MCL1 inhibitors and their applications

Abstract

The present disclosure provides compounds such as compounds of Formula I and compositions that are MCL1 inhibitors.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 065755, filed August 14, 2020, U.S. Provisional Application No. 62 / 964964, filed January 23, 2020, and U.S. Provisional Application No. 62 / 910146, filed October 3, 2019, each of which is incorporated herein by reference in its entirety. Background Art

[0003] The MCL1 (also abbreviated as MCl-1, MCL-1, Mcl or Mcl-1) protein is a member of the BCL2 protein family. The BCL2 family regulates apoptosis. Members of the BCL2 family include the pro-apoptotic proteins BAX and BAK, which, when activated, translocate to the outer mitochondrial membrane where they form homo-oligomers. These oligomers cause pore formation in the outer mitochondrial membrane and trigger apoptosis. Other members of the BCL2 family, including BCL2, BCLXL and MCL1, prevent apoptosis (i.e., they are anti-apoptotic).

[0004] The pathology of certain diseases is known to involve deregulation of apoptosis. For example, increased apoptosis is implicated in the neurodegenerative diseases Parkinson's disease, Alzheimer's disease, and ischemia. Conversely, insufficient apoptosis is implicated in cancer development and chemoresistance, as well as in autoimmune diseases, inflammatory diseases, and viral infections.

[0005] The BCL2 family of anti-apoptotic proteins has been implicated in several cancers, such as colon cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, prostate cancer, lymphoma, myeloma, acute myeloid leukemia (also known as acute myeloid leukemia), chronic lymphocytic leukemia, pancreatic cancer, and ovarian cancer.

[0006] Certain cancers overexpress MCL1. This overexpression prevents cancer cells from undergoing apoptosis, which allows them to survive and leads to disease progression. It is understood in the art that MCL1 inhibitors can be used to treat cancer.

[0007] Therefore, a welcome contribution in the art would be small molecules (i.e., compounds) that inhibit MCL1 activity for the treatment of a broad spectrum of cancers such as myeloma, lymphoma, acute myeloid leukemia, melanoma, sarcoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. Summary of the Invention

[0008] In certain embodiments, the present invention relates to compounds having:

[0009] (a) Formula I structure:

[0010]

[0011] or a pharmaceutically acceptable salt thereof,

[0012] in:

[0013] A is aryl or heteroaryl;

[0014] B is a bond, aryl or heteroaryl;

[0015] The 5,6-membered bicyclic heteroaryl represented by C and D is selected from:

[0016] in Represents the attachment point, * represents the connection with L 1 's attachment point, and ** represents the attachment point to B;

[0017] a1 is CH, N or NH;

[0018] a2 is C(Z 1 ), N or N(Z 2 );

[0019] a3 is C(Z 1 ), N or N(Z 2 ),

[0020] provided that a1, a2 and a3 are selected such that ring D is aromatic;

[0021] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0022] L 2 is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(R X1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0023] W is C(O)OR W1,C(O)N(H)S(O)2R W2 ,S(O)2N(H)C(O)R W2 ,S(O)2N(H)R W3 , in Represents the attachment point;

[0024] X is absent, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy or N(R X1 )(R X2 ), wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0025] Y is aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, N(R X1 )(R X2 ) or hydroxy, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0026] Z 1 is H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0027] Z 2 is H, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0028] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0029] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0030] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0031] R2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0032] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0033] R W2 is C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0034] R W3 is aryl or heteroaryl;

[0035] R W1a is H or C1-C6 alkyl;

[0036] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0037] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0038] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0039] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0040] R X1 and R X2 is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl are each optionally substituted with 1, 2, 3 or 4 RX3 Replace; or

[0041] R X1 and R X2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0042] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0043] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0044] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0045] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0046] R X3c and R X3dTogether with the nitrogen to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen;

[0047] R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0048] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0049] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0050] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0051] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0052] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2)(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0053] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0054] m is 0, 1, 2, or 3;

[0055] n is 0, 1, 2, 3 or 4, provided that in the case where B is a bond n is 0; and

[0056] p is independently 0 or 1 at each occurrence; or

[0057] (b) Formula II structure:

[0058]

