Aryl Hydrocarbon Receptor Agonists and Uses Thereof - Patent application

Abstract

The present invention relates to pharmaceutical compounds of formula (I), as further described herein: JPEG2025504096000143.jpg2556 and pharmaceutical compositions comprising such compounds, and methods of using these compounds to modulate the activity of the aryl hydrocarbon receptor (AhR) and to treat conditions involving inflammation within the gut, including IBD, ulcerative colitis, Crohn's disease, Huntington's disease, and multiple sclerosis, and certain disorders of the central nervous system affected by the gut-brain axis. The present invention includes subgenera of this class of compounds described herein, and preferred embodiments of these compounds include the compounds of Examples 1-58. Compounds of the present invention have been shown to have agonistic activity at AhR.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 306,458, filed February 3, 2022, the disclosure and contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] FIELD OF THEINVENTION The field of the present invention is compounds, pharmaceutical compositions and the methods of making and using them, particularly compounds and compositions that act as agonists of aryl hydrocarbon receptor (AhR).It particularly relates to the method of using such agonists to treat neurodegenerative diseases and inflammatory disorders, especially those that occur in the gut or in relation to the gut-brain axis.The specific conditions that the compounds, compositions and methods of the present invention are suitable for include ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBD), multiple sclerosis and Huntington's disease. [Background technology]

[0003] 2. Background of the Invention The aryl hydrocarbon receptor (AhR) has long been studied for its role in the toxicity of exogenous substances, such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), which binds to AhR and causes it to activate endogenous detoxification mechanisms. However, AhR also recognizes a variety of endogenous ligands, many of which are based on indole and tryptophan analogues, and the evolutionary conservation, tight regulation, and widespread expression of AhR in the immune system strongly suggest that it has important physiological functions. The Aryl Hydrocarbon Receptor: Multitasking in the Immune System, B. Stockinger, et al., Annu. Rev. Immunol. 2014, 32:403-32. Its immune-modulating effects have been the subject of extensive research, demonstrating that AhR agonists have effects in model systems of experimental autoimmune encephalitis (EAE), graft-versus-host disease (GVHD), and mouse models of allergy and transplant tolerance, and also promote regulatory T cell proliferation and secretion of inflammatory cytokines.

[0004] AhR is normally found in the cytosol, bound to actin filaments in an inactive complex along with several chaperone proteins. When a ligand binds to the actin complex, AhR dissociates from actin and translocates to the cell nucleus, where it is released from the chaperone complex. AhR then binds to a partner protein, ARNT (aryl hydrocarbon receptor nuclear transporter), forming a heterodimer. The heterodimer binds to a recognition motif, the dioxin response element (DRE), and induces the expression of key proteins, including CYP1A1, CYP1A2, CYP1B1, and AhR repressor (AhRR), as well as affecting various adaptive immune system components.

[0005] AhR exerts multiple functions in the gastrointestinal tract and serves as an essential sentinel of the gastrointestinal barrier. Dietary AhR ligands ensure the maintenance of intraepithelial lymphocytes (IELs) (e.g., γδT cells and CD8ααT cells) and innate lymphoid cells (ILCs) (e.g., ILC3s) and the proliferation of colonic crypt stem cells. Furthermore, AhR signaling is critically involved in the formation of tertiary lymphoid tissues, such as cryptopatches and intestinal lymphoid follicles (ILFs). AhR deficiency leads to loss of ILC3s and IELs, loss of IL-22, perturbation of colonic crypt stem cell proliferation, and dysregulation of gut bacteria. These studies indicate that AhR plays an essential physiological role in maintaining homeostasis of the gut intestinal barrier function when activated by dietary components acting as AhR agonists.

[0006] AhR agonists, including VAF347 and laquinimod, have demonstrated promising activity against immunological and neurodegenerative disorders. Laquinimod (TV-5600, formerly ABR-215062), a novel synthetic compound with high oral bioavailability, is being tested as an oral formulation for Crohn's disease (CD), multiple sclerosis (MS), Huntington's disease, and lupus nephritis. Preclinical data in various experimental models of colitis and MS suggest that laquinimod has a direct inhibitory effect on antigen-presenting cells and T cells, resulting in downregulation of pro-inflammatory cytokines. A Phase II Study of Laquinimod in Crohn's Disease, D'Haens G, et al. Gut 2015, vol. 64:1227-1235. Although it failed to meet the objectives of a Phase 3 clinical trial for treating MS, it demonstrated significant effects on brain atrophy in both relapsing-remitting multiple sclerosis and Huntington's disease patients, supporting the potential of the AhR as a target site for treating neurodegenerative diseases. [ka]

[0007] Without being bound by theory, it is believed that the compounds of the present invention are effective for treating inflammatory and / or immune disorders that occur in the lower gastrointestinal (GI) tract by activating AhR in the tissue of the lower GI tract.By activating AhR in the tissue of the lower GI tract, the compounds of the present invention can also provide therapeutic effects in certain neuroinflammatory or neurodegenerative diseases through modulating the bidirectional communication between the GI system, which is the gut-brain axis, and the CNS.

[0008] Some of the compounds of the present invention have an arylamine group (Ar-NH 2 ), known compounds having this characteristic and used to treat similar conditions in the lower GI tract may be administered as azo compounds of the general formula Ar-N=N-Ar'. Bacteria in the digestive tract reduce the azo bond to form an arylamine, e.g., Ar-N=N-Ar' → Ar-NH 2 +Ar'-NH 2 For example, sulfasalazine is used to treat ulcerative colitis and Crohn's disease and acts as an anti-inflammatory drug in the colon. It contains an azo bond, which is reduced by gastrointestinal bacteria in the colon to produce a sulfapyridine compound and 5-ASA, as shown below. Thus, sulfasalazine is a prodrug: its reduction in the colon releases 5-ASA, and the anti-inflammatory effect of the drug is concentrated in the colon. Br. J. Clin. Pharmac. (1982), 13, 523-528. [ka]

[0009] Similarly, some compounds of the invention contain an azo bond of the general formula Ar-N=N-Ar', which is reduced in the colon to give a compound of the formula Ar-NH 2It is possible to produce active AhR agonists that contain the group: These compounds are particularly useful for oral administration to treat disorders of the colon or disorders associated with the gut-brain axis. Please note that azo compounds can exist as cis and trans isomers: as used herein, unless expressly described as cis or trans isomers, the structural depiction of the azo compounds of the present invention includes both cis and trans isomers as well as mixtures thereof. At least one topical AhR agonist (Tapinarof) is in development for treating psoriasis and atopic dermatitis, but there is still a need for AhR agonists that are useful for treating neurodegenerative and inflammatory disorders, including inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease.The present invention provides such compounds, including some azo compounds that act as prodrugs to target the delivery of active moieties to the lower GI tract. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] The Aryl Hydrocarbon Receptor: Multitasking in the Immune System, B. Stockinger, et al., Annu. Rev. Immunol. 2014, 32:403-32 [Non-Patent Document 2] A Phase II Study of Laquinimod in Crohn's Disease, D'Haens G, et al. Gut 2015, vol. 64:1227-1235 [Non-Patent Document 3] Br. J. Clin. Pharmac. (1982), 13, 523-528 Summary of the Invention [Means for solving the problem]

[0011] Disclosure of the Invention In one embodiment, the disclosure provides a heterocyclic compound having a structure according to Formula I: [ka] (In the formula: Z 1 and Z 2 One of them is -NH 2 and -N=N-Ar, Z 1 and Z 2 the other of which is H, Ar is phenyl, naphthyl, and [ka] is selected from Phenyl and naphthyl are -OR, COOR, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 optionally substituted with up to three groups selected from R, and halo; R 3 H, CN, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 haloalkoxy; Each R 1 and each R 4 -OR, COOR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 R, halo, and -OR', COOR', C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, -CN, and -NR'2 C optionally substituted with one or two groups selected from 1~4 independently selected from alkyl; Each R 2 and each R 5 , halo, -OR, COOR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 R, as well as -OR', COOR', and C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, -CN, and -NR' 2 C optionally substituted with one or two groups selected from 1~4 independently selected from alkyl; Each R is H, C 1~4 Haloalkyl, as well as -OR', COOR', C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, -CN, and -NR' 2 C optionally substituted with one or two groups selected from 1~4 independently selected from alkyl; Each R' is H and C 1~3 independently selected from alkyl; m, n, p, and q are each independently selected from 0, 1, and 2; [N] represents the bond of Ar to N in -N=N-Ar); or a pharma- ceutically acceptable salt thereof.

[0012] The present invention includes subgenera of this class of compounds described herein, and preferred embodiments of these compounds include the compounds of Examples 1-58. The compounds of the present invention are shown to have agonist activity at the AhR. Some of the compounds have an azo bond and function as prodrugs to deliver the active moiety to the lower GI tract, thus providing localized delivery to treat conditions in that region of the body.

[0013] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention described herein in combination with at least one pharma- ceutically acceptable excipient.

[0014] In another embodiment, the present invention provides a method for treating conditions that affect the gut or are modulated via gut-brain axis, said method comprising administering an effective amount of a compound as described herein or a pharmaceutical composition comprising a compound of the present invention to a subject in need of such treatment.In particular, said method is useful for treating conditions such as inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, and Huntington's disease.It is believed that ulcerative colitis and Crohn's disease are modulated by the local action of the compound of the present invention in the gut, where the compound of the present invention provides an anti-inflammatory effect.It is believed that multiple sclerosis and Huntington's disease are modulated via the bidirectional communication between the central nervous system and the enteric nervous system, which is the gut-brain axis, thereby linking the emotional and cognitive centers of the brain with peripheral gut function, including the gut microbiome.

[0015] In certain embodiments, the pharmaceutical composition is prepared for oral administration and the method comprises oral administration of the compound or pharmaceutical composition.

[0016] The compounds described above can be used for any suitable purpose. In some embodiments, the compounds described above can be used in therapy, particularly in the treatment of inflammatory diseases of the gastrointestinal tract or central nervous system, such as inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, and Huntington's disease.

[0017] In yet another aspect, the present disclosure provides pharmaceutical compositions comprising the above-described compounds in admixture with at least one pharma- ceutically acceptable carrier or excipient, and optionally at least two pharma- ceutically acceptable excipients.

[0018] In yet another aspect, the present disclosure provides a method for treating and / or preventing a condition selected from inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, and Huntington's disease, comprising administering an effective amount of the above-mentioned compound or the above-mentioned pharmaceutical composition to a subject in need thereof.

[0019] In yet another aspect, the disclosure provides the use of a compound as described above for the manufacture of a medicament.

[0020] In another aspect, the present invention provides a compound as described herein for use in therapy, particularly for therapeutic use for treating inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease.

[0021] In yet another aspect, the disclosure provides a combination for treating and / or preventing inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease in a subject, comprising an effective amount of the compound described above, or a pharma- ceutically acceptable salt thereof, and an effective amount of a second prophylactic or therapeutic agent for treating and / or preventing inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease in a subject.

[0022] In yet another aspect, the present disclosure provides a method for treating and / or preventing inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease in a subject, comprising administering to a subject in need thereof an effective amount of the above-mentioned combination.

[0023] In yet another aspect, the present disclosure provides a method for increasing activity of the aryl hydrocarbon receptor (AhR) and associated pathways in a cell or a subject, comprising contacting the AhR or a cell or a subject in need thereof with an effective amount of a compound of the present invention or the pharmaceutical composition described above or the combination described above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description General definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.All patents, applications, published applications and other publications mentioned herein are incorporated by reference in their entirety.If the definitions set forth in this section are reversed or otherwise inconsistent with the definitions set forth in the patents, applications or other publications incorporated by reference herein, the definitions set forth in this section shall take precedence over the definitions incorporated by reference herein.

[0025] As used herein, "a" or "an" means "at least one" or "one or more."

[0026] The term "alkyl," as used herein, refers to a saturated hydrocarbon group of a straight, branched, or cyclic arrangement, or any combination thereof; specifically contemplated alkyl groups include those having 10 or fewer carbon atoms, particularly those having 1 to 6 carbon atoms, and lower alkyl groups having 1 to 4 carbon atoms. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, and the like.

[0027] Alkyl groups can be unsubstituted or substituted to the extent that such substitution makes sense chemically. Exemplary substituents include, but are not limited to, halo, =O, =N-CN, =N-OR. a , =NR a , -OR a , -NR a 2 , -SR a , -SO 2 R a , -SO 2 NR a 2 , -NR a SO 2 R a , -NR a CONR a 2 , -NR a COOR a , -NR a COR a , -CN, -COOR a , -CONR a 2 , -OOCR a , -COR a , and -NO 2 where each R ais independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclic alkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, or C5-C10 heteroaryl; and each R a is halo, =O, =N-CN, =N-OR b , =NR b , OR b , N.R. b 2 , S.R. b , S.O. 2 R b , S.O. 2 NR b 2 , N.R. b SO 2 R b , N.R. b CONR b 2 , N.R. b COOR b , N.R. b COR b , CN, COOR b ,CONR b 2 ,OOCR b , C.O.R. b , and NO 2 where each R b are independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclic alkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl. The alkyl, alkenyl and alkynyl groups may also be substituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl, each of which may be substituted by suitable substituents for the particular group. The substituents may be two R on the same atom or adjacent atoms. a or R b When the group contains a -NR b 2, or -NR b -C(O)Rb ), two R a or R b Groups may optionally be taken together with atoms in the substituent to which they are attached to form a ring having 5 to 8 ring members, which ring may be selected from the group consisting of R a or R b It may be substituted as permitted per se, and may contain additional heteroatoms (N, O or S) as ring members.

[0028] The term "alkenyl" as used herein refers to an alkyl as defined above having at least two carbon atoms and at least one carbon-carbon double bond. Thus, particularly contemplated alkenyl groups include linear, branched, or cyclic alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, etc.) having 2 to 10 carbon atoms, or for cyclic alkenyl groups, having 5 to 10 atoms. Alkenyl groups are optionally substituted with groups suitable for alkyl groups as set forth herein.

[0029] Similarly, the term "alkynyl" as used herein refers to an alkyl or alkenyl as defined above having at least 2 (preferably 3) carbon atoms and at least one carbon-carbon triple bond. Particularly contemplated alkynyls include linear, branched, or cyclic alkynes having a total of 2 to 10 carbon atoms (e.g., ethynyl, propynyl, butynyl, cyclopropylethynyl, etc.). Alkynyl groups are optionally substituted with groups suitable for alkyl groups as indicated herein.

[0030] The term "cycloalkyl" as used herein refers to a cyclic alkane (i.e., a chain of hydrocarbon carbon atoms forming a ring), preferably containing 3 to 8 carbon atoms. Thus, exemplary cycloalkanes include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls also contain one or two double bonds, which form a "cycloalkenyl" group. Cycloalkyl groups are optionally substituted with groups suitable for alkyl groups as set forth herein.

[0031] The term "aryl" or "aromatic moiety" as used herein refers to an aromatic ring system that may further include one or more non-carbon atoms. These are typically 5-6 membered isolated rings or 8-10 membered bicyclic groups, which may be substituted. Thus, contemplated aryl groups include (e.g., phenyl, naphthyl, etc.) and pyridyl. Further contemplated aryl groups may be fused (i.e., covalently bonded to two atoms on the first aromatic ring) with one or two 5- or 6-membered aryl or heterocyclic groups, and thus referred to as "fused aryl" or "fused aromatic."

[0032] Aromatic groups containing one or more heteroatoms (typically N, O or S) as ring members may be referred to as heteroaryl or heteroaromatic groups. Typical heteroaromatic groups include monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and imidazolyl, as well as fused bicyclic moieties formed by one of these monocyclic groups being fused with a phenyl ring or with any of the heteroaromatic monocyclic groups to form a C8-C10 bicyclic group, such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, pyrazolopyrimidyl, quinazolinyl, quinoxalinyl, cinnolinyl, and the like. Any monocyclic or fused ring bicyclic system that has the characteristics of aromaticity with respect to the electron distribution throughout the ring system is included in this definition. It also includes bicyclic groups in which at least the ring that is directly attached to the remainder of the molecule has the characteristics of aromaticity. Typically, the ring system contains 5 to 12 ring member atoms.

[0033] Also as used herein, the terms "heterocycle", "cycloheteroalkyl", and "heterocyclic moiety" are used interchangeably herein and refer to any compound in which multiple atoms form a ring through multiple covalent bonds, and the ring contains at least one atom other than a carbon atom as a ring member. Particularly contemplated heterocyclic rings include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine, indole, pyridine, thiazole, tetrazole, etc.). Typically, these rings contain 0-1 oxygen or sulfur atoms, at least 1, typically 2-3 carbon atoms, and up to 4 nitrogen atoms as ring members. Additionally contemplated heterocycles may be fused (i.e., covalently bonded to two atoms on the first heterocyclic ring) with one or two carbocyclic or heterocyclic rings, and thus are referred to as "fused heterocyclic rings" or "fused heterocyclic rings" or "fused heterocyclic moieties" as used herein. When the rings are aromatic, they may be referred to herein as "heteroaryl" or heteroaromatic groups.

[0034] Heterocyclic groups that are not aromatic may be substituted with groups suitable for alkyl group substituents, as set forth above.

