Anti-inflammatory compounds

Abstract

The invention provides compounds of Formula (I): and pharmaceutically acceptable salts and pharmaceutical compositions thereof, which are useful as inhibitors of STAT family members, and methods for using such compounds to treat, ameliorate or prevent an inflammatory disease or an allergic disease, including asthma and atopic dermatitis associated with STAT proteins, especially associated with IL-4 signaling.

Description

[0001] Docket No. 4014.1410 WO

[0002] ANTI-INFLAMMATORY COMPOUNDS

[0003] RELATED APPLICATIONS

[0004] This application claims the benefit of U. S. Provisional Application No. 63 / 771,207, filed March 13, 2025, and U. S. Provisional Application No. 63 / 858,103, filed August 5, 2025. The entire teachings of the above applications are incorporated herein by reference.

[0005] TECHNICAL FIELD

[0006] The present invention relates generally to compounds and pharmaceutical compositions useful as inhibitors of STAT family members. Specifically, the present invention relates to compounds that are useful in treating diseases mediated by STAT proteins.

[0007] BACKGROUND OF THE INVENTION

[0008] Members of the Signal Transducer and Activator of Transcription (STAT) protein family are transcription factors that play central roles in cell processes including immunity, metabolism, proliferation, differentiation, apoptosis and angiogenesis. The human genome encodes seven STAT proteins: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. STAT3 and STAT6 have prominent roles in processes relevant to inflammatory and autoimmune diseases.

[0009] STAT3 is apleotropic cytokine involved in host defense, development of hematopoietic stem cells (HSCs) and non-HSCs, metabolism, and autoimmunity. STAT3 plays a central role in the development of T helper 17 (Thl7) and T follicular helper (Ta) cells and is a critical component of signaling pathways of inflammatory cytokines, including IL-6, IL-23, and IL-31. Therapeutic targeting of these cytokines with monoclonal antibodies has been used to treat autoimmune and autoinflammatory diseases. Inhibitors of JAK tyrosine kinases involved in promulgating inflammatory signaling upstream of STAT3 have been used as treatments for autoimmune disorders as well as in oncology for myeloproliferative neoplasms and solid tumors.

[0010] STAT6 is a necessary and critical node of the JAK / STAT signaling pathway that is activated upon interaction of the cytokines IL-4 and IL-13 with their receptor containing the IL-4Ra subunit. This process has been found to play a central role in the development of type 2 inflammatory’ diseases including asthma and atopic dermatitis. Antibodies targeting IL-4Ra can achieve therapeutic blockade of both IL-4 and IL-13 mediated signaling, while antibodies

[0011] PAGE 1 OF 152Docket No. 4014.1410 WO

[0012] that selectively target the IL- 13 cytokine have also been used in the clinic. Furthermore, the importance of this pathway is highlighted by missense variants of STAT6 that have recently been shown to protect against asthma and dampen the type 2 inflammatory response.

[0013] CN120230147A, CN120230148A WO2014182928, WO2023192960, WO2023164680, WO2023133336, WO2024071439, WO2025103477, WO2025147509, WO2025147320, and WO2025133961, disclose small molecule STAT6 inhibitors. WO2024238598, WO2024238603, WO2024233639, W02025049820, and WO2025049821 describe degraders of STAT6 protein. However, an oral inhibitor of STAT6 has not been approved, and there remains a need in the art for novel therapeutic agents that treat or ameliorate inflammatory diseases associated with IL-4 and IL- 13 signaling.

[0014] SUMMARY OF THE INVENTION

[0015] The present invention relates to novel anti-inflammatory compounds, pharmaceutical compositions comprising such compounds, as well as methods to treat a subject in need of therapy with said compounds. Compounds of the present invention bind STAT family members, thereby inhibiting the transcription of genes mediated by STAT proteins, particularly STAT3 and STAT6.

[0016] The present invention provides compounds represented by Formula (I)

[0017]

[0018] and pharmaceutically acceptable salts, N-oxides, esters and prodrugs thereof, wherein;

[0019] RAis selected from the group consisting of:

[0020] 1) Optionally substituted 4- to 8- membered heterocycloalky l;

[0021] 2) Optionally substituted aryl;

[0022] 3) Optionally substituted arylalkyl;

[0023] 4) Optionally substituted heteroaiyl;

[0024] 5) Optionally substituted heteroarylalkyl;

[0025] 6) -CCOMR’XR2);

[0026] 7) -N(R1)C(O)(R2);

[0027]

[0028] 8) -NCR^CCOjOCR2); and

[0029] PAGE 2 OF 152Docket No. 4014.1410 WO

[0030] 9) -N(R3)C(O)N(R1)(R2);

[0031] RBis selected from the group consisting of hydrogen, halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalky l, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR1, -C(O)N(R1)(R2), -NR1R2, -SR1, -SO2R1, -NCR^QOXR2), -N(R1)C(O)O(R2), -N

[0032]

[0033] (R3)C(O)NR1R2, -N(R1)S(O)2(R2), and -P(O)R1R2;

[0034] Rcis selected from the group consisting of hydrogen, halogen, cyano, optionally substituted -Ci-Cs alkyl. optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalk l. optionally substituted 4- to 8- membered heterocycloalkyd, optionally substituted ary l, optionally substituted heteroary l, -OR1, -SR1, - C(O)N(R1)(R2), -NR'R2. -SO2R1, -NCR'KCOXR2), -N(R1)C(O)O(R2), -N(R3)C(O)NR1R2, -N

[0035]

[0036] (R1)S(O)2(R2), and -P(O)R1R2:

[0037] RDis selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alky 1, optionally substituted -C2-C8 alkenyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroaryl alky 1, optionally substituted aryl, and optionally substituted heteroaryl;

[0038] REis selected from the group consisting of:

[0039] 1) Hydrogen;

[0040] 2) Halogen

[0041] 3) Cyano;

[0042] 4) Optionally substituted -Ci-Cs alkyl;

[0043] 5) Optionally substituted -C3-C8 cycloalkyl;

[0044] 6) Optionally substituted -Ci-Cs alkoxy;

[0045] 7) Optionally substituted 4- to 8- membered heterocycloalky l;

[0046] 8) Optionally substituted aryl;

[0047] 9) Optionally substituted heteroaryl; and

[0048] 10)- C(O)N(R1)(R2);

[0049] Y1and Y2are independently selected from the group consisting of N and CRF;

[0050] X1, X2, and X3are each independently selected from the group consisting of N and CRG;

[0051] PAGE 3 OF 152Docket No. 4014.1410 WO

[0052] L is -L'- -L2-: wherein L1is connected to the amide nitrogen atom and L2is connected to Z;

[0053] L1is -C(R4)(R5)[C(R6)(R7)]n-, wherein n is 0, 1, 2, 3, or 4;

[0054] W is absent or W1; W1is selected from the group consisting of -O-, -SO2-, -NR9-, -C(O)NR9-, -NR9C(O)-, -SO2NR9-, and -NR9SO2-;

[0055] L2is absent or -[C(R6)(R7)]m-wherein m is 1 or 2;

[0056] Z is C or N;

[0057] A is an optionally substituted aryl or optionally substituted heteroaryl;

[0058] each RFis independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyL optionally substituted -(N-Cs cycloalkyl, optionally substituted 4-to 8- membered heterocycloalkyl, optionally substituted ary l, optionally substituted heteroaryl, -OR1. -NR'R2. -SR1, -SO2R1, -C(O)N(R1)(R2), -N(R1)C(O)(R2), -N(R1)C(O)O(R2), -N(R3)C(O)NR1R2, and -N(R1)S(O)2(R2);

[0059] each RGis independently selected from the group consisting of:

[0060] 1) Hydrogen;

[0061] 2) Halogen;

[0062] 3) Cyano;

[0063] 4) Hydroxy;

[0064] 5) Optionally substituted Ci-Cs alkyl;

[0065] 6) Optionally substituted Cs-Cs cycloalkyl;

[0066] 7) Optionally substituted 4- to 8-membered heterocycloalkyl;

[0067] 8) Optionally substituted aryl;

[0068] 9) Optionally substituted heteroaryl;

[0069] 10) Optionally substituted -Ci-Cs alkoxy;

[0070] IQ-CCOMR'XR2);

[0071] 12)-N(R1)C(O)(R2);

[0072] Bl-NIR^R2);

[0073] 14)-SR1;

[0074] 15) -S(O)2R1;

[0075] 16)-N(R1)C(O)O(R2);

[0076] 17)-N(R1)S(O)2(R2); and

[0077]

[0078] 18)-P(O)R1R2;

[0079] PAGE 4 OF 152Docket No. 4014.1410 WO

[0080] Each R1, R2, andR3is independently selected from hydrogen, optionally substituted -Ci-Os alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted ary l, optionally substituted arylalkyl, optionally substituted heteroaryl alkyl, and optionally substituted heteroaryl; alternatively, R1and R2are both attached to a nitrogen atom and R1and R2are taken together with the nitrogen atom to form an optionally substituted 4- to 8-membered heterocyclic containing 0, 1, 2, or 3 double bonds;

[0081] R4andR5are each independently selected from hydrogen, halogen, optionally substituted -Ci-Cs alkyd, optionally substituted -C2-C8 alkenyl, optionally substituted -C3-C8 cycloalkyd, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0082] Each R6is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C3-C8 cycloalky l, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and -C(O)N(R1)(R2);

[0083] Each R7is independently7selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted -Ci-Cs alkyd, optionally substituted -C3-C8 cycloalky7!, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -Ci-Cs alkoxy, -NR'R2. -SR1, -SO2R1, -C(O)N(R1)(R2), -N(R1)C(O)(R2), - N(R1)C(O)O(R2), -N(R3)C(O)NR1R2, and -N(R1)S(O)2(R2);

[0084] alternatively, R4and R5are taken together with the carbon atom to which they are attached to form optionally7substituted -C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic containing 0, 1, 2, or 3 double bonds;

[0085] alternatively, R5and R6are taken together with the carbon atoms to which they are attached and any intervening carbon atoms to form optionally substituted -Cs-Cs cycloalky7! or an optionally substituted 4- to 8- membered heterocyclic containing 0, 1, 2, or 3 double bonds;

[0086] alternatively, R6and R7are taken together with the carbon atom to which they are attached to form optionally7substituted -C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic containing 0, 1, 2, or 3 double bonds; and

[0087] R9is selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C3-C8 cycloalkyl,

[0088] PAGE 5 OF 152Docket No. 4014.1410 WO

[0089] optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarydalkyl, optionally substituted heteroaryl, -S(O)2R1,

[0090] -C(O)N(R1)(R2), -CCOXR1), and -C(O)OR1.

[0091] DETAILED DESCRIPTION OF THE INVENTION

[0092] In one embodiment, the compound of Formula (I) is as described above or a pharmaceutically acceptable salt thereof.

[0093] In certain embodiments of the compounds of Formula (I), wherein RAis optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 4- to 12-membered heterocycloalkyd.

[0094] In certain embodiments of the compounds of Formula (I), RAis optionally substituted aryl or optionally substituted heteroaryl.

[0095] In certain embodiments of the present invention, R

[0096]

[0097] Ais

[0098] o

[0099]

[0100] r, wherein

[0101] R11is selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alkyl, optionally substituted -Cs-Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted ar l, optionally substituted arylalkyd, optionally substituted heteroarylalkyl, and optionally substituted heteroaryl;

[0102] R12is selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -Cs-Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted ar l, optionally substituted ar dalkyl, optionally substituted heteroarydalkyl, and optionally substituted heteroaryl;

[0103] alternatively, RAis

[0104]

[0105] R12 Nand R11and R12are taken together with the nitrogen atom and carbon atom to which they are respectively attached to form an optionally substituted heteroarvl or an optionally substituted 5-8 membered heterocycloalkv 1;

[0106] PAGE 6 OF 152Docket No. 4014.1410 WO

[0107] alternatively,

[0108]

[0109] RAis R12and R11and R12are taken together with the nitrogen atom and carbon atom to which they are respectively attached to form an optionally substituted 4-12 membered heterocycloalkyl which is bridged with the triazole ring;

[0110] each R13is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, and optionally substituted -Ci-Cs alkoxy;

[0111] alternatively, two R13groups are taken together with the carbon atom to which they are attached to form an optionally substituted -Cd-Cs cycloalkyl or optionally substituted 4-to 8- membered heterocycloalkyl;

[0112] each R14is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, and optionally substituted -Ci-Cs alkoxy;

[0113] alternatively, two R14groups are taken together with the carbon atom to which they are attached to form an optionally substituted -Cd-C’s cycloalkyl or optionally substituted 4-to 8- membered heterocycloalkyd;

[0114] each R15is independently selected from the group consisting of hydrogen and optionally substituted -Ci-Cs alkyl;

[0115] alternatively, two R15groups are taken together with the carbon atom to which they are correspondingly attached to form an optionally substituted -Cs-Cs cycloalkyl or optionally substituted 4- to 8- membered heterocycloalkyl;

[0116] alternatively, RAis

[0117]

[0118] and one R13and one R14are taken together with the carbon atoms to which they are attached to form an optionally substituted -Cs-Cs cycloalkyl or optionally substituted 4- to 8-membered heterocycloalkyl;

[0119] alternatively, RAis

[0120]

[0121] PAGE 7 OF 152Docket No. 4014.1410 WO

[0122] and one R13and one R14are taken together with the carbon atoms to which they are attached and the intervening oxygen atom to optionally substituted 4- to 12- membered heterocycloalkyl which is bridged with the morpholine ring;

[0123] alternatively, one R14and one R13are taken together with the carbon atoms to which they are attached to form an optionally substituted -C3-C8 cycloalkyl or an optionally substituted 4- to 8- membered heterocycloalkyl;

[0124] 0

[0125] Me. J!

[0126] I N—

[0127] In certain embodiments of the compounds of Formula (I), RAisN^ /

[0128] p p

[0129] ^4

[0130]

[0131] Me, or Me. In certain embodiments, RAis p

[0132] N-|

[0133] In certain embodiments of the compounds of Formula (I), RAis

[0134]

[0135] p p o 4RI®R16£ JLJ 4

[0136]

[0137] \= / , or, » wherein R16is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C3-C8 cycloalkyl and optionally substituted -Ci-Cs alkoxy.

[0138] In certain embodiments of the compounds of Formula (I), RBis hydrogen, halogen, or optionally substituted -Ci-Cs alkyl. Preferably, RBis hydrogen or optionally substituted methyl.

[0139] In certain embodiments of the compounds of Formula (I), Rcis hydrogen, halogen, optionally substituted -Ci-Cs alkyl, or optionally substituted -Ci-Cs alkoxy.

[0140] In certain embodiments of the compounds of Formula (I). RDis hydrogen or optionally substituted -Ci-Cs alkyl.

[0141] In certain embodiments of the compounds of Formula (I), RDis optionally substituted

[0142] methyl, optionally substituted ethyl,

[0143]

[0144] '—owe. or. In certain embodiments, RDis ethyl. In certain embodiments, R

[0145]

[0146] Dis OMe.

[0147] In certain embodiments of the compounds of Formula (I), REis hydrogen or optionally substituted -Ci-Cs alkyl.

[0148] PAGE 8 OF 152Docket No. 4014.1410 WO

[0149] In certain embodiments of the compounds of Formula (I), REis optionally substituted methyl or phenyl.

[0150] In certain embodiments of the compounds of Formula (I), X1is CRG, and RGis hydrogen, halogen, or optionally substituted -Ci-Cs alkyd. Preferably, X1is CH.

[0151] In certain embodiments of the compounds of Formula (I), X2is CRG, and R is hydrogen, halogen, or optionally substituted -Ci-Cs alkyl. Preferably, X2is C-CF3.

[0152] In certain embodiments of the compounds of Formula (I), X3is CRG, and RGis hydrogen, halogen, or optionally substituted -Ci-Cs alky 1. Preferably, X3is CH.

[0153] In certain embodiments of the compounds of Formula (I). X1is CRG, X2is CRG, and X3is N or CRG, wherein RGis as previously defined.

[0154] In certain embodiments of the compounds of Formula (I), X1is CH, X2is CRG, and X3is N or CH, and RGis as previously defined. Preferably RGis optionally substituted -Ci-Cs alkyl, more preferably RGis -CF3.

[0155] In certain embodiments of the compounds of Formula (I), Y1is CRF, wherein RFis as previously defined. Preferably, Y1is CH.

[0156] In certain embodiments of the compounds of Formula (I), Y2is CRF, wherein RFis as previously defined. Preferably, Y2is CH.

[0157] In certain embodiments of the compounds of Formula (I), Y1is CH, and Y2is CH.

[0158] In certain embodiments of the compounds of Formula (I),

[0159]

[0160] is derived from one of the following by removing two adjacent hydrogen atoms and is optionally substituted

[0161] PAGE 9 OF 152Docket No. 4014.1410 WO

[0162]

[0163] (A)

[0164] In certain embodiments of the compounds of Formula (I), z is optionally substituted benzo.

[0165] In certain embodiments of the compounds of Formula (I), L is selected from:

[0166]

[0167] In certain embodiments of the present invention, R

[0168]

[0169] Ais, wherein R11, R12, and R13are previously defined.

[0170] In certain embodiments of the present invention, RAis

[0171]

[0172] PAGE 10 OF 152Docket No. 4014.1410 WO

[0173] In certain embodiments of the present invention, RDis ethyl.

[0174] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formula (II):

[0175]

[0176] wherein RF1is RFand RF2is RF; and RA, RB, Rc, RD, RE, X1, X2, X3, L, Z, and A are as previously defined.

[0177] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formula (III):

[0178]

[0179] wherein RA, RB, Rc, RD, RE, X1, X2, X3, L, Z, and A are as previously defined.

[0180] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formula (IV):

[0181]

[0182] wherein RG1is RG, RG2is RG, RG3is RG; RA, RB, Rc, RD, RE, Y1, Y2, L, Z, and A are as previously defined. In certain embodiments, RG2is CF3, methyl, cyclopropyl, or halogen, such as chloro or fluoro. In certain embodiments RG2is CF3, chloro or fluoro, preferably CF3. In certain embodiments, RG2is CF3 and RG1and RG3are hydrogen.

[0183] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formula (IV-a) ~ (IV-c):

[0184] PAGE 11 OF 152Docket No. 4014.1410 WO

[0185]

[0186] wherein RG1, RG2, RG3, RA, RB, Rc, RD, RE, Y1, Y2, L, Z, and A are as previously defined.

[0187] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formula (V-l) ~ (V-4):

[0188]

[0189] wherein RG2, RA, RB, Rc, RD, RE, L, Z, and A are as previously defined.

[0190] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formula (VI):

[0191]

[0192] wherein two of V1, V2, V3, and V4independently are N, CH, or CR17and the remainder are independently CH or CR17; R17is selected from the group consisting of halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C3-C8 cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -P(O)R1R2, and -C(O)N(R1)(R2); and RA, RB, Rc, RD, RE, Y1, Y2, X1, X2, X3, and L are as previously defined.

[0193] PAGE 12 OF 152Docket No. 4014.1410 WO

[0194] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (VII-1) ~ (VII-8):

[0195] (VII-4) (VII-5) (VII-6)

[0196]

[0197] wherein W1Ais -O-, -SO2-, or -NRs-; W1Bis -O-, -SO2-. -NRs-, -C(O)NRs-, -NRsC(O)-, -SO2NR8-, or -NR8SO2-; and RA, RB, Rc, RD, RE, R4, R5, R6, R7, W1, X1, X2, X3, Y1, Y2, V1, V2, V3, and V4are as previously defined.

[0198] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (VIII-1) ~ (VIII-8):

[0199] PAGE 13 OF 152Docket No. 4014.1410 WO

[0200] (VIII-2)

[0201]

[0202] wherein r is 0, 1, 2, 3, or 4; and RA, RB, Rc, RD, RE, R4, R5, R6, R7, W1A, W1B, X1, X2, X?, Y1, Y2, and R17are as previously defined. In certain embodiments r is 1. In certain embodiments r is 2.

[0203] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (Vlll-la) ~ (VIII-8a):

[0204] PAGE 14 OF 152Docket No. 4014.1410 WO

[0205]

[0206] wherein q is 0, 1. 2, or 3; and RA, RB, Rc, RD, RE, R4, R5, R6, R7, W1A, W1B, X1, X2, X3, Y1, Y2, R1and R17are as previously defined. In certain embodiments q is 0. In certain embodiments q is 1.

[0207] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (IX-1) ~ (IX-8):

[0208] PAGE 15 OF 152Docket No. 4014.1410 WO

[0209]

[0210] wherein r, RA, RB, Rc, RD, RE, RG2, R4, R5, R6, R7, WI. W1B. and R17are as previously defined.

[0211] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (X-l) ~ (X-8):

[0212] PAGE 16 OF 152Docket No. 4014.1410 WO

[0213]

[0214] wherein r, RA, RB, Rc, RD, RE, RG2, R4, R5, R6, R7, WI. W1B. and R17are as previously defined.

[0215] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XI-1) ~ (XI-10):

[0216] PAGE 17 OF 152Docket No. 4014.1410 WO

[0217]

[0218] wherein, RA, RB, Rc, RD, RE, R4, R5, R6, R7, R9, Y1, Y2, X1, X2, X3, V1, V2, V3, and V4are as previously defined.

[0219] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XII-1) ~ (XII-10):

[0220] PAGE 18 OF 152Docket No. 4014.1410 WO

[0221]

[0222] wherein r, RA, RB, Rc, RD, RE, R4, R5, R6, R7, R9, X1, X2, X3, Y1, Y2, and R17are as previously defined.

[0223] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XIII-1 ) ~ (XIII- 10):

[0224] PAGE 19 OF 152Docket No. 4014.1410 WO

[0225]

[0226] wherein r, RA, RB, Rc, RD, RE, RG2, R4, R5, R6, R7, R9and R17are as previously defined.

[0227] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XIV- 1) ~ (XIV- 10):

[0228] PAGE 20 OF 152Docket No. 4014.1410 WO

[0229]

[0230] wherein r, RA, RB, Rc, RD, RE, RG2, R4, R5, R6, R7, R9and R17are as previously defined.

[0231] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XV- 1) ~ (XV- 10):

[0232] PAGE 21 OF 152Docket No. 4014.1410 WO

[0233]

[0234] wherein r, RA, RD, RG2, R4, R5, R6, R7, R9, and R17are as previously defined.

[0235] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XVI- 1) ~ (XVI- 10):

[0236] PAGE 22 OF 152Docket No. 4014.1410 WO

[0237]

[0238] wherein r, RA, RD, RG2, R4, R5, R6, R7, R9and R17are as previously defined.

[0239] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XVII- 1) ~ (XVII- 10):

[0240] PAGE 23 OF 152Docket No. 4014.1410 WO

[0241]

[0242] wherein r, R11, R12, RD, RG2, R4, R5, R6, R7, R9and R17are as previously defined.

[0243] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XVIII-1) ~ (XVIII-10):

[0244] PAGE 24 OF 152Docket No. 4014.1410 WO

[0245]

[0246] wherein r, R11, R12, RD, RG2, R4, R5, R6, R7, R9and R17are as previously defined.

[0247] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XIX- 1) ~ (XIX- 10):

[0248] PAGE 25 OF 152Docket No. 4014.1410 WO

[0249]

[0250] wherein r, R4, R5, R6, R7, R9and R17are as previously defined.

[0251] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XX-1) ~ (XX-10):

[0252] PAGE 26 OF 152Docket No. 4014.1410 WO

[0253]

[0254] wherein r, R4, R5, R6, R7, R9and R17are as previously defined.

[0255] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XXI-1) ~ (XXI-20):

[0256] PAGE 27 OF 152Docket No. 4014.1410 WO

[0257]

[0258] PAGE 28 OF 152Docket No. 4014.1410 WO

[0259]

[0260] wherein q, R11, R12, RD, RG2, R1, R4, R5, R6, R7, R9and R17are as previously defined. In certain embodiments, R1is Ci-C4-alkyl, preferably methyl or ethyl and more preferably methyl. In certain embodiments, R1is hydrogen.

[0261] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XXII-1) ~ (XXII-20):

[0262] PAGE 29 OF 152Docket No. 4014.1410 WO

[0263]

[0264] PAGE 30 OF 152Docket No. 4014.1410 WO

[0265]

[0266] wherein q. RD, R1. R4. R5, R6, R7, R9and R17are as previously defined.

