Inhibition of human integrin alpha4beta7

Abstract

Disclosed are compounds and methods for treating or preventing diseases or conditions that respond to inhibition of human α4β7 integrin by administering the disclosed compounds (such as compounds of formula (I) or (VI)) or pharmaceutically acceptable salts thereof to patients in need. Many diseases and conditions can be treated by administering the disclosed compounds (such as compounds of formula (I)), including, for example, inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease.

Description

[0001] Cross-references to related applications This application claims priority and interest in 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 which are hereby incorporated by reference. Technical Field

[0002] This application discloses a method for treating diseases and conditions by inhibiting α4β7 integrin. Diseases and conditions that respond to α4β7 integrin inhibition include, for example, inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD). Background Technology

[0003] Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD), both related idiopathic conditions characterized by chronic inflammation of the gastrointestinal tract. While UC affects only the colon, CD is characterized by transmural inflammation that can involve any part of the entire gastrointestinal tract, from the mouth to the perianal region. The choice of CD treatment varies depending on anatomical location, disease severity and behavior, and whether the treatment goal is to induce or maintain remission. Conventional therapies such as 5-aminosalicylic acid are generally ineffective for moderate to severe active CD, while long-term use of corticosteroids can have adverse effects.

[0004] Integrins are a group of receptors known to regulate the mucosal inflammatory state that underlies the progression of CD. CD is associated with the activation of immune cells expressing integrin α4β7 and the migration of these cells from the bloodstream to the intestine and surrounding tissues to promote chronic inflammation. Specific inhibition of α4β7 is an empirical mechanism for the treatment of IBD, as demonstrated by vedelizumab (Entyvio®, a monoclonal antibody administered via intravenous infusion).

[0005] Specific integrin-ligand interaction inhibitors have been used to treat a variety of diseases. For many years, the primary treatment modalities have been oral and topical salicylates and corticosteroids, various immunosuppressants, and biologics. Monoclonal antibodies exhibiting high binding affinity for α4β7 have shown therapeutic benefits in gastrointestinal autoinflammatory / autoimmune diseases such as Crohn's disease and ulcerative colitis. Anti-integrin antibody therapy for IBD was initially introduced after the approval of the nonspecific α4-integrin inhibitor natezumab for Crohn's disease, following its initial approval for multiple sclerosis. Vedolizumab, a monoclonal antibody inhibitor of integrin α4β7, is approved for inducing and maintaining remission in advanced ulcerative colitis without a boxed warning. Vedolizumab is also approved as a treatment option for advanced Crohn's disease. However, these therapies also possess certain characteristics that are not desirable to patients. Monoclonal antibody α4β7 integrin inhibitors are administered via non-gastrointestinal routes, have long half-lives, cannot rapidly alter exposure, and exhibit reduced activity due to the formation of anti-drug antibodies. In addition to administration issues, the production of monoclonal antibody therapies may be challenging compared to "small molecule" therapies.

[0006] There remains a medical need for effective and safe oral α4β7 integrin inhibitors, which would be an important complement to treatment options for α4β7 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 small molecules designed to inhibit integrin α4β7, including the need for such oral small molecules to avoid the need for regular therapeutic infusions and complications associated with such drug administration. Summary of the Invention

[0008] In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof: in: It is optional to be halogenated, C 1-5 Alkyl or C 1-4 Alkoxy-substituted 3- to 12-membered heterocyclic ring structures, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens; a is 0, 1, 2, or 3; X1 is N or CR a ; R a It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; X2 is NR b or CR b ´R b ´´; R b It is H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R b ´ and R b Each of them independently consists of H, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R1 is H or -COOR1b ; R 1b Is it H or C? 1-4 alkyl; R2 is H or C 1-4 alkyl; R3 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; n is 0, 1, 2, 3 or 4; R4 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; p is 0, 1, 2, 3, 4 or 5; R5 is H, C 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R7 groups; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each R7 is a halogen independently.

[0009] In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein yes ,and Y1 is N or CR c ; R c It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; Y2 is NR d or CR d ´R d ´´; R d It is H, halogen, C 1-4 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-4 Alkyl or 3-6 membered heterocyclic alkyl groups may optionally be substituted with one or more halogens; R d ´ and R dEach is independently H, halogen, or C. 1-4 Alkyl groups, and each C 1-4 Alkyl groups are optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; R6 is H, C 1-5 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R8 groups; and Each R8 is a halogen independently.

[0010] In one aspect, the invention is characterized by a compound of formula (I) having the chemical structure of formula (II) or formula (II-A), or a pharmaceutically acceptable salt thereof. Where X1, X2, Y1, and Y2 are each as defined in equation (I), and R3', R3'', R4', and R4'' are each independently H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl.

[0011] In one aspect, the invention is characterized by a compound of formula (I) having a chemical structure of formula (III) or formula (III-A), or a pharmaceutically acceptable salt thereof. Where X1, X2, Y1, and Y2 are each as defined in equation (I), and R3', R3'', R4', and R4'' are each independently H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl.

[0012] In one aspect, the invention is characterized by a compound of formula (I) having the chemical structure of formula (IV) or (IV-A), or a pharmaceutically acceptable salt thereof. in Y1 is N or CR c ; R c It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; Y2 is NR d or CR d ´R d ´´; R d It is H, halogen, C 1-4 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-4 Alkyl or 3-6 membered heterocyclic alkyl groups may optionally be substituted with one or more halogens; R d ´ and R d Each is independently H, halogen, or C. 1-4 Alkyl groups, and each C 1-4 Alkyl groups are optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R6 is H, C 1-5 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R8 groups; q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each R8 is a halogen independently.

[0013] In one aspect, the invention is characterized by a compound of formula (I) having the chemical structure of formula (V) or formula (VA), or a pharmaceutically acceptable salt thereof. in, a is 1 or 2; R3´, R3´´, R4´, and R4´´ are each independently H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; R5 is H, C 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R7 groups; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each R7 is a halogen independently.

[0014] In some embodiments, the compound is a compound of formula (VI) or a pharmaceutically acceptable salt thereof. in Y1, Y2, Y3, Y4, Y5 and Z1, Z2 and Z3 are each CH or N, provided that at least three of Y1, Y2, Y3, Y4 and Y5 are CH and at least one of Z1, Z2 and Z3 is CH. It is optional to be halogenated, C 1-5 Alkyl or C 1-4 Alkoxy-substituted 3- to 12-membered heterocyclic ring structures (including monocyclic heterocyclic, bicyclic bridging, and bicyclic spirocyclic ring structures), wherein C 1-4 Alkyl (e.g., methyl) and C 1-4 Alkyl groups (e.g., methoxy groups) are optionally substituted with one or more halogens (e.g., one or more fluorine groups); a is 0, 1, 2, or 3; X1 is N or CR a ; R a It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; X2 is NR b or CR b ´R b ´´; R b It is H, halogen, C1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R b ´ and R b Each of them independently consists of H, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R1 is H or -COOR 1b ; R 1b Is it H or C? 1-4 alkyl; R2 is H or C 1-4alkyl; R3 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; n is 0, 1, 2, 3 or 4; R4 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; p is 0, 1, 2, 3, 4 or 5; R5 is H, C 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R7 groups; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each R7 is a halogen independently.

[0015] In some embodiments, the compound is a compound selected from the group consisting of: Or, or a pharmaceutically acceptable salt thereof. Attached Figure Description

[0016] Figure 1 This is a table of the compounds disclosed in this article. Detailed Implementation

[0017] Compounds including formulas (Ia), (Ib) and (Ic) and their respective pharmaceutically acceptable salt forms of formula (I) compounds are small molecule integrin therapeutic agents that target α4β7. These integrin therapeutic agents can be administered to treat patients with diseases and conditions that respond to inhibition of α4β7 integrins.

[0018] In particular, the methods described herein are effective in treating inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. For example, administration of compound (I) according to the methods described herein over a twelve-week course of therapy has provided unexpected therapeutic benefits to patients with moderate to severe active ulcerative colitis, including those who have previously received advanced therapy (AT) for ulcerative colitis and / or those with a baseline endoscopic score of 3. Furthermore, the methods described herein demonstrate that administration of compound (I) according to formula (I) is well tolerated and has a favorable safety profile.

[0019] Therefore, the method described in this article can be expanded to be used as a therapy for subjects with inflammatory bowel diseases such as ulcerative colitis or Crohn's disease.

[0020] Compound of formula (I) In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof: in: It is optional to be halogenated, C 1-5 Alkyl or C 1-4 Alkoxy-substituted 3- to 12-membered heterocyclic ring structures (including monocyclic heterocyclic, bicyclic bridging, and bicyclic spirocyclic ring structures), wherein C 1-4 Alkyl (e.g., methyl) and C 1-4 The alkoxy group (e.g., methoxy group) is optionally substituted with one or more halogens (e.g., one or more fluorines); a is 0, 1, 2, or 3; X1 is N or CR a ; R a It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; X2 is NR b or CR b ´R b ´´; R b It is H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R b ´ and R b Each of them independently consists of H, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R1 is H or -COOR 1b ; R 1b Is it H or C? 1-4 alkyl; R2 is H or C 1-4 alkyl; R3 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; n is 0, 1, 2, 3 or 4; R4 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; p is 0, 1, 2, 3, 4 or 5; R5 is H, C 1-4 Alkyl, halogen, C 1-4Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R7 groups; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each R7 is a halogen independently.

[0021] In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein yes ,and Y1 is N or CR c ; R c It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; Y2 is NR d or CR d ´R d ´´; R d It is H, halogen, C 1-4 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-4 Alkyl or 3-6 membered heterocyclic alkyl groups may optionally be substituted with one or more halogens; R d ´ and R d Each is independently H, halogen, or C. 1-4 Alkyl groups, and each C 1-4 Alkyl groups are optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; R6 is H, C 1-5 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R8 groups; and Each R8 is a halogen independently.

[0022] In one aspect, the invention is characterized by a compound of formula (I) having the chemical structure of formula (II), or a pharmaceutically acceptable salt thereof. Where X1, X2, Y1, and Y2 are each as defined in equation (I), and R3', R3'', R4', and R4'' are each independently H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl.

[0023] In one aspect, the invention is characterized by a compound of formula (I) having the chemical structure of formula (III), or a pharmaceutically acceptable salt thereof. Where X1, X2, Y1, and Y2 are each as defined in equation (I), and R3', R3'', R4', and R4'' are each independently H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl.

[0024] In one aspect, the invention is characterized by a compound of formula (IV) or a pharmaceutically acceptable salt thereof: in: X1 is N or CR a ; R a It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; X2 is NR b or CR b ´R b ´´; R b It is H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R b ´ and R b Each of them independently consists of H, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; Y1 is N or CR c ; R c It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; Y2 is NR d or CR d ´R d ´´; R d It is H, halogen, C 1-4 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-4 Alkyl or 3-6 membered heterocyclic alkyl groups may optionally be substituted with one or more halogens; R d ´ and R d Each is independently H, halogen, or C. 1-4 Alkyl groups, and each C 1-4 Alkyl groups are optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R1 is H or -COOR 1b ; R 1b Is it H or C? 1-4 alkyl; R2 is H or C 1-4 alkyl; R3 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; n is 0, 1, 2, 3 or 4; R4 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; p is 0, 1, 2, 3, 4 or 5; R5 is H, C 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R7 groups; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; R6 is H, C 1-5 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C1-4 The alkoxy group is optionally substituted with 1 to 4 R8 groups; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each R7 is independently a halogen; and Each R8 is a halogen independently.

[0025] In one aspect, the invention is characterized by a compound of formula (V) or a pharmaceutically acceptable salt thereof: It is optional to be halogenated, C 1-5 Alkyl or C 1-4 Alkoxy-substituted 3- to 12-membered heterocyclic ring structures (including monocyclic heterocyclic, bicyclic bridging, and bicyclic spirocyclic ring structures), wherein C 1-4 Alkyl (e.g., methyl) and C 1-4 Alkyl groups (e.g., methoxy groups) are optionally substituted with one or more halogens (e.g., one or more fluorine groups); and Each is independently a 5-6 membered aryl or heteroaryl ring structure; and a, R4, p, R2, R1, R3, n, X1, X2, R5 and m are as described in formula (I) of this paper.

[0026] In some embodiments, the compound is a compound of formula (I), wherein R1 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 R1 is -COOH and R2 is -methyl.

[0027] In some embodiments, the compound is a compound of formula (I), wherein X1 is CH. In some embodiments, the compound is a compound of formula (I), wherein X2 is CHR. b In some embodiments, the compound is a compound of formula (I), wherein X1 is CH and X2 is CHR. b In some embodiments, the compound is a compound of formula (I), wherein X1 is CH and X2 is CHR. b And R b ´is C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkoxy groups, and each R b 'Optionally constituting one or more halogens or C 1-4 Alkyl substitution. In some embodiments, the compound is of formula (I), wherein X1 is CH and X2 is CHR. b And R b ´is C1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkoxy, and each R b ´ is optionally substituted with one or more fluorines. In some embodiments, the compound is a compound of formula (I) wherein X1 is CH and X2 is CHR b ´ and R b ´ is C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkoxy, and each R b ´ is optionally substituted with one or more fluorines.

[0028] In some embodiments, the compound is a compound of formula (I) wherein R1 is -COOH and R2 is -methyl, and X1 is CH and X2 is CHR b ´ and R b ´ is -O-R b2 ´ or -CH2-R b2 ´, wherein R b2 ´ is C 1-4 alkyl or C optionally substituted with one or more halogens or C 1-4 alkyl-substituted C 3-6 cycloalkyl. In some embodiments, the compound is a compound of formula (I) wherein R1 is -COOH and R2 is -methyl, X1 is CH and X2 is CHR b ´ and R b ´ is -O-R b2 ´, wherein R b2 ´ is C 1-4 alkyl or cyclopropyl optionally substituted with one or more halogens or C 1-4 alkyl. In some embodiments, the compound is a compound of formula (I) wherein R1 is -COOH and R2 is -methyl, X1 is CH and X2 is CHR b ´ and R b ´ is -O-R b2 ´, wherein R b2 ´ is C 1-4 alkyl optionally substituted with one or more fluorines. In some embodiments, the compound is a compound of formula (I) wherein R1 is -COOH and R2 is -methyl, X1 is CH and X2 is CHR b ´ and R b ´ is -O-R b2 ´, wherein R b2 ´ is cyclopropyl optionally substituted with one or more C 1-4 alkyl. In some embodiments, the compound is a compound of formula (I) wherein R1 is -COOH and R2 is -methyl, X1 is CH and X2 is CHRb ´ and R b ´ is -O-R b2 ´, wherein R b2 ´ is a cyclopropyl optionally substituted with one or more methyl groups. In some embodiments, the compound is a compound of formula (I) wherein X1 is CH and X2 is CHR b ´ and R b ´ is -CH2-R b2 ´, wherein R b2 ´ is C 1-4 alkyl or a C 1-4 alkyl optionally substituted with one or more halogens or C 3-6 cycloalkyl. In some embodiments, the compound is a compound of formula (I) wherein X1 is CH and X2 is CHR b ´ and R b ´ is -CH2-R b2 ´, wherein R b2 ´ is a C 1-4 alkyl optionally substituted with one or more fluorines.

[0029] In some embodiments, the compound is a compound of formula (I) wherein X2 is CHR b ´ and R b ´ is . In some embodiments, the compound is a compound of formula (I) wherein R1 is -COOH and R2 is -methyl, X1 is CH and X2 is CHR b ´ and R b ´ is .

[0030] In some embodiments, the compound is a compound of formula (I) wherein X1 is CH. In some embodiments, the compound is a compound of formula (I) wherein X2 is CHR b ´. In some embodiments, the compound is a compound of formula (I) wherein X1 is CH and X2 is CHR b ´. In some embodiments, the compound is a compound of formula (I) wherein X1 is CH and X2 is CHR b ´ and R b ´ is C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkoxy, and each R b ´ is optionally substituted with one or more halogens or C 1-4 alkyl. In some embodiments, the compound is a compound of formula (I) wherein X1 is CH and X2 is CHR b ´ and Rb ´is C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkoxy groups, and each R b 'Optionally replaced by one or more methyl or fluorine compounds.

[0031] In some embodiments, the compound is a compound of formula (I), wherein X2 is NR. d In some embodiments, the compound is a compound of formula (I), wherein X2 is NR. d And R d C is a carbon that is optionally substituted with one or more halogens. 1-4 Alkyl group. In some embodiments, the compound is of formula (I), wherein X1 is CH and X2 is NR. d In some embodiments, the compound is a compound of formula (I), wherein X1 is CH and X2 is NR. d And R d C is C that can be optionally replaced by one or more Fs. 1-4 Alkyl group. In some embodiments, the compound is of formula (I), wherein X1 is CH and X2 is NR. d And R d It is -CH2-CF3.

[0032] In some embodiments, the compound is a compound of formula (I), wherein X1 is N. In some embodiments, the compound is a compound of formula (I), wherein X1 is N, R1 is -COOH, and R2 is -methyl. In some embodiments, the compound is a compound of formula (I), wherein X1 is N and X2 is CHR. b In some embodiments, the compound is a compound of formula (I), wherein X1 is N and X2 is CHR. b And R b ´is C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkoxy groups, and each R b 'Optionally constituting one or more halogens or C 1-4 Alkyl substitution. In some embodiments, the compound is of formula (I), wherein R1 is -COOH, R2 is -methyl, X1 is N and X2 is CHR. b And R b ´is C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkoxy groups, and each R b ´ is optionally replaced by one or more fluorine molecules.

[0033] In some embodiments, the compound is a compound of formula (I), wherein R1 is -COOH and R2 is -methyl, X1 is N and X2 is CHR. b And R b yes In some embodiments, the compound is a compound of formula (I), wherein R1 is -COOH and R2 is -methyl, X1 is N and X2 is CHR. b And R b yes .

[0034] In some embodiments, the compound is a compound of formula (I), wherein R3 is a halogen, or C3 optionally substituted with one or more halogens. 1-4 Alkyl group, and n is 0, 1, or 2. In some embodiments, the compound is a compound of formula (I), wherein R4 is a halogen, or C4 optionally substituted with one or more halogens. 1-4 Alkyl group, and p is 0, 1, or 2. In some embodiments, the compound is a compound of formula (I), wherein R3 is a halogen, or C substituted with one or more halogens. 1-4 Alkyl group, n is 0, 1, or 2; R4 is a halogen, or C substituted with one or more halogens. 1-4 Alkyl group, and p is 0, 1, or 2. In some embodiments, the compound is a compound of formula (I), wherein R3 is fluorine or chlorine, or optionally C substituted with one or more fluorine molecules. 1-4 Alkyl group, n is 0, 1, or 2; R4 is fluorine or chlorine, or C4 optionally substituted with one or more fluorine molecules. 1-4 Alkyl group, and p is 0, 1, or 2. In some embodiments, the compound is a compound of formula (I), wherein R3 is fluorine or chlorine, or a methyl group optionally substituted with one or more fluorine molecules, n is 0, 1, or 2; R4 is fluorine or chlorine, or a methyl group optionally substituted with one or more fluorine molecules, 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 R1 is COOH, R2 is a methyl group, 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 R6 is a halogen, or C optionally substituted with one or more halogens. 1-5Alkyl group. In some embodiments, the compound is a compound of formula (I), wherein m is 0, 1, or 2, and R5 is a halogen, or C substituted with one or more halogens. 1-4 Alkyl group. 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 R1 is COOH, R2 is methyl, R5 is a methyl group optionally substituted with one or more fluorine molecules; m is 0, 1, or 2; R6 is a methyl group optionally substituted with one or more fluorine molecules, and q is 0, 1, or 2.

[0037] In some embodiments, the compound is a compound of formula (II), (III), or (IV), wherein Y1 is N or CR. c And R c It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), wherein Y1 is N. In some embodiments, the compound is a compound of formula (I), wherein Y1 is CR. c And R c It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl.

[0038] In some embodiments, the compound is a compound of formula (II), (III), or (IV), wherein Y2 is NR. d And R d It is H, halogen, C 1-4 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-4 The alkyl group or 3-6 membered heterocyclic alkyl group is optionally substituted with one or more halogens. In some embodiments, the compound is of formula (I), wherein Y2 is a CR d ´R d ´´;and R d ´ and R d Each can be independently H, halogen, or C. 1-4 Alkyl groups, and each C 1-4 Alkyl groups are optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution. In some embodiments, the compound is of formula (I), wherein Y1 is N and Y2 is NR. d And R d It is H.

[0039] In some embodiments, the compound is a compound of formula (II), (III), or (IV), wherein Y1 is N and Y2 is NR. d And R dIt is a 3-6 membered heterocyclic alkyl group optionally substituted with one or more halogens, or a C group optionally substituted with one or more halogens. 1-4 Alkyl group. In some embodiments, the compound is of formula (I), wherein Y1 is N and Y2 is NR. d And R d It is a 6-membered heterocyclic alkyl group optionally substituted with one or more halogens, or a methyl group optionally substituted with one or more halogens. In some embodiments, the compound is a compound of formula (I), wherein Y1 is N and Y2 is NR. d And R d It is a 6-membered heterocyclic alkyl group. In some embodiments, the compound is of formula (I), wherein Y1 is N and X2 is NR. d And R d It is tetrahydrofuran.

[0040] In some embodiments, the compound is a compound of formula (II), (III), or (IV), wherein Y1 is CH and Y2 is NR. d And R d It is a 3-6 membered heterocyclic alkyl group optionally substituted with one or more halogens, or a C group optionally substituted with one or more halogens. 1-4 Alkyl group. In some embodiments, the compound is of formula (I), wherein Y1 is CH and Y2 is NR. d And R d It is a 6-membered heterocyclic alkyl group optionally substituted with one or more halogens, or a methyl group optionally substituted with one or more halogens. In some embodiments, the compound is a compound of formula (I), wherein Y1 is CH and Y2 is NR. d And R d It is a 6-membered heterocyclic alkyl group. In some embodiments, the compound is a compound of formula (II), (III), or (IV), wherein Y1 is CH and X2 is NR. d And R d It is tetrahydrofuran.

[0041] In some embodiments, the compound is a compound of formula (V), wherein and Each is independently a 6-membered aryl or heteroaryl ring structure. In some embodiments, the compound is a compound of formula (V), wherein... and Each is independently phenyl, pyridine, or pyrimidine. In some embodiments, the compound is a compound of formula (V), wherein... and Each is independently phenyl, pyridine, or pyrimidine. In some embodiments, the compound is a compound of formula (V), wherein... It is phenyl and It is pyridine or pyrimidine. In some embodiments, the compound is a compound of formula (V), wherein... It is phenyl and It is pyridine. In some embodiments, the compound is a compound of formula (V), wherein... It is phenyl and It is a pyrimidine. In some implementations, yes , where R 4 As defined in equation (I) or equation (V) and It is phenyl, pyridine, or pyrimidine. In some embodiments, yes , where R 4 As defined in equation (I) or equation (V) and It is phenyl. In some implementations, yes , where R3, X1, X2, R5, n and m are as defined for equation (I) or equation (V).

[0042] In some embodiments, the compound is a compound of formula (VI) or a pharmaceutically acceptable salt thereof: in R1, R2, R3, R4, R5, a, p, n, and m are as defined above for formula (V) or formula (I), and Y1, Y2, Y3, Y4, Y5, and Z1, Z2, and Z3 are each CH or N. In some embodiments, the compound is a compound of formula (VI), wherein... R1, R2, R3, R4, R5, a, p, n, and m are defined above for equation (V) or equation (I), and Y1, Y2, Y3, Y4, Y5, and Z1, Z2, and Z3 are each CH or N, provided that at least three of Y1, Y2, Y3, Y4, and Y5 are CH and at least one of Z1, Z2, and Z3 is CH.

[0043] definition For convenience, certain terms used in this specification, embodiments, and appended claims are collected herein before further description of the invention. These definitions should be read in light of the remainder of this disclosure and will be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0044] To make the invention easier to understand, certain terms and phrases will be defined below and throughout the specification.

[0045] The articles “a” and “an” are used in this text to refer to one or more of the grammatical objects of the article (i.e., at least one). For example, “a species” means one or more elements.

[0046] The phrase “and / or” as used herein in the specification and claims should be understood to mean “any one or both” of the elements so connected, that is, elements that exist jointly in some cases and separately in others. Multiple elements listed using “and / or” should be interpreted in the same way, that is, “one or more” of the elements so connected. Optionally, other elements may exist besides those specifically identified by the “and / or” entry, whether related to or not related to those specifically identified elements. Thus, as a non-limiting example, references to “A and / or B” used in conjunction with open-ended language such as “comprising” may, in one embodiment, refer only to A (optionally including elements other than B); in another embodiment, refer only to B (optionally including elements other than A); in yet another embodiment, refer to both A and B (optionally including other elements); and so on.

[0047] The word “or” as used in this specification and claims shall 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 inclusive, that is, including multiple elements or at least one of the elements in the list, and including more than one of them, and optionally including additional unlisted items. Terms that clearly indicate the opposite, such as “only one of…” or “exact one of…” or, when used in claims, “consisting of…”, will refer to including multiple elements or exactly one of the elements in the list. Generally, the term “or” as used herein shall only be interpreted as indicating an exclusive alternative (i.e., “one or the other, but not both”) when preceded by an exclusive term such as “any of…”, “one of…”, “only one of…”, or “exact one of…”. When used in claims, “consisting substantially of…” shall have its ordinary meaning as used in the field of patent law.

[0048] The phrase "at least one" as used in this specification and claims, when referring to a list of one or more elements, should be understood to mean at least one element selected from any one or more elements in the list, but does not necessarily include at least one of every element specifically listed in the list and does not exclude any combination of elements in the list. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase "at least one," whether related to or unrelated to those specifically identified elements. 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") in one embodiment may refer to at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment may refer to at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment may refer 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); and so on.

[0049] It should also be understood that, unless explicitly instructed otherwise, in any method claimed herein that includes more than one step or operation, the order of the steps or operations of the method is not necessarily limited to the order in which the steps or operations of the method are described.

[0050] In the claims and in the foregoing description, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “possessing,” “constituting,” “of,” and similar phrases shall be understood as open-ended, that is, referring to including but not limited to. As set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures, only the transitional phrases “constituting of” and “substantially consisting of” shall be closed or semi-closed transitional phrases, respectively.

[0051] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. Furthermore, the polymers of the present invention may also be optically active. The present invention covers all such compounds within its scope, including cis and trans isomers, R-enantiomers and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0052] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary agent, wherein the resulting diastereomeric mixture is isolated and the auxiliary groups are cleaved to provide the desired enantiomer in pure form. Alternatively, in the case where the molecule contains a basic functional group such as an amine or an acidic functional group such as a carboxyl group, a diastereomeric salt is formed with a suitable optically active acid or base, and the resulting diastereomeric salt is then resolved by stepwise crystallization or chromatographic methods well known in the art, and the pure enantiomer is subsequently recovered.

[0053] The structures described in this article are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or by using enriched... 13 C or 14 Compounds produced by replacing carbon with carbon in C are within the scope of this invention.

[0054] The terms “αvβ8”, “avB8”, “avb8”, “α-vβ-8”, and “αvβ8” and similar terms used in this article all refer to α v β8.

[0055] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in the transport or delivery of the subject chemical substance from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with other components of the formulation, harmless to the patient, and substantially pyrogenic. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (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, corn oil, and soybean oil. (10) Diols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Pyrogen-free water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) Phosphate buffer solution; and (21) Other non-toxic and compatible substances used in the pharmaceutical formulation. In some embodiments, the pharmaceutical compositions of the present invention are pyrogen-free, i.e., they do not induce a significant increase in temperature when administered to a patient.

[0056] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of one or more compounds. Such salts can be prepared in situ during the final separation and purification of one or more compounds, or by reacting one or more purified compounds in free base form with suitable organic or inorganic acids and then separating the resulting salt. Representative salts include hydrobromides, hydrochlorides, sulfates, hydrogen sulfates, phosphates, nitrates, acetates, valerates, oleates, palmitates, stearates, laurates, benzoates, lactates, phosphates, toluenesulfonates, citrates, maleates, fumarates, succinates, tartrates, naphthalenedicarboxates, methanesulfonates, glucono-p-ethyl, lactobionates, and laurylsulfonates, etc. (See, for example, Berge et al. (1977), "Pharmaceutical Salts") J. Pharm. Sci (66:1-19.) In other cases, compounds used in the methods of this invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salt" in these cases refers to a relatively non-toxic inorganic or organic base addition salt of one or more compounds. Such salts can also be prepared in situ during the final separation and purification of one or more compounds, or by reacting one or more purified compounds in free acid form with suitable bases, such as hydroxides, carbonates, or bicarbonates of pharmaceutically acceptable metal cations, with ammonia, or with pharmaceutically acceptable primary, secondary, or tertiary organic amines. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., above).

[0057] The "therapeutic effective amount" (or "effective amount") of a compound used for treatment refers to the amount of a compound in a formulation that, when administered as part of a desired dosage regimen (to mammals, preferably humans), relieves symptoms, improves a condition, or slows the onset of a disease condition, based on clinically acceptable criteria for the treatment of the disorder or condition or for cosmetic purposes, such as a reasonable benefit / risk ratio applicable to any medical treatment.