[0035] The aryl and heteroaryl groups can be optionally substituted where permissible. Suitable substituents include, but are not limited to, halo, -OR a , -NR a 2 , -SR a , -SO 2 R a , -SO 2 NR a 2 , -NR a SO 2 R a , -NR a CONR a 2 , -NR a COOR a , -NR a COR a, -CN, -COOR a , -CONR a 2 , -OOCR a , -COR a , and -NO 2 where each R a is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclic alkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, or C5-C10 heteroaryl; and each R a is halo, =O, =N-CN, =N-OR b , =NR b , OR b , N.R. b 2 , S.R. b , S.O. 2 R b , S.O. 2 NR b 2 , N.R. b SO 2 R b , N.R. b CONR b 2 , N.R. b COOR b , N.R. b COR b , CN, COOR b ,CONR b 2 ,OOCR b , C.O.R. b , and NO 2 where each R bare independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclic alkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl. The alkyl, alkenyl and alkynyl groups may also be substituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl, each of which may be substituted by suitable substituents for the particular group. The substituents may be two R on the same atom or adjacent atoms. a or R b When the group contains a -NR b 2, or -NR b -C(O)R b ), two R a or R b Groups may optionally be taken together with atoms in the substituent to which they are attached to form a ring having 5 to 8 ring members, which ring may be selected from the group consisting of R a or R b It may be substituted as permitted per se, and may contain additional heteroatoms (N, O or S) as ring members.

[0036] The term "alkoxy" as used herein refers to a hydrocarbon group connected via an oxygen atom, e.g., -O-Hc, where the hydrocarbon portion Hc may have any number of carbon atoms, typically 1-10 carbon atoms, may further contain a double or triple bond, may contain one or two oxygen, sulfur or nitrogen atoms in the alkyl chain, and may be substituted with aryl, heteroaryl, cycloalkyl, and / or heterocyclyl groups. For example, suitable alkoxy groups include methoxy, ethoxy, propyloxy, isopropoxy, methoxyethoxy, benzyloxy, allyloxy, and the like. Similarly, the term "alkylthio" refers to an alkyl sulfide of the general formula -S-Hc, where the hydrocarbon portion Hc is as described for the alkoxy group. For example, contemplated alkylthio groups include methylthio, ethylthio, isopropylthio, methoxyethylthio, benzylthio, allylthio, and the like.

[0037] The term "amino" as used herein means -NH 2 The term "alkylamino" refers to an amino group in which one or both hydrogen atoms are replaced by a hydrocarbon group Hc as described above, where the amino nitrogen "N" may be substituted by one or two Hc groups as described above for the alkoxy group. Exemplary alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, and the like. The term "substituted amino" refers to an amino group in which one or both hydrogen atoms are replaced by a hydrocarbon group Hc as described above, where the amino nitrogen "N" may be substituted by one or two Hc groups as described above for the alkoxy group.

[0038] The term "acyl" as used herein refers to a group of formula -C(=O)-D, where D represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle as described above. Typical examples are groups where D is C1-C10 alkyl, C2-C10 alkenyl or alkynyl, or phenyl, each of which is optionally substituted. In some embodiments, D is H, Me, Et, isopropyl, propyl, butyl, -OH, -OMe, or NH 2 It may be C1-C4 alkyl, phenyl, halophenyl, alkylphenyl, or the like substituted with.

[0039] The term "aryloxy" as used herein refers to an aryl group connected to an oxygen atom, where the aryl group may be further substituted. For example, suitable aryloxy groups include phenyloxy and the like. Similarly, the term "arylthio" as used herein refers to an aryl group connected to a sulfur atom, where the aryl group may be further substituted. For example, suitable arylthio groups include phenylthio and the like.

[0040] The hydrocarbon moieties, such as each alkoxy, each alkylthio, each alkylamino, and each aryloxy, may be appropriately substituted on the associated hydrocarbon moiety.

[0041] The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine. When present as a substituent, halogen or halo typically refers to F or Cl or Br, more typically F or Cl.

[0042] The term "haloalkyl" refers to an alkyl group as described above in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, and the like.

[0043] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group and includes, by way of example, groups such as trifluoromethoxy.

[0044] It should further be appreciated that all of the above defined groups may be further substituted with one or more substituents, which in turn may be substituted with hydroxy, amino, cyano, C1-C4 alkyl, halo, or C1-C4 haloalkyl. For example, a hydrogen atom in an alkyl or aryl may be replaced by an amino, halo, or C1-4 haloalkyl or alkyl group.

[0045] The term "substituted," as used herein, refers to the replacement of a hydrogen atom of an unsubstituted group with a functional group; specifically contemplated functional groups include nucleophilic groups (e.g., -NH 2 , -OH, -SH, -CN, etc.), electrophilic groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., heterocycles, aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH 3 + ), and halogens (e.g., -F, -Cl), NHCOR, NHCONH 2 , O.C.H. 2 COOH, OCH 2 CONH 2 , O.C.H. 2 CONHR, NHCH 2 COOH, NHCH 2 CONH 2 , N.H.S.O. 2 R, O.C.H. 2 -Heterocycle, PO 3 H, SO 3H, amino acids, and all chemically reasonable combinations thereof. Additionally, the term "substituted" also includes multiple degrees of substitution, such that where multiple substituents are disclosed or claimed, the substituted compounds may be independently substituted with one or more of the disclosed or claimed substituent moieties.

[0046] Further to the disclosure herein, in certain embodiments, a substituted group has 1, 2, 3 or 4 substituents, 1, 2 or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0047] In all the substituted groups defined above, it is understood that compounds obtained by defining a substituent with further substituents on itself (such as substituted aryl with a substituted aryl group as a substituent, which is itself substituted with a substituted aryl group, which is further substituted with a substituted aryl group, etc.) are not intended to be encompassed herein.In such cases, the maximum number of such substitutions is 3.For example, the sequential substitution of substituted aryl groups specifically contemplated herein is limited to substituted aryl-(substituted aryl)-substituted aryl.

[0048] Unless otherwise indicated, the nomenclature of substituents not expressly defined herein is derived by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0049] With respect to any of the groups disclosed herein that contain one or more substituents, it is of course understood that such groups do not contain any substitutions or substitution patterns that are sterically impractical and / or synthetically infeasible.Furthermore, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0050] The term "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient, such as a mammal, such as a human, with a counterion that has acceptable mammalian safety for a given dosing regimen. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a compound, which is derived from a variety of organic and inorganic counterions well known in the art, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; if the molecule contains a basic functional group, it includes salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.

[0051] The term "salt thereof" refers to a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation, as a counterion, or when a basic group, such as an amine in a compound, is protonated or alkylated, such that the compound has a positive charge and is associated with an anionic counterion. Where applicable, the salt is a pharma- ceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. By way of example, salts of the present compounds include those in which the compound is protonated with an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0052] The compounds and compositions described herein can be administered to a subject who needs to be treated for inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease.The subject is typically a mammalian animal diagnosed as needing to be treated for one or more of these diseases or conditions, and in many cases the subject is a human.The method comprises administering an effective amount of at least one compound of the present invention; if necessary, the compound can be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful for treating conditions or disorders that afflict certain subjects.

[0053] The embodiments listed below represent certain aspects of the present invention. 1. Formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Z 1 and Z 2 One of them is -NH 2 and -N=N-Ar, Z 1 and Z 2 the other of which is H, Ar is phenyl, naphthyl, and [ka] is selected from Phenyl and naphthyl are -OR, COOR, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 optionally substituted with up to three groups selected from R, and halo; R 3 H, CN, halo, C 1~4 Alkyl, C1~4 Haloalkyl, and C 1~4 haloalkoxy; Each R 1 and each R 4 -OR, COOR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 R, halo, and -OR', COOR', C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, -CN, and -NR' 2 C optionally substituted with one or two groups selected from 1~4 independently selected from alkyl; Each R 2 and each R 5 , halo, -OR, COOR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 R, as well as -OR', COOR', and C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, -CN, and -NR' 2 C optionally substituted with one or two groups selected from 1~4 independently selected from alkyl; Each R is H, C 1~4 Haloalkyl, as well as -OR', COOR', C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, -CN, and -NR' 2 C optionally substituted with one or two groups selected from 1~4 independently selected from alkyl; Each R' is H and C 1~3 independently selected from alkyl; m, n, p, and q are each independently selected from 0, 1, and 2; [N] represents the bond of Ar to N in -N=N-Ar; The compound, or a pharma- ceutically acceptable salt thereof. In some of these embodiments of particular interest, Z 2 NH 2 In an alternative embodiment of particular interest, Z 2 is -N=N-Ar. In certain embodiments, these compounds have the formula: [ka] It is a compound of the formula: 2.Z 1 and Z 2 One of them is -NH 2 and Z 1 and Z 2 and the other of is H; or a pharma- ceutically acceptable salt thereof. 3.Z 1 and Z 2 One of them is -N=N-Ar, and Z 1 and Z 2 and the other of is H; or a pharma- ceutically acceptable salt thereof. In these embodiments, the azo bond can be cis or trans, or a mixture of cis and trans. These compounds are Z-linked, with the azo bond likely being reduced by the activity of the gut microbiome. 1 or Z 2 NH 2 can function as a prodrug to deliver a compound that results in direct delivery of the compound to the gastrointestinal tract. 4. Ar is phenyl or naphthyl, -OR, COOR, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3R 2 , -SO 2 R, -SO 3 The compound of embodiment 3, optionally substituted with up to three groups selected from: R, and halo; or a pharma- ceutically acceptable salt thereof. 5.R 3 The compound of any one of embodiments 1 to 4, wherein is H; or a pharma- ceutically acceptable salt thereof. 6. The compound according to any of embodiments 1 to 5, wherein p and q are independently selected from 0 and 1; or a pharma- ceutically acceptable salt thereof. 7. The compound has the formula (IA): [ka] The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt thereof. 8.Formula (IB): [ka] The compound according to embodiment 7, or a pharma- ceutically acceptable salt thereof. 9.Z 2 Ga-NH 2 The compound of embodiment 7 or 8, wherein or a pharma- ceutically acceptable salt thereof. 10.Z 2 The compound according to embodiment 7 or 8, wherein is -N=N-Ar; or a pharma- ceutically acceptable salt thereof. 11. The compound according to embodiment 9 or 10, wherein n is 0; or a pharma- ceutically acceptable salt thereof. 12.R 1 CF 3 The compound of embodiment 11, wherein or a pharma- ceutically acceptable salt thereof. 13.Ar: [ka] wherein the dashed bond indicates which atom of Ar is bonded to N=N; or a pharma- ceutically acceptable salt thereof. 14. Ar [ka] wherein the dashed bond indicates which atom of Ar is bonded to N=N; or a pharma- ceutically acceptable salt thereof. 15.Formula (IC): [ka] The compound of embodiment 1, which is a compound of or a pharma- ceutically acceptable salt thereof. 16.Formula: [ka] The compound of embodiment 15, having the formula: or a pharma- ceutically acceptable salt thereof. 17. m is the same as p; n is equal to q; R 1 R 4 is the same as; R 2 R 5 The compound according to embodiment 16, wherein or a pharma- ceutically acceptable salt thereof. 18.Formula: [ka] 18. The compound of embodiment 16 or 17, which is a compound of the formula: m is 0 or 1; A compound wherein p is 0 or 1; or a pharma- ceutically acceptable salt thereof. 19. A compound according to any of the preceding embodiments selected from the compounds in the table below, or a pharma- ceutically acceptable salt thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] 20. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 19 in admixture with at least one pharma- ceutically acceptable excipient. In some of these embodiments, the compound is in admixture with two or more pharma- ceutically acceptable excipients. 21. A method for treating a condition affecting the gut or modulated via the gut-brain axis, said method comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of embodiments 1 to 19. 22. The method of embodiment 21, wherein the condition is inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease. 23. The method according to embodiment 21 or 22, wherein the compound according to any one of claims 1 to 19 or the pharmaceutical composition according to embodiment 20 is administered orally and is therefore prepared or formulated for oral administration. For all of these embodiments, the compounds of Examples 1-58 and 60-62 are preferred compounds of formula (I). 24. The method of any one of embodiments 21 to 23, wherein the method further comprises administering to the subject an additional therapeutic agent that is useful for treating the condition.

[0054] Examples of additional therapeutic agents suitable for use in these methods include prednisone and other steroids, 5-aminosalicylates, immune modulators including mesalamine, azathioprine, mercaptopurine, and methotrexate, and certain biologics including infliximab, adalimumab, and certolizumab pegol. Pharmaceutical Compositions, Combinations, and Other Related Uses

[0055] In one embodiment, the disclosure provides a pharmaceutical composition comprising the above-described compound in admixture with at least one pharma- ceutically acceptable carrier or excipient.

[0056] The above-mentioned compounds can be used for any suitable purpose.For example, the compounds can be used in therapy and / or testing.They are particularly useful for treating the conditions mentioned herein.

[0057] Any suitable formulation of the compounds described herein can be prepared. See generally Remington's Pharmaceutical Sciences, (2000) Hoover, JE editor, 20th edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pages 780-857. Formulations are selected that are suitable for the appropriate route of administration. When a compound is sufficiently basic or acidic to form a stable non-toxic acid or base salt, administration of the compound as a salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts can also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by combining a sufficiently basic compound, such as an amine, with a suitable acid that provides a physiologically acceptable anion.Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids are also included and are prepared by conventional methods.

[0058] When the contemplated compounds are administered in a pharmacological composition, it is contemplated that the compounds may be formulated in admixture with pharma- ceutically acceptable excipients and / or carriers. For example, the contemplated compounds may be administered orally as neutral compounds or pharma- ceutically acceptable salts, or intravenously in physiological saline solution. For this purpose, conventional buffers, such as phosphates, bicarbonates, or citrates, may be used. Of course, those skilled in the art may modify the formulations within the teachings of the specification to provide multiple formulations for a particular route of administration. In particular, the contemplated compounds may be modified to increase their solubility in water or other vehicles, which may be easily achieved, for example, by minor modifications (salt formulations, esterification, etc.) well within the ordinary skill of the art. It is also well within the ordinary skill of the art to modify the route of administration and dosing regimen of a particular compound in order to manage the pharmacokinetics of the compound for maximum beneficial effect in patients.

[0059] The compounds described herein are generally soluble in organic solvents, such as chloroform, dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and the like. In one embodiment, the invention provides a formulation prepared by mixing a compound of the invention with a pharma- ceutically acceptable carrier. In one aspect, the formulation may be prepared using a method comprising: a) dissolving the compound described in a water-soluble organic solvent, a non-ionic solvent, a water-soluble lipid, a cyclodextrin, a vitamin, such as tocopherol, a fatty acid, a fatty acid ester, a phospholipid, or a combination thereof to provide a solution; and b) adding a saline or buffer solution containing 1-10% carbohydrate solution. In one example, the carbohydrate comprises dextrose. The pharmaceutical composition obtained using the method is stable and useful for veterinary and clinical applications.

[0060] Illustrative examples of water-soluble organic solvents for use in the present method include, but are not limited to, polyethylene glycol (PEG), alcohol, acetonitrile, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, or combinations thereof. Examples of alcohols include, but are not limited to, methanol, ethanol, isopropanol, glycerol, or propylene glycol.

[0061] Illustrative examples of water-soluble non-ionic surfactants for use in the present methods include, but are not limited to, CREMOPHOR® EL, polyethylene glycol modified CREMOPHOR® (polyoxyethylene glycerol triricinoleate 35), hydrogenated CREMOPHOR® RH40, hydrogenated CREMOPHOR® RH60, PEG-succinate, polysorbate 20, polysorbate 80, SOLUTOL® HS (polyethylene glycol 660 12-hydroxystearate), sorbitan monooleate, poloxamer, LABRAFIL® (ethoxylated persic oil), LABRASOL® (capryl-caproyl macrogol-8-glyceride), GELUCIRE® (glycerol esters), SOFTIGEN® (PEG 6 caprylic acid glyceride), glycerin, glycol-polysorbate, or combinations thereof.

[0062] Illustrative examples of water-soluble lipids for use in the present methods include, but are not limited to, vegetable oils, triglycerides, plant oils, or combinations thereof. Examples of lipid oils include, but are not limited to, castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, coconut oil, palm seed oil, and hydrogenated forms of these triglycerides, or combinations thereof.

[0063] Illustrative examples of fatty acids and fatty acid esters for use in the present methods include, but are not limited to, oleic acid, monoglycerides, diglycerides, mono- or di-fatty acid esters of PEG, or combinations thereof.

[0064] Illustrative examples of cyclodextrins for use in the present methods include, but are not limited to, alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, or sulfobutylether-beta-cyclodextrin.

[0065] Illustrative examples of phospholipids for use in the present methods include, but are not limited to, soybean phosphatidylcholine, or distearoylphosphatidylglycerol, and hydrogenated forms thereof, or combinations thereof.

[0066] In some embodiments, the compounds of the present invention are formulated for oral administration.

[0067] Those skilled in the art can prepare or modify formulations within the teachings of the specification, and alternatives known to those skilled in the art, to provide a number of formulations for specific administration routes.In particular, compounds can be modified to increase their solubility in water or other vehicles.It is also well within the ordinary skill of the art to modify the administration route and dosage regimen of a particular compound in order to manage the pharmacokinetics of the compound for maximum beneficial effect in patients. Drug Combinations

[0068] The method of the embodiment comprises administering an effective amount of at least one exemplary compound of the present disclosure; if necessary, the compound can be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful for treating inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease. Additional therapeutic agents are considered to be used in combination with the compounds of the present invention when the timing of administration of the two agents allows them to act simultaneously in the subject.

[0069] Examples of suitable additional therapeutic agents include prednisone and other steroids, 5-aminosalicylates, immune modulators including mesalamine, azathioprine, mercaptopurine, and methotrexate, and certain biologics including infliximab, adalimumab, and certolizumab pegol.