[0267] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (XXIII-1) ~ (XXIII-20):

[0268] PAGE 31 OF 152Docket No. 4014.1410 WO

[0269]

[0270] wherein R4, R5, R6, R7. and R9are as previously defined.

[0271] In certain embodiments of the present invention, the compound of Formula (I) is represented by Formulae (XXIV- 1) ~ (XXIV-20):

[0272] PAGE 32 OF 152Docket No. 4014.1410 WO

[0273]

[0274] PAGE 33 OF 152Docket No. 4014.1410 WO

[0275]

[0276] wherein R4, R6, R7, and R9are as previously defined.

[0277] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (XXV- 1) ~ (XXV -4):

[0278]

[0279] wherein R18is selected from the group consisting of halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -Cs-Cs cycloalkyl,

[0280] PAGE 34 OF 152Docket No. 4014.1410 WO

[0281] and optionally substituted 4- to 8- membered heterocycloalkyl; p is 0, 1 or 2; RA, RD. RG1, RG2RG3 R1R4 R6 R17anc| garepreviously defined.

[0282]

[0283] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (XXVI- 1) ~ (XXVI-4)

[0284]

[0285] wherein RA, RD, RG1, RG2, RG3, R4, R6, R17and q are as previously defined.

[0286] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (XXVII- 1) ~ (XXVII-4):

[0287]

[0288] wherein RD, RG1. RG2, RG3, R4, R6, R17and q are as previously defined.

[0289] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (XXVIII-1) ~ (XXVIII-8):

[0290]

[0291] wherein RA, RG1. RG2, RG3, R17and q are as previously defined.

[0292] PAGE 35 OF 152Docket No. 4014.1410 WO

[0293] In certain embodiments of the present invention, the compound of Formula (I) is represented by one of Formulae (XXIX- 1) ~ (XXIX-8):

[0294]

[0295] wherein RG1, RG2, RG3, R17and q are as previously defined. Preferably, RG2is halogen, optionally substituted -C1-C4 alkyl, or optionally substituted -C1-C4 alkoxy; RG1is hydrogen or halogen; RG’ is hydrogen or halogen; R17is halogen, and q is 0 or 1. More preferably, RG2is halogen or CF3; RG1is hydrogen; RG3is hydrogen; R17is halogen, preferably chloro or fluoro, and q is 0 or 1. In certain embodiments, q is 0. In certain embodiments, q is 1.

[0296] Each preferred group stated above can be taken in combination with one, any or all other preferred groups.

[0297] It will be appreciated that the description of the present invention herein should be construed in congruity with the laws and principles of chemical bonding. In some instances, it may be necessary to remove a hydrogen atom in order to accommodate a substituent at any- given location.

[0298] It will be appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.

[0299] The compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of the present invention

[0300] PAGE 36 OF 152Docket No. 4014.1410 WO

[0301] and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be achieved by concomitant administration in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.

[0302] In certain embodiments of the combination therapy, the additional therapeutic agent is administered at a lower dose and / or dosing frequency as compared to dose and / or dosing frequency of the additional therapeutic agent required to achieve similar results in treating or preventing as inhibitors for STAT family members.

[0303] It should be understood that the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agent.

[0304] DEFINITIONS

[0305] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0306] The term "aryl," as used herein, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring. Preferred aryl groups are Ce-C 12-ary 1 groups, including, but not limited to. phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.

[0307] Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.

[0308] The term "heteroaryl," as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. In certain embodiments, a heteroaryl group is a 5- to 10-membered heteroaryl, such as a 5- or 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl. Heteroaiyl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl. thiadiazolyl, oxadiazolyl, thiophenyl, furanyl. quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaiy l can comprise fused rings, covalently attached rings or a combination thereof. A heteroaryl group can be C-attached orN-attached where possible.

[0309] In accordance with the invention, ary l and heteroaryl groups can be substituted or unsubstituted.

[0310] PAGE 37 OF 152Docket No. 4014.1410 WO

[0311] The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached.

[0312] The term “alkyl” as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals. " C1-C4 alkyl,” " Ci-C6alkyl,” “Ci-Cs alkyl,” “C1-C12 alkyl," " C2-C4 alkyl,” and " C3-C6 alkyd,” refer to alkyl groups containing from 1 to 4, 1 to 6, 1 to 8, 1 to 12, 2 to 4 and 3 to 6 carbon atoms respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, w-butyl, sec-butyl, tert-butyl, n-pentyl, neopenty l, n-hexyl, n-heptyl and n-octyl radicals.

[0313] The term “alkenyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond. “C2-C8 alkenyl,” “C2-C12 alkenyl." “C2-C4 alkenyl,” “C3-C4 alkenyl,” and “C -C6 alkenyl,” refer to alkenyl groups containing from 2 to 8, 2 to 12, 2 to 4, 3 to 4, or 3 to 6 carbon atoms respectively. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like.

[0314] The term “alkynyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond. “C2-C8 alkynyl,” “C2-C12 alkynyl," “C2-C4 alkynyl,” “C3-C4 alkynyl,” and “C3-C6 alkynyl,” refer to alkynyl groups containing from 2 to 8t, 2 to 12, 2 to 4, 3 to 4. or 3 to 6 carbon atoms respectively. Representative alkynyl groups include, but are not limited to. ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, and the like.

[0315] The term “cycloalkyl”, as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring, such as a bi- or tri-cyclic fused, bridged or spiro system. The ring carbon atoms are optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkyl groups include C3-C12 cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2. l]heptyl, bicyclo[3.1.0]hexyl. spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl. spiro[4.4]nonanyl, and the like.

[0316] The term “cycloalkenyl”, as used herein, refers to monocyclic or polycyclic carbocyclic ring, such as a bi- or tri-cyclic fused, bridged or spiro system having at least one carbon-carbon double bond. The ring carbon atoms are optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkenyl groups include C3-C12 cycloalkenyl, C4-Ci2-cycloalkenyl, C3-C8 cycloalkenyl, C4-Cs cycloalkenyl

[0317] PAGE 38 OF 152Docket No. 4014.1410 WO

[0318] and C5-C7 cycloalkenyl groups. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-2-enyl, bicyclo[4.2. l]non-3-en-12-yl, and the like.

[0319] As used herein, the term “arylalkyl” means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -(CH2)n-phenyl, where n is 1 to 12, preferably 1 to 6 and more preferably 1 or 2. The term “substituted arylalkyl” means an arylalkyl functional group in which the aryl group is substituted. Similarly, the term “heteroarylalkyl” means a functional group wherein an alkylene chain, is attached to a heteroaryl group, e.g., -(CH2)n-heteroaiyl, where n is 1 to 12, preferably 1 to 6 and more preferably 1 or 2. The term “substituted heteroarylalkyl” means a heteroarylalkyl functional group in which the heteroaryl group is substituted.

[0320] As used herein, the term “alkoxy” refers to a radical in which an alkyl group having the designated number of carbon atoms is connected to the rest of the molecule via an oxygen atom. Alkoxy groups include Ci-Ci2-alkoxy, Ci-Cs-alkoxy, Ci-Ce-alkoxy, Ci-C4-alkoxy and Ci-C3-alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred alkoxy is C1-C3 alkoxy.

[0321] An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and / or triple bonds.

[0322] Examples of aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH. NHS(O)2NH, NHS(O)2NH2. C(O)NHS(O)2. C(O)NHS(O)2NH or C(O)NHS(O)2NH2, and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group. Carbon atoms of an aliphatic group can be optionally oxo-substituted. An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.

[0323] PAGE 39 OF 152Docket No. 4014.1410 WO

[0324] The terms “heterocyclic’' and “heterocycloalkyl” can be used interchangeably and refer to anon-aromatic ring or a polycyclic ring system, such as a bi- or tri-cyclic fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quatemized. (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond. Representative heterocycloalkyd groups include, but are not limited to, 1,3-di oxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyL 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 2-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic or heterocycloalky 1 groups may be further substituted. A heterocycloalkyl or heterocyclic group can be C-attached or N-attached where possible.

[0325] It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s). One skilled in the art can readily determine the valence of any such group from the context in which it occurs.

[0326] The term “substituted” refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, Ci-Ci2-alkyl; C2-C 12- alkenyl, C2-C 12-alkynyl, -C3-Ci2-cycloalkyl, protected hydroxy, -NO2, -Ns, -CN, -NH2, protected amino, oxo, thioxo, -NH-Ci-Ci2-alkyl. -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-Cs-C -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci2-alkyl, -O-C2-Cs-alkenyl, -O-C2-Cs-alkynyl, -O-C3-Ci2-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-Ci-Ci2-alkyl, -C(O)-C2-C8-alkenyl. -C(O)-C2-C8-alkynyl, -C(O)-C3-Ci2-cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-Ci-Ci2-alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-Ci2-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-Ci-Ci2-alkyl, -OCO2-C2-Cs-alkenyl, -OCO2-C2-Cs-alkynyl, -OCO2-C3-Ci2-cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-Ci-Ci2alkyl, -CO2-C2-C8alkenyl. -CO2-C2-C8 alkynyl. -CO2-C3-Ci2-cycloalkyl, -CO2-aryl, -CO2-heteroaryl, -CO2-heterocyloalkyl, -OCONH2, -OCONH-

[0327] PAGE 40 OF 152Docket No. 4014.1410 WO

[0328] Ci-Ci2-alkyl, -OCONH-Cz-Cs-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-CI2-cycloalkyl, -OCONH-aryl. -OCONH-heteroaryl, -OCONH-heterocycloalkyl. -NHC(O)H, -NHC(O)-Ci-Ci2-alkyl, -NHC(O)-C2-Cs-alkenyL -NHC(O)-C2-C8-alkynyL -NHC(O)-C3-CI2-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2-CI-Ci2-alkyl, -NHCO2-C2-C8-alkenyl, -NHCO2-C2-C8-alkynyl, -NHCO2-C3-Ci2-cycloalkyl, -NHCO2-aryl. -NHCO2-heteroaryl, -NHCO2- heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-Ci-Ci2-alkyl, -NHC(O)NH-C2-C8-alkenyl. -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C6-CI2-cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, -NHC(S)NH2, -NHC(S)NH-Ci-Ci2-alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8-alkynyl, -NHC(S)NH-C3-Ci2-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-Ci-Ci2-alkyl, -NHC(NH)NH-C2-Cs-alkenyl, -NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-Ci2-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaiyl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-Ci-Ci2-alkyl, -NHC(NH)-C2-C8-alkenyl, -NHC(NH)-C2-C8-alkynyl, -NHC(NH)-C3-CI2-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl. -NHC(NH)-heterocycloalkyl, -C(NH)NH2, -C(NH)NH-Ci-Ci2-alkyl, -C(NH)NH-C2-C8-alkenyl, -C(NH)NH-C2-C8-alkynyl, -C(NH)NH-C3-Ci2-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-Ci-Ci2-alkyl, -S(O)-C2-C8-alkenyl, - S(O)-C2-C8-alkynyl, -S(O)-C3-Ci2-cycloalkyl. -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-CI-Ci2-alkyl, -SO2NH-C2-C8-alkenyl. -SO2NH-C2-C8-alkynyl, -SO2-Ci-Ci2-alkyl, -SO2-C2-C8-alkenyl, -SO2-C2-C8-alkynyl, -SO2-C3-Ci2-cycloalkyl, -SO2-aryl, -SO2-heteroaryl, -SO2-heterocycloalkyl, -SO2NH-C3-Ci2-cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO₂NH-heterocycloalkyl, -NHSO2-Ci-Ci2-alkyl, -NHSO2-C2-C8-alkenyl, - NHSO2-C2-C8-alkynyl, -NHSO2-C3-Ci2-cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-Ci2-cycloalkyl, poly alkoxy alky l, poly alkoxy, -methoxy methoxy, -methoxy ethoxy, -SH, -S-Ci-Ci2-alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-Ci2-cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthio-methyl. In certain embodiments, the substituents are independently selected from halo, preferably Cl and F; Ci-C4-alkyl, preferably methyl and ethyl; halo-Ci-C4-alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4-alkenyl; halo-C2-C4-alkenyl; Cs-Ce-cycloalkyl, such as cyclopropyl; Ci-C4-alkoxy, such as methoxy and ethoxy; halo-Ci -Cr-alkoxy. such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; -CN; -OH; NH2; Ci-C4-alkylamino; di(Ci-C4-alkyl)amino; and NO2. It is understood that an aryl, heteroaryl, alkyl, alkenyl, alkynyl,

[0329] PAGE 41 OF 152Docket No. 4014.1410 WO

[0330] cycloalkyl, or heterocycloalkyl in a substituent can be further substituted. In certain embodiments, a substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from Ci-C4-alkyk -CF?, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN, and -NH2. Preferably, a substituted alky l group is substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms.

[0331] The term "halo’’ or halogen” alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.

[0332] The term “optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e.. the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

[0333] The term “hydrogen” includes hydrogen and deuterium. In addition, the recitation of an element includes all isotopes of that element so long as the resulting compound is pharmaceutically acceptable. In certain embodiments, the isotopes of an element are present at a particular position according to their natural abundance. In other embodiments, one or more isotopes of an element at a particular position are enriched beyond their natural abundance.

[0334] The term “hydroxy activating group.” as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction. Examples of hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

[0335] The term “activated hydroxyl,” as used herein, refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including, but not limited to mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups.

[0336] The term “hydroxy protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s), the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in P. G. M. Wuts, Greene’s Protective Groups in Organic Synthesis, 5th edition. John Wiley & Sons, Hoboken, NJ (2014). Examples of hydroxyl protecting groups include, but are not limited to, benzyloxy carbonyl, 4-methoxybenzyloxycarbonyL

[0337] PAGE 42 OF 152Docket No. 4014.1410 WO

[0338] tert-butoxy-carbonyl, isopropoxy carbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl. allyloxy carbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, meth oxy acetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

[0339] The term "protected hydroxy," as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including but not limited to, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.

[0340] The term “hydroxy prodrug group,” as used herein, refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs. Topical and Ocular Drug Delivery. (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).

[0341] The term “amino protecting group,” as used herein, refers to a labile chemical moiety' which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in P. G. M. Wuts, Greene’s Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons, Hoboken, NJ (2014). Examples of amino protecting groups include, but are not limited to, methoxy carbonyl, t-butoxy carbonyl. 12-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.

[0342] The term “protected amino,” as used herein, refers to an amino group protected with an amino protecting group as defined above.

[0343] The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.

[0344] The term "aprotic solvent," as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to,

[0345] PAGE 43 OF 152Docket No. 4014.1410 WO

[0346] hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY. 1986.

[0347] The term '‘protic solvent,” as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the sol ubi 1 i ty of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick et al.. Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0348] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable,” as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0349] The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R.

[0350] PAGE 44 OF 152Docket No. 4014.1410 WO

[0351] Larock, Comprehensive Organic Transformations. 2ndEd. Wiley-VCH (1999); P. G. M. Wuts, Greene's Protective Groups in Organic Synthesis. 5th edition. John Wiley & Sons, Hoboken. NJ (2014); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis. John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent edirions thereof.

[0352] The term “subject," as used herein, refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. A subject also refers to, for example, a dog, cat, horse, cow, pig, guinea pig, fish, bird and the like.

[0353] The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

[0354] The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers. Racemates, and Resolutions (John Wiley & Sons. 1981). When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers or cis- and trans- isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers may be in cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.

[0355] Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation

[0356] PAGE 45 OF 152Docket No. 4014.1410 WO

[0357] about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0358] As used herein, the term "pharmaceutically acceptable salt," refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / nsk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 2-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate. hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate,?- toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0359] As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,

[0360] PAGE 46 OF 152Docket No. 4014.1410 WO

[0361] cycloalkanoic and alkanedioic acids, in which each alky l or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0362] PHARMACEUTICAL COMPOSITIONS

[0363] The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.

[0364] As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary’ of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin: talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols such as propylene glycol: esters such as ethyl oleate and ethyl laurate: agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0365] The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0366] PAGE 47 OF 152Docket No. 4014.1410 WO

[0367] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0368] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0369] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0370] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release

[0371] PAGE 48 OF 152Docket No. 4014.1410 WO

[0372] can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0373] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository’ wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0374] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cety l alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0375] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0376] The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0377] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be

[0378] PAGE 49 OF 152Docket No. 4014.1410 WO

[0379] required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

[0380] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0381] Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0382] Transdermal patches have the added advantage of providing controlled delivery’ of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0383] For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory’ system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U. S. Pat. No.

[0384] 5,767,068 to Van Devanter et al., U. S. Pat. No. 5,508,269 to Smith et al., and WO 98 / 43650 by Montgomery, all of which are incorporated herein by reference).

[0385] ABBREVIATIONS

[0386] Abbreviations which may be used in the descriptions of the scheme and the examples that follow are: Ac for acetyl; AcOH for acetic acid; B2pin2 for bis(pinacolato)diboron.

[0387] BOC2O for di- / e / 7-butyl-dicarbonate; Boc for / -but oxy carbonyl; BuOH for n-butyl alcohol; Bz for benzoyl; Bn for benzyl; t-BuOK for potassium tert-butoxide; Brine for sodium chloride solution in water; CDI for carbonyldiimidazole; DCM or CH2CI2 for di chloromethane; CH3 for methyl; CH3CN for acetonitrile; CS2CO3 for cesium carbonate; CuCl for copper (I) chloride; Cui for copper (I) iodide; dba for dibenzylidene acetone; DBU for 1,8-diazabicyclo[5.4.0]-undec-7-ene; DEAD for di ethylazodicarboxylate; DIAD for diisopropyl

[0388] PAGE 50 OF 152Docket No. 4014.1410 WO

[0389] azodicarboxylate; DIPEA or (i-Pr)2EtN for N, N, -diisopropylethyl amine; DMP or Dess-Martin periodinane for l,l,2-tris(acetyloxy)-l,2-dihydro-l,2-benziodoxol-3-(lH)-one;

[0390] DMAP for 4-dimethylamino-pyridine; DME for 1,2-dimethoxy ethane; DMF for N, N-dimethylformamide; DMSO for dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH for ethanol; Et2O for diethyl ether; HATU for O-(7-azabenzotriazol-2-yl)-N, N, N’, N’,-tetramethyluronium Hexafluoro-phosphate; HC1 for hydrogen chloride; K2CO3 for potassium carbonate; w-BuLi for w-butyl lithium; DDQ for 2,3-dichloro-5,6-dicyano-l,4-benzoquinone; LDAfor lithium diisopropylamide; LiTMP for lithium 2,2,6,6-tetramethyl-piperidinate; MeOH for methanol; Mg for magnesium; MOM for methoxymethyl; Ms for mesyl or -SO2-CH3; NaHMDS for sodium bis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodium hydride; NaHCOs for sodium bicarbonate or sodium hydrogen carbonate; Na2COs sodium carbonate; NaOH for sodium hydroxide; Na2SO4 for sodium sulfate; NaHSOs for sodium bisulfite or sodium hydrogen sulfite; Na2S20s for sodium thiosulfate; NH2NH2 for hydrazine; NH4CI for ammonium chloride; Ni for nickel; NMI for 1 -methylimidazole; NMO for N-methylmorpholine N-oxide; OH for hydroxyl; OsO4 for osmium tetroxide; OTf for triflate; PPA for polyphophonc acid; PTSA for -toluenesullbnic acid; PPTS for pyridinium / 2-toluenesul fonate; TBAF for tetrabutylammonium fluoride; TEA or EtsN for triethylamine; TES for triethylsilyl; TESC1 for triethylsilyl chloride; TESOTf for triethylsilyl trifluoromethanesulfonate; TFA for trifluoroacetic acid; THF for tetrahydrofuran; TMEDA for N, N, N’, N’-tetramethylethylene-diamine; TPP or PPI13 for triphenyl-phosphine; Tos orTs for tosyl or -SO2-C6H4CH3; TS2O for tolylsulfonic anhydride or tosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for palladium; Ph for phenyl; Pd2(dba)s for tris(diben-zylideneacetone) dipalladium (0); Pd(PPh3)4 for tetrakis(triphenylphosphine)-palladium (0); PdCb(PPh3)2 for trans-dichlorobis-(triphenylphosphine)palladium (II); PdCh(dppl) for 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pt for platinum; Rh for rhodium; rt for room temperature; Ru for ruthenium; TBS for tert-butyl dimethylsilyl; TCFH for (N, N, N', / V'-tctramcthylchloroformamidinium hexafluorophosphate); TMS for trimethylsilyl; or TMSC1 for trimethylsilyl chloride.

[0391] SYNTHETIC METHODS

[0392] The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared, which are intended as an illustration only and not to limit the scope of the invention. Various changes and modifications to the disclosed

[0393] PAGE 51 OF 152Docket No. 4014.1410 WO

[0394] embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, and / or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

[0395] Non-limiting examples of synthetic schemes demonstrating the making of compounds of the invention are illustrated in Schemes 1-5.

[0396] Scheme 1

[0397]

[0398] Scheme 1 illustrates a general method to prepare the compound of formula (1-3), wherein RA, RB, RC, RD, RE, X1, X2, X3, Y1, Y2, Z, and A are as previously described. Carboxylic acid (1- 1) is coupled with cyclic aryl amine (1-2) under standard amide coupling conditions (TCFH, HATU, EDC, etc.) or as described by Ayman El-Faham and Fernando Albericio in Chem. Rev. 2011, 111, 11. 6557-6602 to afford (1-3).

[0399] Scheme 2

[0400]

[0401] Scheme 2 illustrates an alternative method for the preparation of compounds of formula (1-1). Carboxylic acid (2-1) is first coupled with ester containing cyclic amine (2-2), wherein G1is an optionally substituted Ci-Cs alkyl group, under standard amide coupling conditions. Next,

[0402] PAGE 52 OF 152Docket No. 4014.1410 WO

[0403] hydrolysis of (2-3) in the presence of base and water affords carboxylic acid (2-4).

[0404] Alternatively, the hydrolysis of (2-3) to afford (2-4) may be promoted by strong acid (G1= tert-alkyl) or metal mediated hydrogenolysis (G1= benzyl). Finally, carboxylic acid (2-4) is coupled with ammonia or a solid ammonia source (NHrCl) under standard amide coupling conditions to afford (1-1).

[0405] Scheme 3

[0406]

[0407] Scheme 3 illustrates an additional method for the preparation of compounds of formula (1-1) from carboxylic acid (3-1) and cyclic aryl amine (3-2) wherein G2represents a (pseudo)halogen. First (3-1) and (3-2) are coupled under standard amide coupling conditions to afford (3-3). Next. G2is converted to a nitrile via a transition metal catalyzed cyanation reaction to afford (3-4). Hydrolysis of nitrile (3-4) using standard conditions (H2O2 / base or Ghaffar-Parkins catalyst) affords (1-1).

[0408] Scheme 4

[0409] v2*^v4

[0410]

[0411] (4-5) Scheme 4 illustrates a general method for the preparation of cyclic aryl amines of formula (4-5) wherein V1, V2, V3, V4, W1, R6, and R7are as previously defined. G3is an optionally substituted Ci-Cs alkyl group and G4is a (pseudo)halogen or hydroxyl group. First (4-1) is reacted with (4-2) under basic conditions (G4is (pseudo)halogen) or under Mitsunobu reaction conditions (G3= OH) to displace G4and afford (4-3). Next, the nitro functionality is

[0412] PAGE 53 OF 152Docket No. 4014.1410 WO

[0413] reduced with concomitant cyclization to afford cyclic amide (4-4). Finally, cyclic amide (4-4) is reduced to cyclic aryl amine (4-5) in the presence of a hydride reducing agent.

[0414] Scheme 5

[0415]

[0416] Scheme 5 provides a synthesis of the compound of formula (5-5). First, carboxylic ester (5-1), wherein G4is an optionally substituted Ci-Cs alkyd group, is synthesized according to Scheme 4. Next, (5-1) is coupled with carboxylic acid (5-2) to provide (5-3). Intermediate (5-3) is hydrolyzed in the presence of base and water. Alternatively, the hydrolysis of (5-3) to afford (5-4) may be promoted by strong acid (G1= / e / 7-alk\ 1) or metal mediated hydrogenolysis (G1= benzyl), to afford carboxylc acid (5-4). Finally, carboxylic acid (5-4) is coupled with ammonia or a solid ammonia source (NH4CI) under standard amide coupling conditions to afford (5-5).

