COMPOUNDS TO INHIBIT HUMAN α4β7 INTEGRIN AND PHARMACEUTICALS CONTAINING THEM

Abstract

The invention reveals compounds for the treatment or prevention of diseases or conditions responsive to inhibition of human α4β7 integrin, such as compound (I) or compound , or its pharmaceutical salt. Many diseases and disease conditions can be treated by administration of the compounds revealed herein as compounds (I), including, for example, inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease. The invention also reveals pharmaceuticals containing these compounds.

Description

INHIBITING HUMAN INTEGRIN «4p7CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. provisional application No. 63 / 687,191, filed August 26, 2024, and U.S. provisional application No. 63 / 583,193, filed September 15, 2023, the contents of each of which are hereby incorporated by reference in their entireties.FIELD OF THE INVENTION

[0002] This application discloses methods of treating diseases and conditions by inhibiting a4p7 integrin. Diseases and conditions responsive to a4p7 integrin inhibition include, for example, inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD).BACKGROUND

[0003] Inflammatory bowel disease (IBD) comprises ulcerative colitis (UC) and Crohn’s disease (CD), related idiopathic conditions characterized by chronic inflammation of the gastrointestinal tract. While UC affects only the colon, CD is characterized by transmural inflammation involving any portion of luminal gastrointestinal tract, from the oral cavity to the perianal area. The choice of therapy for CD varies depending upon the anatomic location, severity, and the behavior of the disease, and whether the treatment goal is to induce or maintain remission. Conventional therapies such as 5-aminosalicylates are often ineffective for moderately to severely active CD, while long-term use of corticosteroids is associated with adverse effects.

[0004] Integrins are a family of receptors known to regulate aspects of mucosal inflammation that underlie CD progression. CD is associated with activation of immune cells expressing the integrin C / .4P7 and trafficking of these cells from the bloodstream into the gut and the surrounding tissue to promote chronic inflammation. Specific inhibition of C / .4P7 is a validated mechanism for the treatment of IBD, as demonstrated by vedolizumab (Entyvio®), a monoclonal antibody administered via intravenous infusion.

[0005] Inhibitors of specific integrin-ligand interactions have been used for the treatment of various diseases. The mainstays of therapy over many years have been oral and topical salicylates and glucocorticoids, various immunosuppressive agents and biologies. Monoclonalantibodies displaying high binding affinity for a4p7 have displayed therapeutic benefits for gastrointestinal auto-inflammatory / autoimmune diseases, such as Crohn’s disease, and ulcerative colitis. Anti-integrin antibody therapy for IBD was first introduced with the approval of the non-specific a4 integrin inhibitor natalizumab for Crohn’s disease, an indication approved following its initial approval for multiple sclerosis. Vedolizumab, a monoclonal antibody inhibitor of the integrin C / .4P7, is approved for the induction and maintenance of remission in late-line ulcerative colitis and does not carry a black box warning. Vedolizumab is also approved as a late-line option for Crohn’s disease. However, these therapies also have certain undesirable properties for the patient. A monoclonal antibody 014P7 integrin inhibitor is administered by parenteral administration, has a long half-life with inability to rapidly modify exposures, and a reduced activity due to anti-drug antibody formation. In addition to issues with administration, monoclonal antibody therapies can be challenging to manufacture compared to small molecule therapies.

[0006] There remains a medical need for an effective and safe oral ouP? integrin inhibitor as an important addition to the therapeutic armamentarium for ouP? integrin-mediated conditions, such as inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease (CD).

[0007] In particular, there remains an unmet need for a small molecule designed to selectively inhibit integrin 014P7 including a need for such a small molecule for administration orally, avoiding the need for periodic therapeutic infusions and the complications associated with this form of drug administration.SUMMARY

[0008] In one aspect, the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:a 3 to 12 member heterocyclyl ring structure optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen; a is 0, 1, 2 or 3;Xi is N or CRa;Rais H, halogen or C1-4 alkyl optionally substituted with one or more halogen;X2 is NRb or CRb'Rb ;Rb is H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, C3- ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Rb' and Rb'' are each independently H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl- OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3- ecycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Ri is H or -COORib;Rib is H or C 1-4 alkyl;R2 is H or C 1-4 alkyl;R3 is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; n is 0, 1, 2, 3, or 4;R4is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; p is 0, 1, 2, 3, 4 or 5;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each R7 is independently halogen.

[0009] In one aspect, the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof, whereinYi is N or CRc;Rcis H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Y2 is NRa or CRa'RdRd is H, halogen, C1-4 alkyl or 3-6 member heterocycloalkyl, wherein the C1-4 alkyl or 3-6 member heterocycloalkyl is optionally substituted with one or more halogen;Rd' and Rd'' are each independently H, halogen, or C1-4 alkyl, and each C1-4 alkyl is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy; q is O, 1, 2, 3, 4, 5, 6, 7 or 8;Re is H, Ci-salkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci- 4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci- 4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 Rs; and each Rs is independently halogen.

[0010] In one aspect, the invention features a compound of Formula (I) having a chemical structure of Formula (II) or Formula (II-A), or a pharmaceutically acceptable salt thereof,(II-A) wherein Xi, X2, Yi and Y2 are each defined as described in Formula (I) and R3', R3 , R4 , and R4'' are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen.

[0011] In one aspect, the invention features a compound of Formula (I) having a chemical structure of Formula (III), or Formula (III-A), or a pharmaceutically acceptable salt thereof,(III-A)wherein Xi, X2, Yi and Y2 are each defined as described in Formula (I) and R3', R3 ", R4', and R4" are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen.

[0012] In one aspect, the invention features a compound of Formula (I) having a chemical structure of Formula (IV) or Formula (IV-A), or a pharmaceutically acceptable salt thereof,whereinYi is N or CRc;Rcis H, halogen or Ci-4 alkyl optionally substituted with one or more halogen;Y2 is NRa or CRa'Rd ;Rd is H, halogen, C1-4 alkyl or 3-6 member heterocycloalkyl, wherein the C1-4 alkyl or 3- 6 member heterocycloalkyl is optionally substituted with one or more halogen;Rd' and Rd'' are each independently H, halogen, or C1-4 alkyl, and each C1-4 alkyl is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Re is H, Ci-salkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci- 4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 Rs; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each Rs is independently halogen.

[0013] In one aspect, the invention features a compound of Formula (I) having a chemical structure of Formula (V) or Formula (V-A), or a pharmaceutically acceptable salt thereof,wherein, a is 1 or 2;R3', R3 ", R4', and R4" are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci- 4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci- 4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; andeach R7 is independently halogen.

[0014] In some embodiments, the compound is a compound Formula (VI) or a pharmaceutically acceptable salt thereof,whereinYi, Y2, Y3, Y4, Y5 and Zi, Z2 and Z3 are each CH or N, provided that at least three of Yi, Y2, Y3, Y4, and Y5 are CH and at least one of Zi, Z2 and Z3 is CH;a 3 to 12 member heterocyclyl ring structure (including monocyclic heterocyclic, bicyclic bridged, and bicyclic spirocyclic ring structures) optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl (e.g., methyl) and Ci-4alkyloxy (e.g., methoxy) are optionally substituted with one or more halogen (e.g., one or more fluoro); a is 0, 1, 2 or 3;Xi is N or CRa;Rais H, halogen or C1-4 alkyl optionally substituted with one or more halogen;X2 is NRb or CRb'Rb ;Rb is H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, C3- ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Rb' and Rb'' are each independently H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl- OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3- ecycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Ri is H or -COORib;Rib is H or C 1-4 alkyl;R2 is H or C 1-4 alkyl;R3 is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; n is 0, 1, 2, 3, or 4;R4is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; p is 0, 1, 2, 3, 4 or 5;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each R7 is independently halogen.

[0015] In some embodiments, the compound is a compound selected from the groupthereof.BRIEF DESCRIPTION OF THE FIGURES

[0016] Figure l is a table of compounds disclosed herein.DETAILED DESCRIPTION

[0017] Compounds of Formula (I), which includes compounds of Formulae (la), (lb), and (Ic), and their respective pharmaceutically acceptable salt forms, are small-molecule integrin therapeutics targeting a4p7 that can be administered to treat patients with diseases and conditions that are responsive to a4p7 integrin inhibition.

[0018] In particular, methods described herein can be effective in the treatment of inflammatory bowel disease such as ulcerative colitis or Crohn’s disease. For example, administration of a compound of Formula (I) according to methods described herein provides unexpected therapeutic benefit within twelve weeks of therapy to subjects with moderately to severely active ulcerative colitis, including patients who have received prior advanced therapy (AT) for ulcerative colitis and / or those with a baseline endoscopy of 3. Further, methods described herein show that administration of a compound according to Formula (I) can be well- tolerated and with a favorable safety profile.

[0019] Accordingly, methods as described herein can expand the therapies available for subjects with inflammatory bowel disease such as ulcerative colitis or Crohn’s disease.Compounds of Formula (I)

[0020] In one aspect, the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:a 3 to 12 member heterocyclyl ring structure (including monocyclic heterocyclic, bicyclic bridged, and bicyclic spirocyclic ring structures) optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl (e.g., methyl) and Ci-4alkyloxy (e.g., methoxy) are optionally substituted with one or more halogen (e.g., one or more fluoro); a is 0, 1, 2 or 3;Xi is N or CRa;Rais H, halogen or C1-4 alkyl optionally substituted with one or more halogen;X2 is NRb or CRb'Rb ;Rb is H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, C3- ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Rb' and Rb'' are each independently H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl- OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3- ecycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Ri is H or -COORib;Rib is H or C 1-4 alkyl;R2 is H or C 1-4 alkyl;R3 is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; n is 0, 1, 2, 3, or 4;R4is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; p is 0, 1, 2, 3, 4 or 5;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each R7 is independently halogen.

[0021] In one aspect, the invention features a compound of Formula (I), or aYi is N or CRc;Rcis H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Y2 is NRa or CRd'Ra ;Rd is H, halogen, C1-4 alkyl or 3-6 member heterocycloalkyl, wherein the C1-4 alkyl or 3-6 member heterocycloalkyl is optionally substituted with one or more halogen;Rd' and Rd'' are each independently H, halogen, or C1-4 alkyl, and each C1-4 alkyl is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy; q is O, 1, 2, 3, 4, 5, 6, 7 or 8;Re is H, Ci-salkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci- 4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci- 4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 Rs; and each Rs is independently halogen.

[0022] In one aspect, the invention features a compound of Formula (I) having a chemical structure of Formula (II), or a pharmaceutically acceptable salt thereof,(II) wherein Xi, X2, Yi and Y2 are each defined as described in Formula (I) and R3', R3 , R4 , and R4'' are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen.

[0023] In one aspect, the invention features a compound of Formula (I) having a chemical structure of Formula (III), or a pharmaceutically acceptable salt thereof,wherein Xi, X2, Yi and Y2 are each defined as described in Formula (I) and R3', R3 , R4 , and R4'' are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen.

[0024] In one aspect, the invention features a compound of Formula (IV), or a pharmaceutically acceptable salt thereof:wherein:Xi is N or CRa;Rais H, halogen or C1-4 alkyl optionally substituted with one or more halogen;X2 is NRb or CRb'Rb ;Rb is H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, C3- ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Rb' and Rb'' are each independently H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl- OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3- ecycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Yi is N or CRc;Rcis H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Y2 is NRa or CRd'Ra ";Rd is H, halogen, C1-4 alkyl or 3-6 member heterocycloalkyl, wherein the C1-4 alkyl or 3- 6 member heterocycloalkyl is optionally substituted with one or more halogen;Rd' and Rd'' are each independently H, halogen, or C1-4 alkyl, and each C1-4 alkyl is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Ri is H or -COORib;Rib is H or C 1-4 alkyl;R2 is H or C 1-4 alkyl;R3 is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; n is 0, 1, 2, 3, or 4;FU is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen;p is 0, 1, 2, 3, 4 or 5;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;Re is H, Ci-salkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 Rs; q is O, 1, 2, 3, 4, 5, 6, 7 or 8; each R7 is independently halogen; and each Rs is independently halogen.

[0025] In one aspect, the invention features a compound of Formula (V), or a pharmaceutically acceptable salt thereof:a 3 to 12 member heterocyclyl ring structure (including monocyclic heterocyclic, bicyclic bridged, and bicyclic spirocyclic ring structures) optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl (e.g., methyl) and Ci-4alkyloxy (e.g., methoxy) are optionally substituted with one or more halogen (e.g., one or more fluoro);are each independently a 5-6 member aryl or heteroaryl ring structure; and a, R4, p, R2, Ri, R3, n, Xi, X2, Rs and m are as described form Formula (I) herein.

[0026] In some embodiments, the compound is a compound of Formula (I), wherein Ri is -COOH. In some embodiments, the compound is a compound of Formula (I), wherein R2 is - methyl. In some embodiments, the compound is a compound of Formula (I), wherein Ri is - COOH and R2 is -methyl.

[0027] In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH. In some embodiments, the compound is a compound of Formula (I), wherein X2 is CHRb'. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is CHRb'. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is CHRb' and Rb' is C1-4 alkyl, Ci-4alkyloxy, or Cs-ecycloalkyloxy, and each Rb' is optionally substituted with one or more halogen or C1-4 alkyl. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is CHRb' and Rb' is C1-4 alkyl, Ci-4alkyloxy, or Cs-ecycloalkyloxy, and each Rb' is optionally substituted with one or more fluoro. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is CHRb' and Rb' is C1-4 alkyl, Ci-4alkyloxy, or Cs-ecycloalkyloxy, and each Rb' is optionally substituted with one or more fluoro.

[0028] In some embodiments, the compound is a compound of Formula (I), wherein Ri is -COOH and R2 is -methyl, and Xi is CH and X2 is CHRb' and Rb' is -O-Rb2 or -CH2-Rb2 , wherein Rb2 is Ci-4alkyl or Cs-ecycloalkyl optionally substituted with one or more halogen or Ci-4alkyl. In some embodiments, the compound is a compound of Formula (I), wherein Ri is - COOH and R2 is -methyl, Xi is CH and X2 is CHRb' and Rb' is -O-Rb2 , wherein Rb2' is Ci- 4alkyl or cyclopropyl optionally substituted with one or more halogen or Ci-4alkyl. In some embodiments, the compound is a compound of Formula (I), wherein Ri is -COOH and R2 is - methyl, Xi is CH and X2 is CHRb' and Rb' is -O-Rb2 , wherein Rb2' is Ci-4alkyl optionally substituted with one or more fluoro. In some embodiments, the compound is a compound of Formula (I), wherein Ri is -COOH and R2 is -methyl, Xi is CH and X2 is CHRb' and Rb' is -O- Rb2', wherein Rb2' is cyclopropyl optionally substituted with one or more Ci-4alkyl. In some embodiments, the compound is a compound of Formula (I), wherein Ri is -COOH and R2 is - methyl, Xi is CH and X2 is CHRb' and Rb' is -O-Rb2 , wherein Rb2' is cyclopropyl optionally substituted with one or more methyl. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is CHRb' and Rb' is -CH2-Rb2 , wherein Rb2' is Ci-4alkyl or Cs-ecycloalkyl optionally substituted with one or more halogen or Ci-4alkyl. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is CHRb' and Rb' is -CH2-Rb2 , wherein Rb2' is Ci-4alkyl optionally substituted with one or more fluoro.

[0029] In some embodiments, the compound is a compound of Formula (I), wherein X2 isIn some embodiments, the compound is a compound ofFormula (I), wherein Ri is -COOH and R2 is -methyl, Xi is CH and X2 is CHRb' and Rb' is

[0030] In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH. In some embodiments, the compound is a compound of Formula (I), wherein X2 is CHRb'. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is CHRb'. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is CHRb' and Rb' is C1-4 alkyl, Ci-4alkyloxy, or Cs-ecycloalkyloxy, and each Rb' is optionally substituted with one or more halogen or C1-4 alkyl. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is CHRb' and Rb' is C1-4 alkyl, Ci-4alkyloxy, or Cs-ecycloalkyloxy, and each Rb' is optionally substituted with one or methyl or fluoro.

[0031] In some embodiments, the compound is a compound of Formula (I), wherein X2 is NRa. In some embodiments, the compound is a compound of Formula (I), wherein X2 is NRd and Rd is C1-4 alkyl optionally substituted with one or more halogen. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is NRd. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is NRd and Rd is C1-4 alkyl optionally substituted with one or more F. In some embodiments, the compound is a compound of Formula (I), wherein Xi is CH and X2 is NRd and Rd is -CH2-CF3.

[0032] In some embodiments, the compound is a compound of Formula (I), wherein Xi is N. In some embodiments, the compound is a compound of Formula (I), wherein Xi is N, Ri is -COOH and R2 is -methyl. In some embodiments, the compound is a compound of Formula (I), wherein Xi is N and X2 is CHRb'. In some embodiments, the compound is a compound of Formula (I), wherein Xi is N and X2 is CHRb' and Rb' is C1-4 alkyl, Ci-4alkyloxy, or C3- ecycloalkyloxy, and each Rb' is optionally substituted with one or more halogen or C1-4 alkyl. In some embodiments, the compound is a compound of Formula (I), wherein Ri is -COOH, R2 is -methyl, Xi is N and X2 is CHRb' and Rb' is C1-4 alkyl, Ci-4alkyloxy, or Cs-ecycloalkyloxy, and each Rb' is optionally substituted with one or more fluoro.

[0033] In some embodiments, the compound is a compound of Formula (I), wherein Ri isembodiments, the compound is a compound of Formula (I), wherein Ri is -COOH and R2 is -

[0034] In some embodiments, the compound is a compound of Formula (I), wherein R3 is halogen, or Ci-4alkyl optionally substituted with one or more halogen, and n is 0, 1 or 2. In some embodiments, the compound is a compound of Formula (I), wherein R4 is halogen, or Ci- 4alkyl optionally substituted with one or more halogen, and p is 0, 1 or 2. In some embodiments, the compound is a compound of Formula (I), wherein R3 is halogen, or Ci-4alkyl optionally substituted with one or more halogen, n is 0, 1 or 2; R4 is halogen, or Ci-4alkyl optionally substituted with one or more halogen, and p is 0, 1 or 2. In some embodiments, the compound is a compound of Formula (I), wherein R3 is fluoro or chloro, or Ci-4alkyl optionally substituted with one or more fluoro, n is 0, 1 or 2; R4 is fluoro or chloro, or Ci-4alkyl optionally substituted with one or more fluoro, and p is 0, 1 or 2. In some embodiments, the compound is a compound of Formula (I), wherein R3 is fluoro or chloro, or methyl optionally substituted with one or more fluoro, n is 0, 1 or 2; R4 is fluoro or chloro, or methyl optionally substituted with one or more fluoro, and p is 0, 1 or 2.

[0035] In some embodiments, the compound is a compound of Formula (I), wherein q is 0. In some embodiments, the compound is a compound of Formula (I), wherein m is 0. In some embodiments, the compound is a compound of Formula (I), wherein m is 0 and q is 0. In some embodiments, the compound is a compound of Formula (I), wherein Ri is COOH, R2 is methyl, m is 0 and q is 0.

[0036] In some embodiments, the compound is a compound of Formula (I), wherein q is 0, 1 or 2 and Re is halogen, or Ci-salkyl optionally substituted with one or more halogen. In some embodiments, the compound is a compound of Formula (I), wherein m is 0, 1 or 2, and R5 is halogen, or Ci-4alkyl optionally substituted with one or more halogen. In some embodiments,the compound is a compound of Formula (I), wherein m is 0, 1 or 2 and q is 0, 1 or 2. In some embodiments, the compound is a compound of Formula (I), wherein Ri is COOH, R2 is methyl, R5 is methyl optionally substituted with one or more fluoro; m is 0, 1 or 2; Re is methyl optionally substituted with one or more fluoro, and q is 0, 1 or 2.

[0037] In some embodiments, the compound is a compound of Formula (II), (III) or (IV), wherein Yi is N or CRc; and Rcis H, halogen or C1-4 alkyl optionally substituted with one or more halogen. In some embodiments, the compound is a compound of Formula (I), wherein Yi is N. In some embodiments, the compound is a compound of Formula (I), wherein Yi is CRc; and Rc is H, halogen or C1-4 alkyl optionally substituted with one or more halogen.

[0038] In some embodiments, the compound is a compound of Formula (II), (III) or (IV), wherein Y2 is NRa; and Rd is H, halogen, C1-4 alkyl or 3-6 member heterocycloalkyl, wherein the C1-4 alkyl or 3-6 member heterocycloalkyl is optionally substituted with one or more halogen. In some embodiments, the compound is a compound of Formula (I), wherein Y2 is CRa'Ra '; and Rd' and Rd'' are each independently H, halogen, or C1-4 alkyl, and each C1-4 alkyl is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy. In some embodiments, the compound is a compound of Formula (I), wherein Yi is N and Y2 is NRa and Ra is H.

[0039] In some embodiments, the compound is a compound of Formula (II), (III) or (IV), wherein Yi is N and Y2 is NRa and Rd is 3-6 member heterocycloalkyl optionally substituted with one or more halogen, or C1-4 alkyl optionally substituted with one or more halogen. In some embodiments, the compound is a compound of Formula (I), wherein Yi is N and Y2 is NRa and Rd is 6-member heterocycloalkyl optionally substituted with one or more halogen or methyl optionally substituted with one or more halogen. In some embodiments, the compound is a compound of Formula (I), wherein Yi is N and Y2 is NRa and Rd is a 6-member heterocycloalkyl. In some embodiments, the compound is a compound of Formula (I), wherein Yi is N and X2 is NRa and Ra is tetrahydrofuran.

[0040] In some embodiments, the compound is a compound of Formula (II), (III) or (IV), wherein Yi is CH and Y2 is NRa and Ra is 3-6 member heterocycloalkyl optionally substituted with one or more halogen, or C1-4 alkyl optionally substituted with one or more halogen. In some embodiments, the compound is a compound of Formula (I), wherein Yi is CH and Y2 is NRa and Ra is 6-member heterocycloalkyl optionally substituted with one or more halogen or methyl optionally substituted with one or more halogen. In some embodiments, the compoundis a compound of Formula (I), wherein Yi is CH and Y2 is NRd and Rd is a 6-member heterocycloalkyl. In some embodiments, the compound is a compound of Formula (II), (III) or (IV), wherein Yi is CH and X2 is NRd and Rd is tetrahydrofuran.

[0041] In some embodiments, the compound is a compound of Formula (V), whereinare each independently a 6 member aryl or heteroaryl ring structure. In some embodiments, the compound is a compound of Formula (V), whereinare each independently phenyl, pyridine or pyrimidine. In some embodiments, the compound is a compound of Formula (V), whereinare each independently phenyl, pyridine or pyrimidine. In some embodiments, the compound is a compound of Formula (V), whereinis phenyl andis pyridine or pyrimidine. In some embodiments, the compound is a compound of Formula (V), whereinis phenyl andis pyridine.In some embodiments, the compound is a compound of Formula (V), whereinis phenylwherein R4 is as defined in Formula (I) or Formula (V) andisphenyl. In some embodiments,wherein R3, Xi, X2, Rs, n and m are as defined with respect to Formula (I) or Formula (V).

[0042] In some embodiments, the compound is a compound of Formula (VI), or a pharmaceutically acceptable salt thereofwherein, Ri, R2, R3, R4, Rs, a, p, n and m are as defined above with respect to Formula(V) or Formula (I), and Y 1, Y2, Y3, Y4, Ys and Zi, Z2 and Z3 are each CH or N. In some embodiments, the compound is a compound of Formula (VI), wherein, Ri, R2, R3, R4, Rs, a, p, n and m are as defined above with respect to Formula (V) or Formula (I), and Yi, Y2, Y3, Y4, Y5 and Zi, Z2 and Z3 are each CH or N, provided that at least three of Yi, Y2, Y3, Y4, and Y5 are CH and at least one of Zi, Z2 and Z3 is CH.Definitions

[0043] For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0044] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0045] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0046] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0047] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0048] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related orunrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0049] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0050] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi -closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0051] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-i somers, R- and 5-enantiomers, diastereomers, (d)- isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0052] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed byresolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0053] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C- enriched carbon are within the scope of this invention.

[0054] The terms “avP8”, “avB8”, “avb8”, “alpha-v beta-8” and “alpha v beta 8” and the like as used herein all refer to avPs.

[0055] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water;(17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

[0056] The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19.)

[0057] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, di ethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

[0058] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0059] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0060] The term “patient” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

[0061] Whenever a term e.g., alkyl or aryl) or either of their prefix roots (e.g., alk- or ar-) appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., arylene is the divalent moiety of aryl, heteroarylene is the divalent moiety of heteroaryl, and heterocycloalkylene is the divalent moiety of heterocycloalkyl. Similarly, affixing the suffix “-oxy” to a group indicates the group is attached to the parent molecular structure through an oxygen atom (-O-) such as “alkyloxy,” “alkoxy” or “cycloalkoxy” as used herein.

[0062] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0063] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or 1 up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted. As used herein, “Me” and -CH3 both refer to methyl.

[0064] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic oracyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0065] "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. Exemplary cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cycloheptyl(C7), and cyclooctyl (Cs).

[0066] Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0067] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0068] The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.

[0069] The terms “heterocyclyl” or “heterocyclic group” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0070] The term “heterocycloalkyl” as used herein, is a non-aromatic heterocyclyl wherein at least one atom is a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Examples of heterocycloalkyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. The heterocycloalkyl group can be substituted or unsubstituted as recited, e.g., for heterocyclyls as described herein.

[0071] The term “carbonyl” is art-recognized and includes such moieties as can be represented by the formula:wherein X’ is a bond or represents an oxygen or a sulfur, and R15 represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-Rio or a pharmaceutically acceptable salt, Ri6 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-Rio, where m and Rio are as defined above. Where X’ is an oxygen and R15 or Rie is not hydrogen, the formula represents an “ester.” Where X’ is an oxygen, and R15 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R15 is a hydrogen, the formula represents a “carboxylic acid”. Where X’ is an oxygen, and Rie is a hydrogen, the formula represents a “formate.” On the other hand, where X’ is a bond, and R15 is not hydrogen, the above formula represents a “ketone” group. Where X’ is a bond, and R15 is a hydrogen, the above formula represents an “aldehyde” group.

[0072] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above, and for example substituted with one or more substituents selected from alkyl, cycloalkyl, heterocycloalkyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2amine, CH2amine, and CN. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0073] As used herein, the term “nitro” means -NO2; the term “halogen” designates - F, -Cl, -Br, or -I; the term “hydroxyl” means -OH; and the term “cyano” means -CN;.

[0074] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0075] The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common methodfor making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. Accordingly, prodrugs include compounds that are transformed in vivo to yield a disclosed compound or any other pharmaceutically acceptable form of the compound. In embodiments, a prodrug may be inactive when administered to a subject but may be converted in vivo to an active compound, for example, by hydrolysis. See, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Prodrugs can typically be prepared using well known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985). The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject.

[0076] Prodrugs of compounds described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to provide a compound described herein (i.e., the parent active compound). Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like. Other examples of prodrugs include compounds that comprise — NO, — NO2, — ONO, or — ONO2 moieties.

[0077] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.Exemplary Compounds of the Invention

[0078] This disclosure relates to novel chemical compounds and methods useful for inhibiting avPs integrin.

[0079] In some embodiments, the compound is a compound from Figure 1, Table 2, Table 3, or Table 4, or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the compound is a compound from Table 2, or a pharmaceutically acceptable salt thereof.391 392 393Table 3. Additional Compound Table

[0081] In some embodiments, the compound is a compound from Table 4, or a pharmaceutically acceptable salt thereof.

[0082] Exemplary formulas and compounds are described herein. Also provided herein are exemplary embodiments of structural features which may be present in any formula described herein. Any exemplary embodiment of a structural feature may occur in combination with any other exemplary structural feature described herein. Further, and unless otherwise indicated herein, any description of a formula or compound also includes any pharmaceutically acceptable forms of the compound, including but not limited to any pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of disclosed formulas and compounds.Therapeutic Uses of a Compound of Formula (I)

[0083] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals.

[0084] Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0085] In some embodiments, compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, may be used to treat subjects who have or are suspected of having disease states, disorders, and conditions (also collectively referred to as “indications”) responsive or believed to be responsive to the inhibition of a4p7 integrin activity. In some embodiments, the compounds described herein may be used to inhibit the activity of a4p7 integrin. In some embodiments, the compounds described herein may be used to inhibit excessive or destructive immune reactions or growth or a proliferation of a cell, such as a cancer cell, or inhibit immunosuppression.

[0086] In some embodiments, the present disclosure provides a compound described herein useful as an inhibitor of a4p7 integrin. In some embodiments, the present disclosure provides a method of treating or preventing an inflammatory disease or condition comprising administering a compound described herein to a patient.

[0087] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.

[0088] In some embodiments, provided is a compound described herein useful for the treatment of an inflammatory disease or condition in a patient that is mediated, at least in part, by a4p7 integrin.

[0089] Co-administration may also include administering component drugs e.g., one on more compounds described herein and one or more additional (e.g., a second, third, fourth or fifth) therapeutic agent(s). Such combination of one on more compounds described herein and one or more additional therapeutic agent(s) may be administered simultaneously or in sequence (one after the other) within a reasonable period of time of each administration (e.g., about 1 minute to 24 hours) depending on the pharmacokinetic and / or pharmacodynamics properties of each agent or the combination. Co-administration may also involve treatment with a fixed combination wherein agents of the treatment regimen are combinable in a fixed dosage or combined dosage medium e.g., solid, liquid or aerosol.

[0090] In some embodiments, a method of treating diseases or conditions mediated, at least in part, by a4p7 integrin and / or diseases or symptoms that co-present, exacerbated, and / or triggered by the diseases or conditions mediated, at least in part, by a4p7 integrin, e.g., an allergic disorder and / or an autoimmune and / or inflammatory disease, and / or an acute inflammatory reaction, comprises administering to a patient in need thereof an effective amount of a compound described herein optionally in combination with an additional agent (e.g., a second, third, fourth or fifth active agent) which can be useful for treating diseases or conditions mediated, at least in part, by a4p7, an allergic disorder and / or an autoimmune and / or inflammatory disease, and / or an acute inflammatory reaction incident to or copresenting with diseases or conditions mediated, at least in part, by a4p7 integrin.

[0091] Treatment with the second, third, fourth or fifth active agent may be prior to, concomitant with, or following treatment with a compound described herein. In someembodiments, a compound described herein is combined with another active agent in a single dosage form.

[0092] In embodiments, a subject is an adult subject.Dosage Amounts and Frequency

[0093] In some embodiments, compounds of Formula (I) or any pharmaceutically acceptable salt thereof described herein is administered to a human patient in need thereof in an effective amount, such as, from about from about 25 mg to about 400 mg. In other embodiments, compounds of Formula (I) described herein are administered to a human patient in need thereof, in an effective amount, for example about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg.

[0094] In embodiments, methods described herein comprise administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount that is about 25 mg (e.g., administration of a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (V-A)) or Formula (VI), or a pharmaceutically acceptable salt thereof, in an amount that is about 25 mg).

[0095] In embodiments, a subject receives a dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (V-A)) or Formula (VI), or a pharmaceutically acceptable salt thereof) once daily.

[0096] In embodiments, a subject receives a dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (V-A)) or Formula (VI), or a pharmaceutically acceptable salt thereof) twice daily.

[0097] In embodiments, methods described herein comprise administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount that is about 50 mg (e.g., administration of a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (V-A)) or Formula (VI), or a pharmaceutically acceptable salt thereof, in an amount that is about 50 mg).

[0098] In embodiments, methods described herein comprise administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount that is about 100 mg (e.g., administration of a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V),or (V-A)) or Formula (VI), or a pharmaceutically acceptable salt thereof, in an amount that is about 100 mg).

