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 and allergic disease, including asthma and atopic dermatitis associated with STAT proteins, especially associated with IL-4 signaling.

Description

[0001] Docket No. 4014.1407 WO

[0002] ANTI-INFLAMMATORY COMPOUNDS

[0003] RELATED APPLICATION

[0004] This application claims the benefit of U. S. Provisional Application No. 63 / 764,216, filed February727, 2025. The entire teachings of the above application 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 a pleotropic cytokine involved in host defense, development of hematopoietic stem cells (HSCs) and non-HSCs, metabolism, and autoimmunity7. 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 autoinfl ammatory diseases. Inhibitors of JAK tyrosine kinases involved in promulgating inflammatory7signaling 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 necessary7and 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 ty pe 2 inflammatory7diseases 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 77Docket No. 4014.1407 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] WO2014182928, WO2023192960, WO2023164680, WO2023133336, and W02024071439 disclose small molecule STAT6 inhibitors, but 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; RAis selected from the group consisting of:

[0019] 1) Optionally substituted 4- to 12- membered heterocycloalkyl;

[0020] 2) Optionally substituted aryl;

[0021] 3) Optionally substituted arylalkyl;

[0022] 4) Optionally substituted heteroaryl;

[0023] 5) Optionally substituted heteroaiylalkyl;

[0024] 6) -C(O)N(RI)(R2);

[0025] 7) -N(RI)C(O)(R2);

[0026] 8) -N(RI)C(O)OR2; and

[0027] 9) -N(R3)C(O)N(RI)(R2);

[0028] RBis selected from the group consisting of:

[0029] PAGE 2 OF 77Docket No. 4014.1407 WO

[0030] 1) Hydrogen;

[0031] 2) Halogen;

[0032] 3) Cyano;

[0033] 4) Hydroxy;

[0034] 5) Optionally substituted -Ci-Cs alkyl;

[0035] 6) Optionally substituted -C2-C8 alkenyl;

[0036] 7) Optionally substituted -C2-C8 alkynyl;

[0037] 8) Optionally substituted -Ci-Cs alkoxy;

[0038] 9) Optionally substituted -C3-C12 cycloalkyl;

[0039] 10) Optionally substituted 4- to 12- membered heterocycloalkyl;

[0040] 11) Optionally substituted ary l;

[0041] 12) Optionally substituted heteroaryl;

[0042] 13) -C(O)N(RI)(R2);

[0043] 14) -N(RI)C(O)(R2);

[0044] 15) -NRIR2;

[0045] 16) -N(RI)S(O)2(R2);

[0046] 17) -S(O)2RI; and

[0047] 18) -P(O)RIR2

[0048] L1is selected from the group consisting of -[C(Rs)(R6)]n-, -C(Rs)(R6)C(O)-, and -C(RS)=C(R6)-; n is 1 or 2;

[0049] RFis selected from the group consisting of

[0050] 1) Hydrogen;

[0051] 2) Halogen;

[0052] 3) Cyano;

[0053] 4) Optionally substituted -Ci-Cs alkyl;

[0054] 5) Optionally substituted Cs-Cs cycloalkyl;

[0055] 6) Optionally substituted 4- to 8- membered heterocycloalkyl;

[0056] 7) Optionally substituted ar l;

[0057] 8) Optionally substituted heteroaryl;

[0058] 9) Optionally substituted -Ci-Cs alkoxy; and

[0059] 10)-C(O)N(RI)(R2);

[0060] Y1and Y2are each independently selected from the group consisting of N and CRD;

[0061] PAGE 3 OF 77Docket No. 4014.1407 WO

[0062] RDis selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-Cs alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted ~C -Cs cycloalkyl, optionally substituted 4-to 8- membered heterocycloalkyl, optionally substituted -Ci-Cs alkoxy, optionally substituted aryl, optionally substituted heteroaryl, -NR1R2, -SRi, -SO2R1. -C(O)N(RI)(R2), -N(RI)C(O)(R2), - N(RI)C(O)O(R2), -N(RI)S(O)2(R2), and -P(O)RIR2;

[0063] X1, X2, and X3are each independently selected from the group consisting of N and CRE;

[0064] REis independently selected from the group consisting of:

[0065] 1) Hydrogen;

[0066] 2) Halogen;

[0067] 3) Cyano;

[0068] 4) Hydroxy;

[0069] 5) Optionally substituted -Ci-Cs alkyl;

[0070] 6) Optionally substituted -C2-Cs alkenyl;

[0071] 7) Optionally substituted -C2-C8 alkynyl;

[0072] 8) Optionally substituted -Cs-Cs cycloalkyl;

[0073] 9) Optionally substituted 4- to 8- membered heterocycloalkyl;

[0074] 10) Optionally substituted aryl;

[0075] 11) Optionally substituted heteroaryl;

[0076] 12) Optionally substituted -Ci-Cs alkoxy;

[0077] 13)-C(O)N(RI)(R2);

[0078] 14)-N(RI)C(O)(R2);

[0079] 15)-N(RI)(R2);

[0080] 16)-SRI;

[0081] 17)-S(O)2RI;

[0082] 18)-N(RI)C(O)O(R2);

[0083] 19)-N(RI)S(O)2(R2); and

[0084] 20)-P(O)RIR2;

[0085] L2is selected from the group consisting of -C(O)N(Ri)-, -C(R7)(Rs)O-, and -[C(R7)(R8)]2-,

[0086] PAGE 4 OF 77Docket No. 4014.1407 WO

[0087]

[0088] is selected from the group consisting of optionally substituted -C3-C12 cycloalkyl, optionally substituted 3- to 12- membered heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;

[0089] Ri, R2, and Rs are each independently selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C's-C’s cycloalkyl, optionally substituted 3- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyd, optionally substituted heteroarylalkyl, and optionally substituted heteroaryl; when, alternatively, Ri and R2 are attached to the same nitrogen atom and are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds;

[0090] each Rs is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted -Ci-Cs alkyl, optionally substituted -C3-C8 cycloalkyd, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted -Ci-Cs alkoxy, and -C(O)N(Ri)(R2);

[0091] each Re is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -Cs-Cs cycloalkyl. and optionally substituted 4- to 8- membered heterocycloalkyl;

[0092] alternatively, Rs and Re are taken together with the carbon atom to which they are attached to form an optionally substituted C3-C8 cycloalkyl ring or optionally substituted 4- to 8- membered heterocyclic containing 0, 1, 2, or 3 double bonds;

[0093] alternatively, L1is -[C(Rs)(R6)]n- where n is 2, and the two Rs groups are taken together with the carbon atoms to which they are attached to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8- membered heterocyclic containing 0, 1, 2, or 3 double bonds;

[0094] each R?is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Cs-Cs cycloalkyl, and optionally substituted 4- to 8- membered heterocycloalkyl;

[0095] each Rs is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C3-C8 cycloalkyl, and optionally substituted 4- to 8- membered heterocycloalkyl;

[0096] PAGE 5 OF 77Docket No. 4014.1407 WO

[0097] alternatively, R? and Rs are taken together with the carbon atom to which they are attached to form an optionally substituted Cs-Cs cycloalkyl cycloalkyl ring or optionally substituted 4-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds;

[0098] alternatively, L2is -[C(R?)(Rs)]2-, and the two R? groups are taken together with the carbon atoms to which they are correspondingly attached to form an optionally substituted Cs-Cs cycloalkyl or optionally substituted 4-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds.

[0099] DETAILED DESCRIPTION OF THE INVENTION

[0100] In one embodiment, the present invention provides a compound of Formula (I) as described above or a pharmaceutically acceptable salt thereof.

[0101] In certain embodiments of the compounds of Formula (I), Y1is CRD. Preferably, Y1is CH.

[0102] In certain embodiments of the compounds of Formula (I), Y2is CRD. Preferably, Y2is CH.

[0103] In certain embodiments of the compounds of Formula (I), Y1is CH, and Y2is CH. 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.

[0104] In certain embodiments of the compounds of Formula (I), RFis hydrogen, halogen, or optionally substituted -Ci-Cs alkyl. In certain embodiments of the compounds of Formula (I), RFis hydrogen or optionally substituted -Ci-Cs alkyl. In certain embodiments of the compounds of Formula (I), RFis optionally substituted methyl or optionally substituted phenyl.

[0105] Preferably, RFis hy drogen or optionally substituted methy l.

[0106] In certain embodiments of the compounds of Formula (I), X1is CRE, and REis hydrogen, halogen, or optionally substituted -Ci-Cs alkyl. In certain embodiments X1is N. In certain embodiments X1is CH.

[0107] In certain embodiments of the compounds of Formula (I), X2is CRE, and REis hydrogen, halogen, or optionally substituted -Ci-Cs alkyl. In certain embodiments X2is C-CF3.

[0108] PAGE 6 OF 77Docket No. 4014.1407 WO

[0109] In certain embodiments of the compounds of Formula (I), X3is CRE, and REis hydrogen, halogen, or optionally substituted -Ci-Cs alkyl. In certain embodiments X3is N. In certain embodiments, X3is CH.

[0110] In certain embodiments of the compounds of Formula (I), L1is -CH2-, -CH2CH2-, or -CH=CH- In certain embodiments of the compounds of Formula (I). L2is -C(O)N(Ri)-.

[0111] Preferably, L2is -C(O)NH-.

[0112] In certain embodiments of the compounds of Formula (I),

[0113]

[0114] is optionally substituted aryl and optionally substituted hetereoar l. In certain embodiments of the

[0115] compounds of Formula (I), o is derived from one of the following by removal of a hydrogen atom and is optionally substituted

[0116]

[0117] PAGE 7 OF 77Docket No. 4014.1407 WO

[0118] In certain embodiments of the compounds of Formula (I),

[0119]

[0120] is optionally substituted phenyl.

[0121] In certain embodiments of the compounds of Formula (I). RAis optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 4- to 8- membered heterocycloalkyl.

[0122] In certain embodiments of the compounds of Formula (I), RAis optionally substituted aryl or optionally substituted heteroar l.