[0417] PAGE 54 OF 152Docket No. 4014.1410 WO

[0418] Scheme 6

[0419] n O

[0420] O

[0421]

[0422] Scheme 6 provides a method for the synthesis of the compound of formula (6-9). Phenol (6-1), wherein, G5is a (pseudo)halogen group, displaces the alcohol functionality of (6-2), wherein PG is a suitable nitrogen protecting group, by way of a Mitsunobu reaction to afford ether (6-3). The protecting group (PG) is then removed to afford the free amine (6-4). Amine (6-4) is coupled with the carboxylic acid (6-5) under standard amide coupling conditions to afford amide (6-6). Intermediate (6-6) undergoes a metal-catalyzed / mediated carbon-nitrogen coupling with loss of G5to afford (6-7). Intermediate (6-7) is hydrolyzed in the presence of base and water. Alternatively, the hydrolysis of (6-7) to afford (6-8) may be promoted by strong acid (G4= tert-alkyl) or metal mediated hydrogenolysis (G4= benzyl). Finally, carboxylic acid (6-8) is coupled with ammonia or a solid ammonia source (NH4CI) or amine (6-9) under standard amide coupling conditions to afford (6-10).

[0423] PAGE 55 OF 152Docket No. 4014.1410 WO

[0424]

[0425] Scheme 7 illustrates a method for the synthesis of carboxylic acid intermediate (7-10).

[0426] Intermediate (7-1), wherein G6is a (pseudo)halogen undergoes metal-catalyzed reaction with silyl acetylene (7-2) (e.g. Sonogashira coupling) to form intermediate (7-3). Removal of the silyl group of (7-3) is accomplished using standard conditions (TBAF in THF or K2CO3 in methanol) to afford terminal alkyne (7-4). Intermediate (7-4) is then reacted with (7-5), wherein G7is a (pseudo)halogen and G8is an al ky 1 group (e g. Me), under metal -catalyzed coupling conditions (e.g. Sonogashira) to afford intermediate (7-6). Intermediate (7-6) undergoes cyclization under the action of a metal (e.g. PdCh) to form indole intermediate (7-7). Intermediate (7-7) is alkylated with (7-8) in the presence of base, wherein G9is a leaving group, commonly a (pseudo)halogen. Finally, G8may be removed under standard conditions (e.g. basic hydrolysis) to afford intermediate (7-10).

[0427] EXAMPLES

[0428] The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting the scope of the invention. Starting materials were either available from a commercial vendor or produced by methods well known to those skilled in the art.

[0429] General Conditions:

[0430] PAGE 56 OF 152Docket No. 4014.1410 WO

[0431] Mass spectra were run on LC-MS systems using electrospray ionization. These were Agilent 1290 Infinity II systems with an Agilent 6120 Quadrupole detector. Spectra were obtained using ZORBAX Eclipse XDB-C18 column (4.6 x 30 mm, 1.8 micron). Spectra were obtained at 298K using a mobile phase of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Spectra were obtained with the following solvent gradient: 5% (B) from 0-1.5 min, 5-95% (B) from 1.5-4.5 min, and 95% (B) from 4.5-6 min. The solvent flowrate was 1.2 mL / min. Compounds were detected at 210 nm and 254 nm wavelengths. [M+EI]+refers to mono-isotopic molecular weights.

[0432] NMR spectra were run on a Bruker 400 MHz spectrometer. Spectra were measured at 298K and referenced using the solvent peak. Chemical shifts for ’H NMR were reported in parts per million (ppm).

[0433] Compounds were purified via reverse-phase high-performance liquid chromatography (RPHPLC) using a Gilson GX-281 automated liquid handling system. Compounds were purified on a Phenomenex Kinetex EVO C18 column (250 x 21.2 mm, 5 micron), unless otherwise specified. Compounds were purified at 298K using a mobile phase of water (A) and acetonitrile (B) using gradient elution between 0% and 100% (B), unless otherwise specified. The solvent flowrate was 20 mL / min and compounds were detected at 254 nm wavelength.

[0434] Alternatively, compounds were purified via normal-phase liquid chromatography (NPLC) using a Teledyne ISCO Combiflash purification system. Compounds were purified on a REDISEP silica gel cartridge. Compounds were purified at 298K and detected at 254 nm wavelength.

[0435] Ex. 1: Synthesis of 4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l- (2 -methoxy ethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-3,4-dihydro-2H-benzo [b] [1,4] oxazine-8-carboxamide.

[0436]

[0437] PAGE 57 OF 152Docket No. 4014.1410 WO

[0438] Step 1

[0439] To a solution of 3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (60.0 mg. 0.34 mmol, 1.0 eq) in THF (2 mL) was added NH4CI (72.0 mg, 1.34 mmol, 4.0 eq), DIEA (87.0 mg, 0.67 mmol, 2.0 eq) and HATU (139.0 mg, 0.37 mmol, 1.1 eq) at room temperature, the reaction was stirred for 12 h at room temperature. The reaction mixture was quenched with saturated NaHCCh solution (4 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by flash (DCM: MeOH = 94: 6) to give 3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (50.0 mg, yield 84%) as a yellow solid. ESI MS m / z = 179.1 [M+H]+.

[0440] Step 2

[0441] To a solution of 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid (60.0 mg, 0.13 mmol, 1.0 eq) in DCM (3 mL) was added DMF (1.0 mg, 0.01 mmol, 0.1 eq), then oxalyl chloride (50.0 mg, 0.39 mmol, 3.0 eq) was added under N2 atmosphere. The reaction mixture was stirred at room temperature for 0.5 h before being concentrated in vacuum. The residue was dissolved in DCM (3 mL), then 3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (46.0 mg, 0.26 mmol, 2.0 eq) and TEA (66.0 mg, 0.65 mmol, 5.0 eq) were added at 0 °C. The reaction mixture was stirred at room temperature for 12 h under N2 atmosphere. The mixture was diluted with water (2 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers were concentrated and the residue was purified by flash (DCM: MeOH = 96: 4) to give 4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)- 5-(trifluoromethyl)-lH-indole-7-carbonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (3.0 mg, yield 3.7%) as a white solid. 1HNMR (300 MHz, DMSO-dfe): 58.38 -8.09 (m, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.71 - 7.48 (m, 6H), 7.11 - 6.95 (m, 2H), 4.62 - 4.30 (m, 4H), 3.94 - 3.66 (m, 2H), 3.36 (s, 3H), 3.26 - 3.12 (m, 2H), 2.87 (s, 3H), 2.15 (s, 3H). ESI MS m / z = 635.1 [M+H]+.

[0442] PAGE 58 OF 152Docket No. 4014.1410 WO

[0443] The following compounds were prepared in a manner analogous to Ex. 1:

[0444]

[0445] Example 5: Synthesis of (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3.4-dihydro-2H-benzo[b] [l,4]oxazine-8-carboxamide.

[0446]

[0447] Step 1

[0448] In a 40 mL vial equipped with a stir bar, methyl (R)-2-hydroxypropanoate (594.0 mg, 5.7 mmol, 1.5 equiv) and methyl 2-hydroxy-3-nitrobenzoate (750.0 mg, 3.8 mmol, 1.0 equiv) were combined in DCM (12.7 mL, 0.3M) at 0 °C. Next, triphenylphosphine (1.70 g, 6.5

[0449] PAGE 59 OF 152Docket No. 4014.1410 WO

[0450] mmol, 1.7 equiv) was added, followed by the dropwise addition of DIAD (0.96 mL, 4.9 mmol, 1.3 equiv). The resulting mixture was stirred for 16 h and concentrated. The crude residue was then purified directly by silica gel column chromatography (ethyl acetate / cyclohexane gradient, 0 to 40% ethyl acetate) to afford methyl (S)-2-((l -methoxy- 1-oxopropan-2-yl)oxy)-3-nitrobenzoate. ESI MS m / z = 284.2 [M+H]+.

[0451] Step 2

[0452] In a 100 mL round-bottomed flask equipped with a stir bar, methyl (S)-2-((l -methoxy- 1-oxopropan-2-yl)oxy)-3-nitrobenzoate (1.08 g, 3.8 mmol, 1.0 equiv) was dissolved in ethyl acetate under a nitrogen atmosphere. Next, Pd / C (405.0 mg, 10 mol%, 10 wt%) was added, and the flask was sparged with a balloon of hydrogen. A fresh balloon was attached, and the reaction was stirred overnight under an atmosphere of hydrogen. The hydrogen balloon was removed, and the vessel was sparged with nitrogen before filtering the reaction mixture through a pad of celite using ethyl acetate to rinse. Upon concentrating, the crude residue was purified by silica gel column chromatography (cyclohexane / ethyl acetate gradient, 0 to 60% ethyl acetate) to afford methyl (S)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (637.8 mg, 76% yield). ESI MS m / z = 222.0 [M+H]+.

[0453] Step 3

[0454] In a 40 mL vial equipped with a stir bar, methyl (S)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (637.8 mg, 2.9 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (7.2 mL. 0.4M) under a nitrogen atmosphere. The solution was cooled in an ice bath. Next, boron trifluoride diethyl etherate (0.76 mL, 2.09 equiv) was added slowly and the mixture was stirred for 20 min. Sodium borohydride (228.0 mg. 2.09 equiv) was added in several portions. After 40 min, the reaction was quenched by the addition of 1 mL of IM HC1 followed by dilution with saturated aqueous sodium bicarbonate. The aqueous phase was extracted several times with ethyl acetate, and the combined organic layers were dried over sodium sulfate. Upon concentrating, the crude residue was purified by silica gel column chromatography (ethyl acetate / cyclohexane gradient, 0 to 100% ethyl acetate) to afford methyl (S)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (563.4 mg, 94% yield). ESI MS m / z = 207.7 [M+H]+.

[0455] Step 4

[0456] In a microwave vial equipped with a stir bar, 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)- 1 -(2-methoxy ethyl)-5-(trifluoromethyl)- lH-indole-7 -carboxylic acid (60.0 mg, 1.0 equiv) and methyl (S)-2-methyl-3,4-dihydro-2H-benzo[b][1.4]oxazine-8-carboxylate (104.8 mg, 4.0 equiv) were combined in acetonitrile (2.2 mL, 0.06M). Next, 1-

[0457] PAGE 60 OF 152Docket No. 4014.1410 WO

[0458] methylimidazole (81 pL. 8.0 equiv) was added, followed by TCFH (44.4 mg, 1.25 equiv). The resulting mixture was heated at 120 °C for 15 min under microwave irradiation. Upon cooling to room temperature, the reaction mixture was passed through a 1 micron syringe filter using DMF to rinse and purified directly via RPHPLC (MeCN / water. 0.1% formic acid modifier) to afford methyl (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3.4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (27.3 mg, 33% yield). ESI MS m / z = 686.3 [M+Na]+.

[0459] Step 5

[0460] methyl (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (27.3 mg, 1.0 equiv) was dissolved in a mixture of 1,4-dioxane (1.0 mL) and water (0.3 rnL). Next, lithium hydroxide (9.9 mg, 10.0 equiv) was added and the reaction was stirred at room temperature for 21 h. The mixture was acidified by the addition of formic acid (0.2 mL) and passed through a micron syringe filter using DMF to rinse before being purified by RPHPLC (MeCN / water, 0.1% formic acid) to afford (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (22.6 mg, 85% yield). ESI MS m / z = 648.4 [M-H]‘. Step 6

[0461] (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (22.6 mg. 1.0 equiv) was dissolved in DMF (0.7 mL, 0.05M). Next, NH4C1 (18.6 mg, 10.0 equiv), HATU (17.2 mg, 1.3 equiv) and DIPEA (30 pL, 5.0 equiv) were added sequentially. The mixture was stirred at room temperature for 24 h before being directly purified by RPHPLC (MeCN / water, 0.1% formic acid) to afford (S)-4-(2-(4-( 1,3-dimethyl-5-oxo- 1,5-dihy dro-4H- 1,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][L4]oxazine-8-carboxamide (20.2 mg, 90% yield). ESI MS m / z = 649.4 [M+H]+.

[0462] PAGE 61 OF 152Docket No. 4014.1410 WO

[0463] The following compounds were prepared in a manner analogous to Example 5: Example Structure ESI-MS NH2

[0464] 6 [M+H]+

[0465] p ' — I 635.1 / =\ / NVS

[0466] \ ' ^'^CFj

[0467] o

[0468] NH2

[0469] [M+H]+7 "°i °<szNx / k.

[0470] ° i 661.56 A'N'A \ / NTt ^

[0471] OX K Uv

[0472] F PF

[0473] 0 rs=\

[0474] JI L N— <1

[0475] Ok " [M+H]+8 °\ °XzNx / k

[0476] 0\ 1 767.76 Z"-N-X

[0477] w <rOX'

[0478] F F NH2

[0479] -*•0 1 1 [M+H]+9 \ °^zN* J

[0480] O ' - \ 653.3 '7 VJHJJX NF3

[0481] 0r5^

[0482] JL JL«. / N—

[0483] Cv

[0484] [M+H]+10 °\ °^ZN* _

[0485] 7° '"’A 741.21ZN“ \ 1 1

[0486] N^Z \ _ /

[0487] \ r*F

[0488] F

[0489]

[0490] PAGE 62 OF 152Docket No. 4014.1410 WO

[0491] Example 11: Synthesis of 5-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2.3,4,5-tetrahydrobenzo[b] [ 1,4] oxazepine-9-carboxamide.

[0492] o

[0493] / V / .

[0494]

[0495] Step 1

[0496] In a 8 mL vial equipped with a stir bar, 2-(4-(l,3-dimethyl-5-oxo-1.5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid (70 mg, 1.0 equiv.) was dissolved in dry DCM (1 mL) and followed by addition of l-chloro-N N, 2-trimethyl -1 -propenylamine (39 pL, 2.0 equiv., CAS# 26189-59-3) under nitrogen atmosphere. The reaction mixture was stirred for 40 min at room temperature. After 40 min, 9-bromo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepane (100 mg, 3.0 equiv., CAS# 1267996-76-8) and pyridine (1 mL) were sequentially added to the reaction mixture and the mixture was heated at 50° C for Ih in a heating block. Reaction progress was monitored using LC-MS. Once completed, volatiles were removed under vacuum and the crude residue was dissolved in 3 mL DMSO and loaded into 50g gold Cl 8 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford 4-(4-(7-(9-bromo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-5-carbonyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indol-2-yl)phenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (51 mg, 50% yield). ESI MS m / z = 684.3, 686.2 [M+H]+.

[0497] Step 2

[0498] In a 2 mL microwave reaction vial equipped with a stir bar, 4-(4-(7-(9-bromo-2, 3,4,5-tetrahydrobenzo[b] [ 1,4] oxazepine-5-carbonyl)- 1 -(2-methoxy ethyl)-5-(trifluoromethyl)-lH-indol-2-yl)phenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (51 mg, 1 equiv), zinc cyanide (130 mg, 15 equiv., CAS #: 557-21-1), Pd2dba3 (3.4 mg, 0.05 equiv., CAS #: 51364-51-3), and SPhos (3.1 mg, 0.1 equiv., CAS #: 657408-07-6) were combined neat, followed by addition ofDMF (1.1 mL) and Water (43 pL). Reaction mixture was evacuated and backfilled with nitrogen 5 times. The reaction mixture was stirred under microwave condition for Ih at 120 °C. Reaction progress was monitored using LC-MS. The aliquot was directly loaded into 30g gold C18 column for reversed phase flash chromatography purification (10 to 100%

[0499] PAGE 63 OF 152Docket No. 4014.1410 WO

[0500] acetonitrile / water) to afford 5-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2.3,4,5-tetrahydrobenzo[b][l,4]oxazepine-9-carbonitrile (36 mg, 77% yield). ESI MS m / z = 631.6 [M+H]+.

[0501] Step 3

[0502] In a 4 mL vial equipped with a stir bar, 5-(2-(4-(1.3-dimethyl-5-oxo-l,5-dihydro-4H-L2.4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-9-carbonitrile (36 mg, 1.0 equiv.) was dissolved in DMSO (1.1 mL) at room temperature and followed by successive addition of potassium hydroxide (9.6 mg, 3.0 equiv.) and hydrogen peroxide (50% in water, 35 pL. 10.0 equiv). The reaction mixture was stirred at room temperature for 30 min. Reaction progress was monitored using LC-MS. The reaction mixture was filtered through 0.45 pM Syringe filter and filtrate was purified through RPHPLC to afford 5-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2,3,4,5-tetrahydrobenzo[b][l,4] oxazepine-9-carboxamide (22 mg, 59% yield). ESI MS m / z = 649.6 [M+HJ+.

[0503] Example 12: Synthesis of (R)-2-(difluoromethyl)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide.

[0504] NH

[0505] O

[0506] >N*' x

[0507] I N-

[0508]

[0509] Step 1

[0510] In a microwave vial equipped with a stir bar, 2-(4-(l,3-dimethyl-5-oxo-1.5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid (75.0 mg, 0.158 mmol, 1.0 equiv) and methyl 3-amino-2-fluorobenzoate (107.0 mg, 0.632 mmol, 4.0 equiv) were combined in acetonitrile (3.16 mL, 0.05M). Next, 1 -methylimidazole (100 pL, 1.26 mmol, 8.0 equiv) was added, followed by TCFH (55.4 mg, 0.198 mmol, 1.25 equiv). The resulting mixture was heated for 20 min at 100 °C. Upon cooling to room temperature the mixture was purified by RPHPLC to afford methyl 3-(2-(4-(l,3-dimethyl-5-

[0511] PAGE 64 OF 152Docket No. 4014.1410 WO

[0512] oxo- 1,5-dihy dro-4H- 1,2,4-triazol-4-yl)phenyl)- 1 -(2-methoxy ethyl)-5-(trifluoromethyl)- 1H-indole-7-carboxamido)-2-fluorobenzoate (30.9 mg, 31% yield). ESI MS m / z = 626.4 [M+H]+.

[0513] Step 2

[0514] In a 20 mL vial equipped with a stir bar, methyl 3-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H- 1.2.4-triazol-4-yl)phenyl)-l -(2-methoxy ethyl)-5-(trifluoromethyl)-lH-indole-7-carboxamido)-2-fluorobenzoate (30.9 mg, 0.049 mmol, 1.0 equiv) was combined with cesium carbonate (48.3 mg, 0.148 mmol, 3.0 equiv) in DMF (0.99 rnL, 0.05M). Next, (R)-2-(trifluoromethyl)oxirane (8.3 mg, 1.5 equiv) was added. The mixture was then heated at 55 °C for 1 h. The reaction mixture was purified by RPHPLC to afford methyl (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2.4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (23.2 mg, 66% yield). ESI MS m / z = 718.4 [M+H]+. Step 3

[0515] In a 20 mL vial equipped with a stir bar, methyl (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4EI-l, 2, 4-triazol-4-yl)phenyl)-l -(2-methoxy ethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (23.2 mg, 1.0 equiv) was dissolved in a mixture of 1,4-dioxane (0.97 mL) and water (0.32 mL). Lithium hydroxide (3.9 mg. 5.0 equiv) was added, and the mixture was stirred at room temperature until LCMS analysis indicated full consumption of starting material. Upon completion the reaction mixture was purified by RPHPLC to afford (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l, 2, 4-triazol-4-yl)phenyl)-l-(2 -methoxy ethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (21.3 mg, 94% yield). ESI MS m / z = 702.2 [M-H]’.

[0516] Step 4

[0517] In a 20 mL vial equipped with a stir bar, (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H- 1.2.4-triazol-4-yl)phenyl)- 1 -(2-methoxy ethyl)-5-(trifluoromethyl)- lH-indole-7-carbony l)-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (21.3 mg, 1.0 equiv) and ammonium chloride (6.1 mg, 13.0 equiv) were combined in DMF (0.75M). Next, HATU (5.0 mg, 1.5 equiv) was added, followed by DIPEA (11 pL, 7.0 equiv). Upon complete consumption of the starting material, as judged by LCMS analysis, the reaction mixture was directly purified by RPHPLC to afford (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-

[0518] PAGE 65 OF 152Docket No. 4014.1410 WO

[0519] carbonyl)-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (4.0 mg, 65% yield). ESI MS m / z = 703.4 [M+H]+.

[0520] The following compounds were prepared by a procedure analogous to that used for Example 12:

[0521]

[0522] Example 16: Synthesis of (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l -(2 -methoxy ethyl)-5-(trifluoromethyl)-lEI-indole-7-carbonyl)-7-fluoro-2-methyl-3,4-dihy dro-2H-benzo[b] [ 1,4]oxazine-8-carboxamide.

[0523]

[0524] Step 1

[0525] In a 100 mL round-bottomed flask equipped with a stir bar, methyl 6-fluoro-2-hydroxy-3-nitrobenzoate (1.04 g, 4.9 mmol, 1.0 equiv) and methyl (R)-2-hydroxypropanoate (695 pL, 757.7 mg, 7.28 mmol, 1.5 equiv) were combined in DCM (18.1 mL, 0.3M) under a nitrogen

[0526] PAGE 66 OF 152Docket No. 4014.1410 WO

[0527] atmosphere. The solution was cooled in an ice and water bath and triphenylphosphine (2.16 g, 8.3 mmol, 1.7 equiv) was added. Finally, DIAD (1.23 mL, 6.3 mmol, 1.3 equiv) was added dropwise. The resulting mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated and purified by silica gel column chromatography (cyclohexane / ethyl acetate, 0 to 40% ethyl acetate gradient elution) to afford methyl (S)-6-fluoro-2-((l -methoxy- l-oxopropan-2-yl)oxy)-3-nitrobenzoate (1.33 g, 91% yield).

[0528] Step 2

[0529] In a 250 ml round-bottomed flask equipped with a stir bar, methyl (S)-6-fluoro-2-((l-methoxy-l-oxopropan-2-yl)oxy)-3-nitrobenzoate (1.33 g, 4.41 mmol, 1.0 equiv) was combined neat with palladium on carbon (10 wt%, 469.2 mg, 0.441 mmol, 10 mol%) under a nitrogen atmosphere. Next, ethyl acetate (22.0 mL, 0.2M) was added, and the reaction was sparged with hydrogen. The reaction was then stirred overnight under an atmosphere of hydrogen. Upon complete consumption of the starting material, as judged by LCMS analysis of the reaction mixture, the reaction was sparged with nitrogen before being filtered through a pad of celite. Upon concentration the crude residue was purified by silica gel column chromatography (cyclohexane / ethyl acetate, 0 to 100% ethyl acetate gradient elution) to afford methyl (S)-7-fluoro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][L4]oxazine-8-carboxylate (989.0 mg, 94% yield). ESI MS m / z = 239.9 [M+H]+.

[0530] Step 3

[0531] In a 100 mL round-bottomed flask equipped with a stir bar, methyl (S)-7-fluoro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (989.0 mg, 4.1 mmol, 1.0 equiv) was dissolved in THF (10.3 mL, 0.4M). The reaction was cooled in an ice and water bath. Boron trifluoride diethyl etherate (1.10 mL, 8.6 mmol, 2.09 equiv) was added dropwise. After 20 minutes, sodium borohydride (326.8 mg. 8.6 mmol, 2.09 equiv) was added. The resulting mixture was stirred for 1 h before being quenched with IM aqueous hydrochloric acid (1.0 mL). The reaction mixture was neutralized and further diluted with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate. Upon concentration, the crude residue was purified by silica gel column chromatography (cyclohexane / ethyl acetate, 0 to 100% ethyl acetate gradient elution) to afford methyl (S)-7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (594.5 mg, 64% yield). ESI MS m / z = 226.0 [M+H]+. Step 4

[0532] In a micro wave vial equipped with a stir bar, 2-(4-(l,3-dimethyl-5-oxo-1.5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid

[0533] PAGE 67 OF 152Docket No. 4014.1410 WO

[0534] (75.0 mg, 0.16 mmol, 1.0 equiv) was combined neat with methyl (S)-7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (98.0 mg, 0.43 mmol, 2.75 equiv).