[0099] In embodiments, methods described herein comprise administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount that is about 150 mg (e.g., administration of a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (V-A)) or Formula (VI), or a pharmaceutically acceptable salt thereof, in an amount that is about 150 mg).[000100] In embodiments, methods described herein comprise administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount that is about 200 mg (e.g., administration of a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (V-A)) or Formula (VI), or a pharmaceutically acceptable salt thereof, in an amount that is about 200 mg).[000101] In embodiments, methods described herein comprise administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount that is about 400 mg (e.g., administration of a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (V-A)) or Formula (VI), or a pharmaceutically acceptable salt thereof, in an amount that is about 400 mg).[000102] In embodiments, a method comprises administering to a subject in need thereof about 100 mg of a compound of Formula (I- A), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises once daily administration to a subject in need thereof about 100 mg of a compound of Formula (I- A), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises twice daily administration to a subject in need thereof about 100 mg of a compound of Formula (I- A), or a pharmaceutically acceptable salt thereof.[000103] In embodiments, a method comprises administering to a subject in need thereof about 200 mg of a compound of Formula (I- A), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises once daily administration to a subject in need thereof about 200 mg of a compound of Formula (I- A), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises twice daily administration to a subject in need thereof about 200 mg of a compound of Formula (I- A), or a pharmaceutically acceptable salt thereof.[000104] In embodiments, a method comprises administering to a subject in need thereof about 100 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A), or apharmaceutically acceptable salt thereof. In embodiments, a method comprises once daily administration to a subject in need thereof about 100 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises twice daily administration to a subject in need thereof about 100 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A), or a pharmaceutically acceptable salt thereof.[000105] In embodiments, a method comprises administering to a subject in need thereof about 200 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises once daily administration to a subject in need thereof about 200 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises twice daily administration to a subject in need thereof about 200 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A), or a pharmaceutically acceptable salt thereof.[000106] In embodiments, a method comprises administering to a subject in need thereof about 100 mg of a compound of Formula (VI), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises once daily administration to a subject in need thereof about 100 mg of a compound of Formula (VI), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises twice daily administration to a subject in need thereof about 100 mg of a compound of Formula (VI), or a pharmaceutically acceptable salt thereof.[000107] In embodiments, a method comprises administering to a subject in need thereof about 200 mg of a compound of Formula (VI), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises once daily administration to a subject in need thereof about 200 mg of a compound of Formula (VI), or a pharmaceutically acceptable salt thereof. In embodiments, a method comprises twice daily administration to a subject in need thereof about 200 mg of a compound of Formula (VI), or a pharmaceutically acceptable salt thereof.[000108] In some embodiments, administration of a compound of Formula (I) to a patient in need thereof results in a receptor occupancy (RO), indicated the percentage of a4p7 bound by the compound at 12 hours after the dose is administered, of at least about 70%, about 85%, about 95%, or about 99%. In some embodiments, administration of a compound of Formula (I) to a patient in need thereof results in a receptor occupancy (RO), indicated the percentage ofa4p7 bound by the compound at 24 hours after the dose is administered, of at least about 70%, about 85%, about 95%, or about 99%.Integrin Mediated Disease[000109] Diseases that are responsive to a4p7 inhibition include autoimmune diseases, and chronic gastrointestinal and gastroesophageal inflammatory diseases. Inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, gastroesophageal inflammatory disease, Eosinophilic Gastrointestinal Disorders (EGIDs), esosinophilic gastroenteritis, esosinophilic gastritis, eosinophilic duodenitis, and eosinophilic esophagitis (EoE) are examples of diseases that can be treated with a compound of Formula (I).[000110] Methods of treating patients with diseases and conditions that are responsive to a4p7 inhibition with a compound of Formula (I) minimizes off-target risk, because compounds of Formula (I) have been shown to be selective for a4p7 inhibition over other integrins, such as a4pi, which is implicated in the development of progressive multifocal leukoencephalopathy (PML). Compounds of Formula (I) also can be administered orally. In preclinical studies, the compound of Formula (VI) a4p7 exhibited high potency and selectivity for a4p7 integrin, good oral absorption, and pharmacokinetic properties suitable for doses regimens including twice daily dosing.[000111] As further shown herein, methods of the invention can achieve significant therapeutic benefit for subjects having inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s disease).[000112] Compound of Formula (I) are useful for the treatment of diseases or conditions mediated, at least in part, by a4p7 integrin.[000113] In additional embodiments, the methods are provided for alleviating a symptom of a disease or disorder mediated, at least in part, by a4p7 integrin. In some embodiments, the methods include identifying a mammal having a symptom of a disease or disorder mediated, at least in part, by a4p7 integrin, and providing to the mammal an amount of a compound as described herein effective to ameliorate (i.e., lessen the severity of) the symptom.Treatment of Inflammatory Bowel Diseases[000114] In some embodiments, the disease or condition mediated, at least in part, by a4p7 integrin is inflammatory bowel disease (IBD).[000115] The term “inflammatory bowel disease” or “IBD” as used herein is a collective term describing inflammatory disorders of the gastrointestinal tract, the most common forms of which are ulcerative colitis and Crohn’s disease. Other forms of IBD that can be treated with the presently disclosed compounds, compositions and methods include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behcet’s disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation induced enteritis, short bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, and chronic diarrhea.[000116] Treating or preventing IBD also includes ameliorating or reducing one or more symptoms of IBD. As used herein, the term “symptoms of IBD” refers to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications, such as dehydration, anemia and malnutrition. A number of such symptoms are subject to quantitative analysis (e.g. weight loss, fever, anemia, etc.). Some symptoms are readily determined from a blood test (e.g. anemia) or a test that detects the presence of blood (e.g. rectal bleeding). The term “wherein said symptoms are reduced” refers to a qualitative or quantitative reduction in detectable symptoms, including but not limited to a detectable impact on the rate of recovery from disease (e.g. rate of weight gain). The diagnosis is typically determined by way of an endoscopic observation of the mucosa, and pathologic examination of endoscopic biopsy specimens.[000117] The course of IBD varies and is often associated with intermittent periods of disease remission and disease exacerbation. Various methods have been described for characterizing disease activity and severity of IBD as well as response to treatment in subjects having IBD. Treatment according to the present methods is generally applicable to a subject having IBD of any level or degree of disease activity.[000118] Criteria useful for assessment of disease activity in subjects with ulcerative colitis can be found in, e.g., Truelove et al., Br Med J 2: 1041-1048 (1955).) Using these criteria, disease activity can be characterized in a subject having IBD as mild disease activity or severe disease activity. Subjects who do not meet all the criteria for severe disease activity, and who exceed the criteria for mild disease activity are classified as having moderate disease activity.[000119] The presently disclosed treatment methods can also be applied at any point in the course of the disease. In some embodiments, the methods are applied to a subject having IBD during a time period of remission (i.e., inactive disease). In such embodiments, the present methods provide benefit by extending the time period of remission (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In other embodiments, methods may be applied to a subject having IBD during a period of active disease. Such methods provide benefit by reducing the duration of the period of active disease, reducing or ameliorating one or more symptoms of IBD, or treating IBD.[000120] Measures for determining efficacy of treatment of IBD in clinical practice have been described and include, for example, the following: symptom control; fistula closure; extent of corticosteroid therapy required; and improvement in quality of life. Heath-related quality of life (HRQL) can be assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is extensively used in clinical practice to assess quality of life in a subject with IBD. (See Guyatt et al., Gastroenterology 96:804-810 (1989).) In some embodiments, the disease or condition is immune-mediated liver injury, disease or condition.[000121] In embodiments, a subject has not previously received advanced therapy (AT) for treatment of a condition described herein (e.g., an inflammatory bowel disease such as ulcerative colitis or Crohn’s disease) prior to any method comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV- A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof.[000122] In embodiments, a subject has previously received advanced therapy (AT) for treatment of a condition described herein (e.g., an inflammatory bowel disease such as ulcerative colitis or Crohn’s disease) prior to any method comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV- A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof. In embodiments, a subject was intolerant to a previously received advanced therapy. In embodiments, a subject was non-responsive to a previously received advanced therapy. In embodiments, a subject was inadequately responsive to a previously received advanced therapy.[000123] Exemplary advanced therapies (ATs) include therapy comprising administration of immunomodulator therapy (e.g., azathioprine, 6-mercaptopurine, or methotrexate), a TNF blocker, one or more corticosteroids, natalizumab, and / or vedolizumab.[000124] In embodiments, a subject has not previously received advanced therapy (AT) for treatment of a condition described herein (e.g., an inflammatory bowel disease such as ulcerative colitis or Crohn’s disease) prior to any method comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV- A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof. Such subjects may also be referred to as treatment-naive subjects.[000125] In embodiments, a method comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof is a method of maintenance therapy for treating an inflammatory bowel disease (e.g., an inflammatory bowel disease such as ulcerative colitis or Crohn’s disease). In embodiments, a method of maintenance therapy comprising administering a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof follows an initial method of induction therapy comprising administering a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V- A) or (VI)) or any pharmaceutically acceptable salt thereof. In embodiments, a method of maintenance therapy immediately follows a method of induction therapy.[000126] In embodiments, maintenance therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V- A) or (VI)) or any pharmaceutically acceptable salt thereof follows induction therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof. In embodiments, periods of treatment described herein can be the sum of induction and maintenance therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof.Ulcerative Colitis[000127] In embodiments, a compound of Formula (I) (e.g., a compound of any one of Formulae (la), (lb), and (Ic) such as a compound of Formula (VI)), or a pharmaceuticallyacceptable salt thereof, can be used in methods to treat ulcerative colitis in a subject in need thereof.[000128] In one aspect, the invention features a method of treating ulcerative colitis in a subject in need thereof. In embodiments, a method comprises administering a compound of Formula (I) (e.g., a compound of any one of Formulae (la), (lb), and (Ic) such as a compound of Formula (VI)), or a pharmaceutically acceptable salt thereof, to the subject. In embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once daily. In embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily.[000129] In embodiments, a compound of Formula (I- A) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In embodiments, a compound of Formula (I- A) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In embodiments, a compound of Formula (I- A) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In embodiments, a compound of Formula (I- A) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). In embodiments, about 100 mg of a compound of Formula (I- A) is administered twice daily. In embodiments, about 200 mg of a compound of Formula (I- A) is administered twice daily.[000130] In embodiments, a compound of Formula (II-A), (III-A), (IV-A), or (V-A) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In embodiments, a compound of Formula (II-A), (III-A), (IV-A), or (V-A) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In embodiments, a compound of Formula (II-A), (III-A), (IV-A), or (V-A) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In embodiments, a compound of Formula (II-A), (III-A), (IV-A), or (V-A) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). In embodiments, about 100 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A) is administered twice daily. In embodiments, about 200 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A) is administered twice daily.[000131] In embodiments, a compound of Formula (VI) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In embodiments, a compound of Formula (VI) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In embodiments, a compound of Formula (VI) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In embodiments, a compound of Formula (VI) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). In embodiments, about 100 mg of a compound of Formula (VI) is administered twice daily. In embodiments, about 200 mg of a compound of Formula (VI) is administered twice daily.[000132] In embodiments, ulcerative colitis is moderate to severe ulcerative colitis. In embodiments, ulcerative colitis is moderate ulcerative colitis. In embodiments, ulcerative colitis is severe ulcerative colitis.[000133] In embodiments, ulcerative colitis is moderately to severely active ulcerative colitis. In embodiments, ulcerative colitis is moderately active ulcerative colitis. In embodiments, ulcerative colitis is severely active ulcerative colitis.[000134] In embodiments, a subject has a Mayo Endoscopy Score (MES) of 2. In embodiments, a subject has a Mayo Endoscopy Score (MES) of 3. In embodiments, a MES of 2 or 3 is determined prior to commencing any therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV- A), (V), (V-A) or (VI)) or a pharmaceutically acceptable salt thereof. A subject’s MES at time of commencing treatment according to methods described herein may also be referred to as a baseline MES.[000135] Ulcerative colitis can be described according to the Mayo Clinic Score (MCS) for ulcerative colitis as described in Table A.Table A. Mayo Clinic Score for Ulcerative Colitis[000136] In embodiments, a full Mayo Clinic Score (MCS) is used to describe the severity of disease, which comprises all four components of Table A and which ranges from 0-12.[000137] In embodiments, a subject has a Mayo Clinic Score (MCS) of 6-12. In embodiments, a subject has a MCS of 6. In embodiments, a subject with ulcerative colitis has a MCS of 7. In embodiments, a subject has a MCS of 8. In embodiments, a subject has a MCS of 9. In embodiments, a subject has a MCS of 10. In embodiments, a subject has a MCS of 11. In embodiments, a subject has a MCS of 12. In embodiments, a MCS of 6-12 is determined prior to commencing any therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or a pharmaceutically acceptable salt thereof. A subject’s MCS at time of commencing treatment according to methods described herein may also be referred to as a baseline MCS.[000138] In embodiments, a modified Mayo Clinic Score (mMCS) is used to describe the severity of disease, which comprises three components of Table A (stool frequency, rectal bleeding, and endoscopic finding) and which ranges from 0-9.[000139] In embodiments, a subject has a modified Mayo Clinic Score (mMCS) of 5-9. In embodiments, a subject has a mMCS of 5. In embodiments, a subject has a mMCS of 6. In embodiments, a subject with ulcerative colitis has a mMCS of 7. In embodiments, a subject has a mMCS of 8. In embodiments, a subject has a mMCS of 9. In embodiments, a mMCS of 5-9 is determined prior to commencing any therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V- A) or (VI)) or a pharmaceutically acceptable salt thereof. A subject’s mMCS at time of commencing treatment according to methods described herein may also be referred to as a baseline mMCS.[000140] In embodiments, the Robarts Histology Index (RHI) is used to describe severity of disease. The RHI is a histology index derived from the Geboes Score and is calculated by evaluating four histologic items, each on a scale from 0 to 3, and where each item is individually weighted in the RHI formula. The RHI can be calculated according to the below equation and ranges from 0 to 33. See also Table B.RHI = (1 x chronic inflammatory infiltrate score) + (2 x lamina propria neutrophils score) + (3 x neutrophils in epithelium score) + (5 x erosion or ulceration score)Table B. Geboes score (GS) and the derived Robarts histopathological index (RHI)[000141] In embodiments, a subject has a RHI that is > 10. In embodiments, a RHI that is > 10 is determined prior to commencing any therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or a pharmaceutically acceptable salt thereof. A subject’s RHI at time of commencing treatment according to methods described herein may also be referred to as a baseline RHI. Accordingly, in embodiments, a subject has a baseline RHI that is > 10 (e.g., at least about 10-20, such as at least 10 or at least 20). In embodiments, methods described herein achieve a decrease in MCS (e.g., as assessed from a baseline MCS) of at least three points and / or a decrease of at least about 20, 25, or 30% (e.g., as assessed from a baseline MCS). In embodiments, methods described herein achieve a decrease in MCS (e.g., as assessed from a baseline MCS) of at least three points. In embodiments, methods described herein achieve a decrease of at least about 30% (e.g., as assessed from a baseline mMCS). In embodiments, a decrease in mMCS is assessed after about 6-52 weeks of therapy (e.g., as described herein such as after about 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 or 52 weeks of therapy). In embodiments, a decrease in MCS is assessed after about 6 or 12 weeks of therapy (e.g., as described herein). In embodiments, a decrease in MCS is assessed after induction therapy (e.g., as described herein). In embodiments, a decrease in MCS is accompanied by a decrease in the rectal bleeding subscore of at least one point and / or an absolute rectal bleeding subscore that is < 1.[000142] In embodiments, methods described herein achieve a decrease in mMCS (e.g., as assessed from a baseline mMCS) of at least two points and / or a decrease of at least about 20, 25, or 30% (e.g., as assessed from a baseline mMCS). In embodiments, methods described herein achieve a decrease in mMCS (e.g., as assessed from a baseline mMCS) of at least two points. In embodiments, methods described herein achieve a decrease in mMCS (e.g., as assessed from a baseline mMCS) of at least three points. In embodiments, methods described herein achieve a decrease of at least about 30% (e.g., as assessed from a baseline mMCS). In embodiments, a decrease in mMCS is assessed after about 6-52 weeks of therapy (e.g., as described herein such as after about 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 or 52 weeks of therapy). In embodiments, a decrease in mMCS is assessed after about 6 or 12 weeks of therapy (e.g., as described herein). In embodiments, a decrease in mMCS is assessed after induction therapy (e.g., as described herein). In embodiments, a decrease in mMCS is accompanied by a decrease in the rectal bleeding subscore of at least one point and / or an absolute rectal bleeding subscore that is < 1.[000143] In embodiments, methods described herein achieve a decrease in rectal bleeding. In embodiments, methods described herein achieve a decrease in the rectal bleeding subscore of the mMCS (e.g., a baseline mMCS). In embodiments, a method achieves a decrease of at least one point in the rectal bleeding subscore of the mMCS (e.g., a baseline mMCS). In embodiments, methods described herein achieve an absolute rectal bleeding subscore of the mMCS that is 0 or 1.[000144] In embodiments, methods described herein achieve endoscopic improvement. In embodiments, endoscopic improvement is assessed by endoscopic appearance of the mucosa. In embodiments, methods described herein achieve a MES of < 1. In embodiments, methods described herein achieve a MES of 0. In embodiments, methods described herein achieve a MES of 1.[000145] In embodiments, methods described herein achieve a decrease in RHI (e.g., as assessed from a baseline RHI). In embodiments, a decrease in RHI is at least a decrease of one point from a baseline RHI (e.g., a decrease of at least 1-7 points such as a decrease of at least 1,2, 3, 4, 5, 6, or 7 points from a baseline RHI). In embodiments, a decrease in RHI is at least a decrease of seven points from a baseline RHI. In embodiments, a decrease in RHI is at least a decrease of at least about 20% from a baseline RHI (e.g., a decrease of at least about 20%, 25%, 30%, 35%, 40%, 45% or 50% from a baseline RHI).[000146] In embodiments, methods described herein achieve an absolute RHI score that is < 9 (e.g., an absolute RHI score that is < 9, < 8, < 7, < 6, < 5, < 4, or < 3). In embodiments, methods described herein achieve an RHI score where subscores of lamina propria neutrophils and neutrophils is equal to 0 (e.g., with no ulcers or erosions).[000147] In embodiments, methods described herein achieve an absolute RHI score that is <3. In embodiments, methods described herein achieve an RHI score where subscores of lamina propria neutrophils and neutrophils is equal to 0 (e.g., with no ulcers or erosions).[000148] In embodiments, methods described herein achieve mucosal healing. In embodiments, mucosal healing is characterized by a MES of 0 and / or a RHI < 3. In embodiments, a RHI < 3 reflects subscores of 0 for lamina propria neutrophils score and neutrophils in the epithelium score and without ulcers or erosions. In embodiments, methods described herein achieve remission of disease.[000149] In embodiments, methods described herein achieve an absolute rectal bleeding sub score of the mMCS that is 0, a stool frequency sub score of the mMCS that is 0 or 1; no individual subsore of the mMCS that is greater than 1; and / or a MES of 0; and / or a RHI < 2 or < 3. In embodiments, a subject in remission has a MCS score of <2 and no subscore higher than 1.[000150] In embodiments, methods described herein achieve an absolute rectal bleeding sub score of the mMCS that is 0.[000151] In embodiments, methods described herein achieve a stool frequency subscore that is 0 or 1.[000152] In embodiments, methods described herein achieve a MES of 0.[000153] In embodiments, methods described herein achieve a RHI < 2 or < 3.[000154] In embodiments, methods described herein achieve a RHI < 2. In embodiments, a RHI < 2 is with scores of 0 for lamina propria neutrophils score and neutrophils in the epithelium score, and without ulcers or erosions.[000155] In embodiments, methods described herein achieve a RHI < 3. In embodiments, a RHI < 3 is with scores of 0 for lamina propria neutrophils score and neutrophils in the epithelium score, and without ulcers or erosions.[000156] In embodiments, a subject in remission has a MCS score of <2 and no subscore higher than 1.Crohn ’s Disease[000157] In embodiments, a compound of Formula (I) (e.g., a compound of any one of Formulae (la), (lb), and (Ic) such as a compound of Formula (VI)), or a pharmaceutically acceptable salt thereof, can be used in methods to treat Crohn’s disease in a subject in need thereof.[000158] In one aspect, the invention features a method of treating Crohn’s disease in a subject in need thereof. In embodiments, a method comprises administering a compound of Formula (I) (e.g., a compound of any one of Formulae (la), (lb), and (Ic) such as a compound of Formula (VI)), or a pharmaceutically acceptable salt thereof, to the subject. In embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in anamount of about 50-400 mg. In embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once daily. In embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily.[000159] In embodiments, a compound of Formula (I- A) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In embodiments, a compound of Formula (I- A) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In embodiments, a compound of Formula (I- A) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In embodiments, a compound of Formula (I- A) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). In embodiments, about 100 mg of a compound of Formula (I- A) is administered twice daily. In embodiments, about 200 mg of a compound of Formula (I- A) is administered twice daily.[000160] In embodiments, a compound of Formula (II-A), (III-A), (IV-A), or (V-A) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In embodiments, a compound of Formula (II-A), (III-A), (IV-A), or (V-A) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In embodiments, a compound of Formula (II-A), (III-A), (IV-A), or (V-A) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In embodiments, a compound of Formula (II-A), (III-A), (IV-A), or (V-A) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). In embodiments, about 100 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A) is administered twice daily. In embodiments, about 200 mg of a compound of Formula (II-A), (III-A), (IV-A), or (V-A) is administered twice daily.[000161] In embodiments, a compound of Formula (VI) or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In embodiments, a compound of Formula (VI) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In embodiments, a compound of Formula (VI) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In embodiments, a compound of Formula (VI) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). Inembodiments, about 100 mg of a compound of Formula (VI) is administered twice daily. In embodiments, about 200 mg of a compound of Formula (VI) is administered twice daily.[000162] In embodiments, Crohn’s disease is moderate to severe Crohn’s disease. In embodiments, Crohn’s disease is moderate Crohn’s disease. In embodiments, Crohn’s disease is severe ulcerative colitis.[000163] In embodiments, Crohn’s disease is moderately to severely active Crohn’s disease. In embodiments, Crohn’s disease is moderately active Crohn’s disease. In embodiments, Crohn’s disease is severely active Crohn’s disease.Exemplary Embodiments[000164] The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, that would be within the purview of those skilled in the art, and changes in formulation or changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.[000165] Certain examples below relate to methods for treating or preventing a disease responsive to an a4p7 integrin inhibitor by administering a compound of formula (I), (la), (lb), and / or (Ic) to a human in need of such treatment.EXAMPLES[000166] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-i somers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.[000167] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.ExamplesAbbreviationsAbbreviation Chemical NameAc acetylACN AcetonitrileBINAP (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl)Boc tert-butyloxy carbonylBu butylCBS N-cyclohexyl-2-benzothiazolesulfenamide cod cyclooctadieneCp cyclopentadienylDAST diethylaminosulfur trifluoride dba dib enzy li deneacetoneDCM dichloromethaneDCE Di chloroethaneDess-Martin, Dess-Martin1,1,1 -triacetoxy- l,l-dihydro-l,2-benzodioxo-3 (1 H )-one periodinaneDIAD diisopropyl azodicarboxylateDIEA N,N-diisopropylethylamineDIPEA N,N-diisopropylethylamine DMF dimethyl formamide DMSO dimethyl sulfoxide dppf 1 , 1 '-bi s(diphenylphosphino)ferrocene EDCI l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI Electrospray ionization Et Ethyl FA Formic acidO-(7-Azabenzotri zol-l-yl)-Af,yV,A",A?7-tetramethyluronit3mHATU hexafluorophosphateHMDS Hexamthey 1 di sil azy 1 HOBt Hydroxy benzotriazole HPLC High performance liquid chromatography hr hourHz Hertz iPr Isopropyl LAH Lithium aluminum hydride LDA lithium diisopropyl amide Me Methyl Ms Methanesulfonyl MS Mass spectrometry NBS N-bromosuccinimide NMR Nuclear Magnetic Resonance prep-HPLC preparative high performance liquid chromatographyQphos pentaphenyl(di-tert-butylphosphino)ferrocene l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octaneSelectfluor bi s(tetrafluorob orate)RT room temperature SFC supercritical fluid chromatography t-Bu tertiary -butyl TEA triethylamine Tf tri fluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TLC Thin layer chromatography TMS trimethyl silylChloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-Xphos Pd G2 biphenyl)[2-(2'-amino-l, 1 '-biphenyl)]palladium(II)Analytical Methods, Materials, and Instrumentation[000168] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Default methods, materials and instrumentation are listed below.HNMR instrumental information:[000169] Proton nuclear magnetic resonance (NMR) spectra were obtained on one of the following instruments:[000170] BRUKER, AVANCE III 500MHZ, PROBHD 5 mm PABBO BB-, PULPROG zg30, TD 65536, NS 8, DS 0, SWH 10330.578 Hz, DI 1.00000000 sec, NUC1 1H, Pl 13.72 usee, PL1W 13.34460926 W, SFO1 500.1330885 MHz[000171] BRUKER, AVANCE III 400MHZ, PROBHD 5 mm PABBO BB / , PULPROG zg30, TD 65536, NS 8, DS 2, SWH 8223.685 Hz, DI 1.00000000 sec, SFO1 400.1324710 MHz, NUC1 1H, Pl 15.00 usee, PL1W 11.00000000 W[000172] Spectra are given in ppm (d) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.LCMS instrumental information and analysis method:[000173] Compounds were analyzed using LC / MS conditions, with UV detector monitoring at 214 nm and 254 nm, and mass spectrometry scanning 110-1500 amu in ESI+ ionization mode.[000174] LCMS A: column: XBridge C18, 4.6 X 50 mm, 3.5 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient: 5%-95% B in 1.4 min, then 1.7 min hold; flow rate: 1.8 mL / min; oven temperature 45 °C.[000175] LCMS B: column: Sunfire C18, 4.6 X 50 mm, 3.5 pm; mobile phase: A: water(0.1%FA) B: ACN(0.1%FA); gradient: 5%-95% B in 1.5 min, then 1.5 min hold; flow rate: 2 mL / min; oven temperature 50 °C.[000176] LCMS C: column: Sunfire Cl 8, 4.6 X 50 mm, 3.5 pm; mobile phase: A: water(0.01%TFA) B: ACN(0.01%TFA); gradient: 5%-95% B in 1.5 min, then 1.7 min hold; flow rate: 2 mL / min; oven temperature 50 °C.[000177] LCMS D: column: Poroshell 120 EC-C18, 3.0 X 30 mm, 2.7 pm; mobile phase: A: water(0.01%TFA) B: ACN(0.01%TFA); gradient: 5%-95% B in 0.8 min, then 1.0 min hold; flow rate: 2 mL / min; oven temperature 50 °C.Prep HPLC methods:[000178] Crude samples were dissolved in MeOH and purified by prep HPLC using a Gilson 215 instrument, detection wavelength 214 nm:[000179] Prep HPLC A: column: Xtimate Prep Cl 8, 21.2 * 250 mm, 10 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient elution as in text; flow rate: 20 mL / min.[000180] Prep HPLC B: column: Boston pHlex ODS, 21.2 * 250 mm, 10 pm; mobile phase: A water (10 mM formic acid), B CH3CN; gradient elution as in text; flow rate: 20 mL / min.[000181] Prep HPLC C: column: XBridge OBD Cl 8, 19 * 100 mm, 5 pm; mobile phase: A water, B CH3CN; gradient elution as in text; flow rate: 20 mL / min.Prep Chiral SFC Methods:[000182] Racemic products were separated to individual enantiomers by chiral Prep SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm:[000183] Prep chiral SFC A: column: (R,R)-Whelk-Ol, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000184] Prep chiral SFC B: column: AD 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000185] Prep chiral SFC C: column: AS 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000186] Prep chiral SFC D: column: OD 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000187] Prep chiral SFC E: column: Cellulose-SC 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000188] Prep chiral SFC F: column: OZ 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000189] Prep chiral SFC G: column: IC 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000190] Prep chiral SFC H: column: (S,S)-Whelk-01, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000191] Prep chiral SFC I: column: OX-H, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000192] Prep chiral SFC J: column: IG, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000193] Prep chiral SFC K: column: IH, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000194] Prep chiral SFC L: column: OJ, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000195] Prep chiral SFC M: column: Amylose-C Neo, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000196] Prep chiral SFC N: column: ID, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000197] Prep chiral SFC O: column: AY-H, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.