[0070] The additional active ingredient may be administered as a separate pharmaceutical composition from at least one exemplary compound of the present disclosure, or may be included in a single pharmaceutical composition with at least one exemplary compound of the present disclosure. The additional active ingredient may be administered simultaneously with, prior to, or after administration of at least one exemplary compound of the present disclosure. The selection of a suitable additional therapeutic agent and a suitable route of administration is within the ordinary skill in the art. Methods of Using Exemplary Compounds and Pharmaceutical Compositions Thereof

[0071] To practice the methods of the present invention, the compounds of the present invention and pharmaceutical compositions thereof may be administered orally, parenterally, by inhalation, topically, rectally, nasally, bucally, vaginally, via an implanted reservoir, or by other methods of drug administration. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0072] Sterile injectable compositions, for example, sterile injectable aqueous or oily suspensions, can be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents.Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents.Among acceptable vehicles and solvents that may be used, include mannitol, water, Ringer's solution and isotonic sodium chloride solution.Suitable carriers and other pharmaceutical composition components are typically sterilized.

[0073] In addition, sterile fixed oils are commonly used as solvents or suspending media (e.g., synthetic monoglycerides or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable drugs, as are pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants. Various emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solids, liquids, or other dosage forms can also be used for formulation purposes.

[0074] In some embodiments, the compounds and compositions of the present invention are formulated for oral administration. Compositions for oral administration may be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants, such as magnesium stearate, may also be added. For oral administration in capsule form, useful diluents include lactose and dry cornstarch. For oral administration of aqueous suspensions or emulsions, the active ingredient may be suspended or dissolved in the oil phase in combination with an emulsifier or suspending agent. If necessary, certain sweeteners, flavorings, or colorings may be added. Nasal aerosol or inhalation compositions may be prepared according to techniques well known in the art of pharmaceutical formulations, and may be prepared, for example, as a solution in saline, with suitable preservatives (e.g., benzyl alcohol), absorption enhancers to enhance bioavailability, and / or other solubilizers or dispersants known in the art.

[0075] In a preferred embodiment, the compounds of the present invention are formulated for oral administration and are administered orally. 1 or Z 2 is particularly preferred for compounds of the invention in which is an azo-linked aryl group (-N=N-Ar).

[0076] Additionally, any of the compounds having formula I or compounds of Examples 1-58 may be administered alone or in combination with other therapeutic agents, such as therapeutic agents useful in the treatment of disorders, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease. Combination therapy according to the present invention includes administering at least one exemplary compound of the present disclosure and at least one other pharmacologic active ingredient. The active ingredient and pharmacologic active agent may be administered separately or together. Examples of suitable additional pharmacologic active agents for use with the compounds of the present invention include prednisone and other steroids, 5-aminosalicylates, immunomodulators including mesalamine, azathioprine, mercaptopurine, and methotrexate, and certain biologics including infliximab, adalimumab, and certolizumab pegol.

[0077] The amounts of the active ingredients and pharma- ceutical active agents and the timing of administration with respect to each other are selected in order to achieve the desired combined therapeutic effect. General synthetic procedure

[0078] The compounds of the present invention are readily prepared from commonly available compounds using procedures known to those of ordinary skill in the art in light of the examples and schemes provided herein. [ka]

[0079] Z 2 NH 2 Compounds of formula (I), wherein R is a boronic acid / ester, can be prepared according to Scheme 1. Suzuki coupling of compound A with boronic acid / ester B gives intermediate C. Amination of C with substituted aniline D gives intermediate E, and R 3 was converted to the amine to give the final product F. 3 The group is NO 2 , Protected N.H. 2 or halogen, which can be converted to the free NH 2It can be converted to R 1 R may also be further converted to a different substituent. 1 and R 2 Depending on the selection of, the product may be a compound of formula (I) or a precursor of such a compound. [ka]

[0080] Intermediate E may also be prepared according to Scheme 2. Treatment of compound G with DMF-DMA gives intermediate H. Substituted aniline D can be converted to substituted guanidine I. Condensation of H and I forms a pyrimidine ring to give intermediate E. [ka]

[0081] Similar to the route described in Scheme 1, Z 1 NH 2 Compounds of formula (I) where R may also be prepared according to Scheme 3. 2 or R 3 One of them is NH 2 In this case, conversion of compound M to compound N is not required. [ka]

[0082] Z 1 or Z 2 Compounds of formula (I) where -N=N-Ar can be prepared according to Scheme 4. The aniline compound F or N from the previous scheme can be reacted with NaNO 2 R can be converted in situ to the diazonium intermediate O by treatment with HCl / HCl, which reacts with a nucleophile Ar to form the azo compound P. 1 and R 2 Depending on the selection of, the product may be a compound of formula (I) or a precursor of such a compound. [ka]

[0083] The final product P may also be prepared by reacting the aniline product F or N with an aryl nitroso R, which can be prepared by oxidation of an aryl amine Q with oxone (Scheme 5). 1 and R 2 Depending on the selection of, the product may be a compound of formula (I) or a precursor of such a compound. [ka] The aniline compounds F or N can be converted to the nitroso intermediates S by treatment with oxone, and then further converted to the azo compounds P by treatment with arylamines (Scheme 6). 1 and R 2 Depending on the selection of, the product may be a compound of formula (I) or a precursor of such a compound. By using these and known alternative starting materials, one skilled in the art can prepare a variety of compounds of formula (I). EXAMPLES

[0084] Abbreviation Ac Acetyl ACN Acetonitrile AcOEt / EtOAc Ethyl acetate AcOH Acetic acid aq. aqueous solution Ar Aryl Bn Benzyl Bu Butyl (nBu = n-butyl, tBu = tert-butyl) CDI Carbonyldiimidazole CH 3 CN Acetonitrile DBU 1,8-Diazabicyclo[5.4.0]-undec-7-ene Boc2 O Di-tert-butyl dicarbonate BPO Benzoyl Peroxide DCE 1,2-dichloroethane DCM Dichloromethane DIBAL-H Diisobutylaluminum hydride DIPEA N-Ethyldiisopropylamine DMA N,N-Dimethylacetamide DMAP Dimethylaminopyridine DMF N,N-Dimethylformamide DMF-DMA N,N-Dimethylformamide Dimethyl Acetal DMP Dess-Martin Periodinane DMSO Dimethyl sulfoxide EI Electrospray Ionization Et 2 O Diethyl ether Et 3 N-Triethylamine eq equivalent Ether Diethyl ether EtOAc or EA Ethyl Acetate EtOH Ethanol FA Formic Acid FC Flash Chromatography h time HATU O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCl Hydrochloric acid HMPA Hexamethylphosphoramide HOBt 1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography H 2 O water L Liter LC-MS Liquid Chromatography Mass Spectrometry LiHMDS Lithium bis(trimethylsilyl)amide mCPBA meta-chloroperbenzoic acid MgSO 4 Magnesium sulfate Me Methyl MeI Iodomethane MeOH Methanol mg milligram min mL Milliliters MS mass spectrometry MTO Methyltrioxorhenium NaHCO 3 Sodium bicarbonate Na 2 SO 4 Sodium sulfate NBS N-Bromosuccinimide NCS N-chlorosuccinimide NH 2 OH Hydroxylamine Pd / C Palladium on charcoal Pd(OH) 2 Palladium hydroxide PE Petroleum Ether PG protecting group Ph Phenyl Ph 3 P Triphenylphosphine Prep Rf Front Ratio RP Reverse Phase Rt retention time RT or rt Room temperature sat. saturation SiO 2 silica gel SOCl 2 Thionyl chloride TBAF Tetrabutylammonium fluoride TBDMS t-Butyldimethylsilyl TEA Triethylamine TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride TfOH Triflic Acid THF Tetrahydrofuran TLC Thin Layer Chromatography TsCl Toluenesulfonyl chloride Example 1 4-(4-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0085] Step 1: 2-Chloro-4-(4-nitrophenyl)pyrimidine

[0086] Dioxane / H 2 (4-Nitrophenyl)boronic acid (2.0 g, 11.98 mmol, 1.0 eq), 2,4-dichloropyrimidine (1.78 g, 11.98 mmol, 1.0 eq), Na in O (40 mL / 4 mL). 2 CO 3 (2.54g, 23.96mmol, 2.0eq) and PdCl 2 A mixture of (dppf) (854 mg, 1.2 mmol, 0.1 eq) was stirred at 90° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was diluted with DCM / H 2 Dilute with O, separate the organic phase, and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica gel flash chromatography (eluent: PE / EA=4:1) to give the title compound (1.7 g, 60%) as a yellow solid. LC-MS: [M+H] + (m / z)=236.1.

[0087] Step 2: 4-(4-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0088] 2-Chloro-4-(4-nitrophenyl)pyrimidine (200 mg, 0.85 mmol, 1.0 eq), 4-(trifluoromethyl)aniline (150 mg, 0.93 mmol, 1.1 eq), Pd(OAc) in dioxane (3.0 mL)2 (19 mg, 0.085 mmol, 0.1 mmol), Xantphos (49 mg, 0.085 mmol, 0.1 eq) and Cs 2 CO 3 (552 mg, 1.7 mmol, 2.0 eq) was stirred at 110° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was partitioned between DCM / water. The organic phase was separated and diluted with Na 2 SO 4 Drying at 40° C., filtration and concentration gave the title compound, which was used directly in the next step without further purification. LC-MS: [MH] - (m / z)=359.1.

[0089] Step 3: 4-(4-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0090] A mixture of 4-(4-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (300 mg, 0.83 mmol, 1.0 eq) and Pd / C (40 mg) in MeOH (20 mL) was stirred under hydrogen at room temperature for 3 h. The reaction was monitored by LC-MS. The mixture was filtered and the filtrate was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 4 HCO 3 ) to give the title compound (102.1 mg, 50%) as a white solid. LC-MS: [M+H] + (m / z)=331.2; 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.38 (s, 1H), 7.13 (d, J = 5.2 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 4.00 (s, 2H). Example 2 4-(3-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0091] Step 1: 2-Chloro-4-(3-nitrophenyl)pyrimidine

[0092] Dioxane / H 2 (3-Nitrophenyl)boronic acid (2.0 g, 12.0 mmol, 1.0 eq), 2,4-dichloropyrimidine (1.78 g, 12.0 mmol, 1.0 eq), Pd(dppf)Cl in O (20 mL / 4.0 mL). 2 (854mg, 1.2mmol, 0.1eq) and Na 2 CO 3 A mixture of (2.54 g, 24.0 mmol, 2.0 eq) was stirred at 100° C. under Ar overnight. The reaction was monitored by LC-MS. The mixture was filtered, and the filtrate was concentrated and purified by silica gel flash chromatography (eluent: PE / EA=5:1) to give the title compound (1.3 g, 46% yield) as a yellow oil. LC-MS: [M+H] + (m / z)=236.

[0093] Step 2: 4-(3-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0094] 2-Chloro-4-(3-nitrophenyl)pyrimidine (200 mg, 0.85 mmol, 1.0 eq), 4-(trifluoromethyl)aniline (150 mg, 0.93 mmol, 1.1 eq), Pd(OAc) in dioxane (2.0 mL) 2 (38 mg, 0.17 mmol, 0.2 eq) and Cs 2 CO 3A mixture of (552 mg, 1.7 mmol, 2.0 eq) was stirred at 110° C. under Ar overnight. The reaction was monitored by LC-MS. The mixture was filtered, and the filtrate was concentrated and purified by silica gel flash chromatography (eluent: PE / EA=5:1) to give the title compound (200 mg, 65% yield) as a yellow oil. LC-MS: [M+H] + (m / z)=361.

[0095] Step 3: 4-(3-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0096] To a solution of 4-(3-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (200 mg, 0.55 mmol, 1.0 eq) in MeOH (5.0 mL) was added Pd / C (10 mg). The mixture was heated at 37° C. for 1 hour at 37° C. for 2 hours at 37° C. for 2 hours at 37° C. 2 The mixture was stirred at room temperature for 2 hours under reduced pressure. The reaction was monitored by LC-MS until completion. The mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1% FA) and freeze-dried to give the title compound (37.87 mg, 20% yield) as a white solid. LC-MS: [M+H] + (m / z)=331.1; 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (d, J = 4.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.43-7.10 (m, 2H), 7.35 (s, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 5.6 Hz, 1H), 6.86-6.83 (m, 1H), 3.83 (s, 2H). Example 3 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0097] Step 1: 2-Chloro-4-(2-nitrophenyl)pyrimidine

[0098] Dioxane / H 2 (2-Nitrophenyl)boronic acid (500 mg, 3.0 mmol, 1.0 eq), 2,4-dichloropyrimidine (446 mg, 3.0 mmol, 1.0 eq), Pd(dppf)Cl in O (6.0 mL / 1.0 mL). 2 (214mg, 0.3mmol, 0.1eq) and Na 2 CO 3 A mixture of (636 g, 6.0 mmol, 2.0 eq) was stirred at 100° C. under Ar overnight. The reaction was monitored by LC-MS. The mixture was filtered, and the filtrate was concentrated and purified by silica gel flash chromatography (eluent: PE / EA=5:1) to give the title compound (400 mg, 57%) as a yellow oil. LC-MS: [M+H] + (m / z)=236.

[0099] Step 2: 4-(2-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0100] 2-Chloro-4-(2-nitrophenyl)pyrimidine (200 mg, 0.85 mmol, 1.0 eq), 4-(trifluoromethyl)aniline (150 mg, 0.93 mmol, 1.1 eq), Pd(OAc) in dioxane (2.0 mL) 2 (38 mg, 0.17 mmol, 0.2 eq) and Cs 2 CO 3 A mixture of (552 mg, 1.7 mmol, 2.0 eq) was stirred at 110° C. under Ar overnight. The reaction was monitored by LC-MS. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: PE / EA=5:1) to give the title compound (200 mg, 65%) as a yellow oil. LC-MS: [M+H] + (m / z)=361.

[0101] Step 3: 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0102] To a solution of 4-(2-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (200 mg, 0.55 mmol, 1.0 eq) in MeOH (5.0 mL) was added Pd / C (10 mg). The mixture was heated at 37° C. for 2 hours at 37° C. for 1 hour at 37° C. for 2 hours at 37° C. 2 The mixture was stirred at room temperature for 2 hours under reduced pressure. The reaction was monitored by LC-MS. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1% FA) to give the title compound (44 mg, 24%) as a white solid. LC-MS: [M+H] + (m / z)=331.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.72 (dd, J = 8.0, 1.2 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 6.0 Hz, 1H), 7.20-7.15 (m, 1H), 7.03 (br s, 2H), 6.81 (dd, J = 8.0, 0.8 Hz, 1H), 6.63-6.58 (m, 1H). Example 4 4-(2-amino-5-chlorophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0103] Step 1: 1-(4-(trifluoromethyl)phenyl)guanidine

[0104] To a solution of 4-(trifluoromethyl)aniline (5 g, 31 mmol, 1.0 eq) in EtOH (20 mL) was added concentrated HCl (2.6 mL, 1.0 eq). The mixture was heated to 85° C. and cyanamide (1.56 g, 37.2 mmol, 1.2 eq) was added. Heating was continued for 16 h, then the reaction solution was cooled to 60° C. and then diluted with 1.55 M Na 2 CO 3 Aqueous solution (10 mL) was added. After cooling to room temperature, the mixture was filtered and washed with EtOH (10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by crystallization (solvent PE / EA=1:1) to give the title compound (1.5 g, 24%) as a white solid. LC-MS: [M+H] + (m / z)=204.

[0105] Step 2: (E)-1-(5-chloro-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one

[0106] A mixture of 1-(5-chloro-2-nitrophenyl)ethan-1-one (200 mg, 1.0 mmol, 1.0 eq) and DMF-DMA (0.5 mL) in toluene (3.0 mL) was stirred at 100° C. for 16 h under Ar. The reaction was monitored by LC-MS. The mixture was concentrated to give the title compound, which was used directly in the next step without further purification. LC-MS: [M+H] + (m / z)=255.1.

[0107] Step 3: 4-(5-chloro-2-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0108] (E)-1-(5-chloro-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one (240 mg, 0.95 mmol, 1.0 eq), 1-(4-(trifluoromethyl)phenyl)guanidine (288 mg, 1.42 mmol, 1.5 eq) and K in DMF (3.0 mL). 2 CO 3(326 mg, 2.36 mmol, 2.5 eq) was stirred at 120° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was partitioned between EA / water. The organic phase was separated and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by prep-TLC (PE / EA=2:1) ​​to give the title compound (40 mg, 10%) as a white solid. LC-MS: [MH] - (m / z)=393.2.

[0109] Step 4: 4-(2-amino-5-chlorophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0110] EtOH / NH 4 A mixture of 4-(5-chloro-2-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (40 mg, 0.1 mmol, 1.0 eq) and Zn (33 mg, 0.5 mmol, 5.0 eq) in Cl (5.0 mL / 1.0 mL) was stirred at room temperature for 16 h. The mixture was monitored by LC-MS. The mixture was analyzed by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 4 HCO 3 ) to give the title compound (21.5 mg, 58%) as a white solid. LC-MS: [M+H] + (m / z)=365.0; 1 H NMR (400 MHz, CD 3 OD) δ 8.49 (d, J = 5.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 5.6 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H). Example 5 4-(4-amino-3-chlorophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0111] Step 1: 1-(4-amino-3-chlorophenyl)ethan-1-one

[0112] A mixture of 1-(4-aminophenyl)ethan-1-one (1.0 g, 7.4 mmol, 1.0 eq) and NCS (1.08 g, 8.1 mmol, 1.1 eq) in 2-propanol (20.0 mL) was stirred at 60° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was partitioned between DCM / water. The organic phase was separated and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness. The residue was purified by silica gel flash chromatography (PE / EA=6:1) to give the title compound (1.0 g, 81%) as a yellow solid. LC-MS: [M+H] + (m / z)=170.2.

