Inhibiting human integrin Α4Β7

Abstract

Disclosed are compounds for and methods of treating or preventing a disease or condition responsive to inhibition human α4β7 integrin by administering to a patient in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Many diseases and conditions can be treated by administration of the compounds disclosed herein for example, inflammatory bowel disease (IBD), ulcerative colitis, or Crohn's disease.

Description

INHIBITING HUMAN INTEGRIN a407FIELD OF THE INVENTION

[0001] This application discloses methods of treating diseases and conditions by inhibiting a4[37 integrin. Diseases and conditions responsive to a4[37 integrin inhibition include, for example, inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD).BACKGROUND

[0002] Inflammatory bowel disease (IBD) comprises ulcerative colitis (UC) and Crohn’s disease (CD), related idiopathic conditions characterized by chronic inflammation of the gastrointestinal tract. While UC affects only the colon, CD is characterized by transmural inflammation involving any portion of luminal gastrointestinal tract, from the oral cavity to the perianal area. The choice of therapy for CD varies depending upon the anatomic location, severity, and the behavior of the disease, and whether the treatment goal is to induce or maintain remission. Conventional therapies such as 5 -aminosalicylates are often ineffective for moderately to severely active CD, while long-term use of corticosteroids is associated with adverse effects.

[0003] Integrins are a family of receptors known to regulate aspects of mucosal inflammation that underlie CD progression. CD is associated with activation of immune cells expressing the integrin 014P7 and trafficking of these cells from the bloodstream into the gut and the surrounding tissue to promote chronic inflammation. Specific inhibition of (X4P7 is a validated mechanism for the treatment of IBD, as demonstrated by vedolizumab (Entyvio®), a monoclonal antibody administered via intravenous infusion.

[0004] Inhibitors of specific integrin-ligand interactions have been used for the treatment of various diseases. The mainstays of therapy over many years have been oral and topical salicylates and glucocorticoids, various immunosuppressive agents and biologies.Monoclonal antibodies displaying high binding affinity for a4p7 have displayed therapeutic benefits for gastrointestinal auto-inflammatory / autoimmune diseases, such as Crohn’s disease, and ulcerative colitis. Anti-integrin antibody therapy for IBD was first introduced with the approval of the non-specific a4 integrin inhibitor natalizumab for Crohn’s disease, an indication approved following its initial approval for multiple sclerosis. Vedolizumab, a monoclonal antibody inhibitor of the integrin 014P7, is approved for the induction and maintenance of remission in late -line ulcerative colitis and does not carry a black boxwarning. Vedolizumab is also approved as a late-line option for Crohn’s disease. However, these therapies also have certain undesirable properties for the patient. A monoclonal antibody cup? integrin inhibitor is administered by parenteral administration, has a long half¬ life with inability to rapidly modify exposures, and a reduced activity due to anti-drug antibody formation. In addition to issues with administration, monoclonal antibody therapies can be challenging to manufacture compared to small molecule therapies,

[0005] There remains a medical need for an effective and safe oral 0.4 7 integrin inhibitor as an important addition to the therapeutic armamentarium for c P? integrin-mediated conditions, such as inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease (CD).

[0006] In particular, there remains an unmet need for a small molecule designed to selectively inhibit integrin 0407 including a need for such a small molecule for administration orally, avoiding the need for periodic therapeutic infusions and the complications associated with this form of drug administration.SUMMARY10007] In one aspect, the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:is a 3- to 12-membered heterocyclyl optionally substituted with one or more instances of Rs, -N(Ra)-(C3-t2-cycloalkyl) optionally substituted with one or more instances of Rs, or -N(Ra)-Ra-;Ra and Ra’ are each independently is H or C1-4 alkyl;a is 0, 1, 2 or 3;Ri is H or -COORib;Rib is H or Ci-4 alkyl;R2 is H or C1-4 alkyl;each R3 is independently hydrogen, halogen, C1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3- to 8- membered heterocycloalkyl, or C 1-6 alkyloxy,wherein the C1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, and C1-6 alkyloxy are optionally substituted with one or more halogen, C1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkoxy;Xi, X2, X3, X4 and X5 are each N or CR4;each R4 is H, halogen, C 1-4 alkyl optionally substituted with one or more halogen, C1-4 alkyloxy optionally substituted with one or more halogen, or C3-6 cycloalkyl;r \ / !is C5-12 heterocyclyl, optionally substituted with one or more instances of Rs or $;each R5 is independently a C1-6 alkyl, 3- to 12-membered heterocycloalkyl, C3-12 cycloalkyl, each optionally substituted with one or more instances of Rg’;each R$ and $’ is independently C1-6 alkyl, halogen, C1-6 alkyloxy, OH, Ci-galkyl-OH, C1-6 alkyl-Ci-6-alkyloxy, Ci-salkyloxy-Ci-6-alkyloxy, or C3-6 cycloalkyl and each C1-6 alkyl, C1-6 alkyloxy, OH, C1-6 alkyl-OH, C1-6 alkyl-Ci-6-alkyloxy, Ci-salkyloxy-Ci-6-alkyloxy, is optionally substituted with 1 to 4 instances of R7;each R7 is independently halogen, C3-6 cycloalkyl, or C1-6 alkyl optionally substituted with one or more halogen, hydroxy, or C1-6 alkoxy.(A)

[0008] In some embodiments,' is 5- to 8-membered heterocyclyl optionally substituted with one or two instances of R3, wherein R3 halogen, C1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, or C1-6 alkyloxy, or a pharmaceutically acceptable salt thereof.I A I

[0009] In some embodiments,- is azetidine, pyrrolidine, piperidine, piperazine, morpholine, or azepane optionally substituted with one or two instances of R3, wherein R3 is F, methyl, isopropyl, OMe, methoxyethyl, cyclopropyl, cyclobutyl, or oxetanyl, or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, a is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, Ri is -COOH, or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, R2 is methyl, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments:Xi is CR4 and R4 is H, halogen, C1-4 alkyl optionally substituted with one or more halogen, or C 1-4 alkyloxy optionally substituted with one or more halogen,X2 is CR4 and R4 is H, or halogen;X3 is N or CR4 and R4 is H;X4 is CR4 and R4 is H, halogen, C 1-4 alkyl optionally substituted with one or more halogen, or C3-6 cycloalkyl;X5 is N or CR4 and R4 is H,or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments:Xi is CR4 and R4 is H, methyl, F, Cl, or OMe;X2 is CR4 and R4 is H, or F;X3 is N or CR4 and R4 is H;X4 is CR4 and R4 is H, Cl, CF3, CHF2, cyclopropyl, or cyclobutyl;X5 is N or CR4 and R4 is H,or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments,whereinR? is Ci-6 alkyl or a 3- to 12-membered heterocycloalkyl or C3-12 cycloalkyl, each optionally substituted with one or more instances of Rg’;Rga is Ci-6 alkyl or C3-8 cycloalkyl optionally substituted with one or more Rgy Rgh is hydrogen, halogen, -O(C3-s cycloalkyl), C1-6 alkyl, or C 1-6 alkoxy wherein the Ci-6 alkyl or C1-6 alkoxy is optionally substituted with one or more halogen or Ci-s alkoxy; andR is halogen, C1-6 alkyl optionally substituted with one or more halogen, C1-6 alkyloxy optionally substituted with one or more halogen, or OH,or a pharmaceutically acceptable salt thereof.F F A Oi

[0017] In some embodiments, R5 is or i, or a pharmaceutically acceptable salt thereof.0 F A FO0 6In some embodiments, Rgais methyl,?or, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, ib is hydrogen, fluoro, methyl, methoxy, ethoxy, -O(cyclopropyl), -( CHF2), or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments,x---%l1whereinAi, A2, A3 and A4 are each independently oxygen or CRioaRiob, provided that one of Ai, A2, A3 and A4 is oxygen;each ofRioa, andRiob, are independently hydrogen, C 1-4 alkyl optionally substituted with one or more halogen, halogen, C 1-4 alkyloxy, C1-6 cycloalkyl, or OH,Rio is C1-4 alkyl optionally substituted with one or more halogen, halogen, C1-4 alkyloxy, or OH,a is 0, 1, 2, or 3,or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, Ai is CRioaRiob, A2 is O, and A3 and A4 are both CH2, or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, Rioais hydrogen and Riob is selected from methyl, or ethyl, or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, Rio is hydrogen, or fluoro, or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, ora pharmaceutically acceptable salt thereof.

[0024] in some embodiments, the compound is a compound of the chemical formula / -8-100025] In some embodiments, the compound is a compound selected from the group consisting of the compounds in Figure 1, or a pharmaceutically acceptable salt thereof.

[0026] in some embodiments, a pharmaceutical composition comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0027] In some embodiments, a method of treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease, comprises administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein.

[0028] In some embodiments, the present invention provides the use of a compound or pharmaceutically acceptable salt thereof disclosed herein for the manufacture of a medicament for the treatment of inflammatory bowel disease, ulcerative colitis, or Crohn’s disease.

[0029] In some embodiments, the present invention provides any compound or pharmaceutically acceptable salt thereof disclosed herein for use in therapy.

[0030] In some embodiments, the present invention provides any compound or pharmaceutically acceptable salt thereof disclosed herein for use in the treatment of inflammatory bowel disease, ulcerative colitis, or Crohn’s disease.DETAILED DESCRIPTION

[0031] Compounds of Formula (I), which includes compounds of Formulae (I), (II), (II-B), (III) and (III-B), and their respective pharmaceutically acceptable salt forms, aresmall-molecule integrin therapeutics targeting a4[37 that can be administered to treat patients with diseases and conditions that are responsive to a4[37 integrin inhibition.

[0032] In particular, methods described herein can be effective in the treatment of inflammatory bowel disease such as ulcerative colitis or Crohn’s disease. For example, administration of a compound of Formula (I) according to methods described herein provides unexpected therapeutic benefit within twelve weeks of therapy to subjects with moderately to severely active ulcerative colitis, including patients who have received prior advanced therapy (AT) for ulcerative colitis and / or those with a baseline endoscopy of 3. Further, methods described herein show that administration of a compound according to Formula (I) can be well-tolerated and with a favorable safety profile.

[0033] Accordingly, methods as described herein can expand the therapies available for subjects with inflammatory bowel disease such as ulcerative colitis or Crohn’s disease.Compounds of Formula (I)

[0034] In one aspect, the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:is a 3 - to 12-membered heterocyclyl optionally substituted with one or more instances of R3, -N(Ra)-(C3-i2-cycloalkyl) optionally substituted with one or more instances of R3, or -N(Ra)-Ra’;Ra and Ra’ are each independently is H or C1-4 alkyl;a is 0, 1, 2 or 3;Ri is H or -COORib;Rib is H or C1-4 alkyl;R2 is H or C1-4 alkyl;each R3 is independently hydrogen, halogen, C 1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3-to 8- membered heterocycloalkyl, or C1-6 alkyloxy,wherein the C1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, and C1-6 alkyloxy are optionally substituted with one or more halogen, C1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkoxy;Xi, X2, X3, X4 and X5 are each N or CR4each R4 is H, halogen, C 1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkyloxy optionally substituted with one or more halogen;p is 0, 1, 2, 3, 4 or 5;is a 3- to 12-membered heteroaryl, C5-12 aryl, 3- to 12-membered or C5-12 heterocyclyl, each optionally substituted with one or more instances of R5 or Rr>:each R5 is independently a C1-6 alkyl, 3- to 12-membered heterocycloalkyl or C3-12 cycloalkyl, each optionally substituted with one or more instances of Re;each Rg and Rg’ is independently Ci-g alkyl, halogen, Ci-g alkyloxy, OH, Ci-galkyl-OH, C 1-6 alkyl-Ci- -alkyloxy, Ci- alkyloxy-Ci-g-alkyloxy, and each Ci-g alkyl, Ci-g alkyloxy, Ci-g alkyl-OH, Ci-galkyl-Ci-g-alkyloxy, Ci-galkyloxy-Ci-g-alkyloxy, is optionally substituted with 1 to 4 instances of R7;each R7 is independently halogen, or C1-6 alkyl optionally substituted with one or more halogen, hydroxy, or C1-6 alkoxy.

[0035] In some embodiments, the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof:(II),whereinA’ is a 5- to 8-membered heterocyclyl optionally substituted with one or more instances of R3, -N(Ra)-(C5-8-cycloalkyl) optionally substituted with one or more instances of R3, or -N(Ra)-Ra';each R is independently C1-4 alkyl, C1-4 alkoxy, or two R3 form a C3-8 spirocyclic cycloalkyl, spirocyclic 3- to 8-membered heterocyclyl, fused or bridged C3-8 cycloalkyl, fused or bridged 3- to 8-membered heterocycloalkyl, and each R3is optionally substituted with one or more halogen, C1-4 alkyl optionally substituted with one or more halogen, or Ci- 4 alkoxy;Xi, X2, X3, X4 and X5 are each N or CR4;each R4 is H, halogen, C1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkyloxy optionally substituted with one or more halogen;Rs is C1-6 alkyl or a 3- to 12-membered heterocycloalkyl or C3-12 cycloalkyl, each optionally substituted with one or more instances of Rg;R6a is C1-6 alkyl or C3-8 cycloalkyl;R6b is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, wherein the C1-6 alkyl or C1-6 alkoxy is optionally substituted with one or more halogen; andRe’ is halogen, Ci-e alkyl optionally substituted with one or more halogen, Cue alkyloxy optionally substituted with one or more halogen, or OH.

[0036] In some embodiments, the compound is a compound of Formula (I), or Formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (II-B), or a pharmaceutically acceptable salt thereof:(II-B),wherein A Xi, X2, X3, X4, Xs, Ri, Ria, Rib, Rea, Reb and Rs are as defined with respect to Formula (II).

[0037] In some embodiments, the compound is a compound of Formula (III) or a pharmaceutically acceptable salt thereof:whereinA’ is a 5- to 8-membered heterocyclyl optionally substituted with one or more instances of R3, -N(Ra)-(C5-s-cycloalkyl) optionally substituted with one or more instances of R3, or -N(Ra)-Ra’jeach R3 is independently C1-4 alkyl, C1-4 alkoxy, or two Rs form a C3-8 spirocyclic cycloalkyl, spirocyclic 3- to 8-membered heterocyclyl, fused or bridged C3-8 cycloalkyl, fused or bridged 3- to 8-membered heterocycloalkyl, and each R3 is optionally substituted with one or more halogen, C1-4 alkyl optionally substituted with one or more halogen, or Ci- 4 alkoxy;X1, X2, X3, X4 and X5 are each N or CR4;each R4 is H, halogen, C1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkyloxy optionally substituted with one or more halogen;A2, A3 and A4 are each independently oxygen or CR10R10’, provided that 0 or 1 of A2, As and A4 is oxygen;each of Rioa, Riob, Rio and Rio’ are independently C 1-4 alkyl optionally substituted with one or more halogen, halogen, C 1-4 alkyloxy, or OH.

[0038] In some embodiments, the compound is a compound of Formula (I), or Formula (III), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (III-B), or a pharmaceutically acceptable salt thereof:A’(III-B),wherein A’, X], X?„ Xs, X4, X5, A2, A3, A4, Ri, 2, Rioa, and Rwb are as defined with respect to Formula (III).

[0039] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof:X4^X2X5R22R2uaX'b! '■'-x^R-jR2C.b R2(I ),whereinR1 is H or -COOR1b;R1b is H or C1-4 alkyl;Xi, X2, X3, X4 and X5 are each N or CR4;each R4 is H, halogen, C 1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkyloxy optionally substituted with one or more halogen;R20a and R20b together form a 3- to 8-membered heterocyclyl optionally substituted with one or more instances of R3; or R20a is hydrogen or C1-4 alkyl and R20b is C1-4 alkyl or a 3- to 8-membered heterocyclyl optionally substituted with one or more instances of R3;R3 is as defined with respect to Formula (I);R22 is an indazole or an isochromane, each optionally substituted with one or more instances of R5 or R6;each Rs is independently a C1-6 alkyl, 3- to 12-membered heterocycloalkyl or C3- 12 cycloalkyl, each optionally substituted with one or more instances of Rs’;each Re and Re’ is independently C1-6 alkyl, halogen, Ci-6 alkyloxy, OH, Cj-6 alkyl-OH, Ci-ealkyl-Ci-e-alkyloxy, C 1-6 alkyloxy-Ci-6 -alkyloxy, and each Ci-e alkyl, Ci-e alkyloxy, C1-6 alkyl-OH, C 1-6 alkyl-Ci-e -alkyloxy, Ci-ealkyloxy-Ci-6-alkyloxy, is optionally substituted with 1 to 4 instances of R7; andeach R7 is independently halogen, or C1-6 alkyl optionally substituted with one or more halogen, hydroxy, or C1-6 alkoxy.

[0040] In one aspect, the invention features a compound of Formula (V), or a pharmaceutically acceptable salt thereof:(V),is a 3- to 12-membered heterocyclyl ring structure (including monocyclic heterocyclic, bicyclic bridged, and bicyclic spirocyclic ring structures) optionally substituted with halogen, C1-4 alkyl or C1-4 alkyloxy, wherein the C1-4 alkyl (e.g., methyl) and C1-4 alkyloxy (e.g., methoxy) are optionally substituted with one or more halogen (e.g., one or more fluoro);is a 5- to 6-membered aryl or heteroaryl ring structure optionally substituted with one or more instances of R4; andx, a, R1, R2 and R4 are as described for Formula (I) herein.

[0041] In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a piperidine optionally substituted with (A)one or more instances of R3. In some embodiments, / in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a piperidine optionally \A) substituted with one or more instances of methyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B),\A) is a piperidine optionally substituted with isopropyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B),is a piperidine optionally substituted with methoxy. In some embodiments,' in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B),is a piperidine optionally substituted with a bridging methylene. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a piperidine optionally substituted with a bridging ethylene. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a piperidine optionally substituted with a bridging amino.

[0042] In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a piperidine substituted with a spirocyclicC3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B),is a piperidine substituted with a spirocyclic cyclopropyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B),is a piperidine substituted with a spirocyclic cyclobutyl. In some embodiments,' in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B),IA) is a piperidine substituted with a spirocyclic cyclopentyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B),is a piperidine substituted with a spirocyclic cyclohexyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a piperidine substituted with a spirocyclic oxetane.

[0043] In some embodiments,compound of Formulae (II), (II-B), (III) or (III-B), is a piperazine optionally substituted withone or more instances of R3. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a piperazine optionally substituted with one or more instances of methyl.

[0044] In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a pyrrolidine optionally substituted withone or more instances of R3. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a pyrrolidine optionallysubstituted with one or more instances of methyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is apyrrolidine substituted with a geminal dimethyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a pyrrolidine substituted with a spirocyclic C3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl.In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a pyrrolidine substituted with a spirocyclic cyclopropyl.In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a pyrrolidine substituted with a spirocyclic cyclobutyl.In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a pyrrolidine substituted with a spirocyclic cyclopentyl.In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a pyrrolidine substituted with a spirocyclic cyclohexyl.In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a pyrrolidine substituted with a spirocyclic oxetane.

[0045] In some embodiments,compound of Formulae (II), (II-B), (III) or (III-B), is a morpholino optionally substituted withone or more instances of R3. In some embodiments,in a compound of Formulae (I) or(V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is a morpholino optionally substituted with one or more instances of methyl.

[0046] In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is -N(Ra)-(Cs-8-cycloalkyl) optionally substituted with one or more instances of R3, wherein Ra is H or C1-4 alkyl. In someembodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is -N(Ra)-(cyclohexyl) optionally substituted with one or moreinstances of R3, wherein Ra is H or C1-4 alkyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is -N(Ra)-(cyclobutyl) optionally substituted with one or more instances of R3, wherein Ra is H or C1-4 alkyl.

[0047] In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is -N(Ra)-Ra’, wherein Ra and Ra’ are eachindependently is H or C1-4 alkyl. In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is -N(Ra)-Ra’, wherein Ra is methyl, and Ra’ is isobutyl.

[0048] In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is an azepane optionally substituted with one or more instances of R3, and optionally comprising a bridging amino.

[0049] In some embodiments,in a compound of Formulae (I) or (V), or A’ in a compound of Formulae (II), (II-B), (III) or (III-B), is an azocane optionally substituted with one or more instances of R3, and optionally comprising a bridging amino.

[0050] In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV) or (V), wherein each R3 is independently hydrogen, halogen, C 1-6 alkyl, C1-4alkoxy, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, or C1-6 alkyloxy, wherein the C1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, and C1-6 alkyloxy are optionally substituted with one or more halogen, C1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkoxy.In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV) or (V), wherein each Rs is independently hydrogen, fluoro, chloro, C1-4 alkyl optionally substituted with one or more fluoro, C1-4 alkoxy optionally substituted with one or more fluoro,100051 ] In some embodiments, the compound is a compound of Formula (I) or Formula (II) c,.0. °\ y ■'0F5)4 '■CHF wherein R:2gds CHRb' and Rb' isz? ^CF, or <-3. In some embodiments, the compound is a compound of Formula (I), wherein Ri is -C00H and R2 is -methyl, Xi is CH and X2 is'-’CF, - CF-s 4 XHF CHRb' and Rb' is2W, or

[0052] In some embodiments, the compound is a compound of Formula (V), whereinand are each independently a 6-membered ary l or heteroaryl ring structure. Insome embodiments, the compound is a compound of Formula (V), whereinand■— are each independently phenyl, pyridine or pyrimidine. In some embodiments, thecompound is a compound of Formula (V), whereinand are each independently phenyl, pyridine or pyrimidine. In some embodiments, the compound is acompound of Formula (V), whereinis phenyl andis pyridine or pyrimidine.In some embodiments, the compound is a compound of Formula (V), whereinyisphenyl andis pyridine. In some embodiments, the compound is a compound ofFormula (V), whereinis pyrimidine. In some embodiments,Formula (I) or Formula (V) andis phenyl, pyridine or pyrimidine. In somedefined in Formula (I) or Formula (V) and Z is phenyl. In some embodiments,100053] In some embodiments, the compound is a compound of Formula (VI), or a pharmaceutically acceptable salt thereof:(VI),wherein A’, Ri, R2, R4, R5, Rs, R$a, a, n and p are as defined above with respect to Formula (II), and Xi, X2, X3, X4, X5 and Zi, and Z2 are each CH or N. In some embodiments, the compound is a compound of Formula (VI), wherein at least three of Xi, X2, X3, X4, and X are CH and at least one of Zi, and Z2 is CH.Bd.

[0054] In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI) wherein Ri is -COOH. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI) wherein R2 is -methyl. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI), wherein Ri is -COOH and R2 is -methyl.a

[0055] In some embodiments, the compound is a compound of Formulae (I), (V), or (VI) wherein a is 0, 1 or 2. In some embodiments, the compound is a compound of Formulae (I), (V) or (VI), wherein a is 0. In some embodiments, the compound is a compound of Formulae (I), (V) or (VI), wherein a is 1. In some embodiments, the compound is a compound of Formulae (I), (V) or (VI), wherein a is 2.R2

[0056] In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI) wherein R2 is hydrogen, or C1-6 alkyl. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI) wherein R2 is methyl. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI) wherein R2 is C1-4 alkyl. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI) wherein R2 is ethyl. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI) wherein R2 is isopropyl. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI) wherein R2 is butyl. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), (V), or (VI), wherein R2 is isobutyl.Xi, X2, X3, X4, and X5

[0057] In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein Xi, X2, X3, X4 and X5 are each N or CRp and each R4 is independently H, halogen, C 1-4 alkyl optionally substituted with one or more halogen, or C1-4alkyloxy optionally substituted with one or more halogen. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein Xi, X2, X3, X4, and X5 are each CH. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein up to one of Xi, X2, X3, X4 and X5 is N; and each R4 is hydrogen, halogen, methyl or methoxy each optionally substituted with one or more halogen. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein up to one of Xi, X2, X3, X4 and X5 is N; and each R4 is hydrogen, fluoro, chloro, methyl or methoxy each optionally substituted with one or more fluoro.

[0058] In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein Xi, X3, and X5 are each CH, X2 is CF and X3 is CRic, wherein Rte is halogen (e.g., chloro). In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein Xi, X3, X4 and X5 are each CH and X2 is CR.4b, and R.4b is halogen (e.g., chloro). In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein X2, X3, and X5 are each CH, Xi is CRta, wherein FCa is methoxy or methyl optionally substituted with one or more fluoro, and X4 is CR.4d wherein R.4d is chloro or methyl optionally substituted with one or more fluoro. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein Xi, X3 and X5 are each CH; X2 is CRib, and Rib is fluoro or chloro; and X4 is CRid, wherein Rid is methyl optionally substituted with one or more fluoro or methoxy. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein X2 and X3 are both CH; X2 is CRib, wherein Rib is chloro; X4 is CR4d, wherein Rid is fluoro and X5 is CRie, wherein Rie is fluoro or methyl optionally substituted with one or more fluoro. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein X3 and X5 are CH; Xi is CRia, wherein Ria is methyl; X2 is CRib wherein Rib is fluoro; and X4 is CRid, wherein Rid is chloro. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein X3 is N; Xi, X2 and X5 are each CH; and X4 is CRid, wherein Rid is methyl optionally substituted with one or more fluoro. In some embodiments, the compound is a compound of Formulae (I), (II), (II-B), (III), (III-B), (IV), or (VI) wherein Xi is N, X3, X4 and X5 are each CH, and X2 is CRib, wherein Rib is methyl optionally substituted with one or more fluoro.Definitions

[0059] For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0060] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0061] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0062] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0063] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only oneof,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0064] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0065] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0066] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0067] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)- isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in asubstituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0068] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0069] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C-enriched carbon are within the scope of this invention.

[0070] The terms “av[38”, “avB8”, “avb8”, “alpha-v beta-8” and “alpha v beta 8” and the like as used herein all refer to avPs.

[0071] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

[0072] The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19.)

[0073] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

[0074] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or thecosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0075] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0076] The term “patient” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

[0077] Whenever a term (e.g., alkyl or aryl) or either of their prefix roots (e.g., alk- or ar-) appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., arylene is the divalent moiety of aryl, heteroarylene is the divalent moiety of heteroaryl, and heterocycloalkylene is the divalent moiety of heterocycloalkyl. Similarly, affixing the suffix “-oxy” to a group indicates the group is attached to the parent molecular structure through an oxygen atom (-O-) such as “alkyloxy,” “alkoxy” or “cycloalkoxy” as used herein.

[0078] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0079] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or 1 up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl groups may be substituted or unsubstituted. As used herein, “Me” and -CH3 both refer to methyl.

[0080] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0081] " Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. Exemplary cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cycloheptyl(C?), and cyclooctyl (Cs).

[0082] Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0083] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted orunsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0084] The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.

[0085] The terms “heterocyclyl” or “heterocyclic group” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0086] The term “heterocycloalkyl” as used herein, is a non-aromatic heterocyclyl wherein at least one atom is a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Examples of heterocycloalkyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. The heterocycloalkyl group can be substituted or unsubstituted as recited, e.g for heterocyclyls as described herein.

[0087] Tire term “carbonyl” is art-recognized and includes such moieties as can be represented by the formula:OR-16wherein X’ is a bond or represents an oxygen or a sulfur, and R15 represents a hydrogen, an alkyl, an alkenyl, -(CH₂)ₘ-R₁₀ or a pharmaceutically acceptable salt, Rig represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-Rio, where m and Rio are as defined above. Where X’ is an oxygen and R15 or Rig is not hydrogen, the formula represents an “ester.” Where X’ is an oxygen, and R15 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R15 is a hydrogen, the formula represents a “carboxylic acid”. Where X’ is an oxygen, and Rig is a hydrogen, the formula represents a “formate.” On the other hand, where X’ is a bond, and R 15 is not hydrogen, the above formula represents a “ketone” group. Where X’ is a bond, and R15 is a hydrogen, the above formula represents an “aldehyde” group.

[0088] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above, and for example substituted with one or more substituents selected from alkyl, cycloalkyl, heterocycloalkyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH₂amine, CH₂amine, and CN. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0089] As used herein, the term “nitro” means -NO2; the term “halogen” designates - F, -Cl, -Br, or -I; the term “hydroxyl” means -OH; and the term “cyano” means -CN.

[0090] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0091] The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. Accordingly, prodrugs include compounds that are transformed in vivo to yield a disclosed compound or anyother pharmaceutically acceptable form of the compound. In embodiments, a prodrug may be inactive when administered to a subject but may be converted in vivo to an active compound, for example, by hydrolysis. See, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A. C. S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Prodrugs can typically be prepared using well known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985). The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject.

[0092] Prodrugs of compounds described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to provide a compound described herein (i.e., the parent active compound). Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto0group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate > 9and / / benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an a(m / .- \in < A ■—\e \ 1 functional group in the active compound and the like. Other examples of ) £3prodrugs incluX \d / ' / keff F i..; compounds that comprise - -NO, - NO2, - -ONO, or - -ONOzmoieties.

[0093] For p WuXr ■poses of this invention, the chemical elements are identified inraccordance with the Pe 11r Aiodic Table of the Elements, CAS version. Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.Exemplary Compounds of the Invention

[0094] This disclosure relates to novel chemical compounds and methods useful for inhibiting 0,4 7 integrin.

[0095] In some embodiments, the compound is a compound from Table 1, or 1A, or a pharmaceutically acceptable salt thereof.Table 1. Table"lAr" rlf- L X A X / x{J.{1\ 1Q X... x I 'I Aa ' ~ ■ IQ J( J k JkyN1-P2 2-P1C l.. 1 0 ot> IT If \( QQ.... I... I A. X XXXI A- Jl if — A kJ J u - - ’ KJ 2-P2 3-P1 3-P20 1 QA Il I Jv\ V 1.7 " T " T fcifQk kX / X J J JO O y 0 - 34-P1 4-P2 5-P1-34-'T O\ / O i1I 1 / O OG I ] K O ( J cx>.. I _ 1 A._O,. TA.. X.~ I A CI " r j XX 'TXj XX ’ I O 14-P2 15-P1 15-P2 X X J O- [ J co L J LD=. A A ^1 / " JX-I OX1C XX1XX 0X -"Nc 01NO \ 16-P1 16-P2 17-P117 i jv / C 4 _z-!ixO X--""' Cl.!. I\1 1 I 1 X J 1xr '-' T x - " 1 ^ 1 7. 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XT^XA ex r X) UX XT xxxX X-X xXJ^-64--65-7 (.< J,,, 1 1 \ JG O P Xf f 70 X>j 70\Z ’ 7 \ 00, DO1£OPM =o... nZ w w p / O 1 fZ K p >. ^PoVp \ sO OQ'K P O\ J / J J— \, rK \\ / pOO^O-''7' ' > / oo-.''op \. / P / \ 7ss 77Z o > " J P" P( 1 <1). K \ / v.„ 7 80.. o-M> / V / X >“ X47 00«-, i X I -O< J " KO_ < \.> \ rx■» \ rJ0* O 7 07 „,, 1 10 10 CO' I X X 1 J ZO P ZP PP. J i '? K A P co£_ o). ■ - \ O ) \\0J? ZO O,, 1, j O < JO^ O JOJ zp'cCP'' >010X0Oj""'"^orz) JJl OO OJ;Op'" P? Cl - I J s 0,00 00 > I X 1 7 I c S. J ’ ' i Iff 07 OO'-0__ / ftx:-x& XV. U. X CC^ X xp 1 ft < XXxJ' ' Y U..o co1IJJJ oX. -cA ' O ^XC xxXSJ' C. i. j - u j / pj cpc> X. ' 71,. AX,->r XJ - c ro C I JJJ I / X / \ AX <1 IX- AX )^ \ / COi XxX / 4) ) g.X^.,u i XIO1i; i xxx^pUX1 li\ _ ) i A-PC^Xla. U OXjXI i if )X^ftO. rd.. *6X. x xO jy ox KX X / ftx & dft5 / r. IC IJXXI / \ / U \ A s J ( / ( ) < Xfl).. )) A Mr‘ft.... J. Xp X xXC C AIJA k x / Xl _ 1 I ( p..l... 1xJp -I / J~ I I 1 1 lplcPAP Ju txQ-68-X A... AI Ay,.. j. X CC QXy ' X, A / x y X I..J T> sX; «X X^ XzCx l>= / z' ~. Xi XXX * c ”’ \ ) x / I-' / X_A Hi )X.:- ~ ' X A _ J. I / XI.. ■.! Iy r^ I 1 ' f H 'AX. A CC CO-. / ~" A i0XT J. X I 1, JXI I T X X 1O AX x r X IX„ f x CCA I 1 xx cxx X AX < AX'i \ [ X X X1A.., 1 it': I. ' | 7 ' X.1 r AC I f A X. X c O c AX X^1I X / . I r 1. r X Cx O'XI.. A (, O co■. X^T^^^lXXx / \A.XI i 1.. I J■ ' " I l f I' jy cpc, CJ IQl \.. OT"^""'i'Ox

[0096] In some embodiments, the compound is a compound from Table 2, or a pharmaceutically acceptable salt thereof.Table 2. Exemplary Compounds7III Cd X'Azf J IXp c i x AKJ ' ' r 1 Q... A I I A P Xi 6d. XJ^ ~ T If A 103-P2 106-P2 109-P1 " X£ r r p- X... 1 Ip oP.. opP ^.. IP IA(J ~1Aj 'Al XX X Pi p ip '■ i ' 11O-P1 113-P2 115-P21 J.or cP X / xjtp Axf cP P v-AUA j A,-xA i ~ 1 J... i i.. 1 1 V IQ V " 'r1 p ‘ X A V 116-P2 117-P1 118-P1 AxKV / UApzOI X / Xjr ri1p 1 X X '.XX xx> KT - -Tt 1 q X Ips X 'i 122-P1 123-P3 124-P1 O... I ip,c..",1 J ': 1 ' A 7 iiC J EC Ix> O ICO XX CO 7 I „ I 1 r... 'N 1''" 1 'X-.'X".. OP 1 '>i'x1.-X~--• / rj i IQ XJ11z7 127-P2 129-P2 132-P1 o AApl - ^ x dp / Al „ i,1 C? A,i ip X ' J II 'U I 7 TT~^X 7 L ~A "cirQ \ JO co' '•■ r \ ' i Co A / T '134-P1 135-P1 136-P1

[0097] Exemplary formulas and compounds are described herein. Also provided herein are exemplary embodiments of structural features which may be present in any formula described herein. Any exemplary embodiment of a structural feature may occur in combination with any other exemplary structural feature described herein. Further, and unless otherwise indicated herein, any description of a formula or compound also includes any pharmaceutically acceptable forms of the compound, including but not limited to any pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of disclosed formulas and compounds.Therapeutic Uses of a Compound of Formula (I)

[0098] In some embodiments, compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or deuterated analog thereof, may be used to treat subjects who have or are suspected of having disease states, disorders, and conditions (also collectively referred to as “indications”) responsive or believed to be responsive to the inhibition of a4p7 integrin activity. In some embodiments, the compounds described herein may be used to inhibit the activity of a4[37 integrin, In some embodiments, the compounds described herein may be used to inhibit excessive ordestructive immune reactions or growth or a proliferation of a cell, such as a cancer cell, or inhibit immunosuppression.