[0123] In certain embodiments of the compounds of Formula (

[0124]

[0125] I), RAis

[0126]

[0127] R11is independently selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alkyd, optionally substituted -Cs-Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroaryl;

[0128] R12is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C?-Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroaryl;

[0129] alternatively, R11and R12are taken together with the nitrogen atom and carbon atom to which they are respectively attached to form an optionally substituted heteroaryl or an optionally substituted 5-8 membered heterocycloalkyl;

[0130] each R13is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, and optionally substituted -Ci-Cs alkoxy;

[0131] alternatively, two R13 groups are taken together with the carbon atom to which they are attached to form an optionally substituted -C3-C8 cycloalkyl or optionally substituted 4-to 8- membered heterocycloalkyl;

[0132] each R14is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, and optionally substituted -Ci-Cs alkoxy;

[0133] PAGE 8 OF 77Docket No. 4014.1407 WO

[0134] alternatively, two R14groups are taken together with the carbon atom to which they are attached to form an optionally substituted -Cs-Cs cycloalkyl or optionally substituted 4-to 8- membered heterocycloalkyd;

[0135] each R15is independently selected from the group consisting of hydrogen and optionally substituted -Ci-Cs alkyl;

[0136] alternatively, two R15groups are taken together with the carbon atom to which they are correspondingly attached to form an optionally substituted -Cs-C's cycloalkyl or optionally substituted 4- to 8- membered heterocycloalky 1;

[0137] alternatively, RAis

[0138] A

[0139]

[0140] 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 3- to 8-membered heterocycloalkyl;

[0141] alternatively, RAis

[0142]

[0143] and one R13and one R14are taken together with the carbon atoms to which they are attached and the intervening oxygen atom to form an optionally substituted 4- to 8-membered heterocycloalkyl;

[0144] alternatively, one R14and one R15are taken together with the carbon atoms to which they are attached to form an optionally substituted -Cs-Cs cycloalkyl or an optionally substituted 4- to 8- membered heterocycloalkyl;

[0145] Me.

[0146] In certain embodiments of the compounds of Formula (I), RAis

[0147]

[0148] Ni=s / A I N- NSfc /

[0149]

[0150] PAGE 9 OF 77Docket No. 4014.1407 WO

[0151] In certain embodiments of the compounds of Formula (I), RAis

[0152]

[0153] o

[0154]

[0155] , 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.

[0156] In certain embodiments, the compound of Formula (I) is represented by Formula (II):

[0157]

[0158] wherein RD1is RD; RD2is RD; and RA, RB, R1. L1, L2, X1, X2, X3, and

[0159]

[0160] are as previously defined.

[0161] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (III- 1 ) to (III- 3 ):

[0162]

[0163] previously defined.

[0164] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (IV- 1) to (IV-3):

[0165] PAGE 10 OF 77Docket No. 4014.1407 WO

[0166]

[0167] (IV-1) (IV-2) (IV-3)

[0168] wherein RE2, RA, RB, RF, L1, L2, and ' ' are as previously defined.

[0169] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (V-1) to (V-3):

[0170]

[0171] wherein RE2, RA, L1, L2, and

[0172]

[0173] Kz are as previously defined.

[0174] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (VI-1) to (VI-3):

[0175]

[0176] (VI-1) (VI-2) (VI-3) wherein R5ais R5; R5bis R5; R6ais R6; R6bis R6; and Y1, Y2, RA, RB, RF, L2, X1, X2, X3, and A N_z are as previously defined.

[0177] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (VII- 1) to (VII-3):

[0178] PAGE 11 OF 77Docket No. 4014.1407 WO

[0179]

[0180] (VII-1) (VII-2) (VII-3)

[0181] wherein R

[0182]

[0183] 5a, R5b. R6a, R6b, R5, R6, RD1, RD2, RA, RB, RF, L2, X1, X2, X3, and are as previously defined.

[0184] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (VIII- 1) to (VIII-9):

[0185] w

[0186]

[0187] herein R5a, R5b, R6a, R6b, R5, R6, RD1, RD2, RA, RB, RF, L2, RE1, RE2, RE3, and are as previously defined.

[0188] PAGE 12 OF 77Docket No. 4014.1407 WO

[0189] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (IX- 1) to (IX-9):

[0190]

[0191] In certain embodiments, the compound of Formula (I) is represented by Formula (X):

[0192] RF

[0193]

[0194] (X)

[0195] wherein Y1, Y2, RA, RB, R1. L1, R1, X1, X2, X3, and

[0196]

[0197] are as previously defined.

[0198] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (X-a) to (X-c):

[0199] PAGE 13 OF 77Docket No. 4014.1407 WO

[0200] wherein R5ais R5; R5bis R5; R6ais R6; R6bis R6; and Y1, Y2, RA, RB, RF, R1, X1, X2, X3and

[0201]

[0202] are as previously defined.

[0203] In certain embodiments, the compound of Formula (I) is represented by one of

[0204] (XI-1) (XI-2) (XI-3)

[0205]

[0206] PAGE 14 OF 77Docket No. 4014.1407 WO

[0207] wherein R

[0208]

[0209] 5a, R5b, R6a, R6b, R5, R6, RA, RB, RF, R1, RD1, RD2, RE1, RE2, RE3and are as previously defined.

[0210] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XII- 1) to (XII-9):

[0211]

[0212] wherein R5a, R5b. R6a, R6b, R5, R6, RA, RF, R1,

[0213]

[0214] RE2and ' — ' are as previously defined.

[0215] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XIII- 1) to (XIII-9):

[0216] PAGE 15 OF 77Docket No. 4014.1407 WO

[0217]

[0218] wherein R1. R5a, R5b, R6a. R6b, R5, R6, R11, R12, RF, RE2and

[0219]

[0220] X — ' are as previously defined.

[0221] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XIV- 1) to (XIV-9):

[0222] PAGE 16 OF 77Docket No. 4014.1407 WO

[0223]

[0224] wherein m is 0, 1, 2, 3, or 4; R21is selected from the group consisting of:

[0225] 1) Halogen;

[0226] 2) Cyano;

[0227] 3) Hydroxy;

[0228] 4) Optionally substituted -Ci-Cs alkyl;

[0229] 5) Optionally substituted -Cs-Cs cycloalkyl;

[0230] 6) Optionally substituted 4- to 8- membered heterocycloalkyl;

[0231] 7) Optionally substituted aryl;

[0232] 8) Optionally substituted heteroaryl;

[0233] 9) Optionally substituted -Ci-Cs alkoxy;

[0234] 10)-C(O)N(RI)(R2);

[0235] 11)-N(RI)C(O)(R2);

[0236] 12)-N(RI)(R2);

[0237] PAGE 17 OF 77Docket No. 4014.1407 WO

[0238] 13)-SRi;

[0239] 14)-S(O)2RI;

[0240] 15)-N(RI)C(O)O(R2);

[0241] 16)-N(RI)S(O)2(R2); and

[0242] 17)-P(O)RIR2;

[0243] and R5a, R5b, R6a, R6b, R5, R6, R1, R2. R11, R12, RF, and RE2are as previously defined. In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XV- 1) to (XV-9):

[0244]

[0245] wherein r is 0, 1, 2, or 3; R1, R21, R5a, R5b, R6a, R6b, R5, R6, R11, R12, and RE2are as previously defined.

[0246] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XVI- 1) to (XVI-9):

[0247] PAGE 18 OF 77Docket No. 4014.1407 WO

[0248]

[0249] wherein r, R21, R5a. R5b, R6a, R6b, R5. and R6are as previously defined. In certain embodiments, r is 1, 2. or 3 and each R21 is F.

[0250] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XVII- 1) to (XVII-4):

[0251] PAGE 19 OF 77Docket No. 4014.1407 WO

[0252]

[0253] ( B )

[0254] wherein — ' is optionally substituted -C3-C6 cycloalkyl or optionally substituted 4- to 6- ( c )

[0255] membered heterocycloalkyl; is optionally substituted -C3-C6 cycloalkenyl, optionally substituted 4- to 6- membered heterocycloalkyl containing 1, 2, or 3 double bonds, optionally substituted aryl, or optionally substituted heteroary l; and R5, R6, Y1, Y2, RA, RB,

[0256]

[0257] RF, L2, X1, X2, X3, and are as previously defined.

[0258] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XVIII-1) to (XVIII-12):

[0259]

[0260] PAGE 20 OF 77Docket No. 4014.1407 WO

[0261]

[0262] wherein

[0263]

[0264] R5, R6, RA, RE2, RF, L2, and are as previously defined.

[0265] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XIX- 1) to (XIX- 12):

[0266]

[0267] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XX-1) to (XX-12):

[0268] PAGE 21 OF 77Docket No. 4014.1407 WO

[0269]

[0270] R5, R6, R11, R12, RE2, RF, R1, R21, and m are as previously defined.

[0271] In certain embodiments, the compound of Formula (I) is represented by one of Formulas (XXI-1) to (XXI-12):

[0272] PAGE 22 OF 77Docket No. 4014.1407 WO

[0273]

[0274] wherein

[0275]

[0276] , R5, R6, R21and m are as previously defined.

[0277] Each preferred group stated above can be taken in combination with one, any or all other preferred groups.

[0278] 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

[0279] PAGE 23 OF 77Docket No. 4014.1407 WO

[0280] may be necessary to remove a hydrogen atom in order to accommodate a substituent at any given location.

[0281] 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.

[0282] 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 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.

[0283] 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.

[0284] It should be understood that the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agent.

[0285] DEFINITIONS

[0286] 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.

[0287] 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 C6-C10-aryl groups, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic ary l is a polycyclic ring system that comprises at least one aromatic ring.

[0288] Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.

[0289] PAGE 24 OF 77Docket No. 4014.1407 WO

[0290] 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. Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl. pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. A heteroaryl group can be C-attached or N-attached where possible.

[0291] In accordance with the invention, aryl and heteroaryl groups can be substituted or unsubstituted.

[0292] 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.

[0293] 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 alkyd,” and " C3-C6 alkyl,” 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, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl and n-octyl radicals.

[0294] 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.

[0295] 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 “C -C6 alkynyl,” refer to alkynyl groups containing from 2 to 8, 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.

[0296] PAGE 25 OF 77Docket No. 4014.1407 WO

[0297] 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-C12cycloalkyl, C5-C6cycloalkyl, C3-C8cycloalkyl and C4-C7cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.

[0298] 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-C12cycloalkenyl, C4-C12-cycloalkenyl, C3-C8cycloalkenyl, C4-C8cycloalkenyl and C5-C7cycloalkenyl 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.

[0299] 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-heteroaryl, 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.

[0300] 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 C1-C12-alkoxy, C1-C8-alkoxy, C1-C6-alkoxy, C1-C4-alkoxy and C1-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.

[0301] 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.

[0302] PAGE 26 OF 77Docket No. 4014.1407 WO

[0303] 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.

[0304] The terms “heterocyclic’' and “heterocycloalkyf’ can be used interchangeably and refer to a non-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 quaternized. (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 heterocycloalkyl 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. l]-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 heterocycloalkyl groups may be further substituted. A heterocycloalkyl or heterocyclic group can be C-attached or N-attached where possible.

[0305] 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.