[0535] Acetonitrile (2.2 mL, 0.075M) was added, followed by 1 -methylimidazole (100 pL, 8.0 equiv). Finally, TCFH (62.0 mg, 0.22 mmol, 1.4 equiv) was added. The vial was sealed, and the reaction mixture was heated at 120 °C for 45 minutes. Upon cooling to room temperature the reaction mixture was directly purified by RPHPLC to afford methyl (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2.4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (72.6 mg, 67% yield). ESI MS m / z = 682.0 [M+H]+. Step 5

[0536] In a 20 mL vial equipped with a stir bar. methyl (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (72.6 mg, 0.11 mmol, 1.0 equiv) was dissolved in a mixture of 1,4-dioxane (1.6 mL) and water (0.5 mL). Lithium hydroxide (6.4 mg. 0.27 mmol, 2.5 equiv) was added and the reaction mixture was stirred overnight at room temperature. Upon complete conversion, as judged by LCMS analysis of the reaction mixture, the reaction was diluted with 4M aqueous hydrochloric acid. The acidified aqueous layers were extracted with DCM. The combined organic layers were passed through a phase separator and concentrated to afford (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid, which was used directly in the next step without further purification. ESI MS m / z = 666.1 [M-H]'. Step 6

[0537] In a 20 mL vial equipped with a stir bar, (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (71.1 mg, theoretical yield of Step 5) was combined with ammonium chloride (114.0 mg, 2.13 mmol, 20.0 equiv) in DMF (2.3 mL, 0.05M). Next, HATU (60.7 mg. 0.16 mmol, 1.5 equiv) was added, followed by DIPEA (148 pL, 0.85 mmol, 8.0 equiv). After 15 minutes, the reaction mixture was purified directly by RPHPLC to afford (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l, 2, 4-triazol-4-yl)phenyl)-l-(2 -methoxy ethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-7-fluoro-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (55.2 mg, 78% yield). ESI MS m / z = 667.4 [M+H]+.

[0538] PAGE 68 OF 152Docket No. 4014.1410 WO

[0539] The following compounds were prepared by a procedure analogous to that used for Example 16:

[0540] Example Stmcture ESI-MS

[0541] [M+H]+

[0542] 17 637.5

[0543] > z

[0544] J! / \°

[0545] [M+H]

[0546] / \ / \ o o / ==''+

[0547] 18 619.5

[0548] cr

[0549] 0 us

[0550] \ / /

[0551] z z z z——

[0552] / /

[0553] [M+H]+

[0554] 19

[0555] 667.5

[0556] Me-o I T [M+H]+

[0557] 20

[0558] J! L JL 1 663.7

[0559] rt-fyvvS

[0560] N^Z \ _ /

[0561] \ — ^*^ CF3

[0562] [M+H]+

[0563] 21

[0564] 615.7

[0565] XNX / =\ / N'TX]

[0566] M v AXX

[0567] |f< S!J ^NH2

[0568] [M+H]+

[0569] 22

[0570] 635.6

[0571] N^ / \ _ /

[0572]

[0573] PAGE 69 OF 152Docket No. 4014.1410 WO

[0574] Example 23: Synthesis of (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-fluoro-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazine-8-carboxamide.

[0575] 0

[0576] ,|L J*

[0577] ’N^\ N.

[0578] I N'

[0579] N^s /

[0580]

[0581] Step 1

[0582] Methyl 2-amino-3-bromo-5-fluorobenzoate (500 mg, 2.02 mmol, 1.0 eq), 4-(4-ethynylphenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (473 mg, 2.22 mmol, 1.1 eq), and PdC12(PPh3)2 (106 mg, 0.151 mmol, 0.075 eq.) were weighed into a vial with a stirbar, and THF (4.03 mL) was added, followed by the addition of TEA (4.21 mL, 30.2 mmol, 15 eq.). The vial was sealed and the reaction mixture was heated to 70 °C with stirring. After 3 hours, the reaction mixture was concentrated and the crude residue was purified by automated flash chromatography on silica gel (0-100% EtOAc in cyclohexane) to afford methyl 2-amino-3-((4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)ethynyl)-5-fluorobenzoate (112 mg, 73%). ESI MS m / z = 381.30 [M+H]+.

[0583] Step 2

[0584] Methyl 2-amino-3-((4-(l,3-dimethyl-5-oxo-L5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)ethynyl)-5-fluorobenzoate (112 mg, 0.294 mmol, 1.0 eq) was dissolved in MeCN (1.47 mL), and the solution was sparged with nitrogen for 2 minutes. PdCl2 (52.2 mg, 0.294 mmol, 1.0 eq.), was added, and sparging was continued for an additional minute. The vial was then sealed and the reaction mixture was heated to 85 °C with stirring. After 90 minutes the reaction mixture as concentrated and purified by automated reverse phase flash chromatography (0-100% MeCN in H2O) to afford methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-fluoro-lH-indole-7-carboxylate (98 mg, 88%). ESI MS m / z = 381.5 [M+H]+.

[0585] Step 3

[0586] Methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-fluoro-lH-ind ole-7 -carboxy late (50.0 mg, 0.131 mmol, 1.0 eq.) was dissolved in DMF (0.526 mL) and

[0587] PAGE 70 OF 152Docket No. 4014.1410 WO

[0588] CS2CO3 (107 mg, 0.329 mmol, 2.5 eq.) was added followed by the addition of iodoethane (0.021 mL. 0.263 mmol, 2.0 eq.) The reaction mixture was allowed to stir at room temperature for 18h. The reaction mixture was diluted with saturated aqueous ammonium chloride (3 mL), water (3 mL), and EtOAc (3 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 x 5 mL), washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by automated reverse phase flash chromatography (0-100% MeCN in H2O) to afford the pure product (35 mg, 88%). ESI MS m / z = 409.4 [M+H]+.

[0589] Step 4

[0590] Methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-fluoro-lH-indole-7-carboxylate (35 mg, 0.086 mmol, 1.0 eq.) was dissolved in a mixture of THF (0.29 mL), MeOH (0.29 mL), and water (0.29 mL) and LiOH·H2O (21 mg, 0.86 mmol, 10 eq.) was added. The reaction mixture was allowed to stir at room temperature for 18 hours, and then was acidified to pH ~2 with IM HC1, and diluted with water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3 x mL). and 10% MeOH in DCM (3 x 5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford crude 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-fluoro-1H-indole-7-carboxylic acid (ESI MS m / z = 395.4 [M+H]+), which was used in the next step without further purification.

[0591] Step 5

[0592] Methyl (S)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (84 mg, 4.6 eq. 0.41 mmol) was weighed into a vial with a stirbar and MeCN (0.887 mL) was added. Then the aforementioned crude 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-fluoro-lH-indole-7-carboxylic acid (35.0 mg, 0.887 mmol, 1.0 eq.) was added, followed by the addition of TCFH (37.3 mg, 0.133 mmol, 1.5 eq.) and 1-methylimidazole (0.424 mL, 0.532 mmol, 6.0 eq.) sequentially. The vial was then sealed the vial and the reaction mixture was heated to 85 °C with stirring. After 3 hours the reaction mixture was concentrated and the crude residue was purified by automated flash chromatography on silica gel (0-100% EtOAc in cyclohexane) to afford pure Methyl (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-fluoro-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b] [1,4]oxazine-8-carboxylate (21 mg, 41%). ESI MS m / z = 584.4 [M+H]+.

[0593] PAGE 71 OF 152Docket No. 4014.1410 WO

[0594] Step 6

[0595] Methyl (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-fluoro-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (21 mg, 0.036 mmol, 1.0 eq.) was dissolved in a mixture of THF (0.16 mL), MeOH (0.16 rnL), and water (0.16 mL) and LiOH·H2O (8.6 mg, 0.36 mmol, 10 eq.) was added. The reaction mixture was allowed to stir at room temperature for 60h and then was acidified to pH ~2 with IM HC1 and diluted with water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 5 mL), and 10% MeOH in DCM (3 x 5 rnL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford crude (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-fluoro-lH-indole-7-carbonyl)-2-methyl-3.4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (ESI MS m / z = 570.5 [M+H]+) which was used in the next step without further purification.

[0596] Step 7

[0597] The aforementioned crude (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-fluoro-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (25 mg. 0.044 mmol, 1.0 eq.) was dissolved in DMF (0.44 mL) and added ammonium chloride (4.7 mg, 0.088 mmol, 2.0 eq.), HATU (21 mg, 0.55 mmol, 1.25 eq.), and DIPEA (0.038 rnL, 0.22 mmol, 5.0 eq.) were added sequentially. The reaction mixture was allowed to stir at room temperature for 1 hour before being diluted with water and EtOAc. The biphasic mixture was concentrated and the residue was purified by reverse phase HPLC to afford the pure product (6.8 mg. 27%). ESI MS m / z = 569.6 [M+H]+.

[0598] Example 24: Synthesis of (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide.

[0599]

[0600] PAGE 72 OF 152Docket No. 4014.1410 WO

[0601] Step 1

[0602] A mixture of 4-(4-bromophenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (10.0 g, 37.3 mmol, 1.0 eq), TEA (11.3 g, 111.8 mmol, 3.0 eq), TMSA (4.8 g, 48.5 mmol, 1.3 eq), Pd(dppf)Cl2(2.7 g, 3.73 mmol, 0.1 eq) and Cui (0.7 g, 3.73 mmol, 0.1 eq) inTHF (100 mL) was stirred overnight at 75 °C under a nitrogen atmosphere. The resulting mixture was cooled to room temperature. The reaction mixture was then quenched with H2O (100 mL) and the aqueous layer was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 3: 1) to give 2,5-dimethyl-4-(4-((trimethylsilyl)ethynyl)phenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (8.0 g, 75.2%) as a brown oil. 'H NMR (400 MHz, DMSO-d6): 57.63 - 7.58 (m, 2H), 7.46 - 7.41 (m, 2H), 3.33 (s, 3H), 2.09 (s, 3H), 0.25 (s, 9H). ESI MS m / z = 286.1 [M+H]+.

[0603] Step 2

[0604] A mixture of 2,5-dimethyl-4-(4-((trimethylsilyl)ethynyl)phenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (8.0 g, 28.0 mmol, 1.0 eq) andTBAF (1.0 N, 47.6 mL, 47.6 mmol, 1.7 eq) in THF (80 mL) was stirred for overnight at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with H2O (80 mL) and extracted with EtOAc (200 mL x 3). Then the combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 3: 1) to give 4-(4-ethynylphenyl)-2,5-dimethyl-2,4-dihydro-3H-1.2.4-triazol-3-one (4.46 g. 74.6%) as a white solid. 'H NMR (300 MHz, DMSO-d6): 57.63 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 4.32 (s, 1H), 3.33 (s, 3H), 2.09 (s, 3H). ESI MS m / z = 214.1 [M+H]+.

[0605] Step 3

[0606] To a solution of 2-bromo-6-(trifluoromethyl)pyri din-3 -amine (25.0 g. 103.7 mmol, 1.0 eq) in MeOH (100 mL) was added Pd(dppf)Cl2(8.5 g, 10.4 mmol, 0.1 eq) and TEA(31.5 g, 311.2 mmol, 3.0 eq) under CO. The reaction mixture was stirred at 70 °C for 10 h. The solvent was removed by evaporation under reduced pressure. The mixture was diluted with water (50 mL) and extracted with EtOAc (200 mL). The organic phase was purified by silica gel column chromatography (petroleum ether: EtOAc = 10: 1) to give methyl 3-amino-6-(trifluoromethyl)picolinate (13.0 g, yield 56.9%) as a white solid. ’H NMR (400 MHz, CDCh): <57.55 (d, J= 8.8 Hz, 1H), 7.14 (d, J= 8.8 Hz, 1H), 6.10 (s, 2H), 3.98 (s, 3H).

[0607] PAGE 73 OF 152Docket No. 4014.1410 WO

[0608] Step 4

[0609] To a solution of methyl 3-amino-6-(trifluoromethyl)picolinate (13.0 g, 59.1 mmol, 1.0 eq) in acetonitrile (50 mL) was added NBS (15.8 g, 88.6 mmol, 1.5 eq) and Acetic Acid (3.5 g, 59.1 mmol, 1.0 eq), the reaction mixture was stirred at 80 °C for 17 h. LCMS showed ok. The mixture was diluted with water (50 mL) and extracted with EtOAc (200 mL). The organic phase was purified by silica gel column chromatography (petroleum ether: EtOAc = 8: 2) to give methyl 3-amino-4-bromo-6-(trifluoromethyl)picolinate (12.0 g, yield 67.9%) as a white solid.1H NMR (400 MHz, CDCh): b 7.87 (s, 1H), 6.69 (s, 2H), 3.98 (s, 3H).

[0610] Step 5

[0611] To a solution of methyl 3-amino-4-bromo-6-(trifluoromethyl)picolinate (12.0 g, 40.1 mmol, 1.0 eq) and 4-(4-ethynylphenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (10.3 g, 48.2 mmol, 1.2 eq) in THF (60 mL) was added Pd(dppf)C12 (3.3 g, 4.0 mmol, 0.1 eq), Cui (764.0 mg, 4.0 mmol, 0.1 eq) and TEA (12.2 g, 120.2 mmol, 3.0 eq) under N2, the reaction mixture was stirred at 80 °C for 3 h. The mixture was quenched by addition of water (50 mL) and extracted with EtOAc (200 mL). Upon concentration, the organic phase was purified by silica gel column chromatography (petroleum ether: EtOAc = 1: 2) to give methyl 3-amino-4-((4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)ethynyl)-6-(trifluoromethyl)picolinate (16.0 g, yield 92.4%) as a yellow oil. 'H NMR (400 MHz, CDCh): b 7.74 (s, 1H), 7.69 (d, J= 8.4 Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 3.98 (s, 3H), 3.49 (s, 3H), 2.20 (s, 3H).

[0612] Step 6

[0613] To a solution of methyl 3-amino-4-((4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)ethynyl)-6-(trifluoromethyl)picolinate (16.0 g, 37.1 mmol, 1.0 eq) in acetonitrile (100 mL) was added PdCh (656.0 mg, 3.7 mmol, 0.1 eq), the reaction mixture was stirred at 80 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to give methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylate (10.0 g, yield 62.5%) as a white solid. 'H NMR (400 MHz, CDCh): b 10.43 (s, 1H), 8.15 (s, 1H). 7.91 (d, J= 8.4 Hz, 2H). 7.50 (d, J= 8.4 Hz, 2H). 7.03 (s, 1H).

[0614] 4.13 (s, 3H), 3.51 (s, 3H), 2.23 (s, 3H).

[0615] Step 7

[0616] In a 40 mL vial equipped with a stir bar, methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylate (530 mg, 1.23 mmol, 1.0 equiv) and cesium carbonate (1.00 g, 3.07 mmol, 2.5 equiv) were added.

[0617] PAGE 74 OF 152Docket No. 4014.1410 WO

[0618] DMF (6.1 mL, 0.2 M) was added. To the reaction mixture, ethyl iodide (0.13 mL, 1.60 mmol, 1.3 equiv) was added dropwise. The reaction was heated to 80 °C for 24 h. After 24 h, the reaction was transferred to a separatory funnel and diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted 2X with EtOAc. The combined organic layers were concentrated and purified by silica gel column chromatography (0 to 5 % MeOH / DCM) to afford impure methyl 2-(4-(l,3-dimethyl-5-oxo-1.5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylate that was used in the next step as is. ESI MS m / z = 460.6 [M+H]+.

[0619] Step 8

[0620] In a 40 mL vial equipped with a stir bar, methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylate (1.23 mmol assuming full conversion in the first reaction, 1.0 equiv) was added. To the reaction vial, THF (4.1 mL), MeOH (4.1 mL), and 3M aqueous sodium hydroxide (4.1 mL, 10 equiv, total volume = 12.3 mL, 0.1 M) were added sequentially in that order. The reaction was stirred at room temperature for 5 h. After 5 h, the reaction was quenched with the addition of IM HC1 (aq) and extracted 3X with EtOAc. The combined organic layers were concentrated and purified by silica gel column chromatography (0 to 10 % MeOH / DCM) to afford 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylic acid (0.391 g, 0.877 mmol, 71% yield over two steps). ESI MS m / z = 446.5 [M+H]+.

[0621] Step 9

[0622] In a 2 mL microwave vial, 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylic acid (51.3 mg, 0.115 mmol, 1.0 equiv) was added. Next, MeCN (1.4 mL, 0.08 M) was added, followed by NMI (78 pL, 0.98 mmol, 8.5 equiv) and TCFH (48.5 mg, 0.173 mmol, 1.5 equiv). To the reaction mixture, methyl (S)-2-methyl-3,4-dihydro-2H-benzo[b][ 1,4]oxazine-8-carboxylate (95.5 mg, 0.461 mmol, 4 equiv) was added in a single portion and the reaction vial was sealed and heated to 120 ° C under microwave irradiation for 15 min. After 15 min, the reaction was cooled to room temperature and concentrated under nitrogen. The residue was taken up in DMF, filtered, and purified by RPHPLC to provide methyl (S)-4-(2-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)-1-ethyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate (58.0 mg, 0.091 mmol, 79% yield). ESI MS m / z = 635.7 [M+H]+.

[0623] PAGE 75 OF 152Docket No. 4014.1410 WO

[0624] Step 10

[0625] In an 8 mL vial equipped with a stir bar, methyl (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (58.0 mg. 0.091 mmol, 1.0 equiv) was added. To the reaction vial, THF (0.3 mL), MeOH (0.3 mL). and 3M aqueous sodium hydroxide (0.3 mL, 10 equiv, total volume = 0.9 mL, 0.1 M) were added sequentially in that order. The reaction was stirred at room temperature for 4 h. After 4 h, the reaction was quenched with the addition of IM HC1 (aq) and extracted 3X with EtOAc. The combined organic layers were concentrated to provide crude (S)-4-(2-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)-1-ethyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid. ESI MS m / z = 621.8 [M+H]+.

[0626] Step 11

[0627] In an 8 mL vial equipped with a stir bar, crude (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid was added. DMF (0.9 mL, 0.1 M) was added, followed by NH4CI (24.4 mg, 0.457 mmol, 5 equiv), HATU (52.1 mg, 0.137 mmol, 1.5 equiv), and N, N-diisopropylethylamine (80 pL, 0.457 mmol, 5 equiv). The reaction was stirred at room temperature for 3 h. After 3 h, the reaction was diluted with DMF. filtered, and purified by RPHPLC to provide (S)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (44.8 mg, 0.072 mmol, 79% yield). ESI MS m / z = 620.7 [M+H]+.

[0628] The following compounds were prepared by a procedure analogous to that used for Example 24:

[0629] Example Structure ESI-MS

[0630] F O

[0631] [M+Na]+

[0632] 25

[0633] O 660.4 YWWn

[0634] ' -SX^CF3

[0635]

[0636] PAGE 76 OF 152Docket No. 4014.1410 WO

[0637] [M+H]+

[0638] 26

[0639] 650.8

[0640] / [M+H]

[0641] 27 / z z—+

[0642] z z—

[0643] J kI. 552.5

[0644] O TZ

[0645] [M+H]+

[0646] 28 o — y V

[0647] Me. J K / / — v i 632.5

[0648] N- y / TI ’N z

[0649] I y— \ — c i i

[0650] \

[0651] Me

[0652]

[0653] Example 29: Synthesis of (R)-4-(2-(4-(l,3-dimethyl-5-oxo-L5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide.

[0654]

[0655] Step 1

[0656] In a 5 mL microwave vial, 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylic acid (122 mg, 0.274 mmol, 1.0 equiv) was added. Next, MeCN (3.4 mL, 0.08 M) was added, followed by NMI (0.19 mL, 2.33 mmol, 8.5 equiv) and TCFH (115 mg, 0.411 mmol, 1.5 equiv). To the reaction mixture, methyl 3-amino-2,6-difluorobenzoate (205 mg, 1.10 mmol, 4 equiv) was added in a single portion and the reaction vial was sealed and heated to 100 ° C under

[0657] PAGE 77 OF 152Docket No. 4014.1410 WO

[0658] microwave irradiation for 15 min. After 15 min, the reaction was cooled to room temperature and concentrated under nitrogen. The residue was taken up in DMF, filtered, and purified in batches by RPHPLC to provide methyl 3-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)-2,6-difluorobenzoate (139 mg, 0.226 mmol, 83% yield). ESI MS m / z = 615.9 [M+H]+.

[0659] Step 2

[0660] In an 8 mL reaction vial, methyl 3-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)-2,6-difluorobenzoate (40.9 mg, 0.067 mmol. 1.0 equiv) and cesium carbonate (65.1 mg, 0.200 mmol, 3 equiv) were added. DMF (1.3 mL, 0.05 M) was added. To the reaction, a solution of (?)-2-(trifluoromethyl)oxirane (11.5 mg, 0.10 mmol, 1.5 equiv) in 0.25 mL DMF was added dropwise. The reaction was heated to 55 °C in a heating block for 2 h. After 2 h, the reaction was cooled to room temperature, filtered, and purified directly by RPHPLC to provide methyl (J?)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-L2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (31.6 mg, 0.045 mmol, 67% yield). ESI MS m / z = 707.9 [M+H]+.

[0661] Step 3:

[0662] In an 8 mL vial equipped with a stir bar, methyl (7?)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (31.6 mg, 0.045 mmol, 1.0 equiv) was added. To the reaction vial, THF (0.2 mL), MeOH (0.2 mL), and 3M aqueous sodium hydroxide (0.2 mL, 10 equiv, total volume = 0.6 mL, 0.07 M) were added sequentially in that order. The reaction was stirred at room temperature for 3 h. After 3 h, the reaction was quenched with the addition of IM HC1 (aq) and extracted 3X with EtOAc. The combined organic layers were concentrated to provide (7?)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid that was used in the next step without further purification. ESI MS m / z = 693.8 [M+H]+.

[0663] Step 4:

[0664] In an 8 mL vial equipped with a stir bar, crude (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2-(trifluoromethyl)-3,4-dihydro-2H-benzo[b] [ 1,4]oxazine-8-carboxylic

[0665] PAGE 78 OF 152Docket No. 4014.1410 WO

[0666] acid was added. DMF (0.5 mL, 0.1 M) was added, followed by NH4CI (12.0 mg, 0.224 mmol, 5 equiv), HATU (25.5 mg, 0.067 mmol, 1.5 equiv), and N. N-diisopropylethylamine (39 pL, 0.224 mmol, 5 equiv). The reaction was stirred at room temperature for 1 h. After 1 h, the reaction was diluted with DMF, filtered, and purified by RPHPLC to provide (R)-4-(2-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)-1-ethyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2-(trifluoromethyl)-3,4-dihydro-2H-

[0667] benzo[b][1,4]oxazine-8-carboxamide (8.1 mg, 0.012 mmol, 26% yield). ESI MS m / z = 692.6

[0668] \ / \O°

[0669] [M+H]+.

[0670] The following compounds were prepared by a procedure analogous to that used for Example 29:

[0671] Example Structure ESI-MS

[0672] F O

[0673] [M+Na]+

[0674] 30 z z—

[0675] /

[0676] 696.5

[0677] N^Z \ _ /

[0678] 0

[0679] rjz5^p ^NH2

[0680] Ss^s,o [M+H]+

[0681] 31 O - - 1

[0682] _CF3

[0683] Me. JI _ _ 1 674.3

[0684] N " A

[0685] 1, N— V ') I

[0686] \ — CF3

[0687] Me

[0688] [M+H]+

[0689] 32

[0690] 656.4

[0691]

[0692] Example 33: Synthesis of (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lEI-indole-7-carbonyl)-3-methyl-3.4-dihydro-2H-benzo|b]Ll,4]oxazine-8-carboxamide.

[0693] PAGE 79 OF 152Docket No. 4014.1410 WO

[0694]

[0695] Step 1

[0696] In a 40 mL vial equipped with a stir bar, methyl 3-bromo-2 -hydroxybenzoate (560 mg. 1.0 equiv.) and tert-butyl (R)-(l-hydroxypropan-2-yl)carbamate (467 mg, 1.1 equiv.) and triphenyl phosphine (954 mg, 1.5 equiv.) were combined neat and followed by added dry THF (9.7 mL) under nitrogen. The solution was cooled in an ice / water bath prior to the addition of DIAD (0.7 mL, 1.5 equiv.). Then, the ice bath was removed, and the reaction mixture was stirred at rt for 120 min. Volatiles were removed under vacuum and the crude was redissolved in ethyl acetate and washed with water. The aqueous layer was further washed with ethyl acetate (x2). Combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum. The crude reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (0 to 50% EA / cHex) to afford methyl (R)-3-bromo-2-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate (875 mg, 93% yield). ESI MS m / z = 410.2, 412.1 [M+Na]+.

[0697] Step 2

[0698] In a 20 mL vial equipped with a stir bar, methyl (R)-3-bromo-2-(2-((tert-butoxycarbonyl)amino)propoxy)benzoate (875 mg, 1.0 equiv.) was taken, followed by added HC1 (8.4 mL, 15 equiv., 4N in dioxane). The reaction mixture was stirred for 30 min at rt. Reaction progress was monitored using LC-MS. Volatiles were removed under vacuum and crude was used directly in the next step. ESI MS m / z = 288.0, 290.0 [M+H]+.