[0099] In some embodiments, the present disclosure provides a compound described herein useful as an inhibitor of a4[37 integrin. In some embodiments, the present disclosure provides a method of treating or preventing an inflammatory disease or condition comprising administering a compound described herein to a patient.[000100] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.[000101] In some embodiments, provided is a compound described herein useful for the treatment of an inflammatory disease or condition in a patient that is mediated, at least in part, by a4[37 integrin.[000102] In embodiments, a subject is an adult subject.Integrin Mediated Disease[000103] Diseases that are responsive to a4[37 inhibition include autoimmune diseases, and chronic gastrointestinal and gastroesophageal inflammatory diseases. Inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, gastroesophageal inflammatory disease, Eosinophilic Gastrointestinal Disorders (EGIDs), esosinophilic gastroenteritis, esosinophilic gastritis, eosinophilic duodenitis, and eosinophilic esophagitis (EoE) are examples of diseases that can be treated with a compound of Formula (I).[000104] As further shown herein, methods of the invention can achieve significant therapeutic benefit for subjects having inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s disease).[000105] Compound of Formula (I) are useful for the treatment of diseases or conditions mediated, at least in part, by a4[37 integrin.[000106] In additional embodiments, the methods are provided for alleviating a symptom of a disease or disorder mediated, at least in part, by a4[37 integrin. In some embodiments, the methods include identifying a mammal having a symptom of a disease or disorder mediated, at least in part, by a4[37 integrin, and providing to the mammal an amount of a compound as described herein effective to ameliorate (i.e., lessen the severity of) the symptom.Treatment of Inflammatory Bowel Diseases[000107] In some embodiments, the disease or condition mediated, at least in part, by a4[37 integrin is inflammatory bowel disease (IBD).[000108] The term “inflammatory bowel disease” or “IBD” as used herein is a collective term describing inflammatory disorders of the gastrointestinal tract, the most common forms of which are ulcerative colitis and Crohn’s disease. Other forms of IBD that can be treated with the presently disclosed compounds, compositions and methods include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behcet’s disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation induced enteritis, short bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, and chronic diarrhea.[000109] Treating or preventing IBD also includes ameliorating or reducing one or more symptoms of IBD. As used herein, the term “symptoms of IBD” refers to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications, such as dehydration, anemia and malnutrition. A number of such symptoms are subject to quantitative analysis (e.g. weight loss, fever, anemia, etc.). Some symptoms are readily determined from a blood test (e.g. anemia) or a test that detects the presence of blood (e.g. rectal bleeding). The term “wherein said symptoms are reduced” refers to a qualitative or quantitative reduction in detectable symptoms, including but not limited to a detectable impact on the rate of recovery from disease (e.g. rate of weight gain). The diagnosis is typically determined by way of an endoscopic observation of the mucosa, and pathologic examination of endoscopic biopsy specimens.[000110] The course of IBD varies and is often associated with intermittent periods of disease remission and disease exacerbation. Various methods have been described for characterizing disease activity and severity of IBD as well as response to treatment in subjects having IBD. Treatment according to the present methods is generally applicable to a subject having IBD of any level or degree of disease activity.[000111] Criteria useful for assessment of disease activity in subjects with ulcerative colitis can be found in, e.g., Truelove et al., Br Med J 2: 1041-1048 (1955).) Using these criteria,disease activity can be characterized in a subject having IBD as mild disease activity or severe disease activity. Subjects who do not meet all the criteria for severe disease activity, and who exceed the criteria for mild disease activity are classified as having moderate disease activity.[000112] The presently disclosed treatment methods can also be applied at any point in the course of the disease. In some embodiments, the methods are applied to a subject having IBD during a time period of remission (i.e., inactive disease). In such embodiments, the present methods provide benefit by extending the time period of remission (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In other embodiments, methods may be applied to a subject having IBD during a period of active disease. Such methods provide benefit by reducing the duration of the period of active disease, reducing or ameliorating one or more symptoms of IBD, or treating IBD.[000113] Measures for determining efficacy of treatment of IBD in clinical practice have been described and include, for example, the following: symptom control; fistula closure; extent of corticosteroid therapy required; and improvement in quality of life. Health-related quality of life (HRQL) can be assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is extensively used in clinical practice to assess quality of life in a subject with IBD. (See Guyatt et al., Gastroenterology 96:804-810 (1989).) In some embodiments, the disease or condition is immune-mediated liver injury, disease or condition.[000114] In embodiments, a method comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof is a method of maintenance therapy for treating an inflammatory bowel disease (e.g., an inflammatory bowel disease such as ulcerative colitis or Crohn’s disease). In embodiments, a method of maintenance therapy comprising administering a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof follows an initial method of induction therapy comprising administering a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof. In embodiments, a method of maintenance therapy immediately follows a method of induction therapy.[000115] In embodiments, maintenance therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II- A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof follows induction therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof. In embodiments, periods of treatment described herein can be the sum of induction and maintenance therapy comprising administration of a compound of Formula (I) (e.g., a compound of Formula (I), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (V-A) or (VI)) or any pharmaceutically acceptable salt thereof.Ulcerative Colitis[000116] In embodiments, a compound of Formula (I) (e.g., a compound of any one of Formulae (la), (lb), and (Ic) such as a compound of Formula (VI)), or a pharmaceutically acceptable salt thereof, can be used in methods to treat ulcerative colitis in a subject in need thereof.[000117] In embodiments, ulcerative colitis is moderate to severe ulcerative colitis. In embodiments, ulcerative colitis is moderate ulcerative colitis. In embodiments, ulcerative colitis is severe ulcerative colitis.[000118] In embodiments, ulcerative colitis is moderately to severely active ulcerative colitis.In embodiments, ulcerative colitis is moderately active ulcerative colitis. In embodiments, ulcerative colitis is severely active ulcerative colitis.Crohn ’s Disease[000119] In embodiments, a compound of Formula (I) (e.g., a compound of any one of Formulae (la), (lb), and (Ic) such as a compound of Formula (VI)), or a pharmaceutically acceptable salt thereof, can be used in methods to treat Crohn’s disease in a subject in need thereof.[000120] In embodiments, Crohn’s disease is moderate to severe Crohn’s disease. In embodiments, Crohn’s disease is moderate Crohn’s disease. In embodiments, Crohn’s disease is severe ulcerative colitis.[000121] In embodiments, Crohn’s disease is moderately to severely active Crohn’s disease. In embodiments, Crohn’s disease is moderately active Crohn’s disease. In embodiments, Crohn’s disease is severely active Crohn’s disease.Additional Embodiments[000122] The following additional embodiments are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, that would be within the purview of those skilled in the art, and changes in formulation or changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:(I),wherein:is a 3- to 12-membered heterocyclyl optionally substituted with one or more instances of R3, -N(Ra)-(C3-i2-cycloalkyl) optionally substituted with one or more instances of R3, or -N(Ra)-Ra’;Ra and Ra’ are each independently is H or C1-4 alkyl;a is 0, 1, 2 or 3;Ri is H or -COORib;Rib is H or C1-4 alkyl;R2 is H or C1-4 alkyl;each R3 is independently hydrogen, halogen, C1-6 alkyl, C3-8 cycloalkyl, 3-8 member heterocycloalkyl, or C1-6 alkyloxy, wherein the C1-6 alkyl and C1-6 alkyloxy are optionally substituted with one or more halogen;R4 is H, C1-4 alkyl optionally substituted with one or more halogen, or halogen;p is 0, 1, 2, 3, 4 or 5;is a 3- to 12-membered heteroaryl, C5-12 aryl, 3- to 12-membered heterocycloalkyl or C5-12 heterocyclyl, each optionally substituted with one or more instances of Rs or Rs;each Rs is independently a 3- to 12-membered heterocycloalkyl or C3-12 cycloalkyl, each optionally substituted with one or more instances of Rr / :each $ and Re’ is independently C 1-6 alkyl, halogen, C 1-6 alkyloxy, OH, Ci-ealkyl-OH, C 1-6 alkyl-C 1-6 -alkyloxy, C 1-6 alkyl oxy-Ci-6-alkyloxy, and each C 1-6 alkyl, C 1-6 alkyloxy, C1-6 alkyl-OH, C1-6 alkyl-Ci-6-alkyloxy, C 1-6 alkyloxy-C 1-6 -alkyloxy, is optionally substituted with 1 to 4 instances of R7;each R7 is independently halogen, or C1-6 alkyl optionally substituted with one or more halogen, hydroxy, or C1-6 alkoxy.2. The compound of embodiment Ri is -COORib.3. The compound of any one of embodiments 1-2, wherein Rib is H or methyl.4. The compound of embodiment 3, wherein Rib is H.5. The compound of any one of embodiments 1-4, wherein R2 is methyl.6. The compound of any one of embodiments 1-5, wherein each R4 is halogen.7. The compound of embodiment 6, wherein each R4 is independently fluoro or chloro. 8. The compound of any one of embodiments 1-7, wherein p is 2.9. The compound of any one of embodiments 1-8, wherein each R3 is independently halogen, methyl or methoxy.I A I10. The compound of any one of embodiments 1-8, wherein' is a 3- to 8-membered heterocyclyl optionally substituted with halogen, C1-6 alkyl or Ci-galkyloxy, wherein the C1-6 alkyl and C 1-6 -alkyloxy are optionally substituted with one or more halogen.11. The compound of embodiment 10, whereinx' is a 5- or 8-membered heterocyclyl optionally substituted with halogen, C1-6 alkyl or Ci-ealkyloxy, wherein the C1-6 alkyl and Ci-6-alkyloxy are optionally substituted with one or more halogen.The compound of embodiment 10, whereinis a pyrrolidine, piperidine, piperazine or morpholino optionally substituted with halogen, Ci-6 alkyl or Ci-galkyloxy, wherein the Ci-6 alkyl and Ci-6 -alkyloxy are optionally substituted with one or more halogen.I A IThe compound of embodiment 10, whereinis a pyrrolidine, piperidine, piperazine or morpholino optionally substituted with one or more instances of C 1-4 alkyl or Ci-4-alkyloxy.I A IThe compound of embodiment 10, whereinis a pyrrolidine, piperidine, piperazine or morpholino optionally substituted with one or more instances of methyl, ethyl, isopropyl, methoxy.The compound of embodiment 10, whereincycloalkyl) optionally substituted with one or more instances of R3.The compound embodiment 16, whereinis -N(Ra)-(Cs-6-cycloalkyl) optionally substituted with one or more instances of R3.The compound of embodiment 16, whereinis -N(Ra)-(C6-cycloalkyl).The compound of any one of embodiments 16-18, wherein Rais methyl.The compound of any one of embodiments 1-20, whereinis unsubstituted.The compound of any one of embodiments 1-9, whereinis -N(Ra)-Ra’.The compound of embodiment 21, wherein Ra and Ra’ are each independently C1-4 alkyl. The compound of any one of embodiments 21-22, wherein Rais methyl.The compound of any one of embodiments 21-23, wherein Ra’ is C1-4 alkyl.The compound of any one of embodiments 21-24, wherein Ra’ is isobutyl.(cJThe compound of any one of embodiments 1-25, whereinis a 3- to 12-membered heteroaryl, optionally substituted with one or more instances of Rs or R$. / \{ y c / )The compound of embodiment 26, whereinis a 8- to 10-membered bicyclic heteroaryl, optionally substituted with one or more instances of Rs or R$.T \ / The compound of embodiment 26, wherein is a 9-membered bicyclic heteroaryl, substituted with one or more Rs or Rr,.c JThe compound of embodiment 26, whereinis an indazole substituted with one or more Rs or s.The compound of any one of embodiments 1-29, wherein Rs is a 5- to 6-membered heterocycloalkyl or C5-6 cycloalkyl, each optionally substituted with one or more instances of Re’;and Rs is C1-6 alkyl.The compound of any one of embodiments 1-30, wherein Re’ is C1-4 alkyl optionally substituted with one or more halogen, halogen, or C 1-4 alkyloxy optionally substituted with one or more halogen.The compound of any one of embodiments 1-25, wherein** wherein R3 is Rsa, Rsb or Rsc are each independently hydrogen, halogen, C1-6 alkyl, C3-8 cycloalkyl, or Ci-galkyloxy, wherein the C1-6 alkyl and C1-6 alkyloxy are optionally substituted with one or more halogen; and Rs is a 3- to 12-membered heterocycloalkyl or C3-12 heterocyclyl, each optionally substituted with one or more instances of Re’.The compound of embodiment 32, whereinis, wherein R3 is R?aor R3b and Rsa is methyl or cyclopropyl; R?b is hydrogen or halogen; and Rs is a 5 - to 6-membered heterocycloalkyl or C5-6 heterocyclyl, each optionally substituted with one or more instances of $’.The compound of embodiment 33, wherein Rs is cyclohexyl.The compound of embodiment 34, wherein $’ is C1-6 alkyloxy.The compound of embodiment 35, wherein Rs isThe compound of any one of embodiments 33-36, wherein Rsa is methyl.The compound of embodiment 37, wherein R?i, is hydrogen or fluoro.The compound of embodiment 38, wherein Rsi, is hydrogen.The compound of embodiment 32, whereinIS *y' wherein Rsais Ci-6 alkyl, Rsb is hydrogen or halogen, and Rscis Ci-6 alkyl.The compound of embodiment 40, wherein R3a is methyl, R3b is hydrogen, fluoro or chloro, and R3c is C1-6 alkyl.The compound of embodiment 41, wherein RscisI c }The compound of any one of embodiments 1-25, wherein■ / is an isochromane.‘A,A;The compound of embodiment 43, whereinis, wherein each Rio is independently Ci-6 alkyl optionally substituted with one or more halogen, halogen, Ci-6 alkyloxy, or OH; a is 0, 1, 2 or 3; and Ai, A2, A3 and A4 are each independently O or CRioaRiob, wherein Rwaand Riob are each independently hydrogen, C1-6 alkyl optionally substituted with one or more halogen, halogen, C1-6 alkyloxy, or OH, provided that one of Ai, A2, A3 and A4 is O.The compound of embodiment 44, wherein Ai is CRioaRiob, A2 is O and A3 and A4 are each CH2.The compound of embodiment 44, wherein Ai is CRioaRiob, A3 is O and A2 and A4 are each CH2.The compound of embodiment 44, wherein Ai is CRioaRiob, A4 is O and A2 and A3 are each CH2.The compound of any one of embodiments 41-44, wherein Rioais methyl and Riob is hydrogen.The compound of any one of embodiments 1-48, wherein a is 1.The compound of any one of embodiments 1-48, wherein a is 2.. A compound of the chemical formula, ora pharmaceutically acceptable salt thereof., A compound of the chemical formula’ — or a pharmaceutically acceptable salt thereof.. A compound of the chemical formulapharmaceutically acceptable salt thereof.. A compound of the chemical formula\, or a pharmaceutically acceptable salt thereof.A compound of the chemical formula, or a pharmaceutically acceptable salt thereof.A compound of the chemical formulaora pharmaceutically acceptable salt thereof.A compound of the chemical formula. ora pharmaceutically acceptable salt thereof.A compound of the chemical formula, ora pharmaceutically acceptable salt thereof.. A compound of the chemical formula, ora pharmaceutically acceptable salt thereof., A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.. A compound of the chemical formulapharmaceutically acceptable salt thereof.. A compound of the chemical formulapharmaceutically acceptable salt thereof.. A compound of the chemical formula. or a pharmaceutically acceptable salt thereof.. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.. A compound of the chemical formula, or a pharmaceutically acceptable salt thereof., A compound of the chemical formula, or a pharmaceutically acceptable salt thereof.A compound of the chemical formulapharmaceutically acceptable salt thereof.A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.A compound of the chemical formulapharmaceutically acceptable salt thereof.A compound of the chemical formulapharmaceutically acceptable salt thereof.A compound of the chemical formulapharmaceutically acceptable salt thereof.pharmaceutically acceptable salt thereof.A compound of the chemical formulai, or a pharmaceutically acceptable salt thereof.A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.76. A compound of the chemical formulapharmaceutically acceptable salt thereof.77, A compound of the chemical formula, or a pharmaceutically acceptable salt thereof.78. A compound selected from the group consisting of the compounds in Figure 1, or a pharmaceutically acceptable salt thereof.79. A pharmaceutical composition comprising the compound of any one of embodiments 1- 78, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.80. A method of treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-78, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 79.Further Embodiments1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:is a 3 - to 12-membered heterocyclyl optionally substituted with one or more instances of R3, -N(Ra)-(C3-i2-cycloalkyl) optionally substituted with one or more instances of R3, or -N(Ra)-Ra’;Ra and Ra’ are each independently is H or C1-4 alkyl;a is 0, 1, 2 or 3;Ri is H or -COORib;Rib is H or C1-4 alkyl;R2 is H or C1-4 alkyl;each R3 is independently hydrogen, halogen, C 1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3-to 8-membered heterocycloalkyl, or C 1-6 alkyl oxy,wherein the C1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, and C1-6 alkyloxy are optionally substituted with one or more halogen, C1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkoxy;Xi, X2, X3, X4 and X5 are each N or CR4;each R4 is H, halogen, C 1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkyloxy optionally substituted with one or more halogen;p is 0, 1, 2, 3, 4 or 5;\v / is a 3- to 12-membered heteroaryl, C5-12 aryl, 3- to 12-membered heterocycloalkyl or C5-12 heterocyclyl, each optionally substituted with one or more instances of Rs or Rb;each Rs is independently a C1-6 alkyl, 3- to 12-membered heterocycloalkyl or C3-12 cycloalkyl, each optionally substituted with one or more instances of Rg’;each Rs and Rg’ is independently C1-6 alkyl, halogen, Ci-s alkyloxy, OH, Ci-salkyl-OH, C 1-6 alkyl-C i-s -alkyloxy, Ci-salkyloxy-Ci-s-alkyloxy, and each Cns alkyl, C1-6 alkyloxy, Ci-s alkyl-OH, Cusalkyl-Ci-s-alkyloxy, Ci-salkyloxy-Ci-6-alkyIoxy, is optionally substituted with 1 to 4 instances of R7;each R7 is independently halogen, or C1-4 alkyl optionally substituted with one or more halogen, hydroxy, or C1-6 alkoxy.2. The compound of embodiment 1, wherein the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof:(11),whereinA’ is a 5- to 8-membered heterocyclyl optionally substituted with one or more instances of Rs, -N(Ra)-(C5-s-cycloalkyl) optionally substituted with one or more instances of R3, or -NCR -Ra’jeach R3 is independently C1-4 alkyl, or C1-4 alkoxy; or two R3 form a C3-8 spirocyclic cycloalkyl, spirocyclic 3- to 8-membered heterocyclyl, fused or bridged C3-8 cycloalkyl, fused or bridged 3- to 8-membered heterocycloalkyl, and each R3 is optionally substituted with one or more halogen, C1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkoxy;X1, X2, X3, X4 and X5 are each N or CR4; and one of X1, X2, X3, X4 and X5 is optionally absent;each R4 is H, halogen, C1-4 alkyl optionally substituted with one or more halogen, or C 1-4 alkyloxy optionally substituted with one or more halogen;Rs is C1-6 alkyl or a 3- to 12-membered heterocycloalkyl or C3-12 cycloalkyl, each optionally substituted with one or more instances of Rs’;R6a is C1-6 alkyl or C3-8 cycloalkyl;R6b is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy wherein the C1-6 alkyl or C1-6 alkoxy is optionally substituted with one or more halogen or C1-6 alkoxy; andRb’ is halogen, C1-6 alkyl optionally substituted with one or more halogen, C1-6 alkyloxy optionally substituted with one or more halogen, or OH.3. The compound of embodiment 1 or 2, wherein Ri is -COORib.4. The compound of embodiment 3, wherein Rib is hydrogen and each R4 is H, halogen, C1-4 alkyl optionally substituted with one or more halogen, or C 1-4 alkyloxy optionally substituted with one or more halogen.5. The compound of any one of embodiments 1-4, whereina. up to one ofXi, X2, X3, X4 and X5 is N; andb. each R4 is hydrogen, halogen, methyl or methoxy each optionally substituted with one or more halogen,6. The compound of any one of embodiments 1-5, whereina. Xi, Xs, and X5 are each CH, X2 is CF and X3 is CC1;b. Xi, X3, X4 and X5 are each CH and X2 is CC1;c. X2, X3, and X5 are each CH, Xi is CRia, wherein Ria is methoxy or methyl optionally substituted with one or more fluoro, and X4 is CRia wherein Rid is chloro or methyl optionally substituted with one or more fluoro;d. Xi, X3 and X5 are each CH; X2 is CRib, and Rib is fluoro or chloro; and X4 is CRia, wherein Rid is methyl optionally substituted with one or more fluoro or methoxy;e. X2 and X3 are both CH; X2 is CRib, wherein Rib is chloro; X4 is CRia, wherein Ria is fluoro and X5 is CRie, wherein R4e is fluoro or methyl optionally substituted with one or more fluoro;f. X3 and X5 are CH; Xi is CRia, wherein Ria is methyl; X2 is CRib wherein Rib is fluoro; and X4 is CRia, wherein Ria is chloro;g. X3 is N; Xi, X2 and X5 are each CH; and X4 is CR a. wherein Rid is methyl optionally substituted with one or more fluoro; orh. Xi is N, X3, X4 and X5 are each CH, and X2 is CRib, wherein Rib is methyl optionally substituted with one or more fluoro.7. The compound of any one of embodiments 1-6, wherein R6b is hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy, wherein C1-6 alkyl or C1-6 alkoxy is optionally substituted with one or more halogen.The compound of any one of embodiments 1-7, wherein R6a is C1-4 alkyl.The compound of claim 8, wherein R6a is methyl or cyclopropyl.The compound of any one of embodiments 1-9, wherein Rs is cyclohexyl substituted with $’.The compound of embodiment 10, wherein $’ is Ci-6 alkyloxy optionally substituted with one or more halogen.The compound of embodiment any one of claims 1-11, wherein Rs isThe compound of any one of embodiments 1-9, wherein R5 is C1-6 alkyl.vvThe compound of embodiment 13, wherein R5 isThe compound of any one of embodiments 1-14, wherein A’ is a heterocyclyl optionally substituted with one or more instances of R3.The compound of embodiment 15, wherein A’ is a 5- to 6-membered heterocyclyl substituted with one or more R3.The compound of embodiment 15, wherein A’ is pyrrolidine, piperidine, piperazine or morpholino optionally substituted with one or more instances of C1-4 alkyl or C1-4 alkoxyl.The compound of embodiment 17, wherein A’ is substituted with one or more methyl, ethyl, isopropyl, methoxy.The compound of any one of embodiments 1-14, wherein A’ is -N(Ra)-(Cs-8-cycloalkyl) optionally substituted with one or more instances of R3.The compound of embodiment 20, wherein A’ is -N(CH3)-(cyclohexyl).The compound of any one of embodiments 1-14, wherein A’ is -N(Ra)-Ra’.The compound of embodiment 22, wherein Ra and Ra’ are each independently hydrogen or C1-6 alkyl.The compound of any one of embodiments 1-23, wherein R5 is C1-6 alkyl or cyclohexyl substituted with C1-6 alkoxy optionally substituted with one or more halogen.The compound of embodiment 24, whereinA’ is pyrrolidine, piperidine, piperazine or morpholino optionally substituted with one or more instances of C1-4 alkyl or C1-4 alkoxyl;Ri is COOH;R4a is chloro and R4b is fluoro;R6a is methyl or cyclopropyl and R6b is hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy;Rb’ is C1-4 alkyl or C1-6 alkoxy, each optionally substituted with one or more fluoro.The compound of embodiment 25, whereinR6a is methyl;R6b is hydrogen, fluoro, methyl or methoxy;Rb’ is methyl, ethyl, or -OCH3 optionally substituted with one or more fluoro;A’is "‘. or each optionally substituted with one or more instances of C1-4 alkyl or C1-4 alkyloxy, each optionally substituted with one or more fluoro.The compound of any one of embodiments 1-27, wherein the compound is a compound of Formula (II-B), or a pharmaceutically acceptable salt thereof:(II-B),whereinXi, X2, X3, X4, and X5 are each CR4 or N, andeach R4 is independently hydrogen, halogen, C 1-4 alkyl or C1-4 alkoxy each optionally substituted with one or more halogen.The compound of embodiment 1, wherein the compound is a compound of Formula (III) or a pharmaceutically acceptable salt thereof:whereinA’ is a 5- to 8-membered heterocyclyl optionally substituted with one or more instances of R3, -N(Ra)-(Cs-8-cycloalkyl) optionally substituted with one or more instances of R3, or -N(Ra)-Ra’;each R3 is independently C1-4 alkyl, C1-4 alkoxy, or two R3 form a C3-8 spirocyclic cycloalkyl, spirocyclic 3- to 8-membered heterocyclyl, fused or bridged C3-8 cycloalkyl, fused or bridged 3- to 8-membered heterocycloalkyl, and each R3 is optionally substituted with one or more halogen, C1-4 alkyl optionally substituted with one or more halogen, or Ci-4 alkoxy;Xi, X2, X3, X4, and X5 are each CR4 or N;each R4 is independently hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy each optionally substituted with one or more halogen.A2, A3 and A4 are each independently oxygen or CR10R10’, provided that 0 or 1 of A2, A3 and A4 is oxygen;each of Rioa, Riob, Rio and Rio’ are independently C 1-4 alkyl optionally substituted with one or more halogen, halogen, C 1-4 alkyloxy, or OH.30. The compound of embodiment 29, whereinRi is COOH;Ria is chloro and Rib is fluoro;R6b is hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy;A2, A3 and A4 are each independently oxygen or CH2, provided that 1 and only 1 of A2, and A3 is oxygen; andRioa is ethyl, and Riob is hydrogen.27. The compound of any one of embodiments 29-30, wherein A’ is a heterocyclyl optionally substituted with one or more instances of R3.28. The compound of embodiment 27, wherein A’ is a 5- to 6-membered heterocyclyl substituted with one or more R3.29. The compound of embodiment 27, wherein A’ is pyrrolidine, piperidine, piperazine or morpholino optionally substituted with one or more instances of C1-4 alkyl or C1-4 alkoxyl.30. The compound of embodiment 29, wherein A’ is substituted with one or more methyl, ethyl, isopropyl, methoxy.The compound of embodiment 29 or 30, wherein A’ is -N(Ra)-(Cs-8-cycloalkyl) optionally substituted with one or more instances of R3.The compound of embodiment 32, wherein A’ is -N(CH3)-(cyclohexyl).The compound of embodiment 29 or 30, wherein A’ is -N(Ra)-Ra’.The compound of embodiment 34, wherein Ra and Ra’ are each independently hydrogen or C1-6 alkyl.The compound of embodiment 29 or 30, wherein A’ is pyrrolidine, piperidine, piperazine or morpholino optionally substituted with one or more instances of C 1-4 alkyl or C1-4 alkoxyl.The compound of embodiment 29 or 30, wherein A’ is\ / each optionally substituted with one or more instances of C1-4 alkyl or C1-4 alkyloxy, each optionally substituted with one or more fluoro.The compound of any one of embodiments 29-37, wherein the compound is a compound of Formula (III-B), or a pharmaceutically acceptable salt thereof:(II1-B).A compound of the chemical formula. or a pharmaceutically acceptable salt thereof.A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.A compound of the chemical formulaora pharmaceutically acceptable salt thereof., A compound of the chemical formulaora pharmaceutically acceptable salt thereof.. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.. A compound of the chemical formula— ora pharmaceutically acceptable salt thereof., A compound of the chemical formulapharmaceutically acceptable salt thereof., A compound of the chemical formulaa pharmaceutically acceptable salt thereof.A compound of the chemical formula, ora pharmaceutically acceptable salt thereof.pharmaceutically acceptable salt thereof.A compound of the chemical formula, ora pharmaceutically acceptable salt thereof.A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.A compound of the chemical formula, or a pharmaceutically acceptable salt thereof.. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.. A compound of the chemical formula, or a pharmaceutically acceptable salt thereof.. A compound of the chemical formula. or a pharmaceutically acceptable salt thereof., A compound of the chemical formula, or a pharmaceutically acceptable salt thereof.. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof., A compound of the chemical formula, ora pharmaceutically acceptable salt thereof.. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.. A compound of the chemical formulaor a pharmaceutically acceptable salt thereof.XOH' o. A compound of the chemical formula\, ora pharmaceutically acceptable salt thereof.. A compound of the chemical formulaI, or a pharmaceutically acceptable salt thereof.. A compound of the chemical formula'. or a pharmaceutically acceptable salt thereof.. A compound of the chemical formula, or a pharmaceutically acceptable salt thereof., A compound of the chemical formula, ora pharmaceutically acceptable salt thereof.. A compound of the chemical formula, or a pharmaceutically acceptable salt thereof.. A compound selected from the group consisting of the compounds in Figure 1, or a pharmaceutically acceptable salt thereof.. A pharmaceutical composition comprising the compound of any one of embodiments 1- 65, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.. A method of treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease, comprising administering to a subject in need thereof a therapeutically effective amountof a compound of any one of embodiments 1-65, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 66.Exemplary Embodiments[000123] The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, that would be within the purview of those skilled in the art, and changes in formulation or changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.[000124] Certain examples below relate to methods for treating or preventing a disease responsive to an a4[37 integrin inhibitor by administering a compound of formula (I), (la), (lb), and / or (Ic) to a human in need of such treatment.EXAMPLES[000125] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.