[0306] PAGE 27 OF 77Docket No. 4014.1407 WO

[0307] 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-Ci2-alkenyl, C2-Ci2-alkynyl, -C3-Ci2-cycloalkyl, protected hydroxy, -NO2, -Ns, -CN, -NH2, protected amino, oxo, thioxo, -NH-Ci-Ci2-alkyl, -NH-C2-C8-alkenyl, -NH-Ch-Cs-alkynyl. -NH-C3-Ci2-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci2-alkyl, -O-C2-Cs-alkenyl, -O-C2-C8-alkynyl, -O-C3-Ci2-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C12-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-Cs-alkenyl, -CONH-C2-Cs-alkynyl, -CONH-C3-Ci2-cycloalkyl, -CONH-aryl, -CONH-heteroaryl. -CONH-heterocycloalkyl, -OCO2-Ci-Ci2-alkyl, -OCO2-C2-Cs-alkenyl, -OCO2-C2-C8-alkynyl, -OCO2-C3-Ci2-cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C1-C12 alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, -CO2-C3-Ci2-cycloalkyl, -CO2-aryl, -CO2-heteroaryl, -CO2-heterocyloalkyl, -OCONH2, -OCONH-Ci-Ci2-alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-C12-cycloalkyl, -OCONH-aryl. -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)H, -NHC(O)-Ci-Ci2-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2-C1-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-C3-C12-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-C8-alkenyl, -NHC(NH)NH-C2-Cs-alkynyl, -NHC(NH)NH-C3-Ci2-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -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-Cs-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-Cs-alkenyl, - S(O)-C2-C8-alkynyl, -S(O)-C3-C12-cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-C1-Ci2-alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH-C2-C8-alkynyl, -SO2-Ci-Ci2-alkyl, -SO2-C2-C8-

[0308] PAGE 28 OF 77Docket No. 4014.1407 WO

[0309] 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, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C12-alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C12-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; C3-C8-cycloalkyl, such as cyclopropyl; Ci-C4-alkoxy, such as methoxy and ethoxy; halo-Ci-C4-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, 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-alkyl; -CFs, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN, and -NH2. Preferably, a substituted alkyl group is substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms.

[0310] The term “halo” or halogen” alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.

[0311] 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.

[0312] 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.

[0313] PAGE 29 OF 77Docket No. 4014.1407 WO

[0314] 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, / ?-nitrobenzoate, phosphonate and the like.

[0315] 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.

[0316] 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, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, 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.

[0317] 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.

[0318] 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.

[0319] (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).

[0320] 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

[0321] PAGE 30 OF 77Docket No. 4014.1407 WO

[0322] 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.

[0323] The term “protected amino,” as used herein, refers to an amino group protected with an amino protecting group as defined above.

[0324] 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.

[0325] 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. 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.

[0326] 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 solubility 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

[0327] PAGE 31 OF 77Docket No. 4014.1407 WO

[0328] Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.

[0329] 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).

[0330] 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. 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 editions thereof.

[0331] 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.

[0332] 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.

[0333] 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

[0334] PAGE 32 OF 77Docket No. 4014.1407 WO

[0335] 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.

[0336] Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation 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.

[0337] 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 / risk 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.

[0338] PAGE 33 OF 77Docket No. 4014.1407 WO

[0339] 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, / Moluencsul fonate, 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.

[0340] 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, cycloalkanoic and alkanedioic acids, in which each alkyl 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, acry lates and ethylsuccinates.

[0341] PHARMACEUTICAL COMPOSITIONS

[0342] 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.

[0343] 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 ty pe. 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 non-

[0344] PAGE 34 OF 77Docket No. 4014.1407 WO

[0345] toxic 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.

[0346] 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.

[0347] 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.

[0348] 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

[0349] PAGE 35 OF 77Docket No. 4014.1407 WO

[0350] synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0351] 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.

[0352] 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 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.

[0353] 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.

[0354] 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, polyvinylpyrrohdinone, 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, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene

[0355] PAGE 36 OF 77Docket No. 4014.1407 WO

[0356] glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0357] 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.

[0358] 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.

[0359] 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 required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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:

[0364] PAGE 37 OF 77Docket No. 4014.1407 WO

[0365] that is, particles of a size sufficiently small to pass through the mouth and lary nx 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.

[0366] 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).

[0367] ABBREVIATIONS

[0368] 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, BOC2O for di-tert-butyl-dicarbonate; Boc for / -butoxy carbonyl; BuOH for n-butyl alcohol; Bz for benzoyl; Bn for benzyl; t-BuOK for potassium t -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 diethylazodicarboxylate; DIAD for diisopropyl 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;

[0369] DMAP for 4-dimethylamino-pyridine; DME for 1,2-dimethoxy ethane; DMF for N, N-dimethylformamide; DMSO for dimethy l 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; n-BuLi for n-buty l 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 methoxy methyl; 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; Na2S2O3 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 polyphophoric acid; PTSA for -tol uenesul Ionic acid; PPTS for py ridinium / 2-toluenesul fonate; TBAF for tetrabutylammonium fluoride; TEA or Et3N for triethylamine; TES for tri ethylsilyl; TESC1 for triethylsilyl chloride; TESOTf for triethylsilyl trifluoromethanesulfonate; TFA for trifluoroacetic acid; THF for tetrahydrofuran; TMEDA

[0370] PAGE 38 OF 77Docket No. 4014.1407 WO

[0371] for N, N, N’, N’-tetramethylethylene-diamine; TPP or PPh3 for triphenyl-phosphine; Tos or Ts 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)3 for tris(diben-zylideneacetone) dipalladium (0); Pd(PPh3)4 for tetrakis(triphenylphosphine)-palladium (0); PdCl2(PPh3)2 for trans-dichlorobis-(triphenylphosphine)palladium (II); PdCl2(dppf) 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', TV'-tetramethylchloroformamidinium hexafluorophosphate); TMS for trimethylsilyl; or TMSC1 for trimethylsilyl chloride.

[0372] SYNTHETIC METHODS

[0373] 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 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.

[0374] A non-limiting example of a synthetic scheme demonstrating the making of compounds of the invention is illustrated in Scheme 1.

[0375] PAGE 39 OF 77Docket No. 4014.1407 WO

[0376]

[0377] Scheme 1 illustrates a general method for the preparation of compounds of the formula (1-13) from intermediates (1-1), (1-2), and (1-4), wherein RA, RB, RF, R1, R5, R6, X1, X2, X3, Y1, Y2,

[0378] and ( N? — ') are as previously defined. First, arene (1-1) is reacted with olefin (1-2) by way of a metal-catalyzed cross-coupling reaction to furnish (1-3), wherein G1and G2are (pseudo)halogens, G1is selected to be less reactive than G2in this first cross-coupling reaction, and G3represents a metal, including, but not limited to, B(OH)2, BFsK. ZnX, where X is halogen and SnRs, where R is Ci-C4-alkyl. Next, cross-coupling product (1-3) is reacted with (1 -4) via second metal-catalyzed cross coupling event to provide ( 1 -5), wherein PG1represents a viable protecting group, G4represents a metal, including, but not limited to, B(OH)2, BFSK, ZnX, SnRa. and G5is a Ci-Cs alky l group. Protecting groups are described in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons, New York (1999). Alternatively, G4is a (pseudo)halogen, and G1is first converted to a metal (B(OH)2, BFsK, ZnX, SnR?,. etc.) prior to the second metal-catalyzed cross coupling event leading to (1-5). Intermediate (1-5) is then reacted in a hydrometallation reaction to furnish (1-6), wherein [M1]-!! is typically, but not limited to, a dialkylborane group. Oxidation of the intermediate organometallic (1-6) provides alcohol (1-7). Removal of

[0379] PAGE 40 OF 77Docket No. 4014.1407 WO

[0380] the protecting group, PG1, provides (1-8). Alcohol (1-8) is converted to a suitable leaving group, LG1, which includes pseudo(halogens). Treatment of intermediate (1-9) with base affords cyclized (1-10). Conversion of (1-10) to carboxylic acid (1-11) can be accomplished under standard basic hydrolysis conditions. Finally, reaction of (1-11) with amine (1-12) under commonly employed amide coupling conditions (HATU, EDC, DCC, TCFH, Ghosez reagent, etc.) affords (1-13).

[0381] EXAMPLES

[0382] 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.

[0383] General Conditions:

[0384] 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 a 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.

[0385] [M+H]+refers to mono-isotopic molecular weights.

[0386] 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).

[0387] 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.

[0388] Alternatively, compounds were purified via normal-phase liquid chromatography (NPLC) using a Teledyne ISCO Combiflash purification system. Compounds were purified

[0389] PAGE 41 OF 77Docket No. 4014.1407 WO

[0390] on a REDISEP silica gel cartridge. Compounds were purified at 298K and detected at 254 nm wavelength.

[0391] Example 1: Synthesis ofN-(3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5- dihydro-4H-l,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline- carboxamide.

[0392] MeI (1.0 equiv) (2.4 equiv) KOt-Bu (2.0 equiv) (1.5 equiv) MeC(OEt)3(2.4 equiv) DMF (0.4 M) PdCI2(dppf) (5 mol%) pTSA·H2O (0.1 equiv) rt, 3 h Cs2CO3(2.0 equiv) 1-BuOH (0.7M) step 2 120 °C, 40 h dioxane: H20 (7:1), 80 °C step 3 B2Pin2(3.0 equiv) Pd2dba3(0.02 equiv) XPhos (0.04 equiv) KOAc (3.0 equiv) dioxane (0.4 M) 110 °C, 2 h Dioxane: H20 (7:1, 0.2M) step 4 95 °C, 2h step 5 9-BBN (6.0 equiv) THF (0.25M) TFA CBr4 (3.0 equiv) rt, 16h (50.0 equiv) PPh3(2.4 equiv) then DCM (0.2M) CHCI3(0.1M) H2O, NaOH, H2O240 °C, 2h rt, 100 min 0 °C, 30 min step 7 step 8 step 6

[0393] NaOH (4M solnin water) NaH (1.2 eq) (10.0 equiv) DMF (0.1M) THF: MeOH 0 °C, 20 min (1:1. 0.05M)

[0394] 50 °C, 1 h step 9 step 10

[0395] TCFH (2.0 equiv) NMI (4.5 equiv) MeCN (0.033 M) 100 °C, pW, 1h

[0396]

[0397] step 11 STEP 1

[0398] In a 250 mL round bottom flask equipped with a stir bar, 3-bromo-4-chloro aniline (3.0 g, 1.0 equiv., CAS #: 823-54-1), methyl hydrazinecarboxylate (1.57 g, 1.2 equiv., CAS #: 6294-89- 9), 1.1.1 -tri ethoxy ethane (3.20 mL, 1.2 equiv., CAS #: 78-39-7) and pTSA·H₂O (138 mg,

[0399] 0.05 equiv., CAS #: 6192-52-5) were combined neat, followed by addition of 1-BuOH (20.8 mL). The reaction mixture was heated at 120 °C on a heating block. Reaction progress was monitored using LC-MS. After 16h, additional 1,1,1 -tri ethoxy ethane (3.2 mL, 1.2 equiv.),

[0400] PAGE 42 OF 77Docket No. 4014.1407 WO

[0401] methyl hydrazinecarboxylate (1.57 g, 1.2 equiv.) and pTSA·H₂O (138 mg, 0.05 equiv.) were added, and the reaction mixture was stirred for additional 24 h at 120 °C. After completion, 1-BuOH was removed under vacuum. Crude was redissolved in 100 mL ethyl acetate and washed with water (4x, 100 mL). Then the organic layer was dried over sodium sulfate and concentrated under vacuum. The resultant solid was stirred in 40 mL diethyl ether for 20 min and left in the fridge overnight. Then the solid product was collected by filtration and washed with cold diethyl ether and followed by dried under vacuum to afford 4-(3-bromo-4-chlorophenyl)-5-methyl-2,4-dihydro-3H-l,2,4-triazol-3-one (1.3 g, 31% yield). ESI MS m / z = 289.9 [M+H]+. Material was transferred to the next reaction without any further purification.