[0058] The term "preventive or therapeutic" treatment is recognized in the art and includes the administration of one or more of the subject composition to a host. A treatment is preventive (i.e., it protects the host from developing an unwanted condition) if it is administered before the clinical manifestation of an unwanted condition (e.g., a disease or other unwanted state in the host animal), and a treatment is therapeutic (i.e., it aims to reduce, improve, or stabilize an existing unwanted condition or its side effects) if it is administered after the manifestation of an unwanted condition.

[0059] The term "patient" refers to a mammal that requires specific treatment. In some implementations, the patient is a primate, dog, cat, or horse. In some implementations, the patient is a human.

[0060] Whenever a term (e.g., alkyl or aryl) or any of its initials (e.g., alk- or aryl-) appears in the name of a substituent, the name should be interpreted to include the limitations provided herein. For example, attaching the suffix "-" to a group indicates that the group is a divalent moiety, such as arylene being a divalent aryl moiety, heteroarylene being a divalent heteroarylene moiety, and heterocyclic alkyl being a divalent heterocyclic alkyl moiety. Similarly, attaching the suffix "-oxy" to a group indicates that the group is attached to the parent molecule structure via an oxygen atom (-O-), such as "alkyloxy," "alkoxy," or "cycloalkoxy" as used herein.

[0061] Aliphatic chains include the alkyl, alkenyl, and alkynyl categories as defined below. Straight-chain aliphatic chains are limited to the unbranched carbon chain portion. As used herein, the term "aliphatic group" refers to a straight-chain, branched, or cyclic aliphatic hydrocarbon group, and includes both saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0062] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms, or, if not specified, 1 to 30 carbon atoms. For example, an alkyl group having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as those moieties that are positional isomers of such moieties. Alkyl groups having 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, dodecyl, tridecyl, and tetradecyl. In some embodiments, straight-chain or branched alkyl groups have 30 or fewer carbon atoms in their main chain (e.g., for straight-chain C1-C2). 30 For C3-C branches 30 (and more preferably has 20 or fewer carbon atoms. The alkyl group may be substituted or unsubstituted. As used herein, "Me" and -CH3 both refer to methyl.)

[0063] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, such as 2 to 12, containing two connection sites on its longest carbon chain that connect to the rest of the compound. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and so on. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain portions, and may optionally be substituted with one or more substituents.

[0064] "Cycloalkyl" refers to a monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbocyclic ring, each having 3 to 12 carbon atoms. Similarly, preferred cycloalkyl groups have 3-10 carbon atoms in their ring structure, and more preferably 3-6 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted. Exemplary cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cycloheptyl (C7), and cyclooctyl (C8).

[0065] Unless otherwise specified, "low carbon number alkyl" as used herein refers to an alkyl group as defined above, having one to ten carbon atoms, more preferably one to six carbon atoms, in its main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "low carbon number alkenyl" and "low carbon number alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are low carbon number alkyl groups. In some embodiments, substituents referred to herein as alkyl groups are low carbon number alkyl groups.

[0066] As used herein, the term "aryl" includes 3 to 12-membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom in the ring is a carbon (i.e., carbocyclic aryl) or one or more of the atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl comprises 5 to 12-membered rings, more preferably 6 to 10-membered rings. The term "aryl" also includes polycyclic systems having two or more cyclic rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is an aromatic ring, for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. 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, etc. Aryl and heteroaryl groups can be monocyclic, bicyclic, or polycyclic.

[0067] As used herein, the terms “halogen,” “halide,” or “halogen” refer to halogens and include, but are not limited to, fluorine, chlorine, bromine, iodine, etc., in radioactive and non-radioactive forms. In a preferred embodiment, the halogen is selected from the group consisting of fluorine, chlorine, and bromine.

[0068] As used herein, the term "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, and even more preferably a 5- to 10-membered ring, the ring structure comprising one to four heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclic groups include, for example, thiophene, thiathrone, furan, pyran, isobenzofuran, chromene, xanthan, phenoxazine, pyrrole, imidazole, pyrazole, isothiazine, isoxazine, pyridine, pyrazine, pyrimidine, pyridazine, indoleazine, isoindole, indole, indazole, purine, quinolineazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxaline, quinoline, cinnamic acid, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthroxaline, phenazine, phenarsine, phenthiazine, furazine, phenoxazine, pyrrole, oxacyclopentane, thiocyclopentane, oxazole, piperidine, piperazine, morpholine, lactone, lactam (such as aziridine butanone and pyrrolidone), sulfonamide, sulfonyl lactone, etc. The heterocycle may be substituted at one or more positions with the substituents described above, such as halogens, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, thioalkyl, imino, amide, phosphate, phosphonate, phosphonite, carbonyl, carboxyl, silyl, aminesulfonyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0069] As used herein, the term "heterocyclic alkyl" refers to a non-aromatic heterocyclic group in which 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 heterocyclic alkyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, thiooxacyclohexyl, piperazine, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, high-piperidinyl, oxacyclic heptyl, thiocyclic heptyl, oxacyclic aziridine, diazacyclic, thiaazacyclic, 1,2,3,6-tetracycline, etc. Hydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxacyclopentane, pyrazolinyl, dithiaalkyl, dithioheteropentane, dihydropyranyl, dihydrothiopheneyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinazinyl. Heterocyclic alkyl groups may be substituted or unsubstituted, as described, for example, with respect to the heterocyclic groups described herein.

[0070] The term "carbonyl" is recognized in the art and includes the part represented by the following formula: Where X' is a bond or represents oxygen or sulfur, and R 15 Indicates hydrogen, alkyl, alkenyl, -(CH2) m -R 10 Or a pharmaceutically acceptable salt, R 16 Indicates hydrogen, alkyl, alkenyl, or -(CH2). m -R 10 , where m and R 10 As defined above. When X' is oxygen and R 15 or R 16 When X' is not hydrogen, this formula represents "ester". When X' is oxygen and R... 15 As defined above, this part is referred to herein as a carboxyl group, and especially when R 16 When X' is hydrogen, this formula represents "carboxylic acid". When X' is oxygen and R is oxygen, the formula represents "carboxylic acid". 16 When X' is hydrogen, the formula represents "formate ester". On the other hand, when X' is a bond and R... 15 When the hydrogen atom is not hydrogen, the above formula represents a "ketone" group. When X' is a bond and R... 15 When the hydrogen is present, the above formula represents an "aldehyde" group.

[0071] As used herein, the term "substitution" is intended 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 non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described above, and are substituted, for example, with one or more substituents selected from: alkyl, cycloalkyl, heterocyclic alkyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2amine, CH2amine, and CN. For suitable organic compounds, the permissible substituents may be one or more and may be the same or different. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituent of the organic compounds described herein that satisfies the heteroatom valence. This invention is not intended to be limited in any way to the permissible substituents of organic compounds. It should be understood that “substitution” or “being substituted” includes implied limitations, namely, that the substitution is based on the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, a compound that does not spontaneously undergo transformations, such as transformations by rearrangement, cyclization, elimination, etc.

[0072] As used herein, the term "nitro" refers to -NO2; the term "halogen" refers to -F, -Cl, -Br, or -I; the term "hydroxyl" refers to -OH; and the term "cyano" refers to -CN.

[0073] As used herein, when the definitions of expressions such as alkyl, m, n, etc., appear more than once in any structure, they are intended to be independent of their definitions elsewhere in the same structure.

[0074] As used herein, the term "prodrug" encompasses a compound that is converted into a therapeutically active agent under physiological conditions. A common method for manufacturing a prodrug involves hydrolysis under physiological conditions to extract a selected portion of the desired molecule. In other embodiments, the prodrug is converted under the enzymatic activity of a host animal. Thus, a prodrug includes a compound converted in vivo to yield the disclosed compound or any other pharmaceutically acceptable form of the compound. In embodiments, the prodrug may be inactive when administered to a subject, but may be converted in vivo, for example, by hydrolysis, into the active compound. See, for example, Bundgard, H. Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). The discussion of prodrugs is provided by Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series , Vol. 14, and in Bioreversible Carriers in Drug Design , ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both are incorporated herein by reference in their entirety. Prodrugs can usually be processed using well-known methods, such as Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolffed., 5th ed., 1995), and Design of Prodrugs Prepared by the method described in (H. Bundgaard ed., Elselvier, New York, 1985). The term "prodrug" also refers to any covalently bonded carrier that, when administered to a subject, releases the active compound in vivo. Prodrugs of the compounds described herein can be prepared by modifying functional groups present in the active compound in a manner such that such modifications are performed conventionally or cleaved in vivo to provide the compounds described herein (i.e., the parent active compound). Prodrugs include compounds in which a hydroxyl, amino, or thiol group is bonded to any group that, when administered as a prodrug of the active compound to a subject, cleaves to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the alcohol functional group in the active compound, or acetamide, formamide, and benzamide derivatives of the amine functional group in the active compound, etc. Other examples of prodrugs include compounds containing a —NO, —NO2, —ONO, or —ONO2 moiety.

[0075] For the purposes of this invention, the chemical elements are determined according to the CAS version of the periodic table (Handbook of Chemistry and Physics, 67th edition, 1986-87, inner cover).

[0076] Exemplary compounds of the present invention This disclosure relates to substances that can be used to suppress α v Novel compounds and methods for β8 integrin.

[0077] In some implementations, the compound is derived from Figure 1 Compounds or pharmaceutically acceptable salts thereof listed in Tables 2, 3 or 4.

[0078] In some implementations, the compound is a compound from Table 2 or a pharmaceutically acceptable salt thereof.

[0079] Table 2. Other Compounds

[0080] Table 3. Other Compounds

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

[0082] Table 4. Exemplary Compounds

[0083] Exemplary formulas and compounds are described herein. This document also provides exemplary embodiments of structural features that may exist in any of the formulas described herein. Any exemplary embodiment of a structural feature may be combined with any other exemplary structural feature described herein. Furthermore, and unless otherwise indicated herein, any description of a formula or compound includes any pharmaceutically acceptable form of that compound, including but not limited to any pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of the disclosed formulas and compounds.

[0084] Therapeutic uses of compounds of formula (I) The methods described herein can be applied to in vivo or ex vivo cell populations. "In vivo" means within a living individual, such as an animal or human. In this case, the methods described herein can be used therapeutically in a subject. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including body fluids or tissue samples obtained from an individual.

[0085] Information gathered from this use may be used for experimental or clinical purposes to establish in vivo treatment regimens. The selected compounds may be further characterized to examine safety or tolerable doses in human or non-human subjects. Such properties may be examined using methods commonly known to those skilled in the art.

[0086] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, may be used to treat subjects who have or are suspected of having a disease state, disorder, or condition that is responsive to or believed to be responsive to inhibition of α4β7 integrin activity (collectively, the “Indications”). In some embodiments, the compounds described herein may be used to inhibit the activity of α4β7 integrin. In some embodiments, the compounds described herein may be used to inhibit excessive or destructive immune responses or cell growth or proliferation such as cancer cells, or to inhibit immunosuppression.

[0087] In some embodiments, this disclosure provides compounds described herein suitable as inhibitors of α4β7 integrin. In some embodiments, this disclosure provides a method of treating or preventing an inflammatory disease or condition comprising administering the compounds described herein to a patient.

[0088] In some embodiments, this disclosure provides pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable carriers.

[0089] In some embodiments, the compounds described herein are provided for the treatment of inflammatory diseases or conditions in patients that are at least partially mediated by α4β7 integrin.

[0090] Co-administration also includes administering component drugs, such as one or more compounds described herein and one or more additional (e.g., second, third, fourth, or fifth) therapeutic agents. This combination of one or more compounds described herein and one or more additional therapeutic agents may be administered simultaneously or sequentially (one after another) within a reasonable timeframe for each administration (e.g., from about 1 minute to 24 hours), depending on the pharmacokinetic and / or pharmacodynamic characteristics of the individual agents or the combination. Co-administration may also involve treatment with a fixed combination, wherein the agents in the treatment regimen may be combined in a fixed dose or a combined dose medium (e.g., solid, liquid, or aerosol).

[0091] In some embodiments, a method of treating a disease or condition at least partially mediated by α4β7 integrin and / or a disease or condition coexisting with and / or exacerbated or triggered by α4β7 integrin (e.g., allergic disorders and / or autoimmune and / or inflammatory diseases, and / or acute inflammatory reactions) comprises administering an effective amount of the compound described herein to a patient in need, optionally in combination with an additional agent (e.g., a second, third, fourth, or fifth active agent) suitable for treating a disease or condition at least partially mediated by α4β7, accompanied by or coexisting with an allergic disorder and / or autoimmune and / or inflammatory disease, and / or acute inflammatory reaction.

[0092] Treatment with a second, third, fourth, or fifth active agent may be performed before, simultaneously with, or after treatment with the compounds described herein. In some embodiments, the compounds described herein are combined with another active agent in a single dosage form.

[0093] In the implementation plan, the subjects are adult subjects.

[0094] Dosage and frequency In some embodiments, the compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, is administered to a human patient in need in an effective amount (e.g., about 25 mg to about 400 mg). In other embodiments, the compound of formula (I) described herein is administered to a human patient in need in an effective amount, such as about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg.

[0095] In the implementation scheme, the method described herein includes administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 25 mg (e.g., administering a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (VA) or a pharmaceutically acceptable salt thereof in an amount of about 25 mg).

[0096] In the implementation plan, the subject receives a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily (e.g., a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (VA) or a compound of formula (VI) or a pharmaceutically acceptable salt thereof).

[0097] In the implementation plan, the subject receives a compound of formula (I) or a pharmaceutically acceptable salt thereof twice daily (e.g., a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (VA) or a compound of formula (VI) or a pharmaceutically acceptable salt thereof).

[0098] In the implementation scheme, the method described herein includes administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 50 mg (e.g., administering a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (VA) or a pharmaceutically acceptable salt thereof in an amount of about 50 mg).

[0099] In the implementation scheme, the method described herein includes administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 100 mg (e.g., administering a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (VA) or a pharmaceutically acceptable salt thereof in an amount of about 100 mg).

[0100] In the implementation scheme, the method described herein includes administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 150 mg (e.g., administering a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (VA) or a pharmaceutically acceptable salt thereof in an amount of about 150 mg).

[0101] In the implementation scheme, the method described herein includes administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 200 mg (e.g., administering a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (VA) or a pharmaceutically acceptable salt thereof in an amount of about 200 mg).

[0102] In the implementation scheme, the method described herein includes administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 400 mg (e.g., administering a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), or (VA) or a pharmaceutically acceptable salt thereof in an amount of about 400 mg).

[0103] In one implementation, the method includes administering about 100 mg of compound (IA) or a pharmaceutically acceptable salt thereof to a subject in need. In another implementation, the method includes administering about 100 mg of compound (IA) or a pharmaceutically acceptable salt thereof to a subject in need once daily. In yet another implementation, the method includes administering about 100 mg of compound (IA) or a pharmaceutically acceptable salt thereof to a subject in need twice daily.

[0104] In one implementation, the method includes administering about 200 mg of compound (IA) or a pharmaceutically acceptable salt thereof to a subject in need. In another implementation, the method includes administering about 200 mg of compound (IA) or a pharmaceutically acceptable salt thereof to a subject in need once daily. In yet another implementation, the method includes administering about 200 mg of compound (IA) or a pharmaceutically acceptable salt thereof to a subject in need twice daily.

[0105] In one implementation scheme, the method includes administering about 100 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof to a subject in need. In another implementation scheme, the method includes administering about 100 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof to a subject in need once daily. In yet another implementation scheme, the method includes administering about 100 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof to a subject in need twice daily.

[0106] In one implementation scheme, the method includes administering about 200 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof to a subject in need. In another implementation scheme, the method includes administering about 200 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof to a subject in need once daily. In yet another implementation scheme, the method includes administering about 200 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof to a subject in need twice daily.

[0107] In one implementation scheme, the method includes administering about 200 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof to a subject in need. In another implementation scheme, the method includes administering about 200 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof to a subject in need once daily. In yet another implementation scheme, the method includes administering about 200 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof to a subject in need twice daily.

[0108] In one implementation, the method includes administering about 200 mg of compound (VI) or a pharmaceutically acceptable salt thereof to a subject in need. In another implementation, the method includes administering about 200 mg of compound (VI) or a pharmaceutically acceptable salt thereof to a subject in need once daily. In yet another implementation, the method includes administering about 200 mg of compound (VI) or a pharmaceutically acceptable salt thereof to a subject in need twice daily.

[0109] In some embodiments, administration of the formula (I) compound to a patient in need results in a receptor occupancy rate of at least about 70%, about 85%, about 95%, or about 99%, which indicates the percentage of α4β7 bound by the compound 12 hours after administration. In some embodiments, administration of the formula (I) compound to a patient in need results in a receptor occupancy rate of at least about 70%, about 85%, about 95%, or about 99%, which indicates the percentage of α4β7 bound by the compound 24 hours after administration.

[0110] Integrin-mediated diseases Diseases that respond to α4β7 inhibition include autoimmune diseases and chronic inflammatory diseases of the gastrointestinal tract and gastroesophageal tract. Inflammatory bowel disease, ulcerative colitis, Crohn's disease, inflammatory diseases of the gastroesophageal tract, eosinophilic gastrointestinal disorders, eosinophilic gastroenteritis, eosinophilic gastritis, eosinophilic duodenitis, and eosinophilic esophagitis are examples of diseases that can be treated with compounds of formula (I).

[0111] The approach of using compound (I) to treat patients with diseases and conditions that respond to α4β7 inhibition minimizes off-target risks because compound (I) has demonstrated selectivity for α4β7 inhibition over other integrins (such as α4β1), which are involved in the development of progressive multifocal leukoencephalopathy (PML). Compound (I) can also be administered orally. In preclinical studies, compound (VI) demonstrated high potency and selectivity for α4β7 integrins, good oral absorption, and pharmacokinetic properties suitable for dosing regimens including twice-daily administration.

[0112] As further illustrated herein, the method of the present invention can achieve significant therapeutic benefits for subjects suffering from inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease).

[0113] The compounds of formula (I) can be used to treat diseases or conditions that are at least partially mediated by α4β7 integrin.

[0114] In other embodiments, methods are provided for alleviating symptoms of a disease or disorder mediated at least partially by α4β7 integrin. In some embodiments, the method includes identifying a mammal having symptoms of a disease or disorder mediated at least partially by α4β7 integrin and providing the mammal with an amount of the compound described herein that effectively improves the symptoms (i.e., reduces their severity).

[0115] Treatment of inflammatory bowel disease In some implementations, the disease or condition mediated at least in part by α4β7 integrin is inflammatory bowel disease (IBD).

[0116] As used herein, the term "inflammatory bowel disease" or "IBD" 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 compounds, compositions, and methods disclosed in this invention include diverticulitis, 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 enteritis, short bowel syndrome, celiac disease, gastric ulcer, diverticulitis, pouchitis, proctitis, and chronic diarrhea.

[0117] Treatment or prevention of IBD also includes alleviating 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 variety of such symptoms are quantitatively analyzed (e.g., weight loss, fever, anemia, etc.). Some symptoms are easily identified by blood tests (e.g., anemia) or tests that detect the presence of blood (e.g., rectal bleeding). The term "wherein a reduction in the symptom" refers to a qualitative or quantitative reduction in detectable symptoms, including (but not limited to) a detectable effect on the rate of disease recovery (e.g., the rate of weight gain). Diagnosis is usually confirmed by endoscopic observation of the mucosa and pathological examination of endoscopic biopsy samples.

[0118] The course of IBD varies and is often associated with intermittent periods of remission and exacerbation. Various methods have been described for characterizing the activity and severity of IBD and the response of individuals with IBD to treatment. Treatment according to the methods of the present invention is generally applicable to individuals with IBD of any level or degree of activity.

[0119] Criteria applicable to assessing disease activity in individuals with ulcerative colitis can be found, for example, in Truelove et al., Br Med J 2:1041-1048 (1955). Using these criteria, disease activity can be characterized as mild or severe disease activity in individuals with IBD. Individuals who do not meet all the criteria for severe disease activity but exceed the criteria for mild disease activity are classified as having moderate disease activity.

[0120] The treatment methods disclosed in this invention can also be applied at any point in the course of the disease. In some embodiments, the method is applied to an individual with IBD during a period of remission (i.e., inactive disease). In such embodiments, the method of the invention provides benefit by prolonging the period of remission (e.g., prolonging the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In other embodiments, the method can be applied to an individual with IBD during a period of active disease. Such methods provide benefit by reducing the duration of the period of active disease, reducing or alleviating one or more symptoms of IBD, or treating IBD.

[0121] Measures for assessing the efficacy of IBD treatment in clinical practice have been described and include, for example, symptom control; fistula closure; required level of corticosteroid therapy; and improvement in quality of life. Health-related quality of life (HRQL) can be assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is widely used in clinical practice to assess the quality of life of individuals with IBD. (See Guyatt et al., Gastroenterology 96:804-810 (1989).) In some implementations, the disease or condition is immune-mediated liver injury, disease, or condition.

[0122] In the implementation scheme, prior to any method of administering a compound of formula (I) (e.g., a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or any pharmaceutically acceptable salt thereof, the subject has not previously received an emerging therapy (AT) for the treatment of the condition described herein (e.g., inflammatory bowel disease, such as ulcerative colitis or Crohn's disease).

[0123] In the implementation scheme, prior to any method comprising administering a compound of formula (I) (e.g., compounds of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or any pharmaceutically acceptable salt thereof, the subject has previously received an emerging therapy (AT) for the treatment of the condition described herein (e.g., inflammatory bowel disease, such as ulcerative colitis or Crohn's disease). In the implementation scheme, the subject is intolerant to the previously received emerging therapy. In the implementation scheme, the subject does not respond to the previously received emerging therapy. In the implementation scheme, the subject does not respond adequately to the previously received emerging therapy.

[0124] Exemplary emerging therapies (ATs) include the administration of immunomodulatory agents (such as azathioprine, 6-mercaptopurine, or methotrexate), TNF blockers, one or more corticosteroids, natamizumab, and / or vedolizumab.

[0125] In the implementation scheme, prior to any method of administering a compound of formula (I) (e.g., compounds of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or any pharmaceutically acceptable salt thereof, the subject has not previously received an emerging therapy (AT) for the treatment of the condition described herein (e.g., inflammatory bowel disease such as ulcerative colitis or Crohn's disease). Such subjects may also be referred to as treatment-naïve subjects.

[0126] In an embodiment, a method of administering a compound of formula (I) (e.g., compounds of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or any pharmaceutically acceptable salt thereof is a method of maintenance therapy for treating inflammatory bowel disease (e.g., inflammatory bowel disease such as ulcerative colitis or Crohn's disease). In an embodiment, the maintenance therapy method includes administering a compound of formula (I) (e.g., compounds of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or any pharmaceutically acceptable salt thereof after an initial method of induction therapy, which includes administering a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or any pharmaceutically acceptable salt thereof. In an embodiment, the maintenance therapy method immediately follows the induction therapy method.

[0127] In embodiments, maintenance therapy includes administering a compound of formula (I) (e.g., a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or any pharmaceutically acceptable salt thereof after induction therapy, wherein the induction therapy includes administering a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or any pharmaceutically acceptable salt thereof. In embodiments, the treatment period described herein may be the sum of induction and maintenance therapy, which includes administering a compound of formula (I) (e.g., a compound of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or any pharmaceutically acceptable salt thereof.

[0128] Ulcerative colitis In the implementation scheme, a compound of formula (I) (e.g., a compound of any of formulas (Ia), (Ib) and (Ic), such as a compound of formula (VI)) or a pharmaceutically acceptable salt thereof may be used in a method of treating ulcerative colitis in a subject in need.

[0129] In one aspect, the invention is characterized by a method for treating ulcerative colitis in a subject of need. In an embodiment, the method includes administering to the subject a compound of formula (I) (e.g., a compound of any of formulas (Ia), (Ib), and (Ic), such as a compound of formula (VI)) or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In an embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily. In an embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily.

[0130] In the implementation scheme, the compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered to a subject in need. In the implementation scheme, the compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In the implementation scheme, the compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In the implementation scheme, the compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). In the implementation scheme, about 100 mg of the compound of formula (IA) is administered twice daily. In the implementation scheme, about 200 mg of the compound of formula (IA) is administered twice daily.

[0131] In the implementation scheme, a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof is administered to a subject in need. In the implementation scheme, a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In the implementation scheme, a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In the implementation scheme, a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). In the implementation scheme, about 100 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) is administered twice daily. In the implementation plan, approximately 200 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) is administered twice daily.

[0132] In the implementation plan, a compound of formula (VI) or a pharmaceutically acceptable salt thereof is administered to a subject in need. In the implementation plan, the compound of formula (VI) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In the implementation plan, the 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 the implementation plan, the 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 the implementation plan, about 100 mg of compound (VI) is administered twice daily. In the implementation plan, about 200 mg of compound (VI) is administered twice daily.

[0133] In the implementation plan, ulcerative colitis is defined as moderate to severe ulcerative colitis. In the implementation plan, ulcerative colitis is defined as moderate ulcerative colitis. In the implementation plan, ulcerative colitis is defined as severe ulcerative colitis.

[0134] In the implementation plan, ulcerative colitis is defined as moderate to severe active ulcerative colitis. In the implementation plan, ulcerative colitis is defined as moderately active ulcerative colitis. In the implementation plan, ulcerative colitis is defined as severely active ulcerative colitis.

[0135] In this implementation, the subject's Mayo Endoscopy Score (MES) is 2. In this implementation, the subject's Mayo Endoscopy Score (MES) is 3. In this implementation, the MES is determined to be 2 or 3 before initiating any therapy comprising administration of a compound of formula (I) (e.g., compounds of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or a pharmaceutically acceptable salt thereof. The subject's MES at the start of treatment according to the methods described herein may also be referred to as the baseline MES.

[0136] Ulcerative colitis can be described using the Mayo Clinic Score (MCS) for ulcerative colitis as described in Table A.

[0137] Table A. Mayo Criteria for Ulcerative Colitis

[0138] In the implementation plan, the complete Mayo Criterion Score (MCS) is used to describe the severity of the disease, which includes all four components of Table A and ranges from 0 to 12.

[0139] In the implementation plan, the subject's Mayo Criterion Score (MCS) is 6-12. In the implementation plan, the subject's MCS is 6. In the implementation plan, the subject's MCS is 7. In the implementation plan, the subject's MCS is 8. In the implementation plan, the subject's MCS is 9. In the implementation plan, the subject's MCS is 10. In the implementation plan, the subject's MCS is 11. In the implementation plan, the subject's MCS is 12. In the implementation plan, the MCS is determined to be 6-12 before initiating any therapy comprising administration of a compound of formula (I) (e.g., compounds of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or a pharmaceutically acceptable salt thereof. The subject's MCS at the start of treatment according to the methods described herein may also be referred to as the baseline MCS.

[0140] In the implementation plan, the modified Mayo Clinic Score (mMCS) is used to describe the severity of the disease, which includes three components of Table A (defecation frequency, rectal bleeding, and endoscopic results) and ranges from 0 to 9.

[0141] In the implementation plan, the subject's modified Mayo Criterion Score (mMCS) is 5-9. In the implementation plan, the subject's mMCS is 5. In the implementation plan, the subject's mMCS is 6. In the implementation plan, the subject's mMCS is 7. In the implementation plan, the subject's mMCS is 8. In the implementation plan, the subject's mMCS is 9. In the implementation plan, the mMCS is determined to be 5-9 before initiating any therapy comprising administration of a compound of formula (I) (e.g., compounds of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or a pharmaceutically acceptable salt thereof. The subject's mMCS may also be referred to as the baseline mMCS at the start of treatment according to the methods described herein.

[0142] In the implementation plan, the Robarts Histological Index (RHI) is used to describe the severity of the disease. The RHI is a histological index derived from the Geboes score and is calculated by assessing four histological items, each on a scale of 0 to 3, with each item individually weighted in the RHI formula. The RHI can be calculated according to the following equation and ranges from 0 to 33. See also Table B. RHI = (1 × Chronic Inflammatory Infiltration Score) + (2 × Laminaria Profunda Neutrophil Score) + (3 × Epithelial Neutrophil Score) + (5 × Erosion or Ulcer Score).