[000126] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.ExamplesAbbreviationsAbbreviation Chemical NameAc acetylACN AcetonitrileBINAP (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl)Boc tert-butyloxy carbonylBu butylCBS N-cyclohexyl-2-benzothiazolesulfenamidecod cyclooctadieneCp cyclopentadienylDAST diethylaminosulfur trifluoridedba dibenzylideneacetoneDCM dichloromethaneDCE DichloroethaneDess-Martin, Dess-Martin1,1,1 -triacetoxy- 1,1 -dihydro- l,2-benzodioxo-3 (1 H )-one periodinaneDIAD diisopropyl azodicarboxylateDIEA N, N -diisopropylethylamineDIPEA N, N -diisopropylethylamineDMF dimethyl formamideDMSO dimethyl sulfoxidedppf 1, 1 '-bis(diphenylphosphino)ferroceneEDCI 1 -Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide ESI Electrospray ionizationEt EthylFA Formic acidO-(7-Azabenzotriazol-l-yl)-jV, yV' V-tetramethyluronium HATUhexafluorophosphateHMDS HexamtheyldisilazylHOBt Hydroxy benzotriazoleHPLC High performance liquid chromatographyhr hourHz HertziPr IsopropylLAH Lithium aluminum hydrideLDA lithium diisopropyl amideMe MethylMs Methane sulfonylMS Mass spectrometryNBS N-bromosuccinimideNMR Nuclear Magnetic Resonanceprep-HPLC preparative high performance liquid chromatography Qphos pentaphenyl(di-tert-butylphosphino)ferrocene1 -chloromethyl-4-fluoro- 1,4-diazoniabicyclo [2.2.2]octane Selectfluorbis(tetrafluoroborate)RT room temperatureSFC supercritical fluid chromatographyt-Bu tertiary-butylTEA triethylamineTf trifluoromethanesulfonylTFA trifluoroacetic acidTHF tetrahydrofuranTLC Thin layer chromatographyTMS trimethylsilylChloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'- Xphos Pd G2biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) Analytical Methods (Examples 1-6, 7B, and ##-##)NMR MethodsCompounds were analyzed by NMR using one of the following instruments:BRUKER, AVANCE III 500MHZ, PROBHD 5 mm PABBO BB-, PULPROG zg30, TD 65536, NS 8, DS 0, SWH 10330.578 Hz, DI 1.00000000 sec, NUC1 1H, Pl 13.72 psec, PL1W 13.34460926 W, SF01 500.1330885 MHzBRUKER, AVANCE III 400MHZ, PROBHD 5 mm PABBO BB / , PULPROG zg30, TD 65536, NS 8, DS 2, SWH 8223.685 Hz, DI 1.00000000 sec, SFO1 400.1324710 MHz, NUC1 1H, Pl 15.00 psec, PL1W 11.00000000 WLCMS Analytical MethodsCompounds were analyzed using LC / MS conditions, with UV detector monitoring at 214 nm and 254 nm, and mass spectrometry scanning 110-1500 amu in ESI+ ionization mode.LCMS A: column: XBridge C18, 4.6 X 50 mm, 3.5 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient: 5%-95% B in 1.4 min, then 1.7 min hold; flow rate: 1.8 mL / min; oven temperature 45 °C.LCMS B: column: Sunfire C18, 4.6 X 50 mm, 3.5 pm; mobile phase: A: water(0.1%FA) B: ACN(0.1%FA); gradient: 5%-95% B in 1.5 min, then 1.5 min hold; flow rate: 2 mL / min; oven temperature 50 °C.LCMS C: column: Sunfire C18, 4.6 X 50 mm, 3.5 pm; mobile phase: A: water(0.01%TFA) B: ACN(0.01%TFA); gradient: 5%-95% B in 1.5 min, then 1.7 min hold; flow rate: 2 mL / min; oven temperature 50 °C.LCMS D: column: Poroshell 120 EC-C18, 3.0 X 30 mm, 2.7 pm; mobile phase: A: water(0.01%TFA) B: ACN(0.01%TFA); gradient: 5%-95% B in 0.8 min, then 1.0 min hold; flow rate: 2 mL / min; oven temperature 50 °C.Prep-HPLC MethodsCrude samples were dissolved in MeOH and purified by prep HPLC using a Gilson 215 instrument, detection wavelength 214 nm:Prep HPLC A: column: Xtimate Prep C18, 21.2 * 250 mm, 10 pm; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient elution as in text; flow rate: 20 mL / min.Prep HPLC B: column: Boston pHlex ODS, 21.2 * 250 mm, 10 pm; mobile phase: A water (10 mM formic acid), B CH3CN; gradient elution as in text; flow rate: 20 mL / min.Prep HPLC C: column: XBridge OBD C18, 19 * 100 mm, 5 pm; mobile phase: A water, B CH3CN; gradient elution as in text; flow rate: 20 mL / min.Prep Chiral SFC MethodsRacemic products were separated into individual enantiomers by chiral Prep SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm:Prep chiral SFC A: column: (R, R)-Whelk-01, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC B: column: AD 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC C: column: AS 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC D: column: OD 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC E: column: Cellulose-SC 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC F: column: OZ 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC G: column: IC 20*250mm, 10 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC H: column: (S, S)-Whelk-01, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC I: column: OX-H, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC J: column: IG, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC K: column: IH, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC L: column: OJ, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CCh / mcthanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC M: column: Amylose-C Neo, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC N: column: ID, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC O: column: AY-H, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC P: column: IK, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CCh / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep chiral SFC Q: column: IE, 20*250mm, 5 pm (Daicel), column temperature: 35 °C, mobile phase: CCh / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.Prep Chiral HPLC MethodsRacemic products were separated into individual enantiomers by Prep chiral HPLC using a Gilson-281 (Thar, Waters) instrument (detection wavelength 214 / 254 nm):Prep chiral HPLC A: Column: IE, 20*250mm, 10 pm (Daicel). Column temperature: 35 °C. Mobile phase: n-Hexane (0.1% DEA) / ethanol (0.1% DEA). Flow rate: 38 g / min. Back pressure: 100 bar.Prep chiral HPLC B: Column: OJ-H, 20*250mm, 10 pm (Daicel). Column temperature: 35 °C. Mobile phase: n-Hexane (0.1% DEA) / ethanol (0.1% DEA). Flow rate: 38 g / min. Back pressure: 100 bar.Prep chiral HPLC C: Column: IG, 20*250mm, 10 pm (Daicel). Column temperature: 35 °C. Mobile phase: n-Hexane (0.1% DEA) / ethanol (0.1% DEA). Flow rate: 38 g / min. Back pressure: 100 bar.Prep chiral HPLC D: Column: IC, 20*250mm, 10 pm (Daicel). Column temperature: 35 °C. Mobile phase: n-Hexane (0.1% DEA) / ethanol (0.1% DEA). Flow rate: 38 g / min. Back pressure: 100 bar.Analytical Chiral SFC MethodsChiral products were analyzed by chiral SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm:Chiral SFC A: column: (R, R)-Whelk-Ol, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC B: column: AD 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC C: column: AS 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC D: column: OD 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC E: column: Cellulose-SC 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC F: column: OZ 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC G: column: IC 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC H: column: (S, S)-Whelk-01, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CC>2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC I: column: OX-H, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / mcthanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC J: column: IG, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC K: column: IH, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC L: column: OJ, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC M: column: Amylose-C Neo, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CO₂ / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC N: column: ID, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC O: column: AY, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Chiral SFC P: column: IK, 4.6* 100mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: CCh / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.Analytical Chiral HPLC Methods-Ill- Chiral HPLC A: column: OJ-H 4.6*250mm, 5 n (Daicel), column temperature: 40 °C, mobile phase: n-Hexane (0.1% DEA) / ethanol (0.1% DEA), flow rate: 1 g / minChiral HPLC B: column: IE 4.6*250mm, 5 pm (Daicel), column temperature: 40 °C, mobile phase: n-Hexane (0.1 % DEA) / ethanol (0.1 % DEA), flow rate: 1 g / minExample 1. Preparation of 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin- l-yl)pentyl)(methyl)amino)-2-(l-((lr,4R)-4-(difluoromethoxy)cyclohexyI)-3-methyl-lH-indol-7-yl)acetic acid (compounds 83-P1 and 83-P2 )Step 1: ethyl 2-(((S)-3-(5-chloro~2-methylphenyl)~5-(3,3-dimethylpyrrolidin-l- yl)peniyl)(methyl)amino)-2-(l-((]r,4R)-4-(difluoromethoxy)cyclohexyl)-3-methyl-lH-mdol-7-yl)acetateTo a solution of ethyl 2-bromo-2-(l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)-3-methyl-lH-indol-7-yl)acetate (110 mg, 0.25 mmol, 1.0 eq) in acetonitrile (3 mL) was added K2CO3 (103 mg, 0.75 mmol, 3.0 eq.). The mixture was stirred at room temperature for 15 min. (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)-N-methylpentan-l-amine (80 mg, 0.25 mmol, 1.0 eq) was then added. Stirring was continued at 80 °C for another 2 hr. After completion, the reaction mixture was filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (9:1 dichloromethane: MeOH) to give ethyl 2- (((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(l-((lr,4R)-4-(difluoromethoxy)cyclohexyl)-3-methyl-lH-indol-7-yl)acetate as a yellow oil (120 mg, 70%) (ESI 686.3 (M+H]+).Step 2: 2-( ( (S)-3-(5-chloro-2-methylphenyl)-5-(3, 3-dimethylpyrrolidin-]-yl)pentyl)(methyl)amino)-2-(l-((lr,4R)-4-(difluoromethoxy)cyclohexyl)-3-methyl-lH-indol-7-yl)acetic acidTo a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-( 1 -(( lr,4R)-4-(difluoromethoxy)cyclohexyl)-3-methyl- lH-indol-7-yl)acetate (120 mg, 0.17 mmol, 1.0 eq) in ethanol (3 mL) and H2O (1 mL) was added LiOH·H₂O (34 mg, 0.8 mmol, 5.0 eq). The reaction was stirred at room temperature for 16 hr. After completion, the reaction pH was adjusted to 6 - 7 with 2N HC1. Solvents were removed in vacuo. Crude residue was purified by silica gel column chromatography (9:1 dichloromethane:MeOH) to give diastereomeric product 83 as a white solid (50 mg, 43%). Diastereomers were further separated by prep chiral SFC A to give 83-P1 (14 mg) and 83-P2 (18 mg).Compound 83-P1 LC / MS ESI 658.3 [M+H]+. ’HNMR (400 MHz, MeOD) 57.50 - 7.27 (m, 2H), 7.17 - 6.86 (m, 5H), 6.43 (t, J= 76.1 Hz, 1H), 4.98 (s, 2H), 4.18 (s, 1H), 2.98 - 2.41 (m, 11H), 2.22 (dd, J ---- 68.2, 31.4 Hz, 12H), 1.86 - 1.48 (m, 9H), 1.08 (s, 6H).Compound 83-P1 LC / MS ESI 658.3[M+H]+. ’HNMR (400 MHz, MeOD) 57.49 - 7.23 (m, 2H), 7.10 - 6.79 (m, 5H), 6.33 (t,.7= 76.1 Hz, 1H), 4.66 (s, 211), 4.07 (s, 1H), 2.88 - 2.31 (m.11H), 2.11 (dd, J--- 68.2, 31.4 Hz, 12H), 1.79 - 1.40 (m, 9H), 1.01 (s, 6H). / Example 2. Preparation of 2-(((S)-3-(5-chloro-2-methylphenyI)-5-(3,3-dimethyIpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-((lr,4R)-4-methoxycyclohexyl)-l-methyl-lH-indazol-4-yl)acetic acid (compounds 94-P1 and 94-P2 )Step 1: (Ir, 4r)-N, 4-dimethoxy-N-methylcyclohexane-l-carboxamideTo a solution of (lr,4r)-4-methoxycyclohexane-l -carboxylic acid (9.8 g, 62.0 mmol. 1.0 eq) and N, O-dimethylhydroxylamine hydrochloride (3.78 g, 62.0 mmol, 1.0 eq) in dichloromethane (180 mL) was added l-ethyl-3-(3-dimethylaminopropyl-carbodiimide hydrochloride (14,2g, 74.4 mmol, 1.2 eq and 1 -hydroxybenzotriazole (10.0 g, 74.4 mmol, 1.2 eq) followed by N, N- diisopropylethylamine ( 16.0 g, 124.0 mmol, 2.0 eq). The reaction was stirred at room temperature for 1 hour. After completion, the mixture was extracted with EtOAc (4 x 130 ml). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to give (lr,4r)-N,4-dimethoxy-N-methylcyclohexane-l-carboxamide as a pale -yellow' solid (8.6 g, 78%) (ESI 202.2 [M+H]+). Step 2: (2-bromo-6-fluorophenyl)((lr,4r)-4-methoxycyclohexyl)methanoneTo a solution of l-bromo-3-fluoro-2-iodobenzene (11.8 g, 39.4 mmol, 0.92 eq) in tetrahydrofuran (80 mL) at 0 °C was added dropwise n-butyllithium (IM in tetrahydrofuran, 39.4 mL, 39.4 mmol,0.92 eq) over 10 min. The reaction was then warmed to RT over 1hr. (lr,4r)-N,4-dimethoxy-N-methylcyclohexane- 1 -carboxamide (8.6 g, 42.8 mmol, 1.0 eq) was then added and stirred at room temperature for 2 hr. The reaction was then quenched with saturated aqueous NH4CI (100 ml) and extracted with EtOAc (3 x 150 ml). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (9:1 petroleum ether: EtOAc) to give (2-bromo-6-fluorophenyl) ((lr,4r)-4-methoxycyclohexyl) methanone as colorless oil (7.0 g, 62%) (ESI 315.2 [M+H]+).Step 3: 4-bromo-3-( ( I r.4r)-4-methoxycyclohexyl)-l H-indazoleRH XN>~Xr < X * Br' / 0To a solution of (2-bromo-6-fluorophenyl) ((lr,4r)-4-methoxy cyclohexyl) methanone (6.6 g, 20.9 mmol, 1,0 eq.) in dioxane (60 mL) was added 98% hydrazine hydrate (4.2 mL, 83.4 mmol, 4.0 eq) and the reaction mixture was stirred at 130 °C for 3 hr. The mixture was concentrated in vacuo. Crude residue was purified by silica gel column chromatography (3: 1 petroleum ether: EtOAc) to give 4-bromo-3-((lr,4r)-4-methoxycyclohexyl)-lH-indazole as a yellow solid (5.0 g, 86%) (ESI 309.3 [M+H]4).Step 4: 4-bromo-3-((lr,4r)-4-methoxycyclohexyl)-l-methyl-lH-indazole( X>ii X? XT \ Msi 'X XTo a solution of 4-bromo-3-((lr,4r)-4-methoxycyclohexyl)-lH-indazole (4.6g, 14.9 mmol, 1.0 eq.) in tetrahydrofuran (80 mL) at 0 °C was added sodium hydride (60% in mineral oil, 483 mg, 22.3 mmol, 1.5 eq.). The reaction was stirred at 0 °C for Ihr. lodomethane (3.2 g, 22.3 mmol, 1.5 eq) was then added. The reaction was warmed to room temperature and stirring was continued for another 16 hr, quenched with cold saturated aqueous NH4CI (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by prep-HPLC A to give 4-bromo-3-((ls,4s)-4-methoxycyclohexyl)-l-methyl-lH-indazole as a white solid (1.6 g, 31%) (ESI 323.3 [M+H]+).Step 5: ethyl 2-(3-((ls, 4s)-4-methoxycyclohexyl)-l-methyl-lH-indazol-4-yl)acetateTo a solution of 4-bromo-3-((ls,4s)-4-methoxycyclohexyl)-l-ra ethyl- IH-indazole (1,55 g, 4,81 mmol, 1.0 eq.) in tetrahydrofuran (5 ml) was added QPhos (170 mg, 0.24 mmol, 0.05 eq.) and Pd₂(dba)₃ (313 mg, 0.24 mmol, 0.05 eq.) followed by (2 -ethoxy-2 -oxoethyl)zinc(II) bromide (IM in THF, 10.0 mmol, 2.0 eq.), The mixture was stirred at 65 °C under N₂ atmosphere for 1 hr,, then poured into 50 mL saturated aqueous NH4CI solution and extracted with dichloromethane (3 x 80 mL). Combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (3: 1 petroleum ether: EtOAc) to give ethyl 2-(3-((ls,4s)-4-methoxycyclohexyl)-l-methyl-lH-indazol-4-yl)acetate as white solid (1.3g, 90%) (ESI 331.2 [M+H] +).Step 6: ethyl 2-bromo-2-(3-((lr,4r)-4-methoxycyclohexyl)-l-methyl-lH-indazol-4-yl)acetater To a solution of LiHMDS (2M in THF, 1.2 ml, 2.4 mmol, 2.0 eq.) at -78°C, ethyl 2-(3-((ls,4s)-4-methoxycyclohexyl)-l-methyl-lH-indazol-4-yl)acetate (0,4 g, 1.2 mmol, 1.0 eq.) in tetrahydrofuran (20 ml) was added dropwise. The reaction was stirred at -78°C for 0.5 hr. TMSC1 (262 mg, 2.4 mmol, 2.0 eq.) was then added dropwise, and stirring was continued at -78°C for another 15 min. A solution of MBS (427 mg, 2.4 mmol, 2.0 eq.) in tetrahydrofuran (6 mL) was then added dropwise. The reaction was stirred at -78°C for another 1 hr. Reaction was warmed to 0 °C, quenched with saturated aqueous NH4CI solution (50 ml) at 0°C, and extracted with EtOAc (3 x 60 ml). Combined organic layers were washed with brine (3 x 50 ml), dried over Na₂SO₄, filtered, and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(3-((lr,4r)-4-methoxycyclohexyl)-l-methyl-lH-indazol-4-yl)acetate as a colorless oil (360 mg, 73%)(ESI 409.3 [M+H]+).Step 7: ethyl 2-(((R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-((lr,4R)-4-methoxycyclohexyl)-l-methyl-lH-indazol-4-yl)acetateTo a solution of (R)-3-(5-chloro-2-methylphenyI)-5-(3,3-dimethylpyrrolidin-l-yl)-N-methylpentan-1 -amine (138 mg, 0.43 mmol, 1.0 eq) in acetonitrile (7 mL) was added K2CO3 (119 mg, 0.86 mmol, 2.0 eq ). The mixture was stirred at room temperature for 15 mm. Ethyl 2-bromo-2-(3-((lr,4r)-4-methoxycyclohexyI)-l-methyl-lH-indazoI-4-yl)acetate (180 mg 0.43 mmol, 1.0 eq) was then added. Stirring was continued at 70 °C for another 2 hr. After completion, the reaction mixture was filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (96:4 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-((lr,4R)-4-methoxycyclohexyl) -1 -methyl- lH-indazol-4-yl)acetate as a white solid (130 mg, 40%) (ESI 651.3 [M+H]+).Step 8: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-((lr,4R)-4-methoxycyclohexyl)-l-methyl-lH-indazol-4-yl)acetic acidTo a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(3-((lr,4R)-4-methoxycyclohexyl)-l-methyl-lH-indazol-4-yl)acetate (130 mg, 0.2 mmol, 1.0 eq) in EtOH (5 mL) and H₂O (1.5 mL) was added LiOH·H₂O (42 mg, 1.0 mmol, 5.0 eq). The reaction was stirred at 70 °C for 16 hr. The mixture was concentrated in vacuo. Crude residue was purified by prep HPLC A (30 - 70% CH3CN) to give diastereomeric product 94 as a white solid (110 mg, 88%). Diastereomers were further separated by prep chiral SFC J to give 94-P1 (46.4 mg and 94-P2 (40.8 mg).Compound 94-P1 LC / MS ESI 623.4 [M+H]+. ^INMR (400 MHz, MeOD) 57.33 (d, J = 27.6 Hz, 3H), 7.02 (d, J -- 11.9 Hz, 3H), 4.68 - 4.47 (m, 1H), 3.98 (s, 3H), 3.43 (d, J--- 20.4 Hz, 4H), 3.07 (s, 2H), 2.76 (dd, J= 18.0, 11.0 Hz, 5H), 2.50 (d, J= 23.8 Hz, 5H), 2.32 (d, J= 11.8 Hz,1H), 2.21 (s, 2H), 2.03 (d.. / 24.2 Hz, 4H), 1.95 - 1.54 (m, 8H), 1.48 - 1.18 (m, 3H), 1.09 (s, 6H).Compound 94-P2 LC / MS ESI 623.4 [M+H]+. ftlNMR (400 MHz, MeOD) 57.33 (d,.7= 28.7 Hz, 3H), 7.00 (d, J -- 11.6 Hz, 3H), 4.70 (s, 1H), 3.98 (s, 3H), 3.40 (s, 4H), 2.86 (d, J -- 46.7 Hz, 3H), 2.62 (s, 4H), 2.56 - 2.28 (m, 6H), 2.20 (d, J= 10.9 Hz, 2H), 2.07 (s, 4H), 1.72 (t, J= 43.1 Hz, 8H), 1.49 - 1.29 (m, 3H), 1.08 (s, 6H).Example 3. Preparation of 2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3-cyclopropyl-l-((S)-3-methylbutan-2-yl)-lH-indazol-7-yl)acetic acid (compound 37-P1 and 37-P2)Step 1: ethyl 2-( ( (S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-( 3- cyclopropyl- 1 -( (S)-3-methylbutan-2-yl)-lH-indazol- 7-yl)acetateTo a solution of (R)-3-(5-chloro-2-fluorophenyl)-N-methyl-5-(piperidin-l-yl)pentan-l-amine (312 mg, 1,0 mmol, 1.0 eq) in acetonitrile (10 mL) was added K2CO3 (414 mg, 3.0 mmol, 3,0 eq.). The mixture was stirred at room temperature for 15 min. Ethyl 2-bromo-2-(3-cyclopropyl- 1-((S)-3-methylbutan-2-yl)-1H-indazol-7-yl)acetate (392 mg, 1.0 mmol, 1.0 eq) was then added. Stirring vras continued at 80 °C for another 2 hr. After completion, the reaction mixture was filtered and concentrated under reduced pressure. Crude residue w as purified by silica gel column chromatography (9:1 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-5 -(piperidin- 1 -yl)pentyl)(methyl)amino)-2-(3-cyclopropyl- 1 -((S)-3-methylbutan- 2-yl)-1H-indazol-7-yl)acetate as a yellow oil (200 mg, 32%) (ESI 625.3 [M+H]+),Step 2: 2-(((S)-3-(5-chloro-2-jluorophenyl)-5-(piperidm-l-yl)pentyl)(methyl)ammo)-2-(3-cyclopropyl-l-((S)-3-methylbutan-2-yl)-lH-indazol-7-yl)acetic acidLiOH-H2OTo a solution of ethyl 2-(((S)-3-(5-chloro-2-fluorophenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(3-cyclopropyl-l-((S)-3-methylbutan-2-yl)-1H-indazol-7-yl)acetate (200 mg, 0.32 mmol, 1.0 eq) in EtOH (3 mL) and H2O ( 1 mL) was added LiOH·H₂O (68 mg, 1.6 mmol, 5.0 eq). The reaction was stirred at room temperature for 16 hr. After completion, the reaction pH was adjusted to ~ 6 - 7 with 2N HC1. Solvents were removed in vacuo. Crude residue ■was purified by silica gel column chromatography (9:1 dichloromethane: MeOH) to give diastereomeric product 37 as a white solid (130 mg, 68%). Diastereomers w'ere further separated by prep chiral SFC G to give 37-P1 (59.5 mg) and 37-P2 (52 mg).Compound 37-P1 LC / MS ESI 597.3 1H NMR (400 MHz, MeOD) 5 7.67 (d, J = 8.0 Hz, 1H), 7.49 (d, J - 6.6 Hz, 1H), 7.24 - 7.11 (m, 1H), 6.98 (dd, J ==:16.5, 8.3 Hz, 3H), 4.82 (d, J = 13.8 Hz, 2H), 3.14 - 2.25 (m, 12H), 2.29 - 2.13 (m, 2H), 1.93 - 1.18 (m, 13H), 1.12 - 0.83 (m, 7H), 0.56 (t, J = 9.3 Hz, 3H).Compound 37-P2 LC / MS ESI 597.3 1HNMR (400 MHz, MeOD) 58.50 (s, 1H), 7.68 (t, J = 10.2 Hz, 1H), 7.51 (t, J = 13.9 Hz, 1H), 7.27 - 7.10 (m, 2H), 6.99 (m, 2H), 4.80 (d, J = 24.7 Hz, 2H), 3.10 - 2.47 (m, 12H), 2.36 - 1.83 (m, 6H), 1.82 - 1.65 (m, 4H), 1.62 - 1.49 (m, 2H), 1.42 (t, J = 8.8 Hz, 3H), 1.12 - 0.95 (m, 7H), 0.66 (d, J = 6.6 Hz, 3H).Example 4. Preparation of 2-((3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazol-7-yl)acetic acid (compounds 86-P1 and 86-P2)Step 1: 7-bromo-l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazoleF To a mixture of (lr,4r)-4-(7-bromo-lH-benzo[d]imidazol-l-yl)cyclohexan-l-ol (1,0 g, 3.39 mmol, 1.0 eq.), Cui (65 mg, 0.34 mmol, 0.1 eq.) in acetonitrile (10 mL) was added 2-(fluorosulfonyl)difluoroacetic acid (1.2 g, 6.78 mmol, 1.0 eq.). The mixture was stirred at 50 °C for 2 hr. After cooling to room temperature, 100 mL of water was added and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, filtrated and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 dichloromethane: MeOH) to give 7-bromo-l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazole as a yellow solid (150 mg, 15%) (ESI 345.2 [M+H] ).Step 2: ethyl 2~(l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazol-7-yl)acetateTo a solution of 7-bromo-l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazole (920 mg, 2,67 mmol, 1.0 eq.) in tetrahydrofuran (10 mL) was added Pd2(dba)3 (115 mg, 0.13 mmol, 0.05 eq.) and Qphos ( 190.0 mg, 0.27 mmol, 0.1 eq) followed by (2 -ethoxy-2 -oxoethyl)zinc(II) bromide (IM in THF, 8.0 mL, 8.0 mmol, 3.0 eq.). The mixture was stirred at 65 °C under N2 atmosphere for 1 hr., then poured into 50 mL saturated aqueous NH4CI solution and extracted with dichloromethane (3 x 80 mL). Combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1 dichloromethane: MeOH) to give ethyl 2-(l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazol-7-yl)acetate as a red solid (72.0 mg, 76%) (ESI 353.4 [M+H]+).Step 3: ethyl 2-bromo-2~(l -((1 r, 4r)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazol-7-yl)acetateTo a solution of ethyl 2-(l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazol-7-yl)acetate (400 mg, 1.14 mmol, 1.0 eq.) in THF (10 mL) was added LiHMDS(l M in THF, 4.5 mL, 4.5 mmol, 4.0 eq.) at -78°C under N₂ atmosphere. The mixture was stirred at -78°C for 30 min. TMSC1 (743 mg, 6.84 mmol, 6.0 eq.) was added dropwise and stirred at -78°C for 15 min. A solution ofN-bromosuccinimide (345 mg, 1.94 mmol, 1.7 eq.) in THF (3 mL) was added dropwise and stirred at -78°C for another 1 hr., then warmed to 0 °C, quenched with saturated aqueous NH4CI solution (30 ml) at 0°C, and extracted with EtOAc (3 x 30 ml). Combined organic layers were washed with brine (3 x 60 ml), dried over Na2SO4, filtered, and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10: 1petroleum ether: EtOAc) to give ethyl 2-bromo-2-(l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)- lH-benzo[d]imidazol-7-yl)acetate as a yellow solid (310 mg, 63%). (ESI 431.3 [M+H]+), Step 4: ethyl 2-( ( (S)-3-(5-chloro-2-methylphenyl)-5-(3, 3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(l-((lr,4R)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazol- 7-yl)acetateA solution of ethyl 2-bromo-2-(l-((lr,4r)-4-(difluoromethoxy)cyclohexyl)-lH- benzo[d]imidazol-7-yl)acetate (310 mg, 0.72 mmol, 1.0 eq.), (R)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)-N-methylpentan-l-amine (255 mg, 0,79 mmol, 1.1 eq.) and K2CO3 (300 mg, 2.16 mmol, 3.0 eq.) in acetonitrile (5 mb) was stirred at 80 °C for 2 hr. The mixture was filtered, and the filtrate was concentrated in vacuo. Crude residue was purified by silica gel column chromatography (8:1 dichloromethane: MeOH) to give ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyn'olidin-l -yl)pentyl)(methyl)amino)-2-(l-((lr,4R)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d|imidazol-7-yl)acetate as a yellow solid (180 mg, 37%) (ESI 673.2 [M+H]+).Step 5: 2-(((S)-3-(5~chloro~2-methylphenyl)~5-(3,3-dimethylpyrrolidin-l~ yl)peniyl)(methyl)amino)-2-(l-((]r,4S)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazol- 7-yl)acetic acidTo a solution of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(3,3-dimethylpyrrolidin-l-yl)pentyl)(methyl)amino)-2-(l-((lr,4R)-4-(difluoromethoxy)cyclohexyl)-lH-benzo[d]imidazol-7-yl)acetate (180 mg, 0.27 mmol, 1.0 eq) in EtOH (4 mL) and HzOQ mL) was added NaOH (43 mg, 1.07 mmol, 4.0 eq.). The reaction was stirred at 70 °C for 2 hrs. After completion, the reaction pH was adjusted to ~ 6 - 7 with IN HC1. Solvents were removed in vacuo.. Cruderesidue was purified by prep HPLC A (25 - 55% CHsCN) to give 86-P1 (28.0 mg) and 86-P2 (33,5 mg) as white solids.Compound 86-P1 LC / MS ESI 645.3 [M+H]+. ^INMR (500 MHz, MeOD) 58.28 (s, 1H), 7.56 (d, J--- 8.0 Hz, 1H), 7.48 (s, 1H), 7.21 - 7.11 (m, 2H), 7.04 (s, 2H), 6.65 - 6.27 (m, 1H), 5.21 (s, 1H), 4.61 (s, 1H), 4.29 - 4.19 (m, 1H), 3.24 (s, 2, H), 2.98 - 2.73 (m, 4H), 2.73 - 2.66 (m, 2H), 2.35 - 2.13 (m, 11H), 1.99 - 1.71 (m, 10H), 1.12 (d, J= 2.1 Hz, 6H).Compound 86-P2 LC / MS ESI 645.3 [M+H|+. 'H NMR (500 MHz, MeOD) 88.28 (s, 1H), 7.56 (dd, J= 8.0, 0.8 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.16 (t,.7= 7.8 Hz, 1H), 7.07 - 6.99 (m, 3H), 6.65 - 6.27 (m, 1H), 5.26 (s, 1H), 4.64 (s, 1H), 4.31 - 4.20 (m, 1H), 3.26 (s, 211), 3.15 - 2.84 (m, 4H), 2.74 - 2.54 (m, 3H), 2.40 - 2.33(m, 4H), 2.24 - 1.96 (m, 9H), 1.90 - 1.74 (m, 6H), 1.57 (d, J = 9.7 Hz, 1H), 1.1 / Example 5: Preparation of 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yI)pentyl)(methyl)amino)-2-(3-methyl-l-((S)-3-methylbutan-2-yl)-lII-indazoI-7-yI)acetic acid (compounds 18-P1 and 18-P2 )Step 1: diethyl 2-(5-chloro-2-methylbenzylidene)malonate- piperidine, TolueneA solution of 5-chloro-2-methylbenzaldehyde (100.0 g, 0.65 mol), diethyl malonate (155.8 g, 0.97 mol) and piperidine (8.3 g, 97.5 mmol) in toluene (300 mL) was stirred at 110 °C for 16 hr. The mixture was cooled to 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-methylbenzylidene)malonate as colorless oil (180 g, 93%) (ESI 297.3 [M+H]+).Step 2: tetraethyl 2-(5-chloro-2-methylphenyl)propane-l,1, 3, 3-tetracarboxylateTo a solution of diethyl malonate(194.6 g, 1.22 mol) in EtOH(400 mL) at room temperature was added EtONa(88.1 g, 1.3 mmol) and the mixture was stirred for 2hr. Then diethyl 2-(5-chloro-2- m ethylbenzylidene )malonate (180 g, 0.61 mol) was added at room temperature and stirring was continued for another 16 hr. The reaction mixture was concentrated under reduced pressure. Tire residue was diluted with EtOAc(3 x 400 mL), washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (4:1 petroleum ether: EtOAc) to give tetraethyl 2-(5-chloro-2- methylphenyl)propane-l, 1,3, 3-tetracarboxylate as colorless oil(180.0 g, 60%) (ESI 457.2[M-i-H]1).Step 3: 3-(5-chloro-2-methylphenyl)pentanedioic acidA mixture of tetraethyl 2-(5-chloro-2-methylphenyl) propane-1,1, 3, 3 -tetracarboxylate (180.0 g, 0,39 mol) in 36% aqueous HC1 (700 mL) was stirred at 130 °C for 36 hr. The mixture was cooled to 0 °C and stirred at 0 °C for 1 hr. Tire solid formed was filtered and collected to give 3-(5- chloro-2-methylphenyl) pentanedioic acid as a white solid without further purification (100.2 g, 99%) (ESI 279.0 [M+Na]+).Step4: 4-(5-chloro~2-methylphenyl)dihydro-2H-pyran~2, 6( 3H)-dioneOAacetic anhydride \ 9 refluxed.24hA solution of 3 -(5 -chloro-2 -methylphenyl) pentanedioic acid (100.0 g, 0.39 mol) in acetic anhydride (400 mL) was stirred at 130CC for 40 hr. The mixture was concentrated to dryness under reduced pressure, triturated with EiOAc(150 mL). The solid formed was filtered and collected to give 4-(5-chloro-2-methylphenyl) dihydro-2H-pyran-2,6(3H)-dione as a white solid(91.2 g, 97%) (ESI 239.1 [M+H]+).Step 5: 3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acidTo a solution of 3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (91.2 g, 0.38 mol, 1.0 eq ) in THF (300mL) was added methylamine (IM in THF, 1.15L, 1.15 mol, 3.0 eq) and the reaction was stirred at room temperature for 3hr. The reaction mixture was concentrated under reduced pressure and triturated with EtOAcfl 20 i.) The solid formed was filtered and collected to give racemic 3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic as white solid (75.0 g, 73%). Enantiomers were further separated by prep chiral SFC K to give Pl fraction (S)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (31.0 g) and P2 fraction (R)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (31.0 g) as white solids (ESI 270.1 [M+H|+).Step 6: (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-oxo-5-(piperidin-lyl) pentanamideTo a solution of (S)-3-(5-chloro-2-methylphenyl)-5-(methylamino)-5-oxopentanoic acid (16.0 g, 59.4 mmol, 1.0 eq) and piperidine (5.0 g, 59.4 mmol. 1.0 eq) in DMF(60 mL) was added HATU(27.1 g, 71.3 mmol, 1.2 eq) followed by DIEP A ( 15.3 g, 118.9 mmol, 2.0 eq). The reaction was stirred at room temperature for 2 hr. After completion, the mixture was quenched with NH4CI solution (100 ml) and extracted with EtOAc (3 x 150 mL). The combined, organic phase was washed with brine, dried over anhydrous Na₂SO₃, filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (19:1 dichloromethane: MeOH) to give (S)-3-(5-chloro-2-methy’lphenyl)-N-methyl-5-oxo-5-(piperidin-1-yl) pentanamide as a colorless oil (16.3 g. 80%) (ESI 337.2 [M+H]+).Step 7: (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-(piperidin-l-yl) pentan-1 -amineTo a solution of (R)-3-(5-chloro-2-methylphenyl)-N-methyl-5-oxo-5-(piperidin-l-yl) pentanamide(16.3 g, 48.5 mmol, 1.0 eq) in THF (200 mL) at room temperature was added LiAlH₄ (58.2 mL,145.5 mmol, 3.0 eq) dropwise and the reaction was stirred at 55 °C for 1 hr. After cooling to 0 °C, the reaction mixture was quenched with water (5.5 mL) dropwise and stirred at 0 °C for another 10 min. 15% aqueous NaOH (5.5 mL) and water (16.5 mL) were then added sequentially at 0 °C. The mixture was allowed to warm to room temperature and stirred for another 15 min, then filtered and filtrate was concentrated in vacuo to give (S)-3-(5-chloro-2-methylphenyl)-N-methyl-5-(pipendin-l-yl)pentan-l-amine as a white solid used directly in the next reaction( 13.1 g, 80%) (ESI 309.3 [M+H] ).Step 8: 7-bromo-3-methyl-lH-indazoleA mixture of l-(3-bromo-2-fluorophenyl)ethan-l-one (5 g, 23 mmol, 1.0 eq) and 85%N2HrH2O (30mL) was stirred at 120 °C for 16 hr. Tire reaction mixture was poured into 200 ml. water and extracted with 200 mL EtOAc. Tire combined organics were washed -with brine (100 mL), dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (5: 1 petroleum: EtOAc) to give 7-bromo-3-methyl-lH- indazole as white solid (4,1g, 82%) (ESI 210.98 [M+H]4).\Step 9: (S)-7-bromo-3-methyl-l-(3-methylbutan-2-yl)-lH-indazole, HQ / / - DIAD, PPh3TBr3BrTo a solution of 7-bromo-3-methyl-lH-indazole (21.0 g, 100.0 mmol, 1.0 eq), (R)-3- methylbutan-2-ol (8.8 g, 100.0 mmol, 1.0 eq) and PPI13 (31.4 g, 120.0 mmol, 1.2 eq) in THF (100 mL) was added DIAD (30.3 mg, 150.0 mmol, 1.5 eq) dropwise at room temperature. Tire reaction mixture was stirred at room temperature for 16 hr. The reaction was concentrated in vacuo and the residue was purified by silica gel column chromatography (4:1 petroleum: EtOAc) to give (S)-7-bromo-3-methyl-l-(3-methylbutan-2-yl)-lH-indazole (15.0g, 54%) (ESI 281.2 (M+H)4). Step 10: ethyl (S)-2-(3-methyl-l-(3-methylbutan-2-yl)-1H-indazol-7-yl)acetateTo a solution of (S)-7-bromo-3-methyl-l-(3-methylbutan-2-yl)-lH-indazole (15 g, 53.4 mmol, 1.0 eq), Pd2(dba)3(2.4 g, 2.7 mmol, 0.05 eq) and Qphos(1.9 g, 2.7 mmol, 0.05 eq) in THF(50ml) under N2 atmosphere was added (2 -ethoxy-2 -oxoethyl)zinc(II) bromide (160ml,l mol / 1, 160 mmol, 3,0 eq) and the mixture was heated to 80°C for (hr. After completion, saturated NH4C1 aqueous (100 mL) was added, and the solution was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrated was concentrated in vacuo. The residue was purified by silica gel column chromatography (20: 1 petroleum ether: EtOAc) to give ethyl (S)-2-(3-methyl-l-(3-methylbutan- 2-yl)-1H-indazol-7-yl)acetate as a yellow oil (14.0 g). Yield 91% (ESI 289.2(M+H)+).Step 11: ethyl 2-bromo-2-(3-methyl-l-((S)-3-methylbutan-2-yl)-1H-indazol-7-yl)acetateTo a solution of LiHMDS (IM in THF, 110.8 mL, 110.8 mmol, 2,3 eq.) at -78°C, ethyl (S)-2-(3-methyl-l-(3-methylbutan-2-yl)-1H-indazol-7-yl)acetate (14.0 g, 48.6 mmol, 1.0 eq.) in THF (80 mL) was added dropwise. The reaction was stirred at -78°C for 0.5 hr. TMSC1 (12.0 g, 110.8 mmol, 2.3 eq.) was then added dropwise, and stirring was continued at -78°C for another 15 min. A solution of NBS (24.1 g, 110.8 mmol, 2,3 eq) in THF (200 mL) was then added dropwise. The reaction was stirred at -78°C for another 1 hr., then warmed to 0 °C, quenched with saturated aqueous MH4CI solution (200 ml) at 0°C, and extracted with EtOAc (3 x 200 ml). Combined organic layers were washed with brine (3 x 150 ml), dried over Na₂SO₄, filtered, and concentrated in vacuo. Crude residue was purified by silica gel column chromatography (10:1 petroleum ether: EtOAc) to give ethyl 2-bromo-2-(3-methyl-l-((S)-3-methylbutan-2-yl)-1H-indazol-7-yl)acetate (11,7 g) as a colorless oil, yield: 66% (ESI 367.2[M+H]+).Step 12: ethyl 2-( (S)-3-(5-chlom-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-l-((S)-3-methylbutan-2-yl)-1H-indazol-7-yl)acetateCkA mixture of ethyl 2-bromo-2-(3-methyl-l-((S)-3-methylbutan-2-yl)-1H-indazol-7-yl)acetate (11.4, 31.04 mmol, 1.0 eq.), (S)-3-(5-chloro-2-methylphenyl)-N-methyl-5-(piperidin-l- yl)pentan-l -amine (12.0 g, 38.85 mmol, crude) and K2CO3 (12.8 g, 93.12 mmol, 3.0 eq.) in acetonitrile (100 mL) was stirred at 80 °C for 2 hrs. The mixture was filtered and concentrated under reduced pressure. Crude residue w as purified by silica gel column chromatography (10:1 MeOH: DCM) to give ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3-methyl-l-((S)-3-methylbutan-2-yl)-1H-indazol-7-yl)acetate as a yellow' oil (18 g, 78%) (ESI 595.4 [M+H] ’).Step 13: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(3- methyl-1 -( (S)-3-methylbutan~2-yl)-lH-mdazol- 7-yl)acetic acidNaOHEtOH / H2OEthyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyi)(methyl)amino)-2-(3- methyl-l-((S)-3-methylbutan-2-yl)-1H-indazol-7-yl)acetate (18.0 g, 30.24 mmol, 1.0 eq.) was treated with NaOH (12.0 g, 302.4 mmol, 10.0 eq.) in ethanol (100 mL) and water (20 mL) at 80 °C for 1 hr. After completion, the reaction was acidified to pH ~ 6 - 7 with 3N HC1. Solvents were removed in vacuo. The crude residue was purified by reverse phase HPLC (A: 10 mM NH4HCO3; B: MeOH 0-100%) to give racemic product 18 as white solid (16 g, 93%). Enantiomers were further separated by prep chiral SFC D to give 18— Pl (8.06 g) and 18-P2 (5.37 g)Compound 18-P1 LC / MS ESI 567.3 [M+HJT ’H NMR (400 MHz, MeOD) 5 7.56 - 7.54 (m, 1H), 7.44 - 7.39 (m, 1H), 7.00 - 6.86 (m, 3H), 6.80 (d, J= 1.9 Hz, 1H), 4.93 - 4.88 (m, 1H), 4.79 (s, 1H), 2.72 - 2.61 (m, 2H), 2.54 (s, 3H), 2.46 - 2.34 (m, 4H), 2.30 - 2.18 (m, 5H), 2.10 - 1.88 (m, 5H), 1.81 - 1.64 (m, 2H), 1.60 - 1.48 (m, 8H), 1.46 - 1.30 (m, 3H), 1.05 (d, 6.1 Hz, 3H), 0.62 (d, J = 6.7 Hz, 3H).Compound 18-P2 LC / MS ESI 567.4 [M+Hf.!H NMR (400 MHz, MeOD) 5 7.65 - 7.47 (m, 2H), 7.15 - 6.93 (m, 4H), 5.14 - 4.95 (m, 1H), 4.63 (s, 1H), 2.83 - 2.56 (m, 2H), 2.57 - 2.16 (m, 16H), 2.11 - 1.98 (m, 1H), 1.86 - 1.60 (m, 4H), 1.60 - 1.36 (m, 9H), 1.15 - 1.05 (m, 3H), 0.61 (d,.7= 6,6 Hz, 3H).Example 6: Preparation of 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l- yl)pentyl)(methyl)amino)-2-(4-fluoro-l-((lr,4R)-4-methoxycyclohexyl)-3-methyl-lH- indazol-7-yI)acetic acid (compounds 42-P1 and 42-P2)Step 1: ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(4- fluoro-l-((lr,4R)-4-methoxycyclohexyl)-3-methyl-1H-indazol-7-yl)acetateTo a solution of (S)-3-(5-chloro-2-methylphenyl)-N-methyl-5-(piperidin-l-yl)pentan-l-amine (200 mg 0.65 mmol, 1.4 eq.) in acetonitrile (10 mL) was added K2CO3 (520 mg, 3,76 mmol, 8.0 eq.). The mixture was stirred at room temperature for 15 min. Ethyl 2-bromo-2-(4-fluoro-l-((lr,4r)-4-methoxycyclohexyl)-3-methyl-1H-indazol-7-yl)acetate (200 mg, 0.47 mmol, 1.0 eq) was then added. Stirring was continued at 80 °C for another 2 hr. After completion, the reaction mixture was filtered and concentrated under reduced pressure. Crude residue was purified by silica gel column chromatography (19:1 dichloromethane: acetonitrile) to give ethyl 2-(((R)-3- (5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(4-fluoro-l-((lr,4R)-4-methoxycyclohexyl)-3-methyl-1H-indazol-7-yl)acetate as a yellow oil (250 mg, 81%) (ESI 655.3 [M+H]’).Step 2: 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(4-fluoro-l-((lr,4R)-4-methoxycyclohexyl)-3-methyl-lH-indazol-7-yl)acetic acidTo a mixture of ethyl 2-(((S)-3-(5-chloro-2-methylphenyl)-5-(piperidin-l-yl)pentyl)(methyl)amino)-2-(4-fluoro-l-((lr,4R)-4-methoxycyclohexyl)-3-methyl-1H-indazol-7-yl)acetate (250 mg, 0.38 mmol, 1,0 eq) in EtOH (6 mL) and H2O (2 mL) was added NaOH (152 mg, 3.8 mmol, 10 eq) and stirred at 80 °C overnight. The mixture was concentrated in vacuo. Crude residue w as purified by prep HPLC A (30 - 70% CH3CN) to give diastereomeric product 42 as a white solid (200 mg, 83%), Diastereomers were further separated by prep chiral SFC G to give 42-P1 (48 mg) and 42-P2 (82 mg).Compound 42-P1 LC / MS ESI 627.3 [M+H]+. 