 5-membered heteroaryl or heteroalicyl ring system optionally substituted with 1 or 2 substituents selected from halogen, cyano, or Cm alkyl; Roa and Rob are independently selected from the group consisting of hydrogen, Cm alkyl, Cm hydroxyalkyl, and Cm haloalkyl; Ria and Rib are independently selected from the group consisting of hydrogen, hydroxyl, amino, halogen, Cm alkyl, Cm hydroxyalkyl, and Cm haloalkyl;R2 is selected from the group consisting of hydrogen, hydroxyl, amino, cyano, halogen, Cm alkyl, Cm haloalkyl, Cm hydroxyalkyl, C(=O)OH, C(=O)NH2, C(=O)O-(C1-4 alkyl) and substituted or unsubstituted heteroaryl; Rs is selected from the group consisting of Cm alkyl, Cm alkenyl, Cm haloalkyl, Cm hydroxyalkyl, C3-7 cycloalkyl, and C3-7 cycloalkenyl; or R3 and R4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted 4- to 6-membered heteroalicyclic ring system; R4 is hydrogen or Cm alkyl, provided that R3 and R4 are not taken together with the atoms to which they are attached to form a substituted or unsubstituted 4- to 6-membered heteroalicyclic ring system; or R4 and Rs are taken together with the carbon atom to which they are attached to form a C3-4 cycloalkyl; Rs is absent;or is selected from the group consisting of hydrogen and C1-4 alkyl, provided that R4 and R5 are not taken together with the carbon atom to which they are attached to form a C3-4 cycloalkyl; Rea and Reb are independently selected from the group consisting of hydrogen, cyano, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 hydroxyhaloalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, and substituted or unsubstituted heteroaryl, and provided that n is 0 then at least one of Rea and Reb is selected from the group consisting of cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyhaloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxyl, C1-4 haloalkoxyl, and substituted or unsubstituted heteroaryl; or Rea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 6-membered heteroalicyclic or 3- to 6-membered alicyclic ring system comprising 1 to 3 heteroatoms selected from S, O, or N, optionally substituted with one to three halogen atoms;and R7 is selected from the group consisting of hydroxyl, cyano, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxyl, and C1-4 haloalkoxyl.; 2. The compound, stereoisomer or salt according to claim 1, wherein A is fluorine and Y is hydrogen.

3. The compound, stereoisomer, or salt according to claim 1, having the following formula: X is-CRs- or -N-, and R8 is selected from the group consisting of hydrogen, halogen, cyano, and C1-4 alkyl.

4. The compound, stereoisomer or salt according to claim 3, wherein X is -CRs and Rs is selected from the group consisting of hydrogen, cyano and fluorine; or X is -N-.

5. The compound, stereoisomer or salt according to claim 3 or 4, wherein X is —CH-. 116 6. The compound, stereoisomer, or salt according to any one of claims 1-5, wherein Roa is selected from the group consisting of hydrogen, methyl, CH2OH, -CH2CH2OH, -CH2F, and -CHF2; and Rob is selected from the group consisting of hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 haloalkyl.

7. The compound, stereoisomer or salt according to any one of claims 1-6, wherein Roa and Rob are both hydrogen.

8. The compound, stereoisomer or salt according to any one of claims 1-7, wherein at least one of R1, R2 and R2 is not hydrogen.

9. The compound, stereoisomer or salt according to any one of claims 1-8, wherein Ría is selected from the group consisting of hydroxyl, fluoro and CF3; and Rw is selected from the group consisting of hydrogen, fluoro and methyl.

10. The compound, stereoisomer or salt according to any one of claims 1-9, wherein Riaes is hydroxyl or hydrogen.

11. The compound, stereoisomer or salt according to any one of claims 1-10, wherein Rites is hydrogen.

12. The compound, stereoisomer or salt according to any one of claims 1-11, wherein R2 is hydrogen, halogen, hydroxyl, cyano, methyl, ethyl, -CH2OH, -CH2CH2OH or -C(=O)O-C1.2 alkyl.