[0402] STEP 2

[0403] In a 40 mL vial equipped with a stir bar, 4-(3-bromo-4-chlorophenyl)-5-methyl-2,4-dihydro-3H-l,2,4-triazol-3-one (1.3 g, 1.0 equiv.) was dissolved in dry DMF (11 mL) at room temperature, followed by the addition of potassium tert-butoxide (1.0 g, 2.0 equiv.) and dropwise methyl iodide (0.28 mL, 1.0 equiv). Reaction mixture was stirred at room temperature for 3 h. Reaction progress was monitored using LC-MS. Once completed, 50 mL water was added to the reaction mixture. Resultant solid was collected by filtration and washed with water. Wet solid was dried under vacuum to afford 4-(3-bromo-4-chlorophenyl)-2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (1.2 g, 88% yield). ESI MS m / z = 303.9 [M+H]+. Material was transferred to the next reaction without any further purification.

[0404] STEP 3

[0405] In a 40 mL vial equipped with a stir bar, 4-(3-bromo-4-chlorophenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (1.2 g, 1.0 equiv), potassium vinyltrifluoroborate (531 mg, 1.0 equiv., CAS#: 13682-77-4), [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (145 mg, 0.05 equiv., CAS#: 72287-26-4), and cesium carbonate (2.58 g, 2.0 equiv.) were combined neat and followed by dissolved in 1,4-dioxane (17.4 mL) and water (2.48 mL). The reaction vial was purged with N2 and heated to 90 °C in a heating block. The reaction progress was monitored using LC-MS. Upon complete conversion, the reaction mixture was concentrated under vacuum and purified by silica gel column chromatography to afford 4-(4-chloro-3-vinylphenyl)-2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (700 mg, 71% yield). ESI MS m / z = 250.2 [M+H]+.

[0406] STEP 4

[0407] In a 20 mL vial equipped with a stir bar. 4-(4-chloro-3-vinylphenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (200 mg, 1.0 equiv.), bis(pinacolato)diboron (610 mg, 3.0

[0408] PAGE 43 OF 77Docket No. 4014.1407 WO

[0409] equiv.) Tris(dibenzylideneacetone)dipalladium (14.7 mg, 0.02 equiv., CAS #: 51364-51-3), X-Phos (15.3 mg, 0.04 equiv., CAS #: 564483-18-7), and potassium acetate (236 mg, 3.0 equiv.) were combined neat under nitrogen atmosphere, followed by addition of dry 1,4-dioxane (2 mL). Reaction mixture was evacuated and backfilled with nitrogen 5 times. Then the reaction mixture was heated to 110 °C in a heating block for 2h. Reaction progress was monitored using LC-MS. After cooling to the room temperature, the reaction mixture was filtered through a thin pad of celite (eluting with ethyl acetate) and the eluent was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0 to 10% methanol / dichloromethane) to afford 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-vinylphenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (280 mg, 92% yield). ESI MS m / z = 342.0 [M+H]+.

[0410] STEP 5

[0411] In a 40 mL vial equipped with a stir bar, I -(tert-butyl) 7-methyl 2-iodo-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate (650 mg, 1.0 equiv.), 2,5-dimethyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-vinylphenyl)-2,4-dihydro-3H-1.2,4-triazol-3-one (567 mg, 1.2 equiv.). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50.7 mg, 0.05 equiv., CAS#: 72287-26-4) and cesium carbonate (903 mg, 2.0 equiv., CAS#: 534-17-8) were combined neat under nitrogen atmosphere and follow ed by addition of 1,4-di oxane (6.0 mL) and water (0.9 mL). The reaction mixture was heated at 95 °C for 2 h in a heating block. Reaction progress was monitored using LC-MS. Once completed, the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was further extracted with ethyl acetate (x3). Then, the combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (0 to 10% methanol / dichloromethane) to afford 1 -(tert-butyl) 7-methyl 2-(4-(3,5-dimethyl-2-oxo-2,3-dihydro-lH-imidazol-l -yl)-2-vinylphenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate. ESI MS m / z = 557.3 [M+H]+. STEP 6

[0412] In a 40 mL vial equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-vinylphenyl)-5-(trifluoromethyl)-1H-indole-1,7-dicarboxylate (550 mg, 1.0 equiv.) was dissolved in dry tetrahydrofuran (4.0 mL). The solution was cooled in an ice / water bath prior to the dropwise addition of 9-borabicyclo[3.3. l]nonane (0.5 molar in THF, 11.9 mL, 6.0 equiv., CAS#: 280-64-8). Then, the ice / water bath was removed, and reaction mixture was stirred for 16h at room temperature. Reaction progress was monitored using LC-MS. Once the starting material

[0413] PAGE 44 OF 77Docket No. 4014.1407 WO

[0414] disappeared, reaction mixture was transferred into a 100 mL round bottom flask and cooled down to 0 °C with ice / water bath prior to successive addition of water (2.5 mL), H2O2 (50% solnin water, 5.0 mL) and NaOH (4M solnin water, 5.0 mL). Then, the reaction mixture was stirred for 30 min at 0 °C. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was further extracted with ethyl acetate (x3). Then, the combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum. The crude residue was dissolved in 6 mL DMSO and loaded into 100g gold C18 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(2-hydroxyethyl)phenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate (215 mg, 38% yield). ESI MS m / z = 597.3 [M+Na]+.

[0415] STEP 7

[0416] In a 20 mL reaction vial equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(2-hydroxyethyl)phenyl)-5-(trifluoromethyl)-lH-indole- 1,7-dicarboxylate (100 mg, 1.0 equiv.) was dissolved in dry DCM (0.9 mL) and then dropwise added trifluoroacetic acid (0.7 mL, 50 equiv.). Then, the reaction mixture was stirred for 2h at 40 °C in a heating block. Reaction progress was monitored using LC-MS. Once completed, volatiles were removed under vacuum and the crude was redissolved in 2 mL THF. The solution was cooled down to 0 °C ith an ice / w ater bath prior to dropwise addition of NaOH (1M solnin water, 2.0 mL). and the resulting mixture was stirred for 10 min at 0 °C. The reaction mixture was quenched with IN HC1 and diluted with ethyl acetate and then layers w ere separated. The aqueous phase was further extracted with ethyl acetate (x2). Then, the combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum to afford methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(2-hydroxyethyl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate. ESI MS m / z = 475.3 [M+H]+. The crude was moved to the next step without any purification.

[0417] STEP 8

[0418] In a 8 mL reaction vial equipped with a stir bar, methyl 2-(4-(L3-dimethyl-5-oxo-l,5-dihy dro-4H-l, 2, 4-triazol-4-yl)-2-(2 -hydroxy ethyl)phenyl)-5-(trifluoromethyl)- lH-indole-7-carboxylate (20.6 mg, 1.0 equiv.) was dissolved in dry chloroform (0.4 mL) at room temperature. Then, carbon tetrabromide (21.6 mg, 1.5 equiv., CAS#: 558-13-4) and triphenylphosphine (13.7 mg, 1.2 equiv., CAS#: 603-35-0) were added subsequently and the mixture was stirred at room temperature. Reaction progress was monitored using LC-MS.

[0419] PAGE 45 OF 77Docket No. 4014.1407 WO

[0420] After Ih, due to incomplete conversion, additional carbon tetrabromide (21.6 mg, 1.5 equiv.) and triphenylphosphine (13.7 mg, 1.2 equiv.) were added and reaction mixture was stirred for an additional 40 min. Once completed, volatiles were removed under vacuum and the crude was redissolved in 2 mL DMSO and loaded into 15.5g gold C18 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford methyl 2-(2-(2-bromoethyl)-4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (18 mg, 77% yield). ESI MS m / z = 537.2 [M+H]+. STEP 9

[0421] In a 8 mL reaction vial equipped with a stir bar, methyl 2-(2-(2-bromoethyl)-4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2.4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (18 mg, 1 equiv.) was dissolved in dry DMF (0.33 mL) under nitrogen atmosphere. The solution was cooled in an ice / water bath prior to addition NaH (1.1 mg, dry 90% Wt, 1.2 equiv.) and the reaction mixture was stirred at 0 °C for 20 min. Reaction progress was monitored using LC-MS. Then, the reaction mixture was quenched with IN HC1 and diluted with ethyl acetate and layers were separated. The aqueous layer was further extracted with ethyl acetate (x2). Then, the combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum to afford methyl 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylate. ESI MS m / z = 457.3 [M+H]+. The crude was moved to the next step without purification.

[0422] STEP 10

[0423] In a 8 mL vial equipped with a stir bar, methyl 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylate (15 mg, 1.0 equiv.) was dissolved in THF (0.3 mL) and MeOH (0.3 mL), followed by addition of sodium hydroxide (82 pL, 10.0 equiv., 4M solution in 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 IN 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 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-L2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylic acid. ESI MS m / z = 443.3 [M+H]+. The crude was transferred to the next reaction without any further purification.

[0424] PAGE 46 OF 77Docket No. 4014.1407 WO

[0425] STEP 11

[0426] In a 2 mL microwave reaction vial equipped with a stir bar, 3-(l,3-dimethyl-5-oxo-1.5-dihydro-4H-l,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylic acid (10 mg, 1.0 equiv.), 3-amino-2-fluorobenzamide (7.0 mg, 2.0 equiv., CAS #: 1369948-83-3) and TCFH (13 mg, 2.0 equiv., CAS # 94790-35-9) were combined neat and followed by addition of dry acetonitrile (0.46 mL) at room temperature. Then, 1-methyl-lH-imidazole (8.1 pL. 4.5 equiv., CAS # 616-47-7) was added and reaction mixture was stirred under microwave condition for 60 min at 100 °C. The crude reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (0 to 10% methanol / dichloromethane). Isolated material was redissolved in 2.0 mL of dimethyl sulfoxide and repurified through RPHPLC and subsequently purified by reversed phase flash chromatography using 15.5g gold C18 column (10 to 100% acetonitrile / water) to afford N-(3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxamide (5.0 mg, 40% yield). ESI MS m / z = 579.2 [M+H]+.