'H NMR (500 MHz, MeOD) 57.38-7.35 (m, 1H), 7.04-6.94 (m, 3H), 6.59-6.55 (m, 1H), 5.22-5.15 (m, 1H), 4.64-4.61 (m, 1H), 3.41 (s, 3H), 3.14-2.69 (m, 7H), 2.61 (s, 3H), 2.57 - 2.52 (m, 2H), 2.45 (s, 3H), 2.14 - 2.10 (m, 4H), 2.01- 1.76 (m, 10H), 1.60-1.42 (m, 5H).Compound 42-P2 LC / MS ESI 627.3 [M+H]+. 'H NMR (500 MHz, MeOD) 57.42-7.39 (m, 1H), 7.01-6.98 (m, 3H), 6.62-6.57 (m, 1H), 5.27-5.23 (m, 1H), 4.64-4.56 (m, 1H), 3.41 (s, 3H), 2.61-2.57 (m, 5H), 2.46 (s, 4H), 2.24 - 2.22 (m, 7H), 2.06-1.90 (m, 8H), 1.73 - 1.30 (m, 13H).Example 7: Preparation of Compound 90-PI and 90-P2Scheme 1: Synthetic Route for Intermediate LI 53 IAH X BMP X Ji X J”8X J-HC!Scheme 2: Synthetic Route for Intermediate R586AScheme 3: Synthetic Route for 90-PIExperiments for largest scale run:General procedure for preparation of compound 2TEMPO, NaCIO, NaHCO3DCM / HJJO, 0°C, 1 hrstep 1, crude 2 To a solution of compound 1 (125 g, 660.50 mmol, 1 eq), NaHCOs (110.97 g, 1.32 mol, 51.40 mL, 2 eq), TEMPO (5.00 g, 31.80 mmol, 0.048 eq) 111 DCM (1000 mL) and H2O (500 mL) was added NaCIO (600 mL) dropwise at 0~5°C. The mixture was stirred at 0°C for 1 hr. TLC (Petroleum ether: Ethyl acetate = 1:1, Rf = 0.54) showed the starting material was consumed completely, and some new spots with lower polarity were detected. The reaction was quenched by ice water (2000 mL) slowly, extracted with DCM (1000 mL x 2), The combined organic phase was washed with aq. Na2SO3(2000 mL), brine (1500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give compound 2 (117 g, crude) as yellow oil.General procedure for preparation of compound 3Ph3PCHCOOEt toluene, 100°C, 2 hrsstep 2. 66.54%To a solution of compound 2 (117 g, 624.88 mmol, 1 eq) in toluene (1500 mL) was added Ph3CHCOOEt (217.69 g, 624.88 mmol, 1 eq) and the mixture was stirred at 100°C for 2 hrs. TLC (Petroleum ether: Ethyl acetate = 3:1, Rf= 0.54) showed the starting material was consumed completely, and some new spots with larger and lower polarity were detected. The reaction was concentrated in vacuo, triturated with hexanes: MTBE = 3: 1 (2000 mL), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage ®; 440 g SepaFlash ® Silica Flash Column, Eluent of 0-100% Ethyl acetate / hexanes gradient @. 300 mL / min). Compound 3 (107 g, 415.82 mmol, 66.54% yield) was obtained as a yellow oil.NMR: ET30483-2484-P1A CDCl3ZKNJ_02_N_400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 6.96 - 6.87 (m, 1H), 5.85 (d, J = 15.6 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.35 (br t, J = 6.7 Hz, 2H), 2.86 (br s, 3H), 2.42 (br d, J = 5.6 Hz, 2H), 1.45 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H).General procedure for preparation of compound 5HOB'OH4Rh(NBD)2BF4, KOH, S-BINAP dioxane. H2O, 25°C, 16 hstep 3, crudeTwo batches were carried out in parallel. To a solution of compound 4 (64.34 g, 377.56 mmol, 2.00 eq) in dioxane (500 mL) was added s-BINAP (19.80 g, 31.79 mmol, 0.169 eq) and Rh(NBD)2. BF4 (7.28 g, 19.45 mmol, 0.1 eq) under N2. The mixture was stirred at 25°C for 2 hrs. Then compound 3 (48.5 g, 188.48 mmol, 1 eq), TEA (21.59 g, 213.34 mmol, 29.69 mL, 1.13 eq), H2O (80 mL) were added to the solution at 25°C and stirred for 14 hrs. LCMS (ET30483-2488-P1A, Rt = 0.671 min) showed the start material was consumed completely and desired mass was detected. The reaction was quenched by ice water (1000 mL) slowly, extracted with ethyl acetate (500 mL x 2). Hie combined organic phase was washed with brine (1500 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage ®; 440 g SepaFlash ® Silica Flash Column, Eluent of 0-80% Etliyl acetate / Petroleum ether gradient @ 300 mL / min). Compound 5 (170 g, crude) was obtained as yellow oil.LCMS: ET30483-2488-P1A, Rt= 0.671 min, [M-99] = 284.1, 41.95%General procedure for preparation of compound 6LAH THF, 0°C. 1 hrBocstep 4, 85.91% i6 Two batches were carried out in parallel. To a solution of compound 5 (100 g, 260.48 mmol, 1 eq) in THF (1000 mL) was added LiAlH4(2.5 M, 120.00 mL, 1.15 eq) dropwise under N2 and the mixture was stirred at 0°C for 1 hr. TLC (Petroleum ether: Ethyl acetate = 1:1, Rr = 0.29) showed the starting material was consumed completely, and a new spot with larger polarity was detected. The reaction was quenched by Na2SO4.10H2O (50 g) at 0°C, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage ®; 440 g SepaFlash ® Silica Flash Column, Eluent of 0-100% THF / hexanes gradient@ 300 mL / min). Compound 6 (153 g, 447.54 mmol, 85.91% yield) was obtained as yellow oil which confirmed by NMR (ET30483-2491-P1).1H NMR: ET30483-2491-P1 DMSO Bruker_02_R_400MHz1H NMR (400 MHz, DMSO-d6) δ = 7.25 (d, J = 2.0 Hz, 1H), 7.17 - 7.08 (m, 2H), 4.40 (br s, 1H), 3.30 - 3.23 (m, 1H), 3.18 - 3.10 (m, 1H), 3.03 - 2.86 (m, 3H), 2.70 (s, 3H), 2.23 (s, 3H), 1.78 (dt, J = 6.4, 13.0 Hz, 2H), 1.73 - 1.61 (m, 2H), 1.39 - 1.27 (m, 9H).General procedure for preparation of compound 7- DMP DCM, 0-20°C. 2 hrstep 5, crudeTwo batches were carried out in parallel. To a solution of compound 6 (65 g, 190.13 mmol, 1 eq) in DCM (1500 mL) was added DMP (110 g, 259.35 mmol, 80.35 mL, 1.36 eq) at 0°C and the mixture was stirred at 20°C for 2 hr. LCMS (ET30483-2496-P1A1, Rt= 0.614 min) showed the starting material was consumed completely and desired mass was detected. The reaction was quenched by aq. NaHCO3(2000 mL) slowly, extracted with DCM (800 mL x 2). The combined organic phase was washed with aq. Na2SO3(1000 mL x 2), brine (1000 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give compound 7 (150 g, crude) was obtained as yellow oil.LCMS: ET30483-2496-P1A1, Rt= 0.614 min, [M-56] = 284.3, 29.29%General procedure for preparation of compound 9NaBH(OAc)3, DCM Boc 20°C, 2 hrs Step 6, 58.90% & 23.02%Two batches were carried out in parallel. To a solution of compound 8 (32.88 g, 242.40 mmol, 1.26 eq, HC1), compound 7 (75 g, 191.99 mmol, 1 eq) in DCM (800 mL) was added NaBH(OAc)3 (81.38 g, 383.99 mmol, 2 eq) at 0° C and the mixture was stirred at 20°C for 2 hrs. LCMS (ET30483-2497-P1A, Rt= 0.485 min) showed the starting material was consumedcompletely and desired mass was detected. The reaction was quenched by aq. NaOH (2000 mL) slowly, adjusted to pH = 9, extracted with DCM (1000 mL x 2), The combined organic phase was washed with brine (2000 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage ®; 440 g SepaFlash ® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ether to 0-100% MeOH / Ethyl acetate gradient @ 300 mL / min), Compound 9 (104 g, 226.18 mmol, 58.90% yield, 92% purity), 9 (34 g, 44.20 mmol, 23.02% yield, 55% purity) were obtained as a yellow oil.LCMS: ET30483-2497-P1A, Rt= 0.485 min, [M+l] = 423.4, 71.53%1H NMR: ET30483-2497-P1 MeOD Bruker_02_R_400MHz1H NMR (400 MHz, METHANOL-d4) δ = 7.25 (d, J = 2.0 Hz, 1H), 7.16 - 7.05 (m, 2H), 3.06 (br s, 2H), 2.97 - 2.88 (m, 1H), 2.78 (s, 3H), 2.62 - 2.52 (m, 2H), 2.36 - 2.26 (m, 6H), 2.20 (dt, J = 4.6, 11.1 Hz, 1H), 1.99 - 1.85 (m, 2H), 1.83 - 1.71 (m, 2H), 1.57 (t, J= 7.0 Hz, 2H), 1.47 -1.34 (m, 9H), 1.07 (s, 6H).General procedure for preparation of Inter LI 53HCl (g) / dioxane 20°C, 1 hrstep 7, crude L153A mixture of compound 9 (104 g, 226.18 mmol, 1 eq) in HCl / dioxane (4 M, 1000 mL) was stirred at 20°C for 1 hr. LCMS (ET30483-2502-P1A, Rt= 0.336 min) showed the starting material was consumed completely and desired mass was detected. The reaction was concentrated in vacuo to give intermediate L153 (103 g, crude, HC1) as a white solid.LCMS: ET30483-2502-P1A, Rt= 0.336 min, [M+l] = 323.3, 93.23%General procedure for preparation of compound 2LDA, DMFBrFstep 1, 97.66%1 2To a solution of compound 1 (300 g, 1.46 mol, 1 eq) in THF (3000 mL) was added LDA (2 M, 877.95 mL, 1.2 eq) at -70°C under N2. The mixture was stirred at -70°C for 0.5 hrs. DMF (139.04 g, 1.90 mol, 146.36 mL, 1.3 eq) was added at -70°C under N2. The mixture was stirred at -70°C for 0.5 hrs. TLC (Petroleum ether / ethyl acetate = 10 / 1, Rf = 0.2) indicated one new' spot was formed and compound 1 -10% remained. The reaction mixture was quenched by aq. NH4CI (3000 mL) and extracted with ethyl acetate (1000 mL x 2). The combined organic layers were washed with brine (2000 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2 (370 g, 1.43 mol, 97.66% yield, 90% purity) as a yellow solid.1H NMR: ET25230-2859-P1A1 CDCl3Bruker_02_G_400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 10.37 (d, J = 1.1 Hz, 1H), 7.67 (dd, J = 7.7, 8.9 Hz, 1H), 6.80 - 6.66 (m, 1H), 3.94 (s, 3H).General procedure for preparation of compound 3THF, 5-25°C, 2 hrsstep 2, crudeF2 3To a solution of compound 2 (340 g, 1,46 mol, 1 eq) in THF (3000 mL) was added MeMgBr (3 M, 972.68 mL, 2 eq) at 5°C under N2. Tlie mixture w as stirred at 25°C for 2 hrs. LCMS (ET25230-2860-P1A1, Rt= 0.480 min, [M-17] = 231.0, 77.8%) showed compound 2 was consumed completely and one major peak with desired mass was detected. The reaction mixture was quenched by aq. NH4CI (3000 mL) and extracted with ethyl acetate (1000 mL x 2). The combined organic layers were washed with brine (2000 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 3 (354 g, crude) as yellow oil.LCMS: ET25230-2860-P1A1, Rt= 0.480 min, [M-17] = 231.0, 77.8%1H NMR: ET25230-2860-P1A1 CDCl3Bruker_02_G_400MHz’HNMR (400 MHz, CHLOROFORM-d) 5 = 7.42 - 7.36 (m, 1H), 6.62 (d, J= 8.9 Hz, 1H), 5.30 - 5.18 (m, 1H), 3.89 (d.7 1.0 Hz, 3H), 1.57 (d, J- 6.8 Hz, 3H).General procedure for preparation of compound 43 4To a solution of compound 3 (354 g, 1.42 mol, 1 eq) in DCM (3000 mL) was added PCC (612.72 g, 2.84 mol, 2 eq) at 5°C under N2. The mixture was stirred at 20°C for 4 hrs. Then PCC (306.36 g, 1.42 mol, 1 eq) was added at 10°C under N2. The mixture was stirred at 20°C for 16 hrs. LCMS (ET25230-2861-P1B1, Rt = 0.533 min, [M+l] = 246.9, 71.4%) showed compound 3 was consumed completely and one major peak with desired mass was detected. The reaction mixture was added diatomite (300 g) and stirred at 20°C for 10 min. The reaction mixture was filtered. The filter cake was washed by DCM (600 mL x 3), Tire combine was concentrated under reduced pressure to half volume. The combine was washed with aq. NazSOs (2000 mL), extracted with DCM (600 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1). Compound 4 (210 g, 849.99 mmol, 59.81% yield) was obtained as yellow oil.LCMS: ET25230-2861-P1B1, Rt = 0.533 min, [M+1] = 246.9, 71.4%’H NMR: ET25230-2861-P1A1 CDCL, Bruker_02__0__400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 7.50 (dd, J = 7.9, 8.9 Hz, 1H), 6.65 (dd, J = 1.1, 9.0 Hz, 1H), 3.85 (s, 3H), 2.54 (d, J = 1.0 Hz, 3H).General procedure for preparation of compound 6To a solution of compound 4 (105 g, 425.00 mmol, 1 eq) in NMP (1500 mL) was added Cs2CO3(415.42 g, 1.27 mol, 3 eq) and compound 5 (202.06 g, 1.22 mol, 2.87 eq, HC1) at 20°C under N2. The mixture was stirred at 100 °C for 48 hrs. LCMS (ET25230-2864-P1A1, Rt = 0.589 min, [M+l] = 356.0, 39.8%) showed compound 4 was consumed completely and one major peak with desired mass was detected. The reaction mixture was added H2O (10 L) andextracted with ethyl acetate (2 L x 2). The combined organic layers were washed with brine (1 L x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1). Compound 6 (266 g, 746.66 mmol, 87.84% yield) was obtained as a yellow solid. LCMS: ET25230-2864-P1A1, Rt= 0.589 min, [M+1] = 356.0, 39.8%1H NMR: ET25230-2864-P1A1 CDCl3Bruker_02_P_400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 7.43 (d, J = 8.9 Hz, 1H), 6.38 (d, J = 8.9 Hz, 1H), 4.52 (br s, 1H), 3.80 (s, 3H), 3.32 (s, 3H), 3.22 - 3.07 (m, 2H), 2.52 (s, 3H), 2.06 - 1.93 (m, 4H), 1.29 - 1.08 (m, 4H).General procedure for preparation of compound 7To a solution of compound 6 (130 g, 364.91 mmol, 1 eq) in AcOH (1200 mL) and H2O (800 mL) was added NaNO2(50.35 g, 729.82 mmol, 2 eq) at 20°C. The mixture was stirred at 25°C for 0.5 hrs. After cooling to 10-20°C, Zn (238.61 g, 3.65 mol, 10 eq) was added. Stirring was continued at 25°C for another 2 hrs. LCMS (ET25230-2871-P1A1, Rt= 0.675 min, [M+l] = 353.0, 70.7%) showed compound 6 was consumed completely and one major peak with desired mass was detected. Tire reaction mixture was filtered and the filtrate was extracted with EtOAc (3 x 200 mL). Combined organic layers were washed with saturated aqueous Na2CO3(2 L) and added Na2CO3and adjusted the pH of the reaction solution to 6-7, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). Compound 7 (105 g, 297.24 mmol, 81.46% yield) was obtained as a yellow solid.LCMS: ET25230-2871-P1A1, Rt= 0.675 min, [M+l] = 353.0, 70.7%1H NMR: ET25230-2871-P1A2 CDCl3Bruker_02_G_400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 7.35 (d, J = 8.3 Hz, 1H), 6.26 (d, J = 8.3 Hz, 1H), 5.36 (tt, J = 5.2, 10.3 Hz, 1H), 3.90 (s, 3H), 3.39 (s, 3H), 3.29 (t, J = 4.2, 10.9 Hz, 1H), 2.63 (s, 3H), 2.28 - 2.17 (m, 2H), 2.15 - 2.05 (m, 4H), 1.51 - 1.39 (m, 2H).General procedure for preparation of Intermediate R586A! 0'8'0KOAc, Pd(dppf)Cl2·DCM, DMF.20-8Q°C, 6 hrsstep 6, 63.48%R586ATo a solution of compound 7 (42.5 g, 120.31 mmol, 1 eq) in DMF (800 ml) was added compound a (108.70 g, 481.24 mmol, 4 eq), KOAc (59.04 g, 601.55 mmol, 5 eq) and Pd(dppf)Cl2·CH2Cl2(9.83 g, 12.03 mmol, 0.1 eq) at 20°C under N2. The mixture was stirred at 80°C for 6 hrs. LCMS (ET25230-2873-P1A1, Rt= 0.420 min, [M-67] = 319.0, 61.6%) showed compound 7 was consumed completely and one major peak with desired mass was detected. The reaction mixture was quenched by H2O (3000 mL) and extracted with ethyl acetate (1000 mL x 2). The combined organic layers were washed with brine (2000 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). intermediate R586A (59 g, 152.73 mmol, 63.48% yield) was obtained as a yellow solid. LCMS: ET25230-2873-P1A1, Rt= 0.420 min, [M-67] = 319.0, 61.6%1H NMR: ET25230-2873-P1A2 CDCl3Bruker_02_G_400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 7.70 (d, J = 7.9 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 5.03 - 4.89 (m, 1H), 3.93 (s, 3H), 3.83 (s, 4H), 3.41 (s, 3H), 3.31 (tt, J = 4.1, 10.9 Hz, 1H), 2.65 (s, 3H), 2.25 (br d, J = 12.5 Hz, 2H), 2.17 - 2.01 (m, 4H), 1.43 - 1.26 (m, 2H), 1.09 (s, 6H).General procedure for preparation of compound 1CHOCOOH, 4A MS, MeCN 80“C. 1 hrstep 1, 75.91% L153 1Two batches were carried out in parallel. To a solution of intermediate L153 (30 g, 77.63 mmol, 1 eq, HCl), R586A (30.00 g, 69.90 mmol, 0.9 eq), oxaldehydic acid (8.58 g, 93.21 mmol, 6.45 mL, 1.20 eq, H2O) in ACN (500 mL) was added 4A MS (15 g) and the mixture was stirred at 80°C for 1 hr. LCMS (ET30483-2509-P1A, Rt= 1.086 min & 1.109 min) showed the starting material was consumed completely and desired mass was detected. The reaction was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250 x 70 mm x 10 um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 30%-60% B over 20.0 min). Compound 1 (77 g, 117.86 mmol, 75.91% yield) was obtained as yellow oil.LCMS: ET30483-2509-P1 A, Rt= 1.086 min & 1.109 min, [M+l] = 653.3, 39.02%&38.20%General procedure for preparation of 90-P1 and 90-P290-P1 90-P2Structure randomly assigned Structure randomly assigned Compound 1 (46 g, 70.41 mmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IK (250 mm x 50 mm, 10 um); mobile phase: [Heptane-EtOH (0.1% IP Am)]; B%:15%, isocratic elution mode).Peak 4 was randomly assigned as 90-P1 (16.10 g, 24.26 mmol, 34.45% yield, 98.43% purity) was obtained as a white solid which was confirmed by LCMS (ET30483-2511-P4Y, Rt = 2.778 min), SFC (ET30483-2511-P4Y, Rt = 3.042 min) and NMR (ET30483-2511-P4Y).Peak 2 was randomly assigned 90-P2 as (20 g, crude) was obtained as a yellow oil.For 90-P1:LCMS: ET30483-2511-P4Y, Rt= 2.778 min, [M+l] = 653.4, 98.43%SFC: ET30483-2511-P4Y, Rt= 3.042 min, 99.15%1H NMR: ET30483-2511-P4Y MeOD Bruker_02_V_400MHz1H NMR (400 MHz, METHANOL-d4) δ = 7.30 (br d, J = 4.6 Hz, 1H), 7.00 (s, 2H), 6.93 (br s, 1H), 6.36 - 6.29 (m, 1H), 5.19 - 4.91 (m, 1H), 4.66 (br s, 1H), 3.91 (s, 3H), 3.40 (s, 3H), 3.35 (br s, 1H), 3.23 - 3.11 (m, 2H), 2.94 - 2.77 (m, 4H), 2.76 - 2.68 (m, 1H), 2.66 - 2.55 (m, 5H), 2.49 (br s, 3H), 2.22 (br d, J = 10.4 Hz, 3H), 2.11 (s, 4H), 2.00 - 1.82 (m, 4H), 1.79 (br t, J = 7.3 Hz, 3H), 1.51 - 1.32 (m, 3H), 1.12 (s, 6H).Example 8: Preparation of Compound 103-P1 and 103-P2Scheme 1: Synthetic Route for Intermediate R583Scheme 2: Synthetic Route for 103-P1 & 103-P2General procedure for preparation of compound 3OHO1 3trans To a solution of compound 1 (10 g, 46.08 mmol, 1 eq), compound 2 (15.92 g, 138.23 mmol, 3 eq) in dioxane (150 mL) was added Cs2CO3(30.02 g, 92.15 mmol, 2 eq). The reaction was stirred at 120°C for 16 hrs. LCMS (ET29811-1798-P1A, product: Rt = 1.151 min) showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by water (500 mL) at 0°C, extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @. 50 mL / min) to give compound 3 (14.3 g, 45.80 mmol, 99.41%yield) as awhite solid, which was confirmed by1H NMR (ET29811-1798-P1) and NOE (ET29811-1798-P1D).LCMS: ET29811-1798-P1A, R, 1.151 min, [M+ 1] - 312.1, 87.00%1H NMR: ET29811-1798-P1 DMSO Bruker_02_P_400MHz’HNMR (400 MHz, DMSO-c / s) 8 = 7.82 (dd, J= 1.4, 7.9 Hz, 1H), 7.70 (dd, J= 1.3, 7.8 Hz, 1H), 7.34 (d, J= 9.5 Hz, 1H), 6.81 (t, J= 7.9 Hz, 1H), 4.51 (d, J= 4.4 Hz, 1H), 3.65 - 3.55 (m, 1H), 3.39 (br dd, J = 4.6, 9.1 Hz, 1H), 2.59 (s, 3H), 1.87 - 1.73 (m, 4H), 1.20 - 1.08 (m, 4H).General procedure for preparation of compound 4OH HQNaNO2, AcOH, H2OQ wans3To a solution of compound 3 (10 g, 32.03 mmol, 1 eq) in HOAc (75 mL) and H2O (54 mL) was added NaNCh (4.42 g, 64.06 mmol, 2 eq). The mixture was stirred at 25°C for 2 hrs. After cooling to 0°C, Zn (20.94 g, 320.31 mmol, 10 eq) was added in small portions. Stirring was continued at 25°C for another 10 hrs. LCMS (ET29811-1801-P1Z, product: Rt= 1.237 min) showed the starting material was consumed completely and -50.56% of desired mass was detected. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (2 x 200 mL). Combined organic layers were washed with saturated aqueous Na2CO3(200 mL), brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / PetroIeum ether gradient @, 50 mL / min) to give compound 4 (5 g, 16.17 mmol, 50.49% yield) as a yellow solid.;H NMR (ET29811-1801-P1G) was confirmed the desired product.LCMS: ET29811-1801-P1Z, Rt = 1.237 min, [M+l] = 309.0, 50.56%1H NMR: ET29811-1801-P1G DMSO Bruker_02_V_400MHz1H NMR (400 MHz, DMSO-d6) 5 = 7.72 (d, J= 7.9 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 5.38 - 5.15 (m, 1H), 4.67 (d, J= 4.4 Hz, 1H), 3.60 - 3.40 (m, 1H), 2.47 (s, 3H), 1.99 - 1.91 (m, 6H), 1.45 - 1.30 (m, 2H).General procedure for preparation of compound 5HQ -OTo a solution of compound 4 (4 g, 12.94 mmol, 1 eq) in DMF (30 mL) was added NaH (620.96 mg, 15.52 mmol, 60% purity, 1.2 eq) at 0°C. The mixture w'as stirred at 0°C for 0.5 hrs. Then Mel (3.67 g, 25.87 mmol, 1.61 mL, 2 eq) was added. The mixture was stirred at 0-20°C for 2.5 hrs. LC-MS (ET93571-108-P1 A) showed the start material was consumed completely and -57.23% of desired compound was detected. The reaction mixture was quenched by NH4CI (50 mL) at 0°C, and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 * 3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The reactions were combined with ET93571-103. Tire residue waspurified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1). Compound 5 (4.1 g, 12.68 mmol, 87.16% yield) was obtained as a yellow solid.LCMS: ET93571-108-P1A, Rt= 0.626 min, [M+1] = 323.1, 325.1, 32.58%’H NMR: ET93571-108-P1A CDCI3 Bruker 02 V 400MHz1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.59-7.51 (m, 2H), 6.95 (t, J= 7.6 Hz, 1H), 5.44 -5.36 (m, 1H), 3.40 (s, 3H), 3.35 - 3.29 (m, 1H), 2.54 (s, 3H), 2.27 - 2.23 (m, 2H), 2.14 - 2.08 (m, 4H), 1.49 - 1.44 (m, 2H).General procedure for preparation of compound 6"~ 0Sr BrZnCH2COOt-BuJ - Pd(t-Bu3P)2. THF, 25-80°C, 2 hrsstep 4, 30.17%trans5To a solution of compound 5 (4 g, 12.38 mmol, 1 eq) in THF (40 mL) was added Pd(t-Bu3P)2 (632.44 mg, 1.24 mmol, 0.1 eq) and BrZnCH2COOt-Bu (1 M, 24.75 mL, 2 eq) at 25°C. The mixture was stirred at 80°C for 2 hrs under N2atmosphere, TLC (Petroleum ether / Ethyl acetate = 3 / 1, Rf = 0.54) indicated the starting material was consumed completely and one new spot with lager polarity was formed. The reaction mixture was quenched by H2O (100 mL), filtered and the filtrate was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-32% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). Compound 6 (4 g, 11.16 mmol, 90.17% yield) was obtained as yellow oil.’H NMR: ET49057-2061-P1A CDCh Bruker 02 V 400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 7.56 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 6.9 Hz, 1H), 7.09 - 7.02 (m, 1H), 4.60 - 4.49 (m, 1H), 3.90 (s, 2H), 3.40 (s, 3H), 3.38 - 3.27 (m, 1H), 2.55 (s, 3H), 2.32 - 2.13 (m, 4H), 2.07 (br s, 2H), 1.61 (br d, J = 3.4 Hz, 2H), 1.46 (s, 9H).General procedure for preparation of intermediate R583To a solution of compound 6 (800 mg, 2.23 mmol, 1 eq) in THF (10 mL) was added LiHMDS (1 M, 6.70 mL, 3 eq) at -78°C under N2 atmosphere. The mixture was stirred at -78°C for 30 min. TMSC1 (727.36 mg, 6.70 mmol, 849.73 pL, 3 eq was added at -78°C. After stirred at -78°C for 30 min, NBS (1.19 g, 6.70 mmol, 3 eq in THF (10 mL) was added. The mixture was stirred at - 78°C for 1.5 hrs. TLC (Petroleum ether / Ethyl acetate = 3 / 1, Rf= 0.62) indicated the starting material was consumed completely and one new spot with lower polarity was formed. The mixture was combined with the batch on the page ET49057-2063. The reaction mixture was quenched by addition aqueous NH4CI (20 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-27% Ethyl acetate / Petroleum ether gradient @ 70 mL / min). R583 (900 mg, 1.65 mmol, 73.77% yield, 80% purity) was obtained as yellow oil.1H NMR: ET49057-2064-P1A CDCl3Bruker_02_V_400MHz’HNMR (400 MHz, CHLOROFORM-ri) 5 = 7.64 (br d, J 8.0 Hz, 2H), 7.11 (br d, J -- 5.8 Hz, 1H), 5.90 (br s, 1H), 4.75 - 4.51 (m, 1H), 3.41 (s, 3H), 3.39 - 3.29 (m, 1H), 2.55 (s, 3H), 2.31 -2.12 (m, 6H), 1.60 (br s, 2H), 1.50 (s, 9H).General procedure for preparation of compound 2piperidine, Toluene,110°C, 72 hrsstep 1, 43.18%2To a solution of compound 1 (23 g, 131.42 mmol, 1 eq) in toluene (200 mL) was added piperidine (3.92 g, 46.00 mmol, 4.54 mL, 0.35 eq) and diethyl propanedioate (31.57 g, 197.13 mmol, 29.93 mL, 1.5 eq). The mixture was stirred at 110°C for 72 hrs. LCMS (ET54591-846-P1B1, Rt=0.641 min) showed -36.31% of reactant 1 remained, and 35.86% of the desired product was detected. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage®; 660 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient 200 mL / min). Compound 2 (18 g, 56.75 mmol, 43.18% yield) was obtained as yellow oil, which was confirmed byXH NMR (ET54591-845-P1A). LCMS: ET54591-846-P1B1, Rt= 0.641 min, [M+1] = 317.1, 35.86%1H NMR: ET54591-845-P1A CDCl3Bruker_02_O_400MHz1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.92 (s, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.32 - 7.28 (m, 1H), 4.32 (qd,.7= 7.1, 17.5 Hz, 4H), 1.36 (t,. J= 7.1 Hz, 3H), 1.27 - 1.23 (m, 3H).General procedure for preparation of compound 3EtONa, EtOH, 25°C, 48 hrsstep 2, crudeTo a solution of diethyl propanedioate (21.70 g, 135.50 mmol, 20.57 mL, 2,5 eq) in EtOH (240 mL) was added EtONa (14.75 g, 216.80 mmol, 4 eq). The mixture was stirred at 25°C for 2 hrs. Then compound 2 (17.19 g, 54.20 mmol, 1 eq) was added. The mixture was stirred at 25°C for 46 hrs, TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rr = 0.15) indicated the starting material was consumed completely and one new spot with large polarity was formed. The reaction mixture was quenched by water (200 mL), extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage®; 660 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 200 mL / min). Compound 3 (33 g, crude) was obtained as yellow oil, which was confirmed by]H NMR (ET54591-853-P1B).HPLC: ET54591-853-P1A11, Rt= 5.002 min, 89.72%1H NMR: ET54591-853-P1B CDCl3Bruker_02_P_400MHz1H NMR (400 MHz, CHLOROFORM-d) 6 = 7.49 (br s, 1H), 7.26 (br s, 1H), 7.14 (dd, J= 2.4, 8.6 Hz, 1H), 4.79 (br s, 1H), 4.16 - 4.07 (m, 8H), 3.36 (s, 2H), 1.28 - 1.25 (m, 12H).General procedure for preparation of compound 43 4A solution of compound 3 (30 g, 62.85 mmol, 1 eq) in HCl (300 mL) was stirred at 110°C for 16 hrs. LCMS (ET54591-859-P1B, Product: Rt= 0.205 min) showed the starting material was consumed completely and ~ 66.02% with desired Ms was detected. The mixture was cooled to 0 °C and stirred for 1 hr. The precipitate formed was filtered. Compound 4 (11.24 g, 40,56 mmol, 64.54% yield) was obtained as a white solid, which was confirmed by1H NMR (ET54591-859-P1A).LCMS: ET54591-859-P1B, Product: Rt= 0.205 min, [M+18] = 294.0, 66.02%1H NMR: ET54591-859-P1A DMSO Bruker_02_P_400MHz1H NMR (400 MHz, DMSO-d6) δ = 7.52 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.29 (br d, J = 8.6 Hz, 1H), 3.90 - 3.84 (m, 1H), 2.63 (br d, J = 7.3 Hz, 4H).General procedure for preparation of compound 54 5A solution of compound 4 (10 g, 36.09 mmol, 1 eq) in TFAA (100 mL) was stirred at 35°C for 48 hrs. HPLC (ET54591-864-P1A, Rt = 3.915 min) showed - 14.31% of reactant 1 remained, and ~ 82.32% of the desired product was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 5 (11 g, crude) was obtained as a brown solid.HPLC: ET54591-864-P1A, Rt = 3.915 min, 82.32%General procedure for preparation of compound 6Methylamine in THFTHF, 25°C, 1 hrstep 5, 69.00%6To a solution of compound 5 (11 g, 42.46 mmol, 1 eq) in THF (110 mL) was added methanamine (2 M, 42.46 mL, 2 eq). The mixture was stirred at 25°C for Ihr. LCMS (ET54591-870-P1 A, Product: Rt= 0.391 min) showed the starting material was consumed completely and -94.68% with desired Ms was detected. The reaction mixture was added MTBE (30 mL), filtered and concentrated under reduced pressure to give compound 6 (8.5 g, 29.30 mmol, 69.00% yield) as a brown solid.LCMS: ET54591-870-P1A, Product: Rt= 0.391 min, [M+1] = 290.1, 94.68%General procedure for preparation of compound 6A & 6BFC separation6A Structure randomly Assigned Structure randomty Assigned Compound 6 (5 g, 17.23 mmol, 1 eq) was separated by SFC (column: DAICEL CHTRALPAK IC (250 mm * 50 mm, 10 um); mobile phase: [CO2 - IPA; B%: 45%, isocratic elution mode).Peak 1, Compound 6A (2.2 g, 7.58 mmol, 44.00% yield) was obtained as a white solid.Peak 2, Compound 6B (1.89 g, 6.51 mmol, 37.80% yield) was obtained as a white solid.For Monitoring and Separation:SFC: ET54591-863-P1B, Rti- 2.140 mm, 50.30% & Rt2= 2.525 min, 49.70%For 6A (Peak 1):LCMS: ET54591-877-P1A, Rt= 0.388 min, [M+1] = 290.1, 96.68%SFC: ET54591-877-P1X, Rt= 2.159 min, 99.52%1H NMR: ET54591-877-P1A1 DMSO Bruker_02_O_400MHz’HNMR (400 MHz, DMS0-< ) 5 = 7.81 (br d, J= 4.4 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.25 (dd, J = 2.4, 8.6 Hz, 1H), 3.88 - 3.84 (m, 1H), 2.49 (br s, 3H), 2.43 (br t, J= 8.2 Hz, 4H).For 6B (Peak 2):LCMS: ET54591-877-P2B, Rt = 0.393 min, [M+l] = 290.1, 97.79%SFC: ET54591-877-P2X, Rt= 2.563 min, 98.83%’H NMR: ET54591-877-P2B2 DMSO Bruker, 02 O 400MHz1H NMR (400 MHz, DMSO-d6) δ = 7.76 (br d, J = 4.4 Hz, 1H), 7.49 - 7.35 (m, 2H), 7.27 (dd, J = 2.5, 8.6 Hz, 1H), 3.89 (br t, J = 7.3 Hz, 1H), 2.60 (dd, J = 3.5, 7.4 Hz, 2H), 2.49 (br s, 3H), 2.41 (dd, J = 2.3, 7.3 Hz, 2H).General procedure for preparation of compound 76A Structure randomly Assigned Structure randomly Assigned To a solution of compound 6A (500.00 mg, 1.72 mmol, 1 eq) in DMF (10 mL) was added HATU (982.87 mg, 2.58 mmol, 1.5 eq), DIEA (668.17 mg, 5.17 mmol, 900.50 µL, 3 eq) and 3,3-dimethylpyrrolidine (350.61 mg, 2.58 mmol, 1.5 eq, HC1). The mixture was stirred at 25°C for 2 hrs. LCMS (ET54591-906-P1A, Product: Rt= 0.531 min) showed the starting material was consumed completely and ~ 14.26% with desired Ms was detected. The reaction mixture was quenched by water (20 ml,), extracted with ethyl acetate (20 ml, x 3). Tire combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-55% tetrahydrofuran / Petroleum ethergradient @ 45 mL / min). Compound 7 (490 mg, 1.32 mmol, 76.58% yield) was obtained as a yellow solid.LCMS: ET54591-906-P1A, Rt= 0.531 min, [M+l] = 371.3, 14.26%General procedure for preparation of intermediate LI 29DIBAL-H THF, 0-25°C, 3 hrs step 8, 29.29%7 L129 Structure randomly Assigned Structure randomly Assigned To a solution of compound 7 (480.00 mg, 1.29 mmol, 1 eq) in THF (50 mL) was added DIBAL-H (1 M, 38.78 mL, 30 eq) at 0°C under N2. The reaction was allowed to warm up and stirred at 25°C for 3 hrs. LCMS (ET54591-913-P1A, Product: Rt= 0.891 min) showed the starting material was consumed completely and -79.23% with desired Ms was detected. Tire mixture was quenched by adding IM HC1 aqueous (60 mL), extracted with ethyl acetate (80 mL x 3), washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C 18 250 * 50 mm * 15 um; mobile phase: [HzO (0.04% HC1) - ACN]; gradient: 5%-30% B over 10.0 min). L129 (130 mg, 378.64 pmol, 29.29% yield) was obtained as yellow oil.LCMS: ET54591-913-P1A, Product: Rt= 0.891 min, [M+1] = 343.2, 79.23%General procedure for preparation of compound 81R583NaI, DIEA, MeCN, 25°C, 16 hrsstep 9, 77.26%L129Structure randomly AssignedTo a solution of L129 (127 mg, 369.90 pmol, 1 eq) in MeCN (2 mL) was added R583 (121.34 mg, 277.43 pmol, 0.75 eq), Nai (110.89 mg, 739.81 pmol, 2 eq) and DIEA (191.23 mg, 1.48 mmol, 257.72 µL, 4 eq) at 25°C. The mixture was stirred at 25°C for 16 hrs. LCMS (ET54591 -922-P1A, Product: Rt = 1.568 min) showed the starting material was consumed completely and - 49.73% with desired Ms was detected. The reaction mixture was quenched by water (5 mL), extracted with ethyl acetate (5 mL x 3). Tire combined organic layers w7ere washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by flash silica gel chromatography (Biotage®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ 18 mL / min), Compound 8 (200 mg, 285.80 pmol, 77.26% yield) was obtained as yellow oil.LCMS: ET54591-922-P1A, Product: Rt= 1.568 min & Rt=== 1.521 min, [M+l ] === 699.4, 74.57%General procedure for preparation of 103-P1 & 103-P2To a solution of compound 8 (200 mg, 285.80 pmol, 1 eq) in DCM (2 mL) was added TEA (307.00 mg, 2.69 mmol, 0.2 mL, 9.42 eq) at 25°C. The mixture was stirred at 25°C for 16 hrs. LCMS (ET54591-924-P1A, Product: Rt:::1.410 & 1.428 min) showed the starting material was consumed completely and - 65.29% with desired Ms was detected. Hie reaction mixture was concentrated under reduced pressure to give a residue. Tire residue -was purified by prep-HPLC (column: WePure Biotech XP tC 18 150 * 40 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 35%-65% B over 8.0 min).Peak 1: 103-P1 (17.9 mg, 26.99 pmol, 9.44% yield, 97.05% purity) was obtained as a white solid.Peak 2: 103-P2 (26.1 mg, 39.93 pmol, 13.97% yield, 98.48% purity) was obtained as a white solid....For Monitoring and Separation:SFC: ET54591-924-P1A, Rt1= 1.084 min, 45.39% & Rt2= 1.198 min, 54.61%For 724A (Peak 1):LCMS: ET54591-924-P1X, Rt= 2.717 min, [M+l] = 643.3, 97.05%SFC: ET54591-924-P1X, Rt= 1.087 min, 97.87%’H NMR: ET54591-924-P1A MeOD Bruker 02 O 400MHz1HNMR (400 