13. The compound, stereoisomer or salt according to any one of claims 1-12, wherein R2 is hydrogen, fluorine, hydroxyl, or -CH2OH.

14. The compound, stereoisomer or salt according to any of claims 1-13, wherein R2 is hydrogen or hydroxyl.

15. The compound, stereoisomer or salt according to any one of claims 1-14, wherein R2 is hydrogen.

16. The compound, stereoisomer or salt according to any one of claims 1-14, wherein R2 is hydroxyl.

17. The compound, stereoisomer or salt according to any one of claims 1-16, wherein R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, terebutyl, cyclopropyl or cyclobutyl.

18. The compound, stereoisomer or salt according to any one of claims 1-17, wherein R3 is methyl, ethyl, cyclopropyl, or cyclobutyl.

19. The compound, stereoisomer or salt according to any one of claims 1-18, wherein R3 is ethyl or cyclobutyl.

20. The compound, stereoisomer, or salt according to any of claims 1-19, wherein R3 is ethyl. 117 21. The compound, stereoisomer or salt according to any one of claims 1-20, wherein each of FU and Rs independently is hydrogen or methyl, or R4 and Rs are taken together with the carbon atom to which they are attached to form a cyclopropyl.

22. The compound, stereoisomer or salt according to any one of claims 1-21, wherein R4 and Rs are hydrogen.

23. The compound, stereoisomer, or salt according to any one of claims 1-16, wherein the heteroalicyclic ring system comprising R3 and R4 is a 4-membered heteroalicyclyl, 5-membered heteroalicyclyl, or 6-membered heteroalicyclyl; wherein the heteroalicyclic ring system is optionally substituted with one or two substituents selected from halogen, hydroxyl, and C1-4 alkyl.

24. The compound, stereoisomer, or salt according to claim 23, wherein the heteroalicyclic ring system comprising R3 and R4 is azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, 2-azabicyclo[3.1.0]hexanyl, or 3-azabicyclo[3.1.0]hexanyl; wherein the heteroalicyclic ring system is optionally substituted with one or two substituents selected from halogen and methyl, and provided that the heteroalicyclic ring system is substituted or unsubstituted 2-azabicyclo[3.1.0]hexanyl, then Rs is absent.

25. The compound, stereoisomer or salt according to any one of claims 23-24, wherein the heteroalicyclic ring system comprising R3 and R4 is morpholinyl optionally substituted with one or two substituents selected from halogen and methyl, and R5 is hydrogen.

26. The compound, stereoisomer or salt according to any one of claims 23-25, wherein the heteroalicyclic ring system comprising R3 and R4 is unsubstituted morpholinyl, and R5 is hydrogen.

27. The compound, stereoisomer, or salt according to any one of claims 1-26, wherein Rea and Reb are each independently hydrogen, halogen, C1-4 haloalkyl, or C1-4 haloalkoxy, or Rea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 6-membered alicyclic or 3- to 6-membered heteroalicyclic ring system, optionally substituted by one to three halogen atoms.

28. The compound, stereoisomer, or salt according to any one of claims 1-27, wherein Rea is hydrogen, -CF3, -CH2F, -CCH3F2, -OCF3, or -OCHF2, and R6b is hydrogen; or Rea and Reb are taken together with the carbon atom to which they are attached to form a 3- to 4-membered alicyclic ring system, optionally substituted by one to three fluorine atoms, or a 4- to 5-membered heteroalicyclic ring system comprising one, two, or three heteroatoms selected from O and N.

29. The compound, stereoisomer or salt according to any one of claims 1-28, wherein Rea is -CF3, and R6b is hydrogen; or Rea and Reb are taken together with the carbon atom to which they are attached to form an oxethanyl or cyclopropyl optionally substituted with one or two fluorines.

30. The compound, stereoisomer or salt according to any one of claims 1-26, wherein at least one of Rea and Reb is a substituted or unsubstituted heteroaryl.