[0143] Table B. Geboes score (GS) and derived Robarts histopathological index (RHI)

[0144] In the implementation scheme, the subject's RHI ≥ 10. In the implementation scheme, the RHI ≥ 10 is determined before initiating any therapy comprising administration of a compound of formula (I) (e.g., compounds of formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), or (VI)) or a pharmaceutically acceptable salt thereof. The subject's RHI at the start of treatment according to the methods described herein is also referred to as the baseline RHI. Therefore, in the implementation scheme, the subject's baseline RHI ≥ 10 (e.g., at least about 10-20, such as at least 10 or at least 20). In the implementation scheme, the methods described herein achieve an MCS reduction (e.g., as assessed from baseline MCS) of at least three points and / or a reduction of at least about 20%, 25%, or 30% (e.g., as assessed from baseline MCS). In the implementation scheme, the methods described herein achieve an MCS reduction (e.g., as assessed from baseline MCS) of at least three points. In the implementation scheme, the methods described herein achieve a reduction of at least about 30% (e.g., as assessed from baseline mMCS). In the implementation scheme, the reduction in mMCS is assessed after approximately 6–52 weeks of therapy (e.g., as described herein, such as after approximately 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of therapy). In the implementation scheme, the reduction in MCS is assessed after approximately 6 or 12 weeks of therapy (e.g., as described herein). In the implementation scheme, the reduction in MCS is assessed after induction therapy (e.g., as described herein). In the implementation scheme, the reduction in MCS is accompanied by a reduction of at least one point in the rectal bleeding sub-score and / or an absolute rectal bleeding sub-score ≤1.

[0145] In implementations, the methods described herein achieve at least two points of mMCS reduction (e.g., assessed from baseline mMCS) and / or a reduction of at least about 20%, 25%, or 30% (e.g., assessed from baseline mMCS). In implementations, the methods described herein achieve at least two points of mMCS reduction (e.g., assessed from baseline mMCS). In implementations, the methods described herein achieve at least three points of mMCS reduction (e.g., assessed from baseline mMCS). In implementations, the methods described herein achieve at least about 30% reduction (e.g., assessed from baseline mMCS). In implementations, the reduction in mMCS is assessed after approximately 6–52 weeks of therapy (e.g., as described herein, such as after approximately 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of therapy). In implementations, the reduction in mMCS is assessed after approximately 6 or 12 weeks of therapy (e.g., as described herein). In implementations, the reduction in mMCS is assessed after induction therapy (e.g., as described herein). In the implementation plan, a decrease in mMCS is accompanied by a decrease of at least one point in the rectal bleeding sub-score and / or an absolute rectal bleeding sub-score ≤1.

[0146] In the implementation, the method described herein achieves a reduction in rectal bleeding. In the implementation, the method described herein achieves a reduction in the rectal bleeding sub-score of the mMCS (e.g., baseline mMCS). In the implementation, the method achieves a reduction in at least one point in the rectal bleeding sub-score of the mMCS (e.g., baseline mMCS). In the implementation, the method described herein achieves an absolute rectal bleeding sub-score of 0 or 1 for the mMCS.

[0147] In the implementation scheme, the method described herein achieves endoscopic improvement. In the implementation scheme, endoscopic improvement is assessed by the endoscopic appearance of the mucosa. In the implementation scheme, the method described herein achieves a MES of ≤1. In the implementation scheme, the method described herein achieves a MES of 0. In the implementation scheme, the method described herein achieves a MES of 1.

[0148] In the implementation schemes, the methods described herein achieve a reduction in the RHI (e.g., assessed from a baseline RHI). In the implementation schemes, the RHI reduction is at least one point lower than the baseline RHI (e.g., at least 1-7 points lower than the baseline RHI, such as at least 1, 2, 3, 4, 5, 6, or 7 points). In the implementation schemes, the RHI reduction is at least seven points lower than the baseline RHI. In the implementation schemes, the RHI reduction is at least about 20% lower than the baseline RHI (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, or 50% lower than the baseline RHI).

[0149] In implementations, the methods described herein achieve an absolute RHI score of ≤9 (e.g., an absolute RHI score of ≤9, ≤8, ≤7, ≤6, ≤5, ≤4, or ≤3). In implementations, the methods described herein achieve an RHI score where the lamina propria neutrophil and neutrophil sub-scores are equal to 0 (e.g., no ulceration or erosion).

[0150] In the implementation, the method described herein achieves an absolute RHI score of ≤3. In the implementation, the method described herein achieves an RHI score where the lamina propria neutrophil and neutrophil sub-scores are equal to 0 (e.g., no ulceration or erosion).

[0151] In the implementation scheme, the method described herein achieves mucosal healing. In the implementation scheme, mucosal healing is characterized by a MES score of 0 and / or a RHI ≤ 3. In the implementation scheme, an RHI ≤ 3 reflects a sub-score of 0 for both the lamina propria neutrophil score and the epithelial cell neutrophil score. In the implementation scheme, the method described herein achieves disease remission.

[0152] In the implementation scheme, the method described herein achieves an absolute rectal bleeding score of 0 for the mMCS, a defecation frequency score of 0 or 1 for the mMCS, no individual sub-scores greater than 1 for the mMCS, and / or a MES score of 0; and / or a RHI score ≤2 or ≤3. In the implementation scheme, subjects in remission have an MCS score ≤2 and no sub-scores greater than 1.

[0153] In the implementation scheme, the method described herein achieves an absolute rectal bleeding sub-score of 0 for the mMCS.

[0154] In the implementation scheme, the method described herein achieves a defecation frequency sub-score of 0 or 1.

[0155] In the implementation scheme, the method described herein achieves a MES with zero cost.

[0156] In the implementation scheme, the method described herein achieves RHI ≤ 2 or ≤ 3.

[0157] In the implementation scheme, the method described herein achieves an RHI ≤ 2. In the implementation scheme, an RHI ≤ 2 is defined as a score of 0 for both the lamina propria neutrophil score and the epithelial cell score, with no ulceration or erosion.

[0158] In the implementation scheme, the method described herein achieves an RHI ≤ 3. In the implementation scheme, an RHI ≤ 3 is defined as a score of 0 for both the stratum propria neutrophil score and the epithelial cell score, with no ulceration or erosion.

[0159] In the implementation plan, subjects in remission have an MCS score ≤2 and no sub-scores higher than 1.

[0160] Crohn's disease In the implementation scheme, a compound of formula (I) (e.g., a compound of any of formulas (Ia), (Ib) and (Ic), such as a compound of formula (VI)) or a pharmaceutically acceptable salt thereof may be used in a method of treating Crohn's disease in a subject in need.

[0161] In one aspect, the invention is characterized by a method of treating Crohn's disease in a subject in need. In an embodiment, the method includes administering to the subject a compound of formula (I) (e.g., a compound of any of formulas (Ia), (Ib), and (Ic), such as a compound of formula (VI)) or a pharmaceutically acceptable salt thereof. In an embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In an embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily. In an embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily.

[0162] In the implementation scheme, the compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered to a subject in need. In the implementation scheme, the compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In the implementation scheme, the compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In the implementation scheme, the compound of formula (IA) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). In the implementation scheme, about 100 mg of the compound of formula (IA) is administered twice daily. In the implementation scheme, about 200 mg of the compound of formula (IA) is administered twice daily.

[0163] In the implementation scheme, a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof is administered to a subject in need. In the implementation scheme, a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In the implementation scheme, a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof is administered once daily (e.g., about 100 mg or about 200 mg once daily). In the implementation scheme, a compound of formula (II-A), (III-A), (IV-A), or (VA) or a pharmaceutically acceptable salt thereof is administered twice daily (e.g., about 100 mg or about 200 mg twice daily). In the implementation scheme, about 100 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) is administered twice daily. In the implementation plan, approximately 200 mg of a compound of formula (II-A), (III-A), (IV-A), or (VA) is administered twice daily.

[0164] In the implementation plan, a compound of formula (VI) or a pharmaceutically acceptable salt thereof is administered to a subject in need. In the implementation plan, the compound of formula (VI) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-400 mg. In the implementation plan, the 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 the implementation plan, the 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 the implementation plan, about 100 mg of compound (VI) is administered twice daily. In the implementation plan, about 200 mg of compound (VI) is administered twice daily.

[0165] In the implementation plan, Crohn's disease is defined as moderate to severe Crohn's disease. In the implementation plan, Crohn's disease is defined as moderate Crohn's disease. In the implementation plan, Crohn's disease is defined as severe ulcerative colitis.

[0166] In the implementation plan, Crohn's disease is defined as moderate to severe active Crohn's disease. In the implementation plan, Crohn's disease is defined as moderately active Crohn's disease. In the implementation plan, Crohn's disease is defined as severely active Crohn's disease.

[0167] Exemplary Implementation The following examples are illustrated to aid in understanding the invention and should not be construed as limiting the invention described and claimed herein. Such variations of the invention include replacing all currently known or later developed equivalents that will be within the skill of the art, and changes in formulation or experimental design will be considered to fall within the scope of the invention incorporated herein.

[0168] Some of the following embodiments relate to methods for treating or preventing diseases that respond to α4β7 integrin inhibitors by administering compounds of formula (I), (Ia), (Ib) and / or (Ic) to humans who require such treatment. Example

[0169] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. Furthermore, the polymers of the present invention may also be optically active. The present invention covers all such compounds within its scope, including cis and trans isomers, R-enantiomers and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0170] For example, if a specific enantiomer of the compound of the present invention is required, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary agent, wherein the resulting diastereomeric mixture is isolated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, in the case where the molecule contains a basic functional group such as an amine or an acidic functional group such as a carboxyl group, a diastereomeric salt is formed with a suitable optically active acid or base, and the resulting diastereomeric salt is then resolved by stepwise crystallization or chromatographic methods well known in the art, and the pure enantiomer is subsequently recovered. Example

[0171] abbreviation Abbreviated chemical names Acetyl group ACN Acetonitrile BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) Boc tert-butyloxycarbonyl Bu Butyl CBS N-cyclohexyl-2-benzothiazole sulfenamide cod cyclooctadiene Cp cyclopentadienyl DAST Diethylaminosulfonium trifluoride dba dibenzylidene acetone DCM dichloromethane DCE dichloroethane Dys-Martin reagent 1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxacyclopenten-3(1H)-one DIAD (Diisopropyl Azodicarbonate) DIEA N,N-Diisopropylethylamine DIPEA N,N-Diisopropylethylamine DMF (dimethylformamide) DMSO (dimethyl sulfoxide) dppf 1,1′-bis(diphenylphosphine)ferrocene EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI Electrospray Ionization Et Ethyl FA Formic acid HATU hexafluorophosphate O -(7-azabenzotriazol-1-yl)- N , N , N ′, N ′-Tetramethylureon HMDS (Hexamethyldisilazane) HOBt Hydroxybenzotriazole HPLC (High Performance Liquid Chromatography) hr hours Hz Hertz iPr isopropyl LAH Lithium Aluminum Hydrogen LDA (Lithium diisopropylamino) Me methyl Ms. methanesulfonyl MS mass spectrometry NBS N-bromosuccinimide NMR (Nuclear Magnetic Resonance) Preparative HPLC (Preparative High Performance Liquid Chromatography) Qphos pentaphenyl(di-tert-butylphosphino)ferrocene Selectfluor 1-Chloromethyl-4-fluoro-1,4-azabicyclo[2.2.2]octanebis(tetrafluoroborate) RT room temperature SFC Supercritical Fluid Chromatography t-Bu tert-butyl TEA Triethylamine Tf trifluoromethanesulfonyl TFA (trifluoroacetic acid) THF Tetrahydrofuran TLC (Thin Layer Chromatography) TMS trimethylsilyl Xphos Pd G2 Chlorine (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0172] Analytical methods, materials and instruments Unless otherwise noted, reagents and solvents are used in the form received from commercial suppliers. The default methods, materials, and instruments are listed below.

[0173] HNMR instrument information: Proton nuclear magnetic resonance (NMR) spectra were obtained on one of the following instruments: BRUKER, AVANCE III 500MHZ, PROBHD 5 mm PABBO BB-, PULPROG zg30, TD65536, NS 8, DS 0, SWH 10330.578 Hz, D1 1.00000000 sec, NUC1 1H, P1 13.72usec, PL1W 13.34460926 W, SFO1 500.1330885 MHz BRUKER, AVANCE III 400MHZ, PROBHD 5 mm PABBO BB / , PULPROG zg30, TD65536, NS 8, DS 2, SWH 8223.685 Hz, D1 1.00000000 sec, SFO1 400.1324710 MHz, NUC1 1H, P1 15.00 usec, PL1W 11.00000000 W Spectra are given in ppm (δ), and coupling constant J is reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0174] LCMS Instrument Information and Analysis Methods: Compounds were analyzed using LC / MS with UV detector monitoring at 214 nm and 254 nm and mass spectrometry scans of 110–1500 amu in ESI+ ionization mode.

[0175] LCMS A: Column: XBridge C18, 4.6 × 50 mm, 3.5 µm; Mobile phase: A Water (10 mM ammonium bicarbonate), B CH3CN; Gradient: 5%-95% B for 1.4 min, followed by a hold for 1.7 min; Flow rate: 1.8 mL / min; Oven temperature: 45°C.

[0176] LCMS B: Column: Sunfire C18, 4.6 × 50 mm, 3.5 µm; Mobile phase: A: Water (0.1% FA) B: ACN (0.1% FA); Gradient: 5%-95% B for 1.5 min, then hold for 1.5 min; Flow rate: 2 mL / min; Column oven temperature: 50°C.

[0177] LCMS C: Column: Sunfire C18, 4.6 × 50 mm, 3.5 µm; Mobile phase: A: Water (0.01% TFA) B: ACN (0.01% TFA); Gradient: 5%-95% B for 1.5 min, then hold for 1.7 min; Flow rate: 2 mL / min; Oven temperature: 50°C.

[0178] LCMS D: Column: Poroshell 120 EC-C18, 3.0 × 30 mm, 2.7 µm; Mobile phase: A: Water (0.01% TFA) B: ACN (0.01% TFA); Gradient: 5%-95% B over 0.8 min, followed by a hold for 1.0 min; Flow rate: 2 mL / min; Oven temperature: 50°C.

[0179] Preparative HPLC methods: The crude sample was dissolved in MeOH and purified by preparative HPLC using a Gilson 215 instrument at a detection wavelength of 214 nm. Preparative HPLC A: Column: Xtimate preparative C18, 21.2 × 250 mm, 10 µm; Mobile phase: A. Water (10 mM ammonium bicarbonate), B. CH3CN; Gradient elution as described in the text; Flow rate: 20 mL / min.

[0180] Preparative HPLC B: Column: Boston pHlex ODS, 21.2 × 250 mm, 10 µm; Mobile phase: A water (10 mM formic acid), B CH3CN; Gradient elution as described in the text; Flow rate: 20 mL / min.

[0181] Preparative HPLC C: Column: XBridge OBD C18, 19 × 100 mm, 5 µm; Mobile phase: A water, BCH3CN; Gradient elution as described in the text; Flow rate: 20 mL / min.

[0182] Preparative chiral SFC methods: Using chiral preparative SFC, the racemic product was separated into individual enantiomers using an SFC-80 (Thar, Waters) instrument at a detection wavelength of 214 nm: Preparative chiral SFC A: Column: (R,R)-Whelk-O1, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0183] Preparative chiral SFC B: Column: AD 20×250 mm, 10 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0184] Preparative chiral SFC C: Column: AS 20×250 mm, 10 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0185] Preparative chiral SFC D: Column: OD 20×250 mm, 10 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0186] Preparative chiral SFC E: Column: Cellulose-SC 20×250 mm, 10 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0187] Preparative chiral SFC F: Column: OZ 20×250 mm, 10 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0188] Preparative chiral SFC G: Column: IC 20×250 mm, 10 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0189] Preparative chiral SFC H: Column: (S,S)-Whelk-O1, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0190] Preparative chiral SFC I: Column: OX-H, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0191] Preparative chiral SFC J: Column: IG, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0192] Preparative chiral SFC K: Column: IH, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0193] Preparative chiral SFC L: Column: OJ, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0194] Preparative chiral SFC M: Column: Amylose-C Neo, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0195] Preparative chiral SFC N: Column: ID, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0196] Column: AY-H, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0197] Preparative chiral SFC P: Column: IK, 20×250 mm, 5 µm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0198] Preparative chiral HPLC methods Racemic products were separated into individual enantiomers using preparative chiral SFC with a Gilson-281 (Thar, Waters) instrument (detection wavelengths 214 / 254 nm): Preparative chiral HPLC A: Column: IE, 20 × 250 mm, 10 µm (Daicel). Column temperature: 35℃. Mobile phase: n-hexane (0.1% DEA) / ethanol (0.1% DEA). Flow rate: 38 g / min. Back pressure: 100 bar.

[0199] Preparative chiral HPLC B: Column: OJ-H, 20×250 mm, 10 µm (Daicel). Column temperature: 35℃. Mobile phase: n-hexane (0.1% DEA) / ethanol (0.1% DEA). Flow rate: 38 g / min. Back pressure: 100 bar.

[0200] Analytical chiral SFC method Chiral SFC was used with an SFC-80 (Thar, Waters) instrument at a detection wavelength of 214 nm to analyze chiral products. Chiral SFC A: Column: (R,R)-Whelk-O1, 4.6×100 mm, 5 µm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% ammonia-methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0201] Chiral SFC B: Column: AD 4.6×100 mm, 5 µm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0202] Chiral SFC C: Column: AS 4.6×100 mm, 5 µm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0203] Chiral SFC D: Column: OD 4.6×100 mm, 5 µm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0204] Chiral SFC E: Column: Cellulose-SC 4.6×100 mm, 5 µm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0205] Chiral SFC F: Column: OZ 4.6×100 mm, 5 µm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0206] Chiral SFC G: Column: IC 4.6 × 100 mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0207] Chiral SFC H: Column: (S,S)-Whelk-O1, 4.6×100 mm, 5 µm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% ammonia-methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0208] Chiral SFC I: Column: OX-H, 4.6 × 100 mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0209] Chiral SFC J: Column: IG, 4.6 × 100 mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0210] Chiral SFC K: Column: IH, 4.6 × 100 mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0211] Chiral SFC L: Column: OJ, 4.6 × 100 mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0212] Chiral SFC M: Column: Amylose-C Neo, 4.6 × 100 mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% ammonia-methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0213] Chiral SFC N: Column: ID, 4.6 × 100 mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0214] Chiral SFC O: Column: AY, 4.6 × 100 mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0215] Chiral SFC P: Column: IK, 4.6 × 100 mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% ammonia methanol solution), isocratic elution as described herein, flow rate: 4 g / min, back pressure: 120 bar.

[0216] Analytical chiral HPLC methods Chiral HPLC A: Column: OJ-H 4.6×250 mm, 5 µm (Daicel), column temperature: 40℃, mobile phase: n-hexane (0.1% DEA) / ethanol (0.1% DEA), flow rate: 1 g / min.

[0217] Chiral HPLC B: Column: IE 4.6×250 mm, 5 µm (Daicel), column temperature: 40℃, mobile phase: n-hexane (0.1% DEA) / ethanol (0.1% DEA), flow rate: 1 g / min.

[0218] When chiral compounds are separated by HPLC or SFC, the absolute stereochemistry of the product is arbitrarily designated. Unless otherwise specified, the first elution peak from the separation is labeled P1, the second elution peak is labeled P2, and so on. In some cases, chiral intermediates are also prepared and separated. In this case, 1P2 is used to refer to the first elution intermediate, etc., used to prepare the compound of the present invention that is separated as the second elution peak.

[0219] When isomers of compounds containing chiral centers are separated, the absolute stereochemistry of the products is not always determined. In some cases, stereochemistry is arbitrarily assigned to aid in the description of compounds and chemical processes. Those skilled in the art will recognize that if the stereochemistry of the starting material differs from that shown, the stereochemistry of the intermediates and final products may also differ from any particular process or the stereochemistry shown therein.

[0220] Synthesis process Example 1: Preparation of compounds 24-P1 and 24-P2 Step 1: (3-(methoxy(methyl)amino)-3-oxopropyl)(methyl)carbamate tert-butyl ester To a solution of 3-((tert-butoxycarbonyl)(methyl)amino)propionic acid (15 g, 73.9 mmol, 1.0 equivalent), N,O-dimethylhydroxylamine hydrochloride (7.6 g, 77.6 mmol, 1.1 equivalent), 1-hydroxybenzotriazole (10.0 g, 73.9 mmol, 1.0 equivalent), and trimethylamine (16.4 g, 162.5 mmol, 2.2 equivalent) in chloroform (100 mL), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (15.6 g, 81.3 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at 50 °C for 1 hour, then diluted with water (100 mL) and extracted with dichloromethane (2 × 100 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (95:5 dichloromethane:MeOH) to obtain tert-butyl (3-(methoxy(methyl)amino)-3-oxopropyl)(methyl)carbamate (13.6 g, 74.7%) as a yellow solid (ESI 147.2 [M-Boc+H)). + ).

[0221] Step 2: (3-(3-chloro-5-methylphenyl)-3-oxopropyl)(methyl)carbamate tert-butyl ester n-BuLi (26.6 mL, 2.5 M in hexane, 66.4 mmol, 1.2 equivalences) was added dropwise to a solution of 1-bromo-3-chloro-5-methylbenzene (13.6 g, 66.4 mmol, 1.2 equivalences) in anhydrous THF (100 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. Then, a solution of (3-(methoxy(methyl)amino)-3-oxopropyl)(methyl)carbamate tert-butyl ester (13.6 g, 55.3 mmol, 1.0 equivalences) in tetrahydrofuran (50 mL) was added. After stirring at -78 °C for another 1 h, the reaction mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (12:1 petroleum ether: EtOAc) to obtain tert-butyl (3-(3-chloro-5-methylphenyl)-3-oxopropyl)(methyl)carbamate (9.5 g, 55.0%) as a yellow solid (ESI 312.1 [M-Boc+H)). + ).

[0222] Step 3: (R)-(3-(3-chloro-5-methylphenyl)-3-hydroxypropyl)(methyl)carbamate tert-butyl ester Borane (1 M in THF, 35 mL, 35 mmol, 1.1 equivalent) was added dropwise to a solution of (3-(3-chloro-5-methylphenyl)-3-oxopropyl)(methyl)carbamate (9.5 g, 30.4 mmol, 1.0 equivalent) and (S)-3,3-diphenyl-1-methylpyrrolyl[1,2-c]-1,3,2-oxazaboranecyclopentane (4.6 mL, 1 M in toluene, 4.6 mmol, 0.15 mmol) in anhydrous THF (100 mL). The reaction mixture was heated to 0 °C and stirred for 1 hour, quenched with methanol (10 mL), and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to obtain (R)-(3-(3-chloro-5-methylphenyl)-3-hydroxypropyl)(methyl)carbamate tert-butyl ester (8.1 g, 84.9%) as a yellow oil (ESI 336.1 (M+Na)). + ).

[0223] Step 4: Mesylate (R)-3-((tert-Butoxycarbonyl)(methyl)amino)-1-(3-chloro-5-methylphenyl)propyl ester Methanesulfonyl chloride (1.46 g, 12.8 mmol, 1.0 equivalent) was added dropwise to a solution of (R)-(3-(3-chloro-5-methylphenyl)-3-hydroxypropyl)(methyl)carbamate (4.0 g, 12.8 mmol, 1.0 equivalent) and trimethylamine (2.58 g, 25.6 mmol, 2.0 equivalent) in dichloromethane (70 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, quenched with saturated NaHCO3 solution (100 mL), and extracted with EA (2 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain (R)-3-((tert-butoxycarbonyl)(methyl)amino)-1-(3-chloro-5-methylphenyl)propyl methanesulfonic acid (3.5 g, 2.6 mmol, crude product) as a yellow oil (ESI 196.1 (M-OMs-Boc)). + The crude product is used directly in subsequent steps.

[0224] Step 5: (S)-(3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester To a solution of (R)-3-((tert-butoxycarbonyl)(methyl)amino)-1-(3-chloro-5-methylphenyl)propyl methanesulfonic acid (3.5 g, 2.6 mmol, crude, 1.0 equivalent) in acetonitrile (20 mL), 1-methylpiperazine (2.6 g, 26 mmol, 10.0 equivalent) was added, followed by K₂CO₃ (3.59 g, 26 mmol, 10.0 equivalent). The reaction mixture was stirred at 80 °C for 1 hour, then diluted with water (200 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (95:5 dichloromethane:MeOH) to obtain (S)-(3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester (420 mg, 40.8%) as a yellow oil (ESI 396.2 [M+H)). + ).

[0225] Step 6: (S)-3-(3-chloro-5-methylphenyl)-N-methyl-3-(4-methylpiperazin-1-yl)propyl-1-amine Trifluoroacetic acid (1 mL, 13.1 mmol, 11.9 equivalents) was added to a solution of (S)-(3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester (420 mg, 1.1 mmol, 1.0 equivalent) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 30 minutes, followed by vacuum concentration to give (S)-3-(3-chloro-5-methylphenyl)-N-methyl-3-(4-methylpiperazin-1-yl)propyl-1-amine (628 mg, 1.1 mmol, crude) as a yellow oil (ESI 296.2 [M+H)). + The crude product is used directly in subsequent steps.

[0226] Step 7: 4-(3-fluoro-2-methyl-6-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 2-Chloro-4-fluoro-3-methyl-1-nitrobenzene (20 g, 105.5 mmol, 1.0 equivalent), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (48.9 g, 158.3 mmol, 1.5 equivalent), K₂CO₃ (43.7 g, 316.5 mmol, 3.0 equivalent), and Pd(dppf)Cl₂ (7.7 g, 10.55 mmol, 0.1 equivalent) were suspended in a mixture of dioxane (200 mL) and water (20 mL). The reaction mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The contents were then poured into 300 mL of water and extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The 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-1(2H)-carboxylate (23.5 g, 66%) as a yellow solid (ESI 281.1 [M+H-tert-butyl]). + ).

[0227] Step 8: 4-(6-amino-3-fluoro-2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of 12 g (29.8 mmol, 1.0 equivalent) of 4-(3-fluoro-2-methyl-6-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in EtOH (150 mL), 10% Pd / carbon (3 g, 1.5 mmol, 0.025 equivalent) was added. The reaction mixture was stirred at room temperature under a H2 atmosphere for 72 hours. After completion, the reaction mixture was filtered through a diatomaceous earth pad and concentrated under vacuum to give 7.7 g (70%) of 4-(6-amino-3-fluoro-2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester as a brown oil (ESI 283.1 [M+H-tert-butyl]). + The crude product was used directly in subsequent steps without further purification.

[0228] Step 9: tert-butyl 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine-1-carboxylate 12 g (32.3 mmol, 1.0 equivalent) of tert-butyl 4-(6-amino-3-fluoro-2-methylphenyl)piperidin-1-carboxylate was dissolved in acetonitrile (100 mL). Then, tert-butyl nitrite (5 g, 48.45 mmol, 1.5 equivalent) was added dropwise at -10 °C, followed by acetonitrile (50 mL) containing CuBr2 (5.4 g, 24.2 mmol, 0.75 equivalent). After stirring at -10 °C for 10 minutes, the reaction mixture was warmed to room temperature. Stirring was continued at room temperature for 6 hours. The reaction mixture was then diluted with dichloromethane (100 mL) and washed with brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (99:1 dichloromethane:MeOH) to obtain tert-butyl 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine-1-carboxylate (7.5 g, 52%) as a yellow oil (ESI 316.1 [M+H-tert-butyl)). + ).

[0229] Step 10: 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine hydrochloride To a solution of tert-butyl 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine-1-carboxylate (7.5 g, 20.2 mmol, 1.0 equivalent) in dichloromethane (10 mL), dioxane containing HCl (4 M, 20 mL, 80 mmol, 4.0 equivalent) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under vacuum to give 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine hydrochloride (8.3 g, 26.2 mmol, crude product) as a white solid (ESI 272.1 [M+H]). + ).

[0230] Step 11: 4-(6-bromo-3-fluoro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidine K₂CO₃ (11.2 g, 81 mmol, 3.0 equivalent) was added to a solution of 4-(6-bromo-3-fluoro-2-methylphenyl)piperidine hydrochloride (8.3 g, 27 mmol, 1.0 equivalent) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.4 g, 40.5 mmol, 1.5 equivalent) in acetonitrile (100 mL). The reaction mixture was stirred at 80 °C for 3 hours. After completion, the mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (99:1 dichloromethane:MeOH) to give 4-(6-bromo-3-fluoro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidine (6 g, 52%) as a yellow oil (ESI 354.1 [M+H)). + ).

[0231] Step 12: Ethyl 2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl) Pd2(dba)3 (1.56 g, 1.7 mmol, 0.1 equivalence) and Qphos (362.6 mg, 0.51 mmol, 0.03 equivalence) were added to a suspension of 4-(6-bromo-3-fluoro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidine (6 g, 17 mmol, 1.0 equivalence) in THF (50 mL). Then, a solution of (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 51 mL, 51 mmol, 3.0 equivalence) was added, and the reaction mixture was stirred at 65 °C under nitrogen for 1 hour. The contents were then poured into 50 mL of saturated aqueous NH4Cl solution and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (20:1 petroleum ether: EtOAc) to obtain ethyl 2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate (4 g, 65%) as a colorless oil (ESI 362.1 [M+H)). + ).