[0113] Step 2: tert-Butyl (4-acetyl-2-chlorophenyl) (tert-butoxycarbonyl)carbamate

[0114] To a mixture of 1-(4-amino-3-chlorophenyl)ethan-1-one (500 mg, 2.96 mmol, 1.0 eq) and DMAP (36 mg, 0.30 mmol, 0.1 eq) in DCM (10 mL) (Boc) 2 O (709 mg, 3.25 mmol, 1.1 eq) was added. The mixture was stirred at room temperature under Ar for 1 h. The mixture was monitored by TLC. The crude was purified by silica gel FC (PE / EA=10:1) to give the title compound (740 mg, 76%) as a white solid. LC-MS: [M+H] + (m / z) = 214.1 (-Boc-tBu fragment).

[0115] Step 3: tert-Butyl (E)-(tert-butoxycarbonyl)(2-chloro-4-(3-(dimethylamino)acryloyl)phenyl)-carbamate

[0116] A mixture of tert-butyl (4-acetyl-2-chlorophenyl) (tert-butoxycarbonyl)carbamate (400 mg, 1.08 mmol, 1.0 eq) and DMF-DMA (2.0 mL) in toluene (10 mL) was stirred at 100° C. for 16 h under Ar. The reaction was monitored by LC-MS. The mixture was concentrated to dryness and used directly in the next step without further purification. LC-MS: [M+H] + (m / z)=425.1.

[0117] Step 4: 4-(4-amino-3-chlorophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0118] A solution of tert-butyl (E)-(tert-butoxycarbonyl)(2-chloro-4-(3-(dimethylamino)acryloyl)phenyl)-carbamate (350 mg, 0.825 mmol, 1.0 eq), 1-(4-(trifluoromethyl)phenyl)guanidine (251 mg, 1.24 mmol, 1.5 eq) and K in DMF (5.0 mL) was added. 2 CO 3 A mixture of (285 mg, 2.06 mmol, 2.5 eq) was stirred at 120° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was partitioned between EA / water. The organic phase was washed with Na 2 SO 4 The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 4 HCO 3 ) to give the title compound (22.5 mg, 7% for two steps) as a white solid. LC-MS: [M+H] + (m / z)=365.0; 1 H NMR (400 MHz, CD 3OD) δ 8.40 (d, J = 5.6 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.88 (dd, J = 8.8, 2.0 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 5.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H). Example 6 4-(3-amino-5-chlorophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0119] Step 1: (E)-1-(3,5-dichlorophenyl)-3-(dimethylamino)prop-2-en-1-one

[0120] A mixture of 1-(3,5-dichlorophenyl)ethan-1-one (2.0 g, 10.58 mmol, 1.0 eq) and DMF-DMA (30.0 mL) was stirred at 100° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was concentrated to dryness and used directly in the next step. LC-MS: [M+H] + (m / z)=244.1.

[0121] Step 2: 4-(3,5-dichlorophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0122] (E)-1-(3,5-dichlorophenyl)-3-(dimethylamino)prop-2-en-1-one (300 mg, 1.23 mmol, 1.0 eq), 1-(4-(trifluoromethyl)phenyl)guanidine (274 mg, 1.84 mmol, 1.5 eq) and K in DMF (5.0 mL). 2 CO 3(424 mg, 3.07 mmol, 2.5 eq) was stirred at 120° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was partitioned between EA / water. The organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness. The residue was purified by silica gel flash chromatography (PE / EA=6:1) to give the title compound (310 mg, 66% for two steps) as a white solid. LC-MS: [M+H] + (m / z)=384.0.

[0123] Step 3: 4-(3-amino-5-chlorophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine.

[0124] 4-(3,5-dichlorophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (100 mg, 0.26 mmol, 1.0 eq), CuI (50 mg, 0.26 mmol, 1.0 eq), L-proline (48 mg, 0.42 mmol, 1.6 eq) and NaN in DMSO (3.0 mL). 3 (43 mg, 0.65 mmol, 2.5 eq) was stirred at 135° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was partitioned between EA / water. The organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness. The residue was purified by silica gel flash chromatography (PE / EA=2:1) ​​to give the title compound (39 mg, 41%) as a white solid. LC-MS: [M+H] + (m / z)=365.3; 1 H NMR (400 MHz, CD 3 OD) δ 8.51 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.39-7.35 (m, 2H), 7.26 (d, J = 5.2 Hz, 1H), 6.83-6.82 (m, 1H). Example 7 4-Amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid [ka]

[0125] Step 1: Methyl 2-(1-butoxyvinyl)-4-nitrobenzoate

[0126] A solution of methyl 2-bromo-4-nitrobenzoate (2.0 g, 7.7 mmol, 1.0 eq) in MeCN (5.0 mL) was treated with 1-(vinyloxy)butane (3.85 g, 38.5 mmol, 5.0 eq), TEA (0.932 g, 9.2 mmol, 1.2 eq), PPh 3 (302 mg, 1.15 mmol, 0.15 eq) and Pd(OAc) 2 (129 mg, 0.58 mmol, 0.075 eq) was added. The resulting reaction mixture was heated to 100° C. and stirred for 16 h. The reaction suspension was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (eluent: PE / EA=100:1) to give the title compound (1.7 g, 79%) as a yellow oil. LC-MS: [MH] - (m / z)=278.

[0127] Step 2: Methyl 2-acetyl-4-nitrobenzoate

[0128] To a solution of methyl 2-(1-butoxyvinyl)-4-nitrobenzoate (1.7 g, 6.1 mmol, 1.0 eq) in THF (10 mL) was added 1N aqueous HCl (5.0 mL). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (30 mL). The mixture was extracted with EA (3×30 mL). The combined organic layers were concentrated and the residue was purified by flash chromatography on silica gel (eluent: PE / EA=10:1) to give the title compound (1.0 g, 73%) as a yellow oil. LC-MS: [M+H] + (m / z)=224.

[0129] Step 3: Methyl (E)-2-(3-(dimethylamino)acryloyl)-4-nitrobenzoate

[0130] A solution of methyl 2-acetyl-4-nitrobenzoate (1.0 g, 3.6 mmol, 1.0 eq) and DMF-DMA (2.1 mL, 7N, 14.4 mmol, 4.0 eq) in toluene (10 mL) was heated to 100° C. and stirred for 16 h. The reaction mixture was cooled to room temperature, concentrated and purified by flash chromatography on silica gel (eluent: PE / EA=3:1 to 0:1) to give the title compound (1.0 g, 99%) as a yellow oil. LC-MS: [M+H] + (m / z)=279.

[0131] Step 4: Methyl 4-nitro-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate

[0132] A solution of methyl (E)-2-(3-(dimethylamino)acryloyl)-4-nitrobenzoate (200 mg, 0.72 mmol, 1.0 eq) in DMF (10 mL) was diluted with 1-(4-(trifluoromethyl)phenyl)guanidine (161 mg, 0.79 mmol, 1.1 eq) and K 2 CO 3 (238 mg, 1.73 mmol, 2.4 eq) was added. The reaction was heated to 120° C. and stirred under Ar for 16 h. The suspension was cooled to room temperature, filtered and the cake was washed with THF (100 mL). The filtrate was concentrated to give the title compound (300 mg, 100%) as a yellow oil which was used directly in the next step without further purification. LC-MS: [M+H] + (m / z)=419.

[0133] Step 5: 4-Nitro-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid

[0134] To a solution of methyl 4-nitro-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate (300 mg, 0.72 mmol, 1.0 eq) in THF (10 mL) was added 4.0 M aqueous NaOH (5.0 mL). The reaction solution was heated to 70° C. and stirred for 16 h. After cooling to room temperature, the mixture was concentrated and adjusted to pH 1-2 using 4.0 M aqueous HCl. The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were concentrated to give the title compound (250 mg, 86%) as a yellow oil. LC-MS: [M+H] + (m / z)=405.

[0135] Step 6: 4-Amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid

[0136] To a solution of 4-nitro-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid (200 mg, 0.5 mmol, 1.0 eq) in MeOH (5.0 mL) was added Pd / C (100 mg). The mixture was heated at 37° C. for 1 hour at 37° C. for 2 hours at 37° C. for 2 hours at 37° C. 2 The mixture was stirred at room temperature for 16 hours under reduced pressure. The mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (10 mg, 5.4%) as a pale yellow solid. LC-MS: [M+H] + (m / z)=375.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.31 (d, J = 4.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 5.2 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.05 (s, 2H). Example 8 5-Amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid [ka]

[0137] Example 8 was prepared following the procedure for Example 7 by replacing methyl 2-bromo-4-nitrobenzoate in step 1 with methyl 2-bromo-5-nitrobenzoate. The crude product was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (150 mg, 81%) as a pale yellow solid. LC-MS: [M+H] + (m / z)=375.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.88 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.54 (s, 1H), 7.37 (d, J = 5.2 Hz, 1H), 7.35 (s, 1H), 5.60 (br s, 2H). Example 9 5-Amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid [ka]

[0138] Step 1: Methyl 3-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0139] Methyl 2-bromo-3-nitrobenzoate (5 g, 19.22 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.9 g, 23.07 mmol, 1.0 eq), KOAc (5.7 g, 57.68 mmol, 3.0 eq) and Pd(dppf)Cl in dioxane (50 mL). 2 A mixture of (422 mg, 0.58 mmol, 0.03 eq) was stirred at 80° C. under Ar for 16 h. The mixture was partitioned between EA / water. The organic layer was separated, concentrated and purified by flash chromatography on silica gel (eluent: PE:EA=1:0 to 50:1) to give the title compound (3.1 g, 79%).

[0140] Step 2: Methyl 2-(2-chloropyrimidin-4-yl)-3-nitrobenzoate

[0141] Dioxane (30 mL) and H 2 Methyl 3-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.5 g, 4.88 mmol, 1.0 eq), 2,4-dichloropyrimidine (728 mg, 4.88 mmol, 1.0 eq), Na in O (3.0 mL). 2 CO 3 (1.04 g, 9.77 mmol, 2.0 eq) and Pd(dppf)Cl 2 A mixture of (357 mg, 0.49 mmol, 0.1 eq) was stirred at 80° C. under Ar for 16 h. The mixture was partitioned between EA / water. The organic layer was separated, concentrated and purified by flash chromatography on silica gel (eluent: PE:EA=1:0 to 3:1) to give the title compound (462 mg, 33%).

[0142] Step 3: Methyl 3-nitro-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate

[0143] Methyl 2-(2-chloropyrimidin-4-yl)-3-nitrobenzoate (362 mg, 1.23 mmol, 1.0 eq), 4-(trifluoromethyl)aniline (209 mg, 1.29 mmol, 1.05 eq), Cs in dioxane (15 mL). 2 CO 3 (769mg, 2.46mmol, 2.0eq), Pd(OAc) 2 A mixture of (26 mg, 0.12 mmol, 0.1 eq) and Xantphos (68 mg, 0.12 mmol, 0.1 eq) was stirred at 110° C. under Ar for 16 h. The mixture was partitioned between EA / water. The organic layer was separated, concentrated and purified by flash chromatography on silica gel (eluent: PE:EA=1:0 to 3:1) to give the title compound (230 mg, 45%). LC-MS: [M+H] + (m / z)=419.1.

[0144] Step 4: Methyl 3-amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate

[0145] To a solution of methyl 3-nitro-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate (250 mg, 0.6 mmol, 1.0 eq) in MeOH was added Pd / C (100 mg) and the mixture was heated under H 2 The mixture was stirred at room temperature overnight under reduced pressure. The Pd / C was filtered off, and the filtrate was concentrated to give the title compound (130 mg, 56%). LC-MS: [M+H] + (m / z)=389.1.

[0146] Step 5: 5-Amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid

[0147] To a solution of methyl 3-amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate (33 mg, 0.08 mmol, 1.0 eq) in MeOH (5 mL) was added 1N NaOH (2 mL). The mixture was stirred at 50° C. for 16 h. The reaction was monitored by LC-MS. The mixture was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%HCOOH) to give the title compound (7 mg, 22%). LC-MS: [M+H] + (m / z)=375.1; 1 H NMR (400 MHz, CD 3 OD) δ 8.47 (d, J = 5.0 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.23 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 5.1 Hz, 1H). Example 10 2-(4-Amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)acetic acid [ka]

[0148] Example 10 was prepared following the protocol for Example 9 by substituting methyl 2-bromo-3-nitrobenzoate in step 1 with methyl 2-(2-bromo-4-nitrophenyl)acetate. The crude product was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1% formic acid) to give the title compound (19 mg, 32%) as a white solid. LC-MS: [M+H] + (m / z)=389.1; 1 H NMR (400 MHz, CD 3OD) δ 8.50 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 5.2 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.4 Hz, 1H), 3.76 (s, 2H). Example 11 4-Amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenol [ka]

[0149] Step 1: 2-Chloro-4-(2-methoxy-5-nitrophenyl)pyrimidine

[0150] Dioxane / H 2 (2-Methoxy-5-nitrophenyl)boronic acid (240 mg, 1.22 mmol, 1.0 eq), 2,4-dichloropyrimidine (218 mg, 1.46 mmol, 1.2 eq), Na in O (10 mL / 1 mL). 2 CO 3 (258 mg, 2.44 mmol, 2.0 eq) and PdCl 2 A mixture of (dppf) (89 mg, 0.12 mmol, 0.1 eq) was stirred under Ar at 90° C. for 2 h. The reaction was monitored by LC-MS. The residue was dissolved in DCM / H 2 The organic phase was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness. The residue was purified by silica gel flash chromatography (eluent: PE / EA=2:1) ​​to give the title compound (182 mg, 56%) as a yellow solid. LC-MS: [M+H] + (m / z)=266.3.

[0151] Step 2: 4-(2-Methoxy-5-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0152] 2-Chloro-4-(2-methoxy-5-nitrophenyl)pyrimidine (182 mg, 0.68 mmol, 1.0 eq), 4-(trifluoromethyl)aniline (131 mg, 0.81 mmol, 1.2 eq), Pd(OAc) in dioxane (5.0 mL). 2 (30 mg, 0.14 mmol, 0.02 mmol), Xantphos (80 mg, 0.14 mmol, 0.02 mmol) and Cs 2 CO 3 (442 mg, 1.36 mmol, 2.0 eq) was stirred at 105° C. under Ar for 3 h. The mixture was monitored by LC-MS. The reaction mixture was diluted with DCM / H 2 O and the combined organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica gel flash chromatography (eluent: PE / EA=2:1) ​​to give the title compound (169 mg, 63%) as a yellow solid. LC-MS: [M+H] + (m / z)=391.3.

[0153] Step 3: 4-(5-amino-2-methoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0154] A mixture of 4-(2-methoxy-5-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (169 mg, 0.43 mmol, 1.0 eq), Pd / C (20 mg) in MeOH (6.0 mL) / THF (3.0 mL) was reacted with H 2 The mixture was stirred at room temperature for 2 hours under reduced pressure. The mixture was monitored by LC-MS. The residue was filtered and the filtrate was concentrated to give the title compound (138 mg, 89%) as a white solid. LC-MS: [M+H] + (m / z)=361.3.

[0155] Step 4: 4-Amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenol

[0156] A mixture of 4-(5-amino-2-methoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (138 mg, 0.38 mmol, 1.0 eq) and Aliquat®-336 (155 mg, 0.38 mmol, 1.0 eq) in 48% HBr (5.0 mL) was stirred at 105° C. for 16 h. The mixture was monitored by LC-MS. The mixture was analyzed by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 4 HCO 3 ) to give the title compound (55.1 mg, 42%) as a yellow solid. LC-MS: [M+H] + (m / z)=347.2; 1 H NMR (400 MHz, CD 3 OD) δ 8.54 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 5.6 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 6.89 (dd, J = 8.8, 2.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H). Example 12 4-Amino-3-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenol [ka]

[0157] Step 1: 2-Chloro-4-(2-chloro-5-methoxyphenyl)pyrimidine

[0158] Dioxane / H 2(2-Chloro-5-methoxyphenyl)boronic acid (50 mg, 0.27 mmol, 1.0 eq), Pd(dppf)Cl in O (v / v=10:1, 11 mL). 2 (21mg, 0.03mmol, 0.03eq), Na 2 CO 3 A mixture of (57 mg, 0.54 mmol, 2.0 eq) and 2,4-dichloropyrimidine (80 mg, 0.54 mmol, 2.0 eq) was stirred at 100° C. for 16 h. The reaction was monitored by LC-MS. The mixture was diluted with water (10 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by prep-TLC (eluent: PE / EA=3:1) to give the title compound (50 mg, 73.5%) as a yellow oil. LC-MS: [M+H] + (m / z)=255.3.

[0159] Step 2: 4-(2-chloro-5-methoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0160] 2-Chloro-4-(2-chloro-5-methoxyphenyl)pyrimidine (60 mg, 0.24 mmol, 1.0 eq), 4-(trifluoromethyl)aniline (42 mg, 0.29 mmol, 1.1 eq), Pd(OAc) in dioxane (1.0 mL) 2 (6.0 mg, 0.02 mmol, 0.1 eq), Xantphos (14 mg, 0.02 mmol, 0.1 eq) and Cs 2 CO 3 A mixture of (154 mg, 0.47 mmol, 2.0 eq) was stirred at 110° C. under Ar for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: PE / EA=3:1) to give the title compound (48 mg, 53%) as a yellow oil. LC-MS: [M+H] + (m / z)=380.3.

[0161] Step 3: 4-(2-amino-5-methoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0162] NH 3 H 2 4-(2-chloro-5-methoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (40 mg, 0.11 mmol, 1.0 eq), Cu in O and NMP (v / v=1:1, 6.0 mL). 2 A mixture of 2Mg, 0.01mmol, 0.10eq) and 1H2O (2mg, 0.01mmol, 0.10eq) was stirred at 110°C for 72h. The reaction was monitored by LC-MS. The reaction was quenched with ice water (10mL) and the resulting mixture was filtered. The filter cake was washed with water, dried under reduced pressure and purified by silica gel flash chromatography (eluent: PE:EA=20:1 to 5:1) to give the title compound (800.0mg, 55%) as a yellow solid. LC-MS: [M+H] + (m / z)=361.4.