[0059] or a pharmaceutically acceptable salt thereof,

[0060] in:

[0061] A is aryl or heteroaryl;

[0062] B is a bond, aryl or heteroaryl;

[0063] a1 is CH, N or NH;

[0064] a2 is C(Z 1 ), N or N(Z 2 );

[0065] a3 is C(Z 1 ), N or N(Z 2 );

[0066] a4 is S, O or NH,

[0067] provided that a1, a2 and a3 are selected such that ring D is aromatic;

[0068] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0069] L 2 is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(RX1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0070] X is absent, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy or N(R X1 )(R X2 ), wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0071] Y is aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, N(R X1 )(R X2 ) or hydroxy, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0072] Z 1 is H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0073] Z 2 is H, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0074] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0075] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0076] R 2is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0077] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0078] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0079] R W1a is H or C1-C6 alkyl;

[0080] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0081] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0082] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0083] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0084] R X1 and R X2is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3 Replace; or

[0085] R X1 and R X2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0086] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0087] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0088] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0089] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0090] R X3c and R X3d Together with the nitrogen to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen;

[0091] R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0092] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0093] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0094] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0095] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0096] RCy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0097] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0098] m is 0, 1, 2, or 3;

[0099] n is 0, 1, 2, 3 or 4, provided that in the case where B is a bond n is 0; and

[0100] p is independently 0 or 1 at each occurrence; or

[0101] (c) Formula III structure:

[0102]

[0103] or a pharmaceutically acceptable salt thereof,

[0104] in:

[0105] a2 is C(Z 1 ) or N;

[0106] a4 is S, O or NH;

[0107] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0108] L 2 is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(R X1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0109] E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0110] F is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0111] Z 1 is independently H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0112] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0113] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0114] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0115] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0116] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0117] R W1a is H or C1-C6 alkyl;

[0118] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0119] RW2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0120] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0121] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0122] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0123] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0124] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0125] R X3c and R X3dEach is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0126] R X3c and R X3d Together with the nitrogen to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen;

[0127] R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0128] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0129] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0130] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0131] R Z4is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0132] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0133] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0134] m is 0, 1, 2, or 3;

[0135] n is 0, 1, 2, 3, or 4;

[0136] p is independently 0 or 1 at each occurrence; and

[0137] q is independently 0, 1, 2, 3 or 4 at each occurrence, provided that in the absence of E in -(R X3 ) q In this case, q is 0;

[0138] (d) Formula IV structure:

[0139]

[0140] or a pharmaceutically acceptable salt thereof,

[0141] in:

[0142] a 2a is CH or N;

[0143] a4 is S, O or NH;

[0144] L 1 is independently at each occurrence a bond, CH2, O, NH, S, SO or SO2;

[0145] E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0146] F is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0147] Z 1ais H, halogen, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0148] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0149] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0150] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0151] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0152] R W1a is H or C1-C6 alkyl;

[0153] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0154] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0155] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0156] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0157] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0158] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0159] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0160] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0161] R X3c and R X3d Together with the nitrogen to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen;

[0162] R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0163] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0164] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0165] R Z3 is independently at each occurrence aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0166] m is 0, 1, 2, or 3;

[0167] n is 0, 1, 2, 3, or 4; and

[0168] q is independently 0, 1, 2, 3 or 4 at each occurrence, provided that in the absence of E in -(R X3 ) q where q is 0; or

[0169] (e) Formula V structure:

[0170]

[0171] or a pharmaceutically acceptable salt thereof,

[0172] in:

[0173] a2 is C(Z1 ) or N;

[0174] a4 is S, O or NH;

[0175] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0176] L 2 is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(R X1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0177] E is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0178] F is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0179] G is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0180] Z 1 is independently H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0181] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0182] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0183] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R2a )(R 2b );

[0184] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0185] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0186] R W1a is H or C1-C6 alkyl;

[0187] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0188] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0189] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0190] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0191] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0192] RX3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0193] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0194] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0195] R X3c and R X3d Together with the N to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen; R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0196] R Z2is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0197] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0198] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0199] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0200] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0201] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0202] m is 0, 1, 2, or 3;

[0203] n is 0, 1, 2, 3, or 4;