[0232] Step 13: Ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl) LiHMDS (1 M in THF, 38 mL, 38 mmol, 3.0 equivalence) was added dropwise to a solution of ethyl 2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate (4.62 g, 12.8 mmol, 1.0 equivalence) in THF (60 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h. Then, TMSCl (4.8 mL, 38 mmol, 3.0 equivalence) was added dropwise, and stirring was continued at -78 °C for another 15 min. Finally, NBS (5.7 g, 32 mmol, 2.5 equivalence) was added dropwise to a solution of THF (50 mL). The reactants were stirred at -78°C for another hour, then heated to 0°C, quenched with 150 mL of saturated aqueous NH₄Cl solution, and extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (20:1 petroleum ether: EtOAc) to give 4.1 g, 73.2%, ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate as a yellow solid (ESI 440.1 [M+H)). + ).

[0233] Step 14: 2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)ethyl acetate To a solution of (S)-3-(3-chloro-5-methylphenyl)-N-methyl-3-(4-methylpiperazin-1-yl)prop-1-amine (314 mg, 0.53 mmol, crude, 1.0 equivalent) in acetonitrile (5 mL), K₂CO₃ (512 mg, 3.71 mmol, 5.0 equivalent) was added. The mixture was stirred at room temperature for 15 minutes. Then, ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate (210 mg, 0.48 mmol, 0.9 equivalent) was added. The mixture was stirred at 80 °C for another hour, followed by filtration and concentration under reduced pressure. The crude residue was purified by silica gel column chromatography (20:1 dichloromethane:MeOH) to obtain ethyl acetate 2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl) as a yellow oil (260 mg, 82.7%) (ESI 655.3 [M+H)). + ).

[0234] Step 15: 2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetic acid (compound 24) To a solution of ethyl 2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate (260 mg, 0.4 mmol, 1.0 equivalent) in ethanol (4.5 mL) and water (1.5 mL), NaOH (80 mg, 2.0 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 16 hours. After completion, the pH of the reaction mixture was adjusted to approximately 5 to 6 with 1N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give diastereomeric product 24 (200 mg, 80.0%) as a white solid. The diastereomers were further separated by preparative chiral SFC A to obtain 24-P1 (66 mg) and 24-P2 (73 mg).

[0235] Compound 24-P1 LC / MS ESI 627.3 [M+H] + .1 H NMR (400 MHz, MeOD) δ 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] + . 1 H NMR (400 MHz, MeOD) δ 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).

[0236] 24-P1 and 24-P2 are designated as (R)-2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetic acid and (S)-2-(((S)-3-(3-chloro-5-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetic acid, respectively.

[0237] Example 2: Preparation of compounds 62-P1 and 62-P2 Step 1: Diethyl 2-(3-chloro-5-fluorobenzyl)malonate A solution of 3-chloro-5-fluorobenzaldehyde (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 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to give diethyl 2-(3-chloro-5-fluorobenzyl)malonate (51.1 g, 89%) as a colorless oil (ESI 301.0 [M+H]). + ).

[0238] Step 2: Tetraethyl 2-(3-chloro-5-fluorophenyl)propane-1,1,3,3-tetracarboxylate EtONa (18.2 g, 0.26 mmol) was added to a solution of diethyl malonate (41.5 g, 0.3 mol) in EtOH (800 mL), and the reaction mixture was stirred at room temperature for 2 hours. Then, diethyl 2-(3-chloro-5-fluorobenzyl)malonate (38.9 g, 0.13 mol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated NH4Cl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (4:1 petroleum ether: EtOAc) to give tetraethyl 2-(3-chloro-5-fluorophenyl)propane-1,1,3,3-tetracarboxylate (60.1 g, 67%) as a colorless oil (ESI 461.1 [M+H)). + ).

[0239] Step 3: 3-(3-chloro-5-fluorophenyl)glutaric acid A mixture of 180.0 g (0.13 mol) of tetraethyl 2-(3-chloro-5-fluorophenyl)propane-1,1,3,3-tetracarboxylate in 700 mL of 36% HCl aqueous solution was stirred at 130 °C for 36 h. The mixture was cooled and stirred at 0 °C for 1 h. The resulting solid was filtered and collected to give 15.0 g (63%) (ESI 283.0 [M+Na)) as a white solid. + ).

[0240] Step 4: 4-(3-chloro-5-fluorophenyl)dihydro-2H-piperan-2,6(3H)-dione A solution of 3-(3-chloro-5-fluorophenyl)glutaric acid (15.0 g, 57.7 mmol) in acetic anhydride (50 mL) was stirred at 130 °C for 40 hours. The mixture was concentrated under reduced pressure. The residue was wet-milled with EtOAc (150 mL). The resulting solid was filtered and collected to give 14.0 g (95%) of 4-(3-chloro-5-fluorophenyl)dihydro-2H-piperan-2,6(3H)-dione as a white solid (ESI 243.1 (M+H)). + ).

[0241] Step 5: 3-(3-chloro-5-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid Methylamine (2 M in THF, 60 mL, 120 mmol) was added to a solution of 13.0 g (53.7 mmol) of 4-(3-chloro-5-fluorophenyl)dihydro-2H-piperan-2,6(3H)-dione in 100 mL of THF, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and wet-milled with EtOAc (60 mL). The resulting solid was filtered and collected to give 6.6 g (47%) (ESI 274.1 [M+H)) as a white solid. + ).

[0242] Step 6: 3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide To a solution of 3-(3-chloro-5-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid (3.4 g, 12.4 mmol) in DCM (20 mL), piperidine (1.0 g, 12.4 mmol) and HATU (5.7 g, 14.9 mmol) were added, followed by DIPEA (3.2 g, 24.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. After completion, the mixture was quenched with NH4Cl solution (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (20:1 dichloromethane:MeOH) to obtain racemic 3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide (3.0 g, 71%) as a colorless oil. The enantiomers were further separated by preparative chiral SFC J to obtain the P1 fraction (R)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide (1.3 g) and the P2 fraction (S)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide (1.1 g) as a white solid (ESI 341.2 [M+H)). + ).

[0243] Step 7: (R)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-(piperidin-1-yl)pentan-1-amine At room temperature, LiAlH4 (2 M in THF, 5.0 mL, 9.7 mmol, 3.0 equivalent) was added dropwise to a solution of (R)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide (1.1 g, 3.2 mmol, 1.0 equivalent) in 20 mL of THF, and the reaction mixture was stirred at 55 °C for 1 hour. After cooling to 0 °C, the reaction mixture was quenched dropwise with 1 mL of water and stirred at 0 °C for another 10 minutes. Then, 1 mL of 15% NaOH aqueous solution and 3 mL of water were added sequentially at 0 °C. The mixture was heated to room temperature and stirred for another 15 minutes, then filtered and the filtrate was concentrated under vacuum to give (R)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-(piperidin-1-yl)pentane-1-amine as a white solid, which was used directly in the next reaction (1 g, crude product) (ESI 313.3 [M+H)). + ).

[0244] Step 8: 8-(3-fluoro-2-methyl-6-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene 2-Chloro-4-fluoro-3-methylaniline (20 g, 105.5 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaboranecyclopentane (30.9 g, 116.1 mmol, 1.1 equivalent), K₂CO₃ (29.2 g, 211.0 mmol, 2.0 equivalent), and Pd(dppf)Cl₂ (7.7 g, 10.55 mmol, 0.1 equivalent) were suspended in a mixture of dioxane (250 mL) and water (50 mL). The reaction mixture was stirred overnight at 110 °C under nitrogen. After completion, water (300 mL) was added, and the mixture was extracted with EtOAc (3 × 200 mL). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (6:1 petroleum ether: EtOAc) to give 27.0 g (87%) of 8-(3-fluoro-2-methyl-6-nitrophenyl)-1,4-dioxane[4.5]dec-7-ene as a yellow solid (ESI 294.2 [M+H)). + ).

[0245] Step 9: 4-Fluoro-3-methyl-2-(1,4-dioxanespiro[4.5]dec-8-yl)aniline 10% Pd-C (12 g, 11.4 mmol, 0.3 equivalent) was added to a solution of 8-(3-fluoro-2-methyl-6-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (12 g, 41.0 mmol, 1.0 equivalent) in MeOH (200 mL). The reaction mixture was stirred at 60 °C under a hydrogen atmosphere (1 atm, 3 L) for 3 days. The reaction mixture was then filtered through a diatomaceous earth mat and concentrated under vacuum. The crude product was purified by silica gel column chromatography (5:1 petroleum ether: EtOAc) to give 4-fluoro-3-methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)aniline (7.1 g, 65%) (ESI 266.2 [M+H) as a yellow oil. + ).

[0246] Step 10: 4-(6-amino-3-fluoro-2-methylphenyl)cyclohexane-1-one To a solution of 4-fluoro-3-methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)aniline (16.0 g, 60.3 mmol, 1.0 equivalent) in THF (300 mL), 3 M HCl aqueous solution (60.3 mL, 180.9 mmol, 3.0 equivalent) was added, and the contents were stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0 °C, quenched with a saturated aqueous solution of NaHCO3 (pH adjusted to approximately 9), and extracted with EtOAc (3 × 200 mL). The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give 4-(6-amino-3-fluoro-2-methylphenyl)cyclohexane-1-one (13 g, 97%) as a yellow oil (ESI 222.2 [M+H)). + The crude product is used directly in the next step.

[0247] Step 11: 4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexane-1-one An aqueous solution of HCl (6 M, 26.4 mL, 158.4 mmol, 2.5 equivalence) was added to a solution of 4-(6-amino-3-fluoro-2-methylphenyl)cyclohexane-1-one (14 g, 63.3 mmol, 1.0 equivalent) in THF (250 mL) at -35 °C. Then, NaNO₂ (6.6 g in 30 mL water, 95 mmol, 1.5 equivalent) was added dropwise over 15 minutes. The reaction mixture was stirred at -35 °C for 10 minutes. Next, an aqueous solution of KI (15.8 g in 30 mL water, 95 mmol, 1.5 equivalent) was added in portions to the mixture. Stirring was continued at -35 °C for 30 minutes. The reaction mixture was then warmed to room temperature and stirred for another hour. Water (300 mL) and EtOAc (300 mL) were added to the reaction mixture. The organic layer was separated, washed with saturated Na₂SO₃ aqueous solution (300 mL) and brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (15:1 petroleum ether: EtOAc) to give 4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexane-1-one (7.5 g, 35.7%) (ESI 333.0 [M+H)). + ).

[0248] Step 12: (1r,4r)-4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexyl-1-ol CeCl3 (8.9 g, 36.1 mmol, 1.2 equivalent) was added to a solution of 4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexane-1-one (10 g, 30.1 mmol, 1.0 equivalent) in THF (50 mL) and methanol (8 mL) at 0 °C. NaBH4 (1.4 g, 36.1 mmol, 1.2 equivalent) was then added in portions. The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with water (100 mL) at 0 °C and extracted with EtOAc (3 × 150 mL). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (4:1 petroleum ether: EtOAc) to give (1r,4r)-4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexyl-1-ol (8.3 g, 82.8%) as a white solid (ESI 317.0 [M-OH]). + ).

[0249] Step 13: 1-Fluoro-4-iodo-2-methyl-3-((1r,4r)-4-(prop-1-en-2-yloxy)cyclohexyl)benzene A mixture of (1r,4r)-4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexyl-1-ol (4.7 g, 14.1 mmol, 1.0 equivalent), 2-ethoxyprop-1-ene (15 mL), and Hg(OAc)2 (1.3 g, 4.2 mmol, 0.3 equivalent) was stirred overnight at room temperature under a nitrogen atmosphere. After completion, water (200 mL) was added and the mixture was extracted with dichloromethane (3 × 150 mL). The combined organic matter was washed with NaHCO3 (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (98:1 petroleum ether: EtOAc) to obtain 1-fluoro-4-iodo-2-methyl-3-((1r,4r)-4-(prop-1-en-2-yloxy)cyclohexyl)benzene (3.0 g, 56.7%) as a colorless oil.

[0250] Step 14: 1-Fluoro-4-iodo-2-methyl-3-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)benzene Et₂Zn (32.0 mL, 32.0 mmol, 1.0 equivalent) was added to a solution of 1-fluoro-4-iodo-2-methyl-3-((1r,4r)-4-(prop-1-en-2-yloxy)cyclohexyl)benzene (3.0 g, 8.0 mmol, 1.0 equivalent) in dichloromethane (75 mL) at 0 °C. The mixture was stirred at 0 °C under a nitrogen atmosphere for 0.5 h. Then, CH₂I₂ (8.5 g, 32.0 mmol, 4.0 equivalent) was added dropwise to the mixture at 0 °C. The reaction mixture was heated to room temperature and stirred for 6 h. A saturated aqueous solution of NH₄Cl (150 mL) was added, and the mixture was extracted with dichloromethane (3 × 150 mL). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (95:1 petroleum ether: EtOAc) to obtain 1-fluoro-4-iodo-2-methyl-3-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)benzene (1.3 g, 40%) as a colorless oil.

[0251] Step 15: Ethyl 2-(4-fluoro-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)ethyl acetate Pd2dba3 (82.0 mg, 0.09 mmol, 0.03 equivalent) and QPhos (64 mg, 0.09 mmol, 0.03 equivalent) were added to a suspension of 1-fluoro-4-iodo-2-methyl-3-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)benzene (1.3 g, 3.3 mmol, 1.0 equivalent) in tetrahydrofuran (12 mL), followed by the addition of (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 8.2 mL, 8.2 mmol, 2.5 equivalent). The mixture was stirred at 65 °C under a nitrogen atmosphere for 1 hour, then poured into 50 mL of saturated NH4Cl aqueous solution and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to obtain ethyl 2-(4-fluoro-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetate (1.1 g, 90%) as a colorless oil (ESI 371.3 [M+Na)). + ).

[0252] Step 16: Ethyl 2-bromo-2-(4-fluoro-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)ethyl acetate A solution of ethyl 2-(4-fluoro-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetate (1.1 g, 3.2 mmol, 1.0 equivalent) in tetrahydrofuran (20 mL) was added dropwise to a solution of LiHMDS (1 M in THF, 6.4 mL, 6.4 mmol, 2.0 equivalent) at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h. Then, TMSCl (698.0 mg, 6.4 mmol, 2.0 equivalent) was added dropwise, and the mixture was stirred again at -78 °C for 15 min. Finally, a solution of NBS (1.14 g, 6.4 mmol, 2.0 equivalent) in tetrahydrofuran (20 mL) was added dropwise. The reactants were stirred at -78°C for another hour, then heated to 0°C and quenched with saturated NH4Cl aqueous solution (100 mL) at 0°C, followed by extraction with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (19:1 petroleum ether: EtOAc) to obtain ethyl 2-bromo-2-(4-fluoro-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetate (3.72 g, 90%) as a colorless oil (ESI 449.0 [M+Na)). + 451.0 [M+2+Na] + ).

[0253] Step 17: 2-(((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)ethyl acetate K₂CO₃ (331 mg, 2.4 mmol, 3.0 equivalent) was added to a solution of (R)-3-(3-chloro-5-fluorophenyl)-N-methyl-5-(piperidin-1-yl)pentan-1-amine (250 mg, 0.8 mmol, 1.0 equivalent) in acetonitrile (5 mL). The mixture was stirred at room temperature for 15 minutes. Then, ethyl 2-bromo-2-(4-fluoro-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetate (340 mg, 0.8 mmol, 1.0 equivalent) was added. The mixture was stirred at 60 °C for another 3 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (95:5 dichloromethane:MeOH) to obtain ethyl acetate (200 mg, 38%) as a yellow oil, consisting of (((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl) (ESI 659.3 [M+H). + ).

[0254] Step 18: 2-(((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetic acid (compounds 62-P1 and 62-P2) Ethyl 2-(((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)ethyl acetate (200 mg, 0.3 mmol, 1.0 equivalent) was added to a mixture of EtOH (5 mL) and H2O (1 mL) and NaOH (36 mg, 0.9 mmol, 3.0 equivalent) was added. The reaction mixture was stirred at 60 °C for 16 h. The pH of the reaction was adjusted to approximately 5 to 6 with 1N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give 62-P1 (61.7 mg) and 62-P2 (67.0 mg) as white solids.

[0255] Compound 62-P1 LC / MS 631.2 [M+H]+. 1H NMR (400 MHz, MeOD) δ 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).

[0256] Compound 62-P2 LC / MS ESI 631.2 [M+H]+. 1 H NMR (400 MHz, CDCl3) δ 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).

[0257] 62-P1 and 62-P2 are designated as (R)-2-(((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-((1r,4R)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(3-chloro-5-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetic acid, respectively.

[0258] Example 3: Preparation of compounds 89-P1 and 89-P2 Step 1: Diethyl 2-(5-chloro-2-methylbenzyl)malonate 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 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to give diethyl 2-(5-chloro-2-methylbenzylene)malonate (180 g, 93%) as a colorless oil (ESI 297.3 [M+H)). + ).

[0259] Step 2: Tetraethyl 2-(5-chloro-2-methylphenyl)propane-1,1,3,3-tetracarboxylate EtONa (88.1 g, 1.3 mmol) was added to a solution of diethyl malonate (194.6 g, 1.22 mol) in EtOH (400 mL) at room temperature, and the mixture was stirred for 2 hours. Then, 2-(5-chloro-2-methylbenzyl)malonate (180 g, 0.61 mol) was added at room temperature, and stirring continued for another 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (3 × 400 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (4:1 petroleum ether: EtOAc) to give tetraethyl 2-(5-chloro-2-methylphenyl)propane-1,1,3,3-tetracarboxylate (180.0 g, 60%) (ESI 457.2 [M+H)) as a colorless oil. + ).

[0260] Step 3: 3-(5-chloro-2-methylphenyl)glutaric acid A mixture of tetraethyl 2-(5-chloro-2-methylphenyl)propane-1,1,3,3-tetracarboxylate (180.0 g, 0.39 mol) in 700 mL of 36% HCl aqueous solution was stirred at 130 °C for 36 h. The mixture was cooled to 0 °C and stirred at 0 °C for 1 h. The resulting solid was filtered and collected to give 3-(5-chloro-2-methylphenyl)glutaric acid as a white solid, which was not further purified (100.2 g, 99%) (ESI 279.0 [M+Na)).+ ).

[0261] Step 4: 4-(5-chloro-2-methylphenyl)dihydro-2H-piperan-2,6(3H)-dione A solution of 3-(5-chloro-2-methylphenyl)glutaric acid (100.0 g, 0.39 mol) in acetic anhydride (400 mL) was stirred at 130 °C for 40 hours. The mixture was concentrated to dryness under reduced pressure and wet-milled with EtOAc (150 mL). The resulting solid was filtered and collected to give 91.2 g, 97% (ESI 239.1 [M+H]), a white solid. + ).

[0262] Step 5: 3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid Methylamine (1 M in THF, 1.15 L, 1.15 mol, 3.0 equivalent) was added to a solution of 3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (91.2 g, 0.38 mol, 1.0 equivalent) in THF (300 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and wet-milled with EtOAc (120 mL). The resulting solid was filtered and collected to give racemic 3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (75.0 g, 73%) as a white solid. The enantiomers were further separated by preparative chiral SFC K to obtain P1 fraction (R)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxovalerate acid (31.0 g) and P2 fraction (S)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxovalerate acid (31.0 g) as white solids (ESI 270.1 [M+H)). + ).

[0263] Step 6: (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide To a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (16.0 g, 59.4 mmol, 1.0 equivalent) and piperidine (5.0 g, 59.4 mmol, 1.0 equivalent) in DMF (60 mL), HATU (27.1 g, 71.3 mmol, 1.2 equivalent) was added, followed by DIPEA (15.3 g, 118.9 mmol, 2.0 equivalent). The reaction mixture was stirred at room temperature for 2 hours. After completion, the mixture was quenched with NH4Cl solution (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (19:1 dichloromethane:MeOH) to obtain (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide (16.3 g, 80%) as a colorless oil (ESI 337.2 [M+H)). + ).

[0264] Step 7: (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-(piperidin-1-yl)pentan-1-amine At room temperature, LiAlH4 (58.2 mL, 145.5 mmol, 3.0 equivalent) was added dropwise to a solution of (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide (16.3 g, 48.5 mmol, 1.0 equivalent) in 200 mL of THF, and the reaction mixture was stirred at 55 °C for 1 hour. After cooling to 0 °C, the reaction mixture was quenched dropwise with water (5.5 mL) and stirred at 0 °C for another 10 minutes. Then, 15% NaOH aqueous solution (5.5 mL) and water (16.5 mL) were added sequentially at 0 °C. The mixture was heated to room temperature and stirred for another 15 minutes, then filtered and the filtrate was concentrated under vacuum to give (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-(piperidin-1-yl)pentane-1-amine as a white solid, which was used directly in the next reaction (13.1 g, 80%) (ESI 309.3 [M+H)). + ).

[0265] Step 8: Ethyl 2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl) Under a nitrogen atmosphere, a solution of 4-(6-bromo-3-fluoro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidine (6 g, 17 mmol, 1.0 equivalent), Pd2(dba)3 (1.56 g, 1.7 mmol, 0.1 equivalent), and Qphos (362.6 mg, 0.51 mmol, 0.03 equivalent) in THF (50 mL) was added with zinc(II) bromide (51 mL, 1 M, 51 mmol, 3.0 equivalent), and the mixture was heated to 80 °C for 1 hour. After completion, saturated NH4Cl aqueous solution (100 mL) was added, and the solution was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (20:1 petroleum ether: EtOAc) to give ethyl 2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate (4.0 g, 65%) as a yellow oil (ESI 362.1 [M+H)). + ).

[0266] Step 9: Ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl) A solution of ethyl 2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate (20.0 g, 55.4 mmol, 1.0 equivalent) in 80 mL of THF was added dropwise to a solution of LiHMDS (1 M in THF, 110.8 mL). The reaction mixture was stirred at -78 °C for 0.5 h. Then, TMSCl (12.0 g, 110.8 mmol, 2.0 equivalent) was added dropwise, and the mixture was stirred at -78 °C for another 15 min. Finally, a solution of NBS (24.1 g, 110.8 mmol, 2.0 equivalent) in 200 mL of THF was added dropwise. The reactants were stirred at -78°C for another hour, then heated to 0°C and quenched with saturated NH4Cl aqueous solution (200 mL) at 0°C, followed by extraction with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to obtain ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate (20.1 g, 82%) as a colorless oil (ESI 440.1 [M+H)). + ).

[0267] Step 10: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)ethyl acetate K₂CO₃ (10.3 g, 75.0 mmol, 2.0 equivalent) was added to a solution of ethyl 2-bromo-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetate (16.5 g, 37.5 mmol, 1.0 equivalent) and (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-(piperidin-1-yl)pentan-1-amine (13.1 g, 42.5 mmol, 1.1 equivalent) in CH₃CN (50 mL) for 4 hours at 70 °C. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (20:1 dichloromethane:MeOH) to give ethyl acetate 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl) as a brown solid (16.0 g, 64%) (ESI 668.3 [M+H)). + ).

[0268] Step 11: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetic acid (compounds 89-P1 and 89-P2) Ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)ethyl acetate (16.0 g, 23.9 mmol, 1.0 equivalent) was treated at 70 °C with LiOH (5.0 g, 119.7 mmol, 5.0 equivalent) in EtOH (30 mL) and water (3 mL) for 16 h. The reaction mixture was acidified with 1N HCl to a pH of about 5 to 6. The solvent was removed under vacuum. The crude residue was purified by silica gel column chromatography (5:1 dichloromethane:MeOH) to give diastereomeric product 89 (13 g, 85%) as a white solid. The diastereomers were further separated by preparative chiral SFC A to obtain 89-P1 (5.6 g) and 89-P2 (5.7 g) as white solids.

[0269] Compound 89-P1 LC / MS ESI 640.3 [M+H] + . 1H NMR (400 MHz, MeOD) δ 7.44 (d, J =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).

[0270] Compound 89-P2 LC / MS ESI 640.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 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).

[0271] 89-P1 and 89-P2 are designated as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(4-fluoro-3-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)acetic acid, respectively.

[0272] Example 4: Preparation of compounds 85-P1 and 85-P2 Step 1: Diethyl 2-(5-chloro-2-fluorobenzyl)malonate A solution of 5-chloro-2-fluorobenzaldehyde (75.0 g, 0.475 mol), diethyl malonate (152.0 g, 0.95 mol), and piperidine (6.0 g, 71.0 mmol) in toluene (200 mL) was stirred at 110 °C for 20 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give crude product 2-(5-chloro-2-fluorobenzyl)malonate (165 g, crude product) as a yellow oil (ESI 301.0 [M+H)). + The crude product is used directly in the next step.

[0273] Step 2: Tetraethyl 2-(5-chloro-2-fluorophenyl)propane-1,1,3,3-tetracarboxylate EtONa (113.0 g, 1.6 mol) was added to a solution of diethyl malonate (176.0 g, 1.1 mol) in EtOH (2 L) at room temperature, and the mixture was stirred for 2 hours. Then, 2-(5-chloro-2-fluorobenzyl)malonate (165.0 g, 0.55 mol) was added at room temperature, and stirring was continued for another 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (3 × 400 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (4:1 petroleum ether: EtOAc) to give tetraethyl 2-(5-chloro-2-fluorophenyl)propane-1,1,3,3-tetracarboxylate (160.0 g, 63% yield in 2 steps) as a yellow oil (ESI 461.1 [M+H)). + ).

[0274] Step 3: 3-(5-chloro-2-fluorophenyl)glutaric acid A mixture of 80.0 g (0.174 mol) of tetraethyl 2-(5-chloro-2-fluorophenyl)propane-1,1,3,3-tetracarboxylate in 200 mL of 36% HCl aqueous solution was stirred at 130 °C for 36 h. The mixture was cooled to 0 °C and stirred at 0 °C for 1 h. The resulting solid was filtered and collected to give 40.0 g (88%) of 3-(5-chloro-2-fluorophenyl)glutaric acid, which was not further purified (ESI 283.0 [M+Na]). + ).

[0275] Step 4: 4-(5-chloro-2-fluorophenyl)dihydro-2H-piperan-2,6(3H)-dione A solution of 3-(5-chloro-2-fluorophenyl)glutaric acid (70.0 g, 270 mmol) in acetic anhydride (600 mL) was stirred at 130 °C for 40 hours. After cooling to 0 °C, the mixture was concentrated under reduced pressure and wet-milled with EtOAc (150 mL). The resulting solid was filtered and collected to give 59.1 g, 90% (ESI 243.1 [M+H]), a white solid. + ).

[0276] Step 5: 3-(5-chloro-2-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid Methylamine (2 M in THF, 364.5 mL, 729 mmol, 3.0 equivalent) was added to a solution of 4-(5-chloro-2-fluorophenyl)dihydro-2H-piperan-2,6(3H)-dione (59.1 g, 243 mmol, 1.0 equivalent) in THF (300 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and wet-milled with EtOAc (120 mL). The resulting solid was filtered and collected to give 3-(5-chloro-2-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid (59.7 g, 90%) as a white solid (ESI 274.0 [M+H)). + The enantiomers were further separated by preparative chiral SFC K to obtain P1 fraction (R)-3-(5-chloro-2-fluorophenyl)-5-(methylamino)-5-oxovaleric acid (28.2 g) and P2 fraction (S)-3-(5-chloro-2-fluorophenyl)-5-(methylamino)-5-oxovaleric acid (26.0 g) as white solids.

[0277] Step 6: (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide To a solution of (R)-3-(5-chloro-2-fluorophenyl)-5-(methylamino)-5-oxopentanoic acid (41.0 g, 150 mmol, 1.0 equivalent) in DCM (320 mL), piperidine (25.5 g, 300 mmol, 2.0 equivalent) and HATU (68.4 g, 180 mmol, 1.2 equivalent) were added, followed by DIEA (38.7 g, 300 mmol, 2.0 equivalent). The reaction mixture was stirred at room temperature for 2 hours. After completion, the mixture was quenched with NH4Cl solution (1 L) and extracted with dichloromethane (3 × 200 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (5:1 dichloromethane:MeOH) to obtain (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide (46.2 g, 90%) as a colorless oil (ESI 341.1 [M+H)). + ).

[0278] Step 7: (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-(piperidin-1-yl)pentan-1-amine LiAlH4 (2.5 M in THF, 206.7 mL, 516.8 mmol, 3.8 equivalents) was added dropwise to a solution of (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide (46.2 g, 136 mmol, 1.0 equivalent) in 340 mL of THF at room temperature, and the reaction mixture was stirred at 55 °C for 0.5 h. After cooling to 0 °C, the reaction mixture was quenched dropwise with 19 mL of water and stirred at 0 °C for another 10 min. Then, 19 mL of 15% NaOH aqueous solution and 57 mL of water were added sequentially at 0 °C. The mixture was heated to room temperature and stirred for another 15 min, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (99:0.1 MeOH:TEA) to obtain (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-(piperidin-1-yl)pentane-1-amine (13 g, 30%) as a colorless oil (ESI 313.2 [M+H)). + ).