[000198] Prep chiral SFC P: column: IK, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep Chiral HPLC Methods[000199] Racemic products were separated into individual enantiomers by Prep chiral HPLC using an Gilson-281 (Thar, Waters) instrument (detection wavelength 214 / 254 nm):[000200] Prep chiral HPLC A: Column: IE, 20*250mm, 10 pm (Daicel). Column temperature: 35 °C. Mobile phase: n-Hexane (0.1% DEA) / ethanol(0.1% DEA). Flow rate: 38 g / min. Back pressure: 100 bar.[000201] Prep chiral HPLC B: Column: OJ-H, 20*250mm, 10 pm (Daicel). Column temperature: 35 °C. Mobile phase: n-Hexane (0.1% DEA) / ethanol(0.1% DEA). Flow rate: 38 g / min. Back pressure: 100 bar.Analytical Chiral SFC Methods[000202] Chiral products were analyzed by chiral SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm:[000203] Chiral SFC A: column: (R,R)-Whelk-Ol, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000204] Chiral SFC B: column: AD 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000205] Chiral SFC C: column: AS 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000206] Chiral SFC D: column: OD 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000207] Chiral SFC E: column: Cellulose-SC 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000208] Chiral SFC F: column: OZ 4.6*100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000209] Chiral SFC G: column: IC 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000210] Chiral SFC H: column: (S,S)-Whelk-01, 4.6* 100mm, 5 gm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000211] Chiral SFC I: column: OX-H, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000212] Chiral SFC J: column: IG, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000213] Chiral SFC K: column: IH, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000214] Chiral SFC L: column: OJ, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000215] Chiral SFC M: column: Amylose-C Neo, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000216] Chiral SFC N: column: ID, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000217] Chiral SFC O: column: AY, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.[000218] Chiral SFC P: column: IK, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Analytical Chiral HPLC Methods[000219] Chiral HPLC A: column: OJ-H 4.6*250mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: n-Hexane (0.1% DEA) / ethanol(0.1% DEA), flow rate: 1 g / min[000220] Chiral HPLC B: column: IE 4.6*250mm, 5 gm (Daicel), column temperature: 40 °C, mobile phase: n-Hexane (0.1% DEA) / ethanol(0.1% DEA), flow rate: 1 g / min[000221] When chiral compounds are separated by HPLC or SFC, the absolute stereochemistry of the products is arbitrarily assigned. Unless otherwise noted, the first eluting peak from a separation is noted as Pl, the second as P2, etc. In some cases, chiral intermediates have also been prepared and separated. In this case, 1P2 is used to denote a first eluting intermediate used to prepare a compound of the invention isolated as the second eluting peak, etc.[000222] When isomers of compounds containing chiral centers were separated, the absolute stereochemistry of the products was not always determined. In some cases, stereochemistry was arbitrarily assigned in order to aid in the depiction of compounds and chemical schemes. Someone skilled in the art will recognize that if the stereochemistry of the starting materials different than shown arbitrarily, the stereochemistry of intermediates and final products may also be different than those drawn in any particular scheme or table.Synthetic SchemesExample 1: Preparation of Compounds 24-P1 and 24-P2Step 1: tert-butyl (3-(methoxy(methyl)amino)-3-oxopropyl)(methyl)carbamate[000223] To a solution of 3-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (15 g, 73.9 mmol, 1.0 eq.), N,O-dimethylhydroxylamine hydrochloride (7.6 g, 77.6 mmol, 1.1 eq.), 1- Hydroxybenzotriazole (10.0 g, 73.9 mmol, 1.0 eq.) and trimethylamine (16.4 g, 162.5 mmol, 2.2 eq.) in chloroform (100 ml) was added l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (15.6 g, 81.3 mmol, 1.1 eq.). The reaction was stirred at 50 °C for 1 hr, then diluted with water (100 mL) and extracted with dichloromethane (2 x 100 mL). The organics were washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (95:5 di chloromethane: MeOH) to give tert-butyl (3-(methoxy(methyl)amino)-3-oxopropyl)(methyl)carbamate as a yellow solid (13.6 g, 74.7%) (ESI 147.2 [M-Boc+H]+).Step 2: tert-butyl (3-(3-chloro-5-methylphenyl)-3-oxopropyl)(methyl)carbamate[000224] To a solution of l-bromo-3 -chi oro-5 -methylbenzene (13.6 g, 66.4 mmol, 1.2 eq.) in anhydrous THF (100 mL) at -78 °C was added n-BuLi (26.6 mL, 2.5 M in hexane, 66.4 mmol, 1.2 eq.) dropwise. The reaction was stirred at -78 °C for 30 min. A solution of tert-butyl (3- (methoxy(methyl)amino)-3-oxopropyl)(methyl)carbamate (13.6 g, 55.3 mmol, 1.0 eq.) in tetrahydrofuran (50 mL) was then added. After stirring at -78 °C for another 1 hr., the reaction mixture was quenched with saturated NH4CI solution (100 mL) and extracted with EtOAc (2 x 100 mL). Combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (12: 1 petroleum ether: EtOAc) to give tert-butyl (3-(3-chloro-5- methylphenyl)-3-oxopropyl)(methyl)carbamate as a yellow solid (9.5 g, 55.0%) (ESI 312.1 [M-Boc+H]+).Step 3: tert-butyl (R)-(3-(3-chloro-5-methylphenyl)-3-hydroxypropyl)(methyl)carbamate[000225] To a solution of tert-butyl (3-(3-chloro-5-methylphenyl)-3- oxopropyl)(methyl)carbamate (9.5 g, 30.4 mmol, 1.0 eq.) and (S)-3,3-Diphenyl-l- methylpyrrolidino[l,2-c]-l,3,2-oxazaborole (4.6 mL, 1 M in toluene, 4.6 mmol, 0.15 mmol) in anhydrous THF (100 mL) at -78 °C was added borane (1 M in THF, 35 mL, 35 mmol, 1.1 eq.) dropwise. The reaction was allowed to warm to 0 °C and stirred for 1 hr, quenched with methanol (10 mL) and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give tert-butyl tert-butyl (R)-(3-(3-chloro-5- methylphenyl)-3-hydroxypropyl)(methyl)carbamate as a yellow oil (8.1 g, 84.9%) (ESI 336.1 (M+Na)+).Step 4: (R)-3-((tert-butoxycarbonyl)(methyl)amino)-l-(3-chloro-5-methylphenyl)propyl methanesulfonate[000226] To a solution of tert-butyl (R)-(3-(3-chloro-5-methylphenyl)-3- hydroxypropyl)(methyl)carbamate (4.0 g, 12.8 mmol, 1.0 eq.) and trimethylamine (2.58 g, 25.6 mmol, 2.0 mmol) in dichloromethane (70 mL) at 0 °C was added methanesulfonyl chloride (1.46 g, 12.8 mmol, 1.0 eq.) dropwise. The reaction was stirred at 0 °C for 1 hr, quenched with saturated NaHCCL solution (100 mL) and extracted with EA (2 x 200 mL). Combined organic layers were washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated in vacuo to give (R)-3-((tert-butoxycarbonyl)(methyl)amino)-l-(3-chloro-5-methylphenyl)propyl methanesulfonate as a yellow oil (3.5 g, 2.6 mmol, crude) (ESI 196.1 (M-OMs-Boc)+). Crude product was used as is in the subsequent step.Step 5: tert-butyl (S)-(3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-l- yl)propyl)(methyl)carbamate[000227] To a solution of (R)-3-((tert-butoxycarbonyl)(methyl)amino)-l-(3-chloro-5- methylphenyl)propyl methanesulfonate (3.5 g, 2.6 mmol, crude, 1.0 eq.) in acetonitrile (20 mL) was added 1 -methylpiperazine (2.6 g, 26 mmol, 10.0 eq.) followed by K2CO3 (3.59 g, 26 mmol, 10.0 eq). The reaction mixture was stirred at 80 °C for 1 hr, then diluted with water (200 mL) and extracted with EtOAc (2 x 100 mL). Combined organic layers were washed with brine (100 mL), dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (95:5 di chloromethane: MeOH) to give tert-butyl (S)-(3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-l-yl)propyl)(methyl)carbamate as a yellow oil (420 mg, 40.8%) (ESI 396.2 [M+H]+).Step 6: (S)-3-(3-chloro-5-methylphenyl)-N-methyl-3-(4-methylpiperazin-l-yl)propan-l- amine[000228] To a solution of tert-butyl (S)-(3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin- l-yl)propyl)(methyl)carbamate (420 mg, 1.1 mmol, 1.0 eq.) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL, 13.1 mmol, 11.9 eq.). The reaction mixture was stirred at RT for 30 min, then concentrated in vacuo to obtain (S)-3-(3-chloro-5-methylphenyl)-N-methyl-3- (4-methylpiperazin-l-yl)propan-l-amineas a yellow oil (628 mg, 1.1 mmol, crude). (ESI 296.2 [M+H]+). Crude product was used as is in the subsequent step.Step 7: tert-butyl 4-(3-fluoro-2-methyl-6-nitrophenyl)-3,6-dihydropyridine-l(2H)- carboxylate[000229] 2-chloro-4-fluoro-3 -methyl- 1 -nitrobenzene (20 g, 105.5 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (48.9 g, 158.3 mmol, 1.5 eq.), K2CO3 (43.7 g, 316.5 mmol, 3.0 eq) and Pd(dppf)C12 (7.7 g, 10.55 mmol, 0.1 eq) were suspended in a mixture of dioxane (200 mL) and water(20 mL). Reaction was stirred overnight at 110 °C under N2 atmosphere. Contents were then poured into 300 mL water and extracted with EtOAc (3 x 200 mL). Combined organic extracts were washed with brine, dried over ISfeSCL, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (15: 1 petroleum ether: EtOAc) to give tert-butyl 4-(3-fluoro- 2-methyl-6-nitrophenyl)-3,6-dihydropyridine-l(2H)-carboxylate as a yellow solid (23.5 g, 66%) (ESI 281.1 [M+H-tButyl]+).Step 8: tert-butyl 4-(6-amino-3-fluoro-2-methylphenyl)piperidine-l-carboxylate[000230] To a solution of tert-butyl 4-(3-fluoro-2-methyl-6-nitrophenyl)-3,6- dihydropyridine-l(2H)-carboxylate (12 g, 29.8 mmol, 1.0 eq) in EtOH (150 mL) was added 10% Pd on carbon (3 g, 1.5 mmol, 0.025 eq.). Reaction was stirred at RT under EE atmosphere for 72 hr. Upon completion, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give tert-butyl 4-(6-amino-3-fluoro-2-methylphenyl)piperidine-l- carboxylate as a brown oil (7.7 g, 70%) (ESI 283.1 [M+H-tButyl]+). Crude product was used directly in the subsequent step without further purification.Step 9: tert-butyl 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine-l-carboxylate[000231] Tert-butyl 4-(6-amino-3-fluoro-2-methylphenyl)piperidine-l -carboxylate (12 g, 32.3 mmol, 1.0 eq) was dissolved in acetonitrile (100 mL). Tert-butyl nitrite (5 g, 48.45 mmol, 1.5 eq) was then added dropwise at -10°C, followed by the addition of CuBr2 (5.4 g, 24.2 mmol, 0.75 eq) in acetonitrile (50 ml). After stirred at -10°C for lOmin, the reaction mixture was allowed to warm to RT. Stirring was continued at RT for 6 hr. Reaction mixture was then diluted with dichloromethane (100 ml) and washed with brine(100 ml). Organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (99: 1 dichloromethane: MeOH) to give tert-butyl 4-(6- bromo-3-fluoro-2-methylphenyl)piperidine-l-carboxylate as a yellow oil (7.5 g, 52%) (ESI 316.1[M+H-tButyl]+).Step 10: 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine hydrochloride[000232] To a solution of tert-butyl 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine-l- carboxylate (7.5 g, 20.2 mmol, 1.0 eq) in dichloromethane (10 mL) was added HC1 in dioxane (4M, 20 ml, 80 mmol, 4.0 eq.). The mixture was stirred at RT for Ihr. Reaction was then concentrated in vacuo to give 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine hydrochloride as a white solid (8.3 g, 26.2 mmol, crude) (ESI 272.1 [M+H]+).Step 11 : 4-(6-bromo-3-fluoro-2-methylphenyl)-l-(2,2,2-trifluoroethyl)piperidine[000233] To a solution of 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine hydrochloride (8.3 g, 27 mmol, 1.0 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(9.4 g, 40.5 mmol, 1.5 eq) in acetonitrile (100 ml) was added K2CO3(11.2 g, 81 mmol, 3.0 eq). The reaction was stirred at 80°C for 3hr. After completion, the mixture was filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (99: 1 dichloromethane: MeOH) to give 4-(6-bromo-3-fluoro-2-methylphenyl)-l -(2,2,2- trifluoroethyl)piperidine as a yellow oil (6 g, 52%) (ESI 354.1 [M+H]+).Step 12: ethyl 2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)acetate[000234] To a suspension of 4-(6-bromo-3 -fluoro-2 -methylphenyl)- 1 -(2,2,2- trifluoroethyl)piperidine (6 g, 17 mmol, 1.0 eq) in THF (50 mL) were added Pd2(dba)3(1.56 g, 1.7 mmol, 0.1 eq) and Qphos (362.6 mg, 0.51 mmol, 0.03 eq). (2-ethoxy-2-oxoethyl)zinc(II) bromide solution (IM in THF, 51mL, 51 mmol, 3.0 eq.) was then added, and the reaction was stirred at 65 °C for 1 hr. under nitrogen. Contents were then poured into 50 mL saturated aqueous NH4CI solution and extracted with EtOAc (3 x 50 mL). Combined organic layers were washed with brine (100 mL), dried over ISfeSCU, filtered and concentrated in vacuo. Cruderesidue was purified by silica gel column chromatography (20: 1 petroleum ether: EtOAc) to give ethyl 2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate as a colorless oil (4 g, 65%) (ESI 362.1 [M+H]+).Step 13: ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)acetate[000235] To a solution of ethyl 2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)acetate (4.62 g, 12.8 mmol, 1.0 eq) in THF (60 mL) at -78°C, LiHMDS (IM in THF, 38 mL, 38 mmol, 3.0eq) was added dropwise. The reaction was stirred at -78°C for 0.5 hr. TMSC1 (4.8mL, 38 mmol, 3.0 eq) was then added dropwise, and stirring was continued at - 78°C for another 15min. A solution of NBS (5.7 g, 32 mmol, 2.5 eq) in THF (50 mL) was added dropwise. The reaction was stirred at -78°C for another 1 hr., then warmed to 0°C, quenched with saturated aqueous NH4CI solution (150 ml), and extracted with EtOAc (2 x 150 mL). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (20: 1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(l-(2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)acetate as a yellow solid (4.1 g, 73.2% ) (ESI 440.1 [M+H]+).Step 14: ethyl 2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-l- yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)acetate[000236] To a solution of (S)-3-(3-chloro-5-methylphenyl)-N-methyl-3-(4-methylpiperazin- l-yl)propan-l -amine (314 mg, 0.53 mmol, crude, 1.0 eq.) in acetonitrile (5 mL) was added K2CO3 (512 mg, 3.71 mmol, 5.0 eq.). The mixture was stirred at RT for 15 min. Ethyl 2- bromo-2-(4-fluoro-3 -methyl-2-(l -(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate (210 mg, 0.48 mmol, 0.9 eq.) was then added. Stirring was continued at 80 °C for another 1 hr, then filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (20: 1 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(3-chloro-5- methylphenyl)-3-(4-methylpiperazin-l-yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l- (2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate as a yellow oil (260 mg, 82.7%) . (ESI 655.3 [M+H]+).Step 15: 2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-l- yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)acetic acid (Compound 24)[000237] To a solution of ethyl 2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-l- yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)acetate (260 mg, 0.4 mmol, 1.0 eq.) in ethanol (4.5 mL) and water (1.5 mL) was added NaOH (80 mg, 2.0 mmol, 5.0 eq.). The reaction was stirred at 80 °C for 16 hr. After completion, the reaction pH was adjusted to ~5 - 6 with IN HC1. Solvents were removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to givediastereomeric product 24 as white solid (200 mg, 80.0%). Diastereomers were further separated by prep chiral SFC A to give 24-P1 (66 mg) and 24-P2 (73 mg).[000238] Compound 24-P1 LC / MS ESI 627.3 [M+H]+.1H NMR (400 MHz, MeOD) 5 7.56 (s, 1H), 7.15 (s, 1H), 7.10 - 6.89 (m, 3H), 4.76 (s, 1H), 3.87 - 3.64 (m, 1H), 3.26 - 3.00 (m, 6H), 2.93 - 2.50 (m, 12H), 2.44 (s, 4H), 2.31 (d, J= 16.1 Hz, 9H), 1.98 - 1.50 (m, 4H).Compound 24-P2 LC / MS ESI 627.3 [M+H]+. 'HNMR (400 MHz, MeOD) 5 7.51 (d, J= 6.5 Hz, 1H), 7.23 - 6.80 (m, 4H), 4.75 (s, 1H), 3.55 - 3.38 (m, 1H), 3.27 - 2.99 (m, 6H), 2.98 - 2.67 (m, 6H), 2.66 - 2.49 (m, 6H), 2.45 (s, 4H), 2.30 (s, 8H), 2.18 - 2.06 (m, 1H), 1.92 - 1.38 (m, 4H).[000239] 24-P1 and 24-P2 were assigned as (R)-2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4- methylpiperazin-l-yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l -(2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)acetic acid and (S)-2-(((S)-3-(3-chloro-5-methylphenyl)-3- (4-methylpiperazin-l-yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l -(2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)acetic acid, respectively.Example 2: Preparation of Compounds 62-P1 and 62-P2Step 1: diethyl 2-(3-chloro-5-fluorobenzylidene)malonate[000240] A solution of 3-chloro-5-fhrorobenzaldehyde(30.0 g,0.19 mol), diethyl malonate (45.6 g, 0.29 mol) and piperidine (3.2 g,38.0 mmol) in toluene (300 mL) was stirred at 110 °C for 16 hrs. The reaction mixture was concentrated under reduce pressure. The residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give diethyl 2- (3-chloro-5-fluorobenzylidene)malonate as colorless oil (51.1 g, 89 % ) (ESI 301.0 [M+H]+).Step 2: tetraethyl 2-(3-chloro-5-fluorophenyl)propane-l,l,3,3-tetracarboxylate[000241] To a solution of diethyl malonate (41.5 g, 0.3 mol) in EtOH(800 mL) was added EtONa(18.2 g, 0.26 mmol) and the reaction mixture was stirred at RT for 2hr. Then diethyl 2- (3 -chi oro-5 -fluorobenzylidene) malonate (38.9 g, 0.13 mol) was added and stirred at RT for 16 hours. The reaction was concentrated under reduce pressure, diluted with saturated NH4CI, extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous ISfeSCU, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (4: 1 petroleum ether: EtOAc) to give tetraethyl 2-(3- chloro-5-fluorophenyl)propane-l,l,3,3-tetracarboxylate as colorless oil (60.1 g, 67 % ) (ESI 461.1[M+H]+).Step 3: 3-(3-chloro-5-fluorophenyl)pentanedioic acid[000242] A mixture of tetraethyl 2-(3-chloro-5-fluorophenyl) propane-1, 1,3,3- tetracarb oxy late (180.0 g, 0.13 mol) in 36% aqueous HCl(700 mL) was stirred at 130 °C for 36 hours. The mixture was cooled and stirred at 0 °C for 1 hr. The solid formed was filtered and collected to give 3-(3-chloro-5-fluorophenyl) pentanedioic acid as a white solid (15.0 g, 63%) (ESI 283.0 [M+Na]+).Step 4-(3-chloro-5-fluorophenyl)dihydro-2H-pyran-2,6(3H)-dione[000243] A solution of 3-(3-chloro-5-fluorophenyl) pentanedioic acid (15.0 g, 57.7 mmol) in acetic anhydride (50 mL) was stirred at 130 °C for 40 hr. The mixture was concentrated under reduced pressure. The residue was triturated with EtOAc (150 mL). The solid formed was filtered and collected to give 4-(3-chloro-5-fluorophenyl) dihydro-2H-pyran-2,6(3H)-dione as a white solid (14.0 g, 95%) (ESI 243.1 (M+H)+.Step 5: 3-(3-chloro-5-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid[000244] To a solution of 4-(3-chloro-5-fluorophenyl)dihydro-2H-pyran-2,6(3H)-dione (13.0 g, 53.7 mmol) in THF (lOOmL) was added methylamine (2M in THF, 60mL, 120mmol) and the reaction was stirred at RT for 3hr. The reaction mixture was concentrated under reduce pressure and triturated with EtOAc(60 mL). The solid formed was filtered and collected to give 3-(3-chloro-5-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid as white solid (6.6 g, 47%) (ESI 274.1 [M+H]+).Step 6: 3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-l-yl)pentanamide[000245] To a solution of 3-(3-chloro-5-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid (3.4 g, 12.4 mmol) in DCM (20 mL) was added piperidine (1.0 g, 12.4 mmol) and HATU(5.7 g, 14.9 mmol) followed by DIEPA( 3.2 g, 24.8 mmol). The reaction was stirred at RT for 2 hr. After completion, the mixture was quenched with NH4CI solution (100 ml) and extracted withEtOAc (3x 100 mL). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (20: 1 dichloromethane: MeOH) to give racemic 3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-l-yl)pentanamide as a colorless oil (3.0 g, 71%). Enantiomers were further separated by prep chiral SFC J to give the Pl fraction (R)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-l-yl)pentanamide (1.3 g) and the P2 fraction (S)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-l-yl)pentanamide (1.1 g) as white solids (ESI 341.2 [M+H]+)Step 7 : (R)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-(piperidin-l-yl)pentan-l-amine[000246] To a solution of (R)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-l- yl)pentanamide (1.1 g, 3.2 mmol, 1.0 eq) in THF (20 mL) at RT was added Li AIH4 (2M in THF, 5.0 mL, 9.7 mmol, 3.0 eq) dropwise and the reaction was stirred at 55 °C for 1 hr. After cooling to 0 °C, the reaction mixture was quenched with water (1 mL) dropwise and stirred at 0 °C for another 10 min. 15% aqueous NaOH (1 mL) and water (3 mL) were then added sequentially at 0 °C. The mixture was allowed to warm to RT and stirred for another 15 min, then filtered and filtrate was concentrated in vacuo to give (R)-3-(3-chloro-5-fluorophenyl)-N- methyl-5-(piperidin-l-yl)pentan-l-amine as a white solid used directly in the next reaction(l g, crude) (ESI 313.3 [M+H]+).Step 8: 8-(3-fluoro-2-methyl-6-nitrophenyl)-l,4-dioxaspiro[4.5]dec-7-ene[000247] 2 -chi oro-4-fluoro-3 -methylaniline (20 g, 105.5 mmol, 1.0 eq), 4,4,5,5-tetramethyl- 2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (30.9 g, 116.1 mmol, 1.1 eq.), K2CO3 (29.2 g, 211.0 mmol, 2.0 eq) and Pd(dppf)C12 (7.7 g, 10.55 mmol, 0.1 eq) were suspended in a mixture of dioxane (250 mL) and water (50 mL). The reaction was stirred at 110 °C overnight under nitrogen. After completion, water (300 mL) was added, and the mixture was extracted with EtOAc (3x 200 mL). Combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (6: 1 petroleum ether: EtOAc) to give 8-(3-fluoro-2- methyl-6-nitrophenyl)-l,4-dioxaspiro[4.5]dec-7-ene as a yellow solid (27.0 g, 87%) (ESI 294.2 [M+H]+).Step 9: 4-fluoro-3-methyl-2-(l,4-dioxaspiro[4.5]decan-8-yl)aniline[000248] To a solution of 8-(3-fluoro-2-methyl-6-nitrophenyl)-l,4-dioxaspiro[4.5]dec-7-ene (12 g, 41.0 mmol, 1.0 eq) in MeOH (200 mL) was added 10% Pd-C (12 g, 11.4mmol, 0.3 eq.). The reaction mixture was stirred at 60 °C under hydrogen atmosphere (1 atm, 3L) for 3 days. The reaction mixture was then filtered through a pad of Celite and concentrated in vacuo.Crude material was purified by silica gel column chromatography (5: 1 petroleum ether: EtOAc) to give 4-fluoro-3-methyl-2-(l,4-dioxaspiro[4.5]decan-8-yl)aniline as a yellow oil (7.1 g, 65%) (ESI 266.2 [M+H]+).Step 10: 4-(6-amino-3-fluoro-2-methylphenyl)cyclohexan-l-one[000249] To a solution of 4-fluoro-3-methyl-2-(l,4-dioxaspiro[4.5]decan-8-yl)aniline (16.0 g, 60.3 mmol, 1.0 eq) in THF (300mL), 3M aqueous HC1 (60.3 mL, 180.9 mmol, 3.0 eq) was added, and the contents were stirred at RT for 1 hr. The reaction mixture was then cooled to 0 °C, quenched with saturated aqueous NaHCCL solution (pH adjusted to ~9), and extracted withEtOAc (3x 200 mL). Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 4-(6-amino-3-fluoro-2-methylphenyl)cyclohexan-l-one as a yellow oil (13 g, 97%) (ESI 222.2 [M+H]+). Crude product was used directly in the next step.Step 11: 4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexan-l-one[000250] To a solution of 4-(6-amino-3-fluoro-2-methylphenyl)cyclohexan-l-one (14 g, 63.3 mmol, 1.0 eq.) in THF (250 mL) at -35 °C was added aqueous HC1 (6M, 26.4mL, 158.4 mmol, 2.5 eq). NaNCE (6.6 g in 30 mL water, 95mmol, 1.5 eq.) was then added dropwise over 15 mins. The reaction was stirred at -35 °C for 10 min. Aqueous KI solution (15.8g in 30 mL water, 95 mmol, 1.5 eq.) was then added portion wise into the mixture. Stirring was continued at -35 °C for 30 min. The reaction was allowed to warm to RT and stirred for another Ihr. Water (300 mL) and EtOAc (300 mL) were added into the reaction. Organic layer was separated, washed with saturated aqueous ISfeSOs (300 mL) and brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (15: 1 petroleum ether: EtOAc) to give 4-(3-fluoro-6-iodo-2- methylphenyl)cyclohexan-l-one (7.5 g, 35.7%) (ESI 333.0 [M+H]+).Step 12: (lr,4r)-4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexan-l-ol[000251] To a solution of 4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexan-l-one (10 g, 30.1 mmol, 1.0 eq.) in THF (50 mL) and methanol (8 mL) at 0 °C was added CeCh (8.9 g, 36.1 mmol, 1.2 eq.). NaBH4 ( 1.4 g, 36.1 mmol, 1.2 eq.) was then added in portions. The mixture was stirred at 0 °C for 0.5 hr. The reaction was quenched with water (100 mL) at 0 °C and extracted with EtOAc (3 x 150 mL). Combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gelcolumn chromatography (4: 1 petroleum ether: EtOAc) to give (lr,4r)-4-(3-fluoro-6-iodo-2- methylphenyl)cyclohexan-l-ol as a white solid (8.3 g, 82.8%) (ESI 317.0 [M-0H]+).Step 13: l-fluoro-4-iodo-2-methyl-3-((lr,4r)-4-(prop-l-en-2-yloxy)cyclohexyl)benzene[000252] A mixture of (lr,4r)-4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexan-l-ol (4.7 g, 14.1 mmol, 1.0 eq.), 2-ethoxyprop-l-ene (15 ml), Hg(OAC)2( 1.3 g, 4.2 mmol, 0.3 eq.) at RT overnight under N2 atmosphere. After completion, water (200 mL) was added and the mixture was extracted with di chloromethane (3 x 150 mL). Combined organics were washed with NaHCCh (100 ml) and brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel conlumn chromatography (98: 1 petroleum ether: EtOAc) to give l-fluoro-4-iodo-2-methyl-3-((lr,4r)-4-(prop-l-en-2-yloxy) cyclohexyl)benzene as a colorless oil (3.0 g , 56.7%)Step 14: l-fluoro-4-iodo-2-methyl-3-((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl) benzene[000253] To a solution of l-fluoro-4-iodo-2-methyl-3-((lr,4r)-4-(prop-l-en-2-yloxy) cyclohexyl)benzene (3.0 g, 8.0 mmol, 1.0 eq.) in dichloromethane (75 mL) at 0 °C was added Et2Zn(32.0 ml, 32.0 mmol, 4.0 eq.). The mixture was stirred at 0 °C for 0.5hr under N2 atmosphere. CELh^.S g, 32.0 mmol, 4.0 eq.) was then added dropwise into the mixture at 0 °C. The reaction was allowed to warm to room temeparure and stirring was continued for 6 hr. Saturated aqueous NH4CI (150 mL) was added, and the mixture was extracted with dichloromethane (3 x 150 mL). Combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel conlumn chromatography (95: 1 petroleum ether: EtOAc) to give l-fluoro-4-iodo-2-methyl-3- ((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl) benzene as a colorless oil (1.3 g, 40%).Step 15: ethyl 2-(4-fluoro-3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)- cyclohexyl)phenyl)acetate[000254] To a suspension of l-fluoro-4-iodo-2-methyl-3-((lr,4r)-4-(l-methylcyclopropoxy)- cyclohexyl) benzene (1.3 g, 3.3 mmol, 1.0 eq.) in tetrahydrofuran (12 mL) was added Pd2dba3 (82.0 mg, 0.09 mmol, 0.03 eq.) and QPhos (64 mg, 0.09 mmol, 0.03 eq.) followed by (2- ethoxy-2-oxoethyl)zinc(II) bromide (IM in THF, 8.2 mL, 8.2 mmol, 2.5 eq.). The mixture was stirred at 65 °C under N2 atmosphere for 1 hr., then poured into 50 mL saturated aqueous NH4CI solution and extracted with EtOAc (3 x 100 mL). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (9: 1 petroleum ether: EtOAc) to give ethyl 2-(4- fluoro-3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl)phenyl)acetate as a colorless oil (1.1 g, 90 %) (ESI 371.3 [M+Na]+).Step 16: ethyl 2-bromo-2-(4-fluoro-3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy) cyclohexyl)phenyl)acetate[000255] To a solution of LiHMDS (IM in THF, 6.4 ml, 6.4 mmol, 2.0 eq.) at -78°C, ethyl 2-(4-fluoro-3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl)phenyl)acetate (1.1 g, 3.2 mmol, 1.0 eq.) in tetrahydrofuran (20 ml) was added dropwise. The reaction was stirred at - 78°C for 0.5 hr. TMSCI (698.0 mg, 6.4 mmol, 2.0 eq.) was then added dropwise, and stirring was continued at -78°C for another 15 min. A solution of NBS (1.14 g, 6.4 mmol, 2.0 eq.) in tetrahydrofuran (20mL) was then added dropwise. The reaction was stirred at -78°C foranother 1 hr., then warmed to 0 °C, quenched with saturated aqueous NH4CI solution (100 ml) at 0°C, and extracted with EtOAc (3 x 150 ml). Combined organic layers were washed with brine (3 x 150 ml), dried over ISfeSCU, filtered, and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (19: 1 petroleum ether: EtOAc) to give ethyl 2- bromo-2-(4-fluoro-3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl)phenyl)acetate as a colorless oil (3.72g, 90%) (ESI 449.0 [M+Na]+;451.0 [M+2+Na]+).Step 17: ethyl 2-(((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-((lr,4S)-4-(l- methylcyclopropoxy)cyclohexyl)phenyl)acetate[000256] To a solution of (R)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-(piperidin-l- yl)pentan-l -amine (250 mg, 0.8 mmol, 1.0 eq.).) in acetonitrile (5 mL) was added K2CO3 (331 mg, 2.4mmol, 3.0 eq.). The mixture was stirred at RT for 15 min. Ethyl 2-bromo-2-(4-fluoro-3- methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl)phenyl)acetate (340 mg, 0.8 mmol, 1.0 eq) was then added. Stirring was continued at 60 °C for another 3 hrs. After completion, the reaction mixture was filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (95:5 di chloromethane: MeOH) to give ethyl 2- (((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(4-fluoro-3- methyl-2-((lr,4S)-4-(l-methylcyclopropoxy)-cyclohexyl)phenyl)acetate as a yellow oil (200 mg, 38%) (ESI 659.3 [M+H]+).Step 18: 2-(((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(4- fluoro-3-methyl-2-((lr,4S)-4-(l-methylcyclopropoxy)cyclohexyl)phenyl)acetic acid (Compounds 62-P1 and 62-P2)[000257] To a mixture of ethyl 2-(((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-((lr,4S)-4-(l- methylcyclopropoxy)cyclohexyl)-phenyl)acetate (200 mg, 0.3 mmol, 1.0 eq) in EtOH(5 mL) and H2O (1 mL) was added NaOH (36 mg, 0.9 mmol, 3.0 eq) and the reaction was stirred at 60 °C for 16 hrs. The reaction pH was adjusted to ~5 - 6 with IN HC1. Solvents were removed in vacuo. Crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give 62-P1 (61.7 mg) and 62-P2 (67.0 mg) as white solids.[000258] Compound 62-P1 LC / MS 631.2 [M+H]+. 'HNMR (400 MHz, MeOD) 6 7.59 - 7.40 (m, 1H), 7.06 - 6.93 (m, 2H), 6.83 (d, J= 8.7 Hz, 2H), 4.59 (d, J = 69.1 Hz, 1H), 3.69 (s, 1H), 3.17 (d, J= 32.3 Hz, 1H), 2.59 (d, J= 39.3 Hz, 9H), 2.41 - 2.19 (m, 5H), 2.16 - 1.75 (m, 9H), 1.73 - 1.32 (m, 13H), 0.79 (t, J= 5.5 Hz, 2H), 0.44 (q, J= 4.7 Hz, 2H).[000259] Compound 62-P2 LC / MS ESI 631.2 [M+H]+.1H NMR (400 MHz, CDCI3) 8 7.72 - 7.38 (m, 1H), 7.14 - 6.77 (m, 4H), 4.53 (d, J = 106.8 Hz, 1H), 3.69 (s, 1H), 3.35 (s, 1H), 2.80 - 2.55 (m, 7H), 2.50 - 2.24 (m, 7H), 2.21 - 1.78 (m, 9H), 1.77 - 1.21 (m, 13H), 0.79 (s, 2H), 0.44 (q, J = 4.7 Hz, 2H).[000260] 62-P1 and 62-P2 were assigned as (R)-2-(((S)-3-(3-chloro-5-fluorophenyl)-5- (piperidin- 1 -yl)pentyl)(methyl)amino)-2-(4-fluoro-3 -methyl-2-(( 1 r,4R)-4-( 1 - methylcyclopropoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(3-chloro-5- fhiorophenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-((lr,4S)-4-(l- methylcyclopropoxy)cyclohexyl)phenyl)acetic acid, respectively.Example 3: Preparation of Compounds 89-P1 and 89-P2Step 1: diethyl 2-(5-chloro-2-methylbenzylidene)malonate[000261] A solution of 5-chloro-2-methylbenzaldehyde (100.0 g, 0.65 mol), diethyl malonate (155.8 g, 0.97 mol) and piperidine (8.3 g, 97.5 mmol) in toluene (300 mL) was stirred at 110 °C for 16 hr. The mixture was cooled to RT and concentrated under reduce pressure. The residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give diethyl 2-(5-chloro-2-methylbenzylidene)malonate as colorless oil (180 g, 93%) (ESI 297.3 [M+H]+).Step 2: tetraethyl 2-(5-chloro-2-methylphenyl)propane-l,l,3,3-tetracarboxylate[000262] To a solution of diethyl malonate(194.6 g, 1.22 mol) in EtOH(400 mL) at RT was added EtONa(88.1 g, 1.3 mmol) and the mixture was stirred for 2hr. Then diethyl 2-(5-chloro- 2-methylbenzylidene)malonate (180 g, 0.61 mol) was added at RT and sitrring was continued for another 16 hr. The reaction mixture was concentrated under reduce pressure. The residue was diluted with EtOAc(3 x 400 mL), washed with brine, dried over anhydrous ISfeSCU, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (4: 1 petroleum ether: EtOAc) to give tetraethyl 2-(5-chloro-2-methylphenyl)propane-l,l,3,3-tetracarboxylate as colorless oil(l 80.0 g, 60%) (ESI 457.2[M+H]+).Step 3: 3-(5-chloro-2-methylphenyl)pentanedioic acid[000263] A mixture of tetraethyl 2-(5-chloro-2-methylphenyl) propane-1, 1,3,3- tetracarb oxy late (180.0 g, 0.39 mol) in 36% aqueous HC1 (700 mL) was stirred at 130 °C for 36 hr. The mixture was cooled to 0 °C and stirred at 0 °C for 1 hr. The solid formed was filtered and collected to give 3-(5-chloro-2-methylphenyl) pentanedioic acid as a white solid without further purification (100.2 g, 99%) (ESI 279.0 [M+Na]+).Step 4-(5-chloro-2-methylphenyl)dihydro-2H-pyran-2,6(3H)-dione[000264] A solution of 3-(5-chloro-2-methylphenyl) pentanedioic acid (100.0 g, 0.39 mol) in acetic anhydride (400 mL) was stirred at 130 °C for 40 hr. The mixture was concentrated to dryness under reduce pressure, triturated with EtOAc(150 mL). The solid formed was filtered and collected to give 4-(5-chloro-2-methylphenyl) dihydro-2H-pyran-2,6(3H)-dione as a white solid(91.2 g, 97%) (ESI 239.1 [M+H]+).Step 5: 3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid[000265] To a solution of 3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (91.2 g, 0.38 mol, 1.0 eq ) in THF (300mL) was added methylamine (IM in THF, 1.15L, 1.15 mol, 3.0 eq) and the reaction was stirred at RT for 3hr. The reaction mixture was concentrated under reduce pressure and triturated with EtOAc(120 mL). The solid formed wasfiltered and collected to give racemic 3-(5-chloro-2-methylphenyl)-5-(methylamino)-5- oxopentanoic as white solid (75.0 g, 73%). Enantiomers were further separated by prep chiral SFC K to give Pl fraction (R)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (31.0 g) and P2 fraction (S)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5- oxopentanoic acid (31.0 g) as white solids (ESI 270.1 [M+H]+).Step 6: (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-oxo-5-(piperidin-lyl) pentanamide[000266] To a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5- oxopentanoic acid (16.0 g, 59.4 mmol, 1.0 eq and piperidine (5.0 g, 59.4 mmol, 1.0 eq) in DMF(60 mL) was added HATU(27.1 g, 71.3 mmol, 1.2 eq) followed by DIEPA ( 15.3 g, 118.9 mmol, 2.0 eq . The reaction was stirred at RT for 2 hr. After completion, the mixture was quenched with NH4CI solution (100 ml) and extracted with EtOAc (3 x 150 mL). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (19: 1 dichloromethane: MeOH) to give (R)-3-(5-chloro-2-methylphenyl)-N- methyl-5-oxo-5-(piperidin-l-yl) pentanamide as a colorless oil (16.3 g, 80%) (ESI 337.2 [M+H]+).Step 7: (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-(piperidin-l-yl) pentan-l-amine[000267] To a solution of (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-oxo-5-(piperidin-l- yl) pentanamide(16.3 g, 48.5 mmol, 1.0 eq) in THF (200 mL) at RT was added LiAlEL (58.2 mL, 145.5 mmol, 3.0 eq) dropwise and the reaction was stirred at 55 °C for 1 hr. After cooling to 0 °C, the reaction mixture was quenched with water (5.5 mL) dropwise and stirred at 0 °C for another 10 min. 15% aqueous NaOH (5.5 mL) and water (16.5 mL) were then addedsequentially at 0 °C. The mixture was allowed to warm to RT and stirred for another 15 min, then filtered and filtrate was concentrated in vacuo to give (R)-3-(5-chloro-2-methylphenyl)-N- methyl-5-(piperidin-l-yl)pentan-l-amine as a white solid used directly in the next reaction(13.1 g, 80%) (ESI 309.3 [M+H]+).Step 8: ethyl 2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate[000268] To a solution of 4-(6-bromo-3-fluoro-2-methylphenyl)-l-(2,2,2-trifluoroethyl) piperidine (6 g, 17 mmol, 1.0 eq), Pd2(dba)3(1.56 g, 1.7 mmol, 0.1 eq) and Qphos(362.6 mg, 0.51 mmol, 0.03 eq) in THF(50ml) under N2 atmosphere was added (2-ethoxy-2- oxoethyl)zinc(II) bromide (51ml,l mol / 1, 51 mmol, 3.0 eq) and the mixture was heated to 80°C for Ihr. After completion, saturated aqueous NH4CI (100 mL) was added and the solution was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrated was concentrated in vacuo. The residue was purified by silica gel column chromatography (20: 1 petroleum ether: EtOAc) to give ethyl 2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl) piperidin-4-yl) phenyl) acetate as a yellow oil (4.0 g, 65%) (ESI 362.1 [M+H]+).Step 9: ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl) piperidin-4-yl) phenyl) acetate[000269] To a solution of LiHMDS (IM in THF, 110.8 mL, 110.8 mmol, 2.0 eq.) at -78°C, ethyl 2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl) piperidin-4-yl) phenyl) acetate (20.0 g, 55.4 mmol, 1.0 eq.) in THF (80 mL) was added dropwise. The reaction was stirred at -78°C for 0.5 hr. TMSC1 (12.0 g, 110.8 mmol, 2.0 eq.) was then added dropwise, and stirring was continued at -78°C for another 15 min. A solution ofNBS (24.1 g, 110.8 mmol, 2.0 eq) in THF (200 mL) was then added dropwise. The reaction was stirred at -78°C for another 1 hr., thenwarmed to 0 °C, quenched with saturated aqueous NH4CI solution (200 ml) at 0°C, and extracted with EtOAc (3 x 200 ml). Combined organic layers were washed with brine (3 x 150 ml), dried over Na2SO4, filtered, and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(4- fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl) piperidin-4-yl) phenyl) acetate (20.1 g, 82%) as a colorless oil, (ESI 440.1 [M+H]+).Step 10: ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)acetate[000270] To a solution of ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(l -(2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)acetate(16.5 g, 37.5 mmol, 1 eq) and (R)-3-(5-chloro-2- methylphenyl)-N-methyl-5-(piperidin-l-yl)pentan-l-amine(13.1 g, 42.5 mmol, 1.1 eq) in CH3CN (50 mL) was added K2CO3 (10.3 g, 75.0 mmol, 2.0 eq) at 70 °C for 4 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (20: 1 dichloromethane: MeOH) to give ethyl 2- (((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(4-fluoro-3- methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate as a brown solid (16.0 g, 64%) (ESI 668.3 [M+H]+).Step 11 : 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2- (4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetic acid (Compounds 89-P1 and 89-P2)[000271] Ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)acetate (16.0 g, 23.9 mmol, 1 eq) was treated with LiOH (5.0 g, 119.7 mmol, 5.0 eq) in EtOH (30 mL) and water (3 mL) at 70 °C for 16 hr. The reaction mixture was acidified to pH ~5-6 with IN HC1. Solvents were removed in vacuo. The crude residue was purified by silica gel column chromatography (5: 1 di chloromethane: MeOH) to give diastereomeric product 89 as white solid (13 g, 85%). Diastereomers were further separated by prep chiral SFC A to give 89-P1 (5.6 g) and 89-P2 (5.7 g) as white solids.[000272] Compound 89-P1 LC / MS ESI 640.3 [M+H]+.1H NMR (400 MHz, MeOD) 5 7.44 (d, .7= 7.0 Hz, 1H), 7.07 (d, J= 20.1 Hz, 3H), 6.83 (s, 1H), 4.39 (s, 1H), 3.30 (s, 1H), 3.15 - 3.00 (m, 4H), 2.91 - 2.43 (m, 12H), 2.39 - 2.06 (m, 10H), 2.06 - 1.74 (m, 4H), 1.47 (dd, J= 68.1, 34.3 Hz, 8H).[000273] Compound 89-P2 LC / MS ESI 640.3 [M+H]+.1H NMR (400 MHz, MeOD) 5 7.49 (m, 1H), 7.30 - 7.01 (m, 3H), 6.84 (t, J= 8.4 Hz, 1H), 4.44 (s, 1H), 3.36 (s, 1H), 3.21 - 2.91 (m, 5H), 2.91 - 2.13 (m, 21H), 2.09 - 1.60 (m, 9H), 1.52 (s, 2H), 1.39 (d, J= 9.7 Hz, 1H).[000274] 89-P1 and 89-P2 were assigned as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5- (piperi din- l-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l -(2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5- (piperi din- l-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(l -(2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)acetic acid, respectively.Example 4: Preparation of Compounds 85-P1 and 85-P2Step 1: Diethyl 2-(5-chloro-2-fluorobenzylidene)malonate[000275] A solution of 5-chloro-2-fluorobenzaldehyde (75.0 g, 0.475 mol), diethyl malonate (152.0 g, 0.95mol) and piperidine (6.0 g, 71.0 mmol) in toluene (200 mL) was stirred at 110 °C for 20 hr. The mixture was cooled to RT and concentrated under reduce pressure to give the crude product diethyl 2-(5-chloro-2-fluorobenzylidene)malonate (165 g, crude) as yellow oil. (ESI 301.0 [M+H]+). Crude product was used directly in the next step.Step 2: tetraethyl 2-(5-chloro-2-fluorophenyl)propane-l,l,3,3-tetracarboxylate[000276] To a solution of diethyl malonate (176.0 g, 1.1 mol) in EtOH (2 L) at RT was added EtONa (113.0 g, 1.6 mol) and the mixture was stirred for 2hr. Then diethyl 2-(5-chloro- 2-fluorobenzylidene)mal onate (165.0 g, 0.55 mol) was added at RT and sitrring was continued for another 16 hr. The reaction mixture was concentrated under reduce pressure. The residue was diluted with EtOAc(3 x 400 mL), washed with brine, dried over anhydrous ISfeSCU, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (4: 1 petroleum ether: EtOAc) to tetraethyl 2-(5-chloro-2- fluorophenyl)propane-l,l,3,3-tetracarboxylate (160.0 g, 2-step yield 63%) as yellow oil. (ESI 461.1[M+H]+).Step 3: 3-(5-chloro-2-fluorophenyl)pentanedioic acid[000277] A mixture of tetraethyl tetraethyl 2-(5-chloro-2-fluorophenyl)propane-l, 1,3,3- tetracarb oxy late (80.0 g, 0.174 mol) in 36% aqueous HC1 (200 mL) was stirred at 130 °C for 36 hr. The mixture was cooled to 0 °C and stirred at 0 °C for 1 hr. The solid formed was filtered and collected to give 3-(5-chloro-2-fluorophenyl)pentanedioic acid (40.0 g, 88%) without further purification. (ESI 283.0 [M+Na]+).Step 4: 4-(5-chloro-2-fluorophenyl)dihydro-2H-pyran-2,6(3H)-dione[000278] A solution of 3-(5-chloro-2-fluorophenyl)pentanedioic acid (70.0 g, 270 mmol) in acetic anhydride (600 mL) was stirred at 130 °C for 40 hr. After cooling to 0 °C, the mixture was concentrated under reduce pressure, triturated with EtOAc(150 mL). The solid formed was filtered and collected to give 4-(5-chloro-2-fluorophenyl)dihydro-2H-pyran-2,6(3H)-dione as a white solid (59.1 g, 90%) (ESI 243.1 [M+H]+).Step 5: 3-(5-chloro-2-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid OHc X o[000279]chloro-2-fluorophenyl)dihydr Io-2H-pyran-2,6(h3H)-dione (59.1 g, 243 mmol, 1.0 eq) in THF (300mL) was added methylamine (2M in THF, 364.5 mL, 729 mmol, 3.0 eq ) and the reaction was stirred at RT for 3hr. The reaction mixture was concentrated under reduce pressure and triturated with EtOAc (120 mL). The solid formed was filtered and collected to give 3-(5-chloro-2-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid (59.7 g, 90%) as white solid (ESI 274.0 [M+H]+). Enantiomers were further separated by Prep chiral SFC K to give Pl fraction (R)-3-(5-chloro-2-fluorophenyl)-5-(methylamino)-5- oxopentanoic acid (28.2 g) and P2 fraction (S)-3-(5-chloro-2-fluorophenyl)-5-(methylamino)- 5-oxopentanoic acid (26.0 g) as white solids.Step 6: (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-l-yl)pentanamide[000280] A solution of (R)-3-(5-chloro-2-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid (41.0 g, 150 mmol, 1.0 eq in DCM (320 mL) was added piperidine (25.5 g, 300 mmol, 2.0 eq) and HATU(68.4 g, 180 mmol, 1.2 eq) followed by DIEA ( 38.7 g, 300 mmol, 2.0 eq).The reaction was stirred at RT for 2 hours. After completion, the mixture was quenched with NH4CI solution (1 L) and extracted with dichloromethane (3 x 200 ml). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. Crude residue was purified by silica gel column chromatography (5: 1 di chloromethane: MeOH) to give (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-oxo-5- (piperidin-l-yl)pentanamide as a colorless oil (46.2 g, 90%) (ESI 341.1 [M+H]+).Step 7 : (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-(piperidin-l-yl)pentan-l-amine[000281] To a solution of (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-l- yl)pentanamide (46.2 g, 136 mmol, 1.0 eq in THF(340 mL) at RT was added dropwise LiAlEL (2.5 M in THF, 206.7 mL, 516.8 mmol, 3.8 eq) and the reaction was stirred at 55 °C for 0.5 hour. After cooling to 0 °C, the reaction mixture was then quenched with water (19 mL) dropwise and stirred at 0 °C for another 10 min. 15% aqueous NaOH (19 mL) and water (57 mL) were then added sequentially at 0 °C. The mixture was allowed to warm to RT and stirred for another 15 min, dried over ISfeSCU, filtered and the filtrate was concentrated in vacuo.Crude residue was purified by silica gel column chromatography (99: 0.1 MeOH: TEA) to give (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-(piperidin-l-yl)pentan-l-amine as a colorless oil (13 g, 30% ) (ESI 313.2 [M+H]+).Step 8: 3-methyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline[000282] 2-bromo-3 -methylaniline (50 g, 268.7 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(l,4- dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (75 g, 282.18 mmol, 1.05 eq.), K2CO3 (63 g, 456.7 mmol, 1.7 eq) and Pd(dppf)C12 (3.9 g, 5.37 mmol, 0.02 eq.) were suspended in a mixture of dioxane (500 mL) and water(100 mL). The reaction was stirred overnight at 100 °Cunder N2 atmosphere. Contents were poured into 300 mL water and extracted with EtOAc (3 x YY mL). Combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (6: 1 petroleum ether: EtOAc) to give 3-methyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline as a yellow solid (54 g, 81.8%) (ESI 246.3 [M+H]+).Step 9: 3-methyl-2-(l,4-dioxaspiro[4.5]decan-8-yl)aniline[000283] To a solution of 3-methyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline (20 g, 81.3 mmol, 1.0 eq.) in EtOH (250 mL) was added 10% Pd / C (5.0 g, 2.2 mmol, 0.03 eq). The reaction mixture was stirred at 65 °C under H2 atmosphere (1 atm, 3L) for 24 hr. Upon completion, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give 3-methyl-2-(l,4-dioxaspiro[4.5]decan-8-yl)aniline as a yellow oil (19.1 g, 95%) (ESI 248.3 [M+H]+). Crude product was used directly in the subsequent step without further purification.Step 10: 4-(2-amino-6-methylphenyl)cyclohexan-l-one[000284] To a solution of 3-methyl-2-(l,4-dioxaspiro[4.5]decan-8-yl)aniline (100 g, 403.2 mmol, 1.0 eq.) in THF (IL) was added 3M aqueous HC1 (407 mL, 1.22 mol, 3 eq.). The reaction was stirred at RT for 1 hr. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NaHCCL solution (pH adjusted to ~8), and extracted with EtOAc (500 mL). The organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 4-(2-amino-6-methylphenyl)cyclohexan-l-one as a yellow oil (72 g, 87.9%) (ESI 204.1 [M+H]+). Crude product was used directly in the next step.Step 11: 4-(2-iodo-6-methylphenyl)cyclohexan-l-one[000285] To a solution of 4-(2-amino-6-methylphenyl)cyclohexan-l-one (36 g, 90 % purity, 177.3 mmol, 1.0 eq.) in THF (250 mL) at -10 °C was added aqueous HC1 (6M, 72 mL, 443.3 mmol, 2.5 eq.) followed by NaNCh (13.4 g in 30 mL water, 195.03 mmol, 1.1 eq.) dropwise over 15 mins. The reaction was stirred at -10 °C for another 30 min. KI solution (44.1 g in 30 mL water, 265.9 mmol, 1.5 eq.) was then added portion wise into the mixture. The reaction was allowed to warm to 0 °C and stirring was continued for 30 min. Water (300 mL) and EtOAc (300 mL) were added into the reaction. The organic layer was separated and washed with saturated aqueous IS^SCL (300 mL) and brine (300 mL), dried over ISfeSCU, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (15:1 petroleum ether: EtOAc) to give the 4-(2-iodo-6-methylphenyl)cyclohexan-l-one as a white solid (12.2 g, 21.8%) (ESI 315.0 [M+H]+).Step 12: (lr,4r)-4-(2-iodo-6-methylphenyl)cyclohexan-l-ol[000286] To a solution of 4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexan-l-one(10 g, 31.8 mmol, 1.0 eq.) in THF (50 mL) and MeOH (8 mL) at 0 °C was added CeCh (9.4 g, 38.2 mmol, 1.2eq) followed by NaBH4 (1.45 g, 38.2 mmol, 1.2 eq) in portions. The mixture was stirred at 0 °C for 0.5 hr. H2O (100 mL) was slowly added at 0 °C, and the mixture was extracted with EtOAc (3 x 150 mL). Combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (4: 1 petroleum ether: EtOAc) to give (lr,4r)-4-(2-iodo-6- methylphenyl)cyclohexan-l-ol as a white solid (8.4 g, 83.5%) (ESI 299.0 [M-0H]+).[000287]1H NMR (400 MHz, CDCI3) 5 7.75 (d, J= 7.8 Hz, 1H), 7.15 - 6.96 (m, 1H), 6.72 (t, J= 7.7 Hz, 1H), 3.74 - 3.63 (m, 1H), 3.30 - 3.22 (m, 1H), 2.44 (s, 3H), 2.12 (d, J = 12.5 Hz, 2H), 1.96 (qd, J= 13.0, 3.1 Hz, 2H), 1.80 (d, J= 11.5 Hz, 2H), 1.47 (ddd, 23.7, 12.4, 3.6 Hz, 2H).Step 13: l-iodo-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)benzene[000288] A solution of (lr,4r)-4-(2-iodo-6-methylphenyl)cyclohexan-l-ol (8.4 g, 26.6 mmol, 1.0 eq ), Selectfluor(14.14 g, 39.9 mmol, 1.5 eq ), KF(6.17 g, 106.4 mmol, 4.0 eq.) and AgOTf (20.5 g, 79.8 mmol, 3.0 eq. ) in EtOAc (200 mL) was stirred at RT for 5 min under N2 atmosphere. 2-fluoropyridine (7.75 g, 79.8 mmol, 3.0 eq.) and TMSCF3 (11.4 g, 79.8 mmol, 3 eq.) were then added. The reaction was stirred at RT for 48 hr. After completion, the reaction mixture was filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (98:2 petroleum ether: EtOAc) to give l-iodo-3-methyl-2- ((lr,4r)-4-(trifluoromethoxy)cyclohexyl)benzene as a white solid (3.2g, 31.4%).Step 14: ethyl 2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate[000289] To a suspension of l-iodo-3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)benzene (4.2 g, 10.9 mmol, 1.0 eq in THF (30 mL) was added Pd2dba3 (100 mg, 0.11 mmol, 0.01 eq) and QPhos ( 154 mg, 0.22 mmol, 0.02 eq) followed by (2-ethoxy-2-oxoethyl)zinc(II) bromide (IM in THF, 32 mL, 32 mmol, 3.0 eq^). The mixture was stirred at 55 °C under N2 atmosphere for 1 hr., then poured into 100 mL saturated aqueous NH4CI and extracted with EtOAc (3 x 100 mL). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (20: 1 petroleum ether: EtOAc) to give ethyl 2-(3-methyl-2- ((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate as a colorless oil (3.5 g, 93 %) (No Mass).Step 15: ethyl 2-bromo-2-(3-methyl-2-(( 1 r,4r)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate[000290] To a solution of Lithium diisopropylamide (2 M in THF, 15.1 mL, 30.3 mmol, 3.0 eq at -78°C, ethyl 2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (3.5g, 10.1 mmol, 1.0 eq) in THF (60 ml) was added dropwise. The reaction was stirred at - 78°C for 0.5 hr. TMSC1 (5.39 g, 30.3 mmol, 3.0 eq) was then added dropwise, and stirring was continued at -78°C for another 15 min. A solution of NBS (5.36 g, 30.3 mmol, 3.0eq) in THF (lOOmL) was then added dropwise. The reaction was stirred at -78°C for another 1 hr., then warmed to 0 °C, quenched with saturated aqueous NH4CI solution (100 ml) at 0°C, and extracted with EtOAc (3 x 150 ml). Combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (9: 1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(3-methyl-2- ((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate as yellow solid (3.2g, 75%) (ESI 445.0 [M+Na]+).Step 16: ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate[000291] To a solution of (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-(piperidin-l- yl)pentan-l -amine (10.0 g, 31.2 mmol, 1.3 eq) in acetonitrile (150 mL), was added K2CO3 (9.9 g, 72 mmol, 3.0 eq . The mixture was stirred at RT for 15 min. The ethyl 2-bromo-2-(3- methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (10.1 g, 24.0 mmol, 1.0 eq was added, the mixture continued stirred at 80 °C for 4 hr. After completion, the reaction mixture was filtered and the filtrated was concentrated in vacuo. The residue was purified by silica gel column chromatography (5;1 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(5- chloro-2-fluorophenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate as a yellow oil (12.4 g, 60.6%) (ESI 655.3 [M+H]+).Step 17: 2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3- methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid[000292] Ethyl 2-(((S)-3-(5-chl oro-2 -fluorophenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (18.2 g, 27.7 mmol, 1.0 eq) was treated with NaOH (5.5 g, 138.5 mmol, 5.0 eq) in ethanol (120 mL) and water (40 mL) at 70 °C for 16 hr. The reaction mixture was acidified to pH ~5-6 with IN HC1. Crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give the diastereomeric product 85 (15.0 g, 86.5%). Diastereomers were further separated by Prep chiral SFC A column to give products 85-P1 (5.4 g) and 85-P2 (4.99 g) as white solids.[000293] Compound 85-P1 LC / MS ESI 627.2 [M+H]+.1H NMR (400 MHz, MeOD) 5 7.58 - 7.37 (m, 1H), 7.23 - 6.96 (m, 5H), 4.73 - 4.29 (m, 2H), 3.09 (d, J= 26.0 Hz, 1H), 2.86 (s, 1H), 2.58 (dd, J= 64.7, 49.7 Hz, 12H), 2.35 - 1.57 (m, 18H), 1.48 (s, 2H).[000294] Compound 85-P2 LC / MS ESI 627.2 [M+H]+.1H NMR (400 MHz, MeOD) 5 7.52 (t, J= 68.3 Hz, 1H), 7.16 (d, J= 5.1 Hz, 2H), 7.08 - 6.90 (m, 3H), 4.40 (d, J= 55.3 Hz, 2H), 3.48 (s, 1H), 2.86 (s, 1H), 2.56 - 2.25 (m, 13H), 2.22 - 2.01 (m, 5H), 1.91 - 1.54 (m, 12H), 1.44 (s, 2H).[000295] 85-P1 and 85-P2 were assigned as (R)-2-(((S)-3-(5-chloro-2-fluorophenyl)-5- (piperidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(trifluoromethoxy)- cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)- phenyl)acetic acid, respectively.Example 5: Preparation of Compounds 99-P1 and 99-P2Step 1: ethyl (E)-3-(5-chloro-2-methylphenyl)acrylate[000296] To a solution of 5-chloro-2-methylbenzaldehyde (5.0 g, 32.5 mmol, 1.0 eq) in DCE (50 mL) was added ethyl 2-(triphenyl-15-phosphaneylidene)acetate (12.5 g, 35.7 mmol, 1.1 eq). The reaction was heated to 50 °C under N2 atmosphere for 3hr. After completion, the reaction was concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give ethyl (E)-3-(5-chloro-2-methylphenyl)acrylate as a colorless oil (7.0 g, 96.3 % ) (ESI 225.1 [M+H]+).Step 2: ethyl 3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-l-yl)propanoate[000297] To a solution of ethyl (E)-3-(5-chloro-2-methylphenyl)acrylate (3.5 g, 15.6 mmol, 1.0 eq) in 1 -methylpiperazine (15 mL) was added LiCICh (3.3 g, 31.2 mmol, 2.0 eq). The reaction was stirred at room temperarute for 16hr. Then the mixture was diluted with EtOAc (100 mL ), washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (9: 1 petroleum ether: EtOAc) to give ethyl 3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-l-yl)propanoate as a white solid (3.0 g, 59.4 %) (ESI 325.1 [M+H]+).Step 3: 3-(5-chloro-2-methylphenyl)-N-methyl-3-(4-methylpiperazin-l-yl)propanamide[000298] A solution of ethyl 3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-l- yl)propanoate (3.0 g, 9.3 mmol, 1.0 eq) in MeNH2 solution (IM in MeOH, 40 ml , 40 mmol, 4.0 eq) was heated to 60°C for 16 hr. The reaction was concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 dichloromethane: MeOH) to give 3- (5-chloro-2-methylphenyl)-N-methyl-3-(4-methylpiperazin-l-yl)propanamide as a white solid (1.5 g, 52.4%). Enantiomers were further separated by prep chiral SFC F to give amide Pl (0.7 g) and amide P2 (0.7 g) (ESI 310.1 [M+H]+).Step 4: (S)-3-(5-chloro-2-methylphenyl)-N-methyl-3-(4-methylpiperazin-l-yl)propan-l- amine[000299] To a solution of P2 amide (S)-3-(5-chloro-2-methylphenyl)-N-methyl-3-(4- methylpiperazin-l-yl)propanamide (700 mg, 2.27 mmol, 1.0 eq) in THF (9 mL) was added LAH (2.3 mL, 5.66 mmol, 2.5 eq) at 0°C and stirred at 60°C for 2 hr. The reaction was quenched with water(1.0 mL) dropwise, NaOH(LO mL,15% in water) and water(3.0 mL) and stirred at 0°C for 15 min, dried over anhydrous Na2SO4, filtrated and the filtrate was concentrated in vacuo to give (S)-3-(5-chloro-2-methylphenyl)-N-methyl-3-(4- methylpiperazin-l-yl)propan-l -amine (600 mg, yield:90.1%) as a yellow oil(ESI 296.1 (M+H)+). Crude product was used directly in the subsequent step without further purification.Step 5: ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(trifluoromethoxy)cyclohexyl)- phenyl)acetate[000300] To a solution of (S)-3-(5-chloro-2-methylphenyl)-N-methyl-3-(4-methylpiperazin- l-yl)propan-l -amine (148mg, 0.5 mmol) and ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate (211 mg, 0.5 mmol) in acetonitrile (5 mL) was added DIEA (200 mg, 1.5 mmol, 3.0 eq). The reaction mixture was stirred at 70 °C for 3 hr, then filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20: 1 dichloromethane: MeOH) to give 2-(((S)-3-(5-chloro-2- methylphenyl)-3-(4-methylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4- (trifluoromethoxy)-cyclohexyl)phenyl)acetate as a yellow liquid (223 mg, 70.1%). (ESI 638.2 [M+H]+).Step 6: 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetic acid[000301] To a solution of 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (212 mg, 0.33 mmol, 1.0 eq.) in ethanol (3 mL) and water (1 mL) was added NaOH (67 mg, 1.7 mmol, 5.0 eq.). The reaction was stirred at 80 °C for 16 hr. After completion, the reaction pH was adjusted to ~ 6 - 7 with IN HC1. Solvents were removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give diastereomeric product 99 as white solid (130 mg, 71.5%). Diastereomers were further separated by prep chiral SFC A to give 99-P1 (52.9 mg) and 99-P2 (44.3 mg).[000302] Compound 99-P1 LC / MS ESI 610.1 [M+H]+. 1H NMR (400 MHz, MeOD) 5 7.52 (d, J = 36.9 Hz, 1H), 7.31 - 7.03 (m, 5H), 4.85 - 4.68 (m, 1H), 4.59 - 4.35 (m, 1H), 4.05(s, 1H), 3.18 (s, 1H), 2.57 (s, 10H), 2.50 (s, 3H), 2.42 (d, J = 12.3 Hz, 3H), 2.37 - 2.24 (m, 7H), 2.15 (dd, J = 43.6, 9.3 Hz, 3H), 2.00 - 1.58 (m, 6H).[000303] Compound 99-P2 LC / MS ESI 610.1 [M+H]+. 1H NMR (400 MHz, MeOD) 5 7.50 (dd, J = 47.5, 7.0 Hz, 1H), 7.19 (m, 5H), 4.88 - 4.76 (m, 1H), 4.37 (s, 1H), 3.68 (s, 1H), 3.24 - 3.12 (m, 1H), 3.03 - 2.55 (m, 10H), 2.52 (s, 3H), 2.37 (dd, J = 32.4, 23.5 Hz, 6H), 2.29 - 2.02 (m, 7H), 1.78 (m, 6H).[000304] 99-P1 and 99-P2 were assigned as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4- methylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-3 -(4-methylpiperazin- 1 -y l)propyl)(methyl)amino)-2-(3 -methyl-2-(( 1 r,4 S)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetic acid, respectively.Example 6: Preparation of Compounds 114-P1 and 114-P2Step 1: ethyl (E)-3-(5-chloro-2-fluorophenyl)acrylate[000305] A solution of 5-chloro-2-fluorobenzaldehyde (125 g, 791 mmol, 1.0 eq.) and ethyl 2-(triphenyl-15-phosphaneylidene)acetate (330 g, 949 mmol, 1.2 eq) in DCE (IL) was stirred at RT for 3 hours. After completion, the reaction was concentrated in vacuo. The residue was diluted with petroleum ether (IL). The reaction was filtered to remove triphenylphosphine oxide. The filtrate was concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give ethyl (E)-3-(5-chloro-2- fhiorophenyl)acrylate as a yellow oil (152 g , 84%) (ESI 229.6[M+H]+).Step 2: ethyl 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propanoate[000306] To a solution of ethyl (E)-3-(5-chloro-2-fluorophenyl)acrylate (152g, 667 mmol, 1.0 eq) in 1 -isopropylpiperazine (106 g, 1000 mmol, 1.5 eq) was addedLiClO4(128 g, 1000 mmol, 1.5 eq.). The reaction was stirred at 60 °C for 16 hours. The reaction mixture was poured into water (1000 mL) and extracted with EtOAc (2000 mL). Combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (97:3 dichloromethane: MeOH) to give tertethyl 3-(5-chloro-2-fluorophenyl)-3-(4- isopropylpiperazin-l-yl)propanoate as a yellow solid (160g, 67%) (ESI 357.8 [M+H]+).Step 3: 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propan-l-ol[000307] To a solution of tertethyl 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propanoate (160 g, 449mmol, 1.0 eq.) in THF (1000 mL) at 0 °C was added LAH (674 mL, 674 mmol, 1.5 eq) under N2. The reaction was stirred at 0 °C for 1 hr. After completion, the reaction mixture was quenched with water (25.5 mL) dropwise and stirred at 0 °C for another 10 min. 15% aqueous NaOH (25.5 mL) and water (76 mL) were then added sequentially at 0 °C. The mixture was allowed to warm to RT and stirred for another 15 min, dried over ISfeSCU, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (80:20 petroleum ether: EtOAc) to give 3-(5-chloro-2-fluorophenyl)- 3-(4-isopropylpiperazin-l-yl)propan-l-ol as a yellow oil (140 g,:99%). Enantiomers were further separated by prep chiral SFC B to give Pl fraction (S)-3-(5-chloro-2-fluorophenyl)-3- (4-isopropylpiperazin-l-yl)propan-l-ol (60 g) and P2 fraction (R)-3-(5-chloro-2-fluorophenyl)- 3-(4-isopropylpiperazin-l-yl)propan-l-ol as a yellow oil (55 g).Step 4: (S)-2-(3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)isoindoline-l, 3-dione[000308] To a solution of (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propan-l-ol (28 g, 89 mmol, 1.0 eq) and isoindoline-1, 3-dione (17 g, 116 mmol, 1.3 eq) in Toluene (300 mL) at 0 °C was added triphenylphosphine (30 g, 116 mmol, 1.3 eq) followed by diethyl azodi carb oxy late (23 g, 116mmol, 1.3 eq). The reaction was stirred at RT for 3 hrs. The reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9: 1 petroleum ether: EtOAc) to give (S)-2-(3-(5-chloro- 2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)isoindoline-l, 3-dione as a yellow oil (33 g, 85 %) (ESI 444.9 [M+H]+).Step 5: (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propan-l-amine[000309] To a solution of (S)-2-(3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)isoindoline-l, 3-dione (33 g, 74 mmol, 1.0 eq) in EtOH (800 mL) at RT was added 98% hydrazine hydrate (19 g, 372 mmol, 5 eq). The reaction mixture was warmed to 80 °C and stirred for 1 hr. After completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (80:20 dichloromethane: MeOH) to give (S)-3-(5-chloro-2-fluorophenyl)-3-(4- isopropylpiperazin-l-yl)propan-l -amine as a yellow oil (23 g, 99%) (ESI 314.8 [M+H]+).Step 6: ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate[000310] To a solution of (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propan-l -amine (13 g , 42 mmol, 1.0 eq.) in acetonitrile (150 mL) was added K2CO3 (17 g, 125 mmol, 3.0 eq.). The mixture was stirred at RT for 15 min. Ethyl 2-bromo-2-(3-methyl-2- ((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (17 g, 42 mmol, 1.0 eq) was then added. Stirring was continued at 60 °C for another 16 hrs. After completion, the reaction mixture was filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (9: 1 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(5- chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)amino)-2-(3-methyl-2-((lr,4S)-4- (trifluoromethoxy)-cyclohexyl)phenyl)acetate as a yellow oil (16 g, 59%) (ESI 656.2 [M+H]+).Step 7: 2 ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)- cyclohexyl)phenyl)acetate[000311] To a solution of ethyl (S)-2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4- isopropylpiperazin-l-yl)propyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (16 g, 25 mmol, 1.0 eq.) in MeOH (140 mL) was added 33% aqueous HCHO (10 g, 100 mmol, 5.0 eq.). The reaction was stirred at RT for 1 hr. NaBH(OAc)s (11 g, 50 mmol, 2.0 eq.) was then added, and stirring was continued at RT for another 3 hrs. After completion, the reaction mixture was poured into water (300 mL) andextracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (95:5 di chloromethane: MeOH) to give ethyl 2- (((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3- methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate as colorless oil (14 g, 86%) (ESI 670.2 [M+H]+).Step 8: 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid[000312] To a mixture of ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin- l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (14 g, 21 mmol, 1.0 eq) in EtOH(100 mL) and H2O (20 mL) was added NaOH (2.5 g, 63 mmol, 3.0 eq) and stirred at 60 °C for 16 hrs. The reaction pH was adjusted to ~5 - 6 with IN HC1. Solvents were removed in vacuo. Crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give diastereomeric product 114 as a white solid (10 g, 75%). Diastereomers were further separated by prep chiral SFC A to give 114-P1 (4.0 g) and 114-P2 (3.98g).[000313] Compound 114-P1 LC / MS 642.1 [M+H]+. 'HNMR (400 MHz, MeOD) 5 7.66 - 7.52 (m, 1H), 7.36 (s, 2H), 7.21 (d, J= 40.1 Hz, 3H), 4.47 (d, J= 62.4 Hz, 3H), 3.48 (s, 1H), 3.13 (s, 1H), 2.97 - 2.48 (m, 13H), 2.43 (s, 2H), 2.34 - 2.07 (m, 5H), 2.03 - 1.53 (m, 6H), 1.06 (d, J= 5.6 Hz, 6H).[000314] Compound 114-P2 LC / MS ESI 642.1 [M+H]+. 'HNMR (400 MHz, MeOD) 5 7.71 - 7.43 (m, 1H), 7.38 - 6.96 (m, 5H), 4.90 (s, 1H), 4.83 - 4.27 (m, 2H), 3.82 (s, 1H), 3.49- 3.33 (m, 1H), 2.71 (d, J= 78.6 Hz, 9H), 2.48 (s, 5H), 2.41 (s, 2H), 2.31 - 1.54 (m, 10H), 1.04 (d, J = 6.3 Hz, 6H).[000315] 114-P1 and 114-P2 were assigned as (R)-2-(((S)-3-(5-chloro-2-nuorophenyl)-3-(4 isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-fluorophenyl)- 3 -(4-isopropylpiperazin- 1 -yl)propyl)(methyl)amino)-2-(3 -methyl-2-(( 1 r,4 S)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetic acid, respectively.Example 7: Preparation of Compounds 115-P1 and 115-P2Step 1: ethyl (E)-3-(5-chloro-2-methylphenyl)acrylate[000316] A mixture of 5-chloro-2-methylbenzaldehyde (5.0 g, 32.3 mmol, 1.0 eq.) and ethyl 2-(triphenyl-15-phosphaneylidene)acetate (11.8 g, 33.9 mmol, 1.05 eq.) in 1,2-di chloroethane (100 mL) was stirred at 50°C for 3 hr. The reaction mixture was concentrated in vacuo. Crude residue was purified by silica gel column chromatography (20: 1 petroleum ether: EtOAc) to give ethyl (E)-3-(5-chloro-2-methylphenyl)acrylate (7.0 g, 96 %) (ESI 225.1 (M+H)+).Step 2: ethyl 3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-l-yl)propanoate[000317] To a solution of ethyl (E)-3-(5-chloro-2-methylphenyl)acrylate (11.5 g, 51.2 mmol, 1.0 eq.) in 1 -isopropylpiperazine (50 mL) was added LiCCU (11.8 g, 102.4 mmol, 2.0 eq.) and stirred at RT for 3 days. The mixture was poured into 200 mL water and extracted with EtOAc (3 x 100 mL). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography(3:1 petroleum ether: EtOAc) to give ethyl 3-(5-chloro-2-methylphenyl)-3-(4- isopropylpiperazin-l-yl)propanoate (8.7 g, 48 %) (ESI 353.2 (M+H)+).Step 3: 3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-l-yl)-N-methylpropanamide[000318] A mixture of ethyl 3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-l- yl)propanoate (8.4 g, 23.8 mmol) in MeNEE solution (IM in MeOH, 300 mL) was stirred RT for 3 days. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (20: 1 dichloromethane: MeOH) to give racemic product as white solid (7.0 g, 87%). Enantiomers were further separated by prep chiral SFC F to give amide Pl (2.9 g) and amide P2 (2.8 g).Step 4: (S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-l-yl)-N-methylpropan-l- amine[000319] To a solution of (S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-l-yl)-N- methylpropanamide (2.8 g, 8.3 mmol, 1.0 eq.) P2 in THF (10 mL) was added LiAlEU (2.5M in THF, 10 mL, 24.9 mmol, 3.0 eq.). The reaction was stirred at 60 °C for Ihr. The mixture was cooled to 0°C. NaSCL-lOEEO was added slowly and the mixture was stirred for 10 mins, filtered through a pad of Celite and the filtrate was concentrated in vacuo to give (S)-3-(5- chloro-2-methylphenyl)-3-(4-isopropylpiperazin-l-yl)-N-methylpropan-l-amine (2.1 g, 6.48 mmol, crude). (ESI 324.3 [M+H]+). Crude product was used directly in the subsequent step without further purification.Step 5: ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)- cyclohexyl)phenyl)acetate[000320] To a solution of (S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-l-yl)-N- methylpropan-1 -amine (200 mg, 0.62 mmol) and ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate (261 mg, 0.62 mmol) in acetonitrile (5 mL) was added K2CO3 (257 mg, 1.9 mmol, 3.0 eq). The reaction mixture was stirred at 70 °C for 3 hr, then filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20: 1 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(5-chloro- 2-methylphenyl)-3-(4-isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)- 4-(trifluoromethoxy)cyclohexyl)phenyl)acetate as a yellow liquid (210 mg, 50%)(ESI 666.2 [M+H]+).Step 6: 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-l-yl)propyl)- (methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid[000321] To a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4- isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate (210 mg, 0.31 mmol, 1.0 eq.) in ethanol (3 mL) and water (1 mL) was added NaOH (60 mg, 1.5 mmol, 5.0 eq.). The reaction was stirred at 80 °C for 16 hr. After completion, the reaction pH was adjusted to ~ 6 - 7 with IN HC1. Solvents were removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give diastereomeric product 115 as white solid (160 mg, 81.0%). Diastereomers were further separated by prep chiral SFC H to give 115-P1 (31.0 mg) and 115-P2 (41.0 mg).[000322] Compound 115-P1 LC / MS ESI 638.2 [M+H]+.1H NMR (400 MHz, MeOD) 57.53 (dd, J= 58.5, 6.9 Hz, 1H), 7.30 - 6.84 (m, 5H), 4.79 - 4.13 (m, 2H), 3.59 (s, 1H), 3.26 - 3.03 (m, 1H), 2.98 - 2.02 (m, 24H), 1.98 - 1.48 (m, 6H), 1.11 (d, J= 5.2 Hz, 6H).[000323] Compound 115-P2 LC / MS ESI 638.2 [M+H]+.1H NMR (400 MHz, MeOD) 57.57 (dd, J= 58.5, 6.9 Hz, 1H), 7.39 - 6.91 (m, 5H), 4.87 - 4.22 (m, 2H), 3.67 (s, 1H), 3.38 - 3.15 (m, 1H), 3.09 - 2.15 (m, 24H), 2.08 - 1.64 (m, 6H), 1.19 (d, J = 5.2 Hz, 6H).[000324] 115-P1 and 115-P2 were assigned as (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-3- (4-i sopropylpiperazin- 1 -yl)propyl)(methyl)amino)-2-(3 -methyl-2-(( 1 r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid and (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-3 -(4-isopropylpiperazin- 1 -yl)propyl)(methyl)amino)-2-(3 -methyl-2-(( 1 r,4 S)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetic acid, respectively.Example 8: Preparation of Compounds 119-P1 and 119-P2Step 1 : (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)-N-methyl-5- oxopentanamide[000325] To a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5- oxopentanoic acid (15.0 g, 55.7 mmol, 1.0 eq and 3,3-dimethylpyrrolidine (5.5 g, 55.7 mmol, 1.0 eq) in DMF(60 mL) was added HATU(25.4 g, 66.8 mmol, 1.2 eq) followed by DIEPA ( 14.4 g, 111.4 mmol, 2.0 eq . The reaction was stirred at RT for 2 hours. After completion, the mixture was quenched with NH4CI solution (100 ml) and extracted with EtOAc (3 x 150 ml). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo, purified by silica gel column chromatography (20: 1 dichloromethane: MeOH) to give (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin- l-yl)-N-methyl-5-oxopentanamide as a colorless oil (16.6 g, 85%) (ESI 351.1 [M+H]+).Step 2: (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)-N-methylpentan- 1-amine[000326] To a solution of (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-oxo-5-(piperidin-l- yl) pentanamide(16.6 g, 47.4 mmol, 1.0 eq) in THF(200 mL) at RT was added LiAlEL (56.9 mL, 142.3 mmol, 3.0 eq) dropwise and the reaction was stirred at 55 °C for 1 hour. After cooling to 0 °C, the reaction mixture was then quenched with water (5.5 mL) dropwise and stirred at 0 °C for another 10 min. 15% aqueous NaOH (5.5 mL) and water (16.5 mL) were then added sequentially at 0 °C. The mixture was allowed to warm to RT and stirred for another 15 min, dried over ISfeSCL, filtered and the filtrate was concentrated in vacuo to give (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)-N-methylpentan-l -amine as a white solid used directly in next reaction (13.1 g, 85% ) (ESI 323.3 [M+H]+).Step 3: l-fluoro-4-iodo-2-methyl-3-((lr,4r)-4-(vinyloxy)cyclohexyl)benzene[000327] To a solution of (lr,4r)-4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexan-l-ol (50.1 g, 150.0 mmol, 1.0 eq), Na2CO3(15.9 g, 150.0 mmol, 1.0 eq) and chloro-l,5-cycooctadiene iridium (I) dimmer (4.04 mg, 6.0 mmol, 0.04 eq) in Toluene (400mL) under N2 atmosphere was added vinyl acetate (38.7 g, 450 mmol, 3.0 eq) and the mixture was stirred at 100 °C for 16 hours. After completion, water (2 L) was added and the solution was extracted with EtOAc (3 x 800 mL). The combined organic layers were washed with brine (1 L), dried over anhydrous ISfeSCU, filtered and the filtrated was concentrated in vacuo. The residue was purified by silica gel conlumn chromatography (9 : 1 petroleum ether: EtOAc) to give 1-fluoro- 4-iodo-2-methyl-3-((lr,4r)-4-(vinyloxy)cyclohexyl)benzene as a yellow oil (27.0 g, 50%) eStep 4: 2-((lr,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-l-iodo-3-methylbenzene[000328] To a solution of l-fluoro-4-iodo-2-methyl-3-((lr,4r)-4- (vinyloxy)cyclohexyl)benzene (27.0 g, 75.0 mmol, 1.0 eq in dichloromethane (250 mL) at 0 °C was added Et2Zn(36.9 g, 300.0 mmol, 4.0 eq) dropwise. The reaction was stirred at 0 °C for 0.5 hr. The CH2l2(10.4 g, 300.0 mmol, 4.0 eq was added dropwise, warmed to room temeparure and stirring was continued for another 6 hr. The reaction was quenched with saturated NH4CI solution (1.5 L) slowly, extracted with dichloromethane (3 x 600 mL). The combined organic phases were washed with brine (900 mL), dried over anhydrous Na2SO4, filtered and the filtrated concentrated in vacuo. The residue was purified by silica gel conlumn chromatography (10: 1 petroleum ether: EtOAc) to give 2-((lr,4r)-4-cyclopropoxycyclohexyl)- 4-fluoro-l-iodo-3 -methylbenzene as a colorless oil (20.2 g, 72%).Step 5: ethyl 2-(2-((lr,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetate[000329] To a solution of 2-((lr,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-l-iodo-3- methylbenzene (20.2 g, 54 mmol, 1.0 eq), Pd2(dba)s (990 mg, 1.08 mmol, 0.02 eq and QPhos (792 mg, 1.08 mmol, 0.02 eq in tetrahydrofuran (100 mL) under N2 atmosphere was added (2- ethoxy-2-oxoethyl)zinc(II) bromide (162 mL, mol / 1, 162 mmol, 3.0 eq and the mixture was heated to 65 °C for Ihr. After completion, saturated NH4CI aqueous solution(500 mL) was added and the solution was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrated was concentrated in vacuo. The residue was purified by silica gel column chromatography (15: 1 petroleum ether: EtOAc) to give ethyl 2-(2-((lr,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3- methylphenyl)acetate as a colorless oil (17.0 g, 72%) (ESI 357.1 [M+Na]+).Step 6: ethyl 2-bromo-2-(2-((lr,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3- methylphenyl)acetate[000330] To a solution of LiHMDS (IM in THF, 102.0 ml, 102.0 mmol, 2.0 eq) at -78°C, ethyl 2-(2-((lr,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetate (17.0 g, 51.0 mmol, 1.0 eq) in tetrahydrofuran (150 ml) was added dropwise. The reaction was stirred at - 78°C for 0.5 hr. TMSC1 (H. lg, 102.0 mmol, 2.0 eq) was then added dropwise, and stirring was continued at -78°C for another 15 min. A solution of NBS (20.2 g, 102.0 mmol, 2.0 eq) in tetrahydrofuran (150 mL) was then added dropwise. The reaction was stirred at -78°C for another 1 hr., then warmed to 0 °C, quenched with saturated aqueous NH4CI solution (1.1 L) at 0°C, extracted with EtOAc (3 x 600 ml). Combined organic layers were washed with brine (500 ml x 3), dried over ISfeSCU, filtered and the filtrated was concentrated in vacuo. The residue was purified by silica gel column chromatography (19: 1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(2-((lr,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetate as a yellow oil (19.0 g, 90.2%) (ESI 435.0 [M+Na]+).Step 7: ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l- yl)pentyl)(methyl)amino)-2-(2-((lr,4S)-4-cyclopropoxycyclohexyl)-4-fluoro-3- methylphenyl)acetate[000331] To a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)- N-methylpentan-l-amine(10.0 g, 31.0 mmol, crude) in acetonitrile (150 mL), was added K2CO3 (12.42 g, 90 mmol, 3.0 eq). The mixture was stirred at RT for 15 min. The ethyl 2- bromo-2-(2-((lr,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetate (12.36 g, 30.0 mmol, 1.0 eq) was added. Stirring was continued at 80 °C for another 4 hr. After completion, the reaction mixture was filtered and the filtrated was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (20: 1 dichloromethane: MeOH) to give ethyl 2-(((S)-3 -(5 -chloro-2-methylphenyl)-5 -(3 , 3 -dimethylpyrrolidin- 1 - yl)pentyl)(methyl)amino)-2-(2-((lr,4S)-4-cyclopropoxycyclohexyl)-4-fluoro-3- methylphenyl)acetate as a yellow oil (14.1 g, 71.7%) (ESI 655.3 [M+H]+).Step 8: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l- yl)pentyl)(methyl)amino)-2-(2-((lr,4S)-4-cyclopropoxycyclohexyl)-4-fluoro-3- methylphenyl)acetic acid (Compound 119)[000332] Ethyl 2-(((S)-3-(5-chl oro-2 -methylphenyl)-5-(3, 3-dimethylpyrrolidin- 1- yl)pentyl)(methyl)amino)-2-(2-((lr,4S)-4-cyclopropoxycyclohexyl)-4-fluoro-3- methylphenyl)acetate (14.1 g, 21.5 mmol, 1.0 eq) was treated with NaOH (3.44 g, 86.0 mmol, 4.0 eq) in ethanol (120 mL) and water (40 mL) at 60 °C for 24 hr. The reaction mixture was acidified to pH ~5-6 with IN HC1. Solvents were removed in vacuo. Crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give the diastereomeric product 119 as white solid (10.6 g, 78.6%). Diastereomers were further separated by Prep chiral SFC P to give products 119-P1 (4.3 g) and 119-P2 (4.1 g) as white solids.[000333] Compound 119-P1 LC / MS ESI 627.4 [M+H]+.1H NMR (400 MHz, MeOD) 5 7.53 (dd, J = 65.0, 56.6 Hz, 1H), 7.08 - 6.93 (m, 3H), 6.73 (t, J = 9.0 Hz, 1H), 4.30 - 4.08 (m, 1H), 3.69 - 3.38 (m, 3H), 2.85 - 2.74 (m, 1H), 2.52 (dd, J = 11.2, 6.7 Hz, 2H), 2.40 - 2.07 (m, 17H), 1.98 (dd, J = 24.8, 11.8 Hz, 2H), 1.82 - 1.63 (m, 4H), 1.55 (t, J = 6.9 Hz, 3H), 1.49 - 1.29 (m, 3H), 1.11 - 0.98 (m, 6H), 0.59 - 0.43 (m, 4H).[000334] Compound 119-P2 LC / MS ESI 627.4 [M+H]+.1H NMR (400 MHz, MeOD) 5 7.57 (d, J= 106.9 Hz, 1H), 7.24 - 7.03 (m, 3H), 6.85 (dt, J= 33.2, 8.7 Hz, 1H), 4.52 (d, J= 85.4 Hz, 1H), 3.66 - 3.32 (m, 3H), 3.05 (dd, J= 26.6, 19.1 Hz, 3H), 2.83 - 2.28 (m, 12H), 2.24 - 1.98 (m, 8H), 1.94 - 1.69 (m, 6H), 1.59 - 1.30 (m, 3H), 1.10 (s, 6H), 0.64 - 0.43 (m, 4H).[000335] 119-P1 and 119-P2 were assigned as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5- (3, 3-dimethylpyrrolidin- l-yl)pentyl)(methyl)amino)-2-(2-((lr,4R)-4-cy cl opropoxy cyclohexyl)- 4-fluoro-3-methylphenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(2-((lr,4S)-4-cyclopropoxycyclohexyl)-4- fluoro-3-methylphenyl)acetic acid, respectively.119-P1 119-P2Example 9: Preparation Compounds 162-P1 and 162-P2Step 1: l-iodo-3-methyl-2-((lr,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)benzene[000336] To a solution of (ls,4s)-4-(2-iodo-6-methylphenyl)cyclohexan-l-ol (4.4 g, 13.9 mmol, 1.0 eq ) and ADDP (7.0 g, 27.8 mmol, 2.0 eq) in toluene (70 mL) at 0°C, PBus (5.6 g, 27.8 mmol, 2.0 eq.) was added dropwise. The reaction was stirred at 0°C for 10 min. 2,2,2- trifluoroethan-l-ol (13.9 g, 139.0 mmol, 10.0 eq.) was then added dropwise. The reaction was heated at 70°C for 16 hr. The reaction was poured into water (60 mL) and extracted with EtOAc (3 x 50 mL). Combined organic layers were washed with brine (3 x 50 ml), dried over Na2SO4, filtered, and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give l-iodo-3-methyl-2-((lr,4r)-4-(2,2,2- trifluoroethoxy)cyclohexyl)benzene as a colorless oil (1.25 g, 26%) (ESI 421.0 [M+Na]+).Step 2: ethyl 2-(3-methyl-2-((lr,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl) phenyl)acetate[000337] To a suspension of l-iodo-3-methyl-2-((lr,4r)-4-(2,2,2- trifhioroethoxy)cyclohexyl) benzene (1.25 g, 3.1 mmol, 1.0 eq.) in THF (10 mL) was added Pd2dba3 (140 mg, 0.16 mmol, 0.05 eq.) and QPhos (88 mg, 0.12 mmol, 0.04 eq.) followed by(2-ethoxy-2-oxoethyl)zinc(II) bromide (IM in THF, 15.5 mL, 15.5 mmol, 5.0 eq.). The mixture was stirred at 65 °C under N2 atmosphere for 1 hr., then poured into 50 mL saturated aqueous NH4CI solution and extracted with EtOAc (3 x 50 mL). Combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (20: 1 petroleum ether: EtOAc) to give ethyl 2-(3-methyl-2-((lr,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl) phenyl)acetate as a colorless oil (540 mg, 45%) (ESI 381.0 [M+Na]+).Step 3: ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl) phenyl)acetate[000338] To a solution of LiHMDS (IM in THF, 2.3 ml, 2.3 mmol, 1.5 eq.) at -78°C, ethyl 2-(3-methyl-2-((lr,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (540 mg, 1.5 mmol, 1.0 eq.) in THF (10 ml) was added dropwise. The reaction was stirred at -78°C for 0.5 hr. TMSC1 (240 mg, 2.3 mmol, 1.5 eq.) was then added dropwise, and stirring was continued at - 78°C for another 15 min. A solution of NBS (400 mg, 2.3 mmol, 1.5 eq) in THF (lOmL) was then added dropwise. The reaction was stirred at -78°C for another 1 hr., then warmed to 0 °C, quenched with saturated aqueous NH4CI solution (50 ml) at 0°C, and extracted with EtOAc (3 x 50 ml). Combined organic layers were washed with brine (3 x 50 ml), dried over Na2SO4, filtered, and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 PE: EA) to give ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetate as a colorless oil (440 mg, 68%) (ESI 459.1 [M+Na]+).Step 4: ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)- 2-(3-methyl-2-((lr,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl) phenyl)acetate[000339] To a solution of ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetate (220 mg, 0.5 mmol, 1.0 eq.) in acetonitrile (6 mL) was added K2CO3 (210 mg, 1.5 mmol, 3.0 eq.) followed by (R)-3-(5-chloro-2-methylphenyl)- N-methyl-5-(piperidin-l-yl)pentan-l-amine (200 mg, 0.65 mmol, 1.3 eq.). The mixture was stirred at 70°C for 3hr. After completion, the reaction mixture was filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (9: 1 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl) phenyl)acetate as a yellow oil (250 mg, 75%) (ESI 665.3 [M+H]+).Step 5: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3- methyl-2-((lr,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid[000340] To a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl) phenyl)acetate (250 mg, 0.38 mmol, 1.0 eq.) in ethanol (3 mL) and water (1 mL) was added NaOH (150 mg, 3.8 mmol, 10.0 eq.). The reaction was stirred at 60 °C for 16 hr. After completion, the reaction pH was adjusted to ~ 6 - 7 with IN HC1. Solvents were removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give diastereomeric product 162 as white solid (160 mg, 64%). Diastereomers were further separated by prep chiral SFC A to give 162-P1 (66 mg) and 162-P2 (68 mg).[000341] Compound 162-P1 LC / MS ESI 637.2 [M+H]+. 1H NMR (400 MHz, MeOD) 57.65 - 7.34 (m, 1H), 7.21 - 6.80 (m, 5H), 4.64 (d, J = 33.6 Hz, 1H), 4.02 - 3.84 (m, 2H), 3.68 -3.45 (m, 1H), 3.25 - 2.96 (m, 1H), 2.93 - 2.55 (m, 5H), 2.54 - 2.29 (m, 9H), 2.23 - 1.71 (m, 13H), 1.66 - 1.52 (m, 5H), 1.51 - 1.31 (m, 4H). RT (cSFC, (R,R)WHELK-O1): 1.54 min[000342] Compound 162-P2 LC / MS ESI 637.2 [M+H]+. 1H NMR (400 MHz, MeOD) 57.64 - 7.39 (m, 1H), 7.32 - 6.96 (m, 5H), 4.64 (d, J = 56.7 Hz, 1H), 4.11 - 3.77 (m, 2H), 3.72 - 3.42 (m, 1H), 3.29 - 2.90 (m, 2H), 2.86 - 2.41 (m, 12H), 2.39 - 2.24 (m, 2H), 2.21 - 1.76 (m, 12H), 1.70 - 1.59 (m, 4H), 1.58 - 1.32 (m, 5H). RT (cSFC, (R,R)WHELK-O1): 1.89 min.[000343] 162-P1 and 162-P2 were assigned as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetic acid, respectively.Example 10: Preparation of Compounds 164-P1 and 164-P2 )Step 1: ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)- (methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate[000344] To a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)- N-methylpentan-1 -amine (218 mg, 0.5 mmol) and ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4- (2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (196 mg, 0.5 mmol) in acetonitrile (5 mL) was added DIEA (200 mg, 1.5 mmol, 3.0 eq). The reaction mixture was stirred at 70 °C for 3 hr, then filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20: 1 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2- ((lr,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate as a yellow liquid (200 mg, 0.29 mmol, 49.1%). (ESI 679.2 [M+H]+).Step 2: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)- (methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid[000345] To a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3- dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetate (200 mg, 0.30 mmol, 1.0 eq.) in ethanol (3 mL) and water (1 mL) was added NaOH (72 mg, 1.8 mmol, 6.0 eq.). The reaction was stirred at 80 °C for 16 hr. After completion, the reaction pH was adjusted to ~ 6 - 7 with IN HC1. Solvents were removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give 164-P1 (44.2 mg) and 164-P2 (50.5 mg) as white solids.[000346] Compound 164-P1 LC / MS ESI 651.1 1H NMR (400 MHz, MeOD) 5 7.46 (dd, J = 44.3, 5.9 Hz, 1H), 7.06 (m, 5H), 4.65 (d, J = 32.3 Hz, 1H), 4.04 - 3.89 (m, 2H), 3.51 (t, J = 11.6 Hz, 1H), 3.13 (m, 1H), 2.84 (d, J = 49.9 Hz, 4H), 2.63 (d, J = 17.5 Hz, 3H), 2.54 - 2.37 (m, 6H), 2.32 (s, 2H), 2.23 - 1.71 (m, 12H), 1.65 (t, J = 7.0 Hz, 2H), 1.58 - 1.31 (m, 3H), 1.11 (d, J = 21.1 Hz, 6H).[000347] Compound 164-P2 LC / MS ESI 651.1 [M+H]+. 1H NMR (400 MHz, MeOD) 5 7.53 (dd, J = 77.8, 5.8 Hz, 1H), 7.10 (m, 5H), 4.61 (d, J = 57.7 Hz, 1H), 3.96 (m, 2H), 3.54 (dd, J = 26.8, 15.7 Hz, 1H), 3.08 - 2.80 (m, 3H), 2.61 (d, J = 11.2 Hz, 4H), 2.56 - 2.30 (m, 8H), 2.25 - 1.73 (m, 13H), 1.67 (dd, J = 14.2, 7.0 Hz, 2H), 1.58 - 1.31 (m, 3H), 1.09 (s, 6H).[000348] 164-P1 and 164-P2 were assigned as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5- (3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5- (3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetic acid, respectively.164-P1 164-P2Example 11: Preparation of Compounds 183-P1 and 183-P2Step 1 : 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)-N-methylpropanamide[000349] A solution of 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)-N- methylpropanamide (27 g, 75.8 mmol, 1.0 eq.) in methylamine (33% in methanol, 35.6 g, 379mmol, 5.0 eq) was stirred at 60°C for 16 hr. The reaction was concentrated in vacuo.. Crude residue was purified by silica gel column chromatography (4: 1 petroleum ether: EtOAc) to give 3-(5-chloro-2-fluorophenyl)-N-methyl-3-(4-methylpiperazin-l-yl)propanamide (22 g, 85%). 10g enantiomers was further separated by prep chiral SFC C to give amide Pl (4.2 g) and amide P2 (4.2 g) as yellow oil (ESI 342.1 [M+H]+).Step 2: (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)-N-methylpropan-l- amine[000350] To a solution of (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)-N- methylpropanamide (4.2 g, 12.3mmol, 1.0 eq.) in THF (50 mL) at 0 °C was added LAH (37 mL, 37.0 mmol, 3 eq) under N2. The reaction was stirred at 60 °C for 20 min under N2. The reaction was quenched with water(1.4 mL) dropwise. NaOH(1.4 mL,15% in water) andwater(4.2 mL) and stirred at 0°C for 15 min, dried over anhydrous Na2SO4, filtrated and the filtrate was concentrated in vacuo. Crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)-N- methylpropan-1 -amine as a colorless oil (560 mg, 14%).Step 3: ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)- (methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2-trifluoroethoxy) cyclohexyl)phenyl)acetate[000351] To a solution of ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetate (200 mg, 0.46 mmol, 1.0 eq.) in acetonitrile (6 mL) was added K2CO3 (190 mg, 1.38 mmol, 3.0 eq.) and (S)-3-(5-chloro-2-fhiorophenyl)-3-(4- isopropylpiperazin-l-yl)-N-methylpropan-l -amine (200 mg, 0.6 mmol, 1.3 eq.). The mixture was stirred at 70°C for 3hr. After completion, the reaction mixture was filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (9: 1 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(5-chloro-2- fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4- (2,2,2-trifluoroethoxy) cyclohexyl)phenyl)acetate as a yellow oil (190 mg, 62%) (ESI 684.3 [M+H]+).Step 4: 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)- (methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl) phenyl)acetic acid (Compound 183)[000352] To a solution of ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin- l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2-trifluoroethoxy) cyclohexyl) phenyl)acetate (190 mg, 0.28 mmol, 1.0 eq.) in ethanol (3 mL) and water (1 mL) was added NaOH (110 mg, 2.8 mmol, 10.0 eq.). The reaction was stirred at 60 °C for 16 hr. After completion, the reaction pH was adjusted to ~ 6 - 7 with IN HC1. Solvents were removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give diastereomeric product 183 as white solid (100 mg, 53%). Diastereomers were further separated by prep chiral SFC A to give 183-P1 (42 mg) and 183-P2 (42 mg).[000353] Compound 183-P1 LC / MS ESI 656.2 [M+H]+. 1H NMR (400 MHz, MeOD) 57.65 - 7.50 (m, 1H), 7.46 - 7.05 (m, 5H), 4.89 (s, 1H), 4.33 (s, 1H), 4.12 - 3.89 (m, 2H), 3.83- 3.50 (m, 2H), 3.28 - 3.08 (m, 2H), 2.98 - 2.34 (m, 15H), 2.30 - 1.82 (m, 7H), 1.79 - 1.35 (m, 3H), 1.20 - 0.99 (m, 6H). RT (chiral SFC A): 1.28 min[000354] Compound 183-P2 LC / MS ESI 656.2 [M+H]+. 1H NMR (400 MHz, MeOD) 5 7.70 - 7.44 (m, 1H), 7.41 - 6.99 (m, 5H), 4.89 (s, 1H), 4.80 (s, 1H), 4.09 - 3.83 (m, 3H), 3.74 - 3.51 (m, 1H), 3.30 - 3.15 (m, 2H), 3.08 - 2.30 (m, 17H), 2.31 - 2.12 (m, 3H), 2.11 - 1.69 (m, 4H), 1.63 - 1.39 (m, 2H), 1.20 - 1.00 (m, 6H). RT (chiral SFC A): 1.80 min[000355] 183-P1 and 183-P2 were assigned as (R)-2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4- isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-fluorophenyl)-3- (4-isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(2,2,2- trifluoroethoxy)cyclohexyl)phenyl)acetic acid, respectively.Example 12: Preparation of Compound 300-P3Step 1: tert-butyl 4-fluoro-4-(methoxy(methyl)carbamoyl)piperidine-l-carboxylate[000356] To a solution of l-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (10 g, 40.4 mmol, 1.0 eq.), A,O-dimethylhydroxylamine hydrochloride (4.7 g, 48.5 mmol, 1.2 eq.), HOBt (6.6 g, 48.5 mmol, 1.2 eq.) and TEA (12.3 g, 121.2 mmol, 3.0 eq.) in DCM (100 ml) was added 1 -ethyl-3 -(3 '-dimethylaminopropyl)carbodiimide hydrochloride (8.5 g, 44.5 mmol, 1.1 eq.). The reaction mixture was allowed to stir at RT for 1 hr, diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (5: 1 petroleum ether: EtOAc) to give tert-butyl 4-fluoro-4-(methoxy(methyl)carbamoyl)piperidine-l -carboxylate as a colorless oil (9.1 g, 77%) (ESI 235.3 [M-tBu+H]+).Step 2: tert-butyl 4-(3-chlorobenzoyl)-4-fluoropiperidine-l-carboxylate[000357] To a solution of l-bromo-3 -chi oro-5 -methylbenzene (6.6 g, 34.4 mmol, 1.1 eq.) in anhydrous THF (100 mL) at -78 °C was added n-BuLi (2.5 M in hexane, 10.4 mL, 26.1 mmol, 1.2 eq.). The reaction mixture was allowed to stir at -78 °C for 30 min. A solution of tert-butyl 4-fluoro-4-(methoxy(methyl)carbamoyl)piperidine-l -carboxylate (9.1 g, 31.3 mmol, 1.0 eq.) in THF (20 mL) was then added. The reaction was allowed to continue to stir at -78 °C for another 1 hr. The reaction was quenched by the addition of saturated aqueous NH4CI (100 mL) and extracted with EtOAc (2 x 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give tert-butyl 4-(3 -chi orobenzoyl)-4-fluoropiperi dine- 1 -carboxylate as a colorless oil (9.0 g, 84.0 %) (ESI 286.1 [M-tBu+H]+).Step 3: tert-butyl (Z)-4-(l-(3-chlorophenyl)-3-ethoxy-3-oxoprop-l-en-l-yl)-4- fluoropiperidine-l-carboxylate[000358] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (7.8 g, 35.1 mmol, 1.5 eq) in anhydrous THF (50 mL) at 0 °C was added NaHMDS (1.0 M in THF, 35.1 mL, 35.1 mmol, 1.5 eq) dropwise. The reaction mixture was allowed to stir at RT for 0.5 hr. A solution of tert-butyl ((lr,3r)-3-(3-chlorophenyl)-3-(2-oxoethyl)cyclobutyl)(methyl)carbamate (8.0 g, 23.4 mmol, 1.0 eq) in THF (25 mL) was then added. The reaction was allowed to continue to stir at 45 °C for another 16 hrs, quenched by the addition of saturated aqueous NH4CI (80 mL) and extracted with EtOAc (3 x 100 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9: 1 petroleum ether: EtOAc) to give tert-butyl (Z)-4-(l-(3- chlorophenyl)-3 -ethoxy-3 -oxoprop- l-en-l-yl)-4-fluoropiperidine-l -carboxylate as a white solid(6.2 g, 64%) (ESI 434.1 [M +Na]+).Step 4: tert-butyl 4-(l-(3-chlorophenyl)-3-ethoxy-3-oxopropyl)-4-fluoropiperidine-l- carboxylate[000359] To a solution of tert-butyl (Z)-4-(l-(3-chlorophenyl)-3-ethoxy-3-oxoprop-l-en-l- yl)-4-fluoropiperidine-l -carboxylate (3.2 g, 7.77 mmol, 1.0 eq.) in EtOH (100 mL) were added PtO? (108 mg, 0.39 mmol, 0.05 eq.) and concentrated H2SO4 (0.05 mL). The reaction mixture was allowed to stir at RT under an atmosphere of H2 (1 atm, 3L) for 30 mins. Upon completion, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9: 1 petroleum ether: EtOAc) to give tert-butyl 4-(l-(3-chlorophenyl)-3-ethoxy-3-oxopropyl)-4- fhioropiperidine-l -carboxylate as a white solid (3.0 g, 93%) (ESI 436.3 [M+Na]+).Step 5: tert-butyl 4-(l-(3-chlorophenyl)-3-oxopropyl)-4-fluoropiperidine-l-carboxylateBoc Boc[000360] To a solution of tert-butyl 4-(l-(3-chlorophenyl)-3-ethoxy-3-oxopropyl)-4- fluoropiperidine-1 -carboxylate (3.0 g, 7.25 mmol, 1.0 eq.) in anhydrous toluene (50 ml) was added DIBA1-H (IM in toluene, 10.88 ml, 10.88 mmol, 1.5 eq.) at -78°C. The reaction mixture was allowed to stir at -78°C for 2 hrs. The reaction was quenched by the addition of saturated aqueous NH4CI (100 ml) and extracted with EtOAc (3 x 50 ml). The organic solutions were combined, washed with brine (3 x 20 ml), dried over ISfeSCU, filtered, and concentrated in vacuo to give tert-butyl 4-(l-(3-chlorophenyl)-3-oxopropyl)-4-fluoropiperidine-l-carboxylate as a colorless oil (crude, 2.0 g, 74%) (ESI 392.1 [M+Na]+). The crude product was used directly in the subsequent step without further purification.Step 6: tert-butyl 4-(l-(3-chlorophenyl)-3-(methylamino)propyl)-4-fluoropiperidine-l- carboxylateBoc Boc[000361] To a solution of tert-butyl 4-(l-(3-chlorophenyl)-3-oxopropyl)-4-fluoropiperidine- 1-carboxylate (2.0 g, 5.41 mmol, 1.0 eq.) in MeOH (100 mL) was added methanamine hydrochloride (1.8 g, 27.05 mmol, 5.0 eq.). The reaction mixture was allowed to stir at RT for 1 hr. NaBH(OAc)s (3.4 g, 16.23 mmol, 3.0 eq.) was then added. The reaction was allowed to continue to stir at RT for another 16 hrs and then concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give tert-butyl 4-(l-(3- chlorophenyl)-3-(methylamino)propyl)-4-fluoropiperidine-l -carboxylate as a colorless oil (750 mg, 36%) (ESI 385.4 [M+H]+).Step 7: tert-butyl 4-(3-((2-(tert-butoxy)-l-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)- cyclohexyl)phenyl)-2-oxoethyl)(methyl)amino)-l-(3-chlorophenyl)propyl)-4- fluoropiperidine-l-carboxylate[000362] To a solution of tert-butyl 4-(l-(3-chlorophenyl)-3-(methylamino)propyl)-4- fluoropiperidine-1 -carboxylate (380 mg 0.99 mmol, 1.0 eq) in ACN (20 mL) was added DIPEA (384 mg, 2.97 mmol, 3.0 eq.) and tert-butyl 2-bromo-2-(3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate (491 mg, 1.09 mmol, 1.1 eq.). The mixture was allowed to stir at 60 °C for 20 hr. The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give tert-butyl 4-(3-((2-(tert-butoxy)-l-(3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)phenyl)-2-oxoethyl)(methyl)amino)-l-(3-chlorophenyl)propyl)- 4-fluoropiperidine-l-carboxylate as a colorless oil (350 mg, 47%) (ESI 755.6 [M+H]+).Step 8: tert-butyl 2-((3-(3-chlorophenyl)-3-(4-fluoropiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate[000363] Tert-butyl 4-(3-((2-(tert-butoxy)-l-(3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)-phenyl)-2-oxoethyl)(methyl)amino)-l-(3-chlorophenyl)propyl)- 4-fluoropiperidine-l-carboxylate (350 mg, 0.46 mmol, 1.0 eq) in dioxane (6 mL) was treated with HCl-MeOH (4M, 5 mL, 20mmol, 43.0 eq). The reaction mixture was allowed to stir at RT for 2 hr and concentrated in vacuo to obtain tert-butyl 2-((3-(3-chlorophenyl)-3-(4- fluoropiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate hydrochloride as a colorless oil (300 mg, 0.46 mmol, crude) (ESI 655.3 [M+H]+). The crude product was used directly in the subsequent step.Step 9: tert-butyl 2-((3-(3-chlorophenyl)-3-(4-fluoro-l-methylpiperidin-4-yl)propyl)- (methyl)amino)-2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate[000364] To a solution of tert-butyl 2-((3-(3-chlorophenyl)-3-(4-fluoropiperidin-4- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (300 mg, 0.46 mmol, 1.0 eq.) in MeOH (20 mL) was added 33% aqueous HCHO (4 mL, 42 mmol, 96.0eq). The reaction mixture was allowed to stir at RT for 1 hr. NaBH(OAc)3 (195 mg, 0.92 mmol, 2.0 eq.) was then added and the reaction was allowed to continue to stir at RT for another 20 hr. The reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9:1 DCM: MeOH) to give tert-butyl 2-((3-(3-chlorophenyl)-3-(4-fluoro-l-methylpiperidin-4- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate as colorless oil (280 mg, 91%) (ESI 669.3 [M+H]+).Step 10: 2-((3-(3-chlorophenyl)-3-(4-fluoro-l-methylpiperidin-4- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid[000365] To a solution of tert-butyl 2-((3-(3-chlorophenyl)-3-(4-fluoro-l-methylpiperidin-4- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (280 mg, 0.42 mmol, 1.0 eq) in DCM (1 mL) was added TFA (5mL, 79 mmol, 189.0 eq). The reaction mixture was allowed to stir overnight at RT. Solvent was removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give a mixture of isomeric compounds 300 as a white solid (200 mg, 78%).Isomers were further separated by prep chiral SFC I to give 300-P1-1 (16.7 mg), 300-P1-2 (16.7 mg), 300-P2 (16.5 mg) and 300-P3 (30.0 mg) as white solids.[000366] 300-P1-1, assigned as (R)-2-(((R)-3-(3-chlorophenyl)-3-(4-fluoro-l- methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 613.2 [M+H]+. *HNMR (400 MHz, MeOD) 5 7.58 - 6.95 (m, 7H), 4.85 - 4.77 (m, 1H), 4.55 - 4.30 (m, 1H), 3.16 - 2.60 (m, 7H), 2.53 - 1.94 (m, 16H), 1.92 - 1.30 (m, 8H).[000367] 300-P1-2, assigned as (S)-2-(((R)-3-(3-chlorophenyl)-3-(4-fluoro-l- methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 613.3 [M+H]+. 'H NMR (400 MHz, MeOD) 5 7.58 - 6.88 (m, 7H), 4.83 - 4.75 (m, 1H), 4.55 - 4.30 (m, 1H), 3.20 - 2.55 (m, 8H), 2.58 - 1.95 (m, 16H), 1.95 - 1.34 (m, 7H).[000368] 300-P2, assigned as (R)-2-(((S)-3-(3-chlorophenyl)-3-(4-fluoro-l-methylpiperidin- 4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 613.3 [M+H]+. *HNMR (400 MHz, MeOD) 5 7.59 - 6.86 (m, 7H), 4.86 - 4.74 (m, 1H), 4.55 - 4.30 (m, 1H), 3.22 - 3.03 (m, 1H), 3.00 -2.58 (m, 6H), 2.54 - 1.98 (m, 16H), 1.98 - 1.37 (m, 8H).[000369] 300-P3, assigned as (S)-2-(((S)-3-(3-chlorophenyl)-3-(4-fluoro-l-methylpiperidin- 4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 613.3 [M+H]+. *HNMR (400 MHz, MeOD) 5 8.51 (s, 0.52H), 7.75 - 6.39 (m, 7H), 4.78 - 4.69 (m, 1H), 4.54 - 4.31 (m, 1H), 3.26 - 2.96 (m, 3H), 2.90 - 1.99 (m, 21H), 1.94 - 1.26 (m, 7H).Example 13: Preparation of Compound 301-P2Step 1: tert-butyl (S)-(3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)(methyl)- carbamate[000370] To a solution of 1 -isopropylpiperazine ( 678 mg 5.3 mmol, 1.0 eq) in ACN (10 mL) was added K2CO3 (2.2 g, 15.9 mmol, 3.0 eq.) and (R)-3-((tert- butoxycarbonyl)(methyl)amino)-l-(3-chlorophenyl)propyl methanesulfonate (2 g, 5.3 mmol, 1.0 eq). The reaction mixture was allowed to stir at 80 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give tert-butyl (S)-(3-(3-chlorophenyl)-3-(4- isopropylpiperazin-l-yl)propyl)(methyl)carbamate as a yellow oil (300 mg, 14%) (ESI 410.2 [M+H]+).Step 2: (S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l-yl)-N-methylpropan-l-amine[000371] To a solution of tert-butyl (S)-(3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)carbamate (300 mg, 0.73 mmol, 1.0 eq) in DCM (2 mL) was added TFA (1 mL, 13.5 mmol, 18.5 eq.). The reaction mixture was allowed to stir at RT for 2 hr and concentrated in vacuo to obtain (S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l-yl)-N- methylpropan-1 -amine as a yellow oil (180 mg, 0.58 mmol, crude) (ESI 310.2 [M+H]+). The crude product was used directly in the subsequent step.Step 3: tert-butyl 2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)-amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate[000372] To a solution of (S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l-yl)-N- methylpropan-1 -amine (180 mg 0.58 mmol, crude) in ACN (10 mL) was added K2CO3 (240 mg, 1.74 mmol, 5.0 eq.). The mixture was allowed to stir at RT for 15 min. Tert-butyl 2-bromo- 2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (262 mg, 0.58 mmol, 1.0 eq) was then added. The reaction was allowed to continue to stir at 80 °C for another 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue purified by silica gel column chromatography (9: 1 DCM: MeOH) to give tert-butyl 2-(((S)-3- (3-chlorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)- 4-(trifluoromethoxy)cyclohexyl)phenyl)acetate as a yellow oil (220 mg, 55%) (ESI 680.4[M+H]+).Step 4: 2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid[000373] To a solution of tert-butyl 2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (220 mg, 0.32 mmol, 1.0 eq) in DCM (1 mL) was added TFA (3 mL, 39 mmol, 122.0 eq). The reaction mixture was allowed to stir overnight at RT. Solvent was removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give a mixture of stereoisomeric compounds 301 as a white solid (160 mg, 80%). Isomers were further separated by prep chiral SFC A to give 301-P1 (65 mg) and 301-P2 (82 mg) as a white solids.[000374] 301-P1, assigned as (R)-2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 634.2 [M+H]+. 1H NMR (400 MHz, CD3OD) 5 7.64-7.51 (m, 1H), 7.45-7.09 (m, 6H), 5.08-4.91 (m, 1H), 4.60-4.32 (m, 1H), 4.20-3.75 (m, 1H), 3.70-3.40 (m, 1H), 3.23-2.98 (m, 2H), 2.90-2.40 (m, 15H), 2.38- 2.13 (m, 4H), 2.10 - 1.55 (m, 6H), 1.34-0.96 (m, 6H).[000375] 301-P2, assigned as (S)-2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 634.2 [M+H]+. 1H NMR (400 MHz, CD3OD) 5 7.61-7.43 (m, 1H), 7.40-7.03 (m, 6H), 5.02-4.89 (m, 1H), 4.62-4.30 (m, 1H), 3.65-3.42 (m, 1H), 3.25-3.10 (m, 1H), 3.08-2.40 (m, 17H), 2.38- 2.12 (m, 4H), 2.09 - 1.58 (m, 6H), 1.33-0.94 (m, 6H).Example 14: Preparation of Compound 302-P2Step 1: tert-butyl (S)-(3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-l- yl)propyl)(methyl)carbamate[000376] To a solution of (R)-3-((tert-butoxycarbonyl)(methyl)amino)-l-(3- chlorophenyl)propyl methanesulfonate (3.5 g, 9.26 mmol, 1.0 eq.) in ACN (30 mL) was added K2CO3 (3.83 g, 27.78 mmol, 3.3 eq.) and N, A-dimethylpiperidin-4-amine (1.19 g, 9.26 mmol, 1.0 eq.). The reaction mixture was allowed to stir at 80 °C for 16 hr., filtered and filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (15: 1 DCM: MeOH) to give tert-butyl (S)-(3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-l-yl)propyl)(methyl)carbamate as a yellow oil (490.0 mg, 12.9%)(ESI 410.3 [M+H]+).Step 2: (S)-l-(l-(3-chlorophenyl)-3-(methylamino)propyl)-N,N-dimethylpiperidin-4-amine[000377] To a solution of tert-butyl (S)-(3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin- l-yl)propyl)(methyl)carbamate (490 mg, 1.2 mmol, 1.0 eq in DCM (2 mL) was added TFA (1 mL, 13.5 mmol, 11.3 eq.). The reaction mixture was allowed to stir at RT for 2 hr. and concentrated in vacuo to obtain (S)-l-(l-(3-chlorophenyl)-3-(methylamino)propyl)-N,N- dimethylpiperidin-4-amine as a yellow oil (420 mg, 1.35 mmol, crude) (ESI 310.3 [M+H]+). The crude product was used directly in the subsequent step.Step 3: tert-butyl 2-(((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)- phenyl)acetate[000378] To a solution of (S)-l-(l-(3-chlorophenyl)-3-(methylamino)propyl)-N,N- dimethylpiperidin-4-amine (210 mg 0.67 mmol, crude) in ACN (10 mL) was added K2CO3 (427 mg, 3.1 mmol, 5.0 eqi). The mixture was allowed to stir at RT for 15 min. Tert-butyl 2- bromo-2-(3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (302 mg, 0.67 mmol, 1.0 eq) was then added. The reaction was allowed to continue to stir at 80 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give tert-butyl 2- (((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-l-yl)propyl)(methyl)amino)-2-(3- methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate as a yellow oil (220 mg, 39.5%) (ESI 680.3 [M+H]+).Step 4: 2-(((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-l-yl)propyl)(methyl)- amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid[000379] To a mixture of ethyl 2-(((ls,3R)-3-(3-chlorophenyl)-3-(2-(piperidin-l- yl)ethyl)cyclobutyl)(methyl)amino)-2-(4-fluoro-l-((lr,4R)-4-methoxycyclohexyl)-3-methyl- lH-indazol-7-yl)acetate (180.0 mg, 0.26 mmol, 1.0 eq) in DCM (1 mL) was added TFA (3mL, 39mmol, 150.0eq). The reaction mixture was allowed to stir overnight at RT. Solvent was removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give a mixture of stereoisomeric compounds 302 as a white solid (110.0 mg, 62%). Stereoisomers were further separated by prep chiral HPLC A to give 302-P1 (30.3 mg) and 302-P2 (25.2 mg) as a white solids.[000380] 302-P1, assigned as (R)-2-(((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 7.59 - 7.48 (m, 1H), 7.40 - 7.09 (m, 6H), 4.70 (s, 1H), 4.45 (d, J = 51.0 Hz, 1H), 4.06 (s, 1H), 3.48 - 3.34 (m, 2H), 3.27 - 2.85 (m, 3H), 2.67 (s, 1H), 2.53 - 2.09 (m, 18H), 2.00 - 1.66 (m, 9H), 1.48 (d, J = 12.2 Hz, 1H).