[0427] 1H NMR (400 MHz, DMSO d 10.77 (s, 1H), 8.18 (s, 1H), 8.07 (d, J= 8.1 Hz, 1H), 7.99 -7.91 (m, 1H), 7.82 (s, 1H), 7.67 (s, 1H), 7.65 - 7.61 (m, 1H), 7.54 - 7.48 (m, 1H), 7.48 - 7.41 (m, 2H), 7.40 (s, 1H), 7.32 (t, J= 7.9 Hz, 1H), 4.40 (t, J= 6.4 Hz, 2H), 3.35 (s, 3H), 3.23 (t, J = 6.4 Hz, 2H), 2.14 (s, 3H).

[0428] Example 2: Synthesis of N-(3-carbamoyl-2-fluorophenyl)-8-(1.3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triaz.ol-4-yl)-2-(trifluoromethyl)-6H-isoindolo[2,l-a]indole-4-carboxamide.

[0429] PAGE 47 OF 77Docket No. 4014.1407 WO

[0430]

[0431] STEP 1

[0432] In a 20 mL reaction vial equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl- 5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-vinylphenyl)-5-(trifluoromethyl)-lH-indole-I,7- dicarboxylate (250 mg, 1.0 equiv.) was dissolved in acetone (3.4 mL) and water (1.1 mL) at room temperature, followed by addition of A-methylmorpholine N-oxide (63.1 mg, 1.2 equiv., CAS #: 7529-22-8) and osmium tetroxide (70.4 pL, 0.02 equiv., 4 wt% in water, CAS #: 20816-12-0). The reaction mixture was stirred at room temperature for 3h. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was quenched by aqueous sodium sulfite (saturated) 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 1 -(tert-buty l) 7-methyl 2-(2-(l,2-dihydroxyethyl)-4- (l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH- indole-l,7-dicarboxylate. ESI MS m / z = 473.4 [M-Boc]‘. The crude was transferred to the next reaction without any further purification.

[0433] STEP 2

[0434] In a 20 mL reaction vial equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-(2-(l,2- dihydroxyethyl)-4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)-5- (trifluoromethyl)-lH-indole-l,7-dicarboxylate (265 mg, 1 equiv.) was dissolved in

[0435] PAGE 48 OF 77Docket No. 4014.1407 WO

[0436] dichloromethane (1 mL), water (1 mL), and methanol (1 mL) at room temperature, followed by addition of sodium periodate (115 mg, 1.2 equiv., CAS #: 7790-28-5). The reaction mixture was stirred at room temperature for 16h. Reaction progress was monitored using LC-MS. 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 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-formylphenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate. ESI MS m / z = 459.1 [M-Boc]+. The crude was transferred to the next reaction without any further purification.

[0437] STEP 3

[0438] In a 20 mL round-bottomed flask equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-formylphenyl)-5-(trifluoromethyl)-lH-indole- 1,7-dicarboxylate (230 mg, 1 equiv.) was dissolved in dry methanol (4.1 mL). The solution was cooled in an ice / water bath prior to addition of sodium borohydride (31.2 mg, 2 equiv.). Then, the reaction mixture was stirred for 40 min at 0 °C. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was quenched by water and extracted with EA (x3). Combined organic layer was washed w ith brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum. The crude w as dissolved in 6 mL DMSO and loaded into 50g gold Cl 8 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford 1 -(tert-butyl) 7-methyl 2-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(hydroxymethyl)phenyl)-5-(trifluoromethyl)-1H-indole-1,7-dicarboxylate (105 mg, 45% yield). ESI MS m / z = 461.4 [M-Boc]+.

[0439] STEP 4

[0440] In a 20 mL reaction vial equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(hydroxymethyl)phenyl)-5-(trifluoromethyl)-lH-indole- 1,7-dicarboxylate (104 mg, 1.0 equiv.) was dissolved in dry dichloromethane (0.9 mL) and then dropwise added trifluoroacetic acid (0.7 mL, 50 equiv.). Then, the reaction mixture was stirred for Ih at 40 °C in a heating block. Reaction progress was monitored using LC-MS. Once completed, volatiles were removed under vacuum and the crude was redissolved in 2 mL THF. The solution w as cooled down to 0 °C with an ice / water bath prior to dropwise addition of NaOH (IM sol” in water, 2.0 mL). and the resulting mixture was stirred for 10 min at 0 °C. The reaction mixture was quenched with IN HC1 and diluted with water and extracted with ethyl acetate (x3). Then, the combined organic layer was washed

[0441] PAGE 49 OF 77Docket No. 4014.1407 WO

[0442] with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum. The crude was dissolved in 2 mL DMSO and loaded into 30g gold C18 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(hydroxymethyl)phenyl)-5-(trifluoromethyl)- lH-indole-7-carboxylate (53 mg, 62% yield). ESI MS m / z = 461.3 [M+H]+. STEP 5

[0443] In a 8 mL reaction vial equipped with a stir bar, methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(hydroxymethyl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (23 mg, 1 equiv.) was dissolved in dry DCM (0.7 mL). The solution was cooled in an ice / water bath prior to successive addition of methanesulfonic anhydride (11 mg, 1.3 equiv., CAS #: 7143-01-3) and triethylamine (28 pL, 4.0 equiv.). Then, the reaction mixture was stirred for 20 min at 0 °C. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was quenched by water and extracted with DCM (x3). Combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum to afford methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2(((methylsulfonyl)oxy)methyl) phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate. ESI MS m / z = 539.2 [M+H]+. The crude was transferred to the next reaction without any further purification.

[0444] STEP 6

[0445] In a 8 mL reaction vial equipped with a stir bar, methyl 2-(4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(((methylsulfonyl)oxy)methyl)phenyl)-5-(trifluoromethyl)-1H-indole-7-carboxylate (27 mg, 1 equiv.,) was dissolved in dry DMF (1.0 mL) under nitrogen atmosphere. The solution was cooled in an ice / water bath prior to the addition of NaH (1.6 mg, dry 90% Wt, 1.2 equiv.) and the reaction mixture was stirred for 20 min at 0 °C. Reaction progress was monitored using LC-MS. Then, the reaction mixture was quenched with IN HC1 and diluted with ethyl acetate and layers were separated. The aqueous layer was further extracted with ethyl acetate (x2). Then, the combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum. The crude was dissolved in 2 mL DMSO and loaded into 30g gold Cl 8 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford methyl 8-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(trifluoromethyl)-6H-isoindolo[2,l-a]indole-4-carboxylate (15 mg, 68% yield). ESI MS m / z = 443.5 [M+H]+.

[0446] PAGE 50 OF 77Docket No. 4014.1407 WO

[0447] STEP 7

[0448] In a 8 mL vial equipped with a stir bar, methyl 8-(1.3-dimethyl-5-oxo-l,5-dihydro-4H-1.2.4-triazol-4-yl)-2-(trifluoromethyl)-6H-isoindolo[2,l-a]indole-4-carboxylate (15 mg, 1.0 equiv.) was dissolved in THF (0.3 mL) and MeOH (0.3 mL), followed by addition of sodium hydroxide (85 pL, 10.0 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 IN 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 8-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(trifluoromethyl)-6H-isoindolo[2,l-a]indole-4-carboxylic acid. ESI MS m / z = 429.4 [M+H]+. The crude was transferred to the next reaction without any further purification.

[0449] STEP 8

[0450] In a 2 mL microwave reaction vial equipped with a stir bar, 8-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(trifluoromethyl)-6H-isoindolo[2,l-a]indole-4-carboxylic acid (15 mg, 1.0 equiv.), 3-amino-2-fluorobenzamide (11 mg, 2.0 equiv., CAS #: 1369948-83-3) and TCFH (20 mg, 2.0 equiv., CAS #: 94790-35-9) were combined neat and followed by addition of dry acetonitrile (0.46 mL) at room temperature. Then, 1-methyl-lH-imidazole (13 pL. 4.5 equiv., CAS #: 616-47-7) was added and reaction mixture was stirred under microwave condition for 60 min at 100 °C. The crude reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (0 to 10% methanol / dichloromethane). Isolated material was dissolved in 2 mL DMSO and loaded into 15.5g gold C18 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford N-(3-carbamoyl-2-fluorophenyl)-8-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(trifluoromethyl)-6H-isoindolo[2,l-a]indole-4-carboxamide. (5.8 mg, 29% yield). ESI MS m / z = 565.2 [M+H]+.

[0451] 'H NMR (400 MHz, DMSO) 5 10.65 (s, IH), 8.29 (d, J = 1.7 Hz, IH), 8.07 (d, J = 8.1 Hz, IH), 7.93 - 7.83 (m, 2H), 7.81 (s, IH), 7.74 - 7.69 (m, IH). 7.67 (s, IH), 7.56 - 7.49 (m, 2H), 7.33 (t, J= 7.8 Hz, IH), 7.12 (s, IH). 5.40 (s, 2H). 3.36 (s. 3H), 2.12 (s. 3H).

[0452] Examples 3 and 4: (S)-N-(3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-methyl-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxamide and (R)-N-(3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-methyl-10- (trifluoromethyl)-5,6-dihydroindolo[2.1-a]isoquinoline-8-carboxamide

[0453] PAGE 51 OF 77Docket No. 4014.1407 WO

[0454] DMP MeMgBr (2.0 equiv) (1.2 equiv) DCM (0.15 M) THF(0.15 M) 0 °C, 30 min 78 °C, 30 min step 1 step 2

[0455] DMP NaOH (10.0 equiv) (2.0 equiv) (4M solnin water) DCM (0.15 M) THF: MeOH 0 °C, 30 min (1:1, 0.05 M) step 3 50 °C, 1 h step 4 step

[0456] 5

[0457]

[0458] step 6 STEP 1

[0459] In a 8 mL reaction vial equipped with a stir bar, I -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl-5- oxo-1, 5-dihydro-4H-l.2.4-triazol-4-yl)-2-(2 -hy droxyethyl)pheny l)-5-(trifluoromethyl)-lH- indole-1.7-dicarboxylate (100 mg. 1 equiv.) was dissolved in dry DCM (1.16 mL). The solution was cooled in an ice / water bath, prior to the addition of DMP (148 mg, 2.0 equiv., CAS#: 87413-09-0). The reaction mixture was stirred for 30 min at 0 °C. Reaction progress was monitored using LC-MS. After completion, reaction mixture was quenched with

[0460] saturated NaHCOs (aqueous) and diluted with DCM. Then, the layers were separated, and the aqueous layer was further extracted with DCM. Combined organic layer was washed with water (x3) and dried over sodium sulfate and concentrated under vacuum to afford 1 -(tert- butyl) 7-methyl2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(2- oxoethyl)phenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate. ESI MS m / z = 473.2 [M- Boc]’. The crude was transferred to the next reaction without any further purification.