MHz, METHANOL-d₄) 5 = 7.56 (d, J= 8.0 Hz, 1H), 7.51 (brd, J= 7.1 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.22 - 7.14 (m, 2H), 7.02 (t, J= 7.6 Hz, 1H), 5.44 - 4.89 (m, 1H), 4.76 - 4.64 (m, 1H), 3.40 (s, 3H), 3.37 - 3.33 (m, 1H), 3.26 (br s, 2H), 3.14 - 3.08 (m, 1H), 2.93 (br s, 3H), 2.78 - 2.69 (m, 2H), 2.52 (s, 3H), 2.48 (br s, 3H), 2.22 (br d, J= 10.5 Hz, 3H), 2.15 - 1.92 (m, 5H), 1.87 - 1.79 (m, 4H), 1.75 - 1.60 (m, 1H), 1.53 - 1.41 (m, 2H), 1.15 (s, 6H).For 724B (Peak 2):LCMS: ET54591-924-P2X, Rt= 2.779 min, [M+1] = 643.3, 98.48%SFC: ET54591-924-P2X, Rt= 1.201 min, 97.81%1H NMR: ET54591-924-P2B MeOD Bruker_02_O_400MHz’HNMR (400 MHz, METHANOL-d₄) 6 === 7.49 - 7.45 (m, 1H), 7.42 (d, J- 7.1 Hz, 1H), 7.19 (d, J= 8.6 Hz, 1H), 7.09 - 7.04 (m, 1H), 7.02 (s, 1H), 6.91 (t, J= 7.6 Hz, 1H), 5.30 - 4.94 (m, 1H), 4.64 (br s, 1H), 3.31 (s, 3H), 3.29 - 3.24 (m, 1H), 3.18 - 3.08 (m, 3H), 2.89 - 2.72 (m, 3H), 2.67 - 2.53 (m, 3H), 2.43 (s, 3H), 2.36 (s, 3H), 2.20 - 2.08 (m, 3H), 2.05 - 1.82 (m, 4H), 1.73 (br t, 7.4 Hz, 4H), 1.48 - 1.28 (m, 3H), 1.05 (s, 6H).Example 9: Preparation of Compound 106-P1 and 106-P2Scheme 1: Synthetic Route for intermediate R585Scheme 2: Synthetic Route for intermediate LI 25Scheme 3: Synthetic Route for 106-P1 & 106-P2R585 22106-P1 106-P2Structure randomly assigned Structure randomly assignedGeneral procedure for preparation of compound 3O-NHHCi 2CDI, DCM. 0-25°C, 18 hrs / \Step 1, 92.04%To a solution of compound 1 (30 g, 161.11 mmol, 1 eq) in DCM (500 mL) was added CDI (39.19 g, 241.67 mmol, 1.5 eq) at 0°C and the mixture was stirred for 2 hrs. Then compound 2 (23.57 g, 241.67 mmol, 1.5 eq, HC1) was added to the solution and stirred at 25°C for 16 hrs. LCMS (ET49057-2109-P1A, Rt === 0.350 min) showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition H2O (1000 mL), extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-47% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). Compound 3 (34 g, 148.30 mmol, 92.04% yield) was obtained as colorless oil.LCMS: ET49057-2109-P1A, Rt= 0.350 min, [M+l] = 230.1, 53.47%NMR: ET49057-2109-P1A CDCl3Bruker_02_R_400MHz'HNMR (400 MHz, CHLOROFORM-d) 8 - 3.95 (s, 4H), 3.71 (s, 3H), 3.18 (s, 3H), 2.69 (br t, J= 10.0 Hz, 1H), 1.87 - 1.78 (m, 6H), 1.63 - 1.51 (m, 2H).General procedure for preparation of compound 5- LDA, THF, -78°C, 35 hrsstep 2, 94.14%3 Three batches were carried out in parallel. To a solution of compound 4 (6.5 g, 37.14 mmol, 4.15 mL, 1 eq) in THF (100 mL) was added LDA (2 M, 20.43 mL, 1.1 eq) at -78°C. The reaction was stirred at -78°C for 0.5 hrs. Compound 3 (10.22 g, 44.57 mmol, 1.2 eq) in THF (20 mL) was added into the reaction. The reaction was stirred at -78°C for 3 hrs. TLC (Petroleum ether / Ethyl acetate = 3 / 1, R 0.47) indicated the starting material remained and two new spots with lower polarity were formed. The reaction mixture was quenched by addition aqueous NH4Cl (600 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (600 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~32% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). Compound 5 (36 g, 104.90 mmol, 94.14% yield) was obtained as colorless oil.1H NMR: ET49057-2113-P1A DMSO Bruker_02_P_400MHz’HNMR (400 MHz, DMSO-^) 5 = 7.57 (d, J= 7.9 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.42 - 7.36 (m, 1H), 3.85 (s, 4H), 2.89 (br t,. / = 10.4 Hz, 1H), 1.87 (br dd, 2.9, 12.4 Hz, 2H), 1.75 - 1.47 (m, 6H).General procedure for preparation of compound 6NH2NH2. H2O 50-100°C, 165 hrs step 3, 61.06%Two batches were carried out in this page. A solution of compound 5 (10 g, 29.14 mmol, 1 eq) in NH2NH2·H2O (104.79 g, 2.09 mol, 101.54 mL, 71.84 eq) was stirred at 50°C for 0.5 hrs. Then the solution was stirred at 100°C for 16 hrs. LCMS (ET49057-2120-P1A1, Rt = 0.528min) showed the starting material was consumed completely and -70.01% of the peak with desired mass was detected. LCMS (ET49057-2120-P1B1, Rt = 0.522 min) showed the starting material was consumed completely and -69.62% of the peak with desired mass was detected. The reaction mixture was quenched by addition H2O (500 mL) and extracted with ethyl acetate (300 mL x 3). Ihe combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (150 mL). The resulting solid was filtered through a funnel rinsed with ethyl acetate and collected to give compound 6 (12 g, 35.59 mmol, 61.06% yield) as a white solid.LCMS: ET49057-2120-P1A1, Rt= 0.528 min, [M+l] = 337.0, 70.01%LCMS: ET49057-2120-P1B1, Rt= 0.522 min, [M+1] = 337.0, 69.62%1H NMR: ET49057-2120-P1A DMSO Bruker_02_R_400MHz’HNMR (400 MHz, DMSO-c / e) 5 = 12.99 (s, 1H), 7.48 (d, J= 8.1 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.23 - 7.17 (m, 1H), 3.89 (s, 4H), 3.60 - 3.49 (m, 1H), 2.10 - 1.97 (m, 2H), 1.93 - 1.79 (m, 4H), 1.66 (brdd, <7 = 4.1, 13.1 Hz, 2H).General procedure for preparation of compound 7To a solution of compound 6 (12 g, 35.59 mmol, 1 eq) in THF (150 mL) was added NaH (2.13 g, 53.38 mmol, 60% purity, 1.5 eq) at 0°C under N 2 atmosphere. After 30 minutes, MeI (10.10 g, 71.17 mmol, 4.43 mL, 2 eq) was added. The mixture was stirred at 25°C for 2 hrs, TLC (Petroleum ether / Ethyl acetate = 2 / 1, Rt 0.45) indicated the starting material was consumed completely and one new spot with lower polarity was formed. Ihe mixture was combined with the batch on the page ET490.57-2123. The mixture was quenched with NH4CI (600 ml.) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (600 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-38% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). Compound 7 (16 g, 45.55 mmol, 65.31% yield) was obtained as a white solid.1H NMR: ET49057-2122-P1A DMSO Bruker_02_R_400MHz ’H NMR (400 MHz, DMSO-c / g) 5 = 7.59 (d, J= 7.9 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.27 - 7.22 (m, 1H), 3.97 (s, 3H), 3.89 (s, 4H), 3.65 - 3.46 (m, 1H), 2.05 - 1.95 (m, 2H), 1.91 - 1.78 (m, 4H), 1.68 - 1.59 (m, 2H).General procedure for preparation of compound 8HCI THF, 25-50°C, 1 hr step 5, crudeTo a solution of compound 7 (16 g, 45.55 mmol, 1 eq) in THF (90 ml.) was added HCI (3 M, 90 mL, 5.93 eq) at 25°C and the mixture was stirred at 50°C for 1 hr. LCMS (ET49057-2130-P1A, Rt= 0.546 min) showed the starting material was consumed completely and -86.40% of the peak with desired mass was detected, lire mixture was diluted with water (400 mL), adjusted to pH = 7-8 with saturated NaHCOs aqueous at 0°C and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 8 (14 g, erode) as a white solid.LCMS: ET49057-2130-P1A, Rt= 0.546 min, [M+l] = 307.0, 86.40%1H NMR: ET49057-2130-P1A CDCl3Bruker_02_O_400MHzJH NMR (400 MHz, CHLOROFORM- ) 8 === 7.34 - 7.29 (m, 2H), 7.23 - 7.18 (m, 1H), 4.15 - 4.10 (m, 1H), 4.01 (s, 3H), 2.64 - 2.54 (m, 4H), 2.53 - 2.44 (m, 2H), 2.25 - 2.12 (m, 2H).General procedure for preparation of compound 9NaBH4, FeCI3,6H2O MeOH / THF, 0°C, 2 hrs8 9Two batches were carried out in this page. To a solution of compound 8 (7 g, 22.79 mmol, 1 eq) in THF (150 mL) and MeOH (30 mL) was added FeCl3·6H2O (9.85 g, 36.46 mmol, 1.6 eq) and NaBH4(3.49 g, 92.25 mmol, 4.05 eq) at 0°C. The mixture was stirred at 0°C for 2 hrs.LCMS (ET49057-2132-P1A1, Rt= 0.476 min) showed the starting material remained and -46,64% of the peak with desired mass was detected. The reaction mixture was quenched by H2O (500 mL), adjusted to pH = 5-6 with 3 M HC1, then adjusted to pH = 7-8 with saturated NaHCCL aqueous, filtered and the filtrate was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The product was purified by prep-HPLC (column: Phenomenex luna Cl 8250 * 150 mm * 15 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 28%-58% B over 20.0 min) to afford compound 9 (7 g, 22.64 mmol, 49.67% yield) as a white solid.LCMS: ET49057-2132-P1 Al, Rt= 0.476 min, [M+l] = 309.0, 46.64%’H NMR: ET49057-2132-P1A DMSO Bruiser 02 R 400MHzNMR (400 MHz, DMSO-rfc) 5 = 7.58 (d, J = 8.2 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.27 - 7.21 (m, 1H), 4.58 (d, J = 4.5 Hz, 1H), 3.96 (s, 3H), 3.51 - 3.36 (m, 2H), 2.08 - 1.89 (m, 4H), 1.70 - 1.54 (m, 2H), 1.39 - 1.26 (m, 2H).General procedure for preparation of compound 11KHF2DCM / H2O, 25°C, 16 hrs step 7, 91.82%To a solution of compound 9 (3 g, 9.70 mmol, 1 eq) in DCM (30 mL) and H2O (30 mL) was added KHF2 (9.09 g, 116.43 mmol, 3.84 mL, 12 eq) and compound 10 (11.82 g, 58.21 mmol, 6 eq). The mixture was stirred at 25°C for 16 hrs under N2atmosphere. TLC (Petroleum ether / Ethyl acetate = 2 / 1, Rf = 0.60) indicated the starting material was consumed completely and one new spot with lower polarity was formed. Tire mixture was quenched with H2O (60 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (60 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-26% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). Compound 11 (3.2 g, 8.91 mmol, 91.82% yield) was obtained as a yellow solid.1H NMR: ET49057-2143-P1A CDCl3Bruker_02_R_400MHz'HNMR (400 MHz, CHLOROFORM-o) 8 = 7.29 (d, J = 2.0 Hz, 1H), 7.28 (s, 1H), 7.21 - 7.12 (m, 1H), 6.29 (t, J= 75.8 Hz, 1H), 4.27 - 4.12 (m, 1H), 4.00 (s, 3H), 3.67 - 3.55 (m, 1H), 2.29 - 2.13 (m, 4H), 1.86 - 1.63 (m, 4H).General procedure for preparation of compound 12BrZnCH2COOEt Pd(t-Bu3P)2, THE, 25-80°C, 2 hrs step 8, 91.91%To a solution of compound 11 (3.2 g, 8.91 mmol, 1 eq) in THF (50 mL) was added Pd(t-Bu3P)2(455.27 mg, 890.85 pmol, 0.1 eq) and BrZnCH2COOEt (1 M, 22.27 mL, 2.5 eq) at 25°C. The mixture was stirred at 80°C for 2 hrs under N2atmosphere. TLC (Petroleum ether / Ethyl acetate = 2 / 1, Rr = 0.36) indicated the starting material was consumed completely and one new spot with lager polarity was formed. The reaction mixture was quenched by H2O (100 mL), filtered and the filtrate was extracted with ethyl acetate (50 mL x 3). Hie combined organic layers were washed with brine (100 mL), dried over Na2SO4filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-32% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). Compound 12 (3 g, 8.19 mmol, 91.91 % yield) was obtained as a yellow solid.1H NMR: ET49057-2147-P1A CDCl3Bruker_02_R_400MHz'H NMR (400 MHz, CHLOROFORM-^ / ) 8 = 7.35 - 7.29 (m, 1H), 7.28 - 7.25 (m, 1H), 6.97 (d, J = 6.7 Hz, 1H), 6.29 (t, J = 75.7 Hz, 1H), 4.26 - 4.15 (m, 3H), 4.00 (s, 5H), 3.14 (tt, J = 3.4, 11.8 Hz, 1H), 2.26 - 2.15 (m, 2H), 2.15 - 2.04 (m, 2H), 1.92 - 1.77 (m, 2H), 1.72 - 1.56 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).General procedure for preparation of Inter R585LiHMDS, TMSCI, NBS THF, -78°C, 25 hrs step 8, crudeR585 To a solution of compound 12 (2 g, 5.46 mmol, 1 eq) in THF (40 mL) was added LiHMDS (1 M, 16.38 mL, 3 eq) at -78°C under N2 atmosphere. The mixture was stirred at -78°C for 30 min. TMSC1 (1.78 g, 16.38 mmol, 2.08 mL, 3 eq) was added at -78°C. After stirred at -78°C for 30 min, NBS (2.91 g, 16.38 mmol, 3 eq) in THF (20 mL) was added. The mixture was stirred at - 78°C for 1.5 hrs. TLC (Petroleum ether / Ethyl acetate = 2 / 1, Rf= 0.42) indicated the starting material was consumed completely and one new spot with lower polarity was formed. The reaction mixture was quenched by addition aqueous NH4CI (80 mL) and extracted with ethyl acetate (40 mL x 3). Tire combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~28% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min). Intermediate R585 (2.5 g, crude) was obtained as a yellow solid.1H NMR: ET49057-2152-P1A MeOD Bruker_02_O_400MHz4-1 NMR (400 MHz, METHANOL- 4) 5 = 7.54 - 7.47 (m, 1H), 7.42 - 7.30 (m, 2H), 6.45 (t, J = 76.2 Hz, 1H), 6.15 (s, 1H), 4.33 - 4.22 (m, 2H), 4.21 - 4.13 (m, 1H), 4.01 (s, 3H), 3.28 - 3.20 (m, 1H), 2.24 - 2.09 (m, 4H), 1.95 - 1.77 (m, 2H), 1.73 - 1.61 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H).General procedure for preparation of compound 14DMP DCM, 0-25°C, 0.5 hrsstep 10, crude Two batches were carried out in parallel in this page.To a solution of compound 13 (24 g, 126.82 mmol, 1 eq) in DCM (500 mL) was added DMP (56.48 g, 133.16 mmol, 41.25 mL, 1.05 eq) at 0°C and the solution was stirred at 25°C for 0,5 hrs. TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.43) indicated the starting material was consumed completely and one new spot formed. The reaction was quenched with saturatedaqueous Na2SO3(1L) and extracted with DCM (5 x 500 mL). Combined organics were washed with saturated Na2CO3solution (2 x 500 ml,), dried over anhydrous Na2SO4, filtered and concentrated to give compound 14 (48 g, crude) as yellow oil.General procedure for preparation of compound 16O ONaH, THF, 0-25°C, 1 hrstep 11, 42.51% Two batches were carried out in parallel in this page.To a suspension of NaH (6.66 g, 166.64 mmol, 60% purity, 1.3 eq) in THF (300 mL) was added compound 14 (34.48 g, 153.82 mmol, 30.52 mL, 1.2 eq) at 0°C. The reaction was stirred at 0°C for 30 mins. A solution of compound 15 (24 g, 128.18 mmol, 1 eq) in THF (100 mL) was then added to the mixture above slowly. The mixture was allowed to warm to 25°C and stirred for 30 mins. TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf= 0.7) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition aq. NH4CI (1 L) at 0°C, extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 16 (28.04 g, 108.97 mmol, 42.51 % yield) was obtained as yellow oil.1H NMR: ET28542-3351-P1B CDCl3Bruker_02_V_400MHzJH NMR (400 MHz, CHLOROFORM- ) 5 = 6.99 - 6.85 (m, 1H), 5.85 (d, J= 15.6 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.35 (br t, J= 6.8 Hz, 2H), 2.85 (s, 3H), 2.42 (br d, J= 6.6 Hz, 2H), 1.45 (s, 9H), 1.32 - 1.27 (m, 3H).General procedure for preparation of compound 18NKOH, BINAP, (1Z,5Z)" Cycloocta-1,5- diene;rhodium(1+);tetrafluoroborate dioxane, H2O, 25°C, 16 hrsstep 12, 84,21%16 18To a solution of compound 16 (12 g, 46,63 mmol, 1 eq), compound 17 (22.26 g, 116.58 mmol, 2.5 eq), KOH (3.92 g, 69.95 mmol, 1.5 eq), BINAP (2.90 g, 4.66 mmol, 0.1 eq) and (1Z,5Z)- cycloocta-1,5-diene; rhodium(1+); tetrafluoroborate (1.51 g, 3.73 mmol, 0.08 eq) in dioxane (210 mL) and H2O (30 mL) was stirred at 25°C for 16 hrs under N2 atmosphere. LCMS (ET28525-2500-P1A, Rt = 0.577 min) showed ~ 30% of the desired peak was detected. The mixture was partitioned between ethyl acetate (100 mL) and sat. NH₄Cl (100 mL). The mixture was filtered and the filtrate was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-38% Ethyl acetate / Petroleum ether gradient @ 70 mL / min). The crude product was further purified by prep-HPLC (column: Agela DuraShell C18 250 * 70 mm * 10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 45% - 80% B over 17.0 min) to give compound 18 (14.4 g, 35,61 mmol, 84.21% yield) as yellow oil,LCMS: ET28525-2500-P1A, Rt = 0.577 min, [M+1] = 405.2, 30.32%.¹H NMR: ET49057-2096-P1A CDCl₃ Bruker_02_R_400MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.66 (d, J = 5.0 Hz, 1H), 7.54 (s, 1H), 7.37 (br d, J = 4.2 Hz, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.27 - 3.05 (m, 3H), 2.84 - 2.72 (m, 4H), 2.67 - 2.54 (m, 1H), 1.98 - 1.83 (m, 2H), 1.41 (br s, 9H), 1.15 (t, J= 7.1 Hz, 3H).General procedure for preparation of compound 18A & 18B18A 18B ’8Structure randomly assigned Structure randomly assigned To a solution of compound 18 (14 g, 34,62 mmol, 1 eq) in THF (245 mL) was added LiAlH₄ (2.5 M, 16.62 mL, 1.2 eq). The mixture was stirred at 0°C for 1 hr. LCMS (ET93571-152-P1A) showed the start material was consumed completely and ~ 96.68% of desired compound was detected. The reaction was added NH₄Cl·H₂O (10 g) and filtered to give crude product. Then the residue was purified by prep-SFC (column: DAICEL CHIRALCEL OJ (250 mm * 50 mm, 10 um): mobile phase: [CO2 - IP A (0.1% NH3H2O)]; B%: 12%, isocratic elution mode) to give peak 1 was randomly assigned as compound 18A (5.5 g, 15.18 mmol, 43,84% yield) as a yellow oil and peak 2 was randomly assigned as compound 18B (5 g, 13.80 mmol, 39.86% yield) as a yellow oil.LCMS: ET93571-152-P1A, Rt = 0.499 min, [M+1] = 363.2, 96.68%For Compound 18A:SFC: ET93571-152-P1A1, Rt= 1.208 min, 99.20%¹H NMR: ET93571-152-P1A1 MeOD Bruker_02_R_400MHz’H NMR (400 MHz, METHANOL-d₄) 8 === 8.62 (br d, J 4.77 Hz, 1 H), 7.73 (s, 1 H), 7.57 (d, J= 4.53 Hz, 1 H), 3.32 - 3.54 (m, 2 H), 3.01 - 3.21 (m, 2 H), 2.88 - 2.99 (m, 1 H), 2.78 (s, 3 H), 1.78 - 2.04 (m, 4 H), 1.31 - 1.47 (m, 9 H).For Compound 18B:SFC: ET93571-152-P1A2, Rt= 1.498 min, 97.12%¹H NMR: ET93571-152-P1A2 MeOD Bruker_02_R_400MHz’H NMR (400 MHz, METHANOL-d₄) 8 === 8.62 (br d, J--- 4.8 Hz, 1H), 7.73 (s, 1H), 7.57 (d, J -----4.8 Hz, 1H), 3.48 (td, J = 5.5, 10.7 Hz, 1H), 3.39 - 3.32 (m, 1H), 3.09 (br s, 1H), 3.00 - 2.88 (m, 1H), 2.78 (s, 3H), 2.00 - 1.80 (m, 4H), 1.44 - 1.32 (m, 9H)General procedure for preparation of compound 19-N.„BOC DOC18A -jgStructure randomly assigned Structure randomly assigned A solution of compound 18A (5 g, 13.80 mmol, 1 eq) in DCM (100 mL) was added DMP (7.61 g, 17.94 mmol, 5.56 mL, 1.3 eq) at 0°C. The mixture was stirred at 25°C for 2 hrs. TLC indicated Reactant 1 was consumed completely and one new spot formed. The reaction mixture was poured into NaHCO₃ solution (150 mL) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with Na₂SO₃ (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 19 (6,6 g, crude) as a white solid,NMR: ET93571-161-P1C CDCh Bruker__02_V_400MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 9.70 (s, 1H), 8.66 (br d, J = 4.8 Hz, 1H), 7.54 (s, 1H), 7.40 - 7.35 (m, 1H), 3.31 (quin, J= 7.1 Hz, 1H), 3.20 - 3.06 (m, 2H), 2.99 - 2.89 (m, 1H), 2.79 (br s, 3H), 2.04 - 1.74 (m, 3H), 1.42 (br s, 9H).General procedure for preparation of compound 20NH b NaBH(OAc)₃, AcOHDCM, 25°C, 3 hrsstep 15, crude18 20Structure randomly assigned Structure randomly assigned To a solution of compound 19 (5.5 g, 15.26 mmol, 1 eq) and compound b (3.25 g, 38.16 mmol, 3.77 mL, 2.5 eq) in DCM (50 mL) was added NaBH(OAc)₃ (6.47 g, 30.52 mmol, 2 eq) and AcOH (1.5 mL), The mixture was stirred at 25°C for 2 hrs. LCMS (ET93571-166-P1A) showed the start material was completed and -59.87% of desired compound was detected. Tire residue was quenched by water (50 mL) slowly, extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give compound 20 (6.5 g, crude) as a yellow oil.LCMS: ET93571-166-P1A, Rt = 0.440 min, [M+1] = 430.2, 59.87%General procedure for preparation of compound L125step 16, crude / NH20 L125 Structure randomly assigned Structure randomly assigned To a solution of compound 20 (6 g, 13.97 mmol, 1 eq in HCl / dioxane (4 M, 25 mL). The mixture was stirred at 25°C for 1 hr. LCMS (ET93571-171-P1A) showed Reactant 1 was completed and -70.97% of desired compound was detected. The mixture was concentrated under reduced pressure to give a residue. The residue in water (10 mL), was extracted with ethyl acetate (15 mL x 3). The aqueous phase was lyophilized to give L125 (4.5 g, crude, HC1) as a yellow solid.LCMS: ET93571-171-P1A, Rt = 0.282 min, [M+1] = 330.2, 70.97%’H NMR: ET93571-171 -P1B MeOD ZKNJ 02 N 400MHz¹H NMR (400 MHz, METHANOL-d₄) δ = 8.72 (d, J = 5.01 Hz, 1 H), 8.68 (d, J = 4.89 Hz, 1 H), 7.86 (s, 1 H), 7.69 (d, J = 4.40 Hz, 1 H), 3.47 - 3.55 (m, 2 H), 2.95 - 3.22 (m, 4 H), 2.82 - 2.94 (m, 2 H), 2.76 (td, J = 12.04, 6.23 Hz, 2 H), 2.66 (s, 3 H), 2.20 - 2.34 (m, 2 H), 2.04 - 2.18 (m, 2 H), 1.87 - 1.94 (m, 2 H), 1.79 - 1.84 (m, 2 H).General procedure for preparation of compound 21L125 Structure randomly assigned K₂CO₃, NaBr, MeCN 25-80°C, 1.25 hrs step 17, 64.18%R585To a solution of L125 (164.32 mg, 449.14 pmol, 1 eq, HC1) in MeCN (4 mL) was added K2CO3 (310.37 mg, 2.25 mmol, 5 eq) at 25°C, the mixture was stirred at 25°C for 15 min. Then R585 (200 mg, 449.14 pmol, 1 eq) and NaBr (138.64 mg, 1.35 mmol, 43.28 pL, 3 eq) was added, the mixture was stirred at 80°C for 1 hr. LCMS (ET49057-2157-P1A, Rt = 0.425 min) showed the starting material was consumed completely and -54.79% with desired Ms was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-54% Ethyl acetate / Commercial hexanes gradient @ 70 mL / min). Compound 21 (200 mg, 288.27 pmol, 64.18% yield) was obtained as yellow oil. LCMS: ET49057-2157-P1A, Rt = 0.425 min, [M+1] = 694.4, 54.79%General procedure for preparation of compound 2222Structure randomly assignedTo a solution of compound 21 (200 mg, 288.27 pmol, 1 eq) in EtOH (2 mL) and THF (2 mL) and H2O (0.2 mL) was added NaOH (34.59 mg, 864.82 pmol, 3 eq) at 25°C. The reaction was stirred at 50°C for 16 hrs. LCMS (ET49057-2159-P1A, Rt = 1.013 min) showed the starting material was consumed completely and -86.55% with desired Ms was detected. The reaction mixture was adjusted pH to 7-8 by adding aq. HC1 (6 N). Then the mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: WePure Biotech XPt C18150 * 40 * 7 um; mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN]; gradient: 30%-60% B over 8.0 min). Compound 22 (100 mg, 150.21 pmol, 52,11% yield) was obtained as a white solid.LCMS: ET49057-2159-P1A, Rt = 1.013 min, [M+1] = 666.5, 86.55%General procedure for preparation of 106-P1 & 106-P2 -22 106-P2Structure Randomly Assigned Structure randomly assigned Compound 22 (100 mg, 150.21 pmol, 1 eq was separated by SFC (column: DAICEL CHIRALPAK IK (250 mm * 25 mm, 10 urn); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 33%, isocratic elution mode) to give two peaks.Peak 1, (23.6 mg, 35.45 pmol, 23.60% yield, 100% purity) was obtained as a white solid and randomly assigned as 106-P1.Peak 2, (47.4 mg, 71.20 pmol, 47.40% yield, 100% purity) was obtained as a white solid and randomly assigned as 106-P2.For Monitoring and Separation:SFC: ET49057-2159-P1A, Rti = 1.047 min, 46.97% & R. = 1.266 min, 53.03%SFC: ET49057-2165-P1B, Rn = 2.422 min, 8.44% & Rt2= 2.901 min, 91.56% For 106-P1 (Peak 1):LCMS: ET49057-2165-P1S1, Rt = 2.547 min, [M+1] = 666.3, 100.00%SFC: ET49057-2165-P1S1, Rt= 1.009 min, 100.00%¹H NMR: ET49057-2165-P1S MeOD Bruker_02_O_400MHz¹H NMR (400 MHz, METHANOL-d₄) δ = 8.45 (d, J = 5.0 Hz, 1H), 7.49 (s, 1H), 7.39 - 7.22 (m, 3H), 7.18 (br d, J = 4.5 Hz, 1H), 6.45 (t, J = 76.3 Hz, 1H), 4.78 (s, 1H), 4.21 - 4.12 (m, 1H), 3.99 (s, 3H), 3.48 (td, J = 1.6, 3.3 Hz, 1H), 2.86 - 2.70 (m, 5H), 2.70 - 2.53 (m, 3H), 2.50 (s, 3H), 2.44 - 2.31 (m, 2H), 2.22 - 2.07 (m, 3H), 2.04 - 1.82 (m, 5H), 1.76 - 1.60 (m, 7H), 1.59 - 1.49 (m, 2H).For 106-P2 (Peak 2):LCMS: ET49057-2165-P2B1, Rt = 2.581 min, [M+1] = 666.3, 100.00%SFC: ET49057-2165-P2A1, Rt= 1.263 min, 96.90%¹H NMR: ET49057-2165-P2A MeOD Bruker_02_O_400MHz¹H NMR (400 MHz, METHANOL-d₄) δ = 8.51 (d, J = 5.0 Hz, 1H), 7.56 (s, 1H), 7.40 - 7.31 (m, 3H), 7.30 - 7.24 (m, 1H), 6.45 (t, J = 76.4 Hz, 1H), 4.75 (s, 1H), 4.22 - 4.11 (m, 1H), 3.98 (s, 3H), 3.64 - 3.49 (m, 1H), 2.83 (br s, 5H), 2.72 - 2.56 (m, 3H), 2.49 - 2.38 (m, 4H), 2.32 (br d, J = 12.4 Hz, 1H), 2.18 (br d, J = 9.8 Hz, 2H), 2.13 - 2.05 (m, 1H), 2.02 - 1.82 (m, 4H), 1.78 - 1.61 (m, 8H), 1.55 (br d, J = 5.0 Hz, 2H)Example 10: Preparation of Compound 109-P1 and 109-P2Scheme 1: Synthetic Route for Intermediate R586Scheme 2: Synthetic Route for 109-P1 & 109-P2General procedure for preparation of compound 2LDA, DMF, THF, -70°C, 1h step 1, crudeTo a solution of compound 1 (20 g, 97.55 mmol, 1 eq) in THF (200 mL) was added LDA (2 M, 58.53 mL, 1.2 eq) at -70°C. The mixture was stirred at -70°C for 0.5 hrs. DMF (9.27 g, 126.81 mmol, 9.76 mL, 1.3 eq) was added to the mixture at -70°C, the mixture was stirred at -70°C for 0.5 hrs. TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rf = 0.17) indicated the starting material ■was consumed completely and one new spot formed. The reaction mixture was quenched by addition aqueous NH4CI (500 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2 (23.3 g, crude) as a yellow solid.’H NMR: ET28542-3366-P1A CDC13 Bruker 02 R 400 MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 10.37 (d, J = 1.2 Hz, 1H), 7.67 (dd, J = 7.7, 9.0 Hz, 1H), 6.72 (dd, J = 1.1, 9.1 Hz, 1H), 3.94 (s, 3H).General procedure for preparation of compound 3MeMgBrTHF, 0-25°C, 2h step 2, crudeTo a solution of compound 2 (22.3 g, 95.69 mmol, 1 eq) in THF (250 mL) was added MeMgBr (3 M, 63.80 mL, 2 eq) at 0°C under N2. The mixture was stirred at 25°C for 2 hrs. LCMS (ET28542-3369-P1A1, Rt = 0.492 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition aqueous NH4CI (500 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 3 (24 g, crude) as yellow oil.LCMS: ET28542-3369-P1A1, Rt= 0.492 min, [M-17] = 231.0, 80.45%¹H NMR: ET28542-3369-P1A CDCl₃ Bruker_02_V_400MHz ¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.44 - 7.34 (m, 1H), 6.62 (dd, J = 0.9, 8.9 Hz, 1H), 5.24 (br dd, J = 6.8, 10.8 Hz, 1H), 3.89 (s, 3H), 3.21 (d, J = 10.8 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H).General procedure for preparation of compound 4PCC DCM, 25°C, 16hF OH step 3, 99.09%3 4Three batches were carried out in parallel in this page. To a solution of compound 3 (7.8 g, 31.32 mmol, 1 eq) in DCM (120 mL) was added PCC (13.50 g, 62.63 mmol, 2 eq) at 25°C and the solution was stirred at 25°C for 16 hrs. LCMS (ET28542-3371-P1A1, Rt = 0.527 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was filtered. The filter cake was washed by DCM (100 mL x 3). The combined filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO?„ petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Compound 4 (23 g, 93.09 mmol, 99.09% yield) was obtained as yellow oil.LCMS: ET28542-3371-P1A1, Rt = 0.527 min, [M+1] = 246.9, 85.10%¹H NMR: ET28542-3371-P1A CDCl₃ Bruker_02_P_400MHz’HNMR (400 MHz, CHLOROFORM-d) 8 = 7.50 (dd, J= 7.9, 8.8 Hz, 1H), 6.65 (dd, J -- 1.1, 8.9 Hz, 1H), 3.85 (s, 3H), 2.54 (d, J= 0.8 Hz, 3H).General procedure for preparation of compound 5O''F O 120°C, 24 h. step 4, 83.22%To a solution of compound 4 (8 g, 32.38 mmol, 1 eq) in NMP (120 mL) was added Cs2CO3(31.65 g, 97.14 mmol, 3 eq) and compound a (16.09 g, 97.14 mmol, 3 eq, HCl). The mixture was stirred at 100 °C for 24 hrs. LCMS (ET28542-3442-P1M, Rt =0.586 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction was worked up with ET28542-3441-P1. The reaction mixture was quenched by addition H₂O (300 mL) at 0°C, extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 5), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 5 (9 g, 25.26 mmol, 52.01% yield) was obtained as yellow oil.LCMS: ET28542-3442-P1M, Rt = 0.586 min, [M+1] = 356.1, 30.18%¹H NMR: ET28542-3442-P1A CDCl₃ Bruker_02_V_400MHz’HNMR (400 MHz, CHLOROFORM- ) 5 = 7.44 (d, J= 8.8 Hz, 1H), 6.39 (d, J= 8.9 Hz, 1H), 3.80 (s, 3H), 3.32 (s, 3H), 3.23 - 3.07 (m, 2H), 2.52 (s, 3H), 2.04 - 1.95 (m, 4H), 1.26 - 1.08 (m, 4H).General procedure for preparation of compound 6To a solution of compound 5 (7 g, 19.65 mmol, 1 eq) in AcOH (54 mL) and H2O (43.5 mL) was added NaNO₂, (2.71 g, 39,30 mmol, 2 eq). The mixture was stirred at 25°C for 2 hrs. After cooling to 0°C, Zn (21.38 g, 326.96 mmol, 16.64 eq) was added. Stirring was continued at 25°C for another 2 hrs. LCMS (ET28542-3446-P1A1, Rt= 0.663 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was filtered and the filtrate was extracted with EtOAc (3 x 80 mL). Combined organic layers were washed with saturated aqueous Na2CO3(150 mL), brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Compound 6 (9 g, 25.48 mmol, 64.83% yield) was obtained as yellow oil.LCMS: ET28542-3446-P1A1, Rt= 0.663 min, [M+1] = 353.1, 74.67%¹H NMR: ET28542-3446-P1A CDCl₃ Bruker_02_R_400MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.36 (d, J = 8.2 Hz, 1H), 6.27 (d, J = 8.2 Hz, 1H), 5.36 (td, J = 5.2, 10.5 Hz, 1H), 3.90 (s, 3H), 3.40 (s, 3H), 3.29 (tt, J = 4.2, 10.9 Hz, 1H), 2.63 (s, 3H), 2.29 - 2.18 (m, 2H), 2.15 - 2.04 (m, 4H), 1.52 - 1.38 (m, 2H).General procedure for preparation of compound 7BrZnCH₂COOt-Bu THF, 20-80°C, 1h step 6, 96.38%To a solution of compound 6 (3 g, 8,49 mmol, 1 eq) in THF (30 mL) was added Pd(t-Bu₃P)₂ (434.01 mg, 849.25 pmol, 0.1 eq) at 20°C under N2, then BrZnCH2COOt-Bu (1 M, 25.48 mL, 3 eq) was added to the solution at 20°C and the solution was stirred at 70°C for 0.5 hrs. LCMS (ET28542-3450-P1 A, t = 0.633 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (30 mL) and ethyl acetate (30 mL), then filtered. The filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 7 (3.3 g, 7.64 mmol, 90.02% yield, 90% purity) was obtained as yellow oil.LCMS: ET28542-3450-P1A, Rt= 0.633 min, [M+l] = 389.3, 89.85%¹H NMR: ET28542-3450-P1A CDCl₃ Bruker_02_R_400MHz’HNMR (400 MHz, CHLOROFORM- ) 5 = 7.00 (d, J= 7.9 Hz, 1H), 6.33 (d, J= 7.9 Hz, 1H), 4.48 (tt, J= 4.0, 11.3 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 2H), 3.40 (s, 3H), 3.31 (tt, J= 4.1, 10.8 Hz, 1H), 2.64 (s, 3H), 2.28 - 2.21 (m, 2H), 2.19 - 2.10 (m, 2H), 2.05 - 1.99 (m, 2H), 1.45 (s, 9H), 1.44 - 1.34 (m52H).General procedure for preparation ofR586LDA, NBS. TMSCI THF, -70°C, 1.5h step 7, crudeR586 To a solution of compound 7 (1.7 g, 4.38 mmol, 1 eq) in THF (15 mL) was added LDA (2 M, 6.56 mL, 3 eq) at -70°C under N2atmosphere. The mixture was stirred at -70°C for 30 min. TMSC1 (1.43 g, 13.13 mmol, 1.67 mL, 3 eq) was added at - 70°C. After stirred at - 70°C for 30 min, NBS (2.34 g, 13.13 mmol, 3 eq) in THF (15 mL) was added, The mixture was stirred at -70°C for 0.5 hrs. LCMS (ET54591-943-P1B, Product: Rt = 0.571 min) showed the starting material was consumed completely and ~ 68.36% with desired Ms was detected. The reaction mixture was quenched by addition aqueous HC1 (IN, 50 mL), and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give R586 (3.3 g, crude) as yellow oil. LCMS: ET54591-943-P1B, Product: Rt = 0.571 min, [M+l] = 405.2, 68.36%General procedure for preparation, of compound 9DMP DCM, 0-25°C, 0.5 hrsstep 8. crude Two batches were carried out in parallel in this page. To a solution of compound 8 (25 g, 132.10 mmol, 1 eq) in DCM (500 mL) was added DMP (58.83 g, 138.70 mmol, 42.97 mL, 1.05 eq) at 0°C and the solution was stirred at 25°C for 0.5 hrs. TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf= 0.43) indicated the starting material was consumed completely and one new spot formed. The reaction was quenched with saturated aqueous Na₂SO₃ (2 L) and extracted with DCM (5 x 500 mL). Combined organics were washed with saturated Na₂CO₃ solution (2 x 1L), dried over anhydrous Na₂SO₄, filtered and concentrated to give compound 9 (34 g, crude) as yellow oil.General procedure for preparation of compound 10O ONaH, THF, 0-25°C, 1 hrstep 9, 25.68% Two batches were carried out in parallel in this page. To a suspension of NaH (4.72 g, 118.03 mmol, 60% purity, 1.3 eq) in THF (200 mL) was added compound b (24.43 g, 108.95 mmol, 21.62 mL, 1.2 eq) at 0°C. The reaction was stirred at 0°C for 30 minutes. A solution of compound 9 (17 g, 90.79 mmol, 1 eq) in THF (80 mL) was then added to the mixture above slowly. The mixture was allowed to warm to 25°C and stirred for 30 mins. TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.7) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition aq. NH4CI (1 L) at 0°C, extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 10 (12 g, 46.63 mmol, 25.68% yield) was obtained as yellow oil.¹H NMR: ET28542-3434-P1A CDCl₃ Bruker_02_V_400MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 6.98 - 6.83 (m, 1H), 5.85 (d, J = 15.8 Hz, 1H), 4.24 - 4.15 (m, 2H), 3.35 (t, J = 6.9 Hz, 2H), 2.85 (s, 3H), 2.47 - 2.40 (m, 2H), 1.45 (s, 9H), 1.27 (d, J = 7.1 Hz, 3H).General procedure for preparation of compound 11Rh(NBD)₂BF₄, TEA, S-BINAP dioxane, H₂O, 20°C, 16 hstep 10, 80.43%Two batches were carried out in parallel. To a solution of compound c (5.00 g, 29.34 mmol, 1.51 eq) in dioxane (100 mL) and H₂O (10 mL) was added S-BINAP (1.45 g, 2.33 mmol, 0.12 eq) and Rh(NBD)2. BF4 (726.68 mg, 1.94 mmol, 0.1 eq) under N2. The mixture was stirred at 20°C for 2 hrs. Then compound 10 (5 g, 19.43 mmol, 1 eq), TEA (1.97 g, 19.43 mmol, 2.70 mL, 1 eq) was added to the solution at 20°C and stirred for 14 hrs. LCMS (ET30483-2411-P1A, Rt= 0.653 min) showed the starting material was consumed completely and desired mass was detected. The reaction was quenched by ice water (100 mL) slowly, extracted with ethyl acetate (80 mL x 2). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage ®; 120 g SepaFIash ® Silica Flash Column, Eluent of 0-80% Ethyl acetate / Petroleum ether gradient @ 150 mL / min). Compound 11 (12 g, 31.26 mmol, 80.43% yield) was obtained as yellow oil which confirmed bylH NMR (ET30483-2411-P1).LCMS: ET30483-2411-P1A, Rt= 0.653 min, [M-99] = 284.2, 35.37%¹H NMR: ET30483-2411-P1 CDCl₃ Bruker_02_R_400MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.14 (s, 1H), 7.07 (s, 2H), 4.04 (br d, J = 6.6 Hz, 2H), 3.42 - 3.17 (m, 2H), 3.14 - 2.93 (m, 2H), 2.79 (br s, 2H), 2.32 (s, 3H), 1.91 - 1.77 (m, 2H), 1.49 - 1.36 (m, 11H), 1.14 (br t, J = 6.9 Hz, 3H).General procedure for preparation of compound 12 & 12A. BocTo a solution of compound 11 (12 g, 31.26 mmol, 1 eq) in THF (200 mL) was added LiAlH₄ (2.5 M, 16.25 mL, 1.3 eq) dropwise under N2 and the mixture was stirred at 0°C for 1 hr. TLC (Petroleum ether: Ethyl acetate = 1:1, Rf = 0.22) showed tire starting material was consumed completely, and a new spot with larger polarity was detected. The reaction was quenched by Na₂SO₄·10H₂O (5 g) at 0°C, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage ®; 120 g SepaFIash ® Silica Flash Column, Eluent of 0-100% THF / Petroleum ether gradient @ 150 mL / min) to give a racemic product which was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm x 50 mm, 10 um); mobile phase: [CO2-IPA (0.1% NH₃H₂O)]; B%: 10%, isocratic elution mode). Peak 1 was assigned as compound 12 (8 g, 23.40 mmol, 90.91% yield) was obtained as a colorless oil. Peak2 was assigned as compound 12A (1 g, crude) was obtained as a colorless oil.LCMS: ET30483-2413-P1, Rt= 0.572 min, [M-99] = 242.2, 100%SFC: ET30483-2413-P1, Rt= 0.664 min, 100%¹H NMR: ET30483-2413-P1 CDCl₃ Bruker_02_R_400MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.14 (s, 1H), 7.07 (s, 2H), 3.59 (br d, J = 5.1 Hz, 1H), 3.43 - 3.34 (m, 1H), 3.08 (br s, 2H), 2.79 (br s, 3H), 2.29 (s, 3H), 2.12 - 1.95 (m, 1H), 1.84 - 1.73 (m, 3H), 1.69 - 1.60 (m, 1H), 1.45 (br s, 9H).General procedure for preparation of compound 13DMP DCM,0-20°C, 2 hrsstep 12, crudeTo a solution of compound 12 (2.5 g, 7.31 mmol, 1 eq) in DCM (40 mL) was added DMP (4.65 g, 10.97 mmol, 3.40 mL, 1.5 eq) at 0°C and the mixture was stirred at 20°C for 1 hr. LCMS (ET30483-2417-P1A, Rt= 0.611 min) showed the starting material was consumed completely and desired mass was detected. The reaction was quenched by aq. NaHCOs (80 mL) slowly, extracted with DCM (50 mL x 2). The combined organic phase was washed with aq. Na2SO3 (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give compound 13 (2.3 g, crude) as yellow oil.LCMS: ET30483-2417-P1 A, Rt= 0.611 min, [M-56] = 284.2, 30.37%General procedure for preparation of compound 14NaBH(OAc)3, DCM 25°C, 16 hrs 13 step 13, crudeA solution of compound 13 (0.494 g, 1.45 mmol, 1 eq) and compound d (233.07 mg, 1.74 mmol, 1.2 eq, HC1) in DCM (10 mL) was stirred at 25°C for 1 hr, NaBH(OAc)3 (924.20 mg, 4.36 mmol, 3 eq) was added to the mixture at 25°C. The mixture was stirred at 25°C for 15 hrs. LCMS (ET54591-941-P1A, Product: Rt= 0.508 min) showed the starting material was consumed completely and ~ 77.19% with desired Ms was detected. The reaction mixture wasquenched by water (15 mL), extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give compound 14 (650 mg, crude) as yellow' oil.LCMS: ET54591-941-P1A, Product: Rt= 0.508 min, [M+1] = 421.3, 77.19%General procedure for preparation of Intermediate LI 54TFA DCM, 25°C, 1.5 hrs step 14, crude14L154To a solution of compound 14 (650 mg, 1.54 mmol, 1 eq) in DCM (10 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 8.72 eq) at 25°C. The mixture was stirred at 25°C for 1.5 hrs. LCMS (ET54591-942-P1B, Product: Rt = 0.347 min) showed the starting material was consumed completely and ~ 85.62% with desired Ms was detected. The reaction mixture was concentrated under reduced pressure to give L154 (1.07 g, crude) as yellow oil.LCMS: ET54591-942-P1B, Product: Rt= 0.347 min, [M+1] = 321.2, 85.62%General procedure for preparation of compound 15MepL15415 To a solution of L154 (1 g, 1.56 mmol, 1 eq) in MeCN (15 mL) was added K₂CO₃ (1.08 g, 7.79 mmol, 5 eq) at 25°C, the mixture was stirred at 25°C for 15 min. Then R586 (849.64 mg, 1.09 mmol, 0.7 eq) andNaBr (480.96 mg, 4.67 mmol, 150.16 uL, 3 eq), 4A MS (1.56 mmol, 1 eq) was added, the mixture was stirred at 80°C for 15.75 hrs. LCMS (ET54591-945-P1A, Product: Rt = 0.502 min & Rt == 0,513 min) showed the starting material was consumed completely and ~ 38.50% with desired Ms was detected. The reaction mixture was quenched by water (20 mL), extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine(50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether and 100-0% Ethyl acetate / Methanol gradient @ 45 mL / min). Compound 15 (460 mg, 650.28 pmol, 41.74% yield) was obtained as yellow oil.LCMS: ET54591-945-P1A, Product: Rt= 0.502 min & Rt= 0.513 min, [M+1] = 707.6, 38.50%General procedure for preparation of compound 16« 16 To a solution of compound 15 (350 mg, 494.78 pmol, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 27.21 eq). The mixture was stirred at 25°C for 16 hrs. LCMS (ET54591-948-P 1A, Product: Rt = 1 057min & Rt= 1.082 min) showed the starting material was consumed completely and ~ 66.26% with desired Ms was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C 18 100 * 30 mm * 5 um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 15%-45% B over 8.0 min). Compound 16 (100 mg, 153.54 nmol, 31.03% yield) was obtained as yellow oilLCMS: ET54591-948-P1A, Product: Rt= 1.057min & Rt= 1.082 mm, [M+l] = 651.5, 66.26%General procedure for preparation of 109-P1 & 109-P2Compound 16 (100 mg, 153.54 pmol, 1 eq) was separated by SFC (column: Daicel ChiralPak IM (250 * 25 mm i.d. 10 urn); mobile phase: [CO₂ - IPA: ACN = 1:1 (0.1% NH3H2O)]; B%: 50%, isocratic elution mode).Peak 1: (22.4 mg, 33.86 pmol, 22.05% yield, 98.45% purity) was assigned as 761A and obtained as a white solid, which wzas confirmed by LCMS (ET54591-955-P1A, Rt = 2.730 min, [M+l] = 651.3, 98.45%), SFC (ET54591-955-P1A, Rt= 1.545 min, 100.00%) and1HNMR(ET54591-955- P1A).Peak 2: (29.4 mg, 45.14 pmol, 29.40% yield, 100% purity) was assigned as 761B and obtained as a white solid, which was confirmed by LCMS (ET54591-955-P2B, Rt= 2.689 min, [M+l]= 651.3, 100.00%), SFC (ET54591-955-P2B, Rt= 1.700 min, 99.74%) and 1 NMR(ET54591- 955-P2B).For Monitoring and Separation:SFC: ET54591-947-P1A, Rti = 1.528 min, 54.30% & Rt2= 1.676 min, 45.70%For 109-P1 (Peak 1):LCMS: ET54591-955-P1A, Rt= 2.730 min, [M+1] = 651.3, 98.45%SFC: ET54591-955-P1A, Rt= 1.545 min, 100.00%’H NMR: ET54591-955-P1A MeOD Broker 02 0 400MHz¹H NMR (400 MHz, METHANOL-d₄) δ = 7.34 (d, J = 8.0 Hz, 1H), 7.04 - 6.98 (m, 2H), 6.95 (s, 1H), 6.36 (d, J = 8.1 Hz, 1H), 5.34 - 4.91 (m, 1H), 4.67 (br s, 1H), 3.91 (s, 3H), 3.40 (s, 3H), 3.35 (br s, 1H), 3.19 (br t, J = 6.4 Hz, 2H), 2.99 - 2.89 (m, 2H), 2.84 (br s, 1H), 2.79 - 2.69 (m, 2H), 2.68 - 2.53 (m, 6H), 2.49 (s, 3H), 2.22 (br d, J = 10.3 Hz, 3H), 2.12 (s, 4H), 1.94 (br t, J = 7.4 Hz, 4H), 1.88 - 1.73 (m, 3H), 1.48 - 1.40 (m, 2H), 0.71 - 0.64 (m, 4H).For 109-P2 (Peak 2):LCMS: ET54591-955-P2B, Rt= 2.689 min, [M+1] = 651.3, 100.00%SFC: ET54591-955-P2B, Rt = 1.700 min, 99.74%¹H NMR: ET54591-955-P2B MeOD Bruker_02_O_400MHz¹H NMR (400 MHz, METHANOL-d₄) δ = 7.39 (br d, J = 7.8 Hz, 1H), 7.07 (s, 1H), 7.05 - 6.98 (m, 2H), 6.40 (d, J = 8.1 Hz, 1H), 5.12 - 4.87 (m, 1H), 4.73 - 4.61 (m, 1H), 3.92 (s, 3H), 3.39 (s, 3H), 3.33 (br s, 1H), 3.23 - 3.14 (m, 2H), 2.95 - 2.85 (m, 2H), 2.84 - 2.73 (m, 3H), 2.73 - 2.54 (m, 6H), 2.54 (br s, 3H), 2.24 - 2.15 (m, 3H), 2.09 (s, 4H), 1.99 - 1.87 (m, 4H), 1.83 (br dd, J = 5.2, 11.3 Hz, 3H), 1.49 - 1.34 (m, 2H), 0.67 (br d, J = 6.4 Hz, 4H).Example 11: Preparation of Compound 110-P1 and 110-P2Scheme 1: Synthetic Route for Intermediate LI 55Scheme 2: Synthetic Route for Intermediate R586ALDA, DMF MeMgBr DCM, 25°C, 15 hrs step 10, 99.09%a NH2NaNO₂, AcOH, H₂O, 25°C, 2 hrs Cs₂CO₃, NMP then, Zn, 0-25°C, 2 hrs 100°C, 32 hrs step 12, 64.83% step 11, 52.01%BrZnCH₂COOt-Bu THF, 20-70°C, 0.5 hrs Step 13, 90.02%Scheme 3: Synthetic Route for 110-P1 & 110-P2General procedure for preparation of compound 2Boc > DMPN. BOO HO'X^X^'N O'DCM, 0-25°C, 0.5 hrsstep 1, crude2Two batches were carried out in parallel. To a solution of compound 1 (25 g, 132.10 mmol, 1 eq) in DCM (500 ml) was added DMP (58.83 g, 138.70 mmol, 42.97 ml, 1.05 eq) at 0°C and the solution was stirred at 25°C for 0.5 hrs. TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.43) indicated the starting material was consumed completely and one new spot formed. The reaction was quenched with saturated aqueous Na₂SO₃ (2 L) and extracted with DCM (5 x 500mL). Combined organics were washed with saturated Na2CO3solution (2 x 1 L), dried over anhydrous Na2SO4, filtered and concentrated. Compound 2 (34 g, crude) was obtained as yellow oil.General procedure for preparation of compound 43 EtOOC NaH, THF, 0-25°C, 1 hr step 2, 25.68%Two batches were carried out in parallel in this page. To a suspension of NaH (4.72 g, 118.03 mmol, 60% purity, 1.3 eq) in THF (200 mL) was added compound 3 (24.43 g, 108.95 mmol, 21.62 mL, 1.2 eq) at 0°C. The reaction was stirred at 0°C for 30 minutes. A solution of compound 2 (17 g, 90.79 mmol, 1 eq) in THF (80 mL) was then added to the mixture above slowly. The mixture was allowed to warm to 25°C and stirred for 30 min. TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.7) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition aq. NH4CI (1 L) at 0°C and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 4 (12 g, 46.63 mmol, 25.68% yield) was obtained as yellow oil.NMR: ET28542-3434-P1A CDCI3 Bruker__02__V__400MHz1H NMR (400 MHz, CHLOROFORM-d 5 = 6.98 - 6.83 (m, 1H), 5.85 (d, J = 15.8 Hz, 1H), 4.24 - 4.15 (m, 2H), 3.35 (t, J= 6.9 Hz, 2H), 2.85 (s, 3H), 2.47 - 2.40 (m, 2H), 1.45 (s, 9H), 1.27 (d, J = 7.1 Hz, 3H)General procedure for preparation of compound 6EtOOC Boc HO ^'OH ®Rn(NBD)2BF4, TEA, s-BINAP dioxane, H2O, 2O';’C, 16 hrsstep 3, 80.43%Two batches were carried out in parallel. To a solution of compound 5 (5.00 g, 29.34 mmol, 1.51 eq) in dioxane (100 mL) and H2O (10 mL) was added S-BINAP (1.45 g, 2.33 mmol, 0.12 eq) and Rh(NBD)2. BF4 (726.68 mg, 1.94 mmol, 0.1 eq) under N2. The mixture was stirred at 20°C for 2 hrs. Then compound 4 (5 g, 19.43 mmol, 1 eq), TEA (1.97 g, 19.43 mmol, 2.70 mL, 1 eq) was added to the solution at 20°C and stirred for 14 hrs. LCMS (ET30483-2411-P1A, Rt = 0.653 min) showed the starting material was consumed completely and desired mass was detected. The reaction was quenched by ice water (100 mL) slowly, extracted with ethyl acetate (80 mL x 2). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage ®; 120 g SepaFlash ® Silica Flash Column, Eluent of 0-80% Ethyl acetate / Petroleum ether gradient @ 150 mL / min). Compound 6 (12 g, 31.26 mmol, 90.04 ee% 80.43% yield) was obtained as yellow oil which confirmed by H NMR (ET30483-2411-Pl).LCMS: ET30483-2411-P1A, Rt= 0.653 min, [M-99] = 284.2, 35.37%General procedure for preparation of compound 7then SFC separation step 4, 90.91%To a solution of compound 6 (12 g, 31.26 mmol, 90.04 ee%, 1 eq) in THF (200 mL) was added Li Al H4 (2.5 M, 16.25 mL, 1.3 eq) dropwise under N2 and the mixture was stirred at 0°C for 1 hr. TLC (Petroleum ether / Ethyl acetate = 1 / 1, Rf = 0.22) showed the starting material was consumed completely and a new spot with larger polarity was detected. The reaction was quenched by Na2SO4. IOH2O (5 g) at 0°C, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage ®; 120 g SepaFlash ® Silica Flash Column, Eluent of 0-100% THF / Petroleum ether gradient @ 150 mL / min). The racemic was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm x 50 mm, 10 um); mobile phase: [CO2-IPA (0.1% NH₃H₂O)]; B%: 10%, isocratic elution mode).Peak 1 (8 g, 23.40 mmol, 90.91% yield) was obtained as a colorless oil and assigned as compound 7. Peak 2 (1 g, crude) was obtained as a colorless oil and assigned as compound 7A.Peak 1:LCMS: ET30483-2413-P1, Rt= 0.572 min, [M-99] = 242.2, 100%SFC: ET30483-2413-P1, Rt= 0.664 min, 100%1H NMR: ET30483-2413-P1 CDCl3Bruker_02_R_400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 7.14 (s, 1H), 7.07 (s, 2H), 3.59 (br d, J = 5.1 Hz, 1H), 3.43 - 3.34 (m, 1H), 3.08 (br s, 2H), 2.79 (br s, 3H), 2.29 (s, 3H), 2.12 - 1.95 (m, 1H), 1.84 - 1.73 (m, 3H), 1.69 - 1.60 (m, 1H), 1.45 (br s, 9H)General procedure for preparation of compound 8DMP DCM, 0-25°C, 1 hr N-Boc step 5, crude7To a solution of compound 7 (500 mg, 1.46 mmol, 1 eq) in DCM (7 mL) was added DMP (806.42 mg, 1.90 mmol, 589.06 pL, 1.3 eq) at 0°C. The mixture was stirred at 0-25°C for 1 hr. LCMS (ET44300-1410-P1A, Rt=0.623 min) showed 36.23% of the desired peak was detected. Hie mixture was quenched with saturated NaHCOs aqueous (2 mL) and saturated Na2SO3 aqueous (2 mL). The solution was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 8 (526 mg, crude) was obtained as a white solid.LCMS: ET44300-1410-P1A, Rt= 0.623 min, [M-55] = 284.1, 36.23%General procedure for preparation of compound 10To a solution of compound 8 (526 mg, 1.55 mmol, 1 eq) and compound 9 (0.270 g, 2.72 mmol, 306.82 µL, 1.76 eq) in DCM (6 mL) was added NaBH(OAc)3 (656.05 mg, 3.10 mmol, 2 eq) at 0°C. The mixture was stirred at 25°C for 2 hrs. LCMS (ET44300-1411-P1B, Rt= 0.505 min) showed 65.89 % of the desired peak was detected. The solution was adjusted to pH = 8 with saturated NaHCCh aqueous at 0°C. The mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column(SiO2, Ethyl acetate / Methanol = 20 / 1). Compound 10 (510 mg, 1.21 mmol, 77.89% yield) was obtained as yellow oil.LCMS: ET44300-1411-P1B, Rt= 0.505 min, [M+1] = 423.3, 65.89%General procedure for preparation of Intermediate L15525°C, 1 hr step 7, crudeL155 A solution of compound 10 (510 mg, 1.21 mmol, 1 eq) in HCl / dioxane (5 mL, 4M) was stirred at 25°C for 1hr. LCMS (ET44300-1412-P1A, Rt= 0.331 min) showed 77.35% of the desired peak was detected. The solution was concentrated. L155 (600 mg, crude, HCl) was obtained as yellow oil.LCMS: ET44300-1412-P1A, Rt= 0.331 min, [M+1] = 323.2, 77.35%General procedure for preparation of compound 12LDA, DMF'V' THF, -70°C, 1 hrF step 8, crude11 12To a solution of compound 11 (20 g, 97.55 mmol, 1 eq) in THF (200 mL) was added LDA (2 M, 58.53 mL, 1.2 eq) at -70°C. The mixture was stirred at -70°C for 0.5 hrs. DMF (9.27 g, 126.81 mmol, 9.76 mL, 1.3 eq) was added to the mixture at -70°C and the mixture was stirred at -70°C for 0.5 hrs. TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rf= 0.17) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition aqueous NH4CI (500 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used directly without further purification. Compound 12 (23.3 g, crude) was obtained as a yellow solid.1H NMR: ET28542-3366-P1A CDCl3Bruker_02_R_400MHz1H NMR (400 MHz, CHLOROFORM-d) 8 === 10.37 (d, J -- 1.2 Hz, 1H), 7.67 (dd, J -- 7.7, 9.0 Hz, 1H), 6.72 (dd, J= 1.1, 9.1 Hz, 1H), 3.94 (s, 3H)General procedure for preparation of compound 13MeMgBrTHF, 0-25°C, 2 hrsstep 9, crude12 13To a solution of compound 12 (22.3 g, 95.69 mmol, 1 eq) in THF (250 ml) was added MeMgBr (3 M, 63.80 mL, 2 eq) at 0°C under N2. The mixture was stirred at 25°C for 2 hrs. LCMS (ET28542-3369-P1A1, Rt = 0.492 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition aqueous NH4CI (500 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 13 (24 g, crude) was obtained as yellow oil.LCMS: ET28542-3369-P1 Al, Rt= 0.492 min, [M-17] = 231.0, 80.45%’H NMR: ET28542-3369-P1 A CDCh Bruker_02_V_400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 7.44 - 7.34 (m, 1H), 6.62 (dd, J = 0.9, 8.9 Hz, 1H), 5.24 (br dd, J= 6.8, 10.8 Hz, 1H), 3.89 (s, 3H), 3.21 (d, J= 10.8 Hz, 1H), 1.56 (d, J= 6.8 Hz, 3H)General procedure for preparation of compound 14DCM. 25°C, 16 hrsstep 10, 99.09%13 14Three batches were carried out in parallel in this page.To a solution of compound 13 (7.8 g, 31.32 mmol, 1 eq) in DCM (120 mL) was added PCC (13.50 g, 62.63 mmol, 2 eq) at 25°C and the solution was stirred at 25°C for 16 hrs. LCMS (ET28542- 3371-P1A1, Rt = 0.527 min) showed the starting material was consumed completely and onepeak with desired mass was detected. LCMS (ET28542-3371-P1A2, Rt= 0.530 min) showed the starting material was consumed completely and one peak with desired mass was detected. LCMS (ET28542-3371-P1B1, Rt = 0.533 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was filtered. The filter cake was washed by DCM (100 mL x 3). The combined filtrate was concentrated under reduced pressure to give a residue. Tire residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Compound 14 (23 g, 93.09 mmol, 99.09% yield) was obtained as yellow oil.LCMS: ET28542-3371-P1A1, Rt= 0.527 min, [M+l] = 246.9, 85.10%LCMS: ET28542-3371-P1 A2, Rt=0.530 min, [M+l] = 247.0, 78.03%LCMS: ET28542-3371-P1B1, Rt= 0.533 min, [M+l] = 247.0, 92.64%XH NMR: ET28542-3371-P1A CDCh Bruker_02J’__400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 7.50 (dd, J = 7.9, 8.8 Hz, 1H), 6.65 (dd, J = 1.1, 8.9 Hz, 1H), 3.85 (s, 3H), 2.54 (d, J = 0.8 Hz, 3H)General procedure for preparation of compound 15Cs2CO3, NMPF 100°C, 32 hrsstep 11, 52.01%To a solution of compound 14 (8 g, 32.38 mmol, 1 eq) in NMP (120 mL) was added Cs2CO3(31.65 g, 97.14 mmol, 3 eq) and 4-methoxycyclohexanamine (16.09 g, 97.14 mmol, 3 eq, HC1). The mixture was stirred at 100 °C for 32 hrs. LCMS (ET28542-3442-P1M, Rt =0.586 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction was worked up with ET28542-3441-P1. The reaction mixture was quenched by addition H? O (300 mL) at 0°C and extracted with ethyl acetate (200 mL x 3), The combined organic layers were washed with brine (200 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 15 (9 g, 25,26 mmol, 52.01% yield) was obtained as yellow oil.LCMS: ET28542-3442-P1M, Rt = 0.586 min, [M+1] = 356.1, 30.18%NMR: ET28542-3442-P1A CDCk Bruker 02 V 400MHz ’HNMR (400 MHz, CHLOROFORM-^ 5 = 7.44 (d, J= 8.8 Hz, 1H), 6.39 (d, J= 8.9 Hz, 1H), 3.80 (s, 3H), 3.32 (s, 3H), 3.23 - 3.07 (m, 2H), 2.52 (s, 3H), 2.04 - 1.95 (m, 4H), 1.26 - 1.08 (m, 4H)General procedure for preparation of compound 16INaNO2, AcOH, H2O, 25°C, 2 hrs then, Zn, 0-25°C. 2 hrs ( \ step 12, 64.83%15 16 To a solution of compound 15 (7 g, 19.65 mmol, 1 eq) in AcOH (54 mL) and H2O (43.5 mL) was added NaNO2 (2.71 g, 39.30 mmol, 2 eq). The mixture was stirred at 25°C for 2 hrs. After cooling to 0°C, Zn (21.38 g, 326,96 mmol, 16.64 eq) was added. Stirring was continued at 25°C for another 2 hrs. LCMS (ET28542-3446-P1A1, Rt = 0.663 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (3 x 80 mL). Combined organic layers were washed with saturated aqueous Na2CO3(150 mL), brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Compound 16 (9 g, 25.48 mmol, 64.83% yield) was obtained as yellow oil.LCMS: ET28542-3446-P1A1, Rt= 0.663 min, [M+1] = 353.1, 74.67%1H NMR: ET28542-3446-P1A CDCl3Bruker_02_R_400MHz1H NMR (400 MHz, CHLOROFORM-d) δ = 7.36 (d, J = 8.2 Hz, 1H), 6.27 (d, J = 8.2 Hz, 1H), 5.36 (td, J = 5.2, 10.5 Hz, 1H), 3.90 (s, 3H), 3.40 (s, 3H), 3.29 (tt, J = 4.2, 10.9 Hz, 1H), 2.63 (s, 3H), 2.29 - 2.18 (m, 2H), 2.15 - 2.04 (m, 4H), 1.52 - 1.38 (m, 2H)General procedure for preparation of compound 17BrZnCH2COOt-Bu THF, 20-70°C, 0.5 hrs step 13, 90.02%16To a solution of compound 16 (3 g, 8.49 mmol, 1 eq) in THF (30 mL) was added Pd(t-Bu3P)2(434.01 mg, 849.25 µmol, 0.1 eq) at 20°C under N2, then BrZnCH2COOt-Bu (1 M, 25.48 mL, 3 eq) was added to the solution at 20°C and the solution was stirred at 70°C for 0.5 hrs. LCMS (ET28542-3450-P1A, Rt = 0.633 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (30 mL) and ethyl acetate (30 mL) was added, then filtered. The filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 17 (3.3 g, 7.64 mmol, 90.02% yield, 90% purity) was obtained as yellow oil.LCMS: ET28542-3450-P1A, Rt= 0.633 min, [M+l] = 389.3, 89.85%1H NMR: ET28542-3450-P1A CDCl3Bruker_02_R_400MHz’HNMR (400 MHz, CHLOROFORM- ) 5 = 7.00 (d, J = 7.9 Hz, 1H), 6.33 (d, J= 7.9 Hz, 1H), 4.48 (tt, J= 4.0, 11.3 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 2H), 3.40 (s, 3H), 3.31 (tt, J= 4.1, 10.8 Hz, 1H), 2.64 (s, 3H), 2.28 - 2.21 (m, 2H), 2.19 - 2.10 (m, 2H), 2.05 - 1.99 (m, 2H), 1.45 (s, 9H), 1.44 - 1.34 (m, 2H)General procedure for preparation ofR586LDA. NBS, TMSCI THF, -70°C, 1.5 hrs step 14, crudeR586 To a solution of compound 17 (2.1 g, 5.41 mmol, 1 eq) in THF (20 mL) was added LDA (2 M, 8.11 mL, 3 eq) at -70°C under N2 atmosphere. The mixture was stirred at -70°C for 30 min. TMSC1 (1.76 g, 16.22 mmol, 2.06 mL, 3 eq) was added at -70°C. After stirred at -70°C for 30 mins, NBS (2.89 g, 16.22 mmol, 3 eq) in THF (20 mL) was added. The mixture was stirred at -70°C for 0.5 hrs. LCMS (ET66058-1347-P1A, Rt = 0.565 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition aqueous HC1 (IN, 20 mL), and extracted with ethyl acetate (30 mL x 3). Tlie combined organic layers were washed with brine (30 mL), dried over N 2SO4, filtered and concentrated under reduced pressure to give R586 (4.1 g, crude) as yellow oil without further purification.LCMS: ET66058-1347-P1A, Rt = 0.565 min, [M-61] = 405.2, 55.42%General procedure for preparation ofL147DIEA, Nal, CH3CN, 4AMS 50°C, 1 hr step 15, 64.84%L155 To a mixture of L155 (200 mg, 556.52 µmol, 1 eq, HCl) and R586 (260.12 mg, 556.52 pmol, 1 eq) in MeCN (5 mL) was added DIEA (359.63 mg, 2.78 mmol, 484.68 µL, 5 eq), 4A MS (50 mg, 556.52 µmol, 1.00 eq) and NaI (41.71 mg, 278.26 µmol, 13.02 µL, 0.5 eq). The mixture was stirred at 50°C for 1 hr. LCMS (ET44300-1431-P1A, Rt = 0.488 min) showed 51.63% of the desired peak was detected. The reaction mixture was quenched by H2O (10 mL). Hie reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (Biotage®; 12 g Sepa Flash ® Silica Flash Column, Eluent of 0-100% Ethyl acetate: Methanol @50 mL / min).Compound 18 (256 mg, 360.87 µmol, 64.84% yield) was obtained as yellow' oil.LCMS: ET44300-1431-P1A, Rt= 0.488 min, [M+1] = 709.5, 1.63%General procedure for preparation of compound 1918 19 A solution of compound 18 (256 mg, 360.87 µmol, 1 eq) in DCM (3 mL) and TFA (1 mL) was stirred at 25°C for 16 hrs. LCMS (ET44300-1435-P1B, Rt = 1.444 min) showed 55.89% of the desired product formed. The solution was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase:[H2O (0.1%TFA)-ACN]; gradient: 15%-45% B over 8.0 min). Compound 19 (100 mg, 130.32 µmol, 36.11% yield, TFA) was obtained as white solid.LCMS: ET44300-1435-P1B, Rt = 1.444 min, [M+1] = 653.4, 55.89%LCMS: ET44300-1435-P1A2, Rt= 0.551 min, [M+l] = 653.6, 99.23%SFC: ET44300-1435-P1A, Rt1= 1.603 min, 54.35%; Rt2= 1.826 min, 45.65%General procedure for preparation of 110-P1 & 110-P2110-P1 110-P2Structure randomly assigned Structure randomly assigned Compound 19 (100 mg, 130.32 µmol, 1 eq, TFA) was separated by SFC (column: Daicel Chiral Pak IM (250* 25 mm i.d. lO um); mobile phase: [CO2-IPA: ACN=1:1 (0.1%NH3H2O)];B%:50%, isocratic elution mode).Peak 1: (26.9 mg, 41.18 µmol, 31.60% yield) was obtained as a white solid and randomly assigned as 110-P1Peak 2, (22.7 mg, 34.75 gmol, 26.66% yield) was obtained as a white solid and randomly assigned as 110-P2For 110-P1 (Peak 1):LCMS: ET44300-1439-P1T (QC check), Rt= 2.020 min, [M+1] = 653.4, 99.77%SFC: ET44300-1439-P1Z, Rt= 1.610 min, 100.00%> H NMR: ET44300-1439-P1V MeOD Bruker_02_R_400MHz'H NMR (400 MHz, METHANOL-d₄) 8 === 7.30 (d, J -- 8.0 Hz, 1H), 7.00 (s, 2H), 6.95 (s, 1H), 6.33 (d, J= 8.1 Hz, 1H), 5.32 - 4.91 (m, 1H), 4.64 (br s, 1H), 3.91 (s, 3H), 3.40 (s, 3H), 3.37 - 3.32 (m, 1H), 3.12 - 2.98 (m, 4H), 2.79 (br dd, J= 9.2, 14.1 Hz, 2H), 2.75 - 2.67 (m, 1H), 2.63 - 2.53 (m, 5H), 2.47 (br s, 3H), 2.22 (br d, J -- 10.7 Hz, 3H), 2.12 (s, 4H), 2.02 - 1.87 (m, 3H), 1.78 (br s, 6H), 1.66 (br d, J= 2.7 Hz, 4H), 1.51 - 1.34 (m, 3H)For 110-P2 (Peak 2):LCMS: ET44300-1439-P2T (QC check), Rt= 2.005 min, [M+1] = 653.4, 100.00%SFC: ET44300-1439-P2Z, Rt= 1.831 min, 96.72%'H NMR: ET44300-1439-P2V MeOD Bruker_02_R_400MHz’HNMR (400 MHz, METHANOL-d₄) 6 === 7.37 (br d, J--- 7.7 Hz, 1H), 7.09 (s, 1H), 7.03 (s, 2H), 6.38 (d, J= 8.1 Hz, 1H), 5.27 - 4.90 (m, 1H), 4.77 - 4.50 (m, 1H), 3.91 (s, 3H), 3.39 (s, 3H), 3.38 - 3.32 (m, IH), 3.07 (br s, 4H), 2.91 - 2.81 (m, IH), 2.79 - 2.68 (m, 2H), 2.60 (s, 4H), 2.48 (br s, 4H), 2.20 (br d, J === 10.7 Hz, 3H), 2.11 (s, 4H), 2.02 - 1.88 (m, 3H), 1.86 - 1.74 (m, 6H), 1.66 (br s, 4H), 1.63 - 1.50 (m, IH), 1.49 - 1.34 (m, 2H)Example 12: Preparation of Compound 113-P1 and 113-P2Scheme 1: Synthetic Route for R586AScheme 2: Synthetic Route for 113-P1 & 113-P2General procedure for preparation of compound 2LDA, DMF “HF, ~70°C. 1 h Fstep 1, 96.78%Two batches were carried out in parallel in this page.To a solution of compound 1 (25 g, 121.94 mmol, 1 eq) in THF (250 mL) was added LDA (2 M, 73.16 mL, 1.2 eq) at -70°C. The mixture was stirred at -70°C for 0.5 hrs, DMF (11.59 g, 158.52 mmol, 12.20 mL, 1.3 eq) was added to the mixture at -70°C, the mixture was stirred at - 70°C for 0.5 hrs. TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rf = 0.17) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition aqueous NH4CI (1 L), and extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2 (55 g, 236.02 mmol, 96.78% yield) as a yellow solid.> H NMR: ET28542-3467-P1 A CDCh Bruker__02„V__400 MHz'H NMR (400 MHz, CHLOROFORM-^ 8 - 10.38 (s, 1H), 7.65 - 7.59 (m, 1H), 6.73 (d, J = 9.0 Hz, 1H), 3.94 (s, 3H).General procedure for preparation of compound 3'Af1"' MeMgBrBr y '' - THF, 0-25 r° -C, 2 hrs Br yp pstep 2, crude OH2 3Two batches were carried out in parallel in this page.To a solution of compound 2 (27.5 g, 118.01 mmol, 1 eq) in THF (270 mL) was added MeMgBr (3 M, 78.67 mL, 2 eq) at 0°C under N2.. The mixture was stirred at 25°C for 2 hrs. LCMS (ET28542-3468-P1A1, Rt= 0.481 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition aqueous NH4CI (800 mL), and extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 3 (60 g, erode) as yellow7oil,LCMS: ET28542-3468-P1A1, Rt= 0.481 min, [M-17] = 231.0, 90.55%XH NMR: ET28542-3468-P1A CDC13 Bruker 02 V 400MHz!H NMR (400 MHz, CHLOROFORM-; / ) 6 = 7.39 (t, J = 8.4 Hz, 1H), 6.62 (d, J= 8.9 Hz, 1H), 5.31 - 5.16 (m, 1H), 3.89 (s, 3H), 3.22 (d, J= 10.9 Hz, 1H), 1.56 (d, J= 6.8 Hz, 3H).General procedure for preparation of compound 4r I 11 -fccSf,* r I Y 11Br'"' 'Vx*xyXDCM, 25°C, 16 hrs Br'^'fp OH step 3, 77.82%p Q3 4Two batches were carried out in parallel in this page.To a solution of compound 3 (28.5 g, 114.42 mmol, 1 eq) in DCM (300 mL) was added PCC (49.33 g, 228.85 mmol, 2 eq) at 25°C and the solution was stirred at 25°C for 16 hrs. LCMS (ET28542-3472-P1C1, Rt=0.518 min) showed the starting material remained and one peak with desired mass was detected, Tire reaction mixture was filtered. The filter cake was washed by DCM (600 mL x 3). The combined filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate == 100 / 1 to 10 / 1). Compound 4 (44 g, 178.09 mmol, 77.82% yield) was obtained as yellow oil.LCMS: ET28542-3472-P1C1, Rt===0.518 mm, [M+ 1 ] ===:356.1, 83.63%1H NMR: ET28542-3472-P1A CDC13 Broker )2 V_400MHz1H NMR (400 MHz, CHLOROFORM-) δ = 7.50 (dd, J= 8.0, 8.8 Hz, 1H), 6.65 (dd, J= 0.9, 8.9 Hz, 1H), 3.85 (s, 3H), 2.54 (d, J 0.8 Hz, 3H).Genera! procedure for preparation of compound 6To a solution of compound 4 (13 g, 52.62 mmol, 1 eq) in NMP (200 mL) was added Cs2CO3(51,43 g, 157.86 mmol, 3 eq) and compound 5 (25 g, 150.91 mmol, 2.87 eq, HC1), The mixture was stirred at 100°C for 36 hrs. LCMS (ET28542-3478-P1C, Rt= 0.583 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (800 mL) at 0°C, extracted with ethyl acetate (500 mL x 3). Tire combined organic layers were washed with brine (500 ml, x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1).Compound 6 (12 g, 33,68 mmol, 64.02% yield) was obtained as yellow oil.LCMS: ET28542-3478-P1C, Rt = 0.588 min, [M+1] = 356.1, 32.42%’H NMR: ET28542-3478-P1A CDC13 Bruker 02 P 400MHzH NMR (400 MHz, CHLOROFORM-ri) 5 = 7.43 (d, J= 8.9 Hz, 1H), 6.39 (d, J= 8.9 Hz, 1H), 4.67 - 4.32 (m, 1H), 3.86 - 3.76 (m, 3H), 3.38 - 3.28 (m, 3H), 3.21 - 3.10 (m, 2H), 2.60 - 2.49 (m, 3H), 2.04 - 1.94 (m, 4H), 1.26 - 1.08 (m, 4H).General procedure for preparation of compound 15 -NaNOz, AcOH. H2O. 25°C, 2 hrs - then, Zn, 0-25°C, 2 hrsstep 5, 70.59%To a solution of compound 6 (6 g, 16.84 mmol, 1 eq) in AcOH (45 mL) and HzO (32.4 mL) was added NaNOz (2.32 g, 33.68 mmol, 2 eq). The mixture was stirred at 25°C for 2 hrs. After cooling to 0°C, Zn (17.58 g, 268.85 mmol, 15.96 eq) was added. Stirring was continued at 25°C for another 2 hrs, LCMS (ET28542-3485-P1 Al, Rt = 0.662 min) showed the starting material was consumed completely and one peak -with desired mass was detected. The reaction mixture was filtered and the filtrate was extracted with EtOAc (3 x 200 mL). Combined organic layers were washed with saturated aqueous Na2CO3(500 mL), brine (500 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Tire residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate::::100 / 1 to 3 / 1). Compound 7 (8.4 g, 23.78 mmol, 70.59% yield) was obtained as yellow oil.LCMS: ET28542-3485-P1 Al, Rt = 0.662 min, [M+1] = 353.1, 54.50%> H NMR: ET28542-3485-P1 A CDC13 Bruker_02__P__400MHzH NMR (400 MHz, CHLOROFORM-ri) 5 = 7.36 (d, J= 8.1 Hz, 1H), 6.27 (d, J= 8.1 Hz, 1H), 5.36 (tt, J= 5.0, 10.4 Hz, 1H), 3.90 (s, 3H), 3.40 (s, 3H), 3.29 (tt, J = 4.2, 10.9 Hz, 1H), 2.63 (s, 3H), 2.29 - 2.18 (m, 2H), 2.14 - 2.03 (m, 4H), 1.45 (br dd, J= 4.8, 11.3 Hz, 2H).General procedure for preparation of R586AKOAc, Pd(dppf)CI2DCM, DMF,20-80°C, 2 hrs step 6, 48.21%To a solution of compound 7 (3.92 g, 11.10 mmol, 1 eq) in DMF (50 mL) was added compound a (12.53 g, 55.48 mmol, 5 eq), KOAc (5,45 g, 55.48 mmol, 5 eq) and Pd(dppf)Cl₂·CH₂Cl₂ (906.21 mg, 1.11 mmol, 0.1 eq) at 20°C under N2 and the solution was stirred at 80°C for 2 hrs. LCMS (ET28542-3505-P1A, Rt = 0.427 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (200 mL) at 0°C, extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). R586A (3.1 g, 6.42 mmol, 48.21 % yield, 80% purity) was obtained as yellow oil.LCMS: ET28542.-3505-P1A, Rt= 0.427 min, [M-67] = 319.0, 20.95%XH NMR: ET28542-3505-P1A CDC13 Bruker_02_P_400MHz^INMR (400 MHz, CHLOROFORM-ri) 5 = 7.70 (d,.7= 7.9 Hz, 1H), 6.39 (d, J= 7.8 Hz, HI), 5.03 - 4.87 (m, 1H), 3.93 (s, 3H), 3.83 (s, 4H), 3.41 (s, 3H), 3.36 - 3.26 (m, 1H), 2.66 (s, 3H), 2.25 (brd, J= 12.6 Hz, 2H), 2.14 - 1.99 (m, 4H), 1.40 - 1.32 (m, 2H), 1.09 (s, 6H).General procedure for preparation of compound 9DMPDCM. 