[000381] 302-P2, assigned as (S)-2-(((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin- l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 7.62 - 7.45 (m, 1H), 7.38 - 7.05 (m, 6H), 4.73 (s, 1H), 4.47 (d, J = 79.9 Hz, 1H), 3.59 - 3.48 (m, 1H), 3.33 (s, 1H), 3.06 (ddd, J = 105.0, 59.7, 37.4 Hz, 7H), 2.58 - 2.03 (m, 16H), 1.99 - 1.55 (m, 10H).51 (dd, J = 28.6, 17.5 Hz, 4H).Example 15: Preparation of Compound 303-1P2Step 1 : 5-(3-chlorobenzylidene)-2,2-dimethyl-l,3-dioxane-4, 6-dione[000382] To a solution of 3 -chlorobenzaldehyde (20.0 g, 142.3 mmol, 1.0 eq) and 2,2- dimethyl-l,3-dioxane-4, 6-dione (20.52 g, 142.3 mmol, 1.0 eq) in EtOH (500 mL) was added K3PO4 (6.0 g, 28.5 mmol, 0.2 eq). The reaction mixture was allowed to stir overnight at RT, then concentrated in vacuo. The crude residue was purified by silica gel column chromatography (3: 1 petroleum ether: EtOAc) to give 5-(3-chlorobenzylidene)-2,2-dimethyl- l,3-dioxane-4, 6-dione as a yellow solid. (15.0 g, 39.6%). 'H NMR (400 MHz, CDCI3) 8 8.34 (s, 1H), 8.04 (d, .7= 1.7 Hz, 1H), 7.87 (d, = 7.8 Hz, 1H), 7.52 (dd, J= 8.1, 0.8 Hz, 1H), 7.42 (dd, J = 9.1, 6.8 Hz, 1H), 1.82 (s, 6H).Step 2: 5-(l-(3-chlorophenyl)-4-(piperidin-l-yl)but-2-yn-l-yl)-2,2-dimethyl-l,3-dioxane-4,6-dione[000383] To a solution of l-(prop-2-yn-l-yl)piperidine (5.0 g, 40.6 mmol, 1.2 eq.) in anhydrous THF (100 mL) at 0 °C was added ethylmagnesium bromide (1 M in THF , 40.6 mL, 40.6 mmol, 1.2 eq.) dropwise. The reaction mixture was allowed to stir at 0 °C for 30 min. The resulting solution was added slowly into a solution of 5-(3-chlorobenzylidene)-2,2- dimethyl-l,3-dioxane-4, 6-dione (9.0 g, 33.8 mmol, 1.0 eq.) at 0 °C. The reaction was allowed to continue to stir at 0 °C for another 1 hr. The reaction was quenched by the addition ofsaturated aqueous NH4CI (200 mL). The solid which formed was filtered, collected and washed with EtOAc (100 mL) to give 5-(l-(3-chlorophenyl)-4-(piperidin-l-yl)but-2-yn-l-yl)-2,2- dimethyl-l,3-dioxane-4, 6-dione as a yellow solid (7.1 g, 53.9%) (ESI 390.1 [M+H]+).Step 3: 3-(3-chlorophenyl)-6-(piperidin-l-yl)hex-4-ynoic acid[000384] To a solution of 5-(l-(3-chlorophenyl)-4-(piperidin-l-yl)but-2-yn-l-yl)-2,2- dimethyl-l,3-dioxane-4, 6-dione (7.1 g, 18.2 mmol, 1.0 eq) in dioxane (75 mL) was added 36% aqueous HC1 (25 mL, 300 mmol, 16.5 eq.). The reaction mixture was allowed to stir at 100 °C for 16 hr. and concentrated in vacuo to obtain 3-(3-chlorophenyl)-6-(piperidin-l-yl)hex-4-ynoic acid as a yellow oil (4.0 g, 13.1 mmol, crude) (ESI 306.1 [M+H]+). The crude product was used directly in the subsequent step.Step 4: methyl 3-(3-chlorophenyl)-6-(piperidin-l-yl)hex-4-ynoate[000385] To a solution of 3-(3-chlorophenyl)-6-(piperidin-l-yl)hex-4-ynoic acid (6 g, 13.1 mmol, 1.0 eq.) in methanol (80 mL) was added H2SO4 (0.5 mL, 9 mmol, 0.69 eq.) dropwise at 0 °C. The mixture was allowed to stir at 65 °C for 1 hr. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (200 mL). The organic solution was washed with saturated aqueous NaHC03(200 mL) and brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (25: 1 DCM: MeOH) to give ethyl methyl 3-(3-chlorophenyl)-6- (piperidin-l-yl)hex-4-ynoate as a yellow oil (3.2 g, 76.3%) (ESI 320.1 [M+H]+).Step 5: methyl 3-(3-chlorophenyl)-6-(pi peridin- l-yl)hexanoate[000386] To a solution of ethyl methyl 3-(3-chlorophenyl)-6-(piperidin-l-yl)hex-4-ynoate (2.8 g, 8.75 mmol, 1.0 eq.) in methanol (32 mL) was added PtCh (100 mg, 0.44 mmol, 0.05 eq.). The reaction mixture was allowed to stir at RT under an atmosphere of H2 (1 atm) for 2 hr. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (25: 1 DCM: MeOH) to give methyl 3-(3-chlorophenyl)-6-(piperidin-l-yl)hexanoate as a yellow oil (1.5 g, 52.9%) (ESI 320.1 [M+H]+).Step 6: 3-(3-chlorophenyl)-N-methyl-6-(piperidin-l-yl)hexanamide[000387] To a solution of methyl 3-(3-chlorophenyl)-6-(piperidin-l-yl)hexanoate (1.5 g, 4.6 mmol, 1.0 eq) in MeOH (lOmL) was added methylamine (4M in THF, 20mL, 80mmol, 17.4 eq) and the reaction mixture was allowed to stir at RT for 16 hr. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (10: 1 DCM: MeOH) to give racemic product 3-(3-chlorophenyl)-N-methyl-6- (piperidin-l-yl)hexanamide (1.1 g, 74.0%) (ESI 323.2 [M+H]+). Enantiomers were separated by prep chiral SFC J to give two compounds. Peak 1 (400 mg), assigned as (S)-3-(3- chlorophenyl)-N-methyl-6-(piperidin-l-yl)hexanamide, and Peak 2 (300 mg), assigned as (R)- 3-(3-chlorophenyl)-N-methyl-6-(piperidin-l-yl)hexanamide.Step 7 : (S)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-l-yl)hexan-l-amine[000388] To a solution of assigned (S)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-l- yl)hexanamide (peak 1 from Step 6, 400 mg, 1.24 mmol, 1.0 eq) in THF (8 mL) at RT was added LAH (2.5M in THF, 1.5 mL, 3.72 mmol, 3.0 eq) dropwise and the reaction mixture was allowed to stir at 65 °C for 1 hr. After cooling to 0 °C, the reaction was quenched carefully with water (0.15 mL) and allowed to stir at 0 °C for another 10 min. 15% aqueous NaOH (0.15 mL) and water (0.45 mL) were then added sequentially at 0 °C. The mixture was allowed to warm to RT and stirred for another 15 min. The mixture was dried over ISfeSCL, filtered and filtrate was concentrated in vacuo to give assigned (S)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-l- yl)hexan-l -amine as a colorless oil used directly in next reaction (300 mg, crude, 78.2%) (ESI 309.2 [M+H]+).Step 8: ethyl 2-(((S)-3-(3-chlorophenyl)-6-(piperidin-l-yl)hexyl)(methyl)amino)-2-(3- methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate[000389] To a solution of assigned (S)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-l- yl)hexan-l -amine (150 mg, 0.49 mmol, crude) in ACN (5 mL) were added K2CO3 (338 mg, 2.45 mmol, 5.0 eq^) and ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)-phenyl)acetate (207 mg, 0.49 mmol, 1.0 eq). The reaction mixture was allowed to stir at 80 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give ethyl 2-(((S)-3-(3-chlorophenyl)-6-(piperidin-l- yl)hexyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate as a yellow oil (170 mg, 53.3%) (ESI 651.3 [M+H]+).Step 9: 2-(((S)-3-(3-chlorophenyl)-6-(piperidin-l-yl)hexyl)(methyl)amino)-2-(3-methyl-2- ((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid[000390] To a mixture of assigned ethyl 2-(((S)-3-(3-chlorophenyl)-6-(piperidin-l- yl)hexyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (170 mg, 0.26 mmol, 1.0 eq) in EtOH (4 mL) and H2O (1 mL) was added NaOH (52 mg, 1.3 mmol, 5.0 eq). The reaction mixture was allowed to stir at 80 °C for 16 hr. and concentrated in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give a mixture of stereoisomeric compounds 303 as a white solid (110 mg, 67.6%). The stereoisomers were further separated by prep chiral SFC A to give 303-1P1 (40 mg) and 303-1P2 (40 mg).[000391] 303-1P1, assigned as (R)-2-(((S)-3-(3-chlorophenyl)-6-(piperidin-l- yl)hexyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H]+. 1H NMR (400 MHz, CD3OD) 5 7.58 - 7.38 (m, 1H), 7.31 - 6.89 (m, 6H), 4.70 - 4.21 (m, 2H), 3.21 - 2.92 (m, 1H), 2.85 - 2.47 (m, 10H), 2.44 (s, 4H), 2.34 (s, 1H), 2.26 - 1.91 (m, 5H), 1.90 - 1.66 (m, 4H), 1.66 - 1.53 (m, 7H), 1.49 (s, 3H), 1.34 - 1.27 (m, 1H).[000392] 303-1P2, assigned as (S)-2-(((S)-3-(3-chlorophenyl)-6-(piperidin-l- yl)hexyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 7.68 - 7.36 (m, 1H), 7.32 - 6.85 (m, 6H), 4.62 - 4.26 (m, 2H), 3.13 (s, 1H), 2.87 - 2.53 (m, 9H), 2.54 - 2.42 (m, 5H), 2.39 (s, 1H), 2.24 - 2.08 (m, 3H), 2.06 - 1.72 (m, 5H), 1.72 - 1.55 (m, 7H), 1.54 - 1.36 (m, 4H), 1.35 - 1.23 (m, 1H).Example 16: Preparation of Compound 304-P2Step 1: 5-fluoro-2-iodo-l-methyl-3-nitrobenzene[000393] To a solution of 4-fhioro-2-methyl-6-nitroaniline (21.7 g, 127.6 mmol, 1.0 eq.) in THF (250 mL) at -10 °C was added aqueous HC1 (6M, 53 mL, 319 mmol, 2.5 eq.) and aqueous NaNO2 (9.7 g in 30 mL water, 140.36 mmol, 1.1 eq.) over 15 mins. The reaction mixture was allowed to stir at -10 °C for another 30 min. Aqueous KI (31.8 g in 30 mL water, 191.4 mmol, 1.5 eq.) was then added portionwise into the mixture. The reaction was allowed to warm to 0 °C and allowed to stir for 30 min. Water (300 mL) and EtOAc (300 mL) were added into the reaction. The organic solution was separated and washed with saturated aqueous Na2SOs (300 mL) and brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (15: 1 petroleum ether: EtOAc) to give 5-fluoro-2-iodo-l-methyl-3-nitrobenzene as a white solid (10.2 g, 28.4%) (ESI 282.0 [M+H]+).Step 2: 8-(4-fluoro-2-methyl-6-nitrophenyl)-l,4-dioxaspiro[4.5]dec-7-ene[000394] 5-fluoro-2-iodo-l-methyl-3-nitrobenzene (10.2 g, 36.30 mmol, 1.0 eq.), 4, 4,5,5- tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (10.1 g, 38.11 mmol, 1.05 eq.), K2CO3 (8.5 g, 61.71 mmol, 1.7 eq) and Pd(dppf)C12 (530 mg, 0.73 mmol, 0.02 eq.) were suspended in a mixture of dioxane (100 mL) and water (50 mL). The reaction mixture was allowed to stir overnight at 100 °C under an atmosphere of N2. The mixture was poured into 150 mL water and extracted with EtOAc (3 x 150 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (6: 1 petroleum ether: EtOAc) to give 8-(4-fluoro-2-methyl-6-nitrophenyl)-l,4-dioxaspiro[4.5]dec-7-ene as a yellow solid (8.3 g, 78.0%) (ESI 294.3 [M+H]+).Step 3: 5-fluoro-3-methyl-2-(l,4-dioxaspiro[4.5]decan-8-yl)aniline[000395] To a solution of 8-(4-fluoro-2-methyl-6-nitrophenyl)-l,4-dioxaspiro[4.5]dec-7-ene (8.3 g, 28.32 mmol, 1.0 eq.) in EtOH (100 mL) was added 10% Pd / C (1.9 g, 0.85 mmol, 0.03 eq). The reaction mixture was allowed to stir at 65 °C under an atmosphere of EE (1 atm, 3L) for 24 hr. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give 5-fhioro-3-methyl-2-(l,4-dioxaspiro[4.5]decan-8-yl)aniline as a yellow oil (5.3 g, 19.9 mmol, crude) (ESI 266.3 [M+H]+). The crude product was used directly in the subsequent step without further purification.Step 4: 4-(2-amino-4-fluoro-6-methylphenyl)cyclohexan-l-one[000396] To a solution of 5-fhioro-3-methyl-2-(l,4-dioxaspiro[4.5]decan-8-yl)aniline (4.6 g, 17.35 mmol, 1.0 eq.) in THF (100 mL) was added 3M aqueous HC1 (17 mL, 52.05 mmol, 3.0 eq.). The reaction mixture was allowed to stir at RT for 1 hr. The reaction mixture was cooled to 0 °C, quenched by the addition of saturated aqueous NaHCCL solution (pH adjusted to ~8), and extracted with EtOAc (100 mL). The organic solution was separated, washed with brine, dried over Na?SO4, filtered, and concentrated in vacuo to give 4-(2-amino-4-fluoro-6- methylphenyl)-cyclohexan-l-one as a yellow oil (3.7 g, 16.74 mmol, crude) (ESI 222.1 [M+H]+). The crude product was used directly in the next step.Step 5: 4-(4-fluoro-2-iodo-6-methylphenyl)cyclohexan-l-one[000397] To a solution of 4-(2-amino-4-fluoro-6-methylphenyl)cyclohexan-l-one (3.7 g, 16.74 mmol, 1.0 eq.) in THF (20 mL) at -10 °C was added aqueous HC1 (6M, 7 mL, 41.8 mmol, 2.5 eq.) followed by aqueous NaNO? (1.3 g in 3 mL water, 18.41 mmol, 1.1 eq.) dropwise over 15 mins. The reaction mixture was allowed to stir at -10 °C for another 30 min.Aqueous KI (4.1 g in 3 mL water, 25.11 mmol, 1.5 eq.) was then added portionwise into the mixture. The reaction was allowed to warm to 0 °C and the reaction mixture was allowed to continue to stir for 30 min. Water (100 mL) and EtOAc (100 mL) were added into the reaction. The organic solution was separated, washed with saturated aqueous ISfeSOs (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (15: 1 petroleum ether: EtOAc) to give 4-(4- fluoro-2-iodo-6-methylphenyl)cyclohexan-l-one as a white solid (2.5 g, 44.9%) (ESI 333.0 [M+H]+).Step 6: (lr,4r)-4-(4-fluoro-2-iodo-6-methylphenyl)cyclohexan-l-ol[000398] To a solution of 4-(4-fluoro-2-iodo-6-methylphenyl)cyclohexan-l-one (2.5 g, 7.53 mmol, 1.0 eq.) in THF (25 mL) and MeOH (4 mL) at 0 °C was added CeCh (2.2 g, 9.03 mmol, 1.2eq) followed by NaBH4 (343 mg, 9.03 mmol, 1.2 eq) in portions. The mixture was allowed to stir at 0 °C for 0.5 hr. H2O (50 mL) was slowly added at 0 °C, and the mixture was extracted with EtOAc (3 x 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (4: 1 petroleum ether: EtOAc) to give assigned (lr,4r)-4-(4- fhioro-2-iodo-6-methylphenyl)cyclohexan-l-ol as a white solid (1.2 g, 47.7%) (ESI 317.0 [M- OH]+).Step 7: 5-fluoro-l-iodo-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)benzene[000399] A mixture of assigned (lr,4r)-4-(4-fluoro-2-iodo-6-methylphenyl)-cyclohexan-l-ol (1.2 g, 3.6 mmol, 1.0 eq ), Selectfluor (1.91 g, 5.4 mmol, 1.5 eq ), KF (838 mg, 14.4 mmol, 4 eq ) and AgOTf (2.76 g, 10.8 mmol, 3.0 eq ) in EtOAc (20 mL) were allwed to stir at RT for 5 min under an atmosphere of N2. 2-fluoropyridine (1050 mg, 10.8 mmol, 3 eq) and TMSCF3 (1.5 g, 10.8 mmol, 3 eq) were then added. The reaction mixture was allowed to stir at RT for48 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (97:3 petroleum ether: EtOAc) to give assigned 5-fluoro-l-iodo-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)- cyclohexyl)benzene as a white solid (680 mg, 46 %) (ESI 403.0 [M+H]+).Step 8: ethyl 2-(5-fluoro-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate[000400] To a solution of assigned 5-fluoro-l-iodo-3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)benzene (680 mg, 1.68 mmol, 1.0 eq), Pd2(dba)s (76 mg, 0.062 mmol, 0.05 eq) and Qphos(60 mg, 0.084 mmol, 0.05 eq) in THF (20 ml) under an atmosphere of N2 was added (2-ethoxy-2-oxoethyl)zinc(II) bromide (IM in THF, 5.04 mL, 5.04 mmol, 3.0 eq) and the mixture was allowed to stir at 80°C for Ihr. Saturated aqueous NH4CI (20 mL) was added, and the solution was extracted with EtOAc (20 mL x 3). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered and the filtrated was concentrated in vacuo. The residue was purified by silica gel column chromatography (20: 1 petroleum ether: EtOAc) to give ethyl 2-(5-fluoro-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)- cyclohexyl)phenyl)acetate as a yellow oil (550 mg, 90%) (ESI 363.2(M+H)+).Step 9: ethyl 2-bromo-2-(5-fhioro-3-methyl-2-((lr,4r)-4-(trifhioromethoxy)- cyclohexyl)phenyl)acetate[000401] To a solution of LiHMDS (IM in THF, 3.5 mL, 3.50 mmol, 2.3 eq.) at -78°C, assigned ethyl 2-(5-fluoro-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)-phenyl)acetate (550 mg, 1.52 mmol, 1.0 eq.) in THF (10 mL) was added dropwise. The reaction mixture was allowed to stir at -78°C for 0.5 hr. TMSCI (380 mg, 3.50 mmol, 2.3 eq.) was then added dropwise, and the reaction was allowed to continue to stir at -78°C for another 15 min. Asolution of NBS (270 mg, 1.52 mmol, 2.3 eq) in THF (5 mL) was then added dropwise. The reaction mixture was allowed to stir at -78°C for another 1 hr., then warmed to 0 °C, quenched by the addition of saturated aqueous NH4CI (20 ml), and extracted with EtOAc (3 x 20 ml). The organic solutions were combined, washed with brine (3 x 20 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(5-fluoro-3-methyl-2- ((lr,4r)-4-(trifluoromethoxy)-cyclohexyl)phenyl)acetate as a colorless oil(300mg, 44 %)(ESI 442.2[M+H]+).Step 10: tert- butyl 4-(2-(methoxy(methyl)amino)-2-oxoethyl)pi peridine- 1-carboxylate[000402] To a solution of 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (10 g, 41.1 mmol, 1.0 eq.), A,O-dimethylhydroxylamine hydrochloride (4.4 g, 45.2 mmol, 1.1 eq.), HOBT (5.5 g, 41.1 mmol, 1.0 eq.) and TEA (5.3 g, 90.42 mmol, 2.2 eq.) in DCM (100 ml) were added l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (8.7 g, 45.2 mmol, 1.1 eq.). The reaction mixture was allowed to stir at 50 °C for 1 hr, then diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (95:5 DCM: MeOH) to give tert-butyl 4-(2- (methoxy(methyl)-amino)-2-oxoethyl)piperidine-l -carboxylate as a yellow solid (9.1 g, 77.4%) (ESI 187.4 [M-Boc+H]+).Step 11: tert- butyl 4-(2-oxo-2-(3-(trifluoro methyl) phenyl) ethyl) piperidine- 1-carboxylate[000403] To a solution of l-bromo-3-(trifhioromethyl)benzene (8.6 g, 38.2 mmol, 1.2 eq.) in anhydrous THF (100 mL) at -78 °C was added n-BuLi (2.5 M in hexane, 15.2 mL, 38.2 mmol, 1.2 eq.). The reaction mixture was allowed to stir at -78 °C for 30 min. A solution of tert-butyl 4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-l-carboxylate (9.1 g, 31.8 mmol, 1.0 eq.)in THF (50 mL) was then added. The reaction was allowed to continue to stir at -78 °C for another 1 hr. The reaction was quenched by the addition of saturated aqueous NH4CI (100 mL) and extracted with EtOAc (2 x 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (12: 1 petroleum ether: EtOAc) to give tert-butyl 4-(2-oxo-2-(3 -(trifluoromethyl) phenyl) ethyl) piperidine- 1 -carboxylate as a yellow solid (5.1 g, 43.2%) (ESI 272.4 [M-Boc+H]+).Step 12: tert-butyl (E)-4-(4-ethoxy-4-oxo-2-(3-(trifluoromethyl)phenyl)but-2-en-l- yl)piperidine-l-carboxylate[000404] To a solution of methyl 2-(dimethoxyphosphoryl)acetate (3.05 g, 16.4 mmol, 1.2 eq) in anhydrous THF (10 mL) at 0 °C was added t-BuOK (1.8 g, 16.4 mmol, 1.2 eq). The reaction mixture was allowed to stir at 0 °C for 30 min. A solution of tert-butyl 4-(2-oxo-2-(3- (trifhroromethyl) phenyl) ethyl) piperidine- 1 -carboxylate (5.1g, 13.7 mmol, 1.0 eq) in THF (10 mL) was then added. The reaction was allowed to continue to stir at 0 °C for another 12 hr, quenched by the addition of saturated aqueous NH4CI (20 mL) and extracted with EtOAc (3 x 20 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (20: 1 petroleum ether: EtOAc) to give tert-butyl (E)-4-(4-ethoxy-4-oxo-2-(3- (trifluoromethyl)phenyl)but-2-en-l-yl)piperidine-l -carboxylate as a yellow oil (3.5 g, 58%) (ESI 442.1 [M+H]+).Step 13: tert-butyl 4-(4-ethoxy-4-oxo-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-l- carboxylate[000405] To a solution of tert-butyl (E)-4-(4-ethoxy-4-oxo-2-(3 -(trifluoromethyl) phenyl) but-2-en-l-yl)piperidine-l -carboxylate (3.5 g, 7.9 mmol, 1.0 eq.) in EtOH (25 mL) was added 10% Pd / C (500mg, 0.24 mmol, 0.03 eq). The reaction mixture was allowed to stir at 65 °C under an atmosphere of EE (1 atm, 3L) for 24 hr. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give tert-butyl 4-(4-ethoxy-4-oxo-2- (3 -(trifluoromethyl)phenyl)butyl)piperidine-l -carboxylate as a yellow oil (3.3 g, 7.4 mmol, crude) (ESI 444.3 [M+H]+). The crude product was used directly in the subsequent step without further purification.Step 14: tert- butyl 4-(4-hydroxy-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-l-carboxylate[000406] To a solution of tert-butyl 4-(4-ethoxy-4-oxo-2-(3-(trifluoromethyl)phenyl)butyl)- piperidine-1 -carboxylate (3.3 g, 7.4 mmol, 1.0 eq.) in THF (20 ml) at 0°C was added LAH (IM in THF, 18.5 mL, 18.5 mmol, 2.5 eq.). The reaction mixture was allowed to stir at 0 °C for 1 hr and quenched by the addition of water (0.1 mL). The reaction was allowed to continue to stir at 0 °C for 10 min. 15% aqueous NaOH (0.1 mL) and water (0.2 mL) were then added sequentially at 0 °C. The reaction mixture was allowed to warm to RT and stirred for another 15 min. The mixture was dried over ISfeSCU, filtered and concentrated in vacuo to give tertbutyl 4-(4-hydroxy-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-l -carboxylate as a crude colorless oil (3.1 g, 7.7 mmol, crude) (ESI 402.0 [M+H]+). The crude product was used directly in the subsequent step without further purification.Step 15: tert-butyl 4-(4-(l,3-dioxoisoindolin-2-yl)-2-(3-(trifluoromethyl)phenyl)butyl)- pi peri dine- 1-carboxylate[000407] To a solution of tert-butyl 4-(4-hydroxy-2-(3-(trifluoromethyl)phenyl)- butyl)piperidine-l -carboxylate (3.1 g, 7.7 mmol, 1.0 eq) and isoindoline-1, 3-dione (1.5 g, 10.01 mmol, 1.3 eq) in toluene (30 mL) at 0 °C were added triphenylphosphine (2.6 g, 10.01 mmol, 1.3 eq) and diisopropyl azodi carb oxy late (2.0 g, 10.01 mmol, 1.3 eq). The reaction mixture was allowed to stir at RT for 3 hr, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to give tert-butyl 4-(4-(l,3-dioxoisoindolin-2-yl)-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-l- carboxylate as a yellow oil (2.9 g, 71 %) (ESI 531.9 [M+H]+).Step 16: tert- butyl 4-(4-amino-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-l-carboxylate[000408] A solution of tert-butyl 4-(4-(l,3-dioxoisoindolin-2-yl)-2-(3-(trifluoromethyl)- phenyl)butyl)piperidine-l -carboxylate (2.9 g, 5.47 mmol, 1.0 eq) and 98% N2H4 H2O (547 mg, 10.94 mmol, 2 eq) in EtOH (10 mL) was allowed to stir at 70 °C for Ihr. The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give tert-butyl 4-(4-amino-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-l- carboxylate as yellow oil (2 g, 91%) (ESI 401.0 [M+H]+).Step 17: tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)- butyl)piperidine-l-carboxylate[000409] To a solution of tert-butyl 4-(4-amino-2-(3- (trifluoromethyl)phenyl)butyl)piperidine-l -carboxylate (2 g, 5.0 mmol, 1.0 eq) and TEA (1.5 g, 15.0 mmol, 3.0 eq) in DCM (30 mL) was added di-tert-butyl dicarbonate (1.6 g, 7.5 mmol, 1.5 eq). The reaction mixture was allowed to stir at RT for 2 hr. The reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (4:1 petroleum ether: EtOAc) to give tert-butyl 4-(4-((tert-butoxy carbonyl)amino)-2-(3-(trifluoromethyl)phenyl)butyl)piperi dine- 1 -carboxylate as a white solid (2.1 g, 84%) (ESI 523.1 [M+Na]+).Step 18: N-methyl-4-(l-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butan-l-amine[000410] To a solution of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-2-(3- (trifluoromethyl)-phenyl)butyl)piperidine-l -carboxylate (2.1 g, 4.2 mmol, 1.0 eq in THF (30 mL) at RT was added LAH (3M in THF, 4.2 mL, 12.6 mmol, 3.0 eq) and the reaction mixture was allowed to stir at 70 °C for 1 hr. After cooling to 0 °C, the reaction was quenched carefully by the addition of water (0.5 mL) and was allowed to stir at 0 °C for another 10 min. 15% aqueous NaOH (0.5 mL) and water (1.5 mL) were then added sequentially at 0 °C. The mixture was allowed to warm to RT and stir for another 15 min. The mixture was dried over Na2SO4, filtered and concentrated in vacuo to give A-methyl-4-(l-methylpiperidin-4-yl)-3-(3- (trifluoromethyl)phenyl)butan-l -amine as a white solid. The crude solid was used directly in next reaction (1 g, 72% ) (ESI 329.3 [M+H]+).Step 19: ethyl 2-(5-fluoro-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2- (methyl(4-(l-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)acetate[000411] To a solution of N-methyl-4-(l-methylpiperidin-4-yl)-3-(3-(trifluoromethyl) phenyl) butan-l-amine (500 mg 1.52 mmol, crude) in ACN (10 mL) was added K2CO3 (1 g, 7.6 mmol, 5.0 eqi). The mixture was allowed to stir at RT for 15 min. ethyl 2-bromo-2-(5- fluoro-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (668 mg, 1.52 mmol, 1.0 eq was then added. The reaction was allowed to continue to stir at 80 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give ethyl 2-(5-fluoro-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)-phenyl)-2-(methyl(4-(l- methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)acetate as a yellow oil (550 mg, 52%) (ESI 689.3 [M+H]+).Step 20: 2-(5-fluoro-3-methyl-2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2- (methyl(4-(l-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)acetic acid[000412] To a solution of ethyl 2-(5-fluoro-3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl(4-(l-methylpiperidin-4-yl)-3-(3- (trifluoromethyl)-phenyl)butyl)amino)acetate (550 mg, 0.80 mmol, 1.0 eq) in EtOH (5 mL) and H2O (1 mL) was added NaOH (160 mg, 4.0 mmol, 5.0 eq). The reaction mixture was allowed to stir at 80 °C for 1 hr. and concentrated in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give a stereoisomeric mixture of compounds 304 as a white solid (480 mg, 90%). Stereoisomers were further separated by prep chiral SFC A to give 304- P1A (94.4 mg), 304-P1B (78.2 mg), 304-P2 (85.5 mg) and 304-P3 (120.5 mg).[000413] 304-P1A, assigned as (R)-2-(5-fluoro-3-methyl-2-((lr,4R)-4- (trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl((R)-4-(l-methylpiperidin-4-yl)-3-(3- (trifluoromethyl)phenyl)butyl)amino)acetic acid. LC / MS ESI 661.2 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 7.50 - 7.23 (m, 5H), 6.81 - 6.78 (m, 1H), 4.68 - 4.48 (m, 1H), 4.37 - 4.31 (m, 1H), 3.33 - 2.80 (m, 5H), 2.58 - 2.22 (m, 12H), 2.2 - 1.92 (m, 6H), 1.82 - 1.57 (m, 7H), 1.38 - 1.20 (m,4H).[000414] 304-P1B, assigned as (R)-2-(5-fluoro-3-methyl-2-((lr,4R)-4- (trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl((S)-4-(l-methylpiperidin-4-yl)-3-(3- (trifluoromethyl)phenyl)butyl)amino)acetic acid. LC / MS ESI 661.3 [M+H]+. *HNMR (400 MHz, CD3OD) 5 7.53 - 7.26 (m, 5H), 6.83 - 6.81 (m, 1H), 4.67-4.51 (m, 1H), 4.38 - 4.32 (m, 1H), 3.33 - 2.79 (m, 5H), 2.71 - 2.39 ( m, 12H), 2.14 -1.87 (m, 6H) 1.82 - 1.54 (m, 7H), 1.35 - 1.20(m, 4H).[000415] 304-P2, assigned as (S)-2-(5-fhioro-3-methyl-2-((lr,4S)-4- (trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl((S)-4-(l-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)acetic acid. LC / MS ESI 661.3 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 7.52 - 7.25 (m, 5H), 6.95 - 6.81 (m, 1H), 4.66 - 4.48 (m, 1H), 4.37 - 4.37 (m, 1H), 3.21 - 2.67 (m, 5H), 2.62 - 2.38 (m, 12H), 2.16 - 1.91 (m, 6H), 1.86 - 1.53 (m, 7H), 1.39 - 1.19 (n, 4H).[000416] 304-P3, assigned as (S)-2-(5-fluoro-3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl((R)-4-(l-methylpiperidin-4-yl)-3-(3- (trifluoromethyl)phenyl)butyl)amino)acetic acid. LC / MS ESI 661.2 [M+H]+. *HNMR (400 MHz, CD3OD) 5 7.50 - 7.23 (m, 5H), 6.86 - 6.75 (m, 1H), 4.62 - 4.46 (m, 1H), 4.36 - 4.31 (m, 1H), 3.32 - 2.66 (m, 5H), 2.56 - 2.31 (m, 12H), 2.21 - 1.86 (m, 6H), 1.92 - 1.57 (m, 7H), 1.39 - 1.18 (m, 4H).Example 17: Preparation of Compound 305-2P1Step 1: tert-butyl (S)-2-(2-(methoxy(methyl)amino)-2-oxoethyl)pyrrolidine-l-carboxylate[000417] To a solution of (S)-2-(l-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (10 g, 43.6 mmol, 1.0 eq.), N,O-dimethylhydroxylamine hydrochloride (5.0 g, 52.4 mmol, 1.2 eq.), HOBt (7.1 g, 52.4 mmol, 1.2 eq.) and DIEA (8.0 g, 87.2 mmol, 2.0 eq.) in DCM (100 ml) was added EDCI (10.0 g, 52.4 mmol, 1.2 eq.). The reaction was allowed to stir at RT for 16 hr, then diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20: 1 dichloromethane: methanol) to give tert-butyl (S)-2-(2-(methoxy(methyl)amino)-2-oxoethyl)pyrrolidine-l- carboxylate as a yellow solid (10.0 g, 85.1%) (ESI 273.3 [M+H]+).Step 2: tert-butyl (S)-2-(2-(3-chloro-5-fluorophenyl)-2-oxoethyl)pyrrolidine-l-carboxylate[000418] To a solution of l-bromo-3-chloro-5-fluorobenzene (6.0 g, 28.6 mmol, 1.3 eq) in THF (20 mL) were added magnesium (792.0 mg, 33.0 mmol, 1.5 eq) and 1,2-dibromoethane (810 mg, 4.4 mmol, 0.2eq). The mixture was allowed to stir at 60 °C for 1 hr. After cooling to RT, the mixture was added dropwise into a solution of tert-butyl (S)-2-(2-(methoxy(methyl)- amino)-2-oxoethyl)pyrrolidine-l-carboxylate (6.0 g, 22.0 mmol, 1.0 eq) in THF (60 mL) at 0 °C. The reaction mixture was then allowed to warm to RT and stirred for 1 hr. The mixture was diluted with saturated NH4CI (200 mL) and extracted with DCM (2 x 200 mL). The organic solutions were combined, washed with brine, dried over ISfeSCU, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (95:5 DCM: MeOH) to give tert-butyl (S)-2-(2-(3-chloro-5-fluorophenyl)-2- oxoethyl)pyrrolidine-l -carboxylate as a colorless oil (4.3 g, 57.2 mmol, 84.6%)(ESI 364.1 [M+Na]+).Step 3: (S)-l-(3-chloro-5-fluorophenyl)-2-(l-methylpyrrolidin-2-yl)ethan-l-one[000419] To a solution of tert-butyl (S)-2-(2-(3-chloro-5-fluorophenyl)-2- oxoethyl)pyrrolidine-l -carboxylate (4.3 g, 12.6 mmol, 1.0 eq) in DCM (5 mL) was added TFA (5 mL, 65.0 mmol, 5.1 eq.). The reaction mixture was allowed to stir at RT for 2 hr and then concentrated. The residue was dissolved in MeOH (140 mL) and 33% aqueous HCHO (6.0 g, 63 mmol, 5.0 eq.) was added to the solution. The mixture was allowed to stir at RT for 1 hr. NaBH(OAc)s (5.3 g, 25.2 mmol, 2.0 eq.) was then added, and the reaction was allowed to continue to stir at RT for another 3 hr. The reaction mixture was poured into water (300 mL) and extracted with DCM (3 x 200 mL). The organic solutions were combined, washed with brine, dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (95:5 DCM: MeOH) to give (S)- 1 -(3 -chi oro-5 -fluorophenyl)-2-(l-methylpyrrolidin-2-yl)ethan-l-one as colorless oil (2.9 g, 83%) (ESI 256.2 [M+H]+).Step 4: ethyl (S,Z)-3-(3-chloro-5-fluorophenyl)-4-(l-methylpyrrolidin-2-yl)but-2-enoate[000420] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (6.1 g, 27.4 mmol, 2.5 eq) in anhydrous THF (120 mL) at RT was added t-BuOK (3.1 g, 27.4 mmol, 2.5 eq). The reaction mixture was allowed to stir at RT for 2 h. A solution of (S)-l-(3-chloro-5-fluorophenyl)-2-(l- methylpyrrolidin-2-yl)ethan-l-one (3.0 g, 11.7 mmol, 1.0 eq) in THF (20 mL) was then added. The reaction was allowed to continue to stir for another 12 hr. The reaction was then quenched by the addition of saturated aqueous NH4CI (100 mL) and extracted with EtOAc (3 x 100 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20: 1 DCM: MeOH) to give ethyl (S,Z)-3-(3-chloro-5-fluorophenyl)-4-(l-methylpyrrolidin-2-yl)but- 2-enoate as a yellow oil (2.2 g, 50.1%) (ESI 326.1 [M+H]+).Step 5: ethyl 3-(3-chloro-5-fluorophenyl)-4-((S)-l-methylpyrrolidin-2-yl)butanoate[000421] To a solution of ethyl (S,Z)-3-(3-chloro-5-fluorophenyl)-4-(l-methylpyrrolidin-2- yl)but-2-enoate (2.2 g, 6.8 mmol, 1.0 eq) in MeOH (35 ml) at RT was added PtO? (227 mg, 1.0 mmol, 0.15eq). The reaction mixture was allowed to stir at RT under an atmosphere of H2 (1 atm, 3L) for 2 hr. The contents were then filtered through a pad of celite and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (25: 1 DCM: MeOH) to give ethyl 3-(3-chloro-5-fluorophenyl)-4-((S)-l-methylpyrrolidin-2-yl)butanoate as a pale brown solid (1.3 g, 51.3%) (ESI 328.2 [M+H]+).Step 6: 3-(3-chloro-5-fluorophenyl)-l-(methyl-12-azaneyl)-4-((S)-l-methylpyrrolidin-2-yl)butan-l-one[000422] A solution of ethyl 3-(3-chloro-5-fluorophenyl)-4-((S)-l-methylpyrrolidin-2- yl)butanoate (1.3 g, 4.0 mmol, 1.0 eq) in MeNH2 (IM in MeOH, 15 mL, 15.0 mmol, 3.7 eq) was allowed to stir at 55 °C for 2 hr. The mixture was then cooled to RT and concentrated in vacuo. The residue was purified by silica gel column chromatography (25: 1 DCM: MeOH) to give 3-(3-chloro-5-fluorophenyl)-l-(methyl-12-azaneyl)-4-((S)-l-methylpyrrolidin-2-yl)butan- l-one as a colorless oil (1.0 g, 81.2 %) (ESI 312.2 [M+H]+).Step 7 : 3-(3-chloro-5-fluorophenyl)-N-methyl-4-((S)-l-methylpyrrolidin-2-yl)butan-l- amine[000423] To a solution of 3-(3-chloro-5-fluorophenyl)-l-(methyl-12-azaneyl)-4-((S)-l- methylpyrrolidin-2-yl)butan-l-one (800 mg, 2.6 mmol, 1.0 eq) in THF (20 mL) at RT was added LAH (3.5M in THF, 1.5 mL, 3.8 mmol, 1.5 eq). The reaction mixture was allowed to stir at RT for 2 hr. After cooling to 0 °C, the reaction mixture was then quenched carefully by the addition of water (0.2 mL) and allowed to stir at 0 °C for another 10 min. 15% aqueous NaOH (0.2 mL) and water (0.6 mL) were then added sequentially at 0 °C. The mixture was then allowed to warm to RT and stir for another 15 min, dried over ISfeSCU, filtered and concentrated in vacuo to give 3-(3-chloro-5-fluorophenyl)-N-methyl-4-((S)-l- methylpyrrolidin-2-yl)butan-l -amine (400 mg, 52.6% ) as a white solid. (ESI 299.1 [M+H]+) The crude solid was used directly in the next step.Step 8: ethyl 2-(2-((lr,4S)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-((3-(3-chloro-5- fluorophenyl)-4-((S)-l-methylpyrrolidin-2-yl)butyl)(methyl)amino)acetate[000424] To a solution of 3-(3-chloro-5-fluorophenyl)-N-methyl-4-((S)-l-methylpyrrolidin- 2-yl)butan-l -amine (200 mg 0.67 mmol, crude) in ACN (8 mL) was added K2CO3 (277 mg, 2.0 mmol, 3.0 eqi). The mixture was allowed to stir at RT for 15 min. ethyl 2-bromo-2-(2- ((lr,4r)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)acetate (275 mg, 0.67 mmol, 1.0 eq) was then added. The reaction was allowed to continue to stir at 80 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give ethyl 2-(2-((lr,4S)-4-(tert- butoxy)cyclohexyl)-3-methylphenyl)-2-((3-(3-chloro-5-fluorophenyl)-4-((S)-l- methylpyrrolidin-2-yl)butyl)(methyl)-amino)acetate as a yellow oil (240 mg, 56.7%) (ESI 629.3 [M+H]+).Step 9: 2-(2-((lr,4S)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-((3-(3-chloro-5- fluorophenyl)-4-((S)-l-methylpyrrolidin-2-yl)butyl)(methyl)amino)acetic acid[000425] To a solution of ethyl 2-(2-((lr,4S)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2- ((3-(3-chloro-5-fluorophenyl)-4-((S)-l-methylpyrrolidin-2-yl)butyl)(methyl)amino)acetate (240 mg, 0.38 mmol, 1.0 eq) in EtOH (3 mL) and H2O (1 mL) was added LiOH-EEO (80 mg, 1.91 mmol, 5.0 eq). The reaction mixture was allowed to stir at RT for 16 hr. The reaction pH was adjusted to ~ 6 - 7 with 2N HC1. Solvents were removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give 305-1 (85mg, 37%) and 305-2 (90mg, 39%) as a white solids. 305-1 was further separated by prep chiral SFC A to give 305-1P1 (21 mg) and 305-1P2 (15 mg). 305-2 was further separated by prep chiral HPLC A to give 305- 2P1 (28 mg) and 305-2P2 (12 mg).[000426] 305-1P1, assigned as (S)-2-(2-((lr,4S)-4-(tert-butoxy)cyclohexyl)-3- methylphenyl)-2-(((S)-3-(3-chloro-5-fluorophenyl)-4-((S)-l-methylpyrrolidin-2- yl)butyl)(methyl)amino)acetic acid. LC / MS ESI 601.3 [M+H]+. *H NMR (400 MHz, CD3OD) 5 7.50-7.37 (m, 1H), 7.13-6.98 (m, 4H), 6.84-6.82(m, 1H), 4.74-4.62 (m, 1H), 3.59-3.54 (m, 1H), 3.20-2.95 (m, 2H), 2.66-2.32 (m, 14H), 2.78-2.15 (m, 11H), 1.21-1.70 (m, 14H).[000427] 305-1P2, assigned as (R)-2-(2-((lr,4R)-4-(tert-butoxy)cyclohexyl)-3- methylphenyl)-2-(((S)-3-(3-chloro-5-fluorophenyl)-4-((S)-l-methylpyrrolidin-2- yl)butyl)(methyl)amino)acetic acid. LC / MS ESI 601.3 [M+H]+. *H NMR (400 MHz, CD3OD) 5 7.52-7.37 (m, 1H), 7.11-6.98 (m, 4H), 6.84-6.82(m, 1H), 4.74-4.61 (m, 1H), 3.59-3.54 (m, 1H), 3.20-2.95 (m, 2H), 2.66-2.32 (m, 14H), 2.78-2.15 (m, 11H), 1.21-1.70 (m, 5H), 1.40(s, 9H).[000428] 305-2P1, assigned as (S)-2-(2-((lr,4S)-4-(tert-butoxy)cyclohexyl)-3- methylphenyl)-2-(((R)-3-(3-chloro-5-fluorophenyl)-4-((S)-l-methylpyrrolidin-2- yl)butyl)(methyl)amino)acetic acid. LC / MS ESI 601.3 [M+H]+. *H NMR (400 MHz, CD3OD) 5 7.50-7.48 (m, 1H), 7.21-6.86 (m, 5H), 4.74-4.61 (m, 1H), 3.60-3.53 (m, 1H), 3.30-3.21 (m, 2H), 2.74-2.49 (m, 11H), 2.43-2.32 (m, 2H), 2.19-1.79 (m, 11H), 1.21-1.70 (m, 15H).