[0461] STEP 2

[0462] In an 8 mL reaction vial equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl- 5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(2-hydroxypropyl)phenyl)-5-(trifluoromethyl)- lH-indole-1.7-dicarboxylate (100 mg. 1.0 equiv.) was dissolved in dry THF (1.16 mL) under nitrogen. Then the reaction mixture was cooled down to -78 °C with a dry ice / acetone bath, prior to the dropwise addition of methyl magnesium bromide (69.9 pL. 1.2 equiv., 3M in Et20). The reaction mixture was stirred for 30 min at -78 °C. Reaction progress was

[0463] PAGE 52 OF 77Docket No. 4014.1407 WO

[0464] monitored using LC-MS. After completion, reaction was quenched with saturated NH4Q (aqueous) and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted again with ethyl acetate (x2). The organic layers were combined washed with brine, water, and dried over sodium sulfate and concentrated under vacuum. The crude was redissolved in DMSO and loaded into 50g gold Cl 8 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water) to afford 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(2-hydroxypropyl)phenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate (40 mg, 39% yield). ESI MS m / z = 611.4 [M+Na]+.

[0465] STEP 3

[0466] In a 8 mL reaction vial, 1 -(tert-butyl) 7-methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H- 1.2.4-triazol-4-yl)-2-(2-hydroxypropyl)phenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate (40 mg, 1.0 equiv.) was dissolved in dry DCM (0.68 mL) and followed addition of TFA (0.26 mL, 50.0 equiv.). The reaction mixture was heated at 40 °C for 2h on a heating block. Reaction progress was monitored using LC-MS. Once completed, reaction mixture was concentrated under vacuum. Crude was redissolved in THF (1.5 mL) and cooled down to 0 °C with an ice / water bath. 1 mL NaOH (IM in water) was added, and reaction mixture was stirred for 20 min at 0 °C. Then the reaction mixture was quenched by IN HC1 (aqueous) and diluted with ethyl acetate. The layers were separated and the aqueous layer was further extracted with ethyl acetate (x2). Then the combined organic layers was washed with brine, water, dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (0 to 10% methanol / di chloro methane) to afford methyl 2-(4-(L3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(2-hydroxypropyl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (20 mg. 60% yield). ESI MS m / z = 489.4 [M+H]+.

[0467] STEP 4

[0468] In a 4 mL vial equipped with a stir bar, methyl 2-(4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H- 1.2.4-triazol-4-yl)-2-(2-hydroxypropyl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (20 mg, 1.0 equiv.) was dissolved in dry THF (0.8 mL) under nitrogen, prior to the addition of triphenylphosphine (15 mg, 1.4 equiv.). The solution was cooled down with an ice / water bath, prior to the dropwdse addition of diisopropyl azodicarboxylate (11 pL, 1.4 equiv.). Then, the ice / water bath was removed, and the reaction mixture was stirred at room temperature for 30 min. Volatiles were removed under vacuum and the crude was redissolved in 2 mL DMSO and loaded into 30g gold Cl 8 column for reversed phase flash chromatography purification

[0469] PAGE 53 OF 77Docket No. 4014.1407 WO

[0470] (10 to 100% acetonitrile / water) to afford methyl 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H- l,2,4-triazol-4-yl)-6-methyl-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylate (13 mg, 67% yield). ESI MS m / z = 471.6 [M+H]+.

[0471] STEP 5

[0472] In a 4 mL vial equipped with a stir bar, methyl 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-methyl-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylate (13 mg, 1.0 equiv.) was dissolved in THF (0.28 mL) and MeOH (0.28 mL), followed by addition of NaOH (69 pL, 10.0 equiv., 4M in 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 IN HC1 (aqueous). Then the crude mixture was diluted with water and extracted with ethyl acetate (x3). Combined organic layer was washed with brine, water, dried over sodium sulfate and concentrated under vacuum to afford 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-methyl-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylic acid. ESI MS m / z = 457.3 [M+H]+. The crude was transferred to the next reaction without any further purification.

[0473] STEP 6

[0474] In a 4 mL reaction vial equipped with a stir bar, 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-methyl-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylic acid (13.0 mg, 1.0 equiv.) was dissolved in DCM (0.43 mL) under nitrogen at room temperature, prior to the addition of 1 -chloro-. VW.2-trimethylprop- 1 -en-1 -amine (7.5 pL, 2.0 equiv., CAS#: 26189-59-3). The reaction mixture was stirred for 40 min at room temperature, then, 3-amino-2-fluorobenzamide (26.0 mg, 6.0 equiv.) and pyridine (0.43 mL) were added sequentially, and the mixture was stirred at 60 °C in a heating block for Ih. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was concentrated under vacuum and crude was redissolved in 2.0 mL of dimethyl sulfoxide and purified through RPHPLC. Isolated material was repurified through chiral HPLC to afford (S)-N-(3-carbamoyl-2-fluorophenyl)-3-(1.3-dimethyl-5-oxo-l,5-dihydro-4H-1,2,4-triazol-4-yl)-6-methyl-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxamide (Example 3, 2.8 mg) and (R)-N-(3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-methyl-10- (trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxamide (Example 4, 2.3 mg).

[0475] PAGE 54 OF 77Docket No. 4014.1407 WO

[0476]

[0477] Examples 5 and 6: (R)-N-(3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-(methoxymethyl)-10-(trifluoromethyl)-5,6-dihydroindolo[2.1-a]isoquinoline-8-carboxamide and (S)-N-(3-carbamoyl-2-fluorophenyl)-3-(E3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-(methoxymethyl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxamide

[0478] PAGE 55 OF 77Docket No. 4014.1407 WO

[0479] B2?in2 (3.0 equiv)<%t^^'Sn(nBu|3Pd2dba3(0.03 equiv) (2.0 equiv) XPhos (0.06 equiv) Rd(RRh3)4(0.1 equiv) KOAc (3.0 equiv) PdCI2(dppf) (0.05 equiv) PhCH3(0.3 M) dioxane (0.3 M) Cs2CO3(2.0 equiv) 110 °C, 2 h 110 °C, 2 h Dioxane: H2O (7:1, 0.2 M) step 1 step 2 90 °C, 90 min step 3

[0480] NMO (1.2 equiv) TFA OsO4(0.02 equiv) (50.0 equiv) Acetone:water DCM (0.2M) (3:1, 0.066 M) 40 °C, 2h rt, 16h step 5 step 4

[0481]

[0482] Step 1

[0483] In a 40 mL reaction vial equipped with a stir bar, 4-(3-bromo-4-chlorophenyl)-2,5-dimethyl- 2,4-dihydro-3H-l,2,4-triazol-3-one (1.0 g. 1.0 equiv.) was dissolved in dry toluene (11 mL) and followed by addition of allyltributylstannane (2.19 g, 2.0 equiv., CAS#: 24850-33-7).

[0484] Nitrogen was bubbled through the solution for 10 min. Then, Pd(PPh3)4 (381.9 mg, 0.1

[0485] equiv., CAS#: 14221-01-3) was added into the vial, and nitrogen was bubbled through the solution for additional 5 min. Then, reaction mixture was heated at 110 °C in a heating block for 2h. Reaction progress was monitored using LC-MS. After completion, volatiles were removed under vacuum and the crude was redissolved in DMSO and loaded into 150g gold

[0486] Cl 8 column for reversed phase flash chromatography purification (10 to 100% acetonitrile / water). followed by purified through silica gel column chromatography (0 to

[0487] PAGE 56 OF 77Docket No. 4014.1407 WO

[0488] 100% ethyl acetate / cyclohexane) to afford 4-(3-allyl-4-chlorophenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (720 mg, 83% yield). ESI MS m / z = 264.1 [M+H]+.

[0489] STEP 2

[0490] In a 40 mL reaction vial equipped with a stir bar, 4-(3-allyl-4-chlorophenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (720 mg, 1.0 equiv.), bis(pinacolato)diboron (2.08 g, 3.0 equiv.) tris(dibenzylideneacetone)dipalladium (75 mg, 0.03 equiv., CAS #: 51364-51-3), X-Phos (78.1 mg, 0.06 equiv., CAS #: 564483-18-7), and potassium acetate (804 mg, 3.0 equiv.) were combined neat under nitrogen atmosphere, followed by addition of dry 1,4-dioxane (9.1 mL). Reaction mixture was evacuated and backfilled wi th nitrogen 5 times. Then the reaction mixture was heated to 110 °C in a heating block for 2h. Reaction progress was monitored using LC-MS. After cooling to the room temperature, the reaction mixture was filtered through a thin pad of celite (eluting with ethyl acetate), then the eluent was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0 to 30% acetone / cyclohexane) to afford 4-(3-allyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,5-dimethyl-2,4-dihydro-3EI-l,2,4-triazol-3-one (1.05 g, 82% yield). ESI MS m / z = 356.2 )M+H]+.

[0491] STEP 3

[0492] In a 40 mL reaction vial equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-iodo-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate (650 mg. 1.0 equiv.), 4-(3-allyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,5-dimethyl-2,4-dihydro-3H-l,2,4-triazol-3-one (591 mg, 1.2 equiv.), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50.7 mg, 0.05 equiv., CAS#: 72287-26-4) and cesium carbonate (903 mg, 2.0 equiv., CAS#: 534-17-8) were combined neat under nitrogen atmosphere and followed by addition of 1,4-dioxane (6.0 mL) and water (0.9 mL). The reaction mixture was heated at 90 °C for 90 min in a heating block. Reaction progress was monitored using LC-MS. Once completed, the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was further extracted with ethyl acetate (x3). Then, the combined organic layer was washed with brine, water and dried over sodium sulfate and concentrated under vacuum. The crude residue w as purified by silica gel column chromatography (0 to 30% acetone / cyclohexane) to afford 1 -(tert-butyl) 7-methyl 2-(2-allyl-4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate (460 mg, 58% yield). ESI MS m / z = 593.2 [M+H]+,

[0493] PAGE 57 OF 77Docket No. 4014.1407 WO

[0494] STEP 4

[0495] In a 20 mL reaction vial equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-(2-allyl-4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate (250 mg, 1.0 equiv.) was dissolved in acetone (5 mL) and water (1.7 mL) at room temperature, followed by addition of / V-methy 1 morpholine / V-oxidc (61.6 mg, 1.2 equiv., CAS #: 7529-22-8) and osmium tetroxide (68.7 LIL. 0.02 equiv., 4 wt% in water, CAS #: 20816-12-0). The reaction mixture was stirred at room temperature for 16h. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was quenched by aqueous sodium sulfite (saturated) and extracted with ethyl acetate (x3). Combined organic layer was washed with brine, water and dried over sodium sulfate and concentrated under vacuum to afford 1 -(tert-butyl) 7-methyl 2-(2-(2,3-dihydroxypropyl)-4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate. ESI MS m / z = 605.2 [M+H]+. The crude was transferred to the next reaction without any further purification.