31. The compound, stereoisomer or salt according to claim 30, wherein at least one of Rea and Reb is a C1-4 alkyl-substituted heteroaryl.

32. The compound, stereoisomer or salt according to any one of claims 1-31, wherein n is 0 or 1.

33. The compound, stereoisomer or salt according to any one of claims 1-32, where n is 1.

34. The compound, stereoisomer or salt according to any one of claims 1-33, wherein R7 is halogen, hydroxyl, cyano, -CF3, -OCHF2, -CHF2 or -OCF3.

35. The compound, stereoisomer or salt according to any one of claims 1-32, where n is 0.

36. The compound, stereoisomer or salt according to claim 1, wherein the compound has the structure MA / t / ZUZZ / UODl^l 120 Ría is hydrogen, fluorine or hydroxyl; Rw is hydrogen or fluorine; R2 is hydrogen or hydroxyl; R3 is methyl, ethyl, cyclopropyl or cyclobutyl; Rea is -CF3; and provided that at least one of Ria, Rw and R2 is not hydrogen.

37. The compound, stereoisomer or salt according to claim 36, wherein Ría is hydrogen or hydroxyl and Rwes is hydrogen.

38. The compound, stereoisomer or salt according to claim 36 or 37, wherein R2 is hydrogen or hydroxyl.

39. The compound, stereoisomer or salt according to claim 38, wherein R2 is hydroxyl.

40. The compound, stereoisomer or salt according to claim 38, wherein R2 is hydrogen.

41. The compound, stereoisomer or salt according to claim 37, wherein R2 is hydrogen and Ria is hydroxyl.

42. The compound, stereoisomer or salt according to claim 37, wherein R2 is hydroxyl and Ria is hydroxyl.

43. The compound, stereoisomer or salt according to any of claims 36-42, wherein R3 is ethyl.

44. The compound, stereoisomer, or salt according to claim 1, wherein: Roa and Rob are both hydrogen; Riay and Rw are independently hydrogen or hydroxyl; R2 is selected from the group consisting of hydrogen and hydroxyl; R is hydrogen; Y is hydrogen and A is fluorine; or Y and A are taken together with the atoms to which they are attached and the pyrimidine ring of formula (I) to form an unsubstituted pyrrolo[2,3-d]pyrimidine; R3 is selected from the group consisting of methyl, ethyl, cyclopropyl, and cyclobutyl, and R4 and Rs are hydrogen; or R3 and R4 are taken together with the atoms to which they are attached to form an unsubstituted morpholinyl, and Rs is hydrogen; n is 0; on is 1 and R7 is fluorine; Rea is -CF3, and Reb is hydrogen; Rea and Reb are taken together with the carbon atom to which they are attached to form an oxetanyl or a cyclopropyl substituted by two fluorines.