[0699] Step 3

[0700] In a 20 mL reaction vial equipped with a stir bar, 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid (400 mg, 1 equiv.), methyl (R)-2-(2-aminopropoxy)-3-bromobenzoate hydrochloride (301 mg, 1.1 equiv.) andHATU (449 mg, 1.4 equiv., CAS #: 148893-10-1) were combined neat, followed by addition of DMF (4.2 mL). DIPEA (0.88 mL, 6.0 equiv.) was added dropwise and reaction mixture was stirred for 120 min at rt. Reaction progress was monitored

[0701] PAGE 80 OF 152Docket No. 4014.1410 WO

[0702] using LC-MS. Reaction mixture was directly loaded into 150 G C18 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford methyl (R)-3-bromo-2-(2-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-L2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxamido)propoxy)benzoate (541 mg, 86% yield). ESI MS m / z = 745.2, 747.2 [M+H]+.

[0703] Step 4

[0704] In a 8 mL reaction vial equipped with a stir bar, methyl (R)-3-bromo-2-(2-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxamido)propoxy)benzoate (150 mg, 1.0 equiv.), CS2CO3 (131 mg, 2.0 equiv.), Pd2dba3 (5.5 mg, 0.03 equiv., CAS# 51364-51-3), xantphos (10.5 mg, 0.09 equiv., CAS# 161265-03-8), were combined neat, followed by addition of dry 1,4-Dioxane (1 mL). The reaction mixture was evacuated and backfilled with nitrogen 3 times. Then the reaction mixture was heated at 100 °C in a heating block for 20 hours. Reaction progress was monitored using LC-MS. Reaction mixture was concentrated under vacuum and dissolved in 2.0 mL of DMSO and purified by reversed phase flash chromatography using 50G gold C 18 column ( 10 to 100% acetonitrile / water) to afford methyl (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (93 mg, 70% yield). ESI MS m / z = 664.2 [M+H]+.

[0705] Step 5

[0706] In a 8 mL vial equipped with a stir bar, methyl (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H- 1,2,4-triazol-4-y l)pheny 1)- 1 -(2-methoxy ethyl)-5-(trifluoromethy 1)- lH-indole-7-carbony 1)-3-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (93 mg, 1.0 equiv.) was dissolved MeOH (1.4 mL) and THF (1.4 mL). followed by addition of NaOH (0.35 mL, 10 equiv., 4M solnin water). The reaction mixture was stirred at 50 °C in a heating block for Ih. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was quenched by 3N HC1. Then the crude mixture was diluted with water and extracted with ethyl acetate (x3). Combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum to afford (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[b] [1,4]oxazine-8-carboxylic acid. ESI MS m / z = 650.2 [M+H]+. The crude was transferred to the next reaction without any further purification.

[0707] PAGE 81 OF 152Docket No. 4014.1410 WO

[0708] Step 6

[0709] In a 4 mL vial equipped with a stir bar (R)-4-(2-(4-(L3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (20 mg, 1.0 equiv.), NHiCI (16 mg, 10.0 equiv.) andHATU (16 mg, 1.4 equiv., CAS #: 148893-10-1) were combined neat and followed by addition of dry DMF (0.6 mL) at room temperature. Then, DIPEA (21 pL, 4.0 equiv.) was added, and reaction mixture was stirred for 30 min at room

[0710] z z

[0711] temperature. Reaction progress was monitored using LC-M^ / \ oS. The reaction mixture was >)U <o=

[0712] O! IZ M—

[0713] filtered through 0.45 pM Syringe filter and filtrate was purified through RPHPLC to afford (R)-4-(2-(4-( 1,3 -dimethyl-5 -oxo- 1,5-dihy dro-4H- 1,2,4 OCA

[0714] ^. Z --triazol-4-yl)phenyl)- 1 -(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (13.5 mg, 68% yield). ESI MS m / z = 649.2 [M+H]+. or

[0715] The following compounds were prepared by a procedure analogous to that used for z z— Example 33: /

[0716] Example Structure ESI-MS

[0717] [M+H]+

[0718] 34 649.2

[0719]

[0720] Example 35: Synthesis of (R)-4-(2-(4-(I,3-dimethyl-5-oxo-l,5-dihydro-4H-I,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[b] [ 1,4] oxazine-8-carboxamide.

[0721]

[0722] Step 1

[0723] In a 20 mL reaction vial equipped with a stir bar, 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H- I,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylic

[0724] PAGE 82 OF 152Docket No. 4014.1410 WO

[0725] acid (135 mg, 1 equiv.), methyl (R)-2-(2-aminopropoxy)-3-bromobenzoate hydrochloride (128 mg, 1.3 equiv.) and HATU (161 mg, 1.4 equiv., CAS #: 148893-10-1) were combined neat, followed by addition of DMF (1.5 mL). DIPEA (0.32 mL, 6.0 equiv.) was added dropwise and reaction mixture was stirred for 60 min at rt. Reaction progress was monitored using LC-MS. Reaction mixture was directly loaded into 50 G Cl 8 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford methyl (R)-3-bromo-2-(2-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2.4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)propoxy)benzoate (200 mg, 92% yield). ESI MS m / z = 715.6, 717.6 [M+H]+.

[0726] Step 2

[0727] In a 8 mL reaction vial equipped with a stir bar, methyl (R)-3-bromo-2-(2-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)propoxy)benzoate (200 mg, 1.0 equiv.), CS2CO3 (182 mg, 2.0 equiv.), Pd₂dba₃ (7.7 mg, 0.03 equiv., CAS# 51364-51-3), xantphos (14.6 mg, 0.09 equiv., CAS# 161265-03-8), were combined neat, followed by addition of dry 1,4-Dioxane (1.1 mL). The reaction mixture was evacuated and backfilled with nitrogen 3 times. Then the reaction mixture was heated at 100 °C in a heating block for 20 hours. Reaction progress was monitored using LC-MS. Reaction mixture was concentrated under vacuum to afford methyl (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-3-methyl-3.4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate. ESI MS m / z = 635.7 [M+H]+. The crude was moved forward to the next reaction without any purification.

[0728] Step 3

[0729] In a 8 mL vial equipped with a stir bar, methyl (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (177 mg, 1.0 equiv.) was dissolved MeOH (1.1 mL) and THF (1.1 mL), followed by addition ofNaOH (0.7 mL, 10 equiv., 4M solnin water). The reaction mixture was stirred at 50 °C in a heating block for Ih. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was quenched by 3N HC1. Then the crude mixture was diluted with water and extracted with ethyl acetate (x3). Combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum and dissolved in 2.0 mL of DMSO and purified by reversed phase flash chromatography using 50G gold C18 column (10 to 100% acetonitrile / water) to afford (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-

[0730] PAGE 83 OF 152Docket No. 4014.1410 WO

[0731] yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (128 mg. 74% yield). ESI MS m / z = 619.6 [M+H]+.

[0732] Step 4

[0733] In a 4 mL vial equipped with a stir bar (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (20 mg, 1.0 equiv.), NEUCl (17 mg, 10.0 equiv.) and HATU (17 mg, 1.4 equiv., CAS #: 148893-10-1) were combined neat and followed by addition of dry' DMF (0.64 mL) at room temperature. Then, DIPEA (22 pL, 4.0 equiv.) was added, and reaction mixture was stirred for 30 min at room temperature. Reaction progress was monitored using LC-MS. The reaction mixture was filtered through 0.45 pM Syringe filter and filtrate was purified through RPHPLC to afford (R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (16.8 mg, 84% yield). ESI MS m / z = 620.9 [M+H]+.

[0734] The following compounds were prepared by a procedure analogous to that used for Example 35:

[0735]

[0736] PAGE 84 OF 152Docket No. 4014.1410 WO

[0737] Example 39: Synthesis of (2S,3R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide.

[0738] Y O

[0739] N

[0740]

[0741] Step 1

[0742] To tert-butyl ((2R,3R)-3-hydroxybutan-2-yl)carbamate (418 mg, 1.1 eq, 2.21 mmol, CAS # 2061909-56-4), methyl 3-bromo-6-fluoro-2-hydroxybenzoate (500 mg. 1 eq. 2.01 mmol), and triphenylphosphine (790 mg, 1.5 eq, 3.01 mmol) in THF (8.03 mL) was added DIAD (586 pL. 1.5 eq, 3.01 mmol) dropwise at 0 °C. The reaction was warmed to room temperature and stirred for 2 hours. Upon complete conversions (monitored by LCMS), the reaction was concentrated and directly subjected to column chromatography to provide methyl 3-bromo-2-(((2S,3R)-3-((tert-butoxycarbonyl)amino)butan-2-yl)oxy)-6-fluorobenzoate (600 mg, 1.43 mmol, 71.1 %). ESI MS m / z = 442.3 [M+Na]+.

[0743] Step 2

[0744] To methyl 3-bromo-2-(((2S,3R)-3-((tert-butoxycarbonyl)amino)butan-2-yl)oxy)-6-fluorobenzoate (600 mg, 1 eq, 1.43 mmol) was added 4 N HC1 in dioxanes (7.14 mL, 4 molar, 20 eq, 28.6 mmol). The reaction was stirred for 30 min then concentrated to provide methyl 2-(((2S,3R)-3-aminobutan-2-yl)oxy)-3-bromo-6-fluorobenzoate hydrochloride (500 mg, 1.40 mmol, 98.2 %), which was used directly in subsequent step. ESI MS m / z = 320.2 [M+H]+.

[0745] Step 3

[0746] To 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylic acid (100 mg, 1 eq, 225 pmol), methyl 2-(((2S,3R)-3-aminobutan-2-yl)oxy)-3-bromo-6-fluorobenzoate hydrochloride (88.1 mg, 1.1 eq, 247 pmol), and HATU (120 mg, 1.4 eq, 314 pmol) in DMF (1.12 mL) was added iPnNEt (232 mg, 313 pL, 8 Eq, 1.80 mmol). The reaction was stirred for 10 minutes and then quenched with 1 N HC1 and extracted with 10% MeOH in DCM. The combined organic layers were concentrated and the residue was directly subjected to column chromatography to

[0747] PAGE 85 OF 152Docket No. 4014.1410 WO

[0748] provide methyl 3-bromo-2-(((2S,3R)-3-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)butan-2-yl)oxy)-6-fluorobenzoate (168 mg, 225 pmol, 100 %). ESI MS m / z = 747.5 [M+H]+.

[0749] Step 4

[0750] To a vial containing methyl 3-bromo-2-(((2S,3R)-3-(2-(4-(l,3-dimethyl-5-oxo-1.5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)butan-2-yl)oxy)-6-fluorobenzoate (168 mg, 1 eq, 225 pmol), XantPhos Pd G3 (10.7 mg, 0.05 eq, 11.2 pmol), and cesium carbonate (146 mg, 2 eq, 449 pmol) was added 1,4-Dioxane (1.12 mL). The solution was degassed and backfilled with N2. The reaction mixture was then heated to 100 °C and stirred overnight. Upon completion, the reaction was diluted with H2O and extracted with 10% MeOH in DCM. The combined organic layers were concentrated and the residue was directly subjected to column chromatography to provide methyl (2S,3R)-4-(2-(4-( 1,3 -dimethy 1-5-oxo- 1,5 -dihy dro-4H- 1,2,4-triazol-4-yl)pheny 1)- 1 -ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-dihydro-2H-benzo|b]Ll,4]oxazine-8-carboxylate (133 mg, 200 pmol, 88.8 %). ESI MS m / z = 667.4 [M+H]+.

[0751] Step 5

[0752] To methyl (2S,3R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (133 mg, 1 Eq, 200 pmol) in THF (998 pL), MeOH (499 pL), and H2O (499 pL) was added lithium hydroxide hydrate (83.7 mg, 10 Eq, 2.00 mmol). The mixture was stirred until complete conversion observed by LCMS. The reaction was quenched with 1 N HC1 and extracted with 10% MeOH in DCM. The combined organic layers were concentrated and the residue was directly subjected to column chromatography to provide(2S,3R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (100 mg, 153 pmol, 76.8 %), which was used directly in subsequent step. ESI MS m / z = 653.5 [M+H]+. Step 6

[0753] To (2S,3R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (100 mg, 1 eq, 153 pmol), 3-bromo-2-(((2S,3R)-3-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-

[0754] PAGE 86 OF 152Docket No. 4014.1410 WO

[0755] (trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)butan-2-yl)oxy)-6-fluorobenzoic acid (112 mg, 1 eq, 153 pmol), and HATU (75.7 mg, 1.3 eq, 199 pmol) in DMF (1.53 mL) was added iPnNEt (0.13 mL, 5 Eq, 766 pmol). The reaction was stirred at room temperature and upon completion, the mixture was directly subjected to purification by reverse-phase HPLC to afford (2S,3R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (20 mg, 31 pmol, 20 %). ESI / Z Z—

[0756] MS m / z = 652.5 [M+H]+. z z—

[0757] J k! J k!.. J / g

[0758] / \ \ if °

[0759] The following compounds were prepared by a procedure analogous to that used for Example 39:

[0760] / \ o='

[0761] T I

[0762] Example Str^ yu*c^^***zture ESI-MS

[0763] ° / =\ /

[0764] 0

[0765] Q Q r- \ \ J - \ / \ / / / [M+H]

[0766] 40 z z z z——+

[0767] / / ZE

[0768] 634.2

[0769] [M+H]+

[0770] 41

[0771] 634.2

[0772] [M+H]+

[0773] 42

[0774] 634.2

[0775] [M+H]+

[0776] 43

[0777] 634.2

[0778]

[0779] PAGE 87 OF 152Docket No. 4014.1410 WO o

[0780] zCv

[0781] O 1 1 ZC) [M+H]+

[0782] — v ] 664.2

[0783] XN-\ / =\ / V

[0784] V W ' vUS^x^CF3

[0785] X

[0786] z z X [M+H]+

[0787] * *

[0788] V J i*

[0789] J < C_ A / 0 \ / \ -° °o3=-682.2

[0790] 50OXCH “- / \ / \ o o==''

[0791] ^Z.

[0792] ^Y A

[0793] [M+H]+

[0794] z z \! \ / l /

[0795] z z—— 700.2

[0796] / /

[0797] sX"

[0798] [M+H]

[0799] 0 — 1 1+XNX / =\ XAN 718.2

[0800] NV V-TAXA

[0801] ' r

[0802] F— I

[0803] F

[0804] ( / ” [M+Na]+

[0805] 0 - J 670.7

[0806] XN--A _ff~

[0807] NV \= / AJLJL ^CF,

[0808] 0

[0809] l<^pXNH2

[0810] <^0 [M+H]+

[0811] » vxS 646.9 N--A / " A / SfX

[0812] NV \= / AJl JL

[0813]

[0814] PAGE 88 OF 152Docket No. 4014.1410 WO o

[0815] [M+Na]+

[0816] 50

[0817] 668.7

[0818] NSa / N— e \ _ ' / ) — c _ _ IL

[0819] I

[0820] / z >

[0821] z z— [M+Na]+

[0822] 51 J k!

[0823] 670.7

[0824] 0 / \ o=

[0825] p [M+H]+

[0826] 52

[0827] _ _ % 600.7

[0828] z z— \ / / z

[0829] /

[0830] [M+H]+

[0831] 53

[0832] 618.7

[0833]

[0834] Example 54: Synthesis of (2aS,8aR)-8-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)- 2,2a,8,8a-tetrahydro-lH-benzo[b]cyclobuta[e][l,4]oxazine-4-carboxamide.

[0835]

[0836] Step 1

[0837] Tert-butyl ((lR,2S)-2-hydroxycyclobutyl)carbamate (25 mg, 1.0 eq. 0.13 mmol) was dissolved in THF (0.67 mL) and the resultant solution was cooled to 0 °C. NaH (60% Wt. in

[0838] PAGE 89 OF 152Docket No. 4014.1410 WO

[0839] mineral oil, 11 mg, 0.27 mmol, 2.0 eq.) was added, and the reaction mixture was allowed to stir at that temperature for 1 hour. After this time the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for an additional hour at room temperature before it was re-cooled to 0 °C, and tert-butyl 3-bromo-2-fluorobenzoate (37 mg, 0.13 mmol, 1.0 eq.) was added. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 18h. After this time, the reaction was quenched with saturated aqueous ammonium chloride, and was diluted with water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, fdtered and concentrated. The crude residue was purified by automated flash chromatography on silica gel (0-60% DCM in cyclohexane) to afford the pure product (31 mg, 52%). ESI MS m / z = 466.5 [M+Na].

[0840] Step 2

[0841] Tert-butyl 3-bromo-2-((lS,2R)-2-((tert-butoxycarbonyl)amino)cyclobutoxy)benzoate (31 mg, 0.070 mmol. 1.0 eq.) was suspended in t-BuOAc (1.4 mL). Concentrated sulfuric acid (0.019 mL, 0.35 mmol, 5.0 eq.) was then added at room temperature. All solids dissolved upon addition of sulfuric acid and the mixture became homogeneous. The reaction mixture was allowed to stir at room temperature for 4 hours, after which time the reaction mixture was neutralized by the dropwise addition of saturated aqueous sodium bicarbonate until gas evolution ceased. The neutralized reaction mixture was diluted with water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc ( x 5 mL). and the combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the crude carboxylic acid which was used in the next step without further purification. ESI MS m / z = 342.5 [M+H]+.

[0842] Step 3

[0843] Tert-butyl 2-((lS,2R)-2-aminocyclobutoxy)-3-bromobenzoate (23.0 mg, 0.0672 mmol, 1.0 eq.) was dissolved in DMF (0.672 mL) and 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxylic acid (32.9 mg, 0.0739 mmol 1.1 eq ), HATU (31.9 mg. 0.084 mmol, 1.25 eq.), and DIPEA (0.0585 mL, 336 mmol, 5.0 eq.) were added sequentially. The reaction mixture was allowed to stir for 90 minutes at room temperature. After this time the reaction mixture was directly purified by automated reverse phase flash chromatography (0-100% MeCN in ELO) to afford pure tertbutyl 3-bromo-2-((lS,2R)-2-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)cyclobutoxy)benzoate (28 mg, 54%). ESI MS m / z = 769.9 [M+H]+.

[0844] PAGE 90 OF 152Docket No. 4014.1410 WO

[0845] Step 4

[0846] Tert-butyl 3-bromo-2-(( 1 S,2R)-2-(2-(4-( 1.3-dimethyl-5-oxo- 1,5-dihy dro-4H- 1.2.4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)cyclobutoxy)benzoate (28 mg, 0.036 mmol, 1.0 eq.) was combined with CS2CO3 (24 mg, 0.073 mmol, 2.0 eq.), Pd2(dba)s (1.2 mg, 0.0018 mmol, 0.05 eq.) and XantPhos (3.2 mg, 0.0055 mmol, 0.15 eq.) in a vial with a stirbar, and 1,4-dioxane (0.50 mL) was added. The resultant suspension was sparged with nitrogen gas for 3 minutes. The vial was then sealed and the reaction mixture was heated to 95 °C with stirring for 18h. After this time, the reaction mixture was concentrated and the crude residue was purified by automated reverse phase flash chromatography (0-100% MeCN in H2O) to afford pure tert-butyl (2aS.8aR)-8-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2,2a,8,8a-tetrahydro-lH-benzo[b]cyclobuta[e][l,4]oxazine-4-carboxylate (16 mg, 64%). ESI MS m / z = 690.1 [M+H]+.

[0847] Step 5

[0848] Tert-butyl (2aS,8aR)-8-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2,2a,8,8a-tetrahydro-lH-benzo [b]cyclobuta[e][l, 4] oxazine-4-carboxy late (16 mg, 0.0232 mmol, 1.0 eq.) was dissolved in DCM (0.47 mL) and TFA (0.027 mL, 0.348 mmol, 15 eq.) was added. The reaction mixture was allowed to stir at room temperature for 90 minutes, and was then concentrated in vacuo to afford crude (2aS,8aR)-8-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2,2a.8.8a-tetrahydro-lH-benzo[b]cyclobuta[e][L4]oxazine-4-carboxylic acid which was used in the next step without further purification. ESI MS m / z = 634.2 [M+H]+. Step 6

[0849] The aforementioned crude (2aS,8aR)-8-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2,2a,8,8a-tetrahydro-lH-benzo[b]cyclobuta[e][l,4]oxazine-4-carboxylic acid (15 mg, 0.024 mmol, 1.0 eq.) was combined with ammonium chloride (2.5 mg, 0.047 mmol, 2.0 eq) and HATU (11 mg, 0.028 mmol, 1.2 eq.) in a vial with a stirbar and DMF (0.24 mL) was added. DIPEA (0.021 mL. 0.12 mmol, 5 eq.) was then added and the reaction mixture was allowed to stir at room temperature for Ih. After this time, the reaction mixture was diluted with water and EtOAc. The biphasic mixture was concentrated and the residue was purified by reverse

[0850] PAGE 91 OF 152Docket No. 4014.1410 WO

[0851] phase HPLC to obtain pure (2aS,8aR)-8-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2,2a,8,8a-tetrahydro-lH-benzo[b]cyclobuta[e][l,4]oxazine-4-carboxamide (12.2 mg, 81%). ESI MS m / z = 633.1 [M+H]+.

[0852] Example 55: Synthesis of (2S,3R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol- 4-yl)phenyl)-l-ethyl-5-methyl-lEI-pyrrolo[2,3-c]pyridine-7-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide.

[0853]

[0854] Step 1

[0855] To a solution of methyl 3-amino-6-chloropicolinate (5.00 g, 1 Eq, 26.8 mmol) in DMF (80 rnL), NBS (5.72 g, E2 Eq, 32.2 mmol) was added at 0 °C. The solution was warmed up to RT overnight. The crude solution was poured into ice water (100 mL), and yellow solid precipitated. The solid was collected through filtration, washed with water and dried over vacuum to yield methyl 3-amino-4-bromo-6-chloropicolinate (5.0 g, 19 mmol, 70 %). ESI MS m / z = 265.3 [M+H]+.

[0856] Step 2

[0857] Under N2 atmosphere, to a solution of 4-(4-ethynylphenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (4.63 g, 1.2 Eq, 21.7 mmol), methyl 3-amino-4-bromo-6-chloropicolinate (4.80 g, 1 Eq, 18.1 mmol) and bis-(triphenylphosphino)-palladous chloride (1.27 g, 0.10 Eq, 1.81 mmol) in THF (60 mL) was added triethylamine (5.49 g, 7.56 mL, 3 Eq, 54.2 mmol). The mixture was stirred at 70 °C over 2 hrs. The crude mixture was filtered through celite. concentrated, and purified with silica gel column chromatography to yield methyl 3-amino-6-chloro-4-((4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)ethynyl)picolinate (2.3 g, 5.8 mmol, 32 %). ESI MS m / z = 398.3 [M+H]+.

[0858] PAGE 92 OF 152Docket No. 4014.1410 WO

[0859] Step 3

[0860] A suspension of methyl 3-amino-6-chloro-4-((4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)ethynyl)picolinate (2.30 g, 1 Eq, 5.78 mmol) and palladium chloride (1.23 g, 361 pL, 1.2 Eq, 6.94 mmol) in acetonitrile (30 mL) was heated to 90 °C over 2 hrs. The crude was filtered through celite, concentrated and used directly in the next step. ESI MS m / z = 398.3 [M+H]+.

[0861] Step 4

[0862] The crude from step 3 (600 mg, 1 Eq, 1.5 mmol) was dissolved in DMF (10 mL). lodoethane (706 mg, 364 pL, 3.0 Eq, 4.52 mmol) and cesium carbonate (1.97 g, 4.0 Eq, 6.03 mmol) was added, and the mixture was heated to 50 °C over 2 hrs. The crude was filtered though celite, diluted with EtOAc and washed with water. The resulting organic layer was dried, concentrated and purified over silica gel column chromatography to yield methyl 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-lH-pyrrolo[2,3-c]pyridine-7-carboxylate (0.35 g, 0.82 mmol, 54 %). ESI MS m / z = 426.3 [M+H]+.