[0279] Step 8: 3-Methyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline 2-Bromo-3-methylaniline (50 g, 268.7 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaboranecyclopentane (75 g, 282.18 mmol, 1.05 equivalent), K₂CO₃ (63 g, 456.7 mmol, 1.7 equivalent), and Pd(dppf)Cl₂ (3.9 g, 5.37 mmol, 0.02 equivalent) were suspended in a mixture of dioxane (500 mL) and water (100 mL). The reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The contents were poured into 300 mL of water and extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (6:1 petroleum ether: EtOAc) to give 3-methyl-2-(1,4-dioxane[4.5]dec-7-en-8-yl)aniline (54 g, 81.8%) as a yellow solid (ESI 246.3 [M+H)). + ).

[0280] Step 9: 3-Methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)aniline 10% Pd / C (5.0 g, 2.2 mmol, 0.03 equivalent) was added to a solution of 3-methyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline (20 g, 81.3 mmol, 1.0 equivalent) in EtOH (250 mL). The reaction mixture was stirred at 65 °C under a H2 atmosphere (1 atm, 3 L) for 24 hours. After completion, the reaction mixture was filtered through a diatomaceous earth mat and concentrated under vacuum to give 3-methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)aniline (19.1 g, 95%) as a yellow oil (ESI 248.3 [M+H)). + The crude product was used directly in subsequent steps without further purification.

[0281] Step 10: 4-(2-amino-6-methylphenyl)cyclohexane-1-one To a solution of 3-methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)aniline (100 g, 403.2 mmol, 1.0 equivalent) in THF (1 L), 3 M HCl aqueous solution (407 mL, 1.22 mol, 3 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C, quenched with saturated NaHCO3 aqueous solution (pH adjusted to approximately 8), and extracted with EtOAc (500 mL). The organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give 4-(2-amino-6-methylphenyl)cyclohexane-1-one (72 g, 87.9%) as a yellow oil (ESI 204.1 [M+H)). + The crude product is used directly in the next step.

[0282] Step 11: 4-(2-iodo-6-methylphenyl)cyclohexane-1-one An aqueous solution of HCl (6 M, 72 mL, 443.3 mmol, 2.5 equivalents) was added to a solution of 4-(2-amino-6-methylphenyl)cyclohexane-1-one (36 g, 90% purity, 177.3 mmol, 1.0 equivalent) in THF (250 mL) at -10 °C. Then, NaNO₂ (13.4 g in 30 mL water, 195.03 mmol, 1.1 equivalents) was added dropwise over 15 minutes. The reaction mixture was stirred at -10 °C for another 30 minutes. Next, a KI solution (44.1 g in 30 mL water, 265.9 mmol, 1.5 equivalents) was added in portions to the mixture. The reaction mixture was heated to 0 °C and stirred for another 30 minutes. Water (300 mL) and EtOAc (300 mL) were then added to the reaction mixture. The organic layer was separated and washed with saturated Na₂SO₃ aqueous solution (300 mL) and brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (15:1 petroleum ether: EtOAc) to give 4-(2-iodo-6-methylphenyl)cyclohexane-1-one (12.2 g, 21.8%) as a white solid (ESI 315.0 [M+H)). + ).

[0283] Step 12: (1r,4r)-4-(2-iodo-6-methylphenyl)cyclohexyl-1-ol CeCl3 (9.4 g, 38.2 mmol, 1.2 equivalent) was added fractionally to a solution of 4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexane-1-one (10 g, 31.8 mmol, 1.0 equivalent) in THF (50 mL) and MeOH (8 mL) at 0 °C, followed by the addition of NaBH4 (1.45 g, 38.2 mmol, 1.2 equivalent). The mixture was stirred at 0 °C for 0.5 h. H2O (100 mL) was slowly added at 0 °C, and the mixture was extracted with EtOAc (3 × 150 mL). The combined organic matter was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (4:1 petroleum ether: EtOAc) to give (1r,4r)-4-(2-iodo-6-methylphenyl)cyclohexyl-1-ol (8.4 g, 83.5%) as a white solid (ESI 299.0 [M-OH]). + ).

[0284] 1 H NMR (400 MHz, CDCl3) δ 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 = 11.5Hz, 2H), 1.47 (ddd, J = 23.7, 12.4, 3.6 Hz, 2H).

[0285] Step 13: 1-Iodo-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)benzene A solution of (1r,4r)-4-(2-iodo-6-methylphenyl)cyclohexyl-1-ol (8.4 g, 26.6 mmol, 1.0 equivalent), Selectfluor (14.14 g, 39.9 mmol, 1.5 equivalent), KF (6.17 g, 106.4 mmol, 4.0 equivalent), and AgOTf (20.5 g, 79.8 mmol, 3.0 equivalent) in EtOAc (200 mL) was stirred for 5 min at room temperature under a nitrogen atmosphere. Then, 2-fluoropyridine (7.75 g, 79.8 mmol, 3.0 equivalent) and TMSCF3 (11.4 g, 79.8 mmol, 3 equivalent) were added. The reaction mixture was stirred at room temperature for 48 h. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (98:2 petroleum ether: EtOAc) to give 1-iodo-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)benzene (3.2 g, 31.4%) as a white solid.

[0286] Step 14: 2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate . Pd2dba3 (100 mg, 0.11 mmol, 0.01 equivalence) and QPhos (154 mg, 0.22 mmol, 0.02 equivalence) were added to a suspension of 1-iodo-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)benzene (4.2 g, 10.9 mmol, 1.0 equivalence) in THF (30 mL), followed by the addition of (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 32 mL, 32 mmol, 3.0 equivalence). The mixture was stirred at 55 °C under a nitrogen atmosphere for 1 hour, then poured into 100 mL of saturated NH4Cl aqueous solution and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (20:1 petroleum ether: EtOAc) to obtain ethyl 2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (3.5 g, 93%) as a colorless oil (no mass data).

[0287] Step 15: 2-Bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate A solution of 2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate (3.5 g, 10.1 mmol, 1.0 equivalent) in 60 mL of THF was added dropwise to a solution of lithium diisopropylamino (2 M in THF, 15.1 mL). The reaction mixture was stirred at -78 °C for 0.5 h. Then, TMSCl (5.39 g, 30.3 mmol, 3.0 equivalent) was added dropwise, and the mixture was stirred again at -78 °C for 15 min. Finally, a solution of NBS (5.36 g, 30.3 mmol, 3.0 equivalent) in 100 mL of THF was added dropwise. The reaction mixture was stirred at -78°C for another hour, then heated to 0°C and quenched with saturated NH4Cl aqueous solution (100 mL) at 0°C, followed by extraction with EtOAc (3 × 150 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (3.2 g, 75%) as a yellow solid (ESI 445.0 [M+Na)). + ).

[0288] Step 16: 2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate K₂CO₃ (9.9 g, 72 mmol, 3.0 equivalent) was added to a solution of (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-(piperidin-1-yl)pentan-1-amine (10.0 g, 31.2 mmol, 1.3 equivalent) in acetonitrile (150 mL). The mixture was stirred at room temperature for 15 minutes. Ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (10.1 g, 24.0 mmol, 1.0 equivalent) was added, and the mixture was stirred at 80 °C for 4 hours. After completion, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (5:1 dichloromethane:MeOH) to give ethyl acetate 2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl) as a yellow oil (12.4 g, 60.6%) (ESI 655.3 [M+H) + ).

[0289] Step 17: 2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid (compounds 85-P1 and 85-P2) Ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate (18.2 g, 27.7 mmol, 1.0 equivalent) was treated at 70 °C with ethanol (120 mL), containing NaOH (5.5 g, 138.5 mmol, 5.0 equivalent), and water (40 mL) for 16 h. The reaction mixture was acidified with 1N HCl to a pH of about 5 to 6. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give diastereomeric product 85 (15.0 g, 86.5%). The diastereomers were further separated by a preparative chiral SFC A column to obtain products 85-P1 (5.4 g) and 85-P2 (4.99 g) as white solids.

[0290] Compound 85-P1 LC / MS ESI 627.2 [M+H] + . 1H NMR (400 MHz, MeOD) δ 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).

[0291] Compound 85-P2 LC / MS ESI 627.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 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 = 55.3Hz, 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).

[0292] 85-P1 and 85-P2 are designated as (R)-2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid, respectively.

[0293] Example 5: Preparation of compounds 99-P1 and 99-P2 Step 1: Ethyl (E)-3-(5-chloro-2-methylphenyl)acrylate Add 2-(triphenyl-λ) to a solution of 5-chloro-2-methylbenzaldehyde (5.0 g, 32.5 mmol, 1.0 equivalent) in DCE (50 mL). 5Ethyl (-phosphononyl)ethyl acetate (12.5 g, 35.7 mmol, 1.1 equivalents). The reactants were heated to 50 °C for 3 hours under a N2 atmosphere. After completion, the reactants were concentrated under vacuum. The crude residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to give ethyl (E)-3-(5-chloro-2-methylphenyl)acrylate (7.0 g, 96.3%) (ESI 225.1 [M+H]+) as a colorless oil.

[0294] Step 2: Ethyl 3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-1-yl)propionate LiClO4 (3.3 g, 31.2 mmol, 2.0 equivalent) was added to a solution of (E)-3-(5-chloro-2-methylphenyl)acrylate (3.5 g, 15.6 mmol, 1.0 equivalent) in 1-methylpiperazine (15 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with EtOAc (100 mL), washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The 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-1-yl)propionate (3.0 g, 59.4%) as a white solid (ESI 325.1 [M+H]). + ).

[0295] Step 3: 3-(5-chloro-2-methylphenyl)-N-methyl-3-(4-methylpiperazin-1-yl)propionamide Ethyl 3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-1-yl)propionate (3.0 g, 9.3 mmol, 1.0 equivalent) in methylamine solution (1 M in MeOH, 40 mL, 40 mmol, 4.0 equivalent) was heated to 60 °C for 16 hours. The reaction mixture was concentrated under vacuum. The 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-1-yl)propionamide (1.5 g, 52.4%) as a white solid. The enantiomers were further separated by preparative chiral SFC F to give amide P1 (0.7 g) and amide P2 (0.7 g) (ESI 310.1 [M+H)). + ).

[0296] Step 4: (S)-3-(5-chloro-2-methylphenyl)-N-methyl-3-(4-methylpiperazin-1-yl)propyl-1-amine LAH (2.3 mL, 5.66 mmol, 2.5 equivalents) was added to a solution of P2 amide (S)-3-(5-chloro-2-methylphenyl)-N-methyl-3-(4-methylpiperazin-1-yl)propionamide (700 mg, 2.27 mmol, 1.0 equivalent) in THF (9 mL) at 0 °C, and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was quenched dropwise with water (1.0 mL), NaOH (1.0 mL, 15% in water), and water (3.0 mL) and stirred at 0 °C for 15 minutes. The mixture was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to give (S)-3-(5-chloro-2-methylphenyl)-N-methyl-3-(4-methylpiperazin-1-yl)prop-1-amine (600 mg, yield 90.1%) as a yellow oil (ESI 296.1 [M+H)). + The crude product was used directly in subsequent steps without further purification.

[0297] Step 5: 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate DIEA (200 mg, 1.5 mmol, 3.0 equivalent) was added to a solution of (S)-3-(5-chloro-2-methylphenyl)-N-methyl-3-(4-methylpiperazin-1-yl)prop-1-amine (148 mg, 0.5 mmol) and 2-bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate (211 mg, 0.5 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 70 °C for 3 hours, then filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20:1 dichloromethane:MeOH) to obtain ethyl acetate 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl) as a yellow liquid (223 mg, 70.1%) (ESI 638.2 [M+H). + ).

[0298] Step 6: 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid (compounds 99-P1 and 99-P2) To a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (212 mg, 0.33 mmol, 1.0 equivalent) in ethanol (3 mL) and water (1 mL), NaOH (67 mg, 1.7 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 16 hours. After completion, the pH of the reaction mixture was adjusted to approximately 6 to 7 with 1N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give diastereomeric product 99 (130 mg, 71.5%) as a white solid. The diastereomers were further separated by preparative chiral SFC A to obtain 99-P1 (52.9 mg) and 99-P2 (44.3 mg).

[0299] Compound 99-P1 LC / MS ESI 610.1 [M+H]+. 1H NMR (400 MHz, MeOD) δ 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).

[0300] Compound 99-P2 LC / MS ESI 610.1 [M+H]+. 1H NMR (400 MHz, MeOD) δ 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).

[0301] 99-P1 and 99-P2 are designated as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-methylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid, respectively.

[0302] Example 6: Preparation of compounds 114-P1 and 114-P2 Step 1: Ethyl (E)-3-(5-chloro-2-fluorophenyl)acrylate 5-Chloro-2-fluorobenzaldehyde (125 g, 791 mmol, 1.0 equivalent) and 2-(triphenyl-λ) 5 A solution of ethyl (330 g, 949 mmol, 1.2 equivalents) in DCE (1 L) was stirred at room temperature for 3 hours. Afterward, the reaction mixture was concentrated under vacuum. The residue was diluted with petroleum ether (1 L). The reaction mixture was filtered to remove triphenylphosphine oxide. The filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (10:1 petroleum ether:EtOAc) to give ethyl (E)-3-(5-chloro-2-fluorophenyl)acrylate (152 g, 84%) as a yellow oil (ESI 229.6 [M+H)). + ).

[0303] Step 2: Ethyl 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propionate LiClO4 (128 g, 1000 mmol, 1.5 equivalents) was added to a solution of (E)-3-(5-chloro-2-fluorophenyl)acrylate (152 g, 667 mmol, 1.0 equivalents) in 1-isopropylpiperazine (106 g, 1000 mmol, 1.5 equivalents). The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was poured into water (1000 mL) and extracted with EtOAc (2000 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (97:3 dichloromethane:MeOH) to obtain ethyl 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propionate (160 g, 67%) as a yellow solid (ESI 357.8 [M+H)). + ).

[0304] Step 3: 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)prop-1-ol LAH (674 mL, 674 mmol, 1.5 equivalent) was added to a solution of ethyl 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propionate (160 g, 449 mmol, 1.0 equivalent) in THF (1000 mL) under N2 protection at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. After completion, the reaction mixture was quenched dropwise with water (25.5 mL) and stirred again at 0 °C for 10 minutes. Then, 15% NaOH aqueous solution (25.5 mL) and water (76 mL) were added sequentially at 0 °C. The mixture was heated to room temperature and stirred for another 15 minutes, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (80:20 petroleum ether: EtOAc) to obtain 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)prop-1-ol (140 g, 99%) as a yellow oil. The enantiomers were further separated by preparative chiral SFC B to obtain the P1 fraction (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)prop-1-ol (60 g) and the P2 fraction (R)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)prop-1-ol (55 g) as the yellow oil.

[0305] Step 4: (S)-2-(3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)isoindoline-1,3-dione Triphenylphosphine (30 g, 116 mmol, 1.3 equivalent) was added to a solution of (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)prop-1-ol (28 g, 89 mmol, 1.0 equivalent) and isoindoline-1,3-dione (17 g, 116 mmol, 1.3 equivalent) in toluene (300 mL) at 0 °C, followed by the addition of diethyl azodicarbonate (23 g, 116 mmol, 1.3 equivalent). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to obtain (S)-2-(3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)isoindoline-1,3-dione (33 g, 85%) as a yellow oil (ESI 444.9 [M+H)). + ).

[0306] Step 5: (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl-1-amine To a solution of (S)-2-(3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)isoindoline-1,3-dione (33 g, 74 mmol, 1.0 equivalent) in EtOH (800 mL), 98% hydrazine hydrate (19 g, 372 mmol, 5 equivalent) was added. The reaction mixture was heated to 80 °C and stirred for 1 hour. After completion, the reaction mixture was filtered and the filtrate was concentrated under vacuum. 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-1-yl)propyl-1-amine (23 g, 99%) as a yellow oil (ESI 314.8 [M+H]). + ).

[0307] Step 6: 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate K₂CO₃ (17 g, 125 mmol, 3.0 equivalent) was added to a solution of (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl-1-amine (13 g, 42 mmol, 1.0 equivalent) in acetonitrile (150 mL). The mixture was stirred at room temperature for 15 minutes. Then, ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (17 g, 42 mmol, 1.0 equivalent) was added. The mixture was stirred at 60 °C for another 16 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9:1 dichloromethane:MeOH) to obtain ethyl acetate 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl) as a yellow oil (16 g, 59%) (ESI 656.2 [M+H). + ).

[0308] Step 7: 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate To a solution of ethyl (16 g, 25 mmol, 1.0 equivalent) of (S)-2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate in MeOH (140 mL), 33% HCHO aqueous solution (10 g, 100 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour. Then, NaBH(OAc)3 (11 g, 50 mmol, 2.0 equivalent) was added and stirring was continued at room temperature for another 3 hours. After completion, the reaction mixture was poured into water (300 mL) and extracted with dichloromethane (3 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (95:5 dichloromethane:MeOH) to obtain ethyl acetate 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl) as a colorless oil (14 g, 86%) (ESI 670.2 [M+H).+ ).

[0309] Step 8: 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid (compounds 114-P1 and 114-P2) To a mixture of ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate (14 g, 21 mmol, 1.0 equivalent) and EtOH (100 mL) and H₂O (20 mL), NaOH (2.5 g, 63 mmol, 3.0 equivalent) was added and the mixture was stirred at 60 °C for 16 h. The pH of the reaction was adjusted to approximately 5 to 6 with 1N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH₃CN) to give diastereomeric product 114 (10 g, 75%) as a white solid. The diastereomers were further separated by preparative chiral SFC A to obtain 114-P1 (4.0 g) and 114-P2 (3.98 g).

[0310] Compound 114-P1 LC / MS 642.1 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 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).

[0311] Compound 114-P2 LC / MS ESI 642.1 [M+H]+. 1H NMR (400 MHz, MeOD) δ 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).

[0312] 114-P1 and 114-P2 are designated as (R)-2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,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-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid, respectively.

[0313] Example 7: Preparation of compounds 115-P1 and 115-P2 Step 1: Ethyl (E)-3-(5-chloro-2-methylphenyl)acrylate 5-Chloro-2-methylbenzaldehyde (5.0 g, 32.3 mmol, 1.0 equivalent) and 2-(triphenyl-λ) 5 A mixture of ethyl (-phosphono)ethyl acetate (11.8 g, 33.9 mmol, 1.05 equivalents) in 1,2-dichloroethane (100 mL) was stirred at 50 °C for 3 hours. The reaction mixture was concentrated under vacuum. The 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)). + ).

[0314] Step 2: Ethyl 3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)propionate LiClO4 (11.8 g, 102.4 mmol, 2.0 equivalent) was added to a solution of (E)-3-(5-chloro-2-methylphenyl)acrylate (11.5 g, 51.2 mmol, 1.0 equivalent) in 1-isopropylpiperazine (50 mL), and the mixture was stirred at room temperature for 3 days. The mixture was poured into 200 mL of water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The 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-1-yl)propionate (8.7 g, 48%) (ESI 353.2 [M+H]). + ).

[0315] Step 3: 3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropionamide Ethyl 3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)propionate (8.4 g, 23.8 mmol) was stirred for 3 days at room temperature in a methylamine solution (1 M in MeOH, 300 mL). The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (20:1 dichloromethane:MeOH) to give a racemic product (7.0 g, 87%) as a white solid. The enantiomers were further separated by preparative chiral SFC F to give amide P1 (2.9 g) and amide P2 (2.8 g).

[0316] Step 4: (S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine LiAlH4 (2.5 M in THF, 10 mL, 24.9 mmol, 3.0 equivalent) was added to a solution of (S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropionamide (2.8 g, 8.3 mmol, 1.0 equivalent) P2 in THF (10 mL). The reaction mixture was stirred at 60 °C for 1 hour. The mixture was cooled to 0 °C. Na2SO4·10H2O was slowly added while stirring for 10 minutes. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated under vacuum to give (S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylprop-1-amine (2.1 g, 6.48 mmol, crude product) (ESI 324.3 [M+H)).+ The crude product was used directly in subsequent steps without further purification.

[0317] Step 5: 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate K₂CO₃ (257 mg, 1.9 mmol, 3.0 equivalent) was added to a solution of (S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine (200 mg, 0.62 mmol) and 2-bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate (261 mg, 0.62 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 70 °C for 3 hours, then filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20:1 dichloromethane:MeOH) to obtain ethyl acetate 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl) as a yellow liquid (210 mg, 50%) (ESI 666.2 [M+H). + ).

[0318] Step 6: 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid (compounds 115-P1 and 115-P2) To a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (210 mg, 0.31 mmol, 1.0 equivalent) in ethanol (3 mL) and water (1 mL), NaOH (60 mg, 1.5 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 16 hours. After completion, the pH of the reaction mixture was adjusted to approximately 6 to 7 with 1N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give diastereomeric product 115 (160 mg, 81.0%) as a white solid. The diastereomers were further separated by preparative chiral SFC H to obtain 115-P1 (31.0 mg) and 115-P2 (41.0 mg).

[0319] Compound 115-P1 LC / MS ESI 638.2 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 7.53(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).

[0320] Compound 115-P2 LC / MS ESI 638.2 [M+H]+. 1 H NMR (400 MHz, MeOD) δ 7.57(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).

[0321] 115-P1 and 115-P2 are designated as (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,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-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid, respectively.

[0322] Example 8: Preparation of compounds 119-P1 and 119-P2 Step 1: (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidone-1-yl)-N-methyl-5-oxopentanamide To a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (15.0 g, 55.7 mmol, 1.0 equivalent) and 3,3-dimethylpyrrolidine (5.5 g, 55.7 mmol, 1.0 equivalent) in DMF (60 mL), HATU (25.4 g, 66.8 mmol, 1.2 equivalent) was added, followed by DIPEA (14.4 g, 111.4 mmol, 2.0 equivalent). The reaction mixture was stirred at room temperature for 2 hours. After completion, the mixture was quenched with NH4Cl solution (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The filtrate was then purified by silica gel column chromatography (20:1 dichloromethane:MeOH) to obtain (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidone-1-yl)-N-methyl-5-oxopentanamide (16.6 g, 85%) as a colorless oil (ESI 351.1 [M+H). + ).

[0323] Step 2: (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)-N-methylpentan-1-amine At room temperature, LiAlH4 (56.9 mL, 142.3 mmol, 3.0 equivalent) was added dropwise to a solution of (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-oxo-5-(piperidin-1-yl)pentanamide (16.6 g, 47.4 mmol, 1.0 equivalent) in 200 mL of THF, and the reaction mixture was stirred at 55 °C for 1 hour. After cooling to 0 °C, the reaction mixture was quenched dropwise with water (5.5 mL) and stirred at 0 °C for another 10 minutes. Then, 15% NaOH aqueous solution (5.5 mL) and water (16.5 mL) were added sequentially at 0 °C. The mixture was heated to room temperature and stirred for 15 minutes, dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to obtain (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolid-1-yl)-N-methylpentane-1-amine as a white solid, which was used directly in the next reaction (13.1 g, 85%) (ESI 323.3 [M+H)). + ).

[0324] Step 3: 1-Fluoro-4-iodo-2-methyl-3-((1r,4r)-4-(vinyloxy)cyclohexyl)benzene Vinyl acetate (38.7 g, 450 mmol, 3.0 equivalent) was added to a solution of (1r,4r)-4-(3-fluoro-6-iodo-2-methylphenyl)cyclohexyl-1-ol (50.1 g, 150.0 mmol, 1.0 equivalent), Na₂CO₃ (15.9 g, 150.0 mmol, 1.0 equivalent), and chloro-1,5-cyclooctadiene iridium(I) chloride dimer (4.04 mg, 6.0 mmol, 0.04 equivalent) in toluene (400 mL) under a nitrogen atmosphere. 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 × 800 mL). The combined organic layers were washed with brine (1 L), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to give 1-fluoro-4-iodo-2-methyl-3-((1r,4r)-4-(vinyloxy)cyclohexyl)benzene (27.0 g, 50%) as a yellow oil.

[0325] Step 4: 2-((1r,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-1-iodo-3-methylbenzene Et₂Zn (36.9 g, 300.0 mmol, 1.0 equivalent) was added dropwise to a solution of 1-fluoro-4-iodo-2-methyl-3-((1r,4r)-4-(vinyloxy)cyclohexyl)benzene (27.0 g, 75.0 mmol, 1.0 equivalent) in dichloromethane (250 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. CH₂I₂ (10.4 g, 300.0 mmol, 4.0 equivalent) was added dropwise, and the mixture was heated to room temperature and stirred for another 6 h. The reaction mixture was slowly quenched with saturated NH₄Cl solution (1.5 L) and extracted with dichloromethane (3 × 600 mL). The combined organic phases were washed with brine (900 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to give 2-((1r,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-1-iodo-3-methylbenzene (20.2 g, 72%) as a colorless oil.

[0326] Step 5: Ethyl 2-(2-((1r,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl) Under a nitrogen atmosphere, a solution of 2-((1r,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-1-iodo-3-methylbenzene (20.2 g, 54 mmol, 1.0 equivalent), Pd2(dba)3 (990 mg, 1.08 mmol, 0.02 equivalent), and QPhos (792 mg, 1.08 mmol, 0.02 equivalent) in tetrahydrofuran (100 mL) was added with zinc(II) bromide (162 mL, 162 mmol, 3.0 equivalent) and the mixture was heated to 65 °C for 1 hour. After completion, a saturated aqueous solution of NH4Cl (500 mL) was added and the solution was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (15:1 petroleum ether: EtOAc) to give ethyl 2-(2-((1r,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetate (17.0 g, 72%) as a colorless oil (ESI 357.1 [M+Na)). + ).

[0327] Step 6: Ethyl 2-bromo-2-(2-((1r,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl) A solution of ethyl 2-(2-((1r,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetate (17.0 g, 51.0 mmol, 1.0 equivalent) in tetrahydrofuran (150 mL) was added dropwise to a solution of LiHMDS (1 M in THF, 102.0 mL). The reaction mixture was stirred at -78 °C for 0.5 h. Then, TMSCl (11.1 g, 102.0 mmol, 2.0 equivalent) was added dropwise, and the mixture was stirred again at -78 °C for 15 min. Finally, a solution of NBS (20.2 g, 102.0 mmol, 2.0 equivalent) in tetrahydrofuran (150 mL) was added dropwise. The reactants were stirred at -78°C for another hour, then heated to 0°C and quenched with saturated NH4Cl aqueous solution (1.1 L) at 0°C. Extraction was performed with EtOAc (3 × 600 mL). The combined organic layers were washed with brine (500 mL × 3), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (19:1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(2-((1r,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetate (19.0 g, 90.2%) as a yellow oil (ESI 435.0 [M+Na)). + ).

[0328] Step 7: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidone-1-yl)pentyl)(methyl)amino)-2-(2-((1r,4S)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)ethyl acetate To a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)-N-methylpentan-1-amine (10.0 g, 31.0 mmol, crude) in acetonitrile (150 mL), K₂CO₃ (12.42 g, 90 mmol, 3.0 equivalent) was added. The mixture was stirred at room temperature for 15 minutes. Ethyl 2-bromo-2-(2-((1r,4r)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetate (12.36 g, 30.0 mmol, 1.0 equivalent) was added. The mixture was stirred at 80 °C for another 4 hours. After completion, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (20:1 dichloromethane:MeOH) to give ethyl acetate 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(2-((1r,4S)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl) as a yellow oil (14.1 g, 71.7%) (ESI 655.3 [M+H) + ).

[0329] Step 8: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(2-((1r,4S)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetic acid (compound 119) Ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(2-((1r,4S)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)ethyl acetate (14.1 g, 21.5 mmol, 1.0 equivalent) was treated at 60 °C with 120 mL of ethanol (3.44 g, 86.0 mmol, 4.0 equivalent) and 40 mL of water for 24 h. The reaction mixture was acidified with 1N HCl to a pH of about 5 to 6. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give diastereomeric product 119 (10.6 g, 78.6%) as a white solid. The diastereomers were further separated by preparative chiral SFC P to obtain products 119-P1 (4.3 g) and 119-P2 (4.1 g) as white solids.

[0330] Compound 119-P1 LC / MS ESI 627.4 [M+H] +。 1 1H NMR (400 MHz, MeOD) δ 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).

[0331] Compound 119-P2 LC / MS ESI 627.4 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 7.57 (d, J J = 106.9 Hz, 1H), 7.24 – 7.03 (m, 3H), 6.85 (dt, J J = 33.2, 8.7 Hz, 1H), 4.52 (d, J J = 85.4 Hz, 1H), 3.66 – 3.32 (m, 3H), 3.05 (dd, J 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).

[0332] 119-P1 and 119-P2 are designated as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidone-1-yl)pentyl)(methyl)amino)-2-(2-(((1r,4R)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidone-1-yl)pentyl)(methyl)amino)-2-(2-(((1r,4S)-4-cyclopropoxycyclohexyl)-4-fluoro-3-methylphenyl)acetic acid, respectively.