[0163] Step 4: 4-Amino-3-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenol

[0164] HBr(H 2 A solution of 4-(2-amino-5-methoxyphenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (100 mg, 0.28 mmol, 1.0 eq), Aliquat®-336 (33.7 mg, 0.08 mmol, 0.3 eq) in 48% in O (4.0 mL) was stirred at 105° C. for 16 h. The reaction was monitored by LC-MS. The reaction mixture was analyzed by prep-HPLC (mobile phase: MeCN / H 2 O / 0.1% FA) to give the title compound (20.0 mg, 21%) as a white solid. LC-MS: [M+H] + (m / z)=347.1; 1 H NMR (400 MHz, CD 3OD) δ 8.52 (d, J = 5.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 7.17 (dd, J = 8.8, 2.4 Hz, 1H). Example 13 4-(2-amino-5-(methylsulfonyl)phenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0165] Step 1: 2-Chloro-4-(2-fluoro-5-(methylsulfonyl)phenyl)pyrimidine

[0166] Dioxane (5 mL) and 2 drops of H 2 2-(2-fluoro-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (650 mg, 2.17 mmol, 1.0 eq), 2,4-dichloropyrimidine (419 mg, 2.82 mmol, 1.3 eq), Pd(dppf)Cl in O 2 (158.4mg, 0.22mmol, 0.1eq), and Na 2 CO 3 A mixture of (459 mg, 4.33 mmol, 2.0 eq) was stirred at 90° C. under Ar for 16 h. The mixture was filtered. The filtrate was concentrated and purified by silica gel flash chromatography (PE:EA=10:1 to 2:1) to give the title compound (462 mg, 60%) as a yellow oil. LC-MS: [M+H] + (m / z)=287.0.

[0167] Step 2: 4-(2-fluoro-5-(methylsulfonyl)phenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0168] 2-Chloro-4-(2-fluoro-5-(methylsulfonyl)phenyl)pyrimidine (462 mg, 1.62 mmol, 1.0 eq), 4-(trifluoromethyl)aniline (287 mg, 1.78 mmol, 1.1 eq), Pd(OAc) in dioxane (10 mL). 2 (73 mg, 0.32 mmol, 0.2 eq) and Cs 2 CO 3 A mixture of (1.05 g, 3.24 mmol, 2.0 eq) was stirred at 90° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel flash chromatography (PE:EA=100:1 to 1:1) to give the title compound (134 mg, 20%) as a yellow oil. LC-MS: [M+H] + (m / z)=412.0.

[0169] Step 3: 4-(2-amino-5-(methylsulfonyl)phenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0170] A solution of 4-(2-fluoro-5-(methylsulfonyl)phenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (134 mg, 0.33 mmol, 1.0 eq) in NMP (1 mL) was added to Cu 2 O (50 mg) and NH 3 H 2 O (4 mL) was added at room temperature. The resulting mixture was stirred at 90° C. for 16 h. The mixture was diluted with water and extracted with EA. The combined organic phase was washed with brine and added with Na 2 SO 4 The residue was purified by prep-HPLC (MeCN / H 2 O / 0.1%HCOOH) to give the title compound (8.8 mg, 6.6%) and 7.02 mg of a by-product. LC-MS: [M+H] + (m / z)=409.0; 1 H NMR (400 MHz, CD 3OD) δ 8.66 (d, J = 5.6 Hz, 1H), 8.55 (d, J = 2.4 Hz, 1H), 7.96 - 7.86 (m, 3H), 7.62 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 5.2 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 3.15 (s, 3H). By-product: LC-MS: [M+H] + (m / z)=410.0; 1 H NMR (400 MHz, CDCl 3 ) δ 13.80 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 8.8, 2.0 Hz, 1H), 7.67 (s, 4H), 7.40 (d, J = 5.6 Hz, 1H), 7.33 (s, 1H), 7.16 (d, J = 8.8 Hz, 1H), 3.09 (s, 3H). Example 14 4-(5-amino-2-(methylsulfonyl)phenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0171] Step 1: 2-Chloro-4-(2-fluoro-5-nitrophenyl)pyrimidine

[0172] Dioxane / H 2 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 1.87 mmol, 1.0 eq), 2,4-dichloropyrimidine (363 mg, 2.43 mmol, 1.3 eq), Pd(dppf)Cl in O (10:1, 10 mL). 2 (68mg, 0.094mmol, 0.05eq) and Na 2 CO 3A mixture of (397 mg, 3.74 mmol, 2.0 eq) was stirred at 90° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: PE / EA=50:1 to 10:1) to give the title compound (300 mg, 67%) as a yellow solid. LC-MS: [M+H] + (m / z)=254.

[0173] Step 2: 4-(2-fluoro-5-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0174] 2-Chloro-4-(2-fluoro-5-nitrophenyl)pyrimidine (300 mg, 1.18 mmol, 1.0 eq), 4-(trifluoromethyl)aniline (229 mg, 1.42 mmol, 1.2 eq), Pd(OAc) in dioxane (10 mL) 2 (13mg, 0.06mmol, 0.05eq), Xantphos (68mg, 0.12mmol, 0.1eq) and Cs 2 CO 3 A mixture of (771 mg, 2.37 mmol, 2.0 eq) was stirred at 100° C. under Ar for 0.5 h. The reaction was monitored by LC-MS. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: PE / EA=100:1 to 10:1) to give the crude product, which was further purified by trituration (PE) to give the title compound (30 mg, 7%) as a yellow solid. LC-MS: [M+H] + (m / z)=379.1.

[0175] Step 3: 4-(2-(methylsulfonyl)-5-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0176] 4-(2-fluoro-5-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (30 mg, 0.08 mmol, 1.0 eq) and MeSO in DMA (10 mL).2 A mixture of Na (40.5 mg, 0.40 mmol, 5.0 eq) was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The mixture was diluted with water and EtOAc. The organic layer was separated, washed with brine and added Na 2 SO 4 and concentrated to give the title compound (35 mg, 100%) as a yellow solid. LC-MS: [M+H] + (m / z)=439.

[0177] Step 4: 4-(5-amino-2-(methylsulfonyl)phenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0178] A solution of 4-(2-(methylsulfonyl)-5-nitrophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (35 mg, 0.08 mmol, 1.0 eq) and SnCl in EtOH (5.0 mL). 2 2H 2 A mixture of 2H2O (90 mg, 0.40 mmol, 5.0 eq) was stirred at 80° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was worked up, concentrated and the residue was purified by prep-TLC (PE / EA=1:1) to give the title compound (23.57 mg, 72%) as a yellow solid. LC-MS: [M+H] + (m / z)=409.1; 1 H NMR (400 MHz, CD 3 OD) δ 8.52 (d, J = 4.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 5.2 Hz, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 3.25 (s, 3H). Example 15 4-(2-aminophenyl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0179] Example 15 was prepared following the procedure for Example 3 by substituting 3-(trifluoromethyl)aniline for 4-(trifluoromethyl)aniline in step 2. The crude product was purified by prep-HPLC (CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (26 mg, 57%) as a yellow solid. LC-MS: [M+H] + (m / z)=331.2; 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 5.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.01 (br s, 2H), 6.81 (dd, J = 8.4, 0.8 Hz, 1H), 6.60 (t, J = 8.0 Hz, 1H). Example 16 4-(3-aminophenyl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine [ka]

[0180] Example 16 was prepared following the procedure for Example 2 by substituting 3-(trifluoromethyl)aniline for 4-(trifluoromethyl)aniline in step 2. The crude product was purified by prep-HPLC (mobile phase: CH 3 CN / H 2O / 0.1%HCOOH) to give the title compound (87 mg, 31.7%) as a yellow solid. LC-MS: [M+H] + (m / z)=331.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.36 (s, 1H), 8.11-8.00 (m, 1H), 7.67 (br s, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.42-7.37 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H). Example 17 4-((4-(2-aminophenyl)pyrimidin-2-yl)amino)benzoic acid [ka]

[0181] Example 17 was prepared following the procedure for Example 3 by substituting methyl 4-aminobenzoate for 4-(trifluoromethyl)aniline in step 2, followed by conversion of the ester to the acid using NaOH. The crude product was purified by prep-HPLC (CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (11 mg, 11%) as a yellow solid. LC-MS: [M+H] + (m / z)=307.2; 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.74-7.69 (m, 3H), 7.29 (d, J = 5.6 Hz, 1H), 7.16-7.14 (m, 1H), 7.03 (br s, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.59 (t, J = 7.6 Hz, 1H). Example 18 4-((4-(3-aminophenyl)pyrimidin-2-yl)amino)benzoic acid [ka]

[0182] Example 18 was prepared following the procedure for Example 2 by substituting methyl 4-aminobenzoate for 4-(trifluoromethyl)aniline in step 2, followed by hydrolysis of the ester to the acid using NaOH. The mixture was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (33 mg, 34%) as a yellow solid. LC-MS: [M+H] + (m / z)=307.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.51 (d, J = 5.2, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.36 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.73 (dd, J = 7.6, 1.6 Hz, 1H), 5.31 (br s, 2H). Example 19 3-((4-(2-aminophenyl)pyrimidin-2-yl)amino)benzoic acid [ka]

[0183] Example 19 was prepared following the procedure for Example 3 by substituting methyl 3-aminobenzoate for 4-(trifluoromethyl)aniline in step 2, followed by conversion of the ester to the acid using NaOH. The crude product was purified by prep-HPLC (CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (10 mg, 10%) as a yellow solid. LC-MS: [M+H] + (m / z)=307.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.56-9.59 (m, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.04-7.99 (m, 1H), 7.81-7.78 (m, 1H), 7.70 (d, J = 6.8 Hz, 1H), 7.46 (m, 1H), 7.21-7.11 (m, 3H), 7.04 (br s, 2H) 6.78 (d, J = 8.0 Hz, 1H), 6.57 (t, J = 7.6 Hz, 1H). Example 20 3-((4-(3-aminophenyl)pyrimidin-2-yl)amino)benzoic acid [ka]

[0184] Example 20 was prepared following the procedure for Example 2 by substituting methyl 3-aminobenzoate for 4-(trifluoromethyl)aniline in step 2, followed by conversion of the ester to the acid using NaOH. The mixture was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (58 mg, 30.3%) as a yellow solid. LC-MS: [M+H] + (m / z)=307.1; 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.80 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 7.76 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.29-7.21 (m, 3H), 7.15 (t, J = 7.6 Hz, 1H), 6.72 (dd, J = 8.0, 1.6 Hz, 1H), 5.35 (br s, 2H). Example 21 N 1 -(4-(3-chlorophenyl)pyrimidin-2-yl)-4-(trifluoromethyl)benzene-1,2-diamine [ka]

[0185] Step 1: 2-Chloro-4-(3-chlorophenyl)pyrimidine

[0186] Dioxane / H 2 (3-Chlorophenyl)boronic acid (1.0 g, 6.4 mmol, 1.0 eq), 2,4-dichloropyrimidine (0.95 g, 6.4 mmol, 1.0 eq), Na in O (20 mL / 2.0 mL). 2 CO 3 (1.36g, 12.8mmol, 2.0eq) and PdCl 2 A mixture of (dppf)·DCM (522 mg, 0.64 mmol, 0.1 eq) was stirred under Ar at 90 °C for 16 h. The reaction was monitored by LC-MS. The mixture was diluted with DCM / H 2 Dilute with O, separate the organic phase, and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica gel flash chromatography (eluent: PE / EA=10:1) to give the title compound (1.11 g, 78%) as a white solid. LC-MS: [M+H] + (m / z)=225.1.

[0187] Step 2: 4-(3-chlorophenyl)-N-(2-nitro-4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0188] 2-Chloro-4-(3-chlorophenyl)pyrimidine (100 mg, 0.485 mmol, 1.0 eq), 2-nitro-4-(trifluoromethyl)aniline (109 mg, 0.49 mmol, 1.0 eq), Pd(OAc) in dioxane (3.0 mL) 2 (22 mg, 0.10 mmol, 0.2 eq), Xantphos (56 mg, 0.10 mmol, 0.2 eq) and Cs 2 CO 3 A mixture of (315 mg, 0.97 mmol, 2.0 eq) was stirred at 105° C. under Ar for 2 h. The mixture was monitored by LC-MS. The mixture was partitioned between DCM / water. The organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness. The residue was purified by prep-TLC (eluent: PE / EA=8:1) to give the title compound (91 mg, 47%) as a yellow solid. LC-MS: [MH] - (m / z)=393.1.

[0189] Step 3: N 1 -(4-(3-chlorophenyl)pyrimidin-2-yl)-4-(trifluoromethyl)benzene-1,2-diamine

[0190] MeOH / NH 4 A mixture of 4-(3-chlorophenyl)-N-(2-nitro-4-(trifluoromethyl)phenyl)pyrimidin-2-amine (80 mg, 0.2 mmol, 1.0 eq), Zn (65 mg, 1.0 mmol, 5.0 eq) in Cl (6.0 mL / 2.0 mL) was stirred at room temperature under Ar for 2 h. The reaction was monitored by LC-MS. The mixture was analyzed by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) and freeze-dried to give the title compound (26.28 mg, 35%) as a white solid. LC-MS: [M+H]+ (m / z)=365.3; 1 H NMR (400 MHz, CD 3 OD) δ 8.43 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 8.03-8.01 (m, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 7.32 (d, J = 5.2 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H). Example 22 N 1 -(4-(3-chlorophenyl)pyrimidin-2-yl)-4-(trifluoromethyl)benzene-1,3-diamine [ka]

[0191] Example 22 was prepared following the protocol for Example 21 by substituting 3-nitro-4-(trifluoromethyl)aniline for 2-nitro-4-(trifluoromethyl)aniline in step 2. The crude product was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (66.09 mg, 66%) as a white solid. LC-MS: [M+H] + (m / z)=365.3; 1 H NMR (400 MHz, CD 3 OD) δ 8.52 (d, J = 5.2 Hz, 1H), 8.20 (s, 1H), 8.09-8.06 (m, 1H), 7.51-7.50 (m, 2H), 7.41 (s, 1H), 7.35 (d, J = 5.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H). Example 23 2-(2-((3-amino-4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid [ka]

[0192] Step 1: Methyl 2-(2-chloropyrimidin-4-yl)benzoate

[0193] Dioxane / H 2 (2-(methoxycarbonyl)phenyl)boronic acid (1.0 g, 5.05 mmol, 1.0 eq), 2,4-dichloropyrimidine (0.83 g, 5.05 mmol, 1.0 eq), Na in O (10 mL / 2 mL). 2 CO 3 (1.18 g, 11.1 mmol, 2.0 eq), and Pd(dppf)Cl 2 (407 mg, 0.6 mmol, 0.1 eq) was stirred at 90° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was diluted with DCM / H 2 The organic phase was diluted with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated to dryness. The residue was purified by silica gel flash chromatography (eluent: PE / EA=5:1) to give the title compound (0.9 g, 66%) as a yellow solid. LC-MS: [M+H] + (m / z)=249.4.

[0194] Step 2: Methyl 2-(2-((3-nitro-4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate

[0195] Methyl 2-(2-chloropyrimidin-4-yl)benzoate (500 mg, 2.01 mmol, 1.0 eq), 3-nitro-4-(trifluoromethyl)aniline (435 mg, 2.11 mmol, 1.05 eq), Pd(OAc) in dioxane (20 mL). 2 (91 mg, 0.40 mmol, 0.2 mmol), Xantphos (116 mg, 0.20 mmol, 0.1 mmol) and Cs2 CO 3 A mixture of (1.31 g, 4.02 mmol, 2.0 eq) was stirred at 110° C. under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was partitioned between DCM / water. The organic phase was separated and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica gel flash chromatography (eluent: PE / EA=3:1) to give the title compound (0.7 g, 83%) as a yellow solid. LC-MS: [M+H] + (m / z)=419.0.

[0196] Step 3: Methyl 2-(2-((3-amino-4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate

[0197] A mixture of methyl 2-(2-((3-nitro-4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate (50 mg, 0.12 mmol, 1.0 eq) and Pd / C (50 mg) in MeOH (5 mL) was heated at 37° C. for 1 hour at 4° C. for 2 hours at 4° C. for 1 hour at 4° C. 2 The mixture was stirred at room temperature for 3 hours under reduced pressure. The reaction was monitored by LC-MS. The mixture was filtered, and the filtrate was purified by silica gel flash chromatography (eluent: PE / EA=3:1) to give the title compound (30 mg, 65%) as a yellow solid. LC-MS: [M+H] + (m / z)=389.4.