[0204] p is independently 0 or 1 in each instance;

[0205] q is independently at each occurrence 0, 1, 2, 3 or 4; and

[0206] r is 0, 1, 2, 3, or 4; or

[0207] (f) Formula VI structure:

[0208]

[0209] or a pharmaceutically acceptable salt thereof,

[0210] in:

[0211] a2 is C(Z 1 ) or N;

[0212] a4 is S, O or NH;

[0213] L 1 is independently at each occurrence a bond, CH2, O, NH, S, SO or SO2;

[0214] E is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0215] F is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0216] G is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0217] Z 1 is independently H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0218] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0219] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0220] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0221] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0222] R W1is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0223] R W1a is H or C1-C6 alkyl;

[0224] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0225] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0226] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0227] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0228] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0229] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0230] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0231] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0232] R X3c and R X3d Together with the N to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen; R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0233] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3Replace; or

[0234] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0235] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0236] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0237] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0238] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0239] m is 0, 1, 2, or 3;

[0240] n is 0, 1, 2, 3, or 4;

[0241] q is independently at each occurrence 0, 1, 2, 3 or 4; and

[0242] r is 0, 1, 2, 3, or 4;

[0243] (g) Formula VII structure:

[0244]

[0245] or a pharmaceutically acceptable salt thereof,

[0246] in:

[0247] a2 is C(Z 1 ) or N;

[0248] a4 is S, O or NH;

[0249] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0250] L 2 is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(R X1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0251] E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0252] Y a is C1-C6 hydroxyalkyl, C1-C6 alkoxy, N(R X1 )(R X2 ) or hydroxyl;

[0253] Z 1 is independently H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0254] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0255] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0256] R 2is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0257] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0258] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0259] R W1a is H or C1-C6 alkyl;

[0260] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0261] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0262] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0263] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0264] R X3is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0265] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0266] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0267] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0268] R X3c and R X3d Together with the N to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen; R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0269] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0270] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0271] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0272] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0273] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0274] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0275] m is 0, 1, 2, or 3;

[0276] n is 0, 1, 2, 3, or 4;

[0277] p is independently 0 or 1 at each occurrence; and

[0278] q is independently 0, 1, 2, 3 or 4 at each occurrence, provided that in the absence of E in -(R X3 ) q In this case, q is 0;

[0279] (h) Formula VIII structure:

[0280]

[0281] or a pharmaceutically acceptable salt thereof,

[0282] in:

[0283] E is heteroaryl;

[0284] L 3 is -CH2- or -CH2CH2-;

[0285] Y b is H, heterocyclyl, -N(CH3)2, -N(CH2CH3)2, -CH2N(CH3)2 or -CH2N(CH2CH3)2; or

[0286] L 3 is not present and Y b It is H;

[0287] Z 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0288] R X3 is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, heterocyclyl and C1-C6 alkoxy are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0289] R X3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0290] RZ1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0291] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0292] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0293] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0294] R Z4 is independently at each occurrence C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano; and

[0295] q is 0, 1, 2, 3, or 4; or

[0296] (i) Formula IX structure:

[0297]

[0298] or a pharmaceutically acceptable salt thereof,

[0299] in:

[0300] E is pyrimidinyl, pyrazolyl, pyridyl or imidazolyl;

[0301] L 3 is -CH2- or -CH2CH2-;

[0302] Y b Morpholinyl, piperazinyl, piperidinyl, N(CH2CH3)2 or N(CH3)2;

[0303] Z 1 is cyclobutyl, benzyl, pyridyl, pyrazolyl or imidazolyl;

[0304] R X3 benzyl, pyridyl, C1-C3 alkoxy or C1-C4 alkyl;

[0305] R X3a-1 and R X3a-2 are each independently H, C1-C3 alkyl, C1-C2 haloalkyl, amino, cyano or halogen; and

[0306] R Z1 is C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or halogen. BRIEF DESCRIPTION OF THE DRAWINGS

[0307] Figure 1 are the results of an AMO-1 myeloma cell line xenograft study using the compound of formula X. Eight mice were used per group, and the mice were administered various concentrations of the compound of formula X by intravenous injection (IV) daily (QD) for the first 5 days of the study.