[0863] Step 5

[0864] Under N2 atmosphere, tetramethyltin (IV) (286 mg, 221 pL, 4 Eq, 1.60 mmol) was added to a suspension of methyl 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-lH-pyrrolo[2,3-c]pyridine-7-carboxylate (170 mg, 1 Eq, 399 pmol) and bis-(triphenylphosphino)-palladous chloride (56.0 mg, 0.2 Eq, 79.8 pmol) in DMF (1 mL). The mixture was heated at 130 °C over 30 min. The crude was filtered through celite, concentrated and purified over silica gel column chromatography to yield methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-methyl-lH-pyrrolo[2,3-c]pyridine-7-carboxylate (123 mg, 303 pmol, 76.0 %). ESI MS m / z = 406.9 [M+H]+.

[0865] Step 6

[0866] LiOH (71.5 mg, 10 Eq, 2.98 mmol) was added to the suspension of methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-methyl-lH-pyrrolo[2,3-c]pyridine-7-carboxylate (121 mg, 1 Eq, 298 pmol) in THF (1 mL) MeOH (0.5 mL) and Water (0.5 mL). The mixture was stirred overnight at RT. HC1 (IM. 3 mL) was added to adjust the pH to 1, and the mixture was extracted with EtOAc. The combined organic layer was dried, concentrated and used directly in the next step.

[0867] Step 7

[0868] DIPEA (0.13 g, 0.17 mL, 4.0 Eq, 0.98 mmol) was added to a mixture of 2-(4-(l,3-dimethyl-5-oxo- 1,5-dihydro-4H- 1,2,4-triazol-4-yl)phenyl)- 1 -ethyl-5-methyl-lH-pyrrolo[2,3-c]pyridine-7-carboxylic acid (96 mg, 1 Eq, 0.25 mmol), methyl 2-(((2S,3R)-3-aminobutan-2-

[0869] PAGE 93 OF 152Docket No. 4014.1410 WO

[0870] yl)oxy)-3-bromobenzoate hydrochloride (83 mg, 1.0 Eq, 0.25 mmol) andHATU (0.14 g, 1.5 Eq. 0.37 mmol). The mixture was stirred over 1 hr, and then concentrated and purified over silica gel column chromatography to yield methyl 3-bromo-2-(((2S,3R)-3-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-methyl-lH-pyrrolo[2,3-c]pyridine-7-carboxamido)butan-2-yl)oxy)benzoate (104 mg, 154 pmol, 63 %). ESI MS m / z = 677.2 [M+H]+.

[0871] Step 8

[0872] Under N2 atmosphere, a suspension of methyl 3-bromo-2-( * z( I(2S,3R)-3-(2-(4-(l,3-dimethyl-5- p ( OZ^—

[0873] \ / \ < D

[0874] oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-methyl-lEI-pyrrolo[2,3-c]pyridine-7-carboxamido)butan-2-yl)oxy)benzoate (104 mg / \ o,=' 1 Eq, 154 pmol), Xantphos Pd G3 (29.2 mg, 0.2 Eq, 30.8 pmol) and cesium carbonate (150 mg, 3 Eq, 462 pmol) in dioxane (1 mL) was heated at 100 °C overnight. The mixture was filtered through celite, concentrated and 0

[0875] purified over silica gel column chromatography to yield methyl (2S,3R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H / -l z z—,2,4-triazol-4-yl)phenyl)-l-ethyl-5-methyl-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (71 mg, 0.12 mmol, 78 %). ESI MS m / z = 596.5 [M+H]+.

[0876] Step 9

[0877] Under N2 atmosphere, a solution ofNaHMDS (91 pL, 1.0 molar, 3.0 Eq, 91 pmol) in THF was added to a solution of methyl (2S.3R)-4-(2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-5-methyl-lH-pynolo[2,3-c]pyridine-7-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (18 mg, 1 Eq, 30 pmol) and borane ammonia complex (1.2 mg, 1.3 Eq, 39 pmol) in THF (1 mL). The solution was stirred at RT over 15 mins, quenched with MeOH and purified over reverse phase HPLC to yield the title compound (5.7 mg, 9.8 pmol. 32%). ESI MS m / z = 581.3 [M+H]+.

[0878] The following compound was prepared by a procedure analogous to that used for Example 55:

[0879] Example Structure ESI-MS

[0880] [M+H]+

[0881] 56

[0882] 598.77

[0883]

[0884] PAGE 94 OF 152Docket No. 4014.1410 WO

[0885] Example 57: Synthesis of (2S,3R)-4-(5-cyclopropyl-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro- 4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)-2,3-dimethyl- 3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide.

[0886] o

[0887]

[0888] Step 1

[0889] Under N2 atmosphere, a suspension of methyl 5-chloro-2-(4-(l,3-dimethyl-5-oxo-1.5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-lH-pyrrolo[2,3-c]pyridine-7-carboxylate (80 mg, 1 Eq, 0.19 mmol), cyclopropylboronic acid (24 mg, 1.5 Eq, 0.28 mmol), PdC12(dppf) (14 mg, 0.1 Eq, 19 pmol) and tripotassium phosphate (0.12 g, 3 Eq, 0.56 mmol) in dioxane (1 mL) was heated at 100 °C overnight. The mixture was fdtered through celite. concentrated and purified over silica gel column chromatography to yield methyl 5-cyclopropyl-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-lEI-pyrrolo[2,3-c]pyridine-7-carboxylate (81 mg, 0.19 mmol, 100 %). ESI MS m / z = 433.1 [M+H]+The procedures for step 2 through step 5 are analogous to step 6 through step 9 for Example 55, and 4.1 mg of the title compound was obtained as a white powder. ESI MS m / z = 607.3 [M+H]+.

[0890] The following compound was prepared by a procedure analogous to that used for Example 57:

[0891]

[0892] PAGE 95 OF 152Docket No. 4014.1410 WO

[0893] Example 59: Synthesis of (2S,3R)-4-(5-(3,3-difluoroazetidin-l-yl)-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-lH-pyrrolo[2,3-c]pyridine-7-carbonyl)- 2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide.

[0894]

[0895] Step 1

[0896] Under N2 atmosphere, a suspension of methyl 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-lH-pyrrolo[2,3-c]pyridine-7-carboxylate (80 mg, 1 Eq, 0.19 mmol), 3, 3 -difluoroazetidine hydrochloride (36 mg. 1.5 Eq. 0.28 mmol), cesium carbonate (0.18 g, 3 Eq, 0.56 mmol) and XPhos Pd G4 (16 mg, 0.1 Eq, 19 pmol) was heated at 100 °C overnight. The mixture was filtered through celite, concentrated and purified over silica gel column chromatography to yield methyl 5-(3,3-difluoroazetidin-l-yl)-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-lH-pyrrolo[2,3-c|pyridine-7-carboxylate (36 mg, 75 pmol, 40 %). ESI MS m / z = 484.0 [M+H]+.

[0897] The procedures for step 2 through step 5 are analogous to step 6 through step 9 for Example 55, and 2.8 mg of the title compound was obtained as a white powder. ESI MS m / z = 658.2 [M+H]+.

[0898] The following compound was prepared by a procedure analogous to that used for Example 59:

[0899]

[0900] PAGE 96 OF 152Docket No. 4014.1410 WO

[0901] Example 61: Synthesis of (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4Hl,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carbonyl)-2,3-dimethyl-3,4-dihydro- 2H-benzo[b][l,4]oxazine-8-carboxamide.

[0902] O

[0903]

[0904] F

[0905] Step 1

[0906] Methyl 2-amino-5-chloro-4-fluorobenzoate (500 mg, 2.46 mmol, 1.0 eq.) was dissolved in MeCN (12.3 mL) and NIS (580 mg, 1.05 eq. 2.58 mmol) was added followed by the addition of TFA (0.199 mL, 2.58 mmol, 1.05 eq.). The reaction mixture was allowed to stir at room temperature for 90 minutes after which time the reaction mixture was concentrated and the crude residue was purified by automated flash chromatography on silica gel (0-30% EtOAc in cyclohexane) to afford the pure product (620 mg, 77%). ESI MS m / z not found

[0907] Step 2

[0908] 4-(4-ethynylphenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (333 mg, 1.56 mmol, 1.25 eq.), methyl 2-amino-5 -chi oro-4-fluoro-3 -iodobenzoate (412 mg, 1.25 mmol, 1.0 eq.), and bis(triphenylphosphine)palladium(II) chloride (176 mg, 0.250 mmol. 0.20 eq.) were weighed into a vial with a stirbar and THF (4.17 mL) was added, followed by the addition of TEA (0.523 mL, 3.75 mmol, 3.0 eq.). The reaction mixture was sparged with nitrogen gas for 3 minutes, then the vial was sealed and the reaction mixture was heated to 70 °C with stirring. After 3 hours, the reaction mixture was concentrated and the crude residue was purified by automated flash chromatography on silica gel (0-100% EtOAc in cyclohexane, then 0-20% MeOH in EtOAc) to afford the pure product (340 mg, 66%). ESI MS m / z = 415.5 Step 3

[0909] Methyl 2-amino-5-chloro-3-((4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)ethynyl)-4-fluorobenzoate (340 mg, 0.820 mmol. 1.0 eq.) and PdCh (174 mg, 0.984 mmol, 1.2 eq.) were weighed into a vial with a stirbar and suspended in MeCN (4.10 mL). The vial was sealed and the reaction mixture was heated to 90 °C with stirring for 2

[0910] PAGE 97 OF 152Docket No. 4014.1410 WO

[0911] hours. After this time the reaction mixture was concentrated, and this crude material was used in the next step without further purification. ESI MS m / z = 415.8

[0912] Step 4

[0913] A portion of the aforementioned crude methyl 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-4-fluoro-lH-indole-7-carboxylate (70.0 mg, 0.169 mmol, 1.0 eq.) and CS2CO3 (165 mg, 0.506 mmol, 3.0 eq.) were weighed into a vial with a stirbar and suspended in DMF (0.675 mL). lodoethane (0.0339 mL, 0.422 mmol, 2.5 eq.) was added and the reaction mixture was allowed to stir at room temperature for 18h. After this time the reaction mixture was diluted wi th saturated aqueous ammonium chloride, water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (4 x 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by automated reverse phase flash chromatography (0-100% MeCN in H2O) to afford pure methyl 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carboxylate (41 mg, 55%). ESI MS m / z = 444.7 [M+H]+.

[0914] Step 5

[0915] Methyl 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carboxylate (41 mg, 0.093 mmol, 1.0 eq.) was dissolved in a mixture of MeOH (0.62 mL), THF (0.62 mL). and water (0.62 mL) and LiOH·H2O (20 mg, 0.83 mmol 9.0 eq.) was added. The reaction mixture was allowed to stir at room temperature for 60h. After this time the reaction mixture was acidified to pH ~2 with IM HC1, diluted with water and EtOAc, and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 5 mL), and three more times with 10% MeOH in DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford crude 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-L2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carboxylic acid which was used in the next step without further purification. ESI MS m / z = 429.7 [M+H]+.

[0916] Step 6

[0917] A portion of the aforementioned crude 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carboxylic acid (20.0 mg, 0.0466 mmol, 1.0 eq.) was weighed into a vial with a stirbar, and solid methyl 3-bromo-2-(((2S,3R)-3 -(chi oro-15 -azaneyl)butan-2-yl)oxy)benzoate (16.7 mg, 0.0583 mmol, 1.25 eq.), and HATU (26.6 mg, 70.0 mmol, 1.5 eq.) were added. The solids were dissolved in DMF (0.466 mL). and DIPEA (0.0406 mL, 233 mmol, 5.0 eq.) was then added. The reaction mixture was

[0918] PAGE 98 OF 152Docket No. 4014.1410 WO

[0919] allowed to stir for 1 hour at room temperature the reaction mixture was directly purified by automated reverse phase flash chromatography (0-100% MeCN in H2O) to afford the pure product. (18.0 mg, 54%). ESI MS m / z = 714.5 [M+H]+.

[0920] Step 7

[0921] Methyl 3-bromo-2-(((2S,3R)-3-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carboxamido)butan-2-yl)oxy)benzoate (18.0 mg, 0.0252 mmol, 1.0 eq.) was weighed into a vial with a stirbar, and CS2CO3 (16.5 mg, 0.0505 mmol, 2.0 eq ), Pd2(dba)s (1.2 mg, 0.0013 mmol, 0.05 eq.) and XPhos (1.8 mg, 0.038 mmol, 0.15 eq.) were added. The solids were suspended in 1,4-di oxane (0.50 mL) and the reaction mixture was sparged with nitrogen gas for 3 minutes. The vial was then sealed and the reaction mixture was heated to 95 °C with stirring for 18h. After this time, the reaction mixture was concentrated and the crude residue was purified by automated reverse phase flash chromatography (0-100% MeCN in H2O) to afford pure methyl (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b] [ 1,4]oxazine-8-carboxylate (10.7 mg, 67%). ESI MS m / z = 632.6 [M+Hf.

[0922] Step 8

[0923] Methyl (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (10.7 mg, 0.0169 mmol, 1.0 eq.) was dissolved in a mixture of MeOH (0.245 mL), THF (0.245 mL), and water (0.245 mL), and LiOH·H2O (4.05 mg, 0.169 mmol, 10 eq.) was added at room temperature. After 1 hour added additional LiOH·H2O (4.05 mg, 0.169 mmol, 10 eq.) was added. After an additional 30 minutes the reaction mixture was acidified to pH ~2 with IM HC1, and diluted with water and EtOAc. The layers were separated layers and the aqueous phase was extracted with EtOAc (3 x 5 mL), and 10% MeOH in DCM (3 x 5 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford crude 2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid which was used in the next step without further purification. ESI MS m / z = 618.7 [M+H]+.

[0924] Step 9

[0925] (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carbonyl)-2.3-dimethyl-3.4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (11.0 mg, 0.0178 mmol, 1.0 eq.), ammonium chloride (1.90 mg, 0.0356

[0926] PAGE 99 OF 152Docket No. 4014.1410 WO

[0927] mmol, 2.0 eq.), and HATU (8.46 mg, 0.0222 mmol, 1.25 eq.) were combined in a vial with a stirbar and dissolved in DMF (0.178 mL). DIPEA (0.0155 mL, 0.0890 mmol, 5.0 eq.) was then added, and the reaction mixture was allowed to stir at room temperature for Ih. After this time the reaction mixture was diluted with water and EtOAc. The biphasic mixture was concentrated and the residue was purified by reverse phase HPLC to obtain pure (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-ethyl-4-fluoro-lH-indole-7-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (7.4 mg, 67%). ESI MS m / z = 618.0 [M+H]+.

[0928] The following compounds were prepared by a procedure analogous to that used for Example 61:

[0929]

[0930] PAGE 100 OF 152Docket No. 4014.1410 WO

[0931] [M+H]+

[0932] 65

[0933] 617.6, 619.5

[0934] X

[0935] * Z

[0936] [M+H]+

[0937] 66

[0938] 635.6. 637.5

[0939] / \ / \ o o==''

[0940] 0

[0941] ^X^ / O 1 1 [M+HJ+ 67 ^^A o.^

[0942] \ \ / / \ %ZNNz\

[0943] 22— z z—T I 647.5, 649.6

[0944] / /

[0945] T N^x / \_K / nC|

[0946] 68 [M+H]+

[0947] 665.7. 667.5

[0948]

[0949] Example 69: (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide.

[0950]

[0951] Step 1

[0952] To the solution of methyl 5 -chloro- lH-indole-7-carboxy late (400 mg, 1 Eq, 1.91 mmol) in DMF (9.54 ml) was added cesium carbonate (1.55 g, 2.5 Eq, 4.77 mmol) and l-bromo-2-methoxyethane (530 mg. 359 pL, 2 Eq, 3.82 mmol). The reaction mixture was heated to 80

[0953] PAGE 101 OF 152Docket No. 4014.1410 WO

[0954] °C for 16 hours. After completion, the reaction mixture was diluted with water (10 mL) and EA (200 mL). The organic layer was separated and washed with brine (20 mL) 2 times. The organic layer was then dried over Na2SO4. The solid was filtered off, and the residue was concentrated and subjected to column (Hex: Ace 100:0 to 0:100) to afford methyl 5-chloro-l-(2-methoxyethyl)-lH-indole-7-carboxylate (346 mg, 1.29 mmol, 67.7 %) as yellowish oil. Step 2

[0955] To a solution of methyl 5-chloro-l-(2-methoxyethyl)-lH-indole-7-carboxylate (346 mg, 1 Eq, 1.29 mmol) and triisopropyl borate (267 mg, 328 pL, 1.1 Eq, 1.42 mmol) in THF (2.42 mL) was treated with LDA (166 mg, 1.55 mL, 1 molar, 1.2 Eq, 1.55 mmol) at 0 °C dropwise. The reaction was stirred at 0 °C for 2 hours. The mixture was quenched with Water (808 pL). The resulting solution was directly used in situ.

[0956] Step 3

[0957] To a 20 mL vial were added 4-(4-bromophenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (270.0 mg, 1 Eq, 1.007 mmol), (5-chloro-7-(methoxycarbonyl)-l-(2-methoxyethyl)-lH-indol-2-yl)boronic acid (407.8 mg, 1.3 Eq, 1.309 mmol), CS2CO3 (656.2 mg, 2 Eq, 2.014 mmol) and XPhos Pd G3 (85.24 mg, 0.1 Eq, 100.7 pmol). The vial was then sealed and purged with N23 times before THF (3.916 mL) and water (1.119 mL) were added. The mixture was heated to 80 °C, and it was allowed to stir at 80 °C for 20 hours. After completion, the reaction mixture was directly subjected to column (Hex: Acetone 100:0 to 0:100) to afford methyl 5-chloro-2-(4-(l,3-dimethyl-5-oxo-L5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carboxylate (140 mg, 308 pmol, 30.6 %).

[0958] Step 4

[0959] To the solution of methyl 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carboxylate (140 mg, 1 Eq, 308 pmol) in THF (2.56 mL), MeOH (1.28 mL) and Water (1.28 mL) was added LiOH (36.9 mg, 5 Eq, 1.54 mmol). The reaction mixture was then heated to 40 °C and stirred at 40 °C for 2 hours. After completion, the reaction was quenched with NH4CI solution (0.5 mL), and the mixture was diluted with water (1 mL) and EA (10 mL). The aqueous layer was extracted with EA (lOmL) 3 times. All organic layers were combined and dried over NazSCL. The solid was filtered off, and the filtrate was concentrated and subjected to column (DCM: MeOH 100:0 to 80:20) to afford 5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carboxylic acid (32 mg, 73 pmol, 24 %).

[0960] PAGE 102 OF 152Docket No. 4014.1410 WO

[0961] Step 5

[0962] To the solution of 5-chloro-2-(4-(l,3-dimethyl-5-oxo-1.5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carboxylic acid (16 mg, 1 Eq, 36 pmol) in DMF (1 mL) were added methyl 2-(((2S,3R)-3-aminobutan-2-yl)oxy)-3-bromo-6-fluorobenzoate hydrochloride (19 mg, 1.5 Eq, 54 pmol), DIPEA (38 mg, 51 pL, 8 Eq, 0.29 mmol) and HATU (21 mg, 1.5 Eq, 54 pmol). After 2 hours, the reaction went to completion. The solvent was evaporated and the residue was subjected to column (Hex: Acetone 100:0 to 0:100) to afford methyl 3-bromo-2-(((2S,3R)-3-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carboxamido)butan-2-yl)oxy)-6-fluorobenzoate (14 mg, 19 pmol,

[0963] 52 %).

[0964] Step 6

[0965] To a 20 mL vial were added methyl 3-bromo-2-(((2S,3R)-3-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-1, 5-dihydro-4H-l, 2, 4-tri azol -4-yl)phenyl)-l -(2 -methoxy ethyl)-lH-indole-7-carboxamido)butan-2-yl)oxy)-6-fluorobenzoate (14 mg, 1 Eq, 19 pmol), CS2CO3 (17 mg, 2.8 Eq, 53 pmol), copper(I) iodide (1.8 mg, 0.5 Eq, 9.4 pmol). The vial was sealed and purged with N23 times before N, N'-Dimethylethylenediamine (3.2 mg, 3.9 pL, 1.9 Eq, 36 pmol) and 1.4-Dioxane (1 mL) were added. The reaction mixture was then heated to 100 °C and it was allowed to stir at 100 °C for 20 hours. After completion, the mixture was directly subjected to column (Hex: Acetone 100:0 to 0: 100) to afford methyl (2S.3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (6 mg, 9 pmol, 50 %).

[0966] Step 7

[0967] To the solution of methyl (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H- 1.2.4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carbonyl)-7-fluoro-2,3-dimethyl- 3.4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (6 mg, 1 Eq, 9 pmol) in 0.12 mL THF and 0.12 mL MeOH was added 0.16 mL (3N NaOH). The reaction mixture was allowed to stir at room temperature for 6 hrs. After completion, saturated NH4CI solution was added to quench the reaction. The mixture was then extracted with EA (5mL) 5 times. All organic layers were combined and dried over Na2SCU. The solid was filtered off, and the filtrated was concentrated to afford (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-

[0968] PAGE 103 OF 152Docket No. 4014.1410 WO

[0969] dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (6 mg, 9 pmol, 100 %) which was used as crude for the next step.

[0970] Step 8

[0971] To the solution of (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (7.0 mg, 1 Eq, 11 pmol) in DMF (200 pL) were added N-ethyl-N-isopropylpropan-2-amine (11 mg, 15 y. L, 8 Eq, 86 pmol), ammonia hydrochloride (2.9 mg, 5 Eq, 54 pmol) and 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouroniumhexafluorophosphate(V) (6.2 mg, 1.5 Eq, 16 pmol). The reaction mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with DMF (1.8 mL) and subjected to prep-HPLC to afford (2S,3R)-4-(5-chloro-2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-l-(2-methoxyethyl)-lH-indole-7-carbonyl)-7-fluoro-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (1.0 mg, 1.5 pmol, 14 %). ESI MS m / z = 647.8 [M+H]+.

[0972] The following compounds were prepared by a procedure analogous to that used for Example 69:

[0973] Example Structure ESI-MS

[0974] [M+H]+

[0975] 70

[0976] 629.7

[0977] cOk

[0978]

[0979] Example 71: Synthesis of (2S,3R)-4-(6-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-ethyl-2-(trifluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide.

[0980] o

[0981]

[0982] Step 1

[0983] A 100-rnL round bottom flask equipped with a magnetic stir bar was charged with 2-(trifluoromethyl)pyrimidin-5-amine (3.00 g, 1.00 Eq, 18.4 mmol) and acetonitrile (60 mL),

[0984] PAGE 104 OF 152Docket No. 4014.1410 WO

[0985] giving an orange solution. NBS (3.93 g, 1.20 Eq, 22.1 mmol) was then added, giving a black solution, which was stirred 60 h. The reaction solution was then concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. Layers were separated and the aqueous phase extracted with ethyl acetate (3 x 100 rnL). The combined organics were dried over sodium sulfate, decanted, concentrated under reduced pressure and purified by flash chromatography on silica gel (330 g) eluting with ethyl acetate in cyclohexane to give the product (1.75 g, 40%) as a bright orange solid. ESI-MS m / z = 242.1 [M+H]+.rH NMR (400 MHz, DMSO) 88.22 (s, 1H), 6.63 (s, 2H).

[0986] Step 2

[0987] A 1000-mL round bottom flask equipped with a magnetic stir bar was charged with 4-bromo-2-(trifluoromethyl)pyrimidin-5-amine (3.74 g. 1.00 Eq, 15.5 mmol), triethylamine (30.9 mL), methanol (18.8 rnL, 30.0 Eq, 464 mmol), and sparged with nitrogen. After 10 min, xantphos (537 mg, 0.06 Eq, 0.927 mmol) and Pd(OAc)2 (104 mg, 0.03 Eq, 0.464 mmol) were added, and the resulting mixture spaged with carbon monoxide. After 5 min, the flask was sealed with a rubber septum, placed under a carbon monoxide atmosphere (balloon pressure), and the reaction mixture brought to 70 °C. After stirring 16 h, the reaction mixture was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel eluting with ethyl acetate in cyclohexane to give product (1.70 g, 50%) as a brown solid. ESI-MS m / z = 222.3 [M+H]+.