[0198] Step 4: 2-(2-((3-amino-4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid

[0199] MeOH / H 2A mixture of methyl 2-(2-((3-amino-4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate (100 mg, 0.26 mmol, 1.0 eq) and NaOH (52 mg, 1.29 mmol, 5.0 eq) in 2H2O (5.5 mL, v / v=10:1) was stirred at 50 °C for 16 h. The reaction was monitored by LC-MS. MeOH was then evaporated. The aqueous layer was adjusted to pH 7 with 1.0 M aqueous HCl. The mixture was analyzed by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (50.3 mg, 32%) as a white solid. LC-MS: [M+H] + (m / z)=375.1; 1 H NMR (400 MHz, CD 3 OD) δ 8.48 (d, J = 5.2 Hz, 1H), 7.78-7.75 (m, 1H), 7.65-7.51 (m, 4H), 7.24 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 6.88 (d, J = 8.0Hz, 1H); 19 F NMR (400 MHz, CD 3 OD) δ -62.84. Example 24 3-(2-((3-amino-4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid [ka]

[0200] Example 24 was prepared following the procedure for Example 23 by substituting (3-(ethoxycarbonyl)phenyl)boronic acid for (2-(methoxycarbonyl)phenyl)boronic acid in step 1. The mixture was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 20) to give the title compound (68.3 mg, 60%) as a white solid. LC-MS: [M+H] + (m / z)=375.1; 1 H NMR (400 MHz, CD 3 OD) δ 8.94 (t, J = 1.6 Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.60 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 9.6 Hz, 1H). Example 25 2-(2-((4-aminophenyl)amino)pyrimidin-4-yl)phenol [ka]

[0201] Step 1: 2-(2-chloropyrimidin-4-yl)phenol

[0202] Dioxane / H 2 (2-Hydroxyphenyl)boronic acid (2.0 g, 14.5 mmol, 1.0 eq), 2,4-dichloropyrimidine (2.16 g, 14.5 mmol, 1.0 eq), Pd(dppf)Cl in O (25 mL / 2.5 mL). 2 (1.03mg, 1.45mmol, 0.1eq) and Na 2 CO 3 A mixture of (3.08 g, 29.0 mmol, 2.0 eq) was stirred at 90° C. under Ar overnight. The reaction was monitored by LCMS. The mixture was filtered, and the filtrate was concentrated and purified by silica gel flash chromatography (PE:EA=5:1) to give the title compound (800 mg, 27%) as a yellow solid. LC-MS: [M+H] + (m / z)=207.1.

[0203] Step 2: 2-(2-((4-aminophenyl)amino)pyrimidin-4-yl)phenol

[0204] 2-(2-chloropyrimidin-4-yl)phenol (150 mg, 0.73 mmol, 1.0 eq), benzene-1,4-diamine (78 mg, 0.73 mmol, 1.0 eq), Pd(OAc) in dioxane (2 mL) 2 (17 mg, 0.07 mmol, 0.1 eq), Xantphos (42 mg, 0.07 mmol, 0.1 eq) and Cs 2 CO 3 A mixture of (466 mg, 1.43 mmol, 2.0 eq) was stirred at 110° C. under Ar for 3 h. The reaction was monitored by LCMS. The mixture was filtered and the filtrate was concentrated and purified by prep-HPLC (CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (27.5 mg, 14%) as a yellow solid. LC-MS: [M+H] + (m / z)=279.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 8.0, 1.6 Hz, 1H), 7.37-7.32 (m, 2H), 7.14 (s, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.57 (d, J = 8.8 Hz, 2H), 4.93 (s, 2H). Example 26 2-(2-((3-aminophenyl)amino)pyrimidin-4-yl)phenol [ka]

[0205] Example 26 was prepared following the procedure for Example 25 by replacing benzene-1,4-diamine with benzene-1,3-diamine in step 2. The crude product was purified by prep-HPLC (MeCN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (29.0 mg, 11%) as a white solid. LC-MS: [M+H] + (m / z)=279.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.00 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 5.6 Hz, 1H), 7.40-7.35 (m, 1H), 6.98-6.88 (m, 4H), 6.80 (d, J = 7.6 Hz, 1H), 6.27 (dd, J = 7.6, 1.6 Hz, 1H), 5.04 (s, 2H). Example 27 (E)-2-Hydroxy-5-((3-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0206] At 0°C, THF (2.0 mL) / H 2 To a mixture of 4-(3-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 2, 100 mg, 0.3 mmol, 1.0 eq) and concentrated HCl (0.5 mL) in 20 (6.0 mL) was added H 2 NaNO in O 2 (22 mg, 0.32 mmol, 1.05 eq) was added. The mixture was stirred at 0° C. for 20 min. The resulting solution was added to a pre-cooled solution of 2-hydroxybenzoic acid (50 mg, 0.36 mmol, 1.2 eq) in 10% aqueous NaOH (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3H 2 0) to give the title compound (40.25 mg, 28%) as a yellow solid. LC-MS: [MH] - (m / z)=477.9; 1 H NMR (400 MHz, CD 3 OD) δ 8.67 (s, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.28 (d, J = 7.6 Hz, 1H), 8.04-8.00 (m, 3H), 7.98 (dd, J = 8.8, 2.4 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 5.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H). Example 28 (E)-4-((3-carboxy-4-hydroxyphenyl)diazenyl)-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid [ka]

[0207] Example 28 was prepared following the procedure for Example 27 by substituting 4-(3-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 2) with 4-amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoic acid (Example 7). The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (5.4 mg, 4.6%) as a yellow solid. LC-MS: [MH] - (m / z)=522.1; 1 H NMR (400 MHz, CD 3OD) δ 8.53-8.48 (m, 2H), 8.18 (d, J = 2.0 Hz, 1H), 8.01-7.93 (m, 4H), 7.70 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 5.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H). Example 29 (E)-5-((4-(carboxymethyl)-3-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)-2-hydroxybenzoic acid [ka]

[0208] Step 1: Methyl 2-hydroxy-5-nitrosobenzoate

[0209] To a solution of methyl 5-amino-2-hydroxybenzoate (100 mg, 0.6 mmol, 1.0 eq) in DCM (3 mL), 2 A solution of oxone (405 mg, 0.66 mmol, 1.1 eq) in 2H2O (3 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The organic layer was separated and diluted with Na 2 SO 4 The residue was purified by silica gel flash chromatography (eluent: PE / EA=5:1) to give the title compound (87 mg, 79%) as a green solid. LC-MS: [M+H] + (m / z)=182.0.

[0210] Step 2: Methyl (E)-2-hydroxy-5-((4-(2-methoxy-2-oxoethyl)-3-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoate

[0211] A mixture of methyl 2-(4-amino-2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)acetate (ester precursor in the final step of Example 10, 100 mg, 0.25 mmol, 1.0 eq), methyl 2-hydroxy-5-nitrosobenzoate (60 mg, 0.33 mmol, 1.3 eq) in AcOH (5 mL) was stirred at 55° C. for 16 h. The reaction was monitored by LC-MS. The mixture was filtered and the solid cake was washed with water. The solid was collected and dried under vacuum to give the title compound (105 mg, 74%) as a red solid. LC-MS: [M+H] + (m / z)=566.2.

[0212] Step 3: (E)-5-((4-(carboxymethyl)-3-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)-2-hydroxybenzoic acid

[0213] To a solution of methyl (E)-2-hydroxy-5-((4-(2-methoxy-2-oxoethyl)-3-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoate (105 mg, 0.19 mmol, 1.0 eq) in MeOH (3 mL) / THF (2 mL) was added 4N NaOH (1.0 mL). The mixture was stirred at 50° C. for 2 h. The reaction was monitored by LC-MS. The mixture was analyzed by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (84.5 mg, 83%) as a yellow solid. LC-MS: [MH] - (m / z)=535.9; 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 1.6 Hz, 1H), 7.85-7.75 (m, 2H), 7.67-7.62 (m, 3H), 7.55 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 3.49 (s, 2H). Example 30 (E)-4,4'-(diazene-1,2-diylbis(3,1-phenylene))bis(N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine) [ka]

[0214] Step 1: 4-(3-nitrosophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0215] To a solution of 4-(3-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 2, 300 mg, 0.91 mmol, 1.0 eq) in DCM (30 mL) was added H 2 A solution of oxone (726 mg, 1.18 mmol, 1.3 eq) in O (30 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The residue was purified by silica gel flash chromatography (PE / EA=5:1) to give the title compound (125 mg, 40%) as a yellow solid. LC-MS: [M+H] + (m / z)=345.1.

[0216] Step 2: (E)-4,4'-(diazene-1,2-diylbis(3,1-phenylene))bis(N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine)

[0217] To a solution of 4-(3-nitrosophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (94 mg, 0.27 mmol, 1.0 eq) in AcOH (20 mL) was added 4-(3-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 2, 90 mg, 0.27 mmol, 1.0 eq). The mixture was stirred at room temperature for 16 h. The reaction was monitored by LC-MS. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (11.15 mg, 6%) as a yellow solid. LC-MS: [MH] - (m / z)=654.9; 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 2H), 8.77 (s, 2H), 8.71-8.70 (m, 2H), 8.43 (d, J = 7.6 Hz, 2H), 8.15 (d, J = 7.6 Hz, 2H), 8.09 (d, J = 8.0 Hz, 4H), 7.85 (t, J = 7.6 Hz, 2H), 7.68-7.66 (m, 6H). Example 31 (E)-4,4'-(diazene-1,2-diylbis(2,1-phenylene))bis(N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine) [ka]

[0218] Step 1: 4-(2-nitrosophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine

[0219] To a solution of 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 3, 200 mg, 0.61 mmol, 1.0 eq) in DCM (15.0 mL) was added H 2A solution of oxone (446 mg, 0.73 mmol, 1.2 eq) in O (15.0 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The residue was purified by silica gel flash chromatography (PE / EA=5:1) to give the title compound (140 mg, 67%) as a yellow solid. LC-MS: [M+H] + (m / z)=345.1.

[0220] Step 2: (E)-4,4'-(diazene-1,2-diylbis(2,1-phenylene))bis(N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine)

[0221] To a solution of 4-(2-nitrosophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (140 mg, 0.42 mmol, 1.0 eq) in HOAc (20 mL) was added 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 3, 70 mg, 0.42 mmol, 1.0 eq). The mixture was stirred at room temperature for 16 h. The reaction was monitored by LC-MS. The crude product was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) and freeze-dried to give the title compound (89.6 mg, 33%) as a yellow solid. LC-MS: [MH] - (m / z)=654.9; 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 2H), 8.63 (d, J = 5.2 Hz, 2H), 7.98 (d, J = 8.4 Hz, 4H), 7.93 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.6 Hz, 2H), 7.57 (t, J = 7.2 Hz, 2H), 7.53-7.50 (m, 6H), 7.16 (d, J = 5.2 Hz, 2H). Example 32 (E)-2-Hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0222] Step 1: Methyl 2-hydroxy-5-nitrosobenzoate

[0223] To a solution of methyl 5-amino-2-hydroxybenzoate (100 mg, 0.6 mmol, 1.0 eq) in DCM (10 mL), 2 A solution of oxone (405 mg, 0.66 mmol, 1.1 eq) in 2H2O (10 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The organic layer was separated and diluted with Na 2 SO 4 The residue was purified by silica gel flash chromatography (eluent: PE / EA=5:1) to give the title compound (81 mg, 75%) as a green solid. LC-MS: [M+H] + (m / z)=182.2.

[0224] Step 2: Methyl (E)-2-hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoate

[0225] To a solution of methyl 2-hydroxy-5-nitrosobenzoate (81 mg, 0.45 mmol, 1.3 eq) in HOAc (15 mL) was added 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 3, 100 mg, 0.3 mmol, 1.0 eq). The mixture was stirred at 45° C. for 48 h. The reaction was monitored by LC-MS. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 20) to give the title compound (45 mg, 30%) as a yellow solid. LC-MS: [M+H] + (m / z)=494.0.

[0226] Step 3: (E)-2-Hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid

[0227] To a solution of methyl (E)-2-hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoate (45 mg, 0.1 mmol, 1.0 eq) in MeOH (3.0 mL) was added NaOH (4.0 M, 1.0 mL). The mixture was stirred at 60° C. for 2 h. The reaction was monitored by LC-MS. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (33.7 mg, 78%) as a yellow solid. LC-MS: [MH] - (m / z)=477.9; 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.93 (dd, J = 7.2, 2.0 Hz, 1H), 7.67-7.60 (m, 4H), 7.56 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H). Example 33 (E)-4-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)phenol [ka]

[0228] To a mixture of 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 3, 50 mg, 0.15 mmol, 1.0 eq) in 6 M HCl (3.0 mL) at 0° C., H 2 NaNO in O 2 A solution of (21 mg, 0.3 mmol, 2.0 eq) was added. The mixture was stirred at 0° C. for 30 min. The resulting solution was added to a pre-cooled solution of phenol (14.3 mg, 0.15 mmol, 1.0 eq) in 10% aqueous NaOH (1 mL) at 0° C., and the pH of the mixture was adjusted to 7-8 with 10% aqueous NaOH. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The mixture was extracted with EA. The combined organic layers were washed with Na 2 SO 4 The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (7.5 mg, 11%) as a yellow solid. LC-MS: [M+H] + (m / z)=436.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.94-7.91 (m, 1H), 7.68 (dd, J = 17.5, 6.0 Hz, 5H), 7.53 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 4.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H). Example 34 (E)-3-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0229] Example 34 was prepared following the procedure for Example 32 by substituting methyl 3-aminobenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The crude product was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (58.7 mg, 60%) as a yellow solid. LC-MS: [M+H] + (m / z)=464.0; 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.30 (s, 1H), 8.02-7.98 (m, 4H), 7.74-7.69 (m, 4H), 7.55 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H). Example 35 (E)-4-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0230] Example 35 was prepared following the procedure for Example 32 by substituting methyl 4-aminobenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The crude product was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1% FA) to give the title compound (58 mg, 28%) as a yellow solid. LC-MS: [M+H] + (m / z)=464.1; 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.99-7.92 (m, 3H), 7.86 (d, J = 8.8 Hz, 2H), 7.81-7.69 (m, 3H), 7.49 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 5.2 Hz, 1H). Example 36 (E)-4-Hydroxy-3-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0231] Example 36 was prepared following the procedure for Example 32 by substituting methyl 3-amino-4-hydroxybenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The crude product was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (79.4 mg, 77%) as a yellow solid. LC-MS: [M+H] + (m / z)=480.0; 1 H NMR (400 MHz, CD 3 OD) δ 8.60 (d, J = 5.2 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 7.99-7.97 (m, 1H), 7.93 (dd, J = 8.8, 2.0 Hz, 1H), 7.89-7.83 (m, 3H), 7.71-7.67 (m, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 5.2 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H). Example 37 (E)-2-Hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)isophthalic acid [ka]

[0232] Example 37 was prepared following the procedure for Example 33 by replacing phenol with dimethyl 2-hydroxyisophthalate followed by hydrolysis with NaOH. The crude product was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (40.31 mg, 51%) as a yellow solid. LC-MS: [M+H] + (m / z)=524.2; 1 H NMR (400 MHz, CD 3 OD) δ 8.54 (s, 2H), 8.52 (d, J = 5.2 Hz, 1H), 7.98-7.96 (m, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.73-7.71 (m, 1H), 7.63-7.59 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 5.2 Hz, 1H). Example 38 (E)-5-Hydroxy-2-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0233] Example 38 was prepared following the procedure for Example 32 by substituting methyl 2-amino-5-hydroxybenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The residue was purified by prep-HPLC (mobile phase: CH 3CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (28.56 mg, 19%) as a yellow solid. LC-MS: [M+H] + (m / z)=480.2; 1 H NMR (400 MHz, CD 3 OD) δ 8.52 (d, J = 5.2 Hz, 1H), 7.98-7.95 (m, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.69-7.61 (m, 3H), 7.53 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 5.2 Hz, 1H), 6.88 (dd, J = 5.2, 2.8 Hz, 1H). Example 39 (E)-2-Hydroxy-4-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0234] Example 39 was prepared following the procedure for Example 32 by substituting methyl 4-amino-2-hydroxybenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (23.4 mg, 31%) as a yellow solid. LC-MS: [M+H] + (m / z)=480.1; 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.02-7.93 (m, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.72-7.67 (m, 3H), 7.57 (d, J = 8.8 Hz, 2H), 7.10-7.06 (m, 2H), 6.98 (d, J = 2.0 Hz, 1H). Example 40 (E)-3-Hydroxy-4-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0235] Example 40 was prepared following the procedure for Example 32 by substituting methyl 4-amino-3-hydroxybenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (33 mg, 43%) as a yellow solid. LC-MS: [M+H] + (m / z)=480.2; 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 7.98-7.92 (m, 3H), 7.91-7.86 (m, 1H), 7.77-7.69 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.53-7.47 (m, 3H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H). Example 41 (E)-4-Methoxy-3-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0236] Example 41 was prepared following the procedure for Example 32 by substituting methyl 3-amino-4-methoxybenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (21.4 mg, 36%) as a yellow solid. LC-MS: [M+H] + (m / z)=494.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.01 (dd, J = 8.4, 2.0 Hz, 1H), 7.97-7.93 (m, 3H), 7.88 (d, J = 2.0 Hz, 1H), 7.71-7.66 (m, 2H), 7.59-7.56 (m, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 4.8 Hz, 1H), 3.99 (s, 3H). Example 42 (E)-2-Methoxy-4-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0237] Example 42 was prepared following the procedure for Example 32 by substituting methyl 4-amino-2-methoxybenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (27.5 mg, 33%) as a yellow solid. LC-MS: [M+H] + (m / z)=494.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.64 (d, J = 4.8 Hz, 1H), 8.01-7.96 (m, 3H), 7.81-7.70 (m, 4H), 7.55 (d, J = 8.8 Hz, 2H), 7.50-7.35 (m, 2H), 7.17 (d, J = 4.8 Hz, 1H), 3.80 (s, 3H). Example 43 (E)-2-Methoxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0238] Example 43 was prepared following the procedure for Example 32 by substituting methyl 5-amino-2-hydroxybenzoate in step 1 with methyl 5-amino-2-methoxybenzoate. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (127.8 mg, 32%) as a yellow solid. LC-MS: [M+H] + (m / z)=494.0; 1 H NMR (400 MHz, DMSO-d 6) δ 10.20 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.96-7.92 (m, 1H), 7.68-7.57 (m, 7H), 7.04-7.01 (m, 2H), 3.78 (s, 3H). Example 44 (E)-4-(trifluoromethoxy)-3-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0239] Example 44 was prepared following the procedure for Example 32 by replacing methyl 5-amino-2-hydroxybenzoate with methyl 3-amino-4-(trifluoromethoxy)benzoate in step 1. The mixture was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (108 mg, 65%) as a yellow solid. LC-MS: [M+H] + (m / z)=548.2; 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.10 (dd, J = 8.4, 2.0 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 7.6, 2.0 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.79-7.72 (m, 2H), 7.64-7.62 (m, 1H), 7.55-7.47 (m, 1H), 7.49 (d, J = 8.0 H, 2H), 7.11 (d, J = 4.8 Hz, 1H). Example 45 (E)-4-Ethoxy-3-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0240] Example 45 was prepared following the procedure for Example 32 by substituting methyl 3-amino-4-ethoxybenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The mixture was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (46.7 mg, 48%) as a yellow solid. LC-MS: [M+H] + (m / z)=508.2; 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.02 (dd, J = 8.8, 2.4 Hz, 1H), 7.96-7.85 (m, 4H), 7.71 (dt, J = 11.2, 3.7 Hz, 2H), 7.64-7.58 (m, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 4.35 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 6.8 Hz, 3H). Example 46 (E)-2-Hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzonitrile [ka]

[0241] Example 46 was prepared following the procedure for Example 33 by replacing phenol with 2-hydroxybenzonitrile. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (69.5 mg, 50%) as a yellow solid. LC-MS: [M+H] + (m / z)=461.0; 1 H NMR (400 MHz, CD 3 OD) δ 8.53 (d, J = 5.2 Hz, 1H), 7.97-7.93 (m, 2H), 7.89-7.85 (m, 3H), 7.72-7.70 (m, 1H), 7.65-7.62 (m, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 4.8 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H). Example 47 (E)-(2-hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)phenyl)phosphonic acid [ka]

[0242] Step 1: Diethyl Phenyl Phosphate

[0243] At 0°C, CCl 4 A mixture of phenol (1.0 g, 10.64 mmol, 1.0 eq) and TEA (1.55 mL, 11.17 mmol, 1.05 eq) in 10 mL of HP(O)(OEt) under Ar was 2 (17 mg, 0.14 mmol, 1.2 eq) was added. The mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated and purified by silica gel flash chromatography (eluent: PE:EA=100:1 to 5:1) to give the title compound (1.8 g, 74%). LC-MS: [M+H] + (m / z)=231.1.