[0308] Figure 2 Shown are the results of tumor volume change studies using the compound of formula X in the AMO-1 myeloma cell line xenograft.

[0309] Figure 3 Figure 5 is a table of daily percent body weight change in mice in an AMO-1 myeloma cell line xenograft study using the compound of formula X. Detailed Description of the Invention

[0311] definition

[0312] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in and techniques of chemistry, cell and tissue culture, molecular biology, cell and cancer biology, immunology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0313] The methods and techniques of the present disclosure are generally (unless otherwise indicated) performed according to conventional methods well known in the art and described in various general and more specific references that are cited and discussed throughout this specification. See, for example, Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0314] Chemical terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms,” Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0315] All of the above and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0316] "Patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0317] "Treating" a condition or patient refers to taking steps to obtain a beneficial or desired outcome, including a clinical outcome. As used herein and as is well understood in the art, "treating" is an approach to obtaining a beneficial or desired outcome (including a clinical outcome). Beneficial or desired clinical outcomes can include, but are not limited to, alleviating or ameliorating one or more symptoms or conditions, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, preventing the spread of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, and alleviating (whether partially or completely), whether detectable or undetectable. "Treatment" can also mean prolonging survival compared to the expected survival if not receiving treatment.

[0318] The term "prevent" is art-recognized and is well understood in the art as it applies to conditions such as local recurrences (e.g., pain), diseases such as cancer, syndromes such as heart failure, or any other medical condition, and includes administering a composition that reduces the frequency of, delays the onset of, or reduces the symptoms of a medical condition in a subject relative to a subject that does not receive the composition. Thus, preventing cancer includes, for example, reducing the number of detectable cancerous growths in a patient population receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population compared to an untreated control population, for example, by a statistically and / or clinically significant amount.

[0319] "Administering" or "administering" a substance, compound, or agent to a subject can be performed using one of various methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinal, intracerebrally, and transdermally (by absorption, e.g., through skin channels). The compound or agent can also be suitably introduced via a rechargeable or biodegradable polymer device or other device, such as a patch and pump, or a formulation that provides for extended, slow, or controlled release of the compound or agent. Administration, for example, can also be performed once, multiple times, and / or over one or more extended time periods.

[0320] The appropriate method of administering a substance, compound, or reagent to a subject will also depend on, for example, the age and / or physical condition of the subject and the chemical and biological properties (e.g., solubility, digestibility, bioavailability, stability, and toxicity) of the compound or reagent. In certain embodiments, the compound or reagent is administered orally, for example, by ingestion. In certain embodiments, the orally administered compound or reagent is in an extended release or sustained release formulation, or is administered with a device suitable for the slow or extended release.

[0321] The term "acyl" is art-recognized and refers to a group of the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0322] An "alkyl" group or "alkane" is a straight-chain or branched, fully saturated, non-aromatic hydrocarbon. Generally, a straight-chain or branched alkyl group has from 1 to about 10 carbon atoms, preferably from 1 to about 6, unless otherwise defined. Examples of straight-chain and branched alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, amyl, and octyl. A C1-C6 straight-chain or branched alkyl group is also referred to as a "lower alkyl" group. Alternatively, where an alkyl group is located between or conjugated to two groups, it is considered an alkylene group.

[0323] In addition, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to alkyl moieties having substituents replacing one or more hydrogens on the hydrocarbon backbone carbon. Such substituents, unless otherwise specified, can include, for example, halogen (e.g., fluorine), hydroxy, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on the substituted alkyl group are selected from C1-C6 alkyl, C3-C6 cycloalkyl, halogen, amino, carbonyl, cyano, or hydroxy. In a more preferred embodiment, the substituents on the substituted alkyl group are selected from fluorine, carbonyl, cyano or hydroxy. Those skilled in the art will appreciate that the portion substituted on the hydrocarbon chain itself can be substituted, if appropriate. For example, the substituents of the substituted alkyl group can include the following substituted and unsubstituted forms: amino, azido, imino, amide, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfamoyl and sulfonates), and silyl, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF3, -CN, etc. Exemplary substituted alkyl groups are described below. Cycloalkyl groups can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc.