45. The composition, stereoisomer or salt of information with indication 1, selected from the group constituted by: re / -2-((3R,4R)-4-(((6-(((1,1-D¡fluoroespiro[2.5]octan-6-yl)met¡l)(et¡l)am¡no)-5fluorop¡r¡m¡din-4-¡l)am¡no)met¡l)-3-hidrox¡p¡per¡d¡n-1 -yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-(methyl(((1r,4R)-4(tr¡fluoromethyl)cyclohexyl)methyl)am¡no)pyrimidin-4-yl)amino)methyl)-3-hidrox¡p¡peridin-1 -yl)acetamida, 2-((3R*,4R*)-4-(((6-(et¡l(((1r,4R)-4-(tr¡fluoromet¡l)c¡clohex¡l)met¡l)amino)-5fluoropyrimidin-4-yl)amino)methyl)-3-hidroxipiperidin-1 -yl)acetamida, 2-((3R*,4R*)-4-(((6-(cyclopropyl(((1 r,4R)-4-(tr¡fluoromet¡l)c¡clohex¡l)met¡l)amino)-5fluoropyrim¡d¡n-4-¡l)amino)methyl)-3-h¡drox¡p¡per¡din-1-yl)acetam¡da, 2-((3RS,4RS)-4-(((6-(cyclobutyl(((1 r,4R)-4-(trifluoromet¡l)c¡clohexil)met¡l)am¡no)-5fluoropyrimidin-4-yl)amino)methyl)-3-hidroxipiperidin-1 -yl)acetamida, re / -2-((3R,4R)-4-((6-(((2-oxaesp¡ro[3.5]nonan-7-¡l)met¡l)(et¡l)am¡no)-5-fluorop¡rim¡d¡n-4¡l)amino)met¡l)-3-h¡drox¡p¡per¡d¡n-1-¡l)acetam¡da, re / -2-((3R,4R)-4-(((6-(etil((1-fluoro-4-(tr¡fluoromet¡l)c¡clohex¡l)metil)am¡no)-5fluorop¡r¡m¡din-4-il)amino)met¡l)-3-h¡droxipiperidin-1-¡l)acetamida, 2-(4-(((5-fluoro-6-((3S)-3-(4-(tr¡fluorometil)ciclohexyl)morphol¡no)pirimidin-4¡l)amino)met¡l)p¡per¡d¡n-1-¡l)acetamida, 2-((3RS,4RS)-4-((4-(Etil(((1r,4R)-4-(tr¡fluorometil)ciclohex¡l)met¡l)am¡no)-7R-p¡nOlo[2,3c / |pirimid¡n-7-il)metil)-3-hidroxip¡peridin-1 -il)acetamida, 2-((3R*,4R*)-4-((4-(Et¡l(((1r,4R)-4-(tr¡fluoromet¡l)c¡clohex¡l)met¡l)am¡no)-7R¡rrolo[2,3d|p¡r¡m¡d¡n-7-il)metil)-3-hidrox¡p¡peridin-1-iljacetamida, 2-((3RS,4RS)-4-((4-(ciclobutil(((1r,4S)-4-(trifluorometil)ciclohexil)metil)am¡no)-7Rp¡rrolo[2,3-d]pirimidin-7-il)metil)-3-hidroxi¡p¡peridin-1-il)acetamida, 2-((3R*,4R*)-4-(((6-(etil(((1 / ',4R)-4-(trifluoromet¡l)c¡clohexil)met¡l)am¡no)-5fluoropyrimidin-4-il)amino)metil)-3,4-dihydroxypiperidin-1-il)acetamide, y 2-((3R*,4R*)-4-((4-(et¡l(((1r,4R)-4-(tr¡fluorometil)c¡clohex¡l)met¡l)am¡no)-7 / - / -p¡rrolo[2,3c / |pirimid¡n-7-il)metil)-3,4-d¡hidrox¡piperidin-1-iljacetamide. IVIA / t / ZUZZ / UOO 14 I 122, 14 47. The compound, stereoisomer or salt of claim 1, selected from the group consisting of: 2-(4-(((6-(((1,1-D¡fluorospiro[2.5]octane-6-¡l)met¡l)(et¡l)amino)-5-fluoropyr¡m¡d¡n-4¡l)amino)met¡l)-3-h¡drox¡p¡p¡d¡l)l) 