[0988] Step 3

[0989] A 1000-mL round bottom flask containing methyl 5-amino-2-(trifluoromethyl)pyrimidine-4-carboxylate (1.70 g, 1.00 Eq, 7.69 mmol) was charged with acetonitrile (20 mL), giving a dark brown solution. NBS (1.37 g, 1.00 Eq, 7.69 mmol) w as added, and the flask flushed with nitrogen, capped with a rubber septum, and placed in a hotblock preheated to 80 °C. After 1 hr, and additional aliquot of NBS (1.37 g, 1.00 Eq, 7.69 mmol) was added, and the walls of the flask rinsed with additional ACN (20 mL). The resulting solution was stirred at 80 °C for an additional hour, at which time a final portion of NBS (0.85 g, 0.62 Eq, 4.77 mmol) was added, and the reaction mixture stirred overnight. The reaction mixture was then concentrated under reduced pressure and punfied by flash chromatography on silica gel (330 g) eluting with ethyl acetate in cyclohexane to give the product (980 mg, 43%) as a white solid. ESI-MS m / z= 298.1 [M-H]’. *HNMR (400 MHz, DMSO) 57.44 (s, 2H), 3.91 (s, 3H).,9F NMR (376 MHz, DMSO) 5 -67.2.

[0990] PAGE 105 OF 152Docket No. 4014.1410 WO

[0991] Step 4

[0992] A 1000-mL round bottom flask equipped with a magnetic stir bar was charged with methyl 5-amino-6-bromo-2-(trifluoromethyl)pyrimidine-4-carboxylate (980 mg, 1.00 Eq, 3.27 mmol), 4-(4-ethynylphenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (766 mg, 1.10 Eq, 3.59 mmol), and XPhos Pd G3 (415 mg, 0.15 Eq, 490 pmol). The flask was flushed with nitrogen, acetonitrile (33 mL) and triethylamine (9.92 g, 13.7 mL, 30.0 Eq. 98.0 mmol) were added, and the resulting mixture was sparged with nitrogen for 30 minutes. The flask was then capped with a rubber septum, placed under positive nitrogen pressure, and heated to 70 °C. After 2.5 h, volatiles were removed under reduced pressure. Fresh acetonitrile (33 mL) was added, affording a red solution which was then sparged with nitrogen. After 5 min PdCh (174 mg, 0.30 Eq. 0.981 mmol) was added, the flask sealed with a rubber septum, and the reaction mixture placed under positive nitrogen pressure. The reaction vessel was then heated to 80 °C. After 5 h, the reaction mixture was allowed to return to room temperature and volatiles were once again removed under reduced pressure. Cesium carbonate (3.20 g, 3.00 Eq, 9.81 mmol). DMF (8 mL), and ethyl iodide (1.32 mL, 5.00 Eq, 16.4 mmol) were added, affording a brown mixture. The flask was flushed with nitrogen, then sealed with a rubber septum and heated to 80 °C. After 1 h, the reaction mixture was brought to room temperature, diluted with ethyl acetate and water, and the resulting layers separated. The aqueous phase was then extracted with ethyl acetate (3x), and the combined organics dried over sodium sulfate, filtered, concentrated under reduced pressure, and placed under high vacuum, ultimately affording the crude ethyl pyrrolopyrimidine as a brown solid. Purification by flash chromatography on silica gel (330 g) eluting with methanol in DCM gave the product (1.50 g, 99%) as a brown solid. ESI-MS m / z = 461.7 [M+H]+.

[0993] Step 5

[0994] A 40-mL glass reaction vial equipped with a magnetic stir bar and containing methyl 6-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l, 2, 4-triazol-4-yl)phenyl)-5-ethyl-2-(tri fluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate (78 mg, 1.00 Eq, 0.17 mmol) w as charged with methanol (0.5 mL) and THF (0.5 mL). affording a homogenous brown solution. 3 MNaOH (0.5 mL) was then added, and the resulting solution stirred 1 h. The reaction mixture was cooled to 0°C and neutralized to pH 7 with 4 M HC1 (0.40 mL). Volatiles were removed under reduced pressure and the resulting residue azeotropically dried once w ith toluene. Methyl 2-(((2S,3R)-3-aminobutan-2-yl)oxy)-3-bromobenzoate hydrochloride (72 mg, 1.25 Eq. 0.21 mmol), HATU (97 mg, 1.50 Eq, 0.26 mmol). DMF (1.7 mL), and DIPEA (0.18 g.

[0995] 0.24 mL, 8.1 Eq, 1.4 mmol) were then added, and the resulting dark brown mixture stirred 20

[0996] PAGE 106 OF 152Docket No. 4014.1410 WO

[0997] minutes. The reaction mixture was then concentrated under reduced pressure and purified by flash chromatography on silica gel (12 g) eluting with methanol in DCM to give a yellow film consistent with product (ESI-MS m / z = 730.7), which was transferred to a 20-mL glass reaction vial equipped with a magnetic stir bar. Cesium carbonate (143 mg, 2.57 Eq, 0.438 mmol), Pd2(dba)s (12 mg, 0.077 Eq, 0.013 mmol), xantphos (23 mg, 0.18 Eq, 0.039 mmol), and 1,4-dioxane (2.2 rnL) were added, and the resulting mixture sparged with nitrogen. After 2 minutes, the reaction vessel was capped, sealed with electrical tape and parafin, and heated to 100 °C. After 43 h, the reaction mixture was brought to room temperature, diluted with ethyl acetate, filtered through Celite, and concentrated under reduced pressure into a 20-mL glass reaction vial. An additional portion of cesium carbonate (214 mg, 3.0 Eq, 0.657 mmol), copper(I) iodide (21 mg. 0.5 Eq. 0.11 mmol), methyl[2-(methylamino)ethyl]amine (47 pL.

[0998] 2.00 Eq, 0.438 mmol)and 1,4-dioxane (2.2 rnL) were added under nitrogen, then sparged with nitrogen. After 2 min, the vial was once again capped, sealed, placed under positive nitrogen pressure, and heated to 100 °C. After stirring overnight, the reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate and water, and the aqueous phase extracted with ethyl acetate (2x). The combined organics were then concentrated under reduced pressure, taken up in THF (0.5 mL) and methanol (0.5 mL), charged to a 20-mL glass reaction vial equipped with a magnetic stir bar, and treated with 3 M aqueous NaOH (0.5 mL). The resulting solution was stirred 2 h, then neutralized with 4 M HC1 (0.38 mL), concentrated under reduced pressure, and purified by flash chromatography on silica gel eluting with methanol in DCM to give (2S,3R)-4-(6-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-ethyl-2-(trifluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (23 mg, 21%). ESI-MS m / z = 634.6 [M-H]’.

[0999] Step 6

[1000] A 20-mL glass reaction vial equipped with a magnetic stir bar and containing (2S,3R)-4-(6-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-ethyl-2-(trifluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (23 mg, 1.00 Eq, 0.036 mmol) was charged with HATU (14 mg, 1.05 Eq, 0.038 mmol), ammonium chloride (19 mg, 10.00 Eq, 0.36 mmol), and DMF (0.36 mL). Hiinig’s base (32 pL, 5.0 Eq, 0.18 mmol) was added, and the resulting mixture stirred overnight. The reaction mixture was then diluted with DMSO (0.64 mL), micron filtered, and purified by RP-HPLC to afford (2S,3R)-4-(6-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-ethyl-2-(trifluoromethyl)-5H-pyrrolo[3,2-

[1001] PAGE 107 OF 152Docket No. 4014.1410 WO

[1002] d]pyrimidine-4-carbonyl)-2,3-dimethyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (7 mg, 30%) as a white solid. ESI-MS m / z = 635.6 [M+H]+.19F NMR (376 MHz, CDCh) 5 -68.5.

[1003] The following compounds were prepared by a procedure analogous to that used for Example 71:

[1004] Example Structure ESI-MS

[1005] [M+H]+

[1006] 72

[1007] 653.9

[1008] A / " TAN

[1009] M V / VLA

[1010]

[1011] Example 73: Synthesis of (S)-4-(2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b] [ 1,4] oxazine-8-carboxamide.

[1012]

[1013] Step 1

[1014] A solution of l,4-dimethyl-l,3-dihydro-2H-imidazol-2-one (236 mg, 1 Eq, 2.10 mmol) and 1-chloro-4-iodobenzene (628 mg, 1.25 Eq, 2.63 mmol) in 1,4-Dioxane (2.2 mL) was treated with copper(I) iodide (40 mg, 0.10 Eq, 0.21 mmol), Nl, N2-dimethylethane-l,2-diamine (37 mg, 0.20 Eq, 0.42 mmol), and tripotassium phosphate (823 mg, 1.84 Eq, 3.88 mmol) under N2. The reaction was warmed to 100 °C and stirred for 20 hours. The mixture was fdtered through celite and rinsed with acetone. The filtrate was concentrated in vacuo. The crude was added to a 12 g silica gel column and eluted by ethyl acetate / cyclohexane from 0% to 100% to give 3-(4-chlorophenyl)-l,4-dimethyl-l,3-dihydro-2H-imidazol-2-one (46 mg, 0.21 mmol, 9.8 %) as a white solid. ESI MS m / z = 223.1, 225.0 [M+H]+.

[1015] PAGE 108 OF 152Docket No. 4014.1410 WO

[1016] Step 2

[1017] A solution of 3-(4-chlorophenyl)-l,4-dimethyl-l,3-dihydro-2H-imidazol-2-one (46 mg, 1 Eq, 0.21 mmol) and (7-(methoxycarbonyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indol-2-yl)boronic acid (77 mg, 1.1 Eq, 0.22 mmol) in THF (1 mL) and Water (0.3 mL) was treated with CS2CO3 (0.142 g, 2.1 Eq, 436 pmol) and XPhos Pd G3 (18 mg, 0.10 Eq, 21 pmol) under N2. The reaction was warmed to 70 °C and stirred for 20 hours. The mixture was added to a 4 g silica gel column and eluted by acetone / cyclohexane from 0% to 100% to give methyl 2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (83 mg, 0.17 mmol, 82 %) as an off-white solid. ESI MS m / z = 488.5 [M+H]+.

[1018] Step 3

[1019] A solution of methyl 2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (83 mg, 1 Eq, 0.17 mmol) in THF (1 mL), MeOH (0.5 mL) and Water (0.5 mL) was treated with LiOH (41 mg, 10 Eq, 1.7 mmol). The reaction was warmed to 50 °C and stirred for 2 hours. The mixture was neutralized with 1 N HC1 until PH = 2. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give crude 2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid (84 mg, 0.18 mmol, 100 %) as an off-white solid. ESI MS m / z = 474.6 [M+H] '.

[1020] Step 4

[1021] A solution of 2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid (24 mg, 1 Eq, 51 pmol) and methyl (S)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (38 mg, 3.6 Eq, 0.18 mmol) in MeCN (0.3 mL) was treated with 1 -methylimidazole (52 mg, 50 pL, 12 Eq, 0.63 mmol) and Chloro-N, N, N', N'-tetramethylformamidinium hexafluorophosphate (TCFH) (65 mg, 4.6 Eq, 0.23 mmol). The reaction was warmed to 120 °C and stirred for 1 hour under microwave irradiation. The mixture was added to a 4 g silica gel column and eluted by acetone / cyclohexane from 0% to 100% to give methyl (S)-4-(2-(4-(3.5-dimethyl-2-oxo-2,3-dihy dro- IH-imidazol- 1 -y l)pheny 1)- 1 -(2-methoxy ethy l)-5 -(trifluoromethyl)- 1 H-indole-7 -carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (5 mg, 8 pmol, 10 %) as a white solid. ESI MS m / z = 663.6 [M+H]+.

[1022] PAGE 109 OF 152Docket No. 4014.1410 WO

[1023] Step 5

[1024] A solution of methyl (S)-4-(2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (5 mg, 1 Eq, 8 pmol) in THF (1 mL), MeOH (0.5 mL) and Water (0.5 mL) was treated with LiOH (3 mg, 2e+l Eq, 0.1 mmol). The reaction was warmed to 50 °C and stirred for 3 hour. The mixture was neutralized with 1 N HC1 until PH = 2. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, fdtered and concentrated in vacuo to give crude (S)-4-(2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)- lH-indole-7 -carbonyl)-2-methyl-3,4-dihy dro-2H-benzo[b] [ 1.4] oxazine-8-carboxylic acid (5 mg, 8 pmol, 100 %) as an off-white solid. ESI MS m / z = 649.5 [M+H]+. Step 6

[1025] A solution of (S)-4-(2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (5 mg, 1 Eq, 8 pmol) in DMF (1 mL) was treated with ammonium chloride (2 mg, 5 Eq, 0.04 mmol), HATU (5.5 mg, 2 Eq, 14 pmol) and DIPEA (0.04 g, 0.05 mL, 40 Eq, 0.3 mmol). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated in vacuo. The crude was diluted with ethyl acetate and quenched with water and brine. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude was added to a 4 g silica gel column and eluted by acetone / cyclohexane from 0% to 100% to give (S)-4-(2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (3 mg, 5 pmol, 60 %) as a white solid. ESI MS m / z = 649.6 [M+H]+.

[1026] Example 74: Synthesis of (S)-4-(l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazine-8-carboxamide.

[1027] PAGE 110 OF 152Docket No. 4014.1410 WO

[1028]

[1029] Step 1

[1030] A solution of l-(4-bromophenyl)-l,3-dihydro-2H-imidazol-2-one (156 mg, 1 Eq, 653 pmol) in THF (2 mL) was treated with sodium hydride (40 mg, 60% Wt, 1.5 Eq, 1.0 mmol) at 0 °C. The reaction was stirred at 0 °C for 15 min, and then treated with Mel (0.18 g, 80 pL, 2.0 Eq, 1.3 mmol) dropwise. The reaction was warmed to 25 °C and stirred for 1 hour. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give crude l-(4-bromophenyl)-3-methyl-l,3-dihydro-2H-imidazol-2-one (185 mg, 731 pmol, 112 %) as an off-white solid. ESI MS m / z = 253.0, 255.0 [M+H]+.

[1031] Step 2

[1032] A solution of l-(4-bromophenyl)-3-methyl-l,3-dihydro-2H-imidazol-2-one (69 mg, 1 Eq, 0.27 mmol) and (7-(methoxycarbonyl)-l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indol-2-yl)boronic acid (100 mg, 1.1 Eq, 290 pmol) in THF (1.2 mL) and water (0.4 mL) was treated with CS2CO3 (0.173 g, 1.9 Eq, 531 pmol) and XPhos Pd G3 (23 mg, 0.10 Eq, 27 pmol) under N2. The reaction was warmed to 70 °C and stirred for 20 hours. The mixture was added to a 4 g silica gel column and eluted by acetone / cyclohexane from 0% to 100% to give methyl l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (148 mg, 313 pmol, 110 %) as an off-white foam. ESI MS m / z = 474.5 [M+H]+.

[1033] Step 3

[1034] A solution of methyl l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (148 mg, 1 Eq, 313 pmol) in THF (1 mL), MeOH (0.5 mL) and Water (0.5 mL) was treated with LiOH (40 mg, 5.3 Eq, 1.7 mmol). Th reaction was warmed to 50 °C and stirred for 3 hour. The reaction was neutralized with 1 N HC1 to PH = 2. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to

[1035] PAGE 111 OF 152Docket No. 4014.1410 WO

[1036] give crude l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid (110 mg. 239 pmol, 76.6 %) as an off-white solid. ESI MS m / z = 460.5 [M+H]+.

[1037] Step 4

[1038] A solution of l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5 -(trifluoromethyl)- lH-indole-7-carboxylic acid (26 mg, 1 Eq, 57 pmol) and methyl (S)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (33 mg, 2.8 Eq, 0.16 mmol) was treated with TCFH (N'-tetramethylformamidinium hexafluorophosphate) (33 mg, 2.1 Eq, 0.12 mmol) and 1 -methylimidazole (31 mg, 30 pL, 6.6 Eq, 0.38 mmol). The reaction was warmed to 120 °C and stirred for 1 hour under micro wave irradiation. The mixture was added to a 4 g silica gel column and eluted by acetone / cyclohexane from 0% to 100% to give methyl (S)-4-(l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (13 mg, 20 pmol, 35 %) as an off-white solid. ESI MS m / z = 649.4 [M+H]+.

[1039] Step 5

[1040] A solution of methyl (S)-4-(l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (13 mg, 1 Eq, 20 pmol) in THF (1 mL), MeOH (0.5 mL) and Water (0.5 mL) was treated with LiOH (10 mg. 21 Eq, 0.42 mmol). The reaction was warmed to 50 °C and stirred for 1 hour. The mixture was neutralized with 1 N HC1 to PH = 2. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give crude (S)-4-(l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (14 mg, 22 pmol, 110 %) as an off-white solid. ESI MS m / z = 635.5 [M+H]+. Step 6

[1041] A solution of (S)-4-(l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (14 mg, 1 Eq, 22 pmol) in DMF (1 mL) was treated with ammonium chloride (5 mg, 4 Eq, 0.09 mmol), HATU (17 mg, 2.0 Eq, 45 pmol) and DIPEA (37 mg, 50 pL, 13 Eq, 0.29 mmol). The reaction was stirred at 25 °C for 20 hour. The mixture was concentrated in vacuo, then diluted with ethyl acetate and quenched with water and brine. The aqueous layer was extracted with ethyl acetate over 3 times. The combined

[1042] PAGE 112 OF 152Docket No. 4014.1410 WO

[1043] organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude was added to a 4 g silica gel column and eluted by acetone / cyclohexane from 0% to 100% to give (S)-4-(l-(2-methoxyethyl)-2-(4-(3-methyl-2-oxo-2,3-dihydro-lH-imidazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxamide (7 mg, 0.01 mmol, 50 %) as a white solid. ESI MS m / z = 634.4 [M+H]+.

[1044] Example 75: Synthesis of (S)-4-(l-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazine-8-carboxamide.

[1045]

[1046] Step 1

[1047] A solution of l-bromo-4-isocyanatobenzene (269 mg, 1 Eq, 1.36 mmol) and azidotrimethylsilane (307 mg, 350 pL, 1.96 Eq, 2.66 mmol) in DMF (2 mL) was warmed to 100 °C and stirred for 24 hour. The mixture was concentrated in vacuo. The crude was treated with EtOH. The suspension was sonicated, filtered and washed with EtOH to give l-(4-bromophenyl)-l,4-dihydro-5H-tetrazol-5-one (144 mg, 597 prnol, 44.0 %) as a white solid. ESI MS m / z = 239.0, 240.9 [M-H]'.

[1048] Step 2

[1049] A solution of l-(4-bromophenyl)-l,4-dihydro-5H-tetrazol-5-one (144 mg, 1 Eq, 597 prnol) in DMF (1.5 mL) was treated with K2CO3 (159 mg, 1.93 Eq, 1.15 mmol) and iodomethane (159 mg, 70.0 pL, 1.87 Eq, 1.12 mmol). The reaction w as stirred at 25 °C for 1 hour. The mixture was concentrated in vacuo. The crude was diluted with acetone. The mixture was filtered through celite and rinsed with acetone. The filtrate was concentrated in vacuo to give crude 1-(4-bromophenyl)-4-methyl-l,4-dihydro-5H-tetrazol -5-one (186 mg, 729 prnol, 122 %) as a white solid. ESI MS m / z = 254.9, 257.0 [M+H]L

[1050] Step 3

[1051] A solution of l-(4-bromophenyl)-4-methyl-l,4-dihydro-5H-tetrazol-5-one (64 mg, 1 Eq, 0.25 mmol) and (7-(methoxy carbonyl)- l-(2-methoxyethyl)-5-(trifluoromethyl)-lH-indol-2-

[1052] PAGE 113 OF 152Docket No. 4014.1410 WO

[1053] yl)boronic acid (88 mg, 1.0 Eq, 0.26 mmol) in THF (1 mL) and Water (0.3 mL) was treated with CS2CO3 (0.18 g, 2.2 Eq, 0.55 mmol) and XPhos Pd G3 (24 mg, 0.11 Eq. 28 pmol) under N2. The reaction was warmed to 70 °C and stirred for 20 hours. The mixture was added to a 12 g silica gel column and eluted by acetone / cyclohexane from 0% to 100% to give methyl 1-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)- lH-indole-7-carboxylate (76 mg, 0.16 mmol, 64 %) as a syrup. ESI MS m / z = 476.4 [M+H]+.

[1054] Step 4

[1055] A solution of methyl l-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (75 mg, 1 Eq, 0.16 mmol) in THF (1 mL), MeOH (0.5 mL) and Water (0.5 mL) was treated with LiOH (28 mg, 7.4 Eq, 1.2 mmol). The reaction was warmed to 50 °C and stirred for 3 hour. The mixture was neutralized with 1 N HC1 to pH = 2. The aqueous layer w as extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give crude l-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4.5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid (72 mg, 0.16 mmol, 99 %) as an off-white solid. ESI MS m / z = 462.2 [M+H]+.

[1056] Step 5

[1057] A solution of l-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylic acid (28 mg, 1 Eq, 61 pmol) and methyl (S)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (38 mg, 3.0 Eq, 0.18 mmol) in MeCN (0.5 mL) was treated with Chloro-N, N, N', N'-tetramethylformamidinium hexafluorophosphate (TCFH) (38 mg, 2.2 Eq, 0.14 mmol) and 1 -methylimidazole (41 mg, 40 pL, 8.3 Eq, 0.50 mmol). The reaction was warmed to 120 °C and stirred for 1 hour under microwave irradiation. The mixture w as added to a 4 g silica gel column and eluted by acetone / cyclohexane from 0% to 100% to give methyl (S)-4-(l-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate (30 mg, 46 pmol, 76 %) as an off-white solid. ESI MS m / z = 651.3 [M+H]+. Step 6

[1058] A solution of methyl (S)-4-(l-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3.4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylate (30 mg, 1 Eq, 46 pmol) in THF (1 mL), MeOH (0.5 mL)

[1059] PAGE 114 OF 152Docket No. 4014.1410 WO

[1060] and Water (0.5 mL) was treated with LiOH (14 mg, 13 Eq, 0.58 mmol). The reaction was warmed to 50 °C and stirred for 2 hours. The mixture was neutralized with 1 N HCL to PH = 2. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give crude (S)-4-(l-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)- lH-indole-7 -carbonyl)-2-methyl-3,4-dihy dro-2H-benzo[b] [ 1.4] oxazine-8-carboxylic acid (30 mg, 47 pmol, 100 %) as an off-white solid. ESI MS m / z = 637.5 [M+H]+. Step 7

[1061] A solution of (S)-4-(l-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carbonyl)-2-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-8-carboxylic acid (30 mg. 1 Eq. 47 pmol) in DMF (1 mL) was treated with ammonium chloride (10 mg, 4.0 Eq, 0.19 mmol), HATU (26 mg, 1.5 Eq, 68 pmol) and DIPEA (37 mg, 50 pL, 6.1 Eq, 0.29 mmol). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated in vacuo, diluted with ethyl acetate and quenched with w ater and brine. The aqueous layer was extracted with ethyl acetate over 3 times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude was added to a 4 g silica gel column and eluted by acetone / cyclohexane from 0% to 100% to give (S)-4-(l-(2-methoxyethyl)-2-(4-(4-methyl-5-oxo-4,5-dihydro-lH-tetrazol-l-yl)phenyl)-5-(trifluoromethyl)- lH-indole-7 -carbonyl)-2-methyl-3,4-dihy dro-2H-benzo[b] [ 1.4] oxazine-8-carboxamide (20 mg, 31 pmol, 67 %) as a white solid. ESI MS m / z = 636.6 [M+H]+.

[1062] The following examples were prepared using procedures similar to those described above:

[1063]

[1064] PAGE 115 OF 152Docket No. 4014.1410 WO

[1065]

[1066] The following examples are prepared using procedures similar to those described

[1067]

[1068] PAGE 116 OF 152Docket No. 4014.1410 WO

[1069]

[1070] PAGE 117 OF 152Docket No. 4014.1410 WO

[1071]

[1072] PAGE 118 OF 152Docket No. 4014.1410 WO

[1073]

[1074] PAGE 119 OF 152Docket No. 4014.1410 WO

[1075]

[1076] PAGE 120 OF 152Docket No. 4014.1410 WO

[1077]

[1078] BIOLOGICAL ACTIVITY STAT6 FP Activity

[1079] For a competition-based fluorescence polarization (FP) assay, the ability of the test compounds to displace the fluorophore-labeled STAT6 peptide substrate at the SH2 binding domain of STAT6 was analyzed. Test compounds were dispersed into a 384-well low volume black ProxiPlate microplate from a DMSO solution using an ECHO 650 acoustic Test

[1080] PAGE 121 OF 152Docket No. 4014.1410 WO

[1081] compounds were dispersed into a 384- well low volume while ProxiPlate microplate from a DMSO solution using an ECHO 650 acoustic dispenser. Recombinant human STAT6 core domain protein (STAT6 H122-T658) at 125 nM in FP assay buffer (10 mM HEPES pH 7.5, 50 mM NaCl, 1 mM EDTA, 0.05% Tween-20, 2 mM DTT) was added to the test or high control wells. FP assay buffer was added to the low control wells. The plate was incubated at RT for 30 min. Next. 2 nM of buffered STAT6 peptide probe [5-FAM-G(pY)VPWQDLI-NH2] solution was added to all wells. The plate was then incubated at RT for another 30 min. FP (milliPolarization - mP value) was measured at RT in an Envision plate reader equipped with 485 nm excitation and 520 nm emission filters, operating in endpoint mode.