[0324] The term "alkenyl" as used herein refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls," the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more alkenyl carbons. The substituents may occur on one or more carbons that are or are not involved in one or more double bonds. In addition, the substituents include all those contemplated for alkyl groups as discussed below, except where prohibited by stability. For example, one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups are contemplated to replace alkenyl groups.

[0325] The term "alkynyl," as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include "unsubstituted alkynyls" and "substituted alkynyls," the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more alkynyl carbons. The substituents may occur on one or more carbons that are or are not involved in one or more triple bonds. In addition, the substituents include all those contemplated for alkyl groups as discussed above, except where prohibited by stability. For example, one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups are contemplated to replace an alkynyl group.

[0326] The term "alkylamino" as used herein refers to an amino group substituted with at least one alkyl group.

[0327] The term "alkylthio" as used herein refers to a mercapto group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0328] The term "C x -C y "" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups containing from x to y carbons in the chain. For example, the term "C x -C y "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight and branched chain alkyl groups containing from x to y carbons in the chain, including haloalkyl groups. Preferred haloalkyl groups include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl. C0 alkyl refers to hydrogen when the group is in the terminal position and to a bond if it is internal. The term "C2-C y Alkenyl" and "C2-C y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group analogous in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively.

[0329] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen group attached thereto. Representative alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0330] The terms "amine" and "amino" are art-recognized and refer to unsubstituted and substituted amines and salts thereof, such as moieties represented by the formula

[0331]

[0332] Among them, each R A independently represent hydrogen or a hydrocarbon group, or two R A Together with the N atom to which they are attached, the heterocycle has 4 to 8 atoms in the ring structure.

[0333] The term "aminoalkyl" as used herein refers to an alkyl group substituted with an amino group.

[0334] The term "aralkyl" as used herein refers to an alkyl group substituted with an aryl group.

[0335] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each ring atom is carbon. Preferably, it is a 6- to 10-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more rings, wherein two adjacent rings share two or more carbon atoms, wherein at least one ring is aromatic, and the other rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Aryl includes benzene, naphthalene, phenanthrene, aniline, etc.

[0336] The term "carbocycle" refers to a saturated or unsaturated ring in which each ring atom is carbon. The term carbocycle includes aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include cycloalkyl rings and cycloalkenyl rings. "Carbocycle" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. The rings of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycle includes bicyclic molecules in which the two rings share 1, 2, or 3 or more atoms. Carbocycle includes bicyclic molecules in which the two rings share 1, 2, or 3 or more atoms. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares 2 adjacent atoms with another ring. The rings of a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring such as phenyl can be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as permitted by valence, is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decahydronaphthalene, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. "Carbocycles" may be substituted at any one or more positions capable of carrying a hydrogen atom.

[0337] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, monocyclic cycloalkyls have 3 to about 10 carbon atoms, 3 to 8 carbon atoms, or more typically 3 to 6 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyls include bicyclic molecules in which the two rings share 1, 2, or 3 or more atoms (e.g., fused bicyclic compounds, bridged bicyclic compounds, and spirocyclic compounds).

[0338] The term "fused bicyclic compound" refers to a bicyclic molecule in which the two rings share two adjacent atoms. In other words, the rings share one covalent bond, i.e., the so-called bridgehead atoms are directly connected (e.g., α-thujene and decalin). For example, in a fused cycloalkyl, each ring shares two adjacent atoms with the other ring, and the second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings.

[0339] The term "spiro compound" or "spirocycle" refers to a bicyclic molecule or group in which the two rings share only a single atom, the spiroatom.

[0340] The terms "heteroaryl" and "heteroaryl group" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "heteroaryl group" also include polycyclic ring systems having two or more rings, wherein two adjacent rings share two or more carbon atoms, wherein at least one ring is heteroaromatic, and the other rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Heteroaryl includes, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, quinoline, quinoxaline, naphthyridine, and the like.