2-(4-(((5-fluoro-6-(met¡l((4-(tr¡fluorometh¡l)c¡clohex¡l)met¡l)am no)p¡r¡m¡n-4¡l)amino)meth¡l)-3-hydrox¡p¡per¡d¡n-1-¡l)acetam¡da, 2-(4-(((6-(et¡l((4-(trifluoromethl)c¡clohexyl)methyl)amno)-5-fluoropyrimidine-4-¡l)amino)methyl)3-hydroxy¡p¡per¡n-1-yl)acetate, 2-(4-(((6-(c¡cloprop¡l((4-(tr¡fluorometh¡l)c¡clohexil)met¡l)amno)-5 -fluorop¡rim¡d¡n-4¡l)amino)meth¡l)-3-hydrox¡p¡per¡d¡n-1-¡l)acetate, 2-(4-(((6-(c¡clobut¡l((4-(tr¡fluorometh¡l)c¡clohex¡l)met¡l)amino)-5- fluorop¡r¡m¡d¡n-4¡l)amino)meth¡l)-3-hydrox¡p¡per¡d¡n-1-¡l)acetate, 2-(4-(((6-(((2-oxahesp¡ro[3.5]nonan-7-yl)methyl)(eth¡l)amino)-5-fluorop¡r¡m¡m¡n-4¡l)am¡no)methyl)-3-h¡drox¡p¡d¡n-l-1,2-(4-(((6-(ethyl((1 -fluoro-4-(trifluorometh¡l)cyclohex¡l)met¡l)am¡no)-5-fluoropyrim¡n-4¡l)am¡no)methyl)-3-hydrox¡p¡d¡n-1-l)ace) 2-(4-(((5-fluoro-6-(3-(4-(tr¡fluorometh¡l)c¡clohex¡l)morphol¡no)prim¡n-4yl)am¡no)met¡l)p¡per¡d¡n-1-l)acetamide, 2-(4-((4-(Ethyl((4-(tr¡fluorometh¡l)c¡clohexyl)meth¡l)amino)-7 / - / -pyrro lo[2,3-d|p¡r¡m¡d¡n-7yl)methyl)-3-hydroxyp¡perid¡n-acetamyl,) 2-(4-((4-(Ethyl((4-(tr¡fluorometh¡l)c¡clohex¡l)met¡l)am¡no)-7 / - / -p¡rrol[2,3-c / |p¡r¡m¡d¡n-7yl)methyl)-3-hydroxypididyne-1-tamidyl) 2-(4-((4-(c¡clobut¡l((4-(tr¡fluorometh¡l)cyclohex¡l)methyl)am¡no)-7 / - / -pyrrole[2,3-d]p¡r¡m¡d¡n-7yl)meth¡l)-3-hydroxyp-1-perdamyl) 2-(4-(((6-(et¡l((4-(tr¡fluorometh¡l)c¡ctohexyl)met¡l)am¡no)-5-fluorophrom¡r¡m¡n-4-¡l)am¡no)meth¡l)- 3,4- dihydroxypiperidine, -1-amyl) 2-(4-((4-(ethyl((4-(trifluoromethyl)cyclohex¡l)methyl)amino)-7 / - / -pyrrolo[2,3-c / ]pyrimidin-7yl)methyl)-3,4-dihydroxypiperid¡n-1 -yl)acetamide., 48. The compound, stereoisomer or salt according to claim 1, selected from the group consisting of: 125 FF 126 MA / IZ / ¿U¿¿ / UOO 141 49. The compound, stereoisomer or salt according to claim 1, selected from the group consisting of: 127 2-((3 / ^,4 / ^)-4-(((6-(6111(((1 r^Rj^-trifluoromethylcyclohexylmethylaminoj-Sfluorop¡r¡m¡din-4-1l)amino)methyl)-3-hydroxypiperidin-1 -yl)acetamide, 2-((3ñS,4 / 7S)-4-(((6(cyclobutyl(((1r,4 / 7)-4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluorop¡r¡m¡din-4-1l)amino)methyl)-3-hydroxypiperidin-1 -yl)acetamide, and 2-((3 / =r,4 / =?*)-4-((4-(ethyl(((1 r,4 / =?)-4-(tr¡fluoromet¡l)cyclohex¡l)met¡l)am¡no)-7 / - / -p¡rrolo[2,3c(|p¡r¡m¡d¡n-7-¡l)met¡l)-3,4-d¡hydrox¡p¡per¡d¡n-1 -yl)acetamide.