[0244] Step 2: Diethyl (2-hydroxyphenyl)phosphonate

[0245] Diethylphenylphosphate (0.5 g, 2.2 mmol, 1.0 eq) in THF was added to LDA (1.1 mL, 2.2 mmol, 1.0 eq) under Ar at −78° C. The resulting mixture was stirred at −78° C. for 1 h and then at 0° C. for 5 h. The reaction was monitored by LC-MS. The reaction was diluted with saturated NH 4 Quench with Cl and Et 2 The organic phase was extracted with Na 2 SO 4 Drying at 40° C., filtration and concentration afforded the title compound (468 mg, 94%) as a yellow solid. LC-MS: M+H] + (m / z)=231.1.

[0246] Step 3: Diethyl (E)-(2-hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)phenyl)phosphonate

[0247] To a solution of 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (100 mg, 0.3 mmol, 1.0 eq) in 6 M HCl (4 mL) at 0 °C, H 2 NaNO in O (7 mL) 2 (42 mg, 0.61 mmol, 2.0 eq) was added. The mixture was stirred at 0° C. for 0.5 h, then a solution of diethyl (2-hydroxyphenyl)phosphonate in 2N NaOH (14 mL) was added. The pH was adjusted to 8 with 2N NaOH, and the resulting mixture was stirred at 0° C. for 1 h. The mixture was adjusted to pH 7, then filtered. The filter cake was dried under vacuum to give the title compound (60 mg, 35%) as a yellow solid. LC-MS: [M+H] + (m / z)=572.2.

[0248] Step 4: (E)-(2-hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)phenyl)phosphonic acid

[0249] To a solution of diethyl (E)-(2-hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)phenyl)phosphonate (60 mg, 0.10 mmol, 1.0 eq) in DCM (3 mL) was added TMSBr (3 mL). The mixture was stirred at 35° C. under Ar for 2 h. The reaction was monitored by LC-MS. The reaction solution was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the title compound (22.3 mg, 43%) as a yellow powder. LC-MS: [MH] - (m / z)=514.2; 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.97-7.91 (m, 2H), 7.68-7.57 (m, 6H), 7.09 (s, 3H), 7.02 (d, J = 5.2 Hz, 1H), 6.73 (dd, J = 8.8, 4.8 Hz, 1H). Example 48 (E)-2-(Methylsulfonyl)-4-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)phenol [ka]

[0250] Example 48 was prepared following the procedure for Example 33 by substituting 2-(methylsulfonyl)phenol for phenol. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 20) to give the title compound (47.1 mg, 30%) as a yellow solid. LC-MS: [M+H] + (m / z)=514.1; 1 H NMR (400 MHz, CD 3 OD) δ 8.56 (d, J = 5.2 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 8.03-7.97 (m, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.79-7.77 (m, 1H), 7.68-7.65 (m, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 5.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 3.22 (m, 3H). Example 49 (R,E)-2-amino-3-(2-hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)phenyl)propanoic acid [ka]

[0251] Example 49 was prepared following the procedure for Example 33 by replacing phenol with methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-hydroxyphenyl)propanoate, followed by hydrolysis and deprotection of the Boc group. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (10.78 mg, 33%) as a yellow solid. LC-MS: [M+H] + (m / z)=523.2; 1 H NMR (400 MHz, CD 3OD) δ 8.52 (d, J = 4.8 Hz, 1H), 7.98-7.95 (m, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 2.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.62-7.59 (m, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.90 (dd, J = 8.8, 4.4 Hz, 1H), 3.41 (dd, J = 14.4, 4.4 Hz, 1H), 2.99 (dd, J = 14.4, 8.4 Hz, 1H). Example 50 (E)-2-Hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzenesulfonic acid [ka]

[0252] Example 50 was prepared following the procedure for Example 33 by replacing phenol with 2-hydroxybenzenesulfonic acid. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (8.0 mg, 3%) as a yellow solid. LC-MS: [MH] - (m / z)=514.0; 1 H NMR (400 MHz, CD 3OD) δ 8.59 (d, J = 4.8 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.04-8.01 (m, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.87-7.85 (m, 1H), 7.78 (dd, J = 8.4, 2.4 Hz, 1H), 7.71-7.67 (m, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 5.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H). Example 51 (E)-5-Hydroxy-2-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzenesulfonic acid [ka]

[0253] Example 51 was prepared following the procedure for Example 33 by replacing phenol with 3-hydroxybenzenesulfonic acid. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (29.95 mg, 10%) as a yellow solid. LC-MS: [M+H] + (m / z)=516.0; 1 H NMR (400 MHz, CD 3 OD) δ 8.49 (d, J = 5.2 Hz, 1H), 8.00-7.92 (m, 4H), 7.61-7.52 (m, 5H), 7.45 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 5.2 Hz, 1H), 6.81 (dd, J = 8.8, 2.8 Hz, 1H). Example 52 (E)-2-Amino-3-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0254] Example 52 was prepared according to the procedure for Example 33 by replacing phenol with methyl 2-aminobenzoate, followed by hydrolysis using NaOH. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (21.1 mg, 55%) as a yellow solid. LC-MS: [M+H] + (m / z)=479.1; 1 H NMR (400 MHz, DMSO-d6) δ 15.63 (s, 1H), 10.12 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.91 (dd, J = 7.6, 1.2 Hz, 1H), 7.78 (dd, J = 7.6, 1.2 Hz, 1H), 7.65-7.50 (m, 6H), 7.40 (td, J = 7.6, 1.2 Hz, 1H), 7.27 (td, J = 7.6, 1.6 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H). Example 53 (E)-5-(Methylamino)-2-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0255] Example 53 was prepared according to the procedure for Example 33 by replacing phenol with methyl 3-(dimethylamino)benzoate, followed by hydrolysis using NaOH. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH3 H 2 0) to give the title compound (29.7 mg, 75%) as a yellow solid. LC-MS: [M+H] + (m / z)=493.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.98 (m, 1H), 7.86 (dd, J = 7.6, 1.2 Hz, 1H), 7.69-7.52 (m, 5H), 7.47 (dd, J = 8.0, 1.6 Hz, 1H), 7.43 (td, J = 7.6, 1.6 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 3.56 (s, 3H). Example 54 (E)-3-Hydroxy-4-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)naphthalene-1-sulfonic acid [ka]

[0256] Example 54 was prepared following the procedure for Example 33 by replacing phenol with 3-hydroxynaphthalene-1-sulfonic acid. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (13.6 mg, 27%) as a yellow solid. LC-MS: [MH] - (m / z)=564.2; 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.76 (d, J = 5.6 Hz, 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.76-7.72 (m, 3H), 7.64 (d, J = 5.6 Hz, 1H), 7.58 (m, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.15 (s, 1H). Example 55 (E)-3-Hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0257] Step 1: Methyl (E)-3-hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoate

[0258] To a solution of 4-(2-nitrosophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 31, Step 1, 80 mg, 0.23 mmol, 1.0 eq) in HOAc (3 mL) was added methyl 3-amino-5-hydroxybenzoate (43 mg, 0.26 mmol, 1.1 eq). The mixture was stirred at 55° C. for 16 h. The reaction was monitored by LC-MS. The mixture was filtered and the solid was washed with water and dried to give the title compound (35 mg, 31%) as a red solid, which was used in the next step without further purification. LC-MS: [M+H] + (m / z)=494.0.

[0259] Step 2: (E)-3-Hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid

[0260] To a solution of methyl (E)-3-hydroxy-5-((2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoate (35 mg, 0.07 mmol, 1.0 eq) in MeOH (5.0 mL) was added NaOH (4.0 M, 2.0 mL). The mixture was stirred at 60° C. for 16 h. The reaction was monitored by LC-MS. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (17.3 mg, 51%) as a yellow solid. LC-MS: [M+H] + (m / z)=480.1; 1 H NMR (400 MHz, CD 3 OD) δ 8.53 (d, J = 5.2 Hz, 1H), 8.02-7.98 (m, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.69-7.63 (m, 2H), 7.54 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.32-7.31 (m, 1H), 7.09 (d, J = 5.2 Hz, 1H). Example 56 (E)-2-Hydroxy-5-((2-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0261] Example 56 was prepared following the procedure for Example 32 by replacing 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 3) with 4-(2-aminophenyl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 15) in step 2. The mixture was concentrated and purified by prep-HPLC (CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound as a yellow solid (24.18 mg, 24%). LC-MS: [MH] - (m / z)=478.3; 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.38 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.94 (dd, J = 7.6, 1.4 Hz, 1H), 7.60-7.70 (m, 4H), 7.46 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H). Example 57 (E)-2-Hydroxy-5-((3-(2-((3-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0262] Example 57 was prepared following the procedure for Example 32 by replacing 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 3) with 4-(3-aminophenyl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine (Example 16) in step 2. The mixture was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (73.73 mg, 25.7%) as a yellow solid. LC-MS: [MH] - (m / z)=478.3; 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.71-8.60 (m, 2H), 8.47 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.88 (dd, J = 8.8, 2.4 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 5.2 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H). Example 58 (E)-5-((5-((4-(3-chlorophenyl)pyrimidin-2-yl)amino)-2-(trifluoromethyl)phenyl)diazenyl)-2-hydroxybenzoic acid [ka]

[0263] N in 6.0 M aqueous HCl (8.0 mL) at 0 °C 1 A solution of -(4-(3-chlorophenyl)pyrimidin-2-yl)-4-(trifluoromethyl)benzene-1,3-diamine (Example 22, 110 mg, 0.28 mmol, 1.0 eq) in water was diluted with NaNO 2A solution of (39 mg, 0.56 mmol, 2.0 eq) was added. The mixture was stirred at 0° C. for 0.5 h, then 2-hydroxybenzoic acid (43 mg, 0.31 mmol, 1.1 eq) in 2.0 M aqueous NaOH was added. The mixture was adjusted to pH ∼8 with 2.0 M aqueous NaOH and then stirred at 0° C. for 1 h. The reaction was monitored by LC-MS. The mixture was adjusted to pH ∼7 with 1.0 M HCl and extracted with EtOAc. The organic layer was concentrated. The residue was purified by prep-HPLC (mobile phase: MeCN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (80.2 mg, 21%) as a yellow solid. LC-MS: [MH] - (m / z)=512.0; 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.70 (d, J = 5.6 Hz, 1H), 8.63 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.25-8.22 (m, 2H), 7.96-7.84 (m, 3H), 7.65-7.61 (m, 3H), 7.05-6.03 (m, 1H). Comparative Example 59: (E)-2-Hydroxy-5-(2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)styryl)benzoic acid [ka]

[0264] Step 1: Methyl 2-(2-chloropyrimidin-4-yl)benzoate

[0265] Dioxane / H 2 (2-(methoxycarbonyl)phenyl)boronic acid (1.5 g, 8.33 mmol, 1.0 eq), 2,4-dichloropyrimidine (1.24 g, 8.33 mmol, 1.0 eq), Pd(dppf)Cl in O (100 mL / 10 mL). 2 (0.61g, 0.83mmol, 0.1eq) and Na 2 CO3 A mixture of (1.77 g, 16.7 mmol, 2.0 eq) was stirred at 90° C. under Ar overnight. The reaction was monitored by LC-MS. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (PE / EA=10:1) to give the title compound (1.4 g, 68%) as a yellow solid. LC-MS: [M+H] + (m / z)=249.0.

[0266] Step 2: Methyl 2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate

[0267] Methyl 2-(2-chloropyrimidin-4-yl)benzoate (1.4 g, 5.65 mmol, 1.0 eq), 4-(trifluoromethyl)aniline (0.95 g, 5.93 mmol, 1.05 eq), Pd(OAc) in dioxane (30 mL). 2 (254 mg, 1.13 mmol, 0.2 eq) and Cs 2 CO 3 A mixture of (3.68 g, 11.3 mmol, 2.0 eq) was stirred at 110° C. under Ar for 2 h. The reaction was monitored by LC-MS. The mixture was filtered, and the filtrate was concentrated and purified by silica gel flash chromatography (PE / EA=1:1) to give the title compound (1.6 g, 76%) as a yellow solid. LC-MS: [M+H] + (m / z)=374.4.

[0268] Step 3: (2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)methanol

[0269] To a solution of methyl 2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzoate (900 mg, 2.41 mmol, 1.0 eq) in DCM (20 mL) at -78°C was added DIBAL-H (11 mL, 10.62 mmol, 4.4 eq). The mixture was stirred under Ar for 2 h. The reaction was monitored by LC-MS. The reaction was quenched with MeOH at -78°C and then warmed to room temperature. The mixture was diluted with saturated Rochelle's salt solution and stirred for 16 h. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=1:1) to give the title compound (400 mg, 48%) as a yellow solid. LC-MS: [M+H] + (m / z)=346.4.

[0270] Step 4: 2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)benzaldehyde

[0271] To a mixture of (2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)phenyl)methanol (100 mg, 0.29 mmol, 1.0 eq) in DCM (15 mL) at 0° C., Dess-Martin periodinane (147 mg, 0.35 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS. The mixture was diluted with NaHCO 3 (aqueous) at 0° C. and extracted with DCM. The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (eluent: PE / EA=4:1) to give the title compound (79 mg, 80%) as a yellow solid. LC-MS: [M+H] + (m / z)=344.4.

[0272] Step 5: Methyl 5-(bromomethyl)-2-methoxybenzoate

[0273] CCl 4 A mixture of methyl 2-methoxy-5-methylbenzoate (2.0 g, 11.11 mmol, 1.0 eq), NBS (2.37 g, 13.33 mmol, 1.2 eq) and BPO (1.61 g, 6.67 mmol, 0.6 eq) in (20 mL) was stirred at 80° C. for 16 h. The reaction was monitored by LC-MS. The mixture was diluted with Na 2 S 2 O 3 (aqueous) at 0° C. and extracted with DCM. The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica gel flash chromatography (eluent: PE / EA=10:1) to give the title compound (2.2 g, 70%) as a white solid. LC-MS: [M+H] + (m / z)=259.3.

[0274] Step 6: Methyl 5-((diethoxyphosphoryl)methyl)-2-methoxybenzoate

[0275] Methyl 5-(bromomethyl)-2-methoxybenzoate (1.23 g, 4.75 mmol, 1.0 eq), Bu 4 A mixture of NI (177 mg, 0.48 mmol, 0.1 eq) and triethyl phosphite (1.2 mL, 6.89 mmol, 1.45 eq) was stirred at 130° C. for 16 h. The reaction was monitored by LC-MS. Triethyl phosphite was removed under reduced pressure to give the title compound (800 mg), which was used in the next step without further purification. LC-MS: [M+H] + (m / z)=317.4.

[0276] Step 7: (E)-2-Methoxy-5-(2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)styryl)benzoic acid

[0277] To a solution of methyl 5-((diethoxyphosphoryl)methyl)-2-methoxybenzoate (28 mg, 0.09 mmol, 1.5 eq) in THF (3 mL) at 0° C., NaH (4 mg, 0.09 mmol, 1.5 eq) was added portionwise under Ar. After 10 min, a solution of methyl 5-((diethoxyphosphoryl)methyl)-2-methoxybenzoate (20 mg, 0.06 mmol, 1.0 eq) in THF (1 mL) was added. The mixture was stirred at room temperature for 16 h. The reaction was monitored by LC-MS. The mixture was diluted with NH 4 The mixture was quenched with Cl(aq) at 0° C. and extracted with DCM. The organic layer was washed with Na 2 SO 4 It was dried at 40° C., concentrated under reduced pressure, and purified by prep-TLC (eluent: DCM / MeOH=20:1) to give the title compound (20 mg, 69%) as a yellow solid. LC-MS: [M+H] + (m / z)=492.6.