0-25°C, 0.5 hrs step 7, crude8 9Two batches were carried out in parallel.To a solution of Compound 8 (25 g, 132.10 mmol, 1 eq) in DCM (500 mL) was added DMP (58.83 g, 138.70 mmol, 42.97 mL, 1.05 eq) at 0°C and the solution was stirred at 25°C for 0.5 hrs. TLC (Petroleum ether / Ethyl acetate:::5 / 1, Rr = 0.43) indicated the starting material was consumed completely and one new spot formed. The reaction was quenched with saturatedaqueous Na₂SO₃ (2 L) and extracted with DCM (5 x 500 mL). Combined organics were washed with saturated Na2CO3solution (2 x IL), dried over anhydrous Na? SO4, filtered and concentrated to give compound 9 (34 g, crude) as yellow oil.General procedure for preparation of compound 11 -0910 NaH, THF, 0-25°C, 1 hr step 8, 25.68%Two batches were carried out in parallel in this page.To a suspension of NaH (4.72 g, 118.03 mmol, 60% purity, 1.3 eq) in THF (200 mL) was added compound 10 (24.43 g, 108.95 mmol, 21.62 mL, 1.2 eq) at 0°C. The reaction was stirred at 0°C for 30 minutes. A solution of compound 9 (17 g, 90.79 mmol, 1 eq) in THF (80 mL) was then added to the mixture above slowly. The mixture was allowed to warm to 25°C and stirred for 30 mins, TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf= 0.7) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition aq. NHjCl (1 L) at 0°C, extracted with ethyl acetate (500 mL x 3). Hie combined organic layers were washed with brine (500 mL x 3), dried over NazSC, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 11 (12 g, 46.63 mmol, 25.68% yield) was obtained as yellow oil.H-I NMR: ET28542-3434-P1A CDCL Bruker__02__V__400MHz1HNMR(400 MHz, CHLOROFORM-d) 5 = 6.98 - 6.83 (m, 1H), 5.85 (d, J ----- 15.8 Hz, 1H), 4.24 - 4.15 (m, 2H), 3.35 (t, J= 6.9 Hz, 2H), 2.85 (s, 3H), 2.47 - 2.40 (m, 2H), 1.45 (s, 9H), 1,27 (d,. / = 7.1 Hz, 3H).General procedure for preparation of compound 13HO'B'OH12Rh(NBD)2BF4, Et3N. S-BiNAPdioxane, H2O, 25°C, 14 h 11 step 9, 61.64% 13To a solution of compound 12 (11.89 g, 58.29 mmol, 3 eq) in dioxane (50 mL) was added Rh (NBD)2. BF4 (726,69 mg, 1.94 mmol, 0.1 eq), S-BINAP (1,21 g, 1.94 mmol, 0,1 eq) under N2, after stirred at 25°C for 2 hrs under nitrogen atmosphere, then was added compound 11 (5.00 g, 19.43 mmol, 1 eq), EtsN (3.93 g, 38.86 mmol, 5.41 mL, 2 eq) and H2O (5 mL), the reaction was stirred at 25°C for 12. hrs under nitrogen atmosphere. LCMS (ET66058-1315-P1A, Rt = 0.668 min) showed the starting material remained and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (50 mL) at 0°C, extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over Na? SO4, filtered and concentrated under reduced pressure to give a residue. Tire residue wus further purified by prep-HPLC (column: Agela DuraShell C18 250 * 70 mm * 10 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 50% - 85% B over 17.0 min) to give compound 13 (5 g, 11.98 mmol, 61.64% yield) as yellow oil.LCMS: ET66058-13 L5-P1A, Rt= 0.668 mm, [M-99] = 318.1, 41.02%XH NMR: ET66058-1315-P1A CDC13 Broker 02 G 400 MHz]H NMR (400 MHz, CHLOROFORM- ) 5 = 7.41 (s, 1H), 7.36 (br d, J= 7.6 Hz, 1H), 7.27 (s, 1H), 4.02 (br d, J= 6.1 Hz, 2H), 3.52 - 3.42 (m, 1H), 3.31 - 2.96 (m, 2H), 2.79 (br s, 3H), 2.70 (br d, J= 7.0 Hz, 1H), 2.64 - 2.56 (m, 1H), 2.42 (s, 3FI), 1.96 - 1.79 (m, 2H), 1.37 (br s, 9H), 1.12 (brt, J= 6.8 Hz, 3H).General procedure for preparation of compound 14LAH- THF. 0°C, 1 h step 10, 75.00%13 14To a solution of compound 13 (4.00 g, 9.58 mmol, 1 eq) in THF (80 mL) at 0°C was added LAH (2.5 M, 4.98 mL, 1.3 eq). The reaction mixture was stirring at 0°C for 1 hr under N2. LCMS (ET66058-1328-P1A, Rt = 1.624 min) showed the starting material as consumed completely and one peak with desired mass was detected. After the reaction mixture was cooled to 0°C, the reaction mixture was quenched by addition of 10 mL of H2O, followed by 10 mL of 15% aqueous NaOH and 30 ml, of H2O. After being stirred at room temperature for 0,5 hrs, the solid. as removed by filtration. The filtrate was concentrated to give crude product. The residue w as purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0to 1 / 1) to give compound 14 (1.2 g, crude). The product was separated by SFC (column:DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 um); mobile phase: [CO2-IPA (0.1 % NH3H2O)]; B%: 10%, isocratic elution mode). Compound 14 (900 mg, 2.40 mmol, 75.00% yield) was obtained as yellow' oil.LCMS: ET66058-1328-P1A, Rt= 1.624 min, [M-54] = 320.2, 98.37%SFC: ET66058-1327-P1A, Rti = 1.283 min, 6.36% R!2= 1.425 min, 93.64%Hl NMR: ET66058-1389-P1A CDC13 Bruker__02_0_400 Iz]H NMR (400 MHz, CHLOROFORM- ) 5 = 7.42 (s, 1H), 7.35 (br d, J= 8.0 Hz, 1H), 7.27 - 7.23 (m, 1H), 3.61 (br d, J= 3.3 Hz, 1H), 3.44 - 3.19 (m, 2H), 3.18 - 3.01 (m, 2H), 2.78 (s, 3H), 2.39 (s, 3H), 2.01 - 1.75 (m, 4H), 1.48 - 1.34 (m, 9H).General procedure for preparation of compound 15DMP DCM, 25°C, 1 h step 11, cmdeTo a solution of compound 14 (500 mg, 1.33 mmol, 1 eq) in DCM (5 mL) was added DMP (1.13 g, 2,66 mmol, 825.25 pL, 2 eq). Hie mixture was stirred at 25°C for 1 hr, LCMS (ET66058-1399-P1A3, Rt:::0.618 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition aq. NaHCOs (5 mL) at 0°C, extracted with DCM (10 mL x 3). The combined organic layers were washed with aq. NaiSCh (8 mL x 3), dried overNa2SO4, filtered and concentrated under reduced pressure to give compound 15 (560 mg, crude) as yellow oil.LCMS: ET66058-1399-P1A3, Rt= 0.618 mm, [M-99] = 272.1, 18.69%General procedure for preparation of compound 17NaBH(OAc)3, TEA, AcOH, DCM, 25°C, 2h step 12, 36.51%17To a solution of compound 15 (560 mg, 1.50 mmol, 1 eq) in DCM (6 mL) was added compound 16 (297.46 mg, 2.19 mmol, 1.46 eq, HC1) and TEA (151.75 mg, 1.50 mmol, 208.74jj. L, 1 eq) at 25°C for Ihr, NaBH(OAc)3 (635.69 mg, 3.00 mmol, 2 eq) and AcOH (90.06 mg, 1,50 mmol, 85.85 qL, 1 eq) was added to the mixture. The mixture was stirred at 25°C for 1 hr. LCMS (ET66058-1404-P1 A, Rt = 0.505 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (10 mL) at 0°C, extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, commercial hexanes / Ethyl acetate = 1 / 0 to 0 / 1, ethyl acetate / MeOH = 1 / 0 to 5 / 1), Compound 17 (250 mg, 547,55 pmol, 36,51% yield) was obtained as yellow oil.LCMS: ET66058-1404-P1 A, Rt= 0.505 min, [M+l] = 457.5, 16.35%General procedure for preparation of LI 72HCi (g) / dioxane 25°C, 1h step 13, crude17 L172 Compound 17 (250 mg, 547,55 pmol, 1 eq) and HCI (g) / dioxane (4 M, 3 mL, 21.92 eq) was stirred at 25°C for 1 hr. LCMS (ET66058-1406-P1A, Rt === 0.354 min) showed the starting material was consumed completely and one peak with desired mass was detected. Tire reaction was concentrated under reduced pressure to give LI72 (150 mg, crude) as yellow oil.LCMS: ET66058-1406-P1A, Rt = 0.354 min, [M+l] = 357.3, 91.61%General procedure for preparation of compound 18OMe,CHOCOOH, 4A MS, MeCN, 8O''C, 2 hrs step 14, 77,85%L172 To a solution of L172 (120 mg, 336.64 pmol, 1 eq) in MeCN (2 mL) was added R586A (130.04 mg, 336.64 pmol, 1 eq), 4A MS (336.64 jimol, 1 eq) and CHOCOOH (37.19 mg, 403.96 pmol, 1.2 eq) at 80°C under N2 and the solution was stirred at 80°C for 2 hrs. LCMS(ET66058-1410-P1A, Rti = 1.126 min & Rt2= 1.150 min) showed the starting material remained and two peaks with desired mass were detected. The reaction was concentrated under reduced pressure to give a residue. The residue was further purified by prep-HPLC (column: WePure Biotech XPt C18 150 * 40 * 7 urn; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 10% - 50% B over 8.0 mm. LCMS: ET66058-1410-P1A, Rti = 1.126 min& Rt2= 1.150 min) to give compound 18 (180 mg, 262.07 pmol, 77.85% yield) as yellow oil, LCMS: ET66058-1410-P1A, Rti = 1.126 min& Rc = 1.150 min, [M+l] = 687.4, 27.09%&23.71%%General procedure for preparation ofll3-Pl & 113-P2Compound 18 (180 mg, 262,07 pmol, 1 eq) was separated by SFC (column: Daicel ChiralPak IM (250 * 25 mm i.d. 10 um); mobile phase: [Heptane-EtOH (0.1% IP Am)]; B%: 15%, isocratic elution mode.Peak 1 (28.4 mg, 40.94 μmol, 15.62% yield, 99% purity) was obtained as a white solid and randomly assigned as 113-P1, confirmed by ¹H NMR (ET66058-1419-P1A), LCMS (ET66058-1419-P1A4, Rt = 2.972 min), SFC (ET66058-1419-P1A, Rt= 2.059 mm).Peak 2 (24.5 mg, 35.31 pmol, 13.48% yield, 99% purity) was obtained as a white solid and randomly assigned as 113-P2, confirmed by ‘HNMR (ET66058-1419-P2A), LCMS (ET66058-1419-P2A, Rt= 2.962 min), SFC (ET66058-1419-P2A, Rt= 2.432 min).For Monitoring and Separation:SFC: ET66058-1410-P1A, Rti= 2.075 min, 53.92%& Rt2= 2.469 min, 46.08%For 113-P1:LCMS: ET66058-1419-P1A, Rt = 2.972 min, [M+1] = 687.4, 99.53% SFC: ET66058-1419-P1A, Rt = 2.059 min, 100% ¹H NMR: ET66058-1419-P1A MeOD Bruker_02_O_400MHz ¹H NMR (400 MHz, METHANOL-d4) 5 = 7.35 (br d,.7= 8.4 Hz, 2H), 7.32 (s, 1H), 7.23 (br d, 7.9 Hz, 1H), 6.35 (d, J= 8.1 Hz, 1H), 5.22 - 4.94 (m, 1H), 4.68 - 4.58 (m, 1H), 3.90 (s, 3H), 3.39 (s, 3H), 3.11 - 2.97 (m, 2H), 2.87 - 2.77 (m, 2H), 2.73 (br d, J= 6.3 Hz, 3H), 2.60 (s, 3H), 2.49 (br s. 4H), 2.19 (br s, 6H), 2.10 - 1.99 (m, 2H), 1.91 (br dd, J = 1.5, 12.3 Hz, 1H), 1.88 - 1.79 (m, 2H), 1.74 (br t, J= 7.2 Hz, 3H), 1.67 - 1.56 (m, 1H), 1.54 - 1.18 (m, 4H), 1.11 (d, J = 1.3 Hz, 6H).For 113-P2:LCMS: ET66058-1419-P2A, Rt = 2.962 min, [M+l] =687.4, 99.28%SFC: ET66058-1419-P2A, Rt = 2.432 min, 99.72%¹H NMR: ET66058-1419-P2A MeOD Bruker_02_O_400MHz¹H NMR (400 MHz, METHANOL-d4) δ = 7.35 (br d, J = 8.0 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.24 (br d, J = 7.9 Hz, 1H), 6.35 (d, J = 8.1 Hz, 1H), 5.18 - 4.96 (m, 1H), 4.70 - 4.60 (m, 1H), 3.90 (s, 3H), 3.39 (s, 3H), 3.14 (br d, J = 7.8 Hz, 2H), 2.97 - 2.85 (m, 2H), 2.84 - 2.72 (m, 3H), 2.67 - 2.61 (m, 1H), 2.59 (s, 4H), 2.46 (br s, 3H), 2.25 - 2.15 (m, 6H), 2.10 (br d, J = 13.8 Hz,1H), 1.98 - 1.81 (m, 5H), 1.78 (br t, J = 7.4 Hz, 2H), 1.55 - 1.27 (m, 4H), 1.12 (d, J = 1.1 Hz, 6H),Example 13: Preparation of Compound 115-P1 and 115-P2 Scheme 1: Synthetic Route for Intermediate LI 84Scheme 2: Synthetic Route for Intermediate R586AIScheme 3: Synthetic Route for 115-P1 & 115-P2CHOCOOH, 4A MS, MeCN, 80°C, 2 hrs step 14, 77.85%MeO115-P1 115-P2Structure randomly assigned Structure randomly assigned General procedure for preparation of compound 2TEMPO, NaHCO3, NaClOBocHO N DCM, H2O, 0°C, 1 hr step 1, crude1A catalytic amount of TEMPO (1.66 g, 10.57 mmol, 0.08 eq) was added to a solution of compound 1 (25 g, 132.10 mmol, 1 eq) and NaHCO3 (22.19 g, 264.20 mmol, 10.28 mL, 2 eq) in DCM (200 mL) and H2O (100 mL) at 0°C. TLC (Commercial hexanes / Ethyl acetate = 3 / 1, Rf = 0.32) indicated tire starting material was consumed and one new spot with lower polarity was formed. NaClO (200 ml, 10%) were then added dropwise to the solution at 0°C. Tire reaction mixture was stirred for a further 1 hr at 0°C. The reaction mixture was quenched by adding 150 mL water and extracted with DCM (200 mL x 3), washed with brine (200 mL x 3), dried over NajSCh, filtered and concentrated under reduced pressure to give compound 2 (27 g, crude) as yellow oil.General procedure for preparation of compound 4Boc >toluene, 100°C, 2 hrsstep 2, 61.78%A solution of compound 2 (27 g, 144.20 mmol, 1 eq) and compound 3 (50.24 g, 144.20 mmol, 1 eq) in toluene (250 mL) was stirred at 100°C for 2 hrs. TLC (Commercial hexanes: Ethyl acetate = 3:1) showed the starting material consumed and a major new spot with lower polarity was detected. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column (Biotage®; 220 g Sepa Flash® Silica Flash Column, Eluent of 12% Ethyl acetate / Petroleum ether gradient @200 mL / min). Compound 4 (21 g, 81.61 mmol, 61.78% yield over 2 steps) was obtained as yellow oil.¹H NMR: ET44300-1463-P1A CDCl3 Bruker_02_R_400MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 6.92 (td, J = 7.3, 15.5 Hz, 1H), 5.86 (d, J = 15.7 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.36 (t, J = 6.9 Hz, 2H), 2.85 (s, 3H), 2.42 (q, J = 6.8 Hz, 2H), 1.45 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H).General procedure for preparation of compound 6ClBoe - N Rh(NBD)2BF4, TEA, S-BINAP O’ dioxane, H2O, 25°C, 14 hrs step 3, 82.44%Two batches in this page: To a solution of compound 4 (4.97 g, 29.15 mmol, 1.5 eq) in dioxane (50 mL) was added Rh(NBD)2. BF4 (726.69 mg, 1.94 mmol, 0.1 eq), S-BINAP (1.5 g, 2.41 mmol, 1.24e-l eq) under N2, after stirred at 25°C for 2 hrs under nitrogen atmosphere, the mixture was added compound 5 (5 g, 19,43 mmol, 1 eq), TEA (1.97 g, 19.43 mmol, 2,70 mL, 1 eq) and H2O (5 mL), the reaction was stirred at 25°C for 12 hrs under nitrogen atmosphere.LCMS (ET53957-1533-P1A1, RtP1= 0.661 min) showed the starting material was consumed completely and ~46.11% desired mass was detected. Water (200 mL) was added, the mixturewas extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 3 / 1). Compound 6 (12.3 g, 32.04 mmol, 82.44% yield) was obtained as yellow' oil.LCMS: ET53957-1533-P1A1, Rt= 0.661 min, [M-99] = 284.1, 46.11%General procedure for preparation of compound 7THF, 0°C, 1 hr step 3, 72.99%To a solution of compound 6 (10 g, 26.05 mmol, 1 eq) in THF (200 mL) at 0°C was added LiAlH₄ (2.5 M, 13.54 mL, 1.3 eq). The reaction mixture was stirring at 0°C for 1 hr under N2. LCMS (ET53957-1538-P1A, RtP1= 0.582 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched with Na2SO4. IOH2O (10 g), then was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 1 / 1). The residue was further separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm * 50 mm, 10 um); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 11%, isocratic elution mode). Compound 7 (6.5 g, 19.01 mmol, 72.99% yield) was obtained as yellow oil,SFC: ET53957-1538-P1A, Rt=== 0.688 & 0.787 min, 95.04% & 4.96%LCMS: ET53957-1538-P1A, Rt = 0.582 min, [M-99] = 242.1, 97.60%General procedure for preparation of compound 8step 4, crude78To a solution of compound 7 (1 g, 2.93 mmol, 1 eq) in DCM (10 mL) was added DMP (1.61 g, 3.80 mmol, 1.18 mL, 1.3 eq) at 0°C. The mixture was stirred at 0-25°C for 1 hr. LCMS (ET28542-3531-P1 A, Rt= 0.622 min) showed the starting material was consumed completely and one peak with desired mass was detected. Aq. NaHCOs (30 mL) was added, the mixture was extracted with DCM (30 mL x 2). The combined organic layers were washed with aq. Na2. SO3 (30 mL x 4), dried over Na₂SO₄, concentrated under reduced pressure to give compound 8 (750 mg, 2.21 mmol, 75.44% yield) as yellow oil.LCMS: ET28542-3531-P1A, Rt = 0.622 min, [M+23] = 362.2, 36.53%General procedure for preparation of compound 10·HClNaBH(OAc)3, TEA, HOAc, DCM, 25°C, 2.25 hrs step 6, 61.59%10 To a solution of compound 8 (300 mg, 882.73 pmol, 1 eq) in DCM (5 mL) was added compound 9 (155.65 mg, 1.15 mmol, 1.3 eq, HC1) and TEA (267.97 mg, 2,65 mmol, 368.60 pL, 3 eq) at 25°C under N2 and the solution was stirred at 25°C for 15 mins, then HOAc (265.04 mg, 4.41 mmol, 252.66 pL, 5 eq) and NaBH(OAc)3 (561.26 mg, 2.65 mmol, 3 eq) was added to the solution at 25°C and the solution was stirred at 25°C for 2 hrs. LCMS (ET28542-3536-P1A, Rt= 0.485 min) showed the starting material remained and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (20 mL) at 0°C, extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate / Methanol = 100 / 1 to 0 / 1).Compound 10 (230 mg, 543.70 pmol, 61.59% yield) was obtained as yellow oil.LCMS: ET28542-3536-P1A, Rt= 0.485 min, [M+l] = 423.2, 74.83%General procedure for preparation ofL184HCl (g) / dioxane 20°C, 0.5 hrs step 7, crude10 L184 A mixture of compound 10 (200 mg, 472.78 μmol, 1 eq) and HCl (g) / dioxane (4 M, 2 mL, 16.92 eq) was stirred at 20°C for 0.5 hrs. LCMS (ET28542-3538-P1A, Rt = 0.345 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction was concentrated under reduced pressure to give L184 (180 mg, crude, HC1 salt) as yellow oil.LCMS: ET28542-3538-P1A, Rt = 0.345 min, [M+1] = 323.2, 94.18%General procedure for preparation of compound 12step 8, 96.78%12Two batches were carried out in parallel in this page.To a solution of compound 11 (25 g, 121.94 mmol, 1 eq) in THF (250 mL) was added LDA (2 M, 73.16 mL, 1.2 eq) at -70°C. The mixture was stirred at -70°C for 0.5 hrs. DMF (11.59 g, 158.52 mmol, 12.20 mL, 1.3 eq) was added to the mixture at -70°C, the mixture was stirred at -70°C for 0.5 hrs. TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rf= 0.17) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition aqueous NH4Cl (1 L), and extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 12 (55 g, 236.02 mmol, 96.78% yield) as a yellow solid.¹H NMR: ET28542-3367-P1A CDCl3 Bruker_02_V_400 MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 10.38 (s, 1H), 7.65 - 7.59 (m, 1H), 6.73 (d, J = 9.0 Hz, 1H), 3.94 (s, 3H)General procedure for preparation of compound 13MeMgBrTHF, 0-25°C, 2hstep 3, crude F OH 12 3Two batches were carried out in parallel in this page.To a solution of compound 12 (27.5 g, 118.01 mmol, 1 eq) in THF (270 mL) was added MeMgBr (3 M, 78.67 mL, 2 eq) at 0°C under N2. The mixture was stirred at 25°C for 2 hrs. LCMS (ET28542-3468-P1A1, Rt= 0.481 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition aqueous NH4CI (800 mL), and extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 13 (60 g, crude) as yellow oil.LCMS: ET28542-3468-P1A1, Rt = 0.481 min, [M-17] = 231.0, 90.55%¹H NMR: ET28542-3468-P1A CDCl3 Bruker_02_V_400MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.39 (t, J = 8.4 Hz, 1H), 6.62 (d, J = 8.9 Hz, 1H), 5.31 - 5.16 (m, 1H), 3.89 (s, 3H), 3.22 (d, J = 10.9 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H).General procedure for preparation of compound 14PCC DCM, 0-25°C, 12hstep 10, 83.00%13 14Two batches were carried out in parallel in this page.To a solution of compound 13 (28.5 g, 114.42 mmol, 1 eq) in DCM (300 mL) was added PCC (49.33 g, 228.85 mmol, 2 eq) at 25°C and the solution was stirred at 25°C for 12 hrs. LCMS (ET28542-3472-P1C1, Rt =0.518 min) showed the starting material remained and one peak with desired mass was detected. The reaction mixture was filtered. The filter cake was washed by DCM (600 mL x 3). Tire combine filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Compound 14 (44 g, 178.09 mmol, 77.82% yield) was obtained as yellow oil,LCMS: ET28542-3472-P1C1, Rt = 0.518 min, [M+1] = 356.1, 83.63%XH NMR: ET28542-3472-P1A CDC13 Broker 02 V 400MHz ’HNMR (400 MHz, CHLOROFORM-^ 5 = 7.50 (dd, J= 8.0, 8.8 Hz, 1H), 6.65 (dd, J= 0.9, 8.9 Hz, 1H), 3.85 (s, 3H), 2.54 (d, J = 0.8 Hz, 3H).General procedure for preparation of compound 16OxNHj 15 BCs2CO3, NMP 100°C, 36 h step 4, 64.02%To a solution of compound 14 (13 g, 52.62 mmol, 1 eq) in NMP (200 mL) was added Cs2CO3(51,43 g, 157.86 mmol, 3 eq) and compound 15 (25 g, 150.91 mmol, 2,87 eq, HC1). Hie mixture was stirred at 100°C for 24 hrs. LCMS (ET28542-3478-P1C, Rt =0.583 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (800 mL) at 0°C, extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 16 (12 g, 33.68 mmol, 64.02% yield) was obtained as yellow oil.LCMS: ET28542-3478-P1C, Rt = 0.588 min, [M+1] = 356.1, 32.42%’H NMR: ET28542-3478-P1A CDC13 Broker 02 P 400MHz¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.43 (d, J = 8.9 Hz, 1H), 6.39 (d, J = 8.9 Hz, 1H), 4.67 - 4.32 (m, 1H), 3.86 - 3.76 (m, 3H), 3.38 - 3.28 (m, 3H), 3.21 - 3.10 (m, 2H), 2.60 - 2.49 (m, 3H), 2.04 - 1.94 (m, 4H), 1.26 - 1.08 (m, 4H).General procedure for preparation of compound 17INaNO2, AcOH, H2O, 25°C, 2 hstep 12, 70.59%16To a solution of compound 16 (6 g, 16.84 mmol, 1 eq) in AcOH (45 mL) and H2O (32.4 mL) was added NaNO2 (2.32 g, 33.68 mmol, 2 eq). The mixture was stirred at 25°C for 2 hrs. After cooling to 0°C, Zn (17.58 g, 268.85 mmol, 15.96 eq) was added. Stirring was continued at 25°C for another 2 hrs. LCMS (ET28542-3485-P1A1, Rt = 0.662 min) showed the starting material was consumed completely and one peak with desired mass was detected, The reaction mixture was filtered and the filtrate was extracted with EtOAc (3 x 200 mL). Combined organic layers were washed with saturated aqueous Na2COs (500 mL), brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). Compound 17 (8.4 g, 23.78 mmol, 70.59% yield) was obtained as yellow oil.LCMS: ET28542-3485-P1A1, Rt=== 0.662 mm, [M+1] = 353.1, 54.50%1H NMR: ET28542-3485-P1A CDCl3 Bruker_02_P_400MHz’HNMR (400 MHz, CHLOROFORM-^ / ) 5 = 7.36 (d, J= 8.1 Hz, 1H), 6.27 (d, J= 8.1 Hz, 1H), 5.36 (tt, J--- 5.0, 10.4 Hz, 1H), 3.90 (s, 3H), 3.40 (s, 3H), 3.29 (tt, J--- 4.2, 10.9 Hz, 1H), 2.63 (s, 3H), 2.29 - 2.18 (m, 2H), 2.14 - 2.03 (m, 4H), 1.45 (br dd, J = 4.8, 11.3 Hz, 2H).General procedure for preparation of Inter R586AKOAc, Pd(dppf)Cl2.DCM, DMF, 20-80°C, 2 hrs step 13, 48.21% O / R586A To a solution of compound 17 (3.92 g, 11.10 mmol, 1 eq) in DMF (50 mL) was added compound a (12.53 g, 55.48 mmol, 5 eq), KOAc (5.45 g, 55,48 mmol, 5 eq) and Pd(dppf)Cl2.CH2Cl2 (906.21 mg, 1.11 mmol, 0.1 eq) at 20°C under N2 and the solution was stirred at 80°C for 2 hrs. LCMS (ET28542-3505-P1A, Rt= 0.427 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (200 mL) at 0°C, extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). R586A (3.1 g, 6,42 mmol, 48.21% yield, 80% purity') was obtained as yellow oil.LCMS: ET28542-3505-P1A, Rt= 0.427 min, [M-67] = 319.0, 20.95%’H NMR: ET28542-3505-P1A CDC13 Broker 02 P 400MHz1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.70 (d, J= 7.9 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 5.03 - 4.87 (m, 1H), 3.93 (s, 3H), 3.83 (s, 4H), 3.41 (s, 3H), 3.36 - 3.26 (m, 1H), 2.66 (s, 3H), 2.25 (brd, J= 12.6 Hz, 2H), 2.14 - 1.99 (m, 4H), 1.40 - 1.32 (m, 2H), 1.09 (s, 6H).General procedure for preparation of compound 18step 14, 31.54%L184 To a solution of L184 (167.46 mg, 465.97 pmol, 1 eq, HC1) in MeCN (5 mL) was added R586A (180 mg, 465.97 pmol, 1 eq), 4A MS (20 mg) and CHOCOOH (51.47 mg, 559.16 μmol, 1.2 eq) at 80°C under N2 and the solution was stirred at 80°C for 2 hrs. LCMS (ET28542-3540-P1A1, Rt = 1.028 & 1.047 min) showed the starting material remained and two peaks with desired mass were detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was further purified by prep-HPLC (column: WePure Biotech XPt C18150 * 40 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) -ACN]; gradient: 25% - 65% B over 8.0 min) to give compound 18 (0.15 g, 229.61 μmol, 49.28% yield) as a white solid.LCMS: ET28542-3540-P1A1, Rt= 1.028 & 1.047 mm, [M+l] = 635.4, 30.37% & 35.10%General procedure for preparation of 115-P1 115-P2115-P1 115-P218 Structure randomly assigned Structure randomly assignedCompound 18 (150 mg, 229.61 μmol, 1 eq) was separated SFC (column: Daicel ChiralPak IM (250*25 mm i.d. lOum); mobile phase: [Heptane - EtOH (0,1% IPAm)]; B%:15%, isocratic elution mode).Peak 1 was randomly assigned as 115-P1 (68.7 mg, 104.94 μmol, 45.70% yield, 99.79% purity), obtained as a white solid which was confirmed by LCMS (ET28542-3551-P1A, Rt = 2.632 min), SFC (ET28542-3551-P1 A, Rt= 2.496 min) and HNMR (ET28542-3551-P1A). Peak 2 was randomly assigned as 115-P2 (64.2 mg, 98.27 μmol, 42.80% yield, 100% purity), obtained as a white solid which was confirmed by LCMS (ET28542-3551-P2A, Rt = 2.667 min), SFC (ET28542-3551-P2A, Rt= 2.944 min) and HNMR (ET28542-3551-P2A).For Monitoring:SFC: ET28542-3540-P1A, Rti== 2.517 min, 62.56% & Rt2=== 2.993 min, 37.44%For 115-P1:LCMS: ET28542-3551-P1A, Rt= 2.632 min, [M+l] = 653.4, 99.79%,SFC: ET28542-3551-P1A, Rt= 2.496 min, 100%1H NMR: ET28542-3551-P1A MeOD Bruker_02_O_400MHz1H NMR (400 MHz, METHANOL-4) δ = 7.37 (br d, J= 7.9 Hz, 1H), 7.10 (br s, 1H), 7.04 (s, 2H), 6.38 (d, J= 8.1 Hz, 1H), 5.19 - 4.92 (m, 1H), 4.67 - 4.57 (m, 1H), 3.91 (s, 3H), 3.39 (s, 3H), 3.21 (br d, J--- 4.3 Hz, 1H), 2.95 - 2.81 (m, 1H), 2.75 (br d, J = 6.9 Hz, 2H), 2.60 (s, 3H), 2.58 - 2.42 (m, 5H), 2.20 (br d, J= 10.0 Hz, 3H), 2.11 (s, 5H), 2.01 (br d, J= 10.3 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.86 - 1.71 (m, 3H), 1.57 (br s, 3H), 1.51 - 1.39 (m, 2H), 1.35 - 1.27 (m, 1H), 1.22 (brd, J= 6.1 Hz, 3H), 1.18 - 1.11 (m, 3H).For 115-P2:LCMS: ET28542-3551-P2A, Rt= 2.667 min, [M+1] = 653.4, 100%,SFC: ET28542-3551-P2A, Rt= 2.944 min, 99.76%1H NMR: ET28542-3551-P2A MeOD Bruker_02_O_400MHz’HNMR (400 MHz, METHANOL-d₄) 5 = 7.30 (d, J= 8.0 Hz, 1H), 7.05 - 6.99 (m, 2H), 6.96 (br s, 1H), 6.33 (d, J--- 8.0 Hz, 1H), 5.17 - 4.97 (m, 1H), 4.66 - 4.58 (m, 1H), 3.91 (s, 3H), 3.40 (s, 3H), 3.27 - 3.23 (m, 1H), 2.95 - 2.85 (m, 1H), 2.84 - 2.71 (m, 2H), 2.60 (s, 3H), 2.59 - 2.41 (m, 2H), 2.49 (br s, 3H), 2.22 (br d,. / = 10.9 Hz, 3H), 2.18 (br d, J= 1.5 Hz, 2H), 2.11 (s, 4H), 2.02 - 1.92 (m, 2H), 1.92 - 1.79 (m, 3H), 1.76 (br d, J--- 12.8 Hz, 1H), 1.61 (br t, J- 5.3 Hz, 2H), 1.51 - 1.37 (m, 3H), 1.37 - 1.27 (m, 1H), 1.24 (br d, J= 6.5 Hz, 3H), 1.17 (br d, J= 6.5 Hz, 3H).Example 14: Preparation of Compound 116-P1 and 116-P2Scheme 1: Synthetic Route for R586AScheme 2: Synthetic Route for Compound 14Scheine 3: Synthetic Route for 116-P1 & 116-P2General procedure for preparation of compound 2step 1, 96.78%1 2Two batches were carried out in parallel in this page.To a solution of compound 1 (25 g, 121.94 mmol, 1 eq) in THF (250 mL) was added LDA (2 M, 73.16 mL, 1.2 eq) at -70°C. The mixture was stirred at -70°C for 0.5 hrs. DMF (11.59 g, 158.52 mmol, 12.20 mL, 1.3 eq) was added to the mixture at -70°C, the mixture was stirred at - 70°C for 0,5 hrs. TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rr= 0.17) indicated the starting material was consumed completely and one new spot formed. The reaction mixture was quenched by addition aqueous NH4CI (1 L), and extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2 (55 g, 236.02 mmol, 96.78% yield) as a yellow solid.1H NMR: ET28542-3367-P1A CDCl3 Bruker_02_V_400 MHz1H NMR (400 MHz, CHLOROFORM-) δ = 10.38 (s, 1H), 7.65 - 7.59 (m, 1H), 6.73 (d,9.0 Hz, 1H), 3.94 (s, 3H).General procedure for preparation of compound 3MeMgBrTHF, 0-25°C, 2 hrs step 2, crudeTwo batches were carried out in parallel in this page.To a solution of compound 2 (27.5 g, 118.01 mmol, 1 eq) in THF (270 mL) was added MeMgBr (3 M, 78.67 mL, 2 eq) at 0°C under N2. The mixture was stirred at 25°C for 2 hrs. LCMS (ET28542-3468-P1A1, Rt= 0.481 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition aqueous NH4CI (800 mL), and extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (1 L). dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 3 (60 g, crude) as yellow oil.LCMS: ET28542-3468-P1A1, Rt= 0.481 min, [M-17] = 231.0, 90.55%1H NMR: ET28542-3468-P1A CDCl3 Bruker_02_V_400MHz1H NMR (400 MHz, CHLOROFORM-) δ = 7.39 (t, J= 8.4 Hz, 1H), 6.62 (d, J= 8.9 Hz, 1H), 5.31 - 5.16 (m, 1H), 3.89 (s, 3H), 3.22 (d, J= 10.9 Hz, 1H), 1.56 (d, J= 6.8 Hz, 3H).General procedure for preparation of compound 4PCC DCM, 25°C, 16 hrsstep 3, 77.32%3 4Two batches were carried out in parallel in this page.To a solution of compound 3 (28.5 g, 114.42 mmol, 1 eq) in DCM (300 mL) was added PCC (49.33 g, 228.85 mmol, 2 eq) at 25°C and the solution was stirred at 25°C for 16 hrs. LCMS (ET28542-3472-P1C1, Rt=0.518 min) showed the starting material remained and one peak with desired mass was detected. The reaction mixture was filtered. The filter cake was washed by DCM (600 mL x 3). The combined filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethylacetate = 100 / 1 to 10 / 1). Compound 4 (44 g, 178.09 mmol. 77.82% yield) was obtained as yellow oil.LCMS: ET28542-3472-P1C1, Rt = 0.518 min, [M+1] = 356.1, 83.63%’H NMR: ET28542-3472-P1A CDCI3 Bruker 02 V 400MHz1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.50 (dd, J= 8.0, 8.8 Hz, 1H), 6.65 (dd, J= 0.9, 8.9 Hz, 1H), 3.85 (s, 3H), 2.54 (d, J= 0.8 Hz, 3H).General procedure for preparation of compound 6O'' ■NH25Cs2CO3, NMP100°C, 36 hstep 4, 64.02%To a solution of compound 4 (13 g, 52.62 mmol, 1 eq) in NMP (200 mL) was added Cs2CO3(51.43 g, 157.86 mmol, 3 eq) and compound 5 (25 g, 150.91 mmol, 2.87 eq, HC1). The mixture was stirred at 100°C for 36 hrs. LCMS (ET28542-3478-P1C, Rt =0.583 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (800 mL) at 0°C, extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Tire residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1).Compound 6 (12 g, 33.68 mmol, 64.02% yield) was obtained as yellow oil.LCMS: ET28542-3478-P1C, Rt = 0.588 min, [M+1] = 356.1, 32.42%1H NMR: ET28542-3478-P1A CDCl3 Bruker_02_P_400MHz1H NMR (400 MHz, CHLOROFORM-) δ = 7.43 (d, J= 8.9 Hz, 1H), 6.39 (d, J= 8.9 Hz, 1H), 4.67 - 4.32 (m, 1H), 3.86 - 3.76 (m, 3H), 3.38 - 3.28 (m, 3H), 3.21 - 3.10 (m, 2H), 2.60 - 2.49 (m, 3H), 2.04 - 1.94 (m, 4H), 1.26 - 1.08 (m, 4H).General procedure for preparation of compound 7NaNO2, AcOH, H2O, 25°C, 2 hrs.then. Zn, 0-25°C, 2 hrsstep 5, 70.59%To a solution of compound 6 (6 g, 16.84 mmol, 1 eq) in AcOH (45 mL) and H2O (32.4 mL) was added NaNO2 (2.32 g, 33.68 mmol, 2 eq). The mixture was stirred at 25°C for 2 hrs. After cooling to 0°C, Zn (17.58 g, 268.85 mmol, 15.96 eq) was added. Stirring was continued at 25°C for another 2 hrs. LCMS (ET28542-3485-P1A1, Rt = 0.662 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was filtered and the filtrate was extracted with EtOAc (3 x 200 mL), Combined organic layers were washed with saturated aqueous Na2COs (500 mL), brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). Compound 7 (8.4 g, 23.78 mmol, 70.59% yield) was obtained as yellow oil.LCMS: ET28542-3485-P1A1, Rt= 0.662 min, [M+1] = 353.1, 54.50%1H NMR: ET28542-3485-P1A CDCl3 Bruker_02_P_400MHz1H NMR (400 MHz, CHLOROFORM-) δ = 7.36 (d, J= 8.1 Hz, 1H), 6.27 (d, J= 8.1 Hz, 1H), 5.36 (tt, J--- 5.0, 10.4 Hz, 1H), 3.90 (s, 3H), 3.40 (s, 3H), 3.29 (tt, J--- 4.2, 10.9 Hz, 1H), 2.63 (s, 3H), 2.29 - 2.18 (m, 2H), 2.14 - 2.03 (m, 4H), 1.45 (br dd, J = 4.8, 11.3 Hz, 2H).General procedure for preparation of Intermediate R586AKOAc, Pd(dppf)Cl2.DCM, DMF, 25-80°C, 2 hrs step 6, 94.06%To a solution of compound 7 (3.5 g, 9.91 mmol, 1 eq) in DMF (50 mL) was added compound 7 (11.19 g, 49.54 mmol, 5 eq), KOAc (4.86 g, 49.54 mmol, 5 eq) and Pd(dppf)Cl2.CH2Cl2 (809.12 mg, 990.79 μmol, 0.1 eq) at 25°C under N2 and the solution was stirred at 80°C for 2hrs. LCMS (ET28542-3489-P1A, Rt= 0.422 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched by addition H2O (200 mL) at 0°C, extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). R586A (4.5 g, 9.32 mmol, 94.06% yield, 80% purity) was obtained as yellow oil.LCMS: ET28542-3489-P1A, Rt= 0.422 min, [M-67] = 319.1, 19.46%XH NMR: ET28542-3489-P1 A CDC13 Bruker_02_G_400MHz1H NMR (400 MHz, CHLOROFORM-) δ = 7.70 (d, J= 7.8 Hz, 1H), 6.39 (d, J= 7.8 Hz, 1H), 5.03 - 4.92 (m, 1H), 3.93 (s, 3H), 3.83 (s, 4H), 3.41 (s, 3H), 3.31 (tt, J--- 4.2, 10.9 Hz, 1H), 2.65 (s, 3H), 2.25 (br d, J= 12.8 Hz, 2H), 2.12 - 2.01 (m, 4H), 1.41 - 1.31 (m, 2H), 1.09 (s, 6H).General procedure for preparation of compound 9„ TEMPO, NaHCO,. NaCiO HO N - *" Q' NDCM, H2O, 0°C, 1 hr step 7, crude8 9A catalytic amount of TEMPO (1.66 g, 10.57 mmol, 0.08 eq) was added to a solution of compound 8 (25 g, 132.10 mmol, 1 eq) and NaHCOs (22.19 g, 264.20 mmol, 10.28 mL, 2 eq) in DCM (200 mL) and H2O (100 mL) at 0°C, TLC (Commercial hexanes: Ethyl acetate = 3 / 1, Rf = 0.32) indicated the starting material was consumed completely and one new spot with lower polarity was formed. NaClO (200 mL, 10%) were then added dropwise to the solution at 0°C. The reaction mixture was stirred for a further 1 hr at 0°C. The reaction mixture was mixed with 150 mL water and mixture -was extracted with DCM (200 mL x 3), washed with brine (200 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 9 (27 g, crude) was obtained as yellow oil.XH NMR: ET44300-1422-P1A CDC13 ZKNJ_02_N_400MHz1H NMR (400 MHz, CHLOROFORM-) δ = 9.83 (s, 1H), 3.56 (t, J= 6.4 Hz, 2H), 2.89 (s, 3H), 2.70 (t, J= 6.4 Hz, 2H), 1.47 (s, 9H).General procedure for preparation of compound 11Boc >toluene, 100°C, 2 hrs step 8, 61.78%A solution of compound 9 (27 g, 144.20 mmol, 1 eq) and compound 10 (50.24 g, 144.20 mmol, 1 eq) in toluene (250 mL) was stirred at 100°C for 2 hrs. TLC (Commercial hexanes: Ethyl acetate = 3:1) showed the starting material consumed and a major new spot with lower polarity was detected. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column (Biotage®; 220 g Sepa Flash® Silica Flash Column, Eluent of 12% Ethyl acetate / Petroleum ether gradient @200 niL / min). Compound 11 (21 g, 81.61 mmol, 61.78% yield over 2 steps) was obtained as yellow oil.’H NMR: ET44300-1463-PLA CDCh Bruker 02 R 400MHz1H NMR (400 MHz, CHLOROFORM-) δ = 6.92 (td, J= 7.3, 15.5 Hz, 1H), 5.86 (d, J= 15.7 Hz, 1H), 4.18 (q, J= 7.2 Hz, 2H), 3.36 (t, J= 6.9 Hz, 2H), 2.85 (s, 3H), 2.42 (q, J= 6.8 Hz, 2H), 1.45 (s, 9H), 1.28 (t, J= 7.2 Hz, 3H).General procedure for preparation of compound 13HO-B-OH Rh(NBD)2BF4, TEA, S-BINAP dioxane, H2O, 25°C, 14 hrs step 3, 82.44%Two batches in this page: To a solution of compound 11 (4.97 g, 29.15 mmol, 1.5 eq) in dioxane (50 mL) was added Rh(NBD)2.BF4(726.69 mg, 1.94 mmol, 0.1 eq), S-BINAP (1.5 g, 2.41 mmol, 1.24e-1 eq) under N2, after stirred at 25°C for 2 hrs under nitrogen atmosphere, then was added compound 11 (5 g, 19.43 mmol, 1 eq), TEA (1.97 g, 19.43 mmol, 2.70 mL, 1 eq) and H2O (5 mL), the reaction was stirred at 25°C for 12 hrs under nitrogen atmosphere. LCMS (ET53957-1533-P1A1, Rtp1= 0.661 min) showed the starting material was consumed completely and -46.11% desired mass was detected. Water (200 mL) was added, the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed withbrine (200mL x 2), dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 3 / 1). Compound 13 (12.3 g, 32.04 mmol, 82.44% yield) was obtained as yellow oil.LCMS: ET53957-1533-P1A1, Rt= 0.661 min, [M-99] = 284.1, 46.11%General procedure for preparation of compound 14LiAlH4, THF, 0°C, 1 hr step 10, 72.99%To a solution of compound 13 (10 g, 26.05 mmol, 1 eq) in THF (200 mL) at 0°C was added LiAlH4 (2,5 M, 13.54 ml.,, 1.3 eq). The reaction mixture was stirring at 0°C for 1 hr under N2. LCMS (ET53957-1538-P1A, Rtp1= 0.582 min) showed the starting material was consumed completely and one peak with desired mass was detected. The reaction mixture was quenched with Na2SO4. IOH2O (10 g), then was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 1 / 1). The residue was further separated by (column: DAICEL CHIRALCEL OJ (250 mm * 50 mm, 10 um); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 11%, isocratic elution mode). Compound 14 (6.5 g, 19.01 mmol, 72.99% yield) was obtained as yellow oil.SFC: ET53957-1538-P1A, Rt=== 0.688 & 0.787 min, 95.04% & 4.96%LCMS: ET53957-1538-P1A, Rt= 0.582 min, [M-99] = 242.1, 97.60%General procedure for preparation of compound 15DCM, 0-25°C, 1 hr step 11, crude15 To a solution of compound 14 (800 mg, 2.34 mmol, 1 eq) in DCM (10 mL) was added DMP (1.49 g, 3.51 mmol, 1.09 mL, 1.5 eq) at 0°C. Tlie mixture was stirred at 0-25°C for 1 hr. LCMS (ET49057-2273-P1A, Rt = 0.624 min) showed the starting material was consumedcompletely and -21.66% with desired Ms was detected. The reaction mixture was quenched with NaHCOs (20 ml,) and extracted with ethyl acetate (10 ml x 3). The combined organic layers were washed with Na2SO3(20 mL x 5) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 15 (900 mg, crude) as colourless oil.LCMS: ET49057-2273-P1A, Rt = 0.624 min, [M-55J = 284.1, 21.66%General procedure for preparation of compound 16NaBH(OAc)3,, DCM, TEA, AcOH I 25°C, 3 hrsstep 12, 52.49%15To a solution of compound 15 (400.00 mg, 1.18 mmol, 1 eq), compound a (105.69 mg, 706.18 μmol, 0.6 eq, HCl) and TEA (1.09 g, 1.50 mL) in DCM (4 mL) was stirred at 25°C for 1 hr. Then was added NaBH(OAc)3 (498.89 mg, 2,35 mmol, 2 eq) and AcOH (1.57 g, 1.5 mL). The mixture was stirred at 25°C for 2 hrs. LCMS (ET93571-270-P1A) showed Reactant 1 was completed and - 18.18% of desired compound was detected. The mixture was quenched with NaHCCh (10 mL) pH~7, was extracted with DCM (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Ethyl acetate / Commercial hexanes = 0 / 1 to 1 / 0). Compound 16 (0.27 g, 617.77 nmol, 52.49% yield) was obtained as a yellow oil. LCMS: ET93571-270-P1A, Rt = 0.516 min, [M+l] = 437.3, 18.18%General procedure for preparation of compound L174HCl (g) / dioxane 25°C, 0.5 hr step 13, crudeL174 To a solution of compound 16 (0.25 g, 572.01 pmol, 1 eq) in HCl / dioxane (4 M, 2 mL) was stirred at 25°C for 0.5 hr. LCMS (ET93571-273-P1A) showed the start material was consumed completely and - 70.93% of desired compound was detected. The mixture wasconcentrated under reduced pressure to give a residue. The residue in water (3 mL), was extracted with ethyl acetate (3 mL x 3), The water phase was lyophilized to give L174 (0.18 g, crude) as a yellow oilLCMS: ET93571-273-P1A, Rt= 0.350 min, [M+l] = 337.2, 70.93%General procedure for preparation of compound 17CHOCOOH, 4A MS, MeCN, 25~80°C, 2 hrs step 14, 40.41%L174 To a solution of L174 (0.18 g, 482.05 μmol, 1 eq, HCl), R586A (186.21 mg, 482.05 μmol, 1 eq) in MeCN (5 mL) was added CHOCOOH (53.25 mg, 578.47 μmol, 1.2 eq) and 4A MS at 25°C, then the mixture was stirred at 80°C for 2 hrs. LCMS (ET93571-276-P1A) showed Reactant 1 was completed and ~ 41.96% of desired compound was detected. The mixture is concentrated under reduced pressure by filtration to obtain the residue. The residue was purified by prep-HPLC (column: WePure Biotech XPt C18150 * 40 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 35% - 65% B over 8.0 min). Compound 17 (0.13 g, 194.81 μmol, 40.41% ...