50. The compound, stereoisomer or salt according to claim 1, selected from the group consisting of: 2-(4-(((6-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-5-fluorop¡r¡m¡d¡n-4-¡l)amino)methyl)3-hydroxy¡p¡períd¡n-1-yl)acetamide, 2-(4-(((6-(cyclobut¡l((4-(trifluoromethyl)cyclohex¡l)methyl)amino)-5-fluorop¡r¡m¡d¡n-4¡l)amino)methyl)-3-hydroxy¡p¡per¡din-1-¡l)acetam¡de, and 2-(4-((4-(ethyl((4-(trifluoromethyl)cyclohexyl)methyl)amino)-7 / - / -pyrrolo[2,3-c / ]pyrimidin-7yl)methyl)-3,4-d¡hydroxy¡p¡perídin-1 -yl)acetamide.

51. The compound, stereoisomer or salt according to claim 1, selected from the group consisting of:

52. The compound, stereoisomer or salt according to claim 1, selected from the group consisting of:

53. A pharmaceutical composition comprising a compound, stereoisomer or salt according to any one of claims 1-52, and at least one pharmaceutically acceptable excipient.

54. A compound, stereoisomer or salt according to any one of claims 1-52 or a pharmaceutical composition according to claim 53, for use as a medicament.

55. A compound, stereoisomer or salt according to any one of claims 1-52 or a pharmaceutical composition according to claim 53, for use in the treatment and / or prevention of an inflammatory, metabolic, oncological or autoimmune disease.

56. A method for treating an inflammatory, metabolic, oncological or autoimmune disease in a subject suffering from it, the method comprising: administering to the subject a compound, stereoisomer or salt according to any of claims 1-52 or a pharmaceutical composition according to claim 53.

57. The compound, stereoisomer, salt, or pharmaceutical composition for use according to claim 53 or the method of claim 56, wherein the disease is selected from the group consisting of asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uveitis, celiac disease and food allergy, atopic dermatitis, lichen planus, cystic fibrosis, lung allograft rejection, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease,ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type II diabetes, and cancer.

58. The compound, stereoisomers or salt or pharmaceutical composition according to claim 55 or the method of claim 56, wherein the disease is selected from the group consisting of acne, atopic dermatitis, lichen planus, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), and lupus erythematosus.

59. A combination product comprising (i) at least one compound, stereoisomer, or salt according to any one of claims 1-52 and (ii) one or more active ingredients selected from the group consisting of: (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; ΜΛ / t / ZUZZ / UOO 14 1 130 f) Anti-inflammatories 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) Antineoplastic agents such as lenalidomide, pomalidomide, pembrolizumab, nivolumab, daratumumab, bortezomib, carfilzomib, ixazomib, bendamustine or ventoclast; j) T-lymphocyte 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-1 beta blockers such as canakinumab; p) IL-alpha blockers such as bermekimab; q) CD6 blockers such as itolizumab; r) IL-36R blockers such as BI-655130 or bimekizumab; s) IL-6 antagonist such as tocilizumab; t) Calcineurin inhibitors such as pimecrolimus, tacrolimus or cyclosporine;u) Phototherapy agents commonly used in phototherapy such as psoralen, methoxypsoralen or 5-methoxypsoralen + UVA (PUVA) or UVB treatment (with or without tar); v) Fixed combinations of corticosteroids and vitamin D derivatives; w) Fixed combinations of corticosteroids and retinoids;x) Corticosteroid tapes ey) one or more agents selected from the group consisting of BMS986165, PF06700841, PF-06826647, piclidenosone, tepilamide fumarate, LYC-30937, LEO-32731, Bl730357, PRCL-02, 1993; LNP-1955, GSK-2982772, CBP-307, KD-025, MP-1032, Petesicatib, JTE451, Hemay-005, SM-04755, EDP-1815, BI-730460, SFA-002 ER, JNJ-3534, SAR-441169, BOS-172767, SCD-044, ABBV-157, BAY-1834845, AUR-101, R-835, PBF-1650, RTA-1701, AZD-0284, mirikizumab, CD20 antagonist, salicylic acid, hulla tar, Mical-1, DUR928, AM-001, BMX-010, TA-102, SNA-125, brepocitinib tosylate, pegcantratinib, ESR-114, NP-000888, SM-04755, BOS-475, SB-414, LEO-134310, CBS-3595, PF-06763809, XCUR-17 and BTX-1308.;