[0333] Example 9: Preparation of compounds 162-P1 and 162-P2 Step 1: 1-Iodo-3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)benzene PBu3 (5.6 g, 27.8 mmol, 2.0 equivalent) was added dropwise to a solution of (1s,4s)-4-(2-iodo-6-methylphenyl)cyclohexyl-1-ol (4.4 g, 13.9 mmol, 1.0 equivalent) and ADDP (7.0 g, 27.8 mmol, 2.0 equivalent) in toluene (70 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. Then, 2,2,2-trifluoroethane-1-ol (13.9 g, 139.0 mmol, 10.0 equivalent) was added dropwise. The reaction mixture was heated at 70 °C for 16 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to obtain 1-iodo-3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)benzene (1.25 g, 26%) (ESI 421.0 [M+Na)) as a colorless oil. + ).

[0334] Step 2: ethyl acetate 2-(3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl) Pd2dba3 (140 mg, 0.16 mmol, 0.05 equivalence) and QPhos (88 mg, 0.12 mmol, 0.04 equivalence) were added to a suspension of 1-iodo-3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)benzene (1.25 g, 3.1 mmol, 1.0 equivalence) in THF (10 mL), followed by the addition of (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 15.5 mL, 15.5 mmol, 5.0 equivalence). The mixture was stirred at 65 °C under a nitrogen atmosphere for 1 hour, then poured into 50 mL of saturated NH4Cl aqueous solution and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (20:1 petroleum ether: EtOAc) to obtain ethyl 2-(3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (540 mg, 45%) as a colorless oil (ESI 381.0 [M+Na)). + ).

[0335] Step 3: 2-Bromo-2-(3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)ethyl acetate A solution of 2-(3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)ethyl acetate (540 mg, 1.5 mmol, 1.0 equivalent) in 10 mL of THF was added dropwise to a solution of LiHMDS (1 M in THF). The reaction mixture was stirred at -78 °C for 0.5 h. Then, TMSCl (240 mg, 2.3 mmol, 1.5 equivalent) was added dropwise, and the mixture was stirred at -78 °C for another 15 min. Finally, a solution of NBS (400 mg, 2.3 mmol, 1.5 equivalent) in 10 mL of THF was added dropwise. The reactants were stirred at -78°C for another hour, then heated to 0°C and quenched with saturated NH4Cl aqueous solution (50 mL) at 0°C, followed by extraction with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (10:1 PE:EA) to obtain ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (440 mg, 68%) as a colorless oil (ESI 459.1 [M+Na)). + ).

[0336] Step 4: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)ethyl acetate To a solution of ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (220 mg, 0.5 mmol, 1.0 equivalent) in acetonitrile (6 mL), K₂CO₃ (210 mg, 1.5 mmol, 3.0 equivalent) was added, followed by (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-(piperidin-1-yl)pentan-1-amine (200 mg, 0.65 mmol, 1.3 equivalent). The mixture was stirred at 70 °C for 3 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9:1 dichloromethane:MeOH) to obtain ethyl acetate (250 mg, 75%) as a yellow oil (ESI 665.3 [M+H)-3-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl) + ).

[0337] Step 5: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid (compound 162) To a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (250 mg, 0.38 mmol, 1.0 equivalent) in ethanol (3 mL) and water (1 mL), NaOH (150 mg, 3.8 mmol, 10.0 equivalent) was added. The reaction mixture was stirred at 60 °C for 16 hours. After completion, the pH of the reaction mixture was adjusted to approximately 6 to 7 with 1N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give diastereomeric product 162 (160 mg, 64%) as a white solid. The diastereomers were further separated by preparative chiral SFC A to obtain 162-P1 (66 mg) and 162-P2 (68 mg).

[0338] Compound 162-P1 LC / MS ESI 637.2 [M+H]+. 1H NMR (400 MHz, MeOD) δ 7.65 –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.

[0339] Compound 162-P2 LC / MS ESI 637.2 [M+H]+. 1H NMR (400 MHz, MeOD) δ 7.64 –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.

[0340] 162-P1 and 162-P2 are designated as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid, respectively.

[0341] Example 10: Preparation of compounds 164-P1 and 164-P2 Step 1: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)ethyl acetate DIEA (200 mg, 1.5 mmol, 3.0 equivalent) was added to a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)-N-methylpentan-1-amine (218 mg, 0.5 mmol) and ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (196 mg, 0.5 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 70 °C for 3 hours, then filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (20:1 dichloromethane:MeOH) to obtain ethyl acetate 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl) as a yellow liquid (200 mg, 0.29 mmol, 49.1%) (ESI 679.2 [M+H)). + ).

[0342] Step 2: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid To a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (200 mg, 0.30 mmol, 1.0 equivalent) in ethanol (3 mL) and water (1 mL), NaOH (72 mg, 1.8 mmol, 6.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 16 hours. After completion, the pH of the reaction mixture was adjusted to approximately 6 to 7 with 1N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give 164-P1 (44.2 mg) and 164-P2 (50.5 mg) as white solids.

[0343] Compound 164-P1 LC / MS ESI 651.1 1H NMR (400 MHz, MeOD) δ 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).

[0344] Compound 164-P2 LC / MS ESI 651.1 [M+H]+. 1H NMR (400 MHz, MeOD) δ 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 = 11.2Hz, 4H), 2.56 – 2.30 (m, 8H), 2.25 – 1.73 (m, 13H), 1.67 (dd, J = 14.2, 7.0Hz, 2H), 1.58 – 1.31 (m, 3H), 1.09 (s, 6H).

[0345] 164-P1 and 164-P2 are designated as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidone-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid and (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidone-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid, respectively.

[0346] Example 11: Preparation of compounds 183-P1 and 183-P2 Step 1: 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropionamide A solution of 3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropionamide (27 g, 75.8 mmol, 1.0 equivalent) in methylamine (33% in methanol, 35.6 g, 379 mmol, 5.0 equivalent) was stirred at 60 °C for 16 hours. The reaction mixture was concentrated under vacuum. The 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-1-yl)propionamide (22 g, 85%). 10 g of the enantiomers were further separated by preparative chiral SFC C to give amide P1 (4.2 g) and amide P2 (4.2 g) as yellow oils (ESI 342.1 [M+H]). + ).

[0347] Step 2: (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine LAH (37 mL, 37.0 mmol, 3 equivalents) was added to a solution of (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropionamide (4.2 g, 12.3 mmol, 1.0 equivalent) in THF (50 mL) under N2 protection at 0 °C. The reaction mixture was stirred in N2 at 60 °C for 20 minutes. The reaction mixture was quenched dropwise with water (1.4 mL). NaOH (1.4 mL, 15% in water) and water (4.2 mL) were stirred at 0 °C for 15 minutes, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to obtain (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine (560 mg, 14%) as a colorless oil.

[0348] Step 3: 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)ethyl acetate To a solution of ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (200 mg, 0.46 mmol, 1.0 equivalent) in acetonitrile (6 mL), K₂CO₃ (190 mg, 1.38 mmol, 3.0 equivalent) and (S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine (200 mg, 0.6 mmol, 1.3 equivalent) were added. The mixture was stirred at 70 °C for 3 hours. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9:1 dichloromethane:MeOH) to obtain ethyl acetate 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl) as a yellow oil (190 mg, 62%) (ESI 684.3 [M+H). + ).

[0349] Step 4: 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid (compound 183) To a solution of ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetate (190 mg, 0.28 mmol, 1.0 equivalent) in ethanol (3 mL) and water (1 mL), NaOH (110 mg, 2.8 mmol, 10.0 equivalent) was added. The reaction mixture was stirred at 60 °C for 16 hours. After completion, the pH of the reaction mixture was adjusted to approximately 6 to 7 with 1N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give diastereomeric product 183 (100 mg, 53%) as a white solid. The diastereomers were further separated by preparative chiral SFC A to obtain 183-P1 (42 mg) and 183-P2 (42 mg).

[0350] Compound 183-P1 LC / MS ESI 656.2 [M+H]+. 1H NMR (400 MHz, MeOD) δ 7.65–7.50 (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.

[0351] Compound 183-P2 LC / MS ESI 656.2 [M+H]+. 1H NMR (400 MHz, MeOD) δ 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.

[0352] 183-P1 and 183-P2 are designated as (R)-2-(((S)-3-(5-chloro-2-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(2,2,2-trifluoroethoxy)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-((1r,4S)-4-(2,2,2-trifluoroethoxy)cyclohexyl)phenyl)acetic acid, respectively.

[0353] Example 12: Preparation of compound 300-P3 Step 1: 4-Fluoro-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (10 g, 40.4 mmol, 1.0 equivalent), N,O-dimethylhydroxylamine hydrochloride (4.7 g, 48.5 mmol, 1.2 equivalent), HOBt (6.6 g, 48.5 mmol, 1.2 equivalent), and TEA (12.3 g, 121.2 mmol, 3.0 equivalent) in DCM (100 mL), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (8.5 g, 44.5 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour, diluted with water (100 mL), and extracted with DCM (2 × 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (5:1 petroleum ether: EtOAc) to obtain tert-butyl 4-fluoro-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (9.1 g, 77%) as a colorless oil (ESI 235.3 [M-tBu+H)). + ).

[0354] Step 2: 4-(3-chlorobenzoyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester To a solution of 1-bromo-3-chloro-5-methylbenzene (6.6 g, 34.4 mmol, 1.1 equivalents) in anhydrous THF (100 mL), n-BuLi (2.5 M in hexane, 10.4 mL, 26.1 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at -78 °C for 30 min. Then, a solution of 4-fluoro-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (9.1 g, 31.3 mmol, 1.0 equivalents) in THF (20 mL) was added. The reaction mixture was stirred at -78 °C for another 1 h. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (2 × 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to obtain tert-butyl 4-(3-chlorobenzoyl)-4-fluoropiperidine-1-carboxylate (9.0 g, 84.0%) as a colorless oil (ESI 286.1 [M-tBu+H)). + ).

[0355] Step 3: (Z)-4-(1-(3-chlorophenyl)-3-ethoxy-3-oxoprop-1-en-1-yl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester NaHMDS (1.0 M in THF, 35.1 mmol, 1.5 equivalent) was added dropwise to a solution of ethyl 2-(diethoxyphosphoryl)ethyl acetate (7.8 g, 35.1 mmol, 1.5 equivalent) in anhydrous THF (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. Then, a solution of ((1r,3r)-3-(3-chlorophenyl)-3-(2-oxoethyl)cyclobutyl)(methyl)carbamate (8.0 g, 23.4 mmol, 1.0 equivalent) in THF (25 mL) was added. The reaction mixture was stirred at 45 °C for another 16 h, quenched by adding saturated NH4Cl aqueous solution (80 mL), and extracted with EtOAc (3 × 100 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to give (Z)-4-(1-(3-chlorophenyl)-3-ethoxy-3-oxoprop-1-en-1-yl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester (6.2 g, 64%) as a white solid (ESI 434.1 [M+Na)). + ).

[0356] Step 4: 4-(1-(3-chlorophenyl)-3-ethoxy-3-oxopropyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester To a solution of (Z)-4-(1-(3-chlorophenyl)-3-ethoxy-3-oxoprop-1-en-1-yl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester (3.2 g, 7.77 mmol, 1.0 equivalent) in EtOH (100 mL), PtO2 (108 mg, 0.39 mmol, 0.05 equivalent) and concentrated H2SO4 (0.05 mL) were added. The reaction mixture was stirred at room temperature under an H2 atmosphere (1 atm, 3 L) for 30 minutes. After completion, the reaction mixture was filtered through a diatomaceous earth mat and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to give tert-butyl 4-(1-(3-chlorophenyl)-3-ethoxy-3-oxopropyl)-4-fluoropiperidine-1-carboxylate (3.0 g, 93%) as a white solid (ESI 436.3 [M+Na)). + ).

[0357] Step 5: 4-(1-(3-chlorophenyl)-3-oxopropyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester DIBAl-H (1 M in toluene, 10.88 mL, 10.88 mmol, 1.5 equivalent) was added to a solution of tert-butyl 4-(1-(3-chlorophenyl)-3-ethoxy-3-oxopropyl)-4-fluoropiperidine-1-carboxylate (3.0 g, 7.25 mmol, 1.0 equivalent) in anhydrous toluene (50 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (3 × 50 mL). The organic solutions were combined, washed with brine (3 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain tert-butyl 4-(1-(3-chlorophenyl)-3-oxopropyl)-4-fluoropiperidine-1-carboxylate (crude product, 2.0 g, 74%) as a colorless oil (ESI 392.1 [M+Na)). + The crude product was used directly in subsequent steps without further purification.

[0358] Step 6: 4-(1-(3-chlorophenyl)-3-(methylamino)propyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester To a solution of tert-butyl 4-(1-(3-chlorophenyl)-3-oxopropyl)-4-fluoropiperidine-1-carboxylate (2.0 g, 5.41 mmol, 1.0 equivalent) in MeOH (100 mL), methylamine hydrochloride (1.8 g, 27.05 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour. Then, NaBH(OAc)3 (3.4 g, 16.23 mmol, 3.0 equivalent) was added. The reaction mixture was stirred at room temperature for another 16 hours and then concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 DCM:MeOH) to give tert-butyl 4-(1-(3-chlorophenyl)-3-(methylamino)propyl)-4-fluoropiperidine-1-carboxylate (750 mg, 36%) (ESI 385.4 [M+H)) as a colorless oil. + ).

[0359] Step 7: 4-(3-((2-(tert-butoxy)-1-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-oxoethyl)(methyl)amino)-1-(3-chlorophenyl)propyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester To a solution of tert-butyl 4-(1-(3-chlorophenyl)-3-(methylamino)propyl)-4-fluoropiperidine-1-carboxylate (380 mg, 0.99 mmol, 1.0 equivalent) in ACN (20 mL), DIPEA (384 mg, 2.97 mmol, 3.0 equivalent) and ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (491 mg, 1.09 mmol, 1.1 equivalent) were added. The mixture was stirred at 60 °C for 20 hours. The reaction mixture was filtered and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 DCM:MeOH) to obtain tert-butyl 4-(3-((2-(tert-butoxy)-1-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-oxoethyl)(methyl)amino)-1-(3-chlorophenyl)propyl)-4-fluoropiperidine-1-carboxylic acid (350 mg, 47%) (ESI 755.6 [M+H)) as a colorless oil. + ).

[0360] Step 8: 2-((3-(3-chlorophenyl)-3-(4-fluoropiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate 4-(3-((2-(tert-butoxy)-1-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-oxoethyl)(methyl)amino)-1-(3-chlorophenyl)propyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester (350 mg, 0.46 mmol, 1.0 equivalent) in dioxane (6 mL) was treated with HCl-MeOH (4 M, 5 mL, 20 mmol, 43.0 equivalent). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to give 2-((3-(3-chlorophenyl)-3-(4-fluoropiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate hydrochloride (300 mg, 0.46 mmol, crude product) (ESI 655.3 [M+H)) as a colorless oil. + The crude product is used directly in subsequent steps.

[0361] Step 9: 2-((3-(3-chlorophenyl)-3-(4-fluoro-1-methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate To a solution of ethyl 2-((3-(3-chlorophenyl)-3-(4-fluoropiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (300 mg, 0.46 mmol, 1.0 equivalent) in MeOH (20 mL), 33% HCHO aqueous solution (4 mL, 42 mmol, 96.0 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour. Then, NaBH(OAc)3 (195 mg, 0.92 mmol, 2.0 equivalent) was added, and the reaction mixture was stirred at room temperature for another 20 hours. The reaction mixture was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 DCM:MeOH) to obtain 2-((3-(3-chlorophenyl)-3-(4-fluoro-1-methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)tert-butyl acetate (280 mg, 91%) (ESI 669.3 [M+H)) as a colorless oil. + ).

[0362] Step 10: 2-((3-(3-chlorophenyl)-3-(4-fluoro-1-methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid TFA (5 mL, 79 mmol, 189.0 equivalents) was added to a solution of 2-((3-(3-chlorophenyl)-3-(4-fluoro-1-methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (280 mg, 0.42 mmol, 1.0 equivalent) in DCM (1 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give a mixture of isomers 300 (200 mg, 78%) as a white solid. The isomers were further separated by preparative chiral SFC I to obtain 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.

[0363] 300-P1-1, specified as (R)-2-(((R)-3-(3-chlorophenyl)-3-(4-fluoro-1-methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 613.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 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).

[0364] 300-P1-2, specified as (S)-2-(((R)-3-(3-chlorophenyl)-3-(4-fluoro-1-methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 613.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 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).

[0365] 300-P2, specified as (R)-2-(((S)-3-(3-chlorophenyl)-3-(4-fluoro-1-methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 613.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 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).

[0366] 300-P3, specified as (S)-2-(((S)-3-(3-chlorophenyl)-3-(4-fluoro-1-methylpiperidin-4-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 613.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 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).

[0367] Example 13: Preparation of compound 301-P2 Step 1: (S)-(3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester To a solution of 1-isopropylpiperazine (678 mg, 5.3 mmol, 1.0 equivalent) in ACN (10 mL), K₂CO₃ (2.2 g, 15.9 mmol, 3.0 equivalent) and (R)-3-((tert-butyloxycarbonyl)(methyl)amino)-1-(3-chlorophenyl)propyl methanesulfonic acid (2 g, 5.3 mmol, 1.0 equivalent) were added. The reaction mixture was stirred at 80 °C for 2 hours. 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 (S)-(3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester (300 mg, 14%) as a yellow oil (ESI 410.2 [M+H)). + ).

[0368] Step 2: (S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine TFA (1 mL, 13.5 mmol, 18.5 equivalents) was added to a solution of (S)-(3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester (300 mg, 0.73 mmol, 1.0 equivalent) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum to give (S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine (180 mg, 0.58 mmol, crude) as a yellow oil (ESI 310.2 [M+H]). + The crude product is used directly in subsequent steps.

[0369] Step 3: 2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)tert-butyl acetate To a solution of (S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine (180 mg, 0.58 mmol, crude) in 10 mL of ACN, K₂CO₃ (240 mg, 1.74 mmol, 5.0 equivalent) was added. The mixture was stirred at room temperature for 15 minutes. Then, tert-butyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (262 mg, 0.58 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at 80 °C for another 2 hours. 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 obtain 2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)tert-butyl acetate (220 mg, 55%) (ESI 680.4 [M+H) as a yellow oil). + ).

[0370] Step 4: 2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid TFA (3 mL, 39 mmol, 122.0 equivalents) was added to a solution of 2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (220 mg, 0.32 mmol, 1.0 equivalent) in DCM (1 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give a mixture of stereoisomers of compound 301 as a white solid (160 mg, 80%). The isomers were further separated by preparative chiral SFCA to give 301-P1 (65 mg) and 301-P2 (82 mg) as white solids.

[0371] 301-P1, specified as (R)-2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 634.2 [M+H]+ . 1H NMR (400 MHz, CD3OD) δ 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).

[0372] 301-P2, specified as (S)-2-(((S)-3-(3-chlorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 634.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 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).

[0373] Example 14: Preparation of compound 302-P2 Step 1: (S)-(3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)propyl)(methyl)carbamate tert-butyl ester To a solution of (R)-3-((tert-butyloxycarbonyl)(methyl)amino)-1-(3-chlorophenyl)propyl methanesulfonic acid (3.5 g, 9.26 mmol, 1.0 equivalent) in ACN (30 mL), K₂CO₃ (3.83 g, 27.78 mmol, 3.3 equivalent) and N,N-dimethylpiperidin-4-amine (1.19 g, 9.26 mmol, 1.0 equivalent) were added. The reaction mixture was stirred at 80 °C for 16 h, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (15:1 DCM:MeOH) to give (S)-(3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)propyl)(methyl)carbamate tert-butyl ester (490.0 mg, 12.9%) as a yellow oil (ESI 410.3 [M+H)). + ).

[0374] Step 2: (S)-1-(1-(3-chlorophenyl)-3-(methylamino)propyl)-N,N-dimethylpiperidin-4-amine TFA (1 mL, 13.5 mmol, 11.3 equivalents) was added to a solution of (S)-(3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)propyl)(methyl)carbamate tert-butyl ester (490 mg, 1.2 mmol, 1.0 equivalent) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum to give (S)-1-(1-(3-chlorophenyl)-3-(methylamino)propyl)-N,N-dimethylpiperidin-4-amine (420 mg, 1.35 mmol, crude) as a yellow oil (ESI 310.3 [M+H]). + The crude product is used directly in subsequent steps.

[0375] Step 3: 2-(((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)tert-butyl acetate To a solution of (S)-1-(1-(3-chlorophenyl)-3-(methylamino)propyl)-N,N-dimethylpiperidin-4-amine (210 mg, 0.67 mmol, crude) in 10 mL of ACN, K₂CO₃ (427 mg, 3.1 mmol, 5.0 equivalent) was added. The mixture was stirred at room temperature for 15 minutes. Then, tert-butyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (302 mg, 0.67 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 2 hours. 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 obtain 2-(((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)tert-butyl acetate (220 mg, 39.5%) as a yellow oil (ESI 680.3 [M+H)). + ).

[0376] Step 4: 2-(((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid TFA (3 mL, 39 mmol, 150.0 equivalents) was added to a mixture of ethyl 2-(((1s,3R)-3-(3-chlorophenyl)-3-(2-(piperidin-1-yl)ethyl)cyclobutyl)(methyl)amino)-2-(4-fluoro-1-((1r,4R)-4-methoxycyclohexyl)-3-methyl-1H-indazole-7-yl)acetate (180.0 mg, 0.26 mmol, 1.0 equivalent) in DCM (1 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give a mixture of stereoisomers 302 (110.0 mg, 62%) as a white solid. The stereoisomers were further separated by preparative chiral HPLC A to obtain 302-P1 (30.3 mg) and 302-P2 (25.2 mg) as white solids.

[0377] 302-P1, designated as (R)-2-(((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H]+. 1 H NMR (400 MHz, CD3OD) δ 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).

[0378] 302-P2, designated as (S)-2-(((S)-3-(3-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 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).

[0379] Example 15: Preparation of compound 303-1P2 Step 1: 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione K3PO4 (6.0 g, 28.5 mmol, 0.2 equivalent) was added to a solution of 3-chlorobenzaldehyde (20.0 g, 142.3 mmol, 1.0 equivalent) in EtOH (500 mL). The reaction mixture was stirred overnight at room temperature, followed by concentration under vacuum. The crude residue was purified by silica gel column chromatography (3:1 petroleum ether: EtOAc) to give 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (15.0 g, 39.6%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H),8.04 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 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-(1-(3-chlorophenyl)-4-(piperidin-1-yl)but-2-yn-1-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione Ethyl magnesium bromide (1 M in THF, 40.6 mL, 1.2 equivalence) was added dropwise to a solution of 1-(prop-2-yn-1-yl)piperidine (5.0 g, 40.6 mmol, 1.2 equivalence) in anhydrous THF (100 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The resulting solution was slowly added at 0 °C to a solution of 5-(3-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (9.0 g, 33.8 mmol, 1.0 equivalence). The reaction mixture was stirred at 0 °C for another 1 h. The reaction mixture was quenched by adding 200 mL of saturated NH4Cl aqueous solution. The resulting solid was filtered, collected, and washed with EtOAc (100 mL) to give 5-(1-(3-chlorophenyl)-4-(piperidin-1-yl)but-2-yn-1-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7.1 g, 53.9%) as a yellow solid (ESI 390.1 [M+H)). + ).

[0380] Step 3: 3-(3-chlorophenyl)-6-(piperidin-1-yl)hex-4-ynyleneic acid To a solution of 5-(1-(3-chlorophenyl)-4-(piperidin-1-yl)but-2-yn-1-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (7.1 g, 18.2 mmol, 1.0 equivalent) in dioxane (75 mL), 25 mL of 36% HCl aqueous solution (300 mmol, 16.5 equivalent) was added. The reaction mixture was stirred at 100 °C for 16 hours and concentrated under vacuum to give 3-(3-chlorophenyl)-6-(piperidin-1-yl)hex-4-ynetic acid (4.0 g, 13.1 mmol, crude product) as a yellow oil (ESI 306.1 [M+H]). + The crude product is used directly in subsequent steps.

[0381] Step 4: Methyl 3-(3-chlorophenyl)-6-(piperidin-1-yl)hex-4-acetylic acid H₂SO₄ (0.5 mL, 9 mmol, 0.69 equivalent) was added dropwise to a solution of 3-(3-chlorophenyl)-6-(piperidin-1-yl)hex-4-ethynic acid (6 g, 13.1 mmol, 1.0 equivalent) in methanol (80 mL) at 0 °C. The mixture was stirred at 65 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (200 mL). The organic solution was washed with saturated aqueous NaHCO₃ solution (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 methyl 3-(3-chlorophenyl)-6-(piperidin-1-yl)hex-4-ethynic acid (3.2 g, 76.3%) as a yellow oil (ESI 320.1 [M+H)). + ).

[0382] Step 5: Methyl 3-(3-chlorophenyl)-6-(piperidin-1-yl)hexanoate PtO2 (100 mg, 0.44 mmol, 0.05 equivalent) was added to a solution of methyl 3-(3-chlorophenyl)-6-(piperidin-1-yl)hexyl-4-acetylginate (2.8 g, 8.75 mmol, 1.0 equivalent) in methanol (32 mL). The reaction mixture was stirred at room temperature under a H2 atmosphere (1 atm) for 2 hours. The reaction mixture was filtered through a diatomaceous earth pad and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (25:1 DCM:MeOH) to give methyl 3-(3-chlorophenyl)-6-(piperidin-1-yl)hexanoate (1.5 g, 52.9%) as a yellow oil (ESI 320.1 [M+H)). + ).

[0383] Step 6: 3-(3-chlorophenyl)-N-methyl-6-(piperidin-1-yl)hexamethyleneamide Methylamine (4 M in THF, 20 mL, 80 mmol, 17.4 equivalents) was added to a solution of methyl 3-(3-chlorophenyl)-6-(piperidin-1-yl)hexanoate (1.5 g, 4.6 mmol, 1.0 equivalents) in MeOH (10 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (10:1 DCM:MeOH) to give the racemic product 3-(3-chlorophenyl)-N-methyl-6-(piperidin-1-yl)hexamide (1.1 g, 74.0%) (ESI 323.2 [M+H)). + The enantiomers were separated by preparative chiral SFC J to give two compounds. Peak 1 (400 mg) was designated as (S)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-1-yl)hexamamide, and peak 2 (300 mg) was designated as (R)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-1-yl)hexamamide.

[0384] Step 7: (S)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-1-yl)hex-1-amine LAH (2.5 M in THF, 1.5 mL, 3.72 mmol, 3.0 equivalent) was added dropwise to a solution of (S)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-1-yl)hexamethyleneamide (from peak 1 of step 6, 400 mg, 1.24 mmol, 1.0 equivalent) in 8 mL of THF at room temperature, and the reaction mixture was stirred at 65 °C for 1 hour. After cooling to 0 °C, the reaction mixture was carefully quenched with water (0.15 mL) and stirred at 0 °C for another 10 minutes. Then, 15% NaOH aqueous solution (0.15 mL) and water (0.45 mL) were added sequentially at 0 °C. The mixture was warmed to room temperature and stirred for another 15 minutes. The mixture was dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain (S)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-1-yl)hex-1-amine as a colorless oil, which was used directly in the next reaction (300 mg, crude product, 78.2%) (ESI 309.2 [M+H)). + ).

[0385] Step 8: 2-(((S)-3-(3-chlorophenyl)-6-(piperidin-1-yl)hexyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate To a solution of (S)-3-(3-chlorophenyl)-N-methyl-6-(piperidin-1-yl)hexyl-1-amine (150 mg, 0.49 mmol, crude) in ACN (5 mL), K₂CO₃ (338 mg, 2.45 mmol, 5.0 equivalent) and ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (207 mg, 0.49 mmol, 1.0 equivalent) were added. The reaction mixture was stirred at 80 °C for 2 hours. 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 obtain ethyl acetate 2-(((S)-3-(3-chlorophenyl)-6-(piperidin-1-yl)hexyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl) as a yellow oil (170 mg, 53.3%) (ESI 651.3 [M+H). + ).

[0386] Step 9: 2-(((S)-3-(3-chlorophenyl)-6-(piperidin-1-yl)hexyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid To a mixture of ethyl 2-(((S)-3-(3-chlorophenyl)-6-(piperidin-1-yl)hexyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (170 mg, 0.26 mmol, 1.0 equivalent) in EtOH (4 mL) and H2O (1 mL), NaOH (52 mg, 1.3 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 16 hours and concentrated under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give a mixture of stereoisomers 303 as a white solid (110 mg, 67.6%). The stereoisomers were further separated by preparative chiral SFC A to give 303-1P1 (40 mg) and 303-1P2 (40 mg).

[0387] 303-1P1, specified as (R)-2-(((S)-3-(3-chlorophenyl)-6-(piperidin-1-yl)hexyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 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).

[0388] 303-1P2, designated as (S)-2-(((S)-3-(3-chlorophenyl)-6-(piperidin-1-yl)hexyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H] + .1 H NMR (400 MHz, CD3OD) δ 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).