[0496] STEP 5

[0497] In a 8 mL reaction vial equipped with a stir bar, 1 -(tert-butyl) 7-methyl 2-(2-(2.3-dihydroxypropyl)-4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-indole-l,7-dicarboxylate (130 mg, 1.0 equiv.) was dissolved in dry DCM (1.1 mL) prior to the dropwise addition of trifluoroacetic acid (0.83 mL, 50 equiv.). Then, the reaction mixture was stirred for 2h at 40 °C in a heating block. Reaction progress was monitored using LC-MS. Once completed, volatiles were removed under vacuum and the crude was redissolved in 2.5 mL THF. The solution was cooled down to 0 °C with an ice / water bath prior to the drop wise addition of 1.5 mL NaOH (IM in water) and the resulting mixture was stirred for 10 min at 0 °C. The reaction mixture was quenched with IN HC1 (aqueous) and diluted with ethyl acetate and then layers were separated. The aqueous phase was further extracted with ethyl acetate (x2). Then, the combined organic layer was washed with brine, water and dried over sodium sulfate and concentrated under vacuum to afford methyl 2-(2-(2.3-dihydroxypropyl)-4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate. ESI MS m / z = 505.2 [M+H]+. The crude was moved to the next step without any purification.

[0498] STEP 6

[0499] In 8 mL reaction vial equipped with a stir bar, methyl 2-(2-(2,3-dihydroxypropyl)-4-(l,3-dimethyl-5-oxo- 1,5-dihydro-4H- 1,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)- lH-indole-7-carboxylate (82 mg, 1.0 equiv.) was dissolved in dry DCM (1.6 mL) under nitrogen. The

[0500] PAGE 58 OF 77Docket No. 4014.1407 WO

[0501] solution was cooled in an ice / water bath prior to the sequential addition of DMAP (4.0 mg, 0.2 equiv.). ElsN (45 pL. 2.0 equiv.), and / -Butyl(chloro)diphenylsilane (46 pL, 1.1 equiv., CAS#: 58479-61-1). Then, ice / water bath was removed, and the reaction mixture was stirred at room temperature. Reaction progress was monitored using LC-MS. After 16h, additional TBDPS-C1 (8.4 pL, 0.2 equiv.) and TEA (9.1 pL, 0.4 equiv.) were added into the reaction mixture and stirred for additional 3h at room temperature. Once completed, volatiles were removed under vacuum and the crude was purified by silica gel column chromatography (0 to 30% acetone / cyclohexane) to afford methyl 2-(2-(3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropyl)-4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (103 mg, 82% yield). ESI MS m / z = 765.3 [M+Na]+.

[0502] STEP 7

[0503] In a 8 mL vial equipped with a stir bar, methyl 2-(2-(3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropyl)-4-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)phenyl)-5-(trifluoromethyl)-lH-indole-7-carboxylate (103 mg, 1.0 equiv.) was dissolved in dry THF (1.4 mL) under nitrogen, priorto the addition of triphenylphosphine (50.9 mg, 1.4 equiv.). The solution was cooled down with an ice / water bath, prior to the dropwise addition of diisopropyl azodicarboxylate (37.7 pL, 1.4 equiv.). Reaction mixture was stirred for 40 min at 0 °C, then, the ice / water bath was removed and stirred for additional 1 h at room temperature. Reaction progress was monitored using LC-MS. Once completed, volatiles were removed under vacuum and the crude was purified by silica gel column chromatography (0 to 30% acetone / cyclohexane) to afford methyl 6-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2.1-a]isoquinoline-8-carboxylate. ESI MS m / z = 725.3 [M+H]+.

[0504] STEP 8

[0505] In a 8 mL reaction vial equipped with a stir bar, methyl 6-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4EI-l,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylate (60 mg, 1.0 equiv.) was dissolved in dry THF (0.83 mL) under nitrogen, followed by dropw ise addition of tetrabutylammonium fluoride (0.33 mL, 4.0 equiv., IM in THF). The reaction mixture was stirred for 30 min at room temperature to afford 9-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-2-(trifluoromethyl)-6a,7-dihydro-4H,6H-5-oxa-6al-azabenzo[a]cyclohepta[def|fluoren-4-one. ESI MS m / z = 455.1 [M+H]+. The aliquot was moved to the next step without any purification.

[0506] PAGE 59 OF 77Docket No. 4014.1407 WO

[0507] STEP 9

[0508] In the aliquot form step 8, NaOH (0.1 mL. 5.0 equiv., 4M in water) was added and the mixture was stirred at room temperature. Reaction progress was monitored using LC-MS. After 16h, additional NaOH (0.2 mL, 10.0 equiv., 4M in water) was added and stirred for additional 2h. After completion, the reaction mixture was quenched with IN HC1 (aqueous) and diluted with ethyl acetate and then layers were separated. The aqueous phase was further extracted with ethyl acetate (x2). Then, the combined organic layer was washed with brine, water and dried over sodium sulfate and concentrated under vacuum to afford 3-(l,3-dimethy 1-5 -oxo- 1,5 -dihy dro-4H- 1,2,4-triazol-4-y l)-6-(hy droxy methyl)- 10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylic acid. ESI MS m / z = 473.1 [M+H]+. The crude was moved to the next step without any purification.

[0509] STEP 10

[0510] In a 4 mL reaction vial equipped with a stir bar, 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-(hydroxymethyl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylic acid (39 mg, 1 equiv.) was dissolved in dry THF (0.83 mL) under nitrogen at room temperature, followed by addition ofNaH (11 mg, 90% Wt, 5 equiv.). The reaction mixture was stirred for 15 min, prior to the dropwise addition of methyl iodide (26 uL. 5.0 equiv.) and stirred for additional 60 min at the room temperature. After completion, the reaction mixture was quenched with IN HC1 (aqueous) and diluted with ethyl acetate. Layers were separated and the aqueous phase was further extracted with ethyl acetate (x2). Then, the combined organic layer w as washed with brine, water and dried over sodium sulfate and concentrated under vacuum. The crude w as purified by silica gel column chromatography (0 to 20% MeOH / DCM) to afford 3-(1.3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-(methoxymethyl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylic acid (15 mg, 37% yield). ESI MS m / z = 487.2 [M+H]+.

[0511] STEP 11

[0512] In a 4 mL reaction vial equipped with a stir bar, 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-(methoxymethyl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylic acid was dissolved in dry DCM (0.48 mL) under nitrogen at room temperature, prior to the addition of l-chloro-NA’.2-trimethylprop-l-en-l-amine (8.4 pL, 2.0 equiv.). The reaction mixture was stirred for 40 min at room temperature, then, 3-amino-2-fluorobenzamide (29.5 mg, 6.0 equiv.) and pyridine (0.48 mL) were sequentially added, and the mixture was stirred at 60 °C in a heating block for Ih. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was concentrated under vacuum and

[0513] PAGE 60 OF 77Docket No. 4014.1407 WO

[0514] crude was redissolved in 2.0 mL of dimethyl sulfoxide and purified through RPHPLC.

[0515] Isolated material was repurified through chiral HPLC to afford (R)-N-(3-carbamoyl-2-fluorophenyl)-3-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-6-(methoxymethyl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxamide (Example 5, 5.2 mg) and (S)-N-(3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-(methoxymethyl)-10-(trifluoromethyl)-5,6-dihydroindolo[2.1-a]isoquinoline-8-carboxamide (Example 6, 5.5 mg).

[0516]

[0517] Example 7: N-(3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol -4-yl)-6-(hy droxy methyl)-! 0-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxamide

[0518] PAGE 61 OF 77Docket No. 4014.1407 WO

[0519] step 2

[0520]

[0521] STEP 1

[0522] In a 4 mL reaction vial, methyl 6-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-1,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxylate (40 mg, 1 equiv.) was dissolved in dry DCE (0.55 mL), followed by addition of trimethyltin hydroxide (0.2 g, 20.0 equiv.). Then, the reaction mixture was heated at 80 °C for 34h in a heating block. Reaction progress was monitored using LC-MS. After completion, reaction mixture was diluted with ethyl acetate and the organic layer was washed with IN aqueous HC1 (3x), brine (lx), and dried over sodium sulfate and concentrated under vacuum. The crude was purified by silica gel column chromatography (0 to 10% MeOH / DCM) to afford 6-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(l,3-dimethyl-5-oxo- 1,5 -dihy dro-4H- 1,2,4-triazol-4-y 1)- 10-(trifluoromethy l)-5,6-dihy droindolo[2, 1 -a]isoquinoline-8-carboxylic acid (39 mg, 81% yield). ESI MS m / z = 711.3 [M+H]+.

[0523] STEP 2

[0524] In a 8 mL reaction vial equipped with a stir bar, 6-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2.1-a]isoquinoline-8-carboxylic acid (35 mg, 1.0 equiv.) was dissolved in dry DCM (1.0 mL) under nitrogen at room temperature, prior to the addition of 1-chloro-N,N,2-trimethylprop-1-en-1-amine (13 µL, 2.0 equiv., CAS#: 26189-59-3). The reaction mixture was stirred for 40 min at room temperature, then, 3-amino-2-fluorobenzamide (46 mg, 6.0 equiv.) and pyridine (1.0 mL) were sequentially added, and the mixture was stirred at 60 °C for Ih in a heating block. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was concentrated under vacuum and crude was redissolved in 2.0 mL of dimethyl sulfoxide and loaded into 30g gold C18 column for reversed phase flash

[0525] PAGE 62 OF 77Docket No. 4014.1407 WO

[0526] chromatography purification (10 to 100% acetonitrile / water) to afford 6-(((tert- butyldiphenylsilyl)oxy)methyl)-N-(3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5- dihydro-4H-l,2,4-triazol-4-yl)-10-(trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8- carboxamide (21 mg, 50% yield). ESI MS m / z = 847.3 [M+H]+.

[0527] STEP 3

[0528] In a 4 mL reaction vial equipped with a stir bar, 6-(((tert-butyldiphenylsilyl)oxy)methyl)-N- (3-carbamoyl-2-fluorophenyl)-3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-10- (trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxamide (19 mg, 1 equiv.) was dissolved in dry THF (0.9 mL) under nitrogen, followed by dropwise addition of tetrabutylammonium fluoride (0.09 mL, 4.0 equiv., IM in THF). The reaction mixture was stirred for 30 min at room temperature. Reaction progress was monitored using LC-MS. After completion, the reaction mixture was quenched with IN HC1 (aqueous) and diluted with ethyl acetate. Layers were separated and aqueous layer was further extracted with ethyl acetated (x2). Combined organic layer was washed with brine (xl), water (xl) and dried over sodium sulfate and concentrated under vacuum. The crude was redissolved in 2.0 mL of dimethyl sulfoxide and purified through RPHPLC to afford N-(3-carbamoyl-2-fluorophenyl)- 3-(l,3-dimethyl-5-oxo-l,5-dihydro-4H-l,2,4-triazol-4-yl)-6-(hydroxymethyl)-10- (trifluoromethyl)-5,6-dihydroindolo[2,l-a]isoquinoline-8-carboxamide (8 mg, 60% yield). ESI MS m / z = 609.2 [M+H]+.