[1082] FP signal (mP values) from high and low control wells were used to calculate normalized STAT6 binding activity at various concentrations of test compounds. The normalized activities were fitted to inhibitor-versus-normalized response fit in GraphPad Prism 7 to determine half-maximal inhibitory concentration (IC50). ECso ranges are reported as follows: A< 1 pM; B 1-10 pM; C 10-50 pM; D > 50 pM.

[1083] Table 1. STAT6 Binding Activity

[1084] Ex.# STAT6 FP IC50 Ex.# STAT6 FP IC50

[1085] 1 A 2 D

[1086] 3 B 4 A

[1087] 5 A 6 B

[1088] 7 A 8 A

[1089] 9 A 10 A

[1090] 11 D 12 A

[1091] 13 A 14 B

[1092] 15 A 16 A

[1093] 17 A 18 A

[1094] 19 C 20 B

[1095] 21 A 22 A

[1096] 23 A 24 A

[1097] 25 A 26 A

[1098] 27 A 28 A

[1099] 29 A 30 A

[1100] 31 A 32 A

[1101] 33 A 34 D

[1102]

[1103] PAGE 122 OF 152Docket No. 4014.1410 WO

[1104] 35 A 36 A

[1105] 37 A 38 A

[1106] 39 A 40 A

[1107] 41 A 42 C

[1108] 43 D 44 A

[1109] 45 A 46 A

[1110] 47 A 48 A

[1111] 49 A 50 C

[1112] 51 A 52 A

[1113] 53 A 54 A

[1114] 55 A 56 A

[1115] 57 A 58 A

[1116] 59 A 60 A

[1117] 61 A 62 A

[1118] 63 A 64 A

[1119] 65 A 66 A

[1120] 67 A 68 A

[1121] 69 A 70 A

[1122] 71 A 72 A

[1123] 73 B 74 A

[1124] 75 A

[1125] 42a C 53a A

[1126] 55a A 57a A

[1127] 58a A 59a A

[1128] 61a A 62a A

[1129] 66a A

[1130]

[1131] STAT6 HEK-BLUE IL-4 & IL- 13 Assay

[1132] HEK-BLUE IL-4 & IL- 13 cells stably expressing STAT6 and a STAT6-inducible secreted embryonic alkaline phosphatase reporter were maintained in growth media consisting of Dulbecco's Modified Eagle Medium plus GlutaMAX supplemented with 10% heat-inactivated fetal bovine serum, 100 U / mL penicillin, 100 pg / mL streptomycin, 100 pg / mL Normocin, 10 pg / mL blasticidin and 100 pg / mLZeocin. Test media consisted of

[1133] PAGE 123 OF 152Docket No. 4014.1410 WO

[1134] growth media with the exclusion of Normocin, blasticidin and Zeocin. All cell maintenance and incubations were performed at 37°C, 5% CO2 in a humidified incubator.

[1135] In a 384-well plate, compounds, solubilized in DMSO, were dispensed using an ECHO 650 acoustic liquid handler. HEK-BLUE IL-4 & IL-13 cells were resuspended in test media at a density7of 12,000 cells per well and incubated with dispensed compounds for three hours. IL-4 was solubilized in 0.1% human serum albumin (HSA) in PBS and cells were stimulated with a pre-determined IL-4 EC75. Plates were incubated overnight. The following day, QUANTI-Blue was added per manufacturer’s instructions. One hour post incubation, absorbance was measured at a wavelength of 620 nm on an Envision plate reader.

[1136] Absorbance values for unstimulated control samples were subtracted from all test samples and percentage inhibition was determined as compared to DMSO stimulated samples.

[1137] GraphPad Prism was used to determine EC50 values using a 4-parameter logistic curve fitting model. EC50 ranges are reported as follows: A< 0.1 pM; B 0.1-1 pM; C 1-10 pM; D > 10 pM.

[1138] Table 2. IL-4 HEK-Blue Activity

[1139] Ex.# HEK-Blue IL-4 IC50 Ex.# HEK-Blue IL-4 IC50 1 A 2 - 3 B 4 A

[1140] 5 A 6 B

[1141] 7 B 8 B

[1142] 9 A 10 A

[1143] 11 - 12 A

[1144] 13 A 14 B

[1145] 15 A 16 A

[1146] 17 A 18 A

[1147] 19 B 20 B

[1148] 21 A 22 A

[1149] 23 A 24 A

[1150] 25 A 26 A

[1151] 27 A 28 A

[1152] 29 A 30 A

[1153] 31 A 32 A

[1154] 33 A 34 -

[1155]

[1156] PAGE 124 OF 152Docket No. 4014.1410 WO

[1157] 35 A 36 A

[1158] 37 A 38 A

[1159] 39 A 40 A

[1160] 41 A 42 C

[1161] 43 - 44 A

[1162] 45 A 46 A

[1163] 47 A 48 A

[1164] 49 A 50 C

[1165] 51 A 52 A

[1166] 53 A 54 A

[1167] 55 A 56 A

[1168] 57 A 58 A

[1169] 59 A 60 A

[1170] 61 A 62 A

[1171] 63 A 64 A

[1172] 65 A 66 A

[1173] 67 A 68 A

[1174] 69 A 70 A

[1175] 71 A 72 A

[1176] 73 A 74 A

[1177] 75 A

[1178] 42a C 53a B

[1179] 55a A 57a A

[1180] 58a A 59a A

[1181] 61a A 62a A

[1182] 66a A 68a A

[1183]

[1184] pSTAT6 PBMC IL-4 Assay

[1185] Human PBMCs were washed in RPMI-1640 supplemented with 10% heat-inactivated fetal bovine serum, 100 U / mL penicillin, 100 pg / mL streptomycin and IX CTL. Following overnight recovery, PBMCs were washed and resuspended in 0.1 % bovine serum albumin in

[1186] PAGE 125 OF 152Docket No. 4014.1410 WO

[1187] Hanks’ Balanced Salt Solution. All recovery and incubations were performed at 37°C, 5% CO2 in a humidified incubator.

[1188] In a 384-well plate, compounds, solubilized in DMSO, were dispensed using an ECHO 650 acoustic liquid handler. PBMCs were incubated with compounds for two hours. PBMCs were then stimulated for 15 minutes with a pre-determined IL-4 EC75. Phospho-STAT6 levels were measured with AlphaLISA SureFire Ultra human Phospho-STAT6 Detection Kit as per manufacturer’s instructions. GraphPad Prism was used to determine EC50 values using a 4-parameter logistic curve fitting model. ECso ranges are reported as follows: A < 0.1 pM; B 0.1-1 pM; C 1-10 pM; D > 10 pM.

[1189] Table 3. pSTAT6 PBMC Activity

[1190] Ex.# PBMC pSTAT6 ICso Ex.# PBMC pSTAT6 ICso 1 A 2 - 3 - 4 - 5 A 6 - 7 - 8 - 9 - 10 A

[1191] 11 - 12 A

[1192] 13 A 14 - 15 - 16 A

[1193] 17 A 18 A

[1194] 19 - 20 - 21 A 22 A

[1195] 23 - 24 A

[1196] 25 A 26 A

[1197] 27 A 28 - 29 - 30 A

[1198] 31 - 32 A

[1199] 33 A 34 - 35 A 36 A

[1200] 37 A 38 A

[1201] 39 A 40 A

[1202] 41 - 42 - 43 - 44 A

[1203]

[1204] PAGE 126 OF 152Docket No. 4014.1410 WO

[1205] 45 A 46 A

[1206] 47 - 48 - 49 - 50 - 51 - 52 A

[1207] 53 A 54 - 55 A 56 A

[1208] 57 A 58 A

[1209] 59 - 60 - 61 A 62 B

[1210] 63 A 64 A

[1211] 65 - 66 - 67 A 68 A

[1212] 69 A 70 A

[1213] 71 A 72 A

[1214] 73 - 74 - 75 A

[1215] 55a A 57a A

[1216] 58a A 59a A

[1217] 61a A 62a A

[1218] 66a A 68a B

[1219]

[1220] pSTAT6 Whole Blood IL-4 Assay

[1221] Compounds, solubilized in DMSO, were dispensed into 96-well plates containing human whole blood and incubated at 37°C for one hour. Whole blood was stimulated with a predetermined IL-4 EC75. Plates were incubated at 37°C for 10 minutes to induce STAT6 phosphorylation. After 10 minutes, cells were lysed and lysate was centrifuged to pellet cell debris. Supernatant was used to detect phosphor-STAT6 levels with AlphaLISA SureFire Ultra human Phospho-STAT6 Detection Kit, according to manufacturer’s instructions.

[1222] GraphPad Prism was used to determine EC50 values using a 4-parameter logistic curve fitting model. ECso ranges are reported as follows: A < 0.1 pM; B 0.1-1 pM; C 1-10 pM.

[1223] PAGE 127 OF 152Docket No. 4014.1410 WO

[1224] Table 4. IL-4 pSTAT6 Whole Blood Activity

[1225] Ex.# hWB pSTAT6 ICso

[1226] 5 B

[1227] 21 B

[1228] 22 C

[1229] 24 B

[1230] 25 B

[1231] 26 B

[1232] 33 B

[1233] 39 B

[1234] 40 B

[1235] 44 B

[1236] 46 C

[1237] 52 A

[1238] 53 A

[1239] 55 A

[1240] 61 B

[1241] 62 B

[1242] 63 A

[1243] 64 B

[1244] 71 A

[1245] 72 B

[1246] 55a B

[1247] 57a B

[1248] 58a B

[1249] 61a B

[1250] 62a B

[1251] 66a B

[1252]

[1253] While this invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

[1254] PAGE 128 OF 152

Claims

1. Docket No. 4014.1410 WOCLAIMSWhat is claimed:

1. A compound represented by Formula (I) or pharmaceutically acceptable salts,wherein;RAis selected from the group consisting of:1) Optionally substituted 4- to 8- membered heterocycloalkyl;2) Optionally substituted aryl;3) Optionally substituted arylalkyl;4) Optionally substituted heteroaryl;5) Optionally substituted heteroarylalkyl;6) -C(O)N(R1)(R2);7) -N(R1)C(O)(R2);8) -N(R')C(O)OR2; and9) -N(R3)C(O)N(R1)(R2);RBis selected from the group consisting of hydrogen, halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyd, optionally substituted 4- to 8- membered heterocycloalky l, optionally substituted aryl, optionally substituted heteroaryl, -OR1, -C(O)N(R1)(R2), -NR1R2. -SR1. -SO2R1, -NCR^CCOXR2), -N(R1)C(O)OR2, -N(R3)C(O)NR1R2, -N(R1)S(O)2(R2), and -P(O)R1R2;Rcis selected from the group consisting of hydrogen, halogen, cyano, optionally substituted -Ci-Cs alky l, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalky 1, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR1, -C(O)N(R1)(R2), -NR'R2. -SR1, -SO2R1, -NCR^CCO^R2), -N(R1)C(O)OR2, -N(R3)C(O)NR1R2, -N(R1)S(O)2(R2). and -P(O)R1R2;PAGE 129 OF 152Docket No. 4014.1410 WORDis selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 4- to 8- membered helerocycloalkyl. optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted ar l, and optionally substituted heteroaryl;REis selected from the group consisting of1) Hydrogen;2) Halogen3) Cyano;4) Optionally substituted -Ci-Cs alkyl;5) Optionally substituted -Cs-Cs cycloalkyl;6) Optionally substituted -Ci-Cs alkoxy;7) Optionally substituted 4- to 8- membered heterocycloalkyl;8) Optionally substituted aryl;9) Optionally substituted heteroaryl; and10)- C(O)N(R1)(R2);Y1and Y2are independently selected from the group consisting of N and CRF;X1, X2, and X3are each independently selected from the group consisting of N and CRG;L is -L’-W-L2-; wherein L1is connected to the amide nitrogen atom and L2is connected to Z;L1is -C(R4)(R5)[C(R6)(R7)]n-, wherein n is 0, 1, 2, 3, or 4;W is absent or W1; W1is selected from the group consisting of -O-, -SO2-, -NR9-, -C(O)NR9-, -NR9C(O)-, -SO2NR9-, and -NR9SO2-;L2is absent or -[C(R6)(R7)]m-wherein m is 1 or 2;Z is C orN;A is an optionally substituted aryl or optionally substituted heteroaryl;each RFis independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Cs-Cs cycloalkyl, optionally substituted 4-to 8- membered heterocycloalkyl, optionally substituted ary l, optionally substituted heteroaryl, -OR1. -NR'R2, -SR1, -SO2R1, -C(O)N(R1)(R2), -N(R1)C(O)(R2), -N(R1)C(O)OR2, -N(R3)C(O)NR1R2, and -N(R1)S(O)2(R2);PAGE 130 OF 152Docket No. 4014.1410 WOeach RGis independently selected from the group consisting of:1) Hydrogen;2) Halogen;3) Cyano;4) Hydroxy;5) Optionally substituted Ci-Cs alkyl;6) Optionally substituted C3-C8 cycloalkyl;7) Optionally substituted 4- to 8-membered heterocycloalkyl;8) Optionally substituted aryl;9) Optionally substituted heteroaryl;10) Optionally substituted -Ci-Cs alkoxy;in-CCO NCR1)^2);12)-N(R1)C(O)(R2);13)-N(R1)(R2);U^SR1;15)-S(O)2R1;16)-N(R1)C(O)OR2;17)-N(R1)S(O)2(R2); and18)-P(O)R1R2;Each R1, R2, andR3is independently selected from hydrogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-Cs alkenyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroaryl; alternatively, R1and R2are both attached to a nitrogen atom and R1and R2are taken together with the nitrogen atom to form an optionally substituted 4- to 8-membered heterocyclic containing 0, 1, 2, or 3 double bonds;R4and R5are each independently selected from hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-Cs alkenyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted ary l, and optionally substituted heteroaryl;Each R6is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C3-C8 cycloalkyl, optionallyPAGE 131 OF 152Docket No. 4014.1410 WOsubstituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and -C(O)N(R1)(R2);Each R7is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted -Ci-Cs alkyl, optionally substituted -Cs-Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -Ci-Cs alkoxy, -NR1R2, -SR1, -SO2R1. -CCOMR^R2). -N(R1)C(O)(R2), - N(R1)C(O)OR2, -N(R3)C(O)NR1R2. and -N(R1)S(O)2(R2); alternatively, R4and R5are taken together with the carbon atom to which they are attached to form optionally substituted -Cs-Cs cycloalkyl or optionally substituted 4- to 8-membered heterocyclic containing 0, 1, 2, or 3 double bonds;alternatively, R3and R6are taken together with the carbon atoms to which they are attached and any intervening carbon atoms to form optionally substituted -C3-C8 cycloalkyl or an optionally substituted 4- to 8- membered heterocyclic containing 0. 1, 2, or 3 double bonds;alternatively, R6and R7are taken together with the carbon atom to which they are attached to form optionally substituted -C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocyclic containing 0, 1, 2. or 3 double bonds; andR9is selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alkyd, optionally substituted -C2-C8 alkenyl, optionally substituted -Cs-Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, -S(O)2R1,-C(O)N(R1)(R2), -CCOXR1), and -C(O)OR1.

2. The compound of claim 1 represented by one of Formula (V-l) ~ (V-4):PAGE 132 OF 152Docket No. 4014.1410 WOare as defined in claim 1.

3. The compound of claim 1 represented by Formula (VI):wherein two of V1, V2, V3, and V4independently are N, CH, or CR17; and the remainder are independently CH or CR17; R17is selected from the group consisting of halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -Cs-Cs cycloalkyd, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -P(O)R1R2, and -C(O)N(R1)(R2); and R1, R2, RA, RB, Rc, RD. RE. Y1. Y2. X1. X2. X3. and L are as defined in claim 1.PAGE 133 OF 152Docket No. 4014.1410 WO4. The compound of claim 1 represented by one of Formulae (XI-1) ~ (XI-10):wherein two of V1, V2, V3, and V4independently are N, CH, or CR17; and the remainder are independently CH or CR17; R17is selected from the group consisting of halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -C -Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -P(O)R1R2, and - C(O)N(R’)(R2); and R1, R2, R4, R5, R6, R7, R9, RA, RR, RC, RD, RF, Y1, Y2, X1, X2, X3, and are as defined in claim 1.PAGE 134 OF 152Docket No. 4014.1410 WO 5. The compound of claim 1 represented by one of Formulae (XXI-1) ~ (XXI-20):PAGE 135 OF 152Docket No. 4014.1410 WOwherein q is 0, 1. 2, or 3;R11is selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alky l, optionally substituted -C3-C8 cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyd, optionally substituted heteroarylalkyl, and optionally substituted heteroaryl;R12is selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alky 1, optionally substituted -C2-C8 alkenyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl alkyl, and optionally substituted heteroaryl;RG2IS RG;PAGE 136 OF 152Docket No. 4014.1410 WOR17is selected from the group consisting of halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -Ci-Cs alkoxy, optionally substituted -Cs-Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -P(O)R1R2, and C(O)N(R1)(R2); and RD, RG, R1, R4, R5, R6, R7, R8, and R9are as defined in claim 1.

6. The compound of claim 1 represented by one of Formulae (XXVI-1) ~ (XXVI-4):wherein q is 0, 1, 2, or 3; R17IS selected from the group consisting of halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -Ci-Cs alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted ary l, optionally substituted heteroaryl, -P(O)R1R2, and -C(O)N(R1)(R2); RG1is RG; RG2is RG; RG3is RG; RA, RG, RD, R1, R2, R4and R6are as defined in claim 1.

7. The compound of claim 1 represented by one of Formulae (XXIX- 1) ~ (XXIX-8):wherein q is 0, 1, 2. or 3; R17is selected from the group consisting of halogen, cyano, optionally substituted -Ci-Cs alkyl, optionally substituted -Ci-Cs alkoxy, optionallyPAGE 137 OF 152Docket No. 4014.1410 WOsubstituted Cs-Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -P(O)R1R2. and - C(O)N(R1)(R2); RG1is RG; RG2is RG; RG3is RG; and RGis as defined in claim 1.Pk J Wl5 8. A compouSn fd sselected from the compounds set forth below, or a pharmaceutically acceptable salt thereof:p\= / pQA- Compound Structure “ O Compound StructureZpI1 2p / \ o=' / z z—■**0 1 > J! / 3 4 / z z—Jl z z—Jlb NP^ / -f \ _W / TTi 6y9 ^ 0 / J°‘** rz z— )( p== ^^***z* NH / 2° Pk\= / Q- r< P y z\ / =—.^ o ' oo=— 9 5 6 ^ ' •O-n TI=- z zXN" N / =\A0 r^\ JLN"^l [1 \ H7 80\ 1F PF F NH2^^^o9 %O^Z'NX9 10XN-X. N _— / =\ ff— / GN^X]N«sZ V ffPAGE 138 OF 152Docket No. 4014.1410 WO z 0*Z CD / O'* e Mi / / / \ / \ o 0=oz='z— zz- zz- J k! 12 *s.^***J M!zJ k!.N^ —Z^^O. Z ZO-Z-^ i As*ZD C YW 'VO>; F9 Q1fj o?6 i T / 1 z z / A / \T I NH2z / zz><- — / z—= o / Q^° 14 v Qs^N _ JC M PP L r’ ^ « oo P \ | 1 P Mw° ° / / < N>2" H X I I KJ Mx6-o-<x> CF316 / \ o= / F 0 J!^Q1\ / / V ^ 18 6 J° ' Xz z—'"‘N / -X / N*~lfkRr r^Me-o C T 61H20P A 1 1 Me. U ' i 1 N 1 ^N N— ( JzT^ V.— / G 'MSN^Z \_ / \ CF3Me22PAGE 139 OF 152Docket No. 4014.1410 WOPAGE 140 OF 152Docket No. 4014.1410 WOPAGE 141 OF 152Docket No. 4014.1410 WOPAGE 142 OF 152Docket No. 4014.1410 WO F O / / zz z z—— ljzS<tKNH2z z z z—— )\ G=J V J! I J J kI.^^.szoz560 — y J JXN~A p \r✓N''ri N d 6 J N«& / \ _ / ^ ^ —zzz— A / / ( >< p p £>\==== / = / / Ji?P2QJ Uz- y=| ^ —\\ / x \ / \ o — ®°=Q 2 / °=- ° °q° t / / / / z 58< X z < z N I> Q X X K N>>IN <* z\ / \ °°\ / p >=■"“WK- W- y\J r 60 / / zz— zz—JI JS^ ^z ^^oo-z6^x c-zzz— A n / °=\ / / 62 5O / zz’“"" / _="l Z\\ v - / o y—Q / < z < z I N> K>F O r^#|p ^NH2*~O 1 I 64 O — i J jXNX / -A / NvSN*s / \ _ / \^<s. JkFPAGE 143 OF 152M C Docket No. 4014.1410 WO X X X z * z > z > \ p \\ 7 \ \ i p \ °° °^~ — UJU J / / z z— z z JI— / \ l\ / \ ° ° ° J J===z^A°z rS.^^Z66Q us 1Nsv^4°zZ\= / zz \ / / ? AI I- vo / z z— / / |Uj JZr^S!Y-SNH2V'wo- < zMei X K> X 680 A 1 \ K> / _V / NV^rFuHllX CMz >\ p\ °— o ^oc -- ]\ o o=U J _ T^O ^■0 1 1 r^\ _^ zZ70p — \ 1 i QTM1-vrAJUL 01J A \ ff F O / z— ' z z— / [|!J ^NH2720 -*\ J |XNX / =V / N-AN' '^^NZ^CF374PAGE 144 OF 152Docket No. 4014.1410 WOPAGE 145 OF 152Docket No. 4014.1410 WOPAGE 146 OF 152Docket No. 4014.1410 WOPAGE 147 OF 152Docket No. 4014.1410 WOPAGE 148 OF 152Docket No. 4014.1410 WOPAGE 149 OF 152Docket No. 4014.1410 WO Cl X* z p(Zo=- F O o 11 *1NH2)\ o=' IT^INH2 / z z— y^0a J k!.N^-zo -z60aO -— yHN-\ / =\ / " IANHN-\ / =\ / N~1I 'NM y XHIA VF3N^ / “ 9W - ~Vl ''A / XCF, F O 0 IAANH2vJ " Ij'^ySin, yA a 62a Q^NU^^A,O '"'A l lX N) / =\ / N'"7I *N NVAMJU OCF3NVA / VUX ^ccr.66a 64aJfV^ _y=\2 / 'Ti2NN\ / ? \A A / z z—k J!.F 0dAa O- ^N^g^JL 66 a- \ |°=\ / / C hrX> YHXA ^CF3° / \ F ^z)oo O=- < z X N>a 68a o^XffiiA 1 TXM-A / =\ / NTIS>N MYTAXA "-CF3o o IT^INHZlf^sl 'NH2y^o a 70aP X V'A oH\<yN'«AXN-\ / =\ / N'1AN XNX / =\ / N'TAN ^ “W ' - ' - VI ^AXF3NVNv ' - / ' vlS^A^CF3PAGE 150 OF 152Docket No. 4014.1410 WO9. A pharmaceutical composition comprising a compound of any one of claims 1 to 8 and a pharmaceutically acceptable earner.

10. A method for treating a disease, disorder, or condition where modulation of STAT6 or STAT3 is implicated, wherein the method comprises administering to a system or subject in need of such treatment an effective amount of a compound of any one of claims 1 to 8.

11. The method of claim 10, wherein said disease involving STAT6 is an allergic disease or an inflammatory disease.

12. The method of claim 11, wherein said the disease involving STAT6 is one or more diseases selected from the group consisting of chronic obstructive pulmonary disease, atopic dermatitis, bronchial asthma, bullous pemphigoid, nasal polyps, chronic sinusitis, allergic rhinitis, eosinophilic esophagitis, prurigo, and urticaria.

13. The method of claim 10, wherein said disease involving STAT3 is one or more diseases selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, and inflammatory bowel disease.PAGE 151 OF 152

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