[0278] Step 8: (E)-2-Hydroxy-5-(2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)styryl)benzoic acid

[0279] A solution of (E)-2-methoxy-5-(2-(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)styryl)benzoic acid (20 mg, 0.04 mmol, 1.0 eq) and LiCl (34 mg, 0.81 mmol, 20 eq) in DMF (1.0 mL) was stirred at 140° C. for 16 h. The reaction was monitored by LC-MS. The residue was purified by prep-HPLC (mobile phase: CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (11.6 mg, 57%) as a yellow solid. LC-MS: [M+H] + (m / z)=478.1; 1 H NMR (400 MHz, CD 3OD) δ 8.45 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.50 (dd, J = 7.2, 0.8 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30-7.26 (m, 4H), 7.20 (d, J = 16.4 Hz, 1H), 7.03 (d, J = 16.0 Hz, 1H), 6.96 (d, J = 5.2 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H). Example 60 4-(2-aminophenyl)-N-(p-tolyl)pyrimidin-2-amine [ka]

[0280] Example 60 was prepared following the procedure for Example 4 by replacing 4-(trifluoromethyl)aniline with methyl 4-aminobenzoate in step 1 and replacing 1-(5-chloro-2-nitrophenyl)ethan-1-one with 1-(2-nitrophenyl)ethan-1-one in step 2. The crude product was purified by prep-HPLC (CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (26 mg, 28%) as a white solid. LC-MS: [M+H] + (m / z)=277.1; 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 5.6 Hz, 1H), 7.16-7.10 (m, 3H), 6.99 (s, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.58 (t, J = 6.8 Hz, 1H), 2.26 (s, 3H). Example 61 (E)-2-Hydroxy-5-((2-(2-(p-tolylamino)pyrimidin-4-yl)phenyl)diazenyl)benzoic acid [ka]

[0281] Example 61 was prepared following the procedure for Example 32 by substituting methyl 4-aminobenzoate for methyl 5-amino-2-hydroxybenzoate in step 1. The crude product was purified by prep-HPLC (CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (43 mg, 31%) as a yellow solid. LC-MS: [M+H] + (m / z)=426.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.47 (d, J = 4.8 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.91-7.88 (m, 1H), 7.68-7.56 (m, 6H), 7.03 (d, J =8.4 Hz, 2H), 6.92 (d, J = 5.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.60 (s, 1H), 2.23 (s, 3H). Example 62 (E)-5-((2-(2-((4-carboxyphenyl)amino)pyrimidin-4-yl)phenyl)diazenyl)-2-hydroxybenzoic acid [ka]

[0282] Example 62 was prepared following the procedure for Example 32 by replacing 4-(2-aminophenyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine in step 2 with 4-((4-(2-aminophenyl)pyrimidin-2-yl)amino)benzoic acid. The crude product was purified by prep-HPLC (CH 3 CN / H 2 O / 0.1%NH 3 H 2 0) to give the title compound (65 mg, 34%) as a yellow solid. LC-MS: [M+H] + (m / z)=456.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.96-7.83 (m, 5H), 7.70-7.62 (m, 4H), 7.05 (d, J = 5.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H). Biological Data 1: HT29AhR Reporter Assay

[0283] HT29-Lucia AhR cells were purchased from Invivogen (catalog number ht21-ahr). HT29-AhR cells were cultured in growth medium (DMEM, 10% FBS (30 min, 56°C), 100 U / ml penicillin, 100 μg / ml streptomycin, 100 μg / ml Normocin TM and 100μg / ml Zeocin TM ) at 5% CO 2The cells were grown once at 37°C in a 5% CO atmosphere. The cell suspension was removed from the growth medium and gently rinsed with pre-warmed PBS (10 mL). Pre-warmed trypsin (1 mL) was added and the cells were kept at 30°C for approximately 5 minutes and then detached with a pipette. The detached cell clumps were gently pipetted up and down. The cells were resuspended in pre-warmed detection medium (DMEM, 10% FBS (30 minutes, 56°C), 100 U / ml penicillin, 100 μg / ml streptomycin, and test article or vehicle) and counted. A cell suspension of approximately 500,000 cells / mL in detection medium was prepared.

[0284] Cells were plated in 96-well plates at a density of 50,000 cells / well and incubated in 5% CO 2 The samples (20 μL / well) were pipetted into a 96-well white (opaque) plate and incubated at 37°C for 18 to 24 hours. TM (50 μL / well) was added. The plate was gently tapped and then read on a luminometer (read time 0.1 sec). Data was analyzed and EC50 curves and values ​​were generated using GraphPad Prism 6.02 software. %Efficacy=100%*(TA-BG) / (Ref-BG) TA is the luminescent reading of the test article. BG is the background reading of the DMSO vehicle; Ref is the reading of the reference compound VAF347. EC50: concentration to reach half the maximal efficacy of the reference compound (VAF347). [ka] [Table 1] Biological Data 2: Stability in human feces

[0285] Azo compounds are not expected to show AhR agonist activity until digestive bacteria-mediated reduction occurs.Therefore, selected azo compounds of the present invention are exposed to human feces under suitable conditions to promote azo reduction.It is expected that efficient reduction will lead to the delivery of active moiety in digestive tract.

[0286] Human feces from two donors were homogenized in isotonic phosphate buffered saline (pH 6.8) at a ratio of 1:10 (w / v). The tubes were sealed using sealing film. The test article was dissolved in isotonic phosphate buffer (pH 6.8) to form a working solution of 20 μM (if solubility permitted). Aliquots (50 μL) of the working solution were added in duplicate to human fecal homogenate (50 μL) at each time point (0, 1, 2, 4, 6, and 24 hours), placed under nitrogen for approximately 1 minute to evacuate, and then incubated at 37°C. After incubation at each pre-determined time point, 1000 μL of acetonitrile containing an internal standard was added to each tube to quench the reaction. The samples were vortexed and centrifuged at 3700 rpm for 10 minutes, and the supernatant was transferred for analysis (diluted as necessary). The concentrations of the test article and its metabolites (Example 3) in the supernatant were determined using an LC-MS / MS method. Sulfasalazine was used as a positive control. All incubations were performed in duplicate. [Table 2]

[0287] The above detailed description is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not limited in scope by the specific embodiments disclosed herein, which are intended to be illustrative of some aspects of the present invention. Any equivalent embodiments are intended to be within the scope of the present invention. Indeed, various modifications of the present invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description without departing from the spirit or scope of the inventive findings. Such modifications are also intended to fall within the scope of the appended claims.

[0288] All publications, patents, patent applications, and other references cited in this application are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. The citation of a reference herein should not be construed as an admission that it is prior art to the present invention. The present invention provides, for example, the following items. (Item 1) Formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein Z 1 and Z 2 One of them is -NH 2 and -N=N-Ar, Z 1 and Z 2 the other of which is H, Ar is phenyl, naphthyl, and [ka] is selected from Phenyl and naphthyl are -OR, COOR, and C1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 and optionally substituted with up to three groups selected from: R, and halo; R 3 H, CN, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, and C 1~4 haloalkoxy; Each R 1 and each R 4 -OR, COOR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 R, halo, and -OR', COOR', C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, -CN, and -NR' 2 C optionally substituted with one or two groups selected from 1~4 independently selected from alkyl, Each R 2 and each R 5 , halo, -OR, COOR, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 R, as well as -OR', COOR', and C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, -CN, and -NR' 2 C optionally substituted with one or two groups selected from 1~4 independently selected from alkyl, Each R is H, C 1~4 Haloalkyl, as well as -OR', COOR', C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, -CN, and -NR' 2 C optionally substituted with one or two groups selected from 1~4 independently selected from alkyl, Each R' is H and C 1~3 independently selected from alkyl, m, n, p, and q are each independently selected from 0, 1, and 2; [N] represents a bond of Ar to N in -N=N-Ar; The compound, or a pharma- ceutically acceptable salt thereof. (Item 2) Z 1 and Z 2 One of them is -NH 2 and Z 1 and Z 2 The compound according to item 1, wherein the other of or a pharma- ceutically acceptable salt thereof. (Item 3) Z 1 and Z 2 One of them is -N=N-Ar, and Z 1 and Z 2 The compound according to item 1, wherein the other of or a pharma- ceutically acceptable salt thereof. (Item 4) Ar is phenyl or naphthyl; -OR, COOR, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, -NR 2 , CN, -PO 3 R 2 , -SO 2 R, -SO 3 The compound according to item 3, optionally substituted with up to three groups selected from R, and halo. or a pharma- ceutically acceptable salt thereof. (Item 5) R 3 is H, or a pharma- ceutically acceptable salt thereof. (Item 6) 6. The compound according to any of items 1 to 5, wherein p and q are independently selected from 0 and 1. or a pharma- ceutically acceptable salt thereof. (Item 7) The compound has formula (IA): [ka] A compound according to any of the preceding items, or a pharma- ceutically acceptable salt thereof. (Item 8) Formula (IB): [ka] Item 7, the compound according to item 7, or a pharma- ceutically acceptable salt thereof. (Item 9) Z 2 Ga-NH 2 Item 9. The compound according to item 8, or a pharma- ceutically acceptable salt thereof. (Item 10) Z 2 The compound according to item 8, wherein is -N=N-Ar; or a pharma- ceutically acceptable salt thereof. (Item 11) 11. The compound according to item 9 or 10, wherein n is 0. or a pharma- ceutically acceptable salt thereof. (Item 12) R 1 CF 3 Item 12. The compound according to item 11, or a pharma- ceutically acceptable salt thereof. (Item 13) Ar: [ka] wherein the dashed bond indicates which atom of Ar is bonded to N=N; or a pharma- ceutically acceptable salt thereof. (Item 14) Ar [ka] where the dashed bond indicates which atom of Ar is bonded to N=N; or a pharma- ceutically acceptable salt thereof. (Item 15) Formula (IC): [ka] The compound according to item 1, or a pharma- ceutically acceptable salt thereof. (Item 16) formula: [ka] Item 16. The compound according to item 15, having the formula or a pharma- ceutically acceptable salt thereof. (Item 17) m is equal to p, n is equal to q, R 1 R 4 is the same as R 2 R 5 The compound according to item 16, which is the same as or a pharma- ceutically acceptable salt thereof. (Item 18) formula: [ka] 18. The compound according to item 16 or 17, which is a compound of the formula m is 0 or 1, p is 0 or 1; or a pharma- ceutically acceptable salt thereof. (Item 19) A compound according to any of the preceding paragraphs selected from the compounds in the table below, or a pharma- ceutically acceptable salt thereof. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] (Item 20) 20. A pharmaceutical composition comprising a compound according to any one of items 1 to 19 in admixture with at least one pharma- ceutically acceptable excipient. (Item 21) A method for treating a condition affecting the gut or modulated via the gut-brain axis, said method comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of items 1 to 19. (Item 22) 22. The method of claim 21, wherein the condition is inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease. (Item 23) 23. The method according to item 21 or 22, wherein the compound according to any one of items 1 to 19 is administered orally. (Item 24) 24. The method of any one of items 21 to 23, wherein the method further comprises administering to the subject an additional therapeutic agent that is useful for treating the condition.

Claims

1. Formula (I): 【Chemistry 93】 or a pharma- ceutically acceptable salt thereof, wherein Z １ and Z ２ One of them is -N=N-Ar, and Z １ and Z ２ the other of which is H; Ar is phenyl, naphthyl, and 【Chemistry 94】 is selected from Phenyl and naphthyl are each -OR, COOR, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Haloalkoxy, -NR ２ , CN, -PO ３ R ２ , -SO ２ R, -SO ３ and optionally substituted with up to three groups selected from halo, R ３ H, CN, halo, C １～４ Alkyl, C １～４ Haloalkyl, and C １～４ haloalkoxy; Each R １ and each R ４ is -OR, COOR, C １～４ Haloalkyl, C １～４ Haloalkoxy, -NR ２ , CN, -PO ３ R ２ , -SO ２ R, -SO ３ R, halo, and -OR', COOR', C １～４ Alkoxy, C １～４ Haloalkoxy, C １～４ Haloalkyl, -CN, and -NR' ２ C optionally substituted with one or two groups selected from １～４ independently selected from alkyl, Each R ２ and each R ５ is halo, -OR, COOR, C １～４ Haloalkyl, C １～４ Haloalkoxy, -NR ２ , CN, -PO ３ R ２ , -SO ２ R, -SO ３ R, and -OR', COOR', C １～４ Alkoxy, C １～４ Haloalkoxy, C １～４ Haloalkyl, -CN, and -NR' ２ C optionally substituted with one or two groups selected from １～４ independently selected from alkyl, Each R is H, C １～４ Haloalkyl, as well as -OR', COOR', C １～４ Alkoxy, C １～４ Haloalkoxy, C １～４ Haloalkyl, -CN, and -NR' ２ C optionally substituted with one or two groups selected from １～４ independently selected from alkyl, Each R' is H and C １～３ independently selected from alkyl, m, n, p, and q are each independently selected from 0, 1, and 2; [N] represents a bond of Ar to N in -N=N-Ar; The compound, or a pharma- ceutically acceptable salt thereof.

2. Ar is phenyl or naphthyl; １～４ Alkyl, C １～４ Haloalkyl, C １～４ Haloalkoxy, -NR ２ , CN, -PO ３ R ２ , -SO ２ R, -SO ３ 2. The compound of claim 1, optionally substituted with up to three groups selected from: R, and halo; or a pharma- ceutically acceptable salt thereof.

3. R ３ is H; or a pharma- ceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, wherein p and q are independently selected from 0 and 1. or a pharma- ceutically acceptable salt thereof.

5. Ar is: 【Chemistry 95】 wherein the dashed bond indicates which atom of Ar is bonded to N=N; or a pharma- ceutically acceptable salt thereof.

6. Ar 【Chemistry 96】 wherein the dashed bond indicates which atom of Ar is bonded to -N=N; or a pharma- ceutically acceptable salt thereof. 【Request 7】 【Table 5-1】 【Table 5-2】 【Table 5-3】 【Table 5-4】 【Table 5-5】 【Table 5-6】 【Table 5-7】 【Table 5-8】 The compound according to claim 1, selected from or a pharma- ceutically acceptable salt thereof.

8. Formula (IA): 【Chemistry 97】 or a pharma- ceutically acceptable salt thereof, wherein Z ２ is -NH ２ and -N=N-Ar; Ar is phenyl, naphthyl, and 【Chemistry 98】 is selected from Phenyl and naphthyl are each -OR, COOR, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Haloalkoxy, -NR ２ , CN, -PO ３ R ２ , -SO ２ R, -SO ３ and optionally substituted with up to three groups selected from halo, R ３ H, CN, halo, C １～４ Alkyl, C １～４ Haloalkyl, and C １～４ haloalkoxy; Each R １ and each R ４ is -OR, COOR, C １～４ Haloalkyl, C １～４ Haloalkoxy, -NR ２ , CN, -PO ３ R ２ , -SO ２ R, -SO ３ R, halo, and -OR', COOR', C １～４ Alkoxy, C １～４ Haloalkoxy, C １～４ Haloalkyl, -CN, and -NR' ２ C optionally substituted with one or two groups selected from １～４ independently selected from alkyl, Each R is H, C １～４ Haloalkyl, as well as -OR', COOR', C １～４ Alkoxy, C １～４ Haloalkoxy, C １～４ Haloalkyl, -CN, and -NR' ２ C optionally substituted with one or two groups selected from １～４ independently selected from alkyl, Each R' is H and C １～３ independently selected from alkyl, m, p, and q are each independently selected from 0, 1, and 2; n is 0, [N] represents a bond of Ar to N in -N=N-Ar; The compound, or a pharma- ceutically acceptable salt thereof.

9. Formula (IB): 【Chemistry 99】 The compound according to claim 8, or a pharma- ceutically acceptable salt thereof.

10. Z ２ Ga-NH ２ The compound according to claim 9, or a pharma- ceutically acceptable salt thereof.

11. Z ２ The compound according to claim 9, wherein is -N=N-Ar; or a pharma- ceutically acceptable salt thereof.

12. R １ is CF ３ The compound according to claim 9, or a pharma- ceutically acceptable salt thereof.

13. Ar is: 【Chemistry 100】 wherein the dashed bond indicates which atom of Ar is bonded to N=N; or a pharma- ceutically acceptable salt thereof.

14. Ar 【Chemistry 101】 14. The compound of claim 13, wherein the dashed bond indicates which atom of Ar is bonded to N=N. or a pharma- ceutically acceptable salt thereof.

15. Formula (IC): 【Chemistry 102】 The compound according to claim 1, or a pharma- ceutically acceptable salt thereof.

16. formula: 【Chemistry 103】 The compound of claim 15 having the formula: or a pharma- ceutically acceptable salt thereof.

17. m is the same as p, n is the same as q, R １ R ４ is the same as R ２ R ５ The compound according to claim 16, or a pharma- ceutically acceptable salt thereof.

18. formula: 【Chemistry 104】 18. The compound according to claim 16 or 17, which is a compound of the formula: m is 0 or 1; p is 0 or 1; or a pharma- ceutically acceptable salt thereof.

19. 10. A compound according to any preceding claim selected from the compounds in the table below, or a pharma- ceutically acceptable salt thereof. 【Table 6-1】 【Table 6-2】 【Table 6-3】 【Table 6-4】 【Table 6-5】 【Table 6-6】 【Table 6-7】

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 in admixture with at least one pharma- ceutically acceptable excipient.

21. 20. A method for treating a condition affecting the gut or modulated via the gut-brain axis, said method comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 19.

22. 22. The method of claim 21, wherein the condition is inflammatory bowel disorder, ulcerative colitis, Crohn's disease, multiple sclerosis, or Huntington's disease.

23. 23. The method of claim 21 or 22, wherein the compound of any one of claims 1 to 19 is administered orally.

24. 24. The method of any one of claims 21 to 23, wherein the method further comprises administering to the subject an additional therapeutic agent that is useful for treating the condition.

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