[0529] The following compound was prepared using procedures similar to those described in Ex. 1:

[0530]

[0531] PAGE 63 OF 77Docket No. 4014.1407 WO

[0532] The following examples are prepared using procedures similar to those described above:

[0533] Compound Structure Compound Structure

[0534] 0 0 *

[0535] z / ^r 'NH2 ^x-- °zu ^s^ X^F H 1 la 2a b

[0536] O / =^ JL i v ') — L IL \= / N>i!* / S'CF30 0 M C

[0537] X

[0538] z / ^s-Z^NHs V X

[0539] \jZ (" U. °=F u

[0540] 3a O^zNH4a 1 o^NH0 / — \ 1 ° / — \ L o? 1 N— (' ') — G. L NCS / ^ ^ \= / NXiZ^CFj ' Ph

[0541] 0 0 X Zv ' NH; ^sO.z

[0542] / \ / n X

[0543] / zz'

[0544] 5a F _ _ NH 6aFo^H° n~ \ AX o N — i / N^rsj|

[0545] i ') — G L JL i / / —Q / GN"*r L l Ilk ^ ^ Xzz /

[0546] F O F O

[0547] Z^< ^NH2 U ^S^ X^F 7a ^ 8a ^

[0548] 0 / — \ L0 / — k T

[0549] i G L ZVN ^

[0550] 0

[0551] | ^F

[0552] 9a 0 < L °<rNH10a

[0553] A V-'-kx Jk.

[0554] \ ^ CF3

[0555]

[0556] PAGE 64 OF 77Docket No. 4014.1407 WO

[0557]

[0558] BIOLOGICAL ACTIVITY STAT6 FP Activity

[0559] 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 compounds were dispersed into a 384-well low volume white 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.

[0560] 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.

[0561] PAGE 65 OF 77Docket No. 4014.1407 WO

[0562] Table 1. STAT6 Binding Activity

[0563] Ex.# STAT6 FP IC50 Ex.# STAT6 FP IC50 1 B 2 D

[0564] 3 A 4 D

[0565] 5 A 6 D

[0566] 7 B 8 B

[0567]

[0568] STAT6 HEK-BLUE IL-4 & IL-13 Assay

[0569] 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 / mL Zeocin. Test media consisted of 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.

[0570] 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 density of 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, QUANTIBlue was added per manufacturer’s instructions. One hour post incubation, absorbance was measured at a wavelength of 620 nm on an Envision plate reader.

[0571] Absorbance values for unstimulated control samples were subtracted from all test samples and percentage inhibition was determined as compared to DMSO stimulated samples.

[0572] 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 Ex.# HEK-Blue ILA IC50 Ex.# HEK-Blue ILA IC50 1 A 2 - 3 A 4 - 5 A 6 - 7 B 8 A

[0573]

[0574] PAGE 66 OF 77Docket No. 4014.1407 WO

[0575] While this invention has been particularly shown and described with references 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.

[0576] PAGE 67 OF 77

Claims

Docket No. 4014.1407 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 12- membered heterocycloalkyl;2) Optionally substituted aryl;3) Optionally substituted arylalkyl;4) Optionally substituted heteroaryl;5) Optionally substituted heteroarylalkyl;6) -C(O)N(RI)(R2);7) -N(RI)C(O)(R2);8) -N(RI)C(O)O(R2); and9) -N(R3)C(O)N(RI)(R2);RBis selected from the group consisting of:1) Hydrogen;2) Halogen;3) Cyano;4) Hydroxy;5) Optionally substituted -C1-C8 alkyl;6) Optionally substituted -C2-Cs alkenyl;7) Optionally substituted -C2-Cs alkynyl;8) Optionally substituted -Ci-Cs alkoxy;9) Optionally substituted -Cs-Ci2cycloalkyl;10) Optionally substituted 4- to 12- membered heterocycloalkyl;11) Optionally substituted aryl;12) Optionally substituted heteroaryl;PAGE 68 OF 77Docket No. 4014.1407 WO13) -C(O)N(RI)(R2);14) -N(RI)C(O)(R2);15)-NRIR2:16)-N(RI)S(O)2(R2);17)-S(O)2RI; and18) -P(O)RIR2L1is selected from the group consisting of -[C(R5)(R6)]n-, -C(Rs)(R6)C(O)-, and -C(R5)=C(R6)-; n is 1 or 2;RFis selected from the group consisting of:1) Hydrogen;2) Halogen;3) Cyano;4) Optionally substituted -Ci-Cs alkyl;5) Optionally substituted Cs-Cs cycloalkyl;6) Optionally substituted 4- to 8- membered heterocycloalkyl;7) Optionally substituted aryl;8) Optionally substituted heteroaryl;9) Optionally substituted -Ci-Cs alkoxy; and10)-C(O)N(RI)(R2);Y1and Y2are each independently selected from the group consisting of N and CRD;RDis selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-Cs alkenyl, optionally substituted -C2-Cs alkynyl, optionally substituted -Cs-Cs cycloalkyl, optionally substituted 4-to 8- membered heterocycloalkyl, optionally substituted -Ci-Cs alkoxy, optionally substituted aryl, optionally substituted heteroaryl, -NRIR2, -SRi, -SO2RI, -C(O)N(RI)(R2), -N(RI)C(O)(R2), - N(RI)C(O)O(R2), -N(RI)S(O)2(R2). and -P(O)RIR2;X1, X2, and X3are each independently selected from the group consisting of N and CRE;REis independently selected from the group consisting of:1) Hydrogen;2) Halogen;3) Cyano;4) Hydroxy;PAGE 69 OF 77Docket No. 4014.1407 WO5) Optionally substituted -Ci-Cs alkyl;6) Optionally substituted -C2-C8 alkenyl;7) Optionally substituted -C2-C8 alkynyl;8) Optionally substituted -C3-C8 cycloalkyl;9) Optionally substituted 4- to 8- membered heterocycloalkyl;10) Optionally substituted aryl;11) Optionally substituted heteroaryl;12) Optionally substituted -Ci-Cs alkoxy;13)-C(O)N(Ri)(R2);14)-N(RI)C(O)(R2);15)-N(RI)(R2);16)-SRI;17)-S(O)2RI;18)-N(RI)C(O)O(R2);19)-N(RI)S(O)2(R2); and20)-P(O)RIR2;L2is selected from the group consisting of -C(O)N(Ri)-, -C(R7)(Rs)O-, and - [C(R7)(R8)]2-;is selected from the group consisting of optionally substituted -C3-C12 cycloalkyl, optionally substituted 3- to 12- membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;R1, R2, and R3 are each independently selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alkyl, 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, and optionally substituted heteroaryl; when Ri and R2 are attached to the same nitrogen atom, alternatively, Ri and R2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds;each R5 is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, optionally substituted -Ci-Cs alkyl, optionally substituted -Cs-CsPAGE 70 OF 77Docket No. 4014.1407 WOcycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted -Ci-Cs alkoxy, and -C(O)N(RI)(R2);each Re is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C3-C8 cycloalkyl, and optionally substituted 4- to 8- membered heterocycloalkyl;alternatively. R5 and Re are taken together with the carbon atom to which they are attached to form an optionally substituted C -C8 cycloalkyl ring or optionally substituted 4- to 8- membered heterocyclic containing 0, 1, 2, or 3 double bonds;alternatively, L1is -[C(Rs)(R6)]n- where n is 2, and the two Rs groups are taken together with the carbon atoms to which they are attached to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8- membered heterocyclic containing 0, 1, 2, or 3 double bonds;each R is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -Cs-Cs cycloalkyl, and optionally substituted 4- to 8- membered heterocycloalkyl;each Rs is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -Cs-Cs cycloalkyl, and optionally substituted 4- to 8- membered heterocycloalkyl;alternatively, R7 and Rs are taken together with the carbon atom to which they are attached to form an optionally substituted C3-C8 cycloalkyl cycloalkyl ring or optionally substituted 4-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds;alternatively, L2is -[C(R7)(Rs)]2-, and the two R7 groups are taken together with the carbon atoms to which they are correspondingly attached to form an optionally substituted C3-C8 cycloalkyl or optionally substituted 4-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds.

2. The compound of claim 1 represented by one of Formula (X-a) to (X-c):PAGE 71 OF 77Docket No. 4014.1407 WOwherein R5ais R5; R5bis R5; R6ais R6; R6bis R6; and R5, R6. Y1, Y2, RA, RB, RF, R1, X1, X2, 3X, and are as defined in claim 1.

3. The compound of claim 1 represented by the compound of Formula (I) is represented by one of Formula (XV- 1) to (XV-9):wherein:PAGE 72 OF 77Docket No. 4014.1407 WOR11is independently 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 aryl, optionally substituted arylalkyl, optionally substituted heteroaryl alkyl, and optionally substituted heteroaryl;R12is independently selected from the group consisting of hydrogen, halogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-Cs alkenyl, optionally substituted -Cs-Cs cycloalkyl, optionally substituted 4- to 8- membered heterocycloalkyl, optionally substituted ary l, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroaryl;R5ais R5; R5bis R5; R6ais R6; R6bis R6; RE2is RE;r is 0, 1, 2, or 3;R21is selected from the group consisting of:1) Halogen;2) Cyano;3) Hydroxy;4) Optionally substituted -Ci-Cs alkyl;5) Optionally substituted -C3-C8 cycloalkyl;6) Optionally substituted 4- to 8- membered heterocycloalkyl;7) Optionally substituted aryl;8) Optionally substituted heteroaryl;9) Optionally substituted -Ci-Cs alkoxy;10)-C(O)N(RI)(R2);11)-N(RI)C(O)(R2);12)-N(RI)(R2);13)-SRI;14)-S(O)2Ri;15)-N(RI)C(O)O(R2);16)-N(RI)S(O)2(R2); and17)-P(O)RIR2;and R1, R2, R5, R6, and REare as defined in claim 1.

4. A compound selected from the compounds set forth below, or a pharmaceutically acceptable salt thereof:PAGE 73 OF 77Docket No. 4014.1407 WOPAGE 74 OF 77Docket No. 4014.1407 WOPAGE 75 OF 77Docket No. 4014.1407 WO5. A pharmaceutical composition comprising the compound of any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

6. A method for treating a disease, disorder, or condition wherein modulation of STAT6 or STAT3 is implicated in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 4.

7. The method of claim 6, wherein the disease involving STAT6 is an allergic disease or an inflammatory disease.

8. The method of claim 7, wherein 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.

9. The method of claim 6, wherein the disease involving STAT3 is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, and inflammatory bowel disease.PAGE 76 OF 77

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