[000429] 305-2P2, assigned as (R)-2-(2-((lr,4R)-4-(tert-butoxy)cyclohexyl)-3- methylphenyl)-2-(((R)-3-(3-chloro-5-fluorophenyl)-4-((S)-l-methylpyrrolidin-2- yl)butyl)(methyl)amino)acetic acid. LC / MS ESI 601.3 [M+H]+. *H NMR (400 MHz, CD3OD) 5 7.50-7.38 (m, 1H), 7.11-6.98 (m, 4H), 6.84-6.82 (m, 1H), 4.77-4.61 (m, 1H), 3.66-3.31 (m, 1H), 3.16-2.99 (m, 2H), 2.66-2.31 (m, 14H), 2.12-1.77 (m, 11H), 1.52-1.24 (m, 14H).Example 18: Preparation of Compound 80-P2Step 1 : l-iodo-3-methyl-2-((lr,4r)-4-((3,3,3-trifluoroprop-l-en-2- yl)oxy)cyclohexyl)benzene[000430] To a solution of (lr,4r)-4-(2-iodo-6-methylphenyl)cyclohexan-l-ol (1 g, 3.2 mmol, 1.0 eq ) in DMF (lOmL) at 0 °C was added sodium hydride (506 mg, 12.7 mmol, 4.0 eq, 60% in mineral oil). The reaction mixture was allowed to stir at 0 °C for 0.5 hr. 2, 3,3,3- tetrafluoroprop-l-ene (latm, 2L) was then added and the reaction was allowed to warm to RT. The reaction was allowed to continue to stir for another 5 hr. The reaction was then quenched by the addition of cold saturated aqueous NH4CI (100 mL) and extracted with EtOAc (3 x 60 mL). The organic solutions were combined, washed with brine, dried over ISfeSCU, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to give l-iodo-3-methyl-2-((lr,4r)-4-((3,3,3-trifluoroprop-l-en- 2-yl)oxy)cyclohexyl)benzene as a white solid (500mg, 38.5 %).Step 2: ethyl 2-(3-methyl-2-((lr,4r)-4-((3,3,3-trifluoroprop-l-en-2-yl)oxy)cyclohexyl)- phenyl)acetate[000431] To a suspension of l-iodo-3-methyl-2-((lr,4r)-4-((3,3,3-trifhioroprop-l-en-2- yl)oxy)cyclohexyl)benzene (1.0 g, 2.4 mmol, 1.0 eq) in THF (15 mL) was added Pd2dba3 (45.0 mg, 0.07 mmol, 0.03 eq) and QPhos (34 mg, 0.07 mmol, 0.03 eq). (2-ethoxy-2- oxoethyl)zinc(II) bromide (IM in THF, 7.2 mL, 7.2 mmol, 3.0 eq) was then added and the mixture was allowed to stir at 50 °C under an atmosphere of N2 for 0.5 hr. The reaction mixture was poured into saturated aqueous NH4CI solution (50 mL) and extracted with EtOAc (3 x 50 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (95:5 petroleum ether: EtOAc) to give ethyl 2-(3-methyl-2-((lr,4r)-4-((3,3,3- trifluoroprop-l-en-2-yl)oxy)cyclohexyl)phenyl)acetate as a brown oil (0.78 g, 92 %) (ESI 393.3 [M+Na]+).Step 3: ethyl 2-(3-methyl-2-((lr,4r)-4-((l,l,l-trifluoropropan-2-yl)oxy)cyclohexyl)- phenyl)acetate[000432] To a solution of ethyl 2-(3-methyl-2-((lr,4r)-4-((3,3,3-trifhioroprop-l-en-2- yl)oxy)cyclohexyl)phenyl)acetate (0.78 g, 2.11 mmol, 1.0 eq) in MeOH (10 mL) was added 10% Pd / C (260 mg, 0.11 mmol, 0.05 eq). The reaction mixture was allowed to stir at RT under an atmosphere of H2 (1 atm, 3L) for 3 hr. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give ethyl 2-(3-methyl-2-((lr,4r)-4-((l,l,l-trifluoropropan- 2-yl)oxy)cyclohexyl)phenyl)acetate as a yellow oil (0.75 g, 97 %)(ESI 395.1 [M+Na]+). The crude product was used directly in the subsequent step without further purification.Step 4: ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4-((l,l,l-trifluoropropan-2- yl)oxy)cyclohexyl)-phenyl)acetate[000433] To a solution of LiHMDS (IM in THF, 4 mL, 4.0 mmol, 2.0 eq) at -78°C, ethyl 2- (3 -methyl-2-(( 1 r,4r)-4-(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy)cy clohexyl)phenyl)acetate (750 mg, 2.0 mmol, 1.0 eq) in THF (10 mL) was added dropwise. The reaction mixture was allowed to stir at -78°C for 0.5 hr. TMSC1 (440.0 mg, 4.0 mmol, 2.0 eq) was added dropwise and the reaction was allowed to continue to stir at -78°C for 15 min. A solution of NBS (720 mg, 4.0 mmol, 2.0 eq) in THF (10 mL) was added. The reaction mixture was allowed to stir at -78°C for another 2 hr., warmed to 0 °C, quenched by the addition of saturated aqueous NH4CI solution (50 mL), and extracted with EtOAc (3 x 50 mL). The organic solutions were combined, washed with brine (3 x 50 mL), dried over ISfeSCU, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (90: 10 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4-((l,l,l-trifluoropropan-2- yl)oxy)cyclohexyl)phenyl)acetate as a colorless oil (800 mg, 95%) (ESI 473.0 [M+Na]+).Step 5: tert-butyl (3-(3-chloro-5-fluorophenyl)-3-oxopropyl)(methyl)carbamate[000434] To a suspension of Mg (970 mg, 39.8 mmol, 1.4 eq) in THF (40 mL) was added 1- bromo-3-chloro-5-fluorobenzene (7.14g, 34.1 mmol, 1.2 eq) dropwise. The mixture was allowed to stir at 60 °C for 1 h. The reaction mixture was cooled to 0 °C and added dropwise into a solution of tert-butyl (3-(methoxy(methyl)amino)-3-oxopropyl)(methyl)carbamate (7 g, 28.4 mmol, 1.0 eq) in THF (40 mL). The reaction mixture was allowed to stir at 0 °C for 2 hr., quenched by the addition of saturated aqueous NH4C1 solution (200 mL) and extracted with EtOAc (3 x 200 mL). The organic solutions were combined, washed with brine (3 x 200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (94:6 petroleum ether: EtOAc) to give tert-butyl (3-(3- chloro-5-fluorophenyl)-3-oxopropyl)(methyl)-carbamate as a yellow oil (4.0 g, 98%) (ESI 260.1 [M-tBu+H]+).Step 6: tert-butyl (3-(3-chloro-5-fluorophenyl)-3-hydroxypropyl)(methyl)carbamate[000435] To a solution of tert-butyl (3-(3-chloro-5-fluorophenyl)-3- oxopropyl)(methyl)carbamate (2.5 g, 7.9 mmol, 1.0 eq) in MeOH (25 mL) at 0 °C was added NaBH4(898.6 mg, 23.7 mmol, 3.0 eq) in portions. The mixture was allowed to stir at RT for 2 hr. Water (100 mL) was slowly added at 0 °C, and the mixture was extracted with EtOAc (3 x 150 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (92:8 DCM: MeOH) to give tert-butyl (3-(3-chloro-5-fluorophenyl)- 3-hydroxypropyl)(methyl)carbamate (2.3 g, 91%) (ESI 340.0 [M+Na]+).Step 7: tert-butyl (3-bromo-3-(3-chloro-5-fluorophenyl)propyl)(methyl)carbamate[000436] To a solution of tert-butyl (3-(3-chloro-5-fluorophenyl)-3-hydroxypropyl)(methyl)- carbamate (2.3 g, 7.24 mmol, 1.0 eq) in DCM (25 mL) was added CB (3.6 g, 10.9 mmol, 1.5 eq) and PPI13 (2.8 g, 10.9 mmol, 1.5 eq). The mixture was allowed to stir at RT for 2 hr and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (93:7 petroleum ether: EtOAc) to give tert-butyl (3-bromo-3-(3-chloro-5-fluorophenyl)propyl)- (methyl)carbamate (1.8 g, 85%) (ESI 324.0 [M-tBu+H]+).Step 8: tert-butyl (3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)carbamate[000437] Tert-butyl (3-bromo-3-(3-chloro-5-fluorophenyl)propyl)(methyl)carbamate (950.0 mg, 2.5 mmol, 1.0 eq), 1 -isopropylpiperazine (478.0 mg, 2.74 mmol, 1.5 eq) and K2CO3 (1.1 g, 7.5 mmol, 3.0 eq) were dissolved in MeCN (10 mL). The mixture was allowed to stir at 60 °C for 3 hr and then concentrated in vacuo. The residue was purified by silica gel column chromatography (95:5 DCM: MeOH) to give racemic tert-butyl (3-(3-chloro-5-fluorophenyl)- 3-(4-isopropylpiperazin-l-yl)propyl)(methyl)carbamate (930 mg, 88%) (ESI 428.3 [M+H]+). Isomers were further separated by prep chiral SFC I to give peak 1, assigned as tert-butyl (R)- (3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)(methyl)carbamate (420 mg), and peak 2, assigned as tert-butyl (S)-(3-(3-chloro-5-fluorophenyl)-3-(4- isopropylpiperazin-l-yl)propyl)(methyl)carbamate (390 mg), as a white solids.Step 9: (S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)-N-methylpropan-l- amine[000438] To a solution of tert-butyl (S)-(3-(3-chloro-5-fluorophenyl)-3-(4- isopropylpiperazin-l-yl)propyl)(methyl)carbamate (390.0 mg, 0.9 mmol, 1.0 eq) in DCM (5mL) was added HC1 (4M in dioxane, 2.5mL, 9.9 mmol, 10.0 eq). The mixture was allowed to stir at RT for 2 hr and then concentrated in vacuo to give (S)-3-(3-chloro-5-fluorophenyl)-3-(4- isopropylpiperazin-l-yl)-N-methylpropan-l -amine (280 mg, 95%) (ESI 328.3 [M+H]+). The crude product was used directly in the subsequent step without further purification.Step 10: ethyl 2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-((l,l,l-trifluoropropan-2- yl)oxy)cyclohexyl)phenyl)acetate[000439] A mixture of (S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-l-yl)-N- methylpropan-1 -amine (280.0 mg, 0.85 mmol, 1.0 eq), ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4- ((l,l,l-trifhioropropan-2-yl)oxy)cyclohexyl)phenyl)acetate (385.0 mg, 0.85 mmol, 1.0 eq) and K2CO3 (355.0 mg, 2.56 mmol, 3.0 eq) in MeCN (3 mL) was allowed to stir at 60 °C for 8 hr. The reaction mixture was then concentrated in vacuo. The crude residue was purified by silica gel column chromatography (92:8 DCM: MeOH) to give ethyl 2-(((S)-3-(3-chloro-5- fhiorophenyl)-3-(4-isopropylpiperazin-l-yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4- ((l,l,l-trifluoropropan-2-yl)oxy)cyclohexyl)phenyl)acetate (320 mg, 94%) (ESI 698.3 [M+H]+).Step 11: Preparation of 2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-l- yl)propyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-((l,l,l-trifluoropropan-2- yl)oxy)cyclohexyl)phenyl)acetic acid[000440] To a solution of ethyl 2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin- 1 -yl)propyl)(methyl)amino)-2-(3 -methyl-2-(( 1 r,4 S)-4-(( 1 , 1 , 1 -trifluoropropan-2- yl)oxy)cyclohexyl)phenyl)acetate (280 mg, 0.40 mmol, 1.0 eq) in EtOH (3 mL) and H2O (1mL) was added NaOH (80 mg, 2 mmol, 5.0 eq). The reaction mixture was allowed to stir at 70 °C for 8 hr. The pH of the mixture was adjusted to ~ 6 - 7 with 2N HC1. Solvents were removed in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give a mixture of stereoisomeric compounds 80 as a white solid (240 mg, 89%). The stereoisomers were further separated by prep chiral SFC A to give 80-P1 (100 mg) and 80-P2 (72 mg). 80-P1 was further separated by prep chiral SFC J to give 80-P1A (31 mg) and 80-P1B (35 mg).[000441] 80-P1A, assigned as (R)-2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4- isopropylpiperazin- 1 -yl)propyl)(methyl)amino)-2-(3 -methyl-2-((lR,4R)-4-(((R)- 1,1,1- trifluoropropan-2-yl)oxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 670.2 1H NMR (400 MHz, CD3OD) 5 7.59-7.53 (m, 1H), 7.26-7.00 (m, 5H), 4.92 (s, 1H), 4.14-4.07 (m, 1H), 3.70- 3.61 (m, 2H), 3.26-3.18 (m, 1H), 2.69-2.36 (m, 15H), 2.23-2.12 (m, 4H), 2.08-1.80 (m, 3H), 1.73-1.69 (m, 1H), 1.63-1.40 (m, 3H), 1.30 (d, J = 6.6 Hz, 4H), 1.06 (d, J = 5.4 Hz, 6H).[000442] 80-P1B, assigned as (R)-2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4- isopropylpiperazin- 1 -yl)propyl)(methyl)amino)-2-(3 -methyl-2-((l S,4R)-4-(((S)- 1,1,1- trifluoropropan-2-yl)oxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 670.2 [M+H]+. 1H NMR (400 MHz, CD3OD) 5 7.59-7.53 (m, 1H), 7.26-7.02 (m, 5H), 4.92 (s, 1H), 4.13-4.07 (m, 1H), 3.70-3.59 (m, 2H), 3.23-3.18 (m, 1H), 2.70-2.41 (m, 15H), 2.34-2.04 (m, 4H), 1.92-1.87 (m, 3H), 1.73-1.70 (m, 1H), 1.58-1.42 (m, 3H), 1.30 (d, J = 6.4 Hz, 4H), 1.06 (d, J = 5.6 Hz, 6H).[000443] 80-P2, assigned as (2S)-2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4- isopropylpiperazin- 1 -yl)propyl)(methyl)amino)-2-(3 -methyl-2-(( lr,4S)-4-(( 1,1,1- trifluoropropan-2-yl)oxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 670.2 [M+H]+. 1H NMR (400 MHz, CD3OD) 5 7.56-7.47 (m, 1H), 7.29-6.93 (m, 5H), 4.93 (s, 1H), 4.13-4.08 (m, 1H), 3.74-3.71 (m, 1H), 3.61-3.48 (m, 2H), 3.20-3.16(m, 1H), 3.05-2.80 (m, 10H), 2.52 (s, 3H), 2.42 (s, 1H), 2.22-2.02 (m, 4H), 1.91-1.85 (m, 4H), 1.71-1.42 (m, 3H), 1.30 (d, J = 6.8 Hz, 4H), 1.12 (d, J = 5.6 Hz, 6H).Example 19: Preparation of Compound 132-P2Step 1: l-iodo-3-methyl-2-((lr,4r)-4-(prop-l-en-2-yloxy)cyclohexyl)benzene[000444] A mixture of (lr,4r)-4-(2-iodo-6-methylphenyl)cyclohexan-l-ol (4.0 g, 12.6 mmol, 1.0 eq.) and Hg(OAc)2 (1.2 g, 3.8 mmol, 0.3 eq.) in 2-methoxyprop-l-ene (30 ml) was allowed to stir at RT overnight under an atmosphere of N2. Water (200 mL) was added, and the mixture was extracted with DCM (3 x 150 mL). The organic solutions were combined, washed sequentially with NaHCCL (100 ml) and brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (19: 1 petroleum ether: EtOAc) to give l-iodo-3-methyl-2-((lr,4r)-4-(prop-l- en-2-yloxy)cyclohexyl)benzeneas a colorless oil (2.2 g, 50.3%).Step 2: l-iodo-3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl)benzene[000445] To a solution of l-iodo-3-methyl-2-((lr,4r)-4-(prop-l-en-2- yloxy)cyclohexyl)benzene (2.2 g, 6.2 mmol, 1.0 eq.) in DCM (40 mL) at 0 °C was added Et2Zn (24.7 ml, 24.7 mmol, 4.0 eq.). The mixture was allowed to stir at 0 °C for 0.5 hr under an atmosphere of N2. CH2I2 (6.6 g, 24.7 mmol, 4.0 eq.) was added dropwise into the mixture at 0 °C. The reaction was allowed to warm to RT and then allowed to continue to stir for 6 hr.Saturated aqueous NH4CI (150 mL) was added, and the mixture was extracted with DCM (3 x 150 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (95: 1 petroleum ether: EtOAc) to give l-iodo-3-methyl-2-((lr,4r)-4-(l- methylcyclo-propoxy)cyclohexyl)benzene as a colorless oil (1.1 g, 47.8 %).Step 3: ethyl 2-(3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl)phenyl)acetate[000446] To a suspension of l-iodo-3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)- cyclohexyl)benzene (1.1 g, 3.0 mmol, 1.0 eq.) in THF (12 mL) was added Pd2dba3 (82.0 mg, 0.09 mmol, 0.03 eq.) and QPhos (64 mg, 0.09 mmol, 0.03 eq.). (2-ethoxy-2-oxoethyl)zinc(II) bromide (IM in THF, 7.4 mL, 7.4 mmol, 2.5 eq.) was then added and the mixture was allowed to stir at 65 °C under an atmosphere of N2 for 1 hr.. Contents were then poured into 50 mL saturated aqueous NH4CI solution and extracted with EtOAc (3 x 100 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9: 1 petroleum ether: EtOAc) to give ethyl 2-(3-methyl-2-((lr,4r)-4-(l- methylcyclopropoxy)cyclohexyl)phenyl)acetate as a colorless oil (1.0 g, 94 %) (ESI 353.3 [M+Na]+).Step 4: ethyl 2-bromo-2-(4-fluoro-3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy) cyclohexyl)phenyl)acetate[000447] To a solution of LiHMDS (IM in THF, 6.0 ml, 6.0 mmol, 2.0 eq.) at -78°C, ethyl 2-(4-fluoro-3-methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl)phenyl)acetate (1.0 g, 3.0 mmol, 1.0 eq.) in THF (20 ml) was added dropwise. The reaction mixture was allowed to stir at -78°C for 0.5 hr. TMSC1 (648.0 mg, 6.0 mmol, 2.0 eq.) was then added dropwise, and The reaction was allowed to continue to stir at -78°C for another 15 min. A solution of NBS (1.07 g, 6.0 mmol, 2.0 eq.) in THF (20mL) was then added dropwise. The reaction mixture was allowed to stir at -78 °C for another 1 hr., warmed to 0 °C, quenched by the addition of saturated aqueous NH4CI solution (100 ml), and extracted with EtOAc (3 x 150 ml). The organic solutions were combined, washed with brine (3 x 150 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9: 1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(4-fluoro-3-methyl-2- ((lr,4r)-4-(l-methylcyclopropoxy)cyclohexyl)phenyl)acetate as a colorless oil (1.1 g, 75%) (ESI 431.0 [M+Na]+;433.0 [M+2+Na]+).Step 5: ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(l-methylcyclopropoxy)cyclohexyl)phe nyl )acetate[000448] To a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)- N-methylpentan-1 -amine (200 mg 0.62 mmol, crude) in ACN (10 mL) was added K2CO3 (427 mg, 3.1 mmol, 5.0 eq.). The mixture was allowed to stir at RT for 15 min. Ethyl 2-bromo-2-(3- methyl-2-((lr,4r)-4-(l-methylcyclopropoxy)-cyclohexyl)phenyl)acetate (253 mg, 0.62 mmol, 1.0 eq) was then added. The reaction was allowed to continue to stir at 80 °C for another 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give ethyl 2-(((S)-3- (5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl- 2-((lr,4S)-4-(l-methylcyclopropoxy)cyclohexyl)phenyl)acetate as a yellow oil (250 mg, 62%) (ESI 651.4 [M+H]+).Step 6: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l- yl)pentyl)(methyl) amino)-2-(3-methyl-2-((lr,4S)-4-(l- methylcyclopropoxy)cyclohexyl)phenyl)acetic acid[000449] To a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3- dimethylpyrrolidin-l-y l)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(l- methylcyclopropoxy)cyclohexyl)phenyl) acetate (250 mg, 0.38 mmol, 1.0 eq) in EtOH (5 mL) and H2O (1 mL) was added NaOH (76 mg, 1.9 mmol, 5.0 eq). The reaction mixture was allowed to stir at 80 °C for 1 hr. and concentrated in vacuo. The crude residue was purified byprep HPLC A (30 - 70% CH3CN) to give a stereoisomeric product mixture 132 as a white solid (140 mg, 58%). Diastereomers were further separated by prep chiral SFC A to give 132-P1 (45 mg) and 132-P2 (61 mg).[000450] 132-P1, assigned as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3- dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(l- methylcyclopropoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 7.59 - 7.36 (m, 1H), 7.13 - 6.95 (m, 5H), 4.55 (d, J= 62.2 Hz, 1H), 3.68-3.61 (m, 1H), 3.24 (s, 1H), 2.93 - 2.53 (m, 5H), 2.52 - 2.14 (m, 13H), 1.87-1.79 (m, 8H), 1.64 - 1.49 (m, 3H), 1.45 - 1.26 (m, 6H), 1.06 (s, 6H), 0.84 - 0.72 (m, 2H), 0.43 (q, J= 4.4 Hz, 2H).[000451] 132-P2, assigned as (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3- dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(l- methylcyclopropoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H]+. *HNMR (400 MHz, CD3OD) 5 7.67 - 7.40 (m, 1H), 7.30 - 7.00 (m, 5H), 4.67 (d, J= 65.5 Hz, 1H), 3.72 (d, J = 41.4 Hz, 1H), 3.13 (s, 1H), 3.03 - 2.80 (m, 3H), 2.70 - 2.32 (m, 12H), 2.18 - 1.64 (m, 14H), 1.52 - 1.27 (m, 6H), 1.09 (s, 6H), 0.79 (s, 2H), 0.52 - 0.38 (m, 2H).132-P1 132-P2Example 20: Preparation of Compound 146-P1Step 1: 4-chloro-5-methylpyridin-3-amine[000452] 2 -bromo-3 -methylaniline (25 g, 120.5 mmol, 1.0 eq.), methylboronic acid (18.0 g, 301.3 mmol, 2.5 eq.), K2CO3 (41.6 g, 301.3 mmol, 2.5 eq) and Pd(dppf)C12 (5.29 g, 7.23 mmol, 0.06 eq.) were suspended in dioxane (300 mL) and water (50 mL). The reaction mixture was allowed to stir overnight at 100 °C under an atmosphere of N2. The reaction mixture was poured into 300 mL water and extracted with EtOAc (3 x 200 mL). The organic solutions werecombined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (1 : 1 petroleum ether: EtOAc) to give 4-chloro-5-methylpyridin-3-amine as a yellow solid (9.6 g, 55.9%) (ESI 143.0 [M+H]+).Step 2: 5-methyl-4-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridin-3-amine[000453] 4 -chloro-5-methylpyridin-3-amine (9.6 g, 67.3 mmol, 1.0 eq.), 4,4,5,5-tetramethyl- 2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (18.8 g, 70.7 mmol, 1.05 eq.), K3PO3 (18.6 g, 134.6 mmol, 2 eq) and XPhosPdG2 (2.1 g, 2.69 mmol, 0.04 eq.) were suspended in dioxane (100 mL) and water (20 mL). The reaction mixture was allowed to stir overnight at 100 °C under an atmosphere of N2. The mixture was poured into 200 mL water and extracted with EtOAc (3 x 100 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (1 : 1 petroleum ether: EtOAc) to give 5-methyl-4-(l,4- dioxaspiro[4.5]dec-7-en-8-yl)pyridin-3-amine as a brown solid (13.1 g, 79.0%) (ESI 247.1 [M+H]+).Step 3: 5-methyl-4-(l,4-dioxaspiro[4.5]decan-8-yl)pyridin-3-amine[000454] To a solution of 5-methyl-4-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridin-3-amine (13.1 g, 53.2 mmol, 1.0 eq.) in EtOH (200 mL) was added 10% Pd / C (5.64 g, 2.66 mmol, 0.05 eq). The reaction mixture was allowed to stir at 65 °C under an atmosphere of H2 (1 atm, 3L) for 24 hr. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give 5-methyl-4-(l,4-dioxaspiro[4.5]decan-8-yl)pyridin-3-amine as a yellow solid (11.1 g, 84.0%) (ESI 249.2 [M+H]+). The crude product was used directly in the subsequent step without further purification.Step 4: 3-iodo-5-methyl-4-(l,4-dioxaspiro[4.5]decan-8-yl)pyridine[000455] To a solution of 5-methyl-4-(l,4-dioxaspiro[4.5]decan-8-yl)pyridin-3-amine (11.1 g, 44.7 mmol, 1.0 eq.) in ACN (150 mL) was added KI (22.3 g, 134.1 mmol, 3 eq.) and tertbutyl nitrite (23.0 g, 223.5 mmol, 5 eq) at 0 °C. The mixture was heated at 40 °C for 2 days. The mixture was poured into 300 mL saturated aqueous ISfeSCL and extracted with EtOAc (3 x 100 mL). The organic solutions were combined, washed with brine, dried over ISfeSCL, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (1 : 1 petroleum ether: EtOAc) to give 3-iodo-5-methyl-4-(l,4- dioxaspiro[4.5]decan-8-yl)pyridine as a yellow solid (7.1 g, 44.2%) (ESI 360.0 [M+H]+).Step 5: 4-(3-iodo-5-methylpyridin-4-yl)cyclohexan-l-one[000456] To a solution of 3-iodo-5-methyl-4-(l,4-dioxaspiro[4.5]decan-8-yl)pyridine (7.1 g, 19.8 mmol, 1.0 eq.) in THF (80 mL) was added 3M aqueous HC1 (19.8 mL, 59.4 mol, 3.0 eq.). The reaction mixture was allowed to stir at RT for 1 hr, cooled to 0 °C, quenched by the addition of saturated aqueous NaHCCL (pH adjusted to ~8), and extracted with EtOAc (2 x 200 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 4-(3-iodo-5-methylpyridin-4-yl)cyclohexan-l-one as a yellow oil (6.2 g, 13.9 mmol, crude) (ESI 316.0 [M+H]+). The crude product was used directly in the next step.Step 6: (lr,4r)-4-(3-iodo-5-methylpyridin-4-yl)cyclohexan-l-ol[000457] To a solution of 4-(3-iodo-5-methylpyridin-4-yl)cyclohexan-l-one (6.2 g, 13.9 mmol, crude, 1.0 eq.) in MeOH (60 mL) at 0 °C was added CeCh (4.1 g, 16.7 mmol, 1.2eq). NaBH4 (635 mg, 16.7 mmol, 1.2 eq) was then added portionwise. The mixture was allowed to stir at 0 °C for 0.5 hr. Water (100 mL) was slowly added at 0 °C, and the mixture was extractedwith EtOAc (3 x 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by HPLC A (30 - 60% ACN) to give (lr,4r)-4-(3-iodo-5-methylpyridin-4-yl)cyclohexan-l-ol as a white solid (2.5 g, 56.7%) (ESI 318.0 [M-0H]+).Step 7 : 3-iodo-5-methyl-4-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)pyridine[000458] To a solution of (lr,4r)-4-(3-iodo-5-methylpyridin-4-yl)cyclohexan-l-ol (2.3 g, 7.26 mmol, 1.0 eq ), Selectfluor (3.86 g, 10.9 mmol, 1.5 eq ), KF (1.68 , 29.0 mmol, 4.0 eq ) and AgOTf (5.6 g, 21.8 mmol, 3.0 eq ) in EtOAc (80 mL) was allowed to stir at RT for 5 min under an atmosphere of N2. 2-fluoropyridine (2.1 g, 21.8 mmol, 3 eq) and TMSCF3 (3.1 g, 21.8 mmol, 3 eq) were then added. The reaction mixture was allowed to stir at RT for 48 hr. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (2: 1 petroleum ether: EtOAc) to give 3-iodo-5- methyl-4-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)pyridine as a yellow oil (280 mg, 10%) (ESI 386.0 [M+H]+).Step 8: ethyl 2-(5-methyl-4-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)pyridin-3-yl)acetate[000459] To a suspension of 3-iodo-5-methyl-4-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)- pyridine (280 mg, 0.73 mmol, 1.0 eq.), QPhos (16 mg, 0.022 mmol, 0.03 eq.) and Pd2dba3 (10 mg, 0.011 mmol, 0.015 eq) in THF (5 mL) was added (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 2.9 mL, 2.9 mmol, 4.0 eq.). The reaction mixture was allowed to stir at 65 °C under an atmosphere of N2 for 1 hr. The reaction mixture was poured into saturated aqueous NH4CI (50 mL) and extracted with EtOAc (2 x 50 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (2: 1 petroleum ether: EtOAc) to give ethyl2-(5-methyl-4-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)pyridin-3-yl)acetate as a yellow oil (180 mg, 71.4%). (ESI 346.2 [M+H]+).Step 9: ethyl 2-bromo-2-(5-methyl-4-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)pyridin-3- yl)acetate[000460] To a solution of ethyl 2-(5-methyl-4-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)pyridin-3-yl)acetate (180 mg, 0.52 mmol, 1.0 eq) in THF (5 ml) at -78°C was added LDA (2M in THF and hexane, 0.65 mL, 1.3 mmol, 2.5 eq). The reaction mixture was allowed to stir at -78°C for 0.5 h. TMSC1 (141 mg, 1.3 mmol, 2.5 eq) was added dropwise at -78°C and the reaction was allowed to continue to stir at -78°C for 15 min. A solution of NBS (184 mg, 1.04 mmol, 2.0 eq) in THF (2 mL) was added. The reaction mixture was allowed to stir at -78°C for 1 h. The reaction was quenched by the addition of saturated aqueous NH4CI (50 ml) and extracted with EtOAc (2 x 50 ml). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (2: 1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(5-methyl-4-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)pyridin-3- yl)acetate as a yellow solid (160 mg, 72.6%). (ESI 424.1 (M+H)+).Step 10: ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l- yl)pentyl)(methyl)amino)-2-(5-methyl-4-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)pyridin- 3-yl)acetate[000461] To a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)-N-methylpentan-1 -amine (123 mg, 0.38 mmol, 1.0 eq) in ACN (5 mL) was added K2CO3 (262mg, 1.9 mmol, 5.0 eqi and ethyl 2-bromo-2-(3-methyl-2-((lr,4r)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate (160 mg, 0.38 mmol, 1.0 eq). The reaction mixture was allowed to stir at 80 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3- dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(5-methyl-4-((lr,4S)-4- (trifluoromethoxy)cyclohexyl)pyridin-3-yl)acetateas a yellow oil (150 mg, 59.2%) (ESI 666.4 [M+H]+).Step 11 : 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l- yl)pentyl)(methyl)amino)-2-(5-methyl-4-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)pyridin- 3-yl)acetic acid[000462] To a mixture of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3- dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(5-methyl-4-((lr,4S)-4-(tri fluoromethoxy)- cy cl ohexyl)pyri din-3 -yl)acetate (150 mg, 0.23 mmol, 1.0 eq) in EtOH (4 mL) and H2O (1 mL) was added NaOH (46 mg, 1.15 mmol, 5.0 eq). The mixture was allowed to stir at 80 °C for 16 hr and concentrated in vacuo. The crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give stereoisomeric mixture of compounds 146 as a white solid (100 mg, 69.7%). The stereoisomers were further separated by prep chiral SFC D to give 146-P1 (32 mg) and 416-P2 (30 mg).[000463] 146-P1, assigned as (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3- dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(5-methyl-4-((lr,4S)-4-(tri fluoromethoxy)- cy cl ohexyl)pyri din-3 -yl)acetic acid. LC / MS ESI 638.3 [M+H]+. *H NMR (400 MHz, CD3OD) 5 9.31 - 8.48 (m, 1H), 8.33 - 7.75 (m, 1H), 7.49 - 6.89 (m, 3H), 4.56 - 4.15 (m, 2H), 3.61 (s, 1H), 3.36 (s, 1H), 3.27 - 3.17 (m, 1H), 3.12 - 2.93 (m, 3H), 2.84 - 2.66 (m, 2H), 2.56 - 2.32 (m, 4H), 2.32 - 2.20 (m, 5H), 2.21 - 1.99 (m, 7H), 1.99 - 1.89 (m, 1H), 1.89 - 1.53 (m, 8H), 1.15 (s, 6H).[000464] 146-P2, assigned as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3- dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(5-methyl-4-((lr,4R)-4-(trifluoromethoxy)- cy cl ohexyl)pyri din-3 -yl)acetic acid. LC / MS ESI 638.3 [M+H]+. *H NMR (400 MHz, CD3OD) 5 8.99 - 8.47 (m, 1H), 8.24 - 7.91 (m, 1H), 7.23 - 6.86 (m, 3H), 4.27 (d, J= 55.6 Hz, 2H), 3.48 (s, 1H), 3.27 (s, 2H), 3.07 - 2.86 (m, 4H), 2.70 (t, J= 9.6 Hz, 1H), 2.49 - 2.27 (m, 7H), 2.26 - 2.09 (m, 6H), 2.08 - 1.85 (m, 5H), 1.81 (t, J= 7.4 Hz, 2H), 1.77 - 1.49 (m, 5H), 1.13 (s, 6H).Example 21: Preparation of Compound 152-P2Step 1: ethyl 5-((tert-butoxycarbonyl)(methyl)amino)-3-(3-(difluoromethyl)phenyl)- pentanoatetetrafluoroborate, Bl NAP[000465] To a solution of (3-(difluoromethyl)phenyl)boronic acid (5.2 g, 30.0 mmol, 2.5 eq.), bis(norbornadiene)rhodium(I) tetrafluoroborate (360 mg, 1.0 mmol, 0.08 eq.), ethyl (E)-5- ((tert-butoxycarbonyl)(methyl)amino)pent-2-enoate (3.0 g, 12.0 mmol, 1 eq.) and BINAP (750 mg, 1.2 mmol, 0.1 eq.) in dioxane (50 mL) was added a solution of KOH (1 .0 g, 18.0 mmol, 1.5 eq.) in H2O (7 mL) under a nitrogen atmosphere. The reaction mixture was allowed to stir at RT for 6 hr. The reaction mixture was poured into 200 mL of water and extracted with EtOAc (3 x 400 mL). The organic solutions were combined, washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (7: 1 petroleum ether: EtOAc) to give ethyl 5-((tert- butoxycarbonyl)(methyl)amino)-3-(3-(difluoromethyl)phenyl)pentanoate (3.0 g, 67%) (ESI 286.2 [M-Boc+H]+).Step 2: : tert- butyl (3-(3-(difluoromethyl)phenyl)-5-hydroxypentyl)(methyl)carbamate[000466] To a solution of ethyl 5-((tert-butoxycarbonyl)(methyl)amino)-3-(3- (difluoromethyl)phenyl)pentanoate (3.0 g, 8.0 mmol, 1.0 eq) in THF (30 mL) at 0 °C was added lithium aluminum hydride (2.5M in THF, 4.0 mL, 10.0 mmol, 1.3 eq). The reaction mixture was allowed to stir at 0 °C for 1 hr and quenched by the addition of water (0.4 mL). The mixture was allowed to continue to stir at 0 °C for another 10 min. 15% aqueous NaOH (0.4 mL) and water (1.2 mL) were then added sequentially at 0 °C. The mixture was allowed to warm to RT. The mixture was allowed to continue to stir for another 15 min. The reaction mixture was then dried over ISfeSCL, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (7:2 petroleum ether: EtOAc) to give tert-butyl (3-(3-(difluoromethyl)phenyl)-5-hydroxypentyl)(methyl)carbamate (1.0 g, 37%)(ESI 344.2 [M+H]+). Enantiomers were separated by prep chiral SFC J to give peak 1, tert-butyl (S)-(3-(3- (difluoromethyl)phenyl)-5-hydroxypentyl)(methyl)carbamate (200mg), and peak 2, tert-butyl (R)-(3-(3-(difluoromethyl)phenyl)-5-hydroxypentyl)(methyl)carbamate (325mg), as a white solids (ESI 362.2 [M+H]+).Step 3: tert-butyl (R)-(3-(3-(difluoromethyl)phenyl)-5-oxopentyl)(methyl)carbamateoc[000467] To a solution of tert-butyl (R)-(3-(3-(difluoromethyl)phenyl)-5- hydroxypentyl)(methyl)carbamate (230 mg, 0.67 mmol, 1.0 eq.) in DCM (6 mL) was added Dess-Martin periodinane (370 mg, 0.87 mmol, 1.3 eq.) at 0 °C. The reaction was then allowed to warm to RT and to stir for 1 hr. The reaction mixture was diluted with saturated aqueous Na2SOs (50 mL) and extracted with DCM (3 x 50 mL). The organic solutions were combined, washed with brine (100 mL), dried over anhydrous ISfeSCU, filtered and concentrated in vacuo to obtain tert-butyl (R)-(3-(3-(difluoromethyl)phenyl)-5-oxopentyl)(methyl)carbamate (230mg, 100%)(ESI 364.0 ([M+Na]+). The crude product was used without purification in the subsequent step.Step 4: tert-butyl (S)-(3-(3-(difluoromethyl)phenyl)-5-(piperidin-l-yl)pentyl)(methyl)- carbamate[000468] To a solution of tert-butyl (R)-(3-(3-(difluoromethyl)phenyl)-5- oxopentyl)(methyl)carbamate (230 mg, 0.67 mmol, 1.0 eq.) in di chloroethane (6 mL) was added piperidine (85 mg, 1.0 mmol, 1.5 eq.). The reaction mixture was allowed to stir at RT for 1 hr. NaBH(OAc)3 (285 mg, 1.34 mmol, 2.0 eq.) was then added into the reaction. The reaction mixture was allowed to continue to stir at RT for another 2 hr. The reaction mixture was then poured into water (50 mL) and extracted with DCM (3 x 50 mL). The organic solutions were combined, washed with brine (50 mL), dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9: 1 DCM: methanol) to give tert-butyl (S)-(3-(3-(difluoromethyl)phenyl)-5-(piperidin-l- yl)pentyl)(methyl)carbamate as yellow oil (160 mg, 60%) (ESI 411.2 [M+H]+).Step 5: (R)-3-(3-(difluoromethyl)phenyl)-N-methyl-5-(piperidin-l-yl)pentan-l-amine[000469] To a solution of tert-butyl (S)-(3-(3-(difluoromethyl)phenyl)-5-(piperidin-l- yl)pentyl)(methyl)carbamate (160 mg, 0.4 mmol, 1.0 eq.) in DCM (2 mL) was added TFA (0.2 mL, 2.8 mmol, 7.0 eq.). The reaction mixture was allowed to stir at RT for 2 hr. and concentrated in vacuo to obtain (R)-3-(3-(difluoromethyl)phenyl)-N-methyl-5-(piperidin-l- yl)pentan-l -amine as a colorless oil (160 mg 0.4 mmol, crude). (ESI 311.3 [M+H]+). The crude product was used without purification in the next step.Step 6: ethyl 2-(((S)-3-(3-(difluoromethyl)phenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate[000470] To a solution of (R)-3-(3-(difluoromethyl)phenyl)-N-methyl-5-(piperidin-l- yl)pentan-l -amine (160 mg 0.4 mmol) in ACN (10 mL) was added K2CO3 (276 mg, 2.0 mmol, 5.0 eq.). The mixture was allowed to stir at RT for 15 min. Ethyl 2-bromo-2-(3-methyl- 2-((lr,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (169 mg, 0.4 mmol, l.Oe ) was then added. The reaction mixture was allowed to continue to stir at 80 °C for another 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9: 1 DCM: MeOH) to give ethyl 2-(((S)-3-(3- (difluoromethyl)phenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4- (trifluoromethoxy)cyclohexyl)phenyl)acetate (190 mg, 59 %) (ESI 653.4 [M+H]+).Step 7 : 2-(((S)-3-(3-(difluoromethyl)phenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3- methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid[000471] To a solution of ethyl 2-(((S)-3-(3-(difluoromethyl)phenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)- phenyl)acetate (190 mg, 0.29 mmol, 1.0 eq) in EtOH (5 mL) and H2O (1 mL) was added NaOH (58 mg, 1.5 mmol, 5.0 eq) and the mixture was allowed to stir at 80 °C for 1 hr. The reaction was concentrated in vacuo and the residue was purified by prep HPLC A (30 - 70% CH3CN) to give 152 as a mixture of stereoisomers (160 mg, 88%). The stereoisomers were further separated by prep chiral SFC A to give 152-P1 (65.1 mg) 152-P2 (69.7 mg).[000472] 152-P1, assigned as (R)-2-(((S)-3-(3-(difluoromethyl)phenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 625.3 [M+H]+. *H NMR (400 MHz, CD3OD) 5 7.63 - 6.91 (m, 7H), 6.84 - 6.54 (m, 1H), 4.78 - 4.15 (m, 2H), 3.26 - 3.00 (m, 1H), 2.99 - 2.44 (m, 10H), 2.44 (s, 3H), 2.32 (s, 1H), 2.27 - 1.64 (m, 11H), 1.70 - 1.05 (m, 8H).[000473] 152-P2, assigned as (S)-2-(((S)-3-(3-(difluoromethyl)phenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-methyl-2-((lr,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 625.3 [M+H]+. ’H NMR (400 MHz, CD3OD) 5 7.75 - 6.92 (m, 7H), 6.86 - 6.57 (m, 1H), 4.75 - 4.23 (m, 2H), 2.98 - 2.53 (m, 8H), 2.52 - 2.39 (m, 6H), 2.39 - 2.24 (m, 2H), 2.22 - 1.71 (m, 10H), 1.70 - 1.55 (m, 6H), 1.54 - 1.40 (m, 2H).Example 22: Preparation of Compound 171-P2Step 1: tert-butyl methyl(3-oxopropyl)carbamate[000474] To a solution of tert-butyl (3-hydroxypropyl)(methyl)carbamate (50 g, 264.6 mmol, 1.0 eq.) in DCM (1 L) was added Dess-Martin periodinane (118 g, 278 mmol, 1.05 eq.) at 0 °C. The reaction mixture was then warmed to RT and stirred for 30 minutes. The reaction was quenched by the addition of saturated aqueous Na2SO3 (800 mL) and extracted with DCM (2 x 500 mL). The organic solutions were combined, washed with saturated Na2COs solution (2 x 800 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give tertbutyl methyl(3-oxopropyl)carbamate as a yellow oil (44 g, 213.9 mmol) (ESI 210 [M+Na]+). The crude product was used without purification in the subsequent step.Step 2: ethyl (E)-5-((tert-butoxycarbonyl)(methyl)amino)pent-2-enoate[000475] To a solution of NaH (60% in oil, 11.1 g, 278 mmol, 1.3 eq.) in THF (500 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (57.5 g, 256.7 mmol, 1.2 eq.) at 0 °C. The reaction mixture was allowed to stir at 0 °C for 30 minutes. A solution of tert-butyl methyl(3- oxopropyl)carbamate(44 g, 213.9 mmol, 1.0 eq.) in THF (200 mL) was then added over 5 min. The mixture was allowed to warm to RT and stirred for 30 min. The reaction was then quenched by the addition of saturated aqueous NH4CI solution (400 mL) and extracted with EtOAc (2 x 400 mL). The organic solutions were combined, washed with brine (400 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (12: 1 petroleum ether: EtOAc) to give ethyl (E)- 5-((tert-butoxycarbonyl)(methyl)amino)pent-2-enoate as a yellow oil (27.5 g, 41.6%) (ESI 158.2 (M-Boc+H)+).Step 3: ethyl 5-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2- methoxyphenyl)pentanoateBis(norbornadiene)rhodium(l) Boc tetrafluoroborate, BINAP[000476] To a solution of (5-chloro-2-methoxyphenyl)boronic acid (5.6 g, 30.0 mmol, 2.5 eq.), bis(norbornadiene)rhodium(I) tetrafluoroborate (360 mg, 1.0 mmol, 0.08 eq.), ethyl (E)-5- ((tert-butoxycarbonyl)(methyl)amino)pent-2-enoate (3.0 g, 12.0 mmol, 1.0 eq.) and BINAP (750 mg, 1.2 mmol, 0.1 eq.) in dioxane (50 mL) was added a solution of KOH (1 .0 g, 18.0 mmol, 1.5 eq.) in H2O (7 mL). The reaction mixture was allowed to stir at RT for 6 hr under nitrogen atmosphere. The reaction mixture was then poured into 200 mL water and extracted with EtOAc (3 x 400 mL). The organic solutions were combined, washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column (7: 1 petroleum ether: EtOAc) to give ethyl 5-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-methoxyphenyl)pentanoate (3.2 g, 68%) (ESI 300.2 ...