[0389] Example 16: Preparation of compound 304-P2 Step 1: 5-Fluoro-2-iodo-1-methyl-3-nitrobenzene At -10°C for 15 minutes, an aqueous solution of HCl (6 M, 53 mL, 319 mmol, 2.5 equivalents) and an aqueous solution of NaNO₂ (9.7 g in 30 mL of water, 140.36 mmol, 1.1 equivalents) were added to the mixture. The reaction mixture was stirred at -10°C for another 30 minutes. Then, an aqueous solution of KI (31.8 g in 30 mL of water, 191.4 mmol, 1.5 equivalents) was added in portions to the mixture. The reaction mixture was heated to 0°C and stirred for 30 minutes. Water (300 mL) and EtOAc (300 mL) were added to the reaction mixture. The organic solution was separated and washed with saturated Na₂SO₃ aqueous solution (300 mL) and brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (15:1 petroleum ether: EtOAc) to give 5-fluoro-2-iodo-1-methyl-3-nitrobenzene (10.2 g, 28.4%) as a white solid (ESI 282.0 [M+H)). + ).

[0390] Step 2: 8-(4-fluoro-2-methyl-6-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene 5-Fluoro-2-iodo-1-methyl-3-nitrobenzene (10.2 g, 36.30 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaboranecyclopentane (10.1 g, 38.11 mmol, 1.05 equivalent), K₂CO₃ (8.5 g, 61.71 mmol, 1.7 equivalent), and Pd(dppf)Cl₂ (530 mg, 0.73 mmol, 0.02 equivalent) were suspended in a mixture of dioxane (100 mL) and water (50 mL). The reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was poured into 150 mL of water and extracted with EtOAc (3 × 150 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (6:1 petroleum ether: EtOAc) to give 8-(4-fluoro-2-methyl-6-nitrophenyl)-1,4-dioxane[4.5]dec-7-ene (8.3 g, 78.0%) as a yellow solid (ESI 294.3 [M+H)). + ).

[0391] Step 3: 5-Fluoro-3-methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)aniline 10% Pd / C (1.9 g, 0.85 mmol, 0.03 equivalent) was added to a solution of 8-(4-fluoro-2-methyl-6-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (8.3 g, 28.32 mmol, 1.0 equivalent) in EtOH (100 mL). The reaction mixture was stirred at 65 °C under a H2 atmosphere (1 atm, 3 L) for 24 hours. The reaction mixture was filtered through a diatomaceous earth mat and concentrated under vacuum to give 5-fluoro-3-methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)aniline (5.3 g, 19.9 mmol, crude) as a yellow oil (ESI 266.3 [M+H)). + The crude product was used directly in subsequent steps without further purification.

[0392] Step 4: 4-(2-amino-4-fluoro-6-methylphenyl)cyclohexane-1-one To a solution of 5-fluoro-3-methyl-2-(1,4-dioxaspiro[4.5]dec-8-yl)aniline (4.6 g, 17.35 mmol, 1.0 equivalent) in THF (100 mL), 3 M HCl aqueous solution (17 mL, 52.05 mmol, 3.0 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C, quenched by adding saturated NaHCO3 aqueous solution (pH adjusted to approximately 8), and extracted with EtOAc (100 mL). The organic solution was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give 4-(2-amino-4-fluoro-6-methylphenyl)cyclohexane-1-one (3.7 g, 16.74 mmol, crude) as a yellow oil (ESI 222.1 [M+H)). + The crude product is used directly in the next step.

[0393] Step 5: 4-(4-fluoro-2-iodo-6-methylphenyl)cyclohexane-1-one At -10°C, an aqueous solution of HCl (6 M, 7 mL, 41.8 mmol, 2.5 equivalence) was added dropwise to a solution of 4-(2-amino-4-fluoro-6-methylphenyl)cyclohexane-1-one (3.7 g, 16.74 mmol, 1.0 equivalence) in THF (20 mL) over 15 minutes. This was followed by the addition of an aqueous solution of NaNO₂ (1.3 g in 3 mL of water, 18.41 mmol, 1.1 equivalence). The reaction mixture was then stirred at -10°C for another 30 minutes. Next, an aqueous solution of KI (4.1 g in 3 mL of water, 25.11 mmol, 1.5 equivalence) was added in portions to the mixture. The reaction mixture was heated to 0°C and stirred for another 30 minutes. Water (100 mL) and EtOAc (100 mL) were then added to the reaction mixture. The organic solution was separated, washed with saturated Na₂SO₃ aqueous solution (100 mL) and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (15:1 petroleum ether: EtOAc) to give 4-(4-fluoro-2-iodo-6-methylphenyl)cyclohexane-1-one (2.5 g, 44.9%) as a white solid (ESI 333.0 [M+H)). + ).

[0394] Step 6: (1r,4r)-4-(4-fluoro-2-iodo-6-methylphenyl)cyclohexyl-1-ol CeCl3 (2.2 g, 9.03 mmol, 1.2 equivalent) was added in portions to a solution of 4-(4-fluoro-2-iodo-6-methylphenyl)cyclohexane-1-one (2.5 g, 7.53 mmol, 1.0 equivalent) in THF (25 mL) and MeOH (4 mL) at 0 °C, followed by the addition of NaBH4 (343 mg, 9.03 mmol, 1.2 equivalent). The mixture was stirred at 0 °C for 0.5 h. H2O (50 mL) was slowly added at 0 °C, and the mixture was extracted with EtOAc (3 × 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (4:1 petroleum ether: EtOAc) to give the specified (1r,4r)-4-(4-fluoro-2-iodo-6-methylphenyl)cyclohexyl-1-ol (1.2 g, 47.7%) as a white solid (ESI 317.0 [M-OH]). + ).

[0395] Step 7: 5-Fluoro-1-iodo-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)benzene A mixture of the specified (1r,4r)-4-(4-fluoro-2-iodo-6-methylphenyl)cyclohexyl-1-ol (1.2 g, 3.6 mmol, 1.0 equivalent), Selectfluor (1.91 g, 5.4 mmol, 1.5 equivalent), KF (838 mg, 14.4 mmol, 4 equivalent), and AgOTf (2.76 g, 10.8 mmol, 3.0 equivalent) in EtOAc (20 mL) was stirred for 5 minutes at room temperature under a nitrogen atmosphere. Then, 2-fluoropyridine (1050 mg, 10.8 mmol, 3 equivalent) and TMSCF3 (1.5 g, 10.8 mmol, 3 equivalent) were added. The reaction mixture was stirred at room temperature for 48 hours. 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 the specified 5-fluoro-1-iodo-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)benzene (680 mg, 46%) as a white solid (ESI 403.0 [M+H)). + ).

[0396] Step 8: Ethyl 2-(5-fluoro-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate Under a nitrogen atmosphere, a solution of 5-fluoro-1-iodo-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)benzene (680 mg, 1.68 mmol, 1.0 equivalent), Pd2(dba)3 (76 mg, 0.062 mmol, 0.05 equivalent), and Qphos (60 mg, 0.084 mmol, 0.05 equivalent) in THF (20 mL) was added to the mixture, and the mixture was stirred at 80 °C for 1 hour. A saturated aqueous solution of NH4Cl (20 mL) was added, and the solution was extracted with EtOAc (20 mL × 3). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (20:1 petroleum ether: EtOAc) to give ethyl 2-(5-fluoro-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (550 mg, 90%) as a yellow oil (ESI 363.2 [M+H)). + ).

[0397] Step 9: 2-Bromo-2-(5-fluoro-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)ethyl acetate A solution of ethyl 2-(5-fluoro-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (550 mg, 1.52 mmol, 1.0 equivalent) in 10 mL of THF was added dropwise to a solution of LiHMDS (1 M in THF, 3.5 mL). The reaction mixture was stirred at -78 °C for 0.5 h. Then, TMSCl (380 mg, 3.50 mmol, 2.3 equivalent) was added dropwise, and the mixture was stirred at -78 °C for another 15 min. Next, a solution of NBS (270 mg, 1.52 mmol, 2.3 equivalent) in 5 mL of THF was added dropwise. The reaction mixture was stirred at -78°C for another hour, then heated to 0°C and quenched by adding saturated NH4Cl aqueous solution (20 mL), followed by extraction with EtOAc (3 × 20 mL). The organic solutions were combined, washed with brine (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. 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-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (300 mg, 44%) as a colorless oil (ESI 442.2 [M+H)). + ).

[0398] Step 10: 4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (10 g, 41.1 mmol, 1.0 equivalent), N,O-dimethylhydroxylamine hydrochloride (4.4 g, 45.2 mmol, 1.1 equivalent), HOBt (5.5 g, 41.1 mmol, 1.0 equivalent), and TEA (5.3 g, 90.42 mmol, 2.2 equivalent) in DCM (100 mL), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (8.7 g, 45.2 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at 50 °C for 1 hour, then diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (95:5 DCM:MeOH) to obtain tert-butyl 4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-1-carboxylate (9.1 g, 77.4%) as a yellow solid (ESI 187.4 [M-Boc+H)). + ).

[0399] Step 11: 4-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of 1-bromo-3-(trifluoromethyl)benzene (8.6 g, 38.2 mmol, 1.2 equivalents) in anhydrous THF (100 mL), n-BuLi (2.5 M in hexane, 15.2 mL, 38.2 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at -78 °C for 30 min. Then, a solution of 4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (9.1 g, 31.8 mmol, 1.0 equivalents) in THF (50 mL) was added. The reaction mixture was stirred at -78 °C for another 1 h. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (2 × 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (12:1 petroleum ether: EtOAc) to obtain tert-butyl 4-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)piperidine-1-carboxylate (5.1 g, 43.2%) as a yellow solid (ESI 272.4 [M-Boc+H)). + ).

[0400] Step 12: (E)-4-(4-ethoxy-4-oxo-2-(3-(trifluoromethyl)phenyl)but-2-en-1-yl)piperidin-1-carboxylic acid tert-butyl ester t-BuOK (1.8 g, 16.4 mmol, 1.2 equivalents) was added to a solution of methyl 2-(dimethoxyphosphoryl)acetate (3.05 g, 16.4 mmol, 1.2 equivalents) in anhydrous THF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, a solution of tert-butyl 4-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)piperidine-1-carboxylate (5.1 g, 13.7 mmol, 1.0 equivalents) in THF (10 mL) was added. The reaction mixture was stirred at 0 °C for another 12 h, quenched by adding saturated NH4Cl aqueous solution (20 mL), and extracted with EtOAc (3 × 20 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (20:1 petroleum ether: EtOAc) to obtain tert-butyl (E)-4-(4-ethoxy-4-oxo-2-(3-(trifluoromethyl)phenyl)but-2-en-1-yl)piperidin-1-carboxylic acid (3.5 g, 58%) as a yellow oil (ESI 442.1 [M+H)). + ).

[0401] Step 13: 4-(4-ethoxy-4-oxo-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of (E)-4-(4-ethoxy-4-oxo-2-(3-(trifluoromethyl)phenyl)but-2-en-1-yl)piperidin-1-carboxylic acid tert-butyl ester (3.5 g, 7.9 mmol, 1.0 equivalent) in EtOH (25 mL), 10% Pd / C (500 mg, 0.24 mmol, 0.03 equivalent) was added. The reaction mixture was stirred at 65 °C under a H2 atmosphere (1 atm, 3 L) for 24 hours. The reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum to give 4-(4-ethoxy-4-oxo-2-(3-(trifluoromethyl)phenyl)butyryl)piperidin-1-carboxylic acid tert-butyl ester (3.3 g, 7.4 mmol, crude) as a yellow oil (ESI 444.3 [M+H]). + The crude product was used directly in subsequent steps without further purification.

[0402] Step 14: 4-(4-hydroxy-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylic acid tert-butyl ester LAH (1 M in THF, 18.5 mL, 18.5 mmol, 2.5 equivalents) was added 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 equivalent) in 20 mL of THF at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and quenched by adding water (0.1 mL). The reaction mixture was stirred at 0 °C for another 10 minutes. Then, 15% NaOH aqueous solution (0.1 mL) and water (0.2 mL) were added sequentially at 0 °C. The reaction mixture was heated to room temperature and stirred for another 15 minutes. The mixture was dried over Na2SO4, filtered, and concentrated under vacuum to obtain tert-butyl 4-(4-hydroxy-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylate (3.1 g, 7.7 mmol, crude product) as crude colorless oil (ESI 402.0 [M+H)). + The crude product was used directly in subsequent steps without further purification.

[0403] Step 15: 4-(4-(1,3-dioxoisoindoline-2-yl)-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylic acid tert-butyl ester Triphenylphosphine (2.6 g, 10.01 mmol, 1.3 equivalent) and diisopropyl azodicarbonate (2.0 g, 10.01 mmol, 1.3 equivalent) were added to a solution of tert-butyl piperidine-1-carboxylate (3.1 g, 7.7 mmol, 1.0 equivalent) and isoindoline-1,3-dione (1.5 g, 10.01 mmol, 1.3 equivalent) in toluene (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to obtain tert-butyl 4-(4-(1,3-dioxoisoindoline-2-yl)-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylate (2.9 g, 71%) as a yellow oil (ESI 531.9 [M+H)). + ).

[0404] Step 16: 4-(4-amino-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 4-(4-(1,3-dioxoisoindoline-2-yl)-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylate (2.9 g, 5.47 mmol, 1.0 equivalent) and 98% N2H4·H2O (547 mg, 10.94 mmol, 2 equivalent) in EtOH (10 mL) was stirred at 70 °C for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give tert-butyl 4-(4-amino-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylate (2 g, 91%) as a yellow oil (ESI 401.0 [M+H)). + ).

[0405] Step 17: 4-(4-((tert-Butoxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylic acid tert-butyl ester To a solution of tert-butyl 4-(4-amino-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylate (2 g, 5.0 mmol, 1.0 equivalent) and TEA (1.5 g, 15.0 mmol, 3.0 equivalent) in DCM (30 mL), ditert-butyl dicarbonate (1.6 g, 7.5 mmol, 1.5 equivalent) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The crude residue was purified by silica gel column chromatography (4:1 petroleum ether: EtOAc) to give tert-butyl 4-(4-((tert-butyloxycarbonyl)amino)-2-(3-(trifluoromethyl)phenyl)butyl)piperidine-1-carboxylate (2.1 g, 84%) as a white solid (ESI 523.1 [M+Na]). + ).

[0406] Step 18: N-Methyl-4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)but-1-amine LAH (3 M in THF, 4.2 mL, 12.6 mmol, 3.0 equivalent) was added to a solution of tert-butyl piperidine-1-carboxylate (2.1 g, 4.2 mmol, 1.0 equivalent) in 30 mL of THF at room temperature, and the reaction mixture was stirred at 70 °C for 1 hour. After cooling to 0 °C, the reaction mixture was carefully quenched by adding water (0.5 mL) and stirred again at 0 °C for 10 minutes. Then, 15% NaOH aqueous solution (0.5 mL) and water (1.5 mL) were added sequentially at 0 °C. The mixture was warmed to room temperature and stirred for another 15 minutes. The mixture was dried over Na₂SO₄, filtered, and concentrated under vacuum to give N-methyl-4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)but-1-amine as a white solid. The crude solid was used directly in the next reaction (1 g, 72%) (ESI 329.3 [M+H)). + ).

[0407] Step 19: 2-(5-fluoro-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl(4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)ethyl acetate K₂CO₃ (1 g, 7.6 mmol, 5.0 equivalent) was added to a solution of N-methyl-4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)but-1-amine (500 mg, 1.52 mmol, crude) in 10 mL of ACN. The mixture was stirred at room temperature for 15 minutes. Then, ethyl 2-bromo-2-(5-fluoro-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)acetate (668 mg, 1.52 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 2 hours. 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 obtain ethyl acetate 2-(5-fluoro-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl(4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino) as a yellow oil (550 mg, 52%) (ESI 689.3 [M+H)). + ).

[0408] Step 20: 2-(5-fluoro-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl(4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)acetic acid To a solution of ethyl 2-(5-fluoro-3-methyl-2-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl(4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)ethyl acetate (550 mg, 0.80 mmol, 1.0 equivalent) in EtOH (5 mL) and H₂O (1 mL), NaOH (160 mg, 4.0 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 1 hour and concentrated under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH₃CN) to give a stereoisomer mixture of compound 304 as a white solid (480 mg, 90%). The stereoisomers were further separated by preparative chiral SFC A to obtain 304-P1A (94.4 mg), 304-P1B (78.2 mg), 304-P2 (85.5 mg) and 304-P3 (120.5 mg).

[0409] 304-P1A, designated as (R)-2-(5-fluoro-3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl((R)-4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)acetic acid. LC / MS ESI 661.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 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).

[0410] 304-P1B, designated as (R)-2-(5-fluoro-3-methyl-2-((1r,4R)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl((S)-4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)acetic acid. LC / MS ESI 661.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 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).

[0411] 304-P2, designated as (S)-2-(5-fluoro-3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl((S)-4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)acetic acid. LC / MS ESI 661.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 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).

[0412] 304-P3, designated as (S)-2-(5-fluoro-3-methyl-2-((1r,4S)-4-(trifluoromethoxy)cyclohexyl)phenyl)-2-(methyl((R)-4-(1-methylpiperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)butyl)amino)acetic acid. LC / MS ESI 661.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 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).

[0413] Example 17: Preparation of compound 305-2P1 Step 1: (S)-2-(2-(methoxy(methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester EDCI (10.0 g, 52.4 mmol, 1.2 equivalence) was added to a solution of (S)-2-(1-(tert-butoxycarbonyl)pyrrolidine-2-yl)acetic acid (10 g, 43.6 mmol, 1.0 equivalence), N,O-dimethylhydroxylamine hydrochloride (5.0 g, 52.4 mmol, 1.2 equivalence), HOBt (7.1 g, 52.4 mmol, 1.2 equivalence), and DIEA (8.0 g, 87.2 mmol, 2.0 equivalence) in DCM (100 mL). The reaction mixture was stirred at room temperature for 16 hours, then diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (20:1 dichloromethane:methanol) to give (S)-2-(2-(methoxy(methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (10.0 g, 85.1%) as a yellow solid (ESI 273.3 [M+H)). + ).

[0414] Step 2: (S)-2-(2-(3-chloro-5-fluorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester Magnesium (792.0 mg, 33.0 mmol, 1.5 equivalents) and 1,2-dibromoethane (810 mg, 4.4 mmol, 0.2 equivalents) were added to a solution of 1-bromo-3-chloro-5-fluorobenzene (6.0 g, 28.6 mmol, 1.3 equivalents) in THF (20 mL). The mixture was stirred at 60 °C for 1 hour. After cooling to room temperature, the mixture was added dropwise at 0 °C to a solution of (S)-2-(2-(methoxy(methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (6.0 g, 22.0 mmol, 1.0 equivalents) in THF (60 mL). The reaction mixture was then heated to room temperature and stirred for 1 hour. The mixture was diluted with saturated NH4Cl (200 mL) and extracted with DCM (2 × 200 mL). The organic solutions were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (95:5 DCM:MeOH) to obtain (S)-2-(2-(3-chloro-5-fluorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.3 g, 57.2 mmol, 84.6%) as a colorless oil (ESI 364.1 [M+Na)). + ).

[0415] Step 3: (S)-1-(3-chloro-5-fluorophenyl)-2-(1-methylpyrrolidone-2-yl)ethyl-1-one TFA (5 mL, 65.0 mmol, 5.1 equivalence) was added to a solution of (S)-2-(2-(3-chloro-5-fluorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.3 g, 12.6 mmol, 1.0 equivalence) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in MeOH (140 mL) and a 33% aqueous solution of HCHO (6.0 g, 63 mmol, 5.0 equivalence) was added to the solution. The mixture was stirred at room temperature for 1 hour. Then NaBH(OAc)3 (5.3 g, 25.2 mmol, 2.0 equivalence) was added, and the reaction mixture was stirred at room temperature for another 3 hours. The reaction mixture was poured into water (300 mL) and extracted with DCM (3 × 200 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (95:5 DCM:MeOH) to obtain (S)-1-(3-chloro-5-fluorophenyl)-2-(1-methylpyrrolidone-2-yl)ethyl-1-one (2.9 g, 83%) as a colorless oil (ESI 256.2 [M+H)). + ).

[0416] Step 4: Ethyl (S,Z)-3-(3-chloro-5-fluorophenyl)-4-(1-methylpyrrolidone-2-yl)but-2-enoate t-BuOK (3.1 g, 27.4 mmol, 2.5 equivalents) was added to a solution of ethyl 2-(diethoxyphosphoryl)acetate (6.1 g, 27.4 mmol, 2.5 equivalents) in anhydrous THF (120 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Then, a solution of (S)-1-(3-chloro-5-fluorophenyl)-2-(1-methylpyrrolidone-2-yl)ethyl-1-one (3.0 g, 11.7 mmol, 1.0 equivalent) in THF (20 mL) was added. The reaction mixture was stirred for another 12 hours. The reaction mixture was then quenched by adding saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (3 × 100 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (20:1 DCM:MeOH) to obtain ethyl (S,Z)-3-(3-chloro-5-fluorophenyl)-4-(1-methylpyrrolidone-2-yl)but-2-enoate (2.2 g, 50.1%) as a yellow oil (ESI 326.1 [M+H)). + ).

[0417] Step 5: Ethyl 3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidone-2-yl)butyrate PtO2 (227 mg, 1.0 mmol, 0.15 equivalent) was added to a solution of ethyl (S,Z)-3-(3-chloro-5-fluorophenyl)-4-(1-methylpyrrolidin-2-yl)but-2-enoate (2.2 g, 6.8 mmol, 1.0 equivalent) in MeOH (35 mL) at room temperature. The reaction mixture was stirred for 2 hours at room temperature under a H2 atmosphere (1 atm, 3 L). The contents were then filtered through a diatomaceous earth mat and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (25:1 DCM:MeOH) to give ethyl 3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidin-2-yl)butyrate (1.3 g, 51.3%) as a light brown solid (ESI 328.2 [M+H)). + ).

[0418] Step 6: 3-(3-chloro-5-fluorophenyl)-1-(methylamino)-4-((S)-1-methylpyrrolidone-2-yl)but-1-one A solution of ethyl 3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidin-2-yl)butyrate (1.3 g, 4.0 mmol, 1.0 equivalent) in methylamine (1 M in MeOH, 15 mL, 15.0 mmol, 3.7 equivalent) was stirred at 55 °C for 2 hours. The mixture was then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (25:1 DCM:MeOH) to give 3-(3-chloro-5-fluorophenyl)-1-(methylamino)-4-((S)-1-methylpyrrolidin-2-yl)but-1-one (1.0 g, 81.2%) (ESI 312.2 [M+H)) as a colorless oil. + ).

[0419] Step 7: 3-(3-chloro-5-fluorophenyl)-N-methyl-4-((S)-1-methylpyrrolidone-2-yl)but-1-amine LAH (3.5 M in THF, 1.5 mL, 3.8 mmol, 1.5 equivalent) was added to a solution of 3-(3-chloro-5-fluorophenyl)-1-(methylamino)-4-((S)-1-methylpyrrolidone-2-yl)but-1-one (800 mg, 2.6 mmol, 1.0 equivalent) in 20 mL of THF at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After cooling to 0 °C, the reaction mixture was carefully quenched by adding water (0.2 mL) and stirred again at 0 °C for 10 minutes. Then, 15% NaOH aqueous solution (0.2 mL) and water (0.6 mL) were added sequentially at 0 °C. The mixture was then heated to room temperature and stirred for another 15 minutes. After drying with Na₂SO₄, it was filtered and concentrated under vacuum to obtain 3-(3-chloro-5-fluorophenyl)-N-methyl-4-((S)-1-methylpyrrolidone-2-yl)but-1-amine (400 mg, 52.6%) as a white solid (ESI 299.1 [M+H)). + The crude solids are used directly in the next step.

[0420] Step 8: 2-(2-((1r,4S)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-((3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidine-2-yl)butyl)(methyl)amino)ethyl acetate To a solution of 3-(3-chloro-5-fluorophenyl)-N-methyl-4-((S)-1-methylpyrrolidin-2-yl)but-1-amine (200 mg, 0.67 mmol, crude) in ACN (8 mL), K₂CO₃ (277 mg, 2.0 mmol, 3.0 equivalent) was added. The mixture was stirred at room temperature for 15 minutes. Then, ethyl 2-bromo-2-(2-((1r,4r)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)acetate (275 mg, 0.67 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 2 hours. 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 acetate 2-(2-((1r,4S)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-((3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidine-2-yl)butyl)(methyl)amino) as a yellow oil (240 mg, 56.7%) (ESI 629.3 [M+H)). + ).

[0421] Step 9: 2-(2-((1r,4S)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-((3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidone-2-yl)butyl)(methyl)amino)acetic acid LiOH·H2O (80 mg, 1.91 mmol, 5.0 equivalent) was added to a solution of ethyl 2-(2-((1r,4S)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-((3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidine-2-yl)butyl)(methyl)amino)ethyl acetate (240 mg, 0.38 mmol, 1.0 equivalent) in EtOH (3 mL) and H2O (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction was adjusted to approximately 6 to 7 with 2N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give 305-1 (85 mg, 37%) and 305-2 (90 mg, 39%) as white solids. 305-1 was further separated by preparative chiral HPLC A to obtain 305-1P1 (21 mg) and 305-1P2 (15 mg). 305-2 was further separated by preparative chiral HPLC A to obtain 305-2P1 (28 mg) and 305-2P2 (12 mg).

[0422] 305-1P1, specified as (S)-2-(2-((1r,4S)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-(((S)-3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidone-2-yl)butyl)(methyl)amino)acetic acid. LC / MS ESI 601.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 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).

[0423] 305-1P2, specified as (R)-2-(2-((1r,4R)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-(((S)-3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidone-2-yl)butyl)(methyl)amino)acetic acid. LC / MS ESI 601.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 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).

[0424] 305-2P1, specified as (S)-2-(2-((1r,4S)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-(((R)-3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidone-2-yl)butyl)(methyl)amino)acetic acid. LC / MS ESI 601.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 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).

[0425] 305-2P2, designated as (R)-2-(2-((1r,4R)-4-(tert-butoxy)cyclohexyl)-3-methylphenyl)-2-(((R)-3-(3-chloro-5-fluorophenyl)-4-((S)-1-methylpyrrolidone-2-yl)butyl)(methyl)amino)acetic acid. LC / MS ESI 601.3 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 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).

[0426] Example 18: Preparation of compound 80-P2 Step 1: 1-Iodo-3-methyl-2-((1r,4r)-4-((3,3,3-trifluoroprop-1-en-2-yl)oxy)cyclohexyl)benzene Sodium hydride (506 mg, 12.7 mmol, 4.0 equivalent, 60% in mineral oil) was added to a solution of (1r,4r)-4-(2-iodo-6-methylphenyl)cyclohexyl-1-ol (1 g, 3.2 mmol, 1.0 equivalent) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then, 2,3,3,3-tetrafluoroprop-1-ene (1 atm, 2 L) was added and the reaction mixture was heated to room temperature. The reaction mixture was stirred for another 5 h. The reaction mixture was then quenched by adding cold saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (3 × 60 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to give 1-iodo-3-methyl-2-((1r,4r)-4-((3,3,3-trifluoroprop-1-en-2-yl)oxy)cyclohexyl)benzene (500 mg, 38.5%) as a white solid.

[0427] Step 2: 2-(3-methyl-2-((1r,4r)-4-((3,3,3-trifluoroprop-1-en-2-yl)oxy)cyclohexyl)phenyl)ethyl acetate Pd2dba3 (45.0 mg, 0.07 mmol, 0.03 equivalent) and QPhos (34 mg, 0.07 mmol, 0.03 equivalent) were added to a suspension of 1-iodo-3-methyl-2-((1r,4r)-4-((3,3,3-trifluoroprop-1-en-2-yl)oxy)cyclohexyl)benzene (1.0 g, 2.4 mmol, 1.0 equivalent) in THF (15 mL). Then, zinc(II) bromide (2-ethoxy-2-oxoethyl)zinc(II) (1 M in THF, 7.2 mL, 7.2 mmol, 3.0 equivalent) was added, and the mixture was stirred at 50 °C under a nitrogen atmosphere for 0.5 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The organic solutions were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (95:5 petroleum ether: EtOAc) to obtain ethyl 2-(3-methyl-2-((1r,4r)-4-((3,3,3-trifluoroprop-1-en-2-yl)oxy)cyclohexyl)phenyl)ethyl acetate (0.78 g, 92%) (ESI 393.3 [M+Na)) as a brown oil. + ).

[0428] Step 3: Ethyl 2-(3-methyl-2-((1r,4r)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)ethyl acetate To a solution of ethyl 2-(3-methyl-2-((1r,4r)-4-((3,3,3-trifluoroprop-1-en-2-yl)oxy)cyclohexyl)phenyl)ethyl acetate (0.78 g, 2.11 mmol, 1.0 equivalent) in MeOH (10 mL), 10% Pd / C (260 mg, 0.11 mmol, 0.05 equivalent) was added. The reaction mixture was stirred at room temperature under a H2 atmosphere (1 atm, 3 L) for 3 hours. The reaction mixture was filtered through a diatomaceous earth pad and concentrated under vacuum to give ethyl 2-(3-methyl-2-((1r,4r)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)ethyl acetate (0.75 g, 97%) as a yellow oil (ESI 395.1 [M+Na]). + The crude product was used directly in subsequent steps without further purification.