Claims

1. CLAIMS1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:(I),wherein:(A / ' is a 3 - to 12-membered heterocyclyl optionally substituted with one or more instances of R3, -N(Ra)-(C3-i2-cycloalkyl) optionally substituted with one or more instances of R3, or -N(Ra)-Ra’;Ra and Ra’ are each independently is H or C1-4 alkyl;a is 0, 1, 2 or 3;Ri is H or -COORib;Rib is H or C1-4 alkyl;R2 is H or C1-4 alkyl;each R3 is independently hydrogen, halogen, C 1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3-to 8-membered heterocycloalkyl, or C 1-6 alkyl oxy,wherein the C1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, and C1-6 alkyloxy are optionally substituted with one or more halogen, C1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkoxy;Xi, X2, X3, X4 and X5 are each N or CR4;each R4 is H, halogen, C 1-4 alkyl optionally substituted with one or more halogen, C1-4 alkyloxy optionally substituted with one or more halogen, or C3-6 cycloalkyl;f'v is C5-12 heterocyclyl, optionally substituted with one or more instances of Rs or R«;each Rs is independently a C1-6 alkyl, 3- to 12-membered heterocycloalkyl, C3-12 cycloalkyl, each optionally substituted with one or more instances of Rg’;each Rs and Rs’ is independently Ci-6 alkyl, halogen, Ci-6 alkyloxy, OH, Ci-salkyl-OH, C 1-6 alkyl-C 1-6 -alkyloxy, Ci-salkyloxy-Ci-6-alkyloxy, or C3-6 cycloalkyl and each C1-6 alkyl, C1-6 alkyloxy, OH, Ci-salkyl-OH, C1-6 alkyl-Ci-6-alkyloxy, Ci-salkyloxy-Ci-6-alkyloxy, is optionally substituted with 1 to 4 instances of R7;each R7 is independently halogen, C3-6 cycloalkyl, or C 1-6 alkyl optionally substituted with one or more halogen, hydroxy, or C1-6 alkoxy.(A)2. The compound of claim 1, whereinis 5- to 8-membered heterocyclyl optionally substituted with one or two instances of R3, wherein R3 halogen, C1-6 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, or C1-6 alkyloxy, or a pharmaceutically acceptable salt thereof.\A)3. The compound of claim 1 or claim 2, whereinis azetidine, pyrrolidine, piperidine, piperazine, morpholine, or azepane optionally substituted with one or two instances of R3, wherein R3 is F, methyl, isopropyl, OMe, methoxyethyl, cyclopropyl, cyclobutyl, or oxetanyl, or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein a is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein Ri is -COOH, or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-5, wherein R2 is methyl, or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, whereinXi is CR4 and R4 is H, halogen, C 1-4 alkyl optionally substituted with one or more halogen, or C1-4 alkyloxy optionally substituted with one or more halogen;X2 is CR4 and R4 is H, or halogen;X3 is N or CR4 and R4 is H;X4 is CR4 and R4 is H, halogen, C 1-4 alkyl optionally substituted with one or more halogen, or C3-6 cycloalkyl;X5 is N or CR4 and R4 is H,or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, whereinXi is CR4 and R4 is H, methyl, F, Cl, or OMe;X2 is CR4 and R4 is H, or F;X3 is N or CR4 and R4 is H;X4 is CR4 and R4 is H, Cl, CF3, CHF2, cyclopropyl, or cyclobutyl;Xs is N or CR4 and R4 is H,or a pharmaceutically acceptable salt thereof.I c;9. The compound of any one of claims 1-8, whereinis:RfibwhereinRs is C1-6 alkyl or a 3- to 12-membered heterocycloalkyl or C3-12 cycloalkyl, each optionally substituted with one or more instances of Re’;$a is C1-6 alkyl or C3-8 cycloalkyl optionally substituted with one or more Rrr: $b is hydrogen, halogen, -O(C3-8 cycloalkyl), C1-6 alkyl, or C1-6 alkoxy wherein the C1-6 alkyl or C1-6 alkoxy is optionally substituted with one or more halogen or C1-6 alkoxy; and$’ is halogen, Ci-6 alkyl optionally substituted with one or more halogen, Ci-6 alkyloxy optionally substituted with one or more halogen, or OH,or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, wherein Rs is R6'or, or a pharmaceutically acceptable salt thereof.The compound of claim 9 or claim 10, wherein Rs is or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 9 to 11, wherein Rgais methyl,or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 9 to 12, wherein Rgb is hydrogen, fluoro, methyl, methoxy, ethoxy, -O(cyclopropyl), -O(CHF2), or a pharmaceutically acceptable salt thereof.i. c •14. The compound of any one of claims 1-8, whereinis:whereinAi, A2, A3 and A4 are each independently oxygen or CRioaRiob, provided that one of Ai, A2, A3 and A4 is oxygen;each ofRioa, andRiob, are independently hydrogen, C 1-4 alkyl optionally substituted with one or more halogen, halogen, C 1-4 alkyloxy, C1-6 cycloalkyl, or OH,Rio is C1-4 alkyl optionally substituted with one or more halogen, halogen, C1-4 alkyloxy, or OH,a is 0, 1, 2, or 3,or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14, wherein Ai is CRioaRiob, A2 is O, and A3 and A4 are both CH2, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 14 or claim 15, wherein Rwais hydrogen and Riob is selected from methyl, or ethyl, or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 14 to 16, wherein Rio is hydrogen, or fluoro, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 14, wherein1, or a pharmaceutically acceptable salt thereof.A compound of claim 1, which is of the chemical formula-388--389-, or, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. A method of treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20.

22. Use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-19 for the manufacture of a medicament for the treatment of inflammatory bowel disease, ulcerative colitis, or Crohn’s disease.

23. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-19 for use in therapy.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-19 for use in tire treatment of inflammatory bowel disease, ulcerative colitis, or Crohn’s disease.

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