Claims

CLAIMS1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:a 3 to 12 member heterocyclyl ring structure optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen; a is 0, 1, 2 or 3;Xi is N or CRa;Rais H, halogen or C1-4 alkyl optionally substituted with one or more halogen;X2 is NRb or CRb'Rb ;Rb is H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, C3- ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Rb' and Rb'' are each independently H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl- OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3- ecycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Ri is H or -COORib;Rib is H or C 1-4 alkyl;R2 is H or C 1-4 alkyl;R3 is H, C1-4 alkyl, or halogen; n is 0, 1, 2, 3, or 4;RHs H, Ci-4 alkyl optionally substituted with one or more halogen, or halogen; p is 0, 1, 2, 3, 4 or 5;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each R7 is independently halogen.

2. The compound of claim 1, wherein Ri is COOH.

3. The compound of any one of claims 1-2, wherein R2 is methyl.

4. The compound of any one of claims 1-3, wherein Rb'' is H.

5. The compound of any one of claims 1-4, wherein Xi is CRa.

6. The compound of claim 5, wherein Rais H.

7. The compound of any one of claims 1-6, wherein X2 is NRb.

8. The compound of claim 7, wherein Rb is Ci-4alkyl optionally substituted with one or more halogen.

9. The compound of claim 8, wherein Rb is Ci-4alkyl optionally substituted with one or more flouro.

10. The compound of claim 9, wherein Rb is -CH2CF3.

11. The compound of any one of claims 1-6, wherein X2 is CRb'Rb ' .

12. The compound of claim 11, wherein Rb'' is H.

13. The compound of any one of claims 11-12, wherein Rb' is -O-C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with one or more halogen.

14. The compound of claim 13, wherein Rb' is -O-C1-4 alkyl or -O-C3-6 cycloalkyl, wherein the C1-4 alkyl is optionally substituted with one or more fluoro.

15. The compound of claim 14, wherein Rb' is -O-CF3.

16. The compound of claim 14, wherein Rb' is -O-CH3.

17. The compound of claim 14, wherein Rb' is -O-C3 cycloalkyl optionally substituted with C1-4 alkyl.

18. The compound of claim 14, wherein Rb' is -O-C3 cycloalkyl optionally substituted with methyl.

19. The compound of claim 13, wherein Rb' is -O-C1-4 alkyl optionally substituted with one or more fluoro.

20. The compound of any one of claims 1-4, wherein Xi is CH and X2 is CHRb' and Rb' is21. The compound of any one of claims 1-20, wherein m is 0.

22. The compound of any one of claims 1-21, wherein R3 and R4 are each independently halogen or C1-4 alkyl optionally substituted with one or more halogen.

23. The compound of any one of claims 1-21, wherein R3 and R4 are each independently fluoro, chloro or methyl optionally substituted with one or more fluoro.

24. The compound of any one of claims 1-23, wherein n and p are each independently 1 or 2.

25. The compound of claim 24, wherein n is 1.

26. The compound of any one of claims 1-25, wherein m is 1.

27. The compound of any one of claims 1-25, wherein m is 2.

28. The compound of any one of claims 1-27, wherein the compound is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof,whereinRcis H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Y2 is NRa or CRa'Rd ;Rd is H, halogen, C1-4 alkyl or 3-6 member heterocycloalkyl, wherein the C1-4 alkyl or 3-6 member heterocycloalkyl is optionally substituted with one or more halogen;Rd' and Rd'' are each independently H, halogen, or C1-4 alkyl, and each C1-4 alkyl is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Re is H, Ci-salkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 Rs; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each Rs is independently halogen.

29. The compound of claim 28, wherein Yi is N and Y2 is NRd.

30. The compound of claim 29, wherein Rd is C1-4 alkyl, C3-6 cycloalkyl or 3-6 member heterocycloalkyl.

31. The compound of claim 30, wherein Rd is methyl.

32. The compound of claim 30, wherein Rd is isopropyl.

33. The compound of claim 30, wherein Rd is cyclopropyl.

34. The compound of claim 30, wherein Rd is tetrahydrofuran.

35. The compound of claim 28, wherein Y2 is CRd'Rd ".

36. The compound of claim 35, wherein Rd'' is H.

37. The compound of claim 36, wherein Rd' is fluoro.

38. The compound of claim 36, wherein Rd' is methoxy.

39. The compound of claim 36, wherein Rd' is methyl.

40. The compound of claim 35, wherein Rd'' is methyl.

41. The compound of claim 28, wherein the compound is a compound of Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof,whereinR3', R3 , R4 , and R4'' are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen.

42. The compound of claim 41, wherein Xi is N.

43. The compound of any one of claims 41-42, wherein X2 is NRb.

44. The compound of claim 43, wherein Rb is Ci-4alkyl optionally substituted with one or more halogen.

45. The compound of claim 43, wherein Rb is Ci-4alkyl optionally substituted with one or more flouro.

46. The compound of claim 43, wherein Rb is -CH2CF3.

47. The compound of any one of claims 41-42, wherein X2 is CRb'Rb '.

48. The compound of claim 47, wherein Rb'' is H.

49. The compound of any one of claims 47-48, wherein Rb is -O-Ci-4 alkyl, wherein the Ci-4 alkyl is optionally substituted with one or more halogen.

50. The compound of claim 49, wherein Rb' is -O-Ci-4 alkyl or -O-C3-6 cycloalkyl, wherein the C1-4 alkyl is optionally substituted with one or more fluoro.

51. The compound of claim 50, wherein Rb' is -O-CF3.

52. The compound of claim 50, wherein Rb' is -O-CH3.

53. The compound of claim 50, wherein Rb' is -O-C3 cycloalkyl optionally substituted with C1-4 alkyl.

54. The compound of claim 50, wherein Rb' is -O-C3 cycloalkyl optionally substituted with methyl.

55. The compound of claim 50, wherein Rb' is -O-C1-4 alkyl optionally substituted with one or more fluoro.

56. The compound of any one of claims 41-55, wherein Yi is N.

57. The compound of claim 56, wherein Y2 is NRd.

58. The compound of claim 57, wherein Rd is C1-4 alkyl, C3-6 cycloalkyl or 3-6 member heterocycloalkyl.

59. The compound of claim 58, wherein Rd is methyl.

60. The compound of claim 58, wherein Rd is isopropyl.

61. The compound of claim 58, wherein Rd is cyclopropyl.

62. The compound of claim 58, wherein Rd is tetrahydrofuran.

63. The compound of claim 56, wherein Y2 is CRd'Rd ".

64. The compound of claim 63, wherein Rd'' is H.

65. The compound of claim 63, wherein Rd' is fluoro.

66. The compound of claim 63, wherein Rd' is methoxy.

67. The compound of claim 63, wherein Rd' is methyl.

68. The compound of claim 63, wherein Rd'' is methyl.

69. The compound of claim 1, wherein the compound is a compound of Formula (V)(V), wherein, a is 1 or 2;R3', R3 ", R4', and R4" are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each R7 is independently halogen.

70. The compound of claim 69, whereina 5- to 10-membered heterocyclyl ring structure, whose ring structures include one to four heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.

71. The compound of claim 70, whereina 5- to 10-membered heterocyclyl ring structure, whose ring structures include one or two heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.(A)72. The compound of claim 71, wherein ' is a 5- to 6-membered monocyclic heterocyclyl ring structure, whose ring structures include one or two heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.

73. The compound of claim 71, whereinis a 7- to 8-membered bicyclic bridged heterocyclyl ring structure, whose ring structures include one or two heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.

74. The compound of claim 71, whereina 7- to 8-membered spirocyclic heterocyclyl ring structure, whose ring structures include one or two heteroatoms, optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl and Ci-4alkyloxy are optionally substituted with one or more halogen.

75. The compound of anyone of claim 70-74, wherein the heterocyclyl ring structure is saturated.

76. The compound of claim 69, whereinis tetrahydrofuran.

77. The compound of claim 69, wherein78. The compound of claim 69, wherein79. The compound of claim 69, wherein80. The compound of claim 69, wherein81. The compound of claim 69, wherein82. The compound of claim 69, wherein83. The compound of claim 69, wherein84. The compound of claim 69, wherein OisO85. The compound of claim 69, wherein86. The compound of claim 69, wherein87. The compound of claim 69, wherein88. The compound of claim 69, wherein89. The compound of claim 69, wherein90. The compound of claim 69, wherein91. The compound of claim 69, wherein92. The compound of claim 69, wherein93. The compound of claim 69, wherein94. The compound of claim 69, wherein95. The compound of claim 69, wherein96. The compound of claim 69, wherein97. The compound of any one of claim 28-40, wherein the compound is a compound of Formula (IV-A), or a pharmaceutically acceptable salt thereof,98. The compound of any one of claim 41-68, wherein the compound is a compound of Formula (II-A), Formula (III), or a pharmaceutically acceptable salt thereof,(in-A) whereinR3', R3 , R4 , and R4'' are each independently H, halogen or C1-4 alkyl optionally substituted with one or more halogen.

99. The compound of any one of claim 69-96, wherein the compound is a compound of Formula (V-A), or a pharmaceutically acceptable salt thereof100. A compound Formula (VI) or a pharmaceutically acceptable salt thereof,whereinYi, Y2, Y3, Y4, Y5 and Zi, Z2 and Z3 are each CH or N, provided that at least three of Yi, Y2, Y3, Y4, and Y5 are CH and at least one of Zi, Z2 and Z3 is CH;a 3 to 12 member heterocyclyl ring structure (including monocyclic heterocyclic, bicyclic bridged, and bicyclic spirocyclic ring structures) optionally substituted with halogen, C1-5 alkyl or Ci-4alkyloxy, wherein the C1-4 alkyl (e.g., methyl) and Ci-4alkyloxy (e.g., methoxy) are optionally substituted with one or more halogen (e.g., one or more fluoro); a is 0, 1, 2 or 3;Xi is N or CRa;Rais H, halogen or C1-4 alkyl optionally substituted with one or more halogen;X2 is NRb or CRb'Rb ;Rb is H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, C3-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Rb' and Rk' are each independently H, halogen, C1-4 alkyl, Ci-4alkyloxy, OH, Ci-4alkyl- OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3- ecycloalkyloxy, and each C1-4 alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, Cs-ecycloalkyloxy, or Ci-4alkyl-C3-6cycloalkyloxy is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy;Ri is H or -COORib;Rib is H or C 1-4 alkyl;R2 is H or C 1-4 alkyl;R3 is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; n is 0, 1, 2, 3, or 4;R4is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen; p is 0, 1, 2, 3, 4 or 5;Rs is H, Ci-4alkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci- 4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-4alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 R7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each R7 is independently halogen.

101. The compound of claim 97, whereinYi is N or CRc;Rcis H, halogen or C1-4 alkyl optionally substituted with one or more halogen;Y2 is NRa or CRd'Ra ;Rd is H, halogen, C1-4 alkyl or 3-6 member heterocycloalkyl, wherein the C1-4 alkyl or 3-6 member heterocycloalkyl is optionally substituted with one or more halogen;Rd' and Rd'' are each independently H, halogen, or C1-4 alkyl, and each C1-4 alkyl is optionally substituted with one or more halogen, C1-4 alkyl or Ci-4alkyloxy; q is O, 1, 2, 3, 4, 5, 6, 7 or 8;Re is H, Ci-salkyl, halogen, Ci-4alkyloxy, OH, Ci-4alkyl-OH, Ci-4alkyl-Cnalkyloxy, Ci-4alkyloxy-Ci-4alkyloxy, and each Ci-4alkyl, Ci-4alkyloxy, Ci-4alkyl-OH, Ci-alkyl-Ci-4alkyloxy, Ci-4alkyloxy-Ci-4alkyloxy,is optionally substituted with 1 to 4 Rs; and each Rs is independently halogen.

102. The compound of claim 98, wherein Yi is N and Y2 is CH2 or C(CH3)2.A compound of the chemical formulapharmaceutically acceptable salt thereof.

104. A compound of the chemical formulapharmaceutically acceptable salt thereof.

105. A compound of the chemical formulapharmaceutically acceptable salt thereof.

106. A compound of the chemical formulapharmaceutically acceptable salt thereof.

107. A compound of the chemical formulapharmaceutically acceptable salt thereof.

108. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.

109. A compound of the chemical formulapharmaceutically acceptable salt thereof.

110. A compound of the chemical formulaa pharmaceutically acceptable salt thereof.

111. A compound of the chemical formulapharmaceutically acceptable salt thereof.

112. A compound of the chemical formulapharmaceutically acceptable salt thereof.

113. A compound of the chemical formulapharmaceutically acceptable salt thereof.

114. A compound of the chemical formulapharmaceutically acceptable salt thereof.

115. A compound of the chemical formulapharmaceutically acceptable salt thereof.

116. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.

117. A compound selected from the group consisting of the compounds in Figure 1, or a pharmaceutically acceptable salt thereof.

118. A compound selected from the group consisting of the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

119. A compound selected from the group consisting of the compounds in Table 3, or a pharmaceutically acceptable salt thereof.

120. A compound selected from the group consisting of the compounds in Table 4, or a pharmaceutically acceptable salt thereof.

121. A pharmaceutical composition comprising the compound of any one of claims 1- 120, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

122. A method of treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-120, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 121.

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