[0429] Step 4: 2-Bromo-2-(3-methyl-2-((1r,4r)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)ethyl acetate A solution of ethyl 2-(3-methyl-2-((1r,4r)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)acetate (750 mg, 2.0 mmol, 1.0 equivalent) in 10 mL of THF was added dropwise to a solution of LiHMDS (1 M in THF, 4 mL). The reaction mixture was stirred at -78 °C for 0.5 h. TMSCl (440.0 mg, 4.0 mmol, 2.0 equivalent) was added dropwise, and the reaction mixture was stirred at -78 °C for another 15 min. A solution of NBS (720 mg, 4.0 mmol, 2.0 equivalent) in 10 mL of THF was added. The reaction mixture was stirred at -78°C for another 2 hours, then heated to 0°C and quenched by adding saturated NH4Cl aqueous solution (50 mL), and extracted with EtOAc (3 × 50 mL). The organic solutions were combined, washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (90:10 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)ethyl acetate (800 mg, 95%) (ESI 473.0 [M+Na)) as a colorless oil. + ).

[0430] Step 5: (3-(3-chloro-5-fluorophenyl)-3-oxopropyl)(methyl)carbamate tert-butyl ester 1-Bromo-3-chloro-5-fluorobenzene (7.14 g, 34.1 mmol, 1.2 equivalents) was added dropwise to a suspension of Mg (970 mg, 39.8 mmol, 1.4 equivalents) in THF (40 mL). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to 0 °C and (3-(methoxy(methyl)amino)-3-oxopropyl)(methyl)carbamate tert-butyl ester (7 g, 28.4 mmol, 1.0 equivalents) was added dropwise to a solution of THF (40 mL). The reaction mixture was stirred at 0 °C for 2 hours, quenched by adding saturated NH4Cl aqueous solution (200 mL), and extracted with EtOAc (3 × 200 mL). The organic solutions were combined, washed with brine (3 × 200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (94:6 petroleum ether: EtOAc) to obtain tert-butyl (3-(3-chloro-5-fluorophenyl)-3-oxopropyl)(methyl)carbamate (4.0 g, 98%) as a yellow oil (ESI 260.1 [M-tBu+H)). + ).

[0431] Step 6: (3-(3-chloro-5-fluorophenyl)-3-hydroxypropyl)(methyl)carbamate tert-butyl ester NaBH4 (898.6 mg, 23.7 mmol, 3.0 equivalent) was added fractionally to a solution of (3-(3-chloro-5-fluorophenyl)-3-oxopropyl)(methyl)carbamate (2.5 g, 7.9 mmol, 1.0 equivalent) in MeOH (25 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours. Water (100 mL) was slowly added at 0 °C, and the mixture was extracted with EtOAc (3 × 150 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (92:8 DCM:MeOH) to give (3-(3-chloro-5-fluorophenyl)-3-hydroxypropyl)(methyl)carbamate (2.3 g, 91%) (ESI 340.0 [M+Na)). + ).

[0432] Step 7: (3-bromo-3-(3-chloro-5-fluorophenyl)propyl)(methyl)carbamate tert-butyl ester To a solution of (3-(3-chloro-5-fluorophenyl)-3-hydroxypropyl)(methyl)carbamate tert-butyl ester (2.3 g, 7.24 mmol, 1.0 equivalent) in DCM (25 mL), CBr4 (3.6 g, 10.9 mmol, 1.5 equivalent) and PPh3 (2.8 g, 10.9 mmol, 1.5 equivalent) were added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (93:7 petroleum ether: EtOAc) to give (3-bromo-3-(3-chloro-5-fluorophenyl)propyl)(methyl)carbamate tert-butyl ester (1.8 g, 85%) (ESI 324.0 [M-tBu+H]). + ).

[0433] Step 8: (3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester (3-bromo-3-(3-chloro-5-fluorophenyl)propyl)(methyl)carbamate tert-butyl ester (950.0 mg, 2.5 mmol, 1.0 equivalent), 1-isopropylpiperazine (478.0 mg, 2.74 mmol, 1.5 equivalent), and K₂CO₃ (1.1 g, 7.5 mmol, 3.0 equivalent) were dissolved in MeCN (10 mL). The mixture was stirred at 60 °C for 3 hours and then concentrated under vacuum. The residue was purified by silica gel column chromatography (95:5 DCM:MeOH) to give racemic (3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester (930 mg, 88%) (ESI 428.3 [M+H)). + The isomers were further separated by preparative chiral SFC I to obtain peak 1, which was identified as (R)-(3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester (420 mg) as a white solid, and peak 2, which was identified as (S)-(3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester (390 mg) as a white solid.

[0434] Step 9: (S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine To a solution of (S)-(3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)carbamate tert-butyl ester (390.0 mg, 0.9 mmol, 1.0 equivalent) in DCM (5 mL), HCl (4 M in dioxane, 2.5 mL, 9.9 mmol, 10.0 equivalent) was added. The mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to give (S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine (280 mg, 95%) (ESI 328.3 [M+H]). + The crude product was used directly in subsequent steps without further purification.

[0435] Step 10: 2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)ethyl acetate A mixture of (S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)-N-methylpropyl-1-amine (280.0 mg, 0.85 mmol, 1.0 equivalent), ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)acetate (385.0 mg, 0.85 mmol, 1.0 equivalent) and K2CO3 (355.0 mg, 2.56 mmol, 3.0 equivalent) in MeCN (3 mL) was stirred at 60 °C for 8 hours. The reaction mixture was then concentrated under vacuum. The crude residue was purified by silica gel column chromatography (92:8 DCM:MeOH) to give ethyl acetate 2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl) (320 mg, 94%) (ESI 698.3 [M+H)). + ).

[0436] Step 11: Preparation of 2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)acetic acid To a solution of ethyl 2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)ethyl acetate (280 mg, 0.40 mmol, 1.0 equivalent) in EtOH (3 mL) and H2O (1 mL), NaOH (80 mg, 2 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at 70 °C for 8 hours. The pH of the mixture was adjusted to approximately 6 to 7 with 2N HCl. The solvent was removed under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give a mixture of stereoisomers 80 (240 mg, 89%) as a white solid. The stereoisomers were further separated by preparative chiral SFC A to obtain 80-P1 (100 mg) and 80-P2 (72 mg). 80-P1 was further separated by preparative chiral SFC J to obtain 80-P1A (31 mg) and 80-P1B (35 mg).

[0437] 80-P1A, which is designated as (R)-2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1R,4R)-4-(((R)-1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 670.2. 1H NMR (400 MHz, CD3OD) δ 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).

[0438] 80-P1B, designated as (R)-2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1S,4R)-4-(((S)-1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 670.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 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 = 5.6Hz, 6H).

[0439] 80-P2, designated as (2S)-2-(((S)-3-(3-chloro-5-fluorophenyl)-3-(4-isopropylpiperazin-1-yl)propyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-((1,1,1-trifluoroprop-2-yl)oxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 670.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 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).

[0440] Example 19: Preparation of compound 132-P2 Step 1: 1-Iodo-3-methyl-2-((1r,4r)-4-(prop-1-en-2-yloxy)cyclohexyl)benzene A mixture of (1r,4r)-4-(2-iodo-6-methylphenyl)cyclohexyl-1-ol (4.0 g, 12.6 mmol, 1.0 equivalent) and Hg(OAc)2 (1.2 g, 3.8 mmol, 0.3 equivalent) in 2-methoxypropyl-1-ene (30 mL) was stirred overnight at room temperature under a nitrogen atmosphere. Water (200 mL) was added, and the mixture was extracted with DCM (3 × 150 mL). The organic solutions were combined, washed successively with NaHCO3 (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (19:1 petroleum ether: EtOAc) to obtain 1-iodo-3-methyl-2-((1r,4r)-4-(prop-1-en-2-yloxy)cyclohexyl)benzene (2.2 g, 50.3%) as a colorless oil.

[0441] Step 2: 1-Iodo-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)benzene Et₂Zn (24.7 mL, 24.7 mmol, 4.0 equivalent) was added to a solution of 1-iodo-3-methyl-2-((1r,4r)-4-(prop-1-en-2-yloxy)cyclohexyl)benzene (2.2 g, 6.2 mmol, 1.0 equivalent) in DCM (40 mL) at 0 °C. The mixture was stirred at 0 °C under a nitrogen atmosphere for 0.5 h. CH₂I₂ (6.6 g, 24.7 mmol, 4.0 equivalent) was added dropwise to the mixture at 0 °C. The reaction mixture was heated to room temperature and then stirred for 6 h. A saturated aqueous solution of NH₄Cl (150 mL) was added, and the mixture was extracted with DCM (3 × 150 mL). The organic solutions were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (95:1 petroleum ether: EtOAc) to obtain 1-iodo-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)benzene (1.1 g, 47.8%) as a colorless oil.

[0442] Step 3: Ethyl 2-(3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)ethyl acetate Pd2dba3 (82.0 mg, 0.09 mmol, 0.03 equivalent) and QPhos (64 mg, 0.09 mmol, 0.03 equivalent) were added to a suspension of 1-iodo-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)benzene (1.1 g, 3.0 mmol, 1.0 equivalent) in THF (12 mL). Then, zinc(II) bromide (2-ethoxy-2-oxoethyl)zinc(II) (1 M in THF, 7.4 mL, 7.4 mmol, 2.5 equivalent) was added, and the mixture was stirred at 65 °C under a nitrogen atmosphere for 1 hour. The contents were then poured into 50 mL of saturated NH4Cl aqueous solution and extracted with EtOAc (3 × 100 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to obtain ethyl 2-(3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetate (1.0 g, 94%) as a colorless oil (ESI 353.3 [M+Na)). + ).

[0443] Step 4: Ethyl 2-bromo-2-(4-fluoro-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)ethyl acetate A solution of ethyl 2-(4-fluoro-3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetate (1.0 g, 3.0 mmol, 1.0 equivalent) in 20 mL of THF was added dropwise to a solution of LiHMDS (1 M in THF, 6.0 mL). The reaction mixture was stirred at -78 °C for 0.5 h. Then, TMSCl (648.0 mg, 6.0 mmol, 2.0 equivalent) was added dropwise, and the mixture was stirred at -78 °C for another 15 min. Next, a solution of NBS (1.07 g, 6.0 mmol, 2.0 equivalent) in 20 mL of THF was added dropwise. The reaction mixture was stirred at -78°C for another hour, then heated to 0°C and quenched by adding saturated NH4Cl aqueous solution (100 mL), and extracted with EtOAc (3 × 150 mL). The organic solutions were combined, washed with brine (3 × 150 mL), dried over Na2SO4, filtered, and concentrated under vacuum. 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-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetate (1.1 g, 75%) as a colorless oil (ESI 431.0 [M+Na)). + 433.0 [M+2+Na] + ).

[0444] Step 5: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidone-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)ethyl acetate K₂CO₃ (427 mg, 3.1 mmol, 5.0 equivalent) was added to a solution of (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)-N-methylpentan-1-amine (200 mg, 0.62 mmol, crude) in 10 mL of ACN. The mixture was stirred at room temperature for 15 minutes. Then, ethyl 2-bromo-2-(3-methyl-2-((1r,4r)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetate (253 mg, 0.62 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at 80 °C for another 2 hours. 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 obtain ethyl acetate 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl) as a yellow oil (250 mg, 62%) (ESI 651.4 [M+H). + ).

[0445] Step 6: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidone-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetic acid To a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetate (250 mg, 0.38 mmol, 1.0 equivalent) in EtOH (5 mL) and H2O (1 mL), NaOH (76 mg, 1.9 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 1 hour and concentrated under vacuum. The crude residue was purified by preparative HPLC A (30-70% CH3CN) to give a mixture of stereoisomers 132 (140 mg, 58%) as a white solid. The diastereomers were further separated by preparative chiral SFC A to obtain 132-P1 (45 mg) and 132-P2 (61 mg).

[0446] 132-P1, designated as (R)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4R)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 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).

[0447] 132-P2, designated as (S)-2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-1-yl)pentyl)(methyl)amino)-2-(3-methyl-2-((1r,4S)-4-(1-methylcyclopropoxy)cyclohexyl)phenyl)acetic acid. LC / MS ESI 623.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 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).

[0448] Example 20: Preparation of compound 146-P1 Step 1: 4-Chloro-5-methylpyridin-3-amine 2-Bromo-3-methylaniline (25 g, 120.5 mmol, 1.0 equivalent), methylboronic acid (18.0 g, 301.3 mmol, 2.5 equivalent), K₂CO₃ (41.6 g, 301.3 mmol, 2.5 equivalent), and Pd(dppf)Cl₂ (5.29 g, 7.23 mmol, 0.06 equivalent) were suspended in dioxane (300 mL) and water (50 mL). The reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was poured into 300 mL of water and extracted with EtOAc (3 × 200 mL). The organic solutions were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (1:1 petroleum ether: EtOAc) to obtain 4-chloro-5-methylpyridin-3-amine (9.6 g, 55.9%) as a yellow solid (ESI 143.0 [M+H]). + ).

[0449] Step 2: 5-Methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-3-amine 4-Chloro-5-methylpyridin-3-amine (9.6 g, 67.3 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane (18.8 g, 70.7 mmol, 1.05 equivalent), K3PO3 (18.6 g, 134.6 mmol, 2 equivalent), and XPhosPdG2 (2.1 g, 2.69 mmol, 0.04 equivalent) were suspended in dioxane (100 mL) and water (20 mL). The reaction mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was poured into 200 mL of water and extracted with EtOAc (3 × 100 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (1:1 petroleum ether: EtOAc) to give 5-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridin-3-amine (13.1 g, 79.0%) as a brown solid (ESI 247.1 [M+H)). + ).

[0450] Step 3: 5-Methyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine-3-amine 10% Pd / C (5.64 g, 2.66 mmol, 0.05 equivalent) was added to a solution of 5-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-3-amine (13.1 g, 53.2 mmol, 1.0 equivalent) in EtOH (200 mL). The reaction mixture was stirred at 65 °C under a H2 atmosphere (1 atm, 3 L) for 24 h. The reaction mixture was filtered through a diatomaceous earth mat and concentrated under vacuum to give 5-methyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine-3-amine (11.1 g, 84.0%) (ESI 249.2 [M+H) as a yellow solid. + The crude product was used directly in subsequent steps without further purification.

[0451] Step 4: 3-Iodo-5-methyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine KI (22.3 g, 134.1 mmol, 3 equivalents) and tert-butyl nitrite (23.0 g, 223.5 mmol, 5 equivalents) were added to a solution of 5-methyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine-3-amine (11.1 g, 44.7 mmol, 1.0 equivalent) in ACN (150 mL) at 0 °C. The mixture was heated at 40 °C for 2 days. The mixture was poured into 300 mL of saturated Na₂SO₃ aqueous solution and extracted with EtOAc (3 × 100 mL). The organic solutions were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (1:1 petroleum ether: EtOAc) to obtain 3-iodo-5-methyl-4-(1,4-dioxanespiro[4.5]dec-8-yl)pyridine (7.1 g, 44.2%) as a yellow solid (ESI 360.0 [M+H)). + ).

[0452] Step 5: 4-(3-iodo-5-methylpyridin-4-yl)cyclohexane-1-one To a solution of 3-iodo-5-methyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine (7.1 g, 19.8 mmol, 1.0 equivalent) in THF (80 mL), 3 M HCl aqueous solution (19.8 mL, 59.4 mmol, 3.0 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour, cooled to 0 °C, quenched by adding saturated NaHCO3 aqueous solution (pH adjusted to approximately 8), and extracted with EtOAc (2 × 200 mL). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give 4-(3-iodo-5-methylpyridin-4-yl)cyclohexane-1-one (6.2 g, 13.9 mmol, crude) as a yellow oil (ESI 316.0 [M+H)). + The crude product is used directly in the next step.

[0453] Step 6: (1r,4r)-4-(3-iodo-5-methylpyridin-4-yl)cyclohexyl-1-ol CeCl3 (4.1 g, 16.7 mmol, 1.2 equivalent) was added to a solution of 4-(3-iodo-5-methylpyridin-4-yl)cyclohexane-1-one (6.2 g, 13.9 mmol, crude product, 1.0 equivalent) in MeOH (60 mL) at 0 °C. NaBH4 (635 mg, 16.7 mmol, 1.2 equivalent) was then added in portions. The mixture was stirred at 0 °C for 0.5 h. Water (100 mL) was slowly added at 0 °C, and the mixture was extracted with EtOAc (3 × 100 mL). The organic solutions were combined, washed with brine, dried over anhydrous N...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: in: It is optional to be halogenated, C 1-5 Alkyl or C 1-4 Alkoxy-substituted 3- to 12-membered heterocyclic ring structures, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens; a is 0, 1, 2, or 3; X1 is N or CR a ; R a It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; X2 is NR b or CR b ´R b ´´; R b It is H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R b ´ and R b Each of them independently consists of H, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R1 is H or -COOR 1b ; R 1b Is it H or C? 1-4 alkyl; R2 is H or C 1-4 alkyl; R3 is H, C 1-4 Alkyl or halogen; n is 0, 1, 2, 3 or 4; R4 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; p is 0, 1, 2, 3, 4 or 5; R5 is H, C 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R7 groups; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each R7 is a halogen independently.

2. The compound of claim 1, wherein R1 is COOH.

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

4. The compound according to any one of claims 1-3, wherein R b ´´ is H.

5. The compound according to any one of claims 1-4, wherein X1 is CR a .

6. The compound of claim 5, wherein R a It is H.

7. The compound according to any one of claims 1-6, wherein X2 is NR. b .

8. The compound of claim 7, wherein R b C is a C that is optionally substituted with one or more halogens. 1-4 alkyl.

9. The compound of claim 8, wherein R b C is optionally replaced by one or more fluorine molecules. 1-4 alkyl.

10. The compound of claim 9, wherein R b It is -CH2CF3.

11. The compound according to any one of claims 1-6, wherein X2 is CR b ´R b ´´.

12. The compound of claim 11, wherein R b ´´ is H.

13. The compound according to any one of claims 11-12, wherein R b ´is-OC 1-4 Alkyl, wherein the C 1-4 The alkyl group may optionally be replaced by one or more halogens.

14. The compound of claim 13, wherein R b ´is-OC 1-4 Alkyl or -OC 3-6 cycloalkyl, wherein the C 1-4 The alkyl group may optionally be substituted with one or more fluorine molecules.

15. The compound according to claim 14, wherein R b ´ is -O-CF3.

16. The compound of claim 14, wherein R b ´is -O-CH3.

17. The compound of claim 14, wherein R b ´ is arbitrarily C 1-4 Alkyl-substituted -O-C3 cycloalkyl groups.

18. The compound of claim 14, wherein R b ´ is an O-C3 cycloalkyl group optionally substituted with methyl.

19. The compound of claim 13, wherein R b ´ is optionally replaced by one or more fluorine molecules -OC 1-4 alkyl.

20. The compound according to any one of claims 1-4, wherein X1 is CH and X2 is CHR. b And R b yes .

21. The compound according to any one of claims 1-20, wherein m is 0.

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

23. The compound according to any one of claims 1-21, wherein R3 and R4 are each independently fluorine, chlorine, or a methyl group optionally substituted with one or more fluorine molecules.

24. The compound according to 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 according to any one of claims 1-25, wherein m is 1.

27. The compound according to 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 of formula (IV) or a pharmaceutically acceptable salt thereof. in Y1 is N or CR c ; R c It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; Y2 is NR d or CR d ´R d ´´; R d It is H, halogen, C 1-4 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-4 Alkyl or 3-6 membered heterocyclic alkyl groups may optionally be substituted with one or more halogens; R d ´ and R d Each is independently H, halogen, or C. 1-4 Alkyl groups, and each C 1-4 Alkyl groups are optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R6 is H, C 1-5 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R8 groups; q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each R8 is a halogen independently.

29. The compound of claim 28, wherein Y1 is N and Y2 is NR. d .

30. The compound of claim 29, wherein R d It is C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

31. The compound of claim 30, wherein R d It is a methyl group.

32. The compound of claim 30, wherein R d It is isopropyl.

33. The compound of claim 30, wherein R d It is cyclopropyl.

34. The compound of claim 30, wherein R d It is tetrahydrofuran.

35. The compound of claim 28, wherein Y2 is CR d ´R d ´´.

36. The compound of claim 35, wherein R d ´´ is H.

37. The compound of claim 36, wherein R d It is fluorine.

38. The compound of claim 36, wherein R d ´ is a methoxy group.

39. The compound of claim 36, wherein R d ´ is methyl.

40. The compound of claim 35, wherein R d ´´ 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. in R3´, R3´´, R4´, and R4´´ are each independently H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl.

42. The compound of claim 41, wherein X1 is N.

43. The compound according to any one of claims 41-42, wherein X2 is NR. b .

44. The compound of claim 43, wherein R b C is a C that is optionally substituted with one or more halogens. 1-4 alkyl.

45. The compound of claim 43, wherein R b C is optionally replaced by one or more fluorine molecules. 1-4 alkyl.

46. ​​The compound of claim 43, wherein R b It is -CH2CF3.

47. The compound according to any one of claims 41-42, wherein X2 is CR b ´R b ´´.

48. The compound of claim 47, wherein R b ´´ is H.

49. The compound according to any one of claims 47-48, wherein R b ´is-OC 1-4 Alkyl, wherein the C 1-4 The alkyl group may optionally be replaced by one or more halogens.

50. The compound of claim 49, wherein R b ´is-OC 1-4 Alkyl or -OC 3-6 cycloalkyl, wherein the C 1-4 The alkyl group may optionally be substituted with one or more fluorine molecules.

51. The compound according to claim 50, wherein R b ´ is -O-CF3.

52. The compound of claim 50, wherein R b ´is -O-CH3.

53. The compound of claim 50, wherein R b ´ is arbitrarily C 1-4 Alkyl-substituted -O-C3 cycloalkyl groups.

54. The compound of claim 50, wherein R b ´ is an O-C3 cycloalkyl group optionally substituted with methyl.

55. The compound of claim 50, wherein R b ´ is optionally replaced by one or more fluorine molecules -OC 1-4 alkyl.

56. The compound according to any one of claims 41-55, wherein Y1 is N.

57. The compound of claim 56, wherein Y2 is NR. d .

58. The compound of claim 57, wherein R d It is C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

59. The compound of claim 58, wherein R d It is a methyl group.

60. The compound of claim 58, wherein R d It is isopropyl.

61. The compound of claim 58, wherein R d It is cyclopropyl.

62. The compound of claim 58, wherein R d It is tetrahydrofuran.

63. The compound of claim 56, wherein Y2 is CR d ´R d ´´.

64. The compound of claim 63, wherein R d ´´ is H.

65. The compound of claim 63, wherein R d It is fluorine.

66. The compound of claim 63, wherein R d ´ is a methoxy group.

67. The compound of claim 63, wherein R d ´ is methyl.

68. The compound of claim 63, wherein R d ´´ is methyl.

69. The compound of claim 1, wherein the compound is a compound of formula (V). in, a is 1 or 2; R3´, R3´´, R4´, and R4´´ are each independently H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; R5 is H, C 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R7 groups; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each R7 is a halogen independently.

70. The compound of claim 69, wherein... It is a 5- to 10-membered heterocyclic ring structure, the ring structure of which includes one to four heteroatoms, which are optionally bonded by halogens, carbon atoms ... 1-5 Alkyl or C 1-4 Alkoxy substitution, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens.

71. The compound of claim 70, wherein... It is a 5- to 10-membered heterocyclic ring structure, the ring structure of which includes one or two heteroatoms, which are optionally bonded by halogens, carbon atoms ... 1-5 Alkyl or C 1-4 Alkoxy substitution, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens.

72. The compound of claim 71, wherein... It is a 5- to 6-membered monocyclic heterocyclic base ring structure, the ring structure of which includes one or two heteroatoms, which are optionally bonded by halogens, carbon atoms ... 1-5 Alkyl or C 1-4 Alkoxy substitution, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens.

73. The compound of claim 71, wherein... It is a 7- to 8-membered bicyclic bridged heterocyclic base ring structure, the ring structure of which includes one or two heteroatoms, which are optionally bonded by halogens, carbon atoms ... 1-5 Alkyl or C 1-4 Alkoxy substitution, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens.

74. The compound of claim 71, wherein... It is a 7- to 8-membered spirocyclic heterocyclic base ring structure, the ring structure of which includes one or two heteroatoms, which are optionally bonded by halogens, carbon atoms, or carbon atoms. 1-5 Alkyl or C 1-4 Alkoxy substitution, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens.

75. The compound of any one of claims 70 to 74, wherein the heterocyclic ring structure is saturated.

76. The compound of claim 69, wherein... It is tetrahydrofuran.

77. The compound of claim 69, wherein... yes .

78. The compound of claim 69, wherein... yes .

79. The compound of claim 69, wherein... yes .

80. The compound of claim 69, wherein... yes .

81. The compound of claim 69, wherein... yes .

82. The compound of claim 69, wherein... yes .

83. The compound of claim 69, wherein... yes .

84. The compound of claim 69, wherein yes .

85. The compound of claim 69, wherein... yes .

86. The compound of claim 69, wherein yes .

87. The compound of claim 69, wherein yes .

88. The compound of claim 69, wherein yes .

89. The compound of claim 69, wherein yes .

90. The compound of claim 69, wherein... yes .

91. The compound of claim 69, wherein... yes .

92. The compound of claim 69, wherein... yes .

93. The compound of claim 69, wherein... yes .

94. The compound of claim 69, wherein... yes .

95. The compound of claim 69, wherein... yes .

96. The compound of claim 69, wherein... yes .

97. The compound of any one of claims 28 to 40, wherein the compound is a compound of formula (IV-A) or a pharmaceutically acceptable salt thereof. 。 98. The compound of any one of claims 41 to 68, wherein the compound is a compound of formula (II-A), formula (III), or a pharmaceutically acceptable salt thereof. in R3´, R3´´, R4´, and R4´´ are each independently H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl.

99. The compound of any one of claims 69 to 96, wherein the compound is a compound of formula (VA) or a pharmaceutically acceptable salt thereof. 。 100. A compound of formula (VI), or a pharmaceutically acceptable salt thereof, in Y1, Y2, Y3, Y4, Y5 and Z1, Z2 and Z3 are each CH or N, provided that at least three of Y1, Y2, Y3, Y4 and Y5 are CH and at least one of Z1, Z2 and Z3 is CH. It is optional to be halogenated, C 1-5 Alkyl or C 1-4 Alkoxy-substituted 3- to 12-membered heterocyclic ring structures (including monocyclic heterocyclic, bicyclic bridging, and bicyclic spirocyclic ring structures), wherein C 1-4 Alkyl (e.g., methyl) and C 1-4 Alkyl groups (e.g., methoxy groups) are optionally substituted with one or more halogens (e.g., one or more fluorine groups); a is 0, 1, 2, or 3; X1 is N or CR a ; R a It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; X2 is NR b or CR b ´R b ´´; R b It is H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R b ´ and R b Each of them independently consists of H, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 Cycloalkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, C 3-6 Cycloalkoxy or C 1-4 Alkyl-C 3-6 The cycloalkoxy group is optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; R1 is H or -COOR 1b ; R 1b Is it H or C? 1-4 alkyl; R2 is H or C 1-4 alkyl; R3 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; n is 0, 1, 2, 3 or 4; R4 is H, C, optionally substituted with one or more halogens. 1-4 Alkyl or halogen; p is 0, 1, 2, 3, 4 or 5; R5 is H, C 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R7 groups; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and Each R7 is a halogen independently.

101. The compound of claim 97, wherein yes ,and Y1 is N or CR c ; R c It is H, a halogen, or C optionally substituted with one or more halogens. 1-4 alkyl; Y2 is NR d or CR d ´R d ´´; R d It is H, halogen, C 1-4 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-4 Alkyl or 3-6 membered heterocyclic alkyl groups may optionally be substituted with one or more halogens; R d ´ and R d Each is independently H, halogen, or C. 1-4 Alkyl groups, and each C 1-4 Alkyl groups are optionally reacted with one or more halogens, C 1-4 Alkyl or C 1-4 Alkyl substitution; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8; R6 is H, C 1-5 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy groups, and each C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 The alkoxy group is optionally substituted with 1 to 4 R8 groups; and Each R8 is a halogen independently.

102. The compound of claim 98, wherein Y1 is N and Y2 is CH2 or C(CH3)2.

103. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

104. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

105. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

106. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

107. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

108. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

109. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

110. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

111. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

112. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

113. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

114. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

115. A chemical formula Compounds thereof, or pharmaceutically acceptable salts thereof.

116. A chemical formula Compounds thereof, or pharmaceutically acceptable salts 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 compounds in Table 2, or a pharmaceutically acceptable salt thereof.

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

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

121. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 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 a therapeutically effective amount of a compound as described in any one of claims 1 to 120 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 121.

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