[0341] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

[0342] The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, preferably 3- to 7-membered rings, more preferably 5- to 6-membered rings, most preferably 5-membered rings in some cases, and most preferably 6-membered rings in other cases, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocycle" also include polycyclic ring systems having two or more cyclic rings in which one, two or more carbon atoms (e.g., fused heterobicyclic compounds, bridged heterobicyclic compounds, and heterospirocyclic compounds) are shared by two adjacent rings, wherein at least one ring is a heterocycle, e.g., the other cyclic ring can be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. The terms "heterocyclyl" and "heterocycle" also include spirocycles in which at least one ring is a heterocycle, for example, the other cyclic ring can be a cycloalkyl, cycloalkenyl, cycloalkynyl and / or heterocyclyl. Heterocyclyl groups include, for example, pyrrolidine, piperidine, piperazine, pyrrolidine, tetrahydropyran, tetrahydrofuran, morpholine, lactone, lactam, oxazoline, imidazoline, and the like.

[0343] The terms "halo" and "halogen" as used herein mean halogen and include chlorine, fluorine, bromine and iodine.

[0344] The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halo groups.

[0345] The term "hydrocarbyl" as used herein refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent and generally has at least one carbon-hydrogen bond and a backbone that is primarily carbon but may optionally include heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl groups for the purposes of this application, but substituents such as acetyl (which has a =O substituent attached to the carbon) and ethoxy (which is attached through an oxygen that is not carbon) are not considered hydrocarbyl groups. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0346] The term "hydroxyalkyl" as used herein refers to an alkyl group substituted with a hydroxy group.

[0347] The term "sulfonamide" is art-recognized and refers to a group represented by the formula

[0348]

[0349] Among them, each R A independently represent hydrogen or a hydrocarbon group such as an alkyl group, or two R A Together with the spacer atoms, the heterocycle has 4 to 8 atoms in the ring structure.

[0350] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R A , where R A Represents a hydrocarbon group.

[0351] The term "sulfonyl" is art-recognized and refers to the group -S(O)2-R A , where R A Represents a hydrocarbon group.

[0352] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more backbone carbons. It is understood that "substituted" or "substituted with" is included provided that the substitution complies with the valencies allowed for the substituted atom and the substituent and that the substitution results in a stable compound, e.g., one that does not spontaneously transform, for example, by rearrangement, cyclization, elimination, or the like. For appropriate organic compounds, the substitutions can be one or more and the same or different.

[0353] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other substances and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0354] "Pharmaceutically acceptable salt" or "salt" as used herein refers to acid addition salts or base addition salts that are suitable for or compatible with patient treatment.

[0355] The term "pharmaceutically acceptable acid addition salt" as used herein refers to any non-toxic organic or inorganic salt of any base compound disclosed herein. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Mono- or di-acid salts can be formed, and the salts can exist in hydrated, solvated or substantially anhydrous forms. In general, the acid addition salts of the compounds disclosed herein are more soluble in water and various hydrophilic organic solvents than their free base forms and generally exhibit higher melting points. The selection of appropriate salts will be known to those skilled in the art. Other non-pharmaceutically acceptable salts such as oxalates may be used, for example, in laboratory isolation of the compounds of the invention or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0356] The term "pharmaceutically acceptable basic addition salt" as used herein refers to any non-toxic organic or inorganic base addition salt of any acid compound of the present invention or any intermediate thereof. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picolinate or ammonia. The selection of appropriate salts will be known to those skilled in the art.

[0357] Many compounds used in the disclosed methods and compositions have at least one stereocenter in their structure. This stereocenter can exist in either R or S configuration, with the R and S symbols being used according to the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms of compounds, their salts, prodrugs, or mixtures, such as enantiomeric and diastereomeric forms (including all possible mixtures of stereoisomers). See, for example, WO 01 / 062726.

[0358] Additionally, certain compounds containing alkenyl groups may exist as Z (cis) or E (trans) isomers. In each case, the disclosure includes both the mixture and the separated individual isomers.

[0359] Certain compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure.

[0360] The present disclosure contemplates all rotamers and atropisomers of the compounds and their salts, drugs, prodrugs, or mixtures (including all possible mixtures of rotamers). Structures not shown with stereochemistry are intended to encompass one, the other, or a mixture of both rotamers or atropisomers.

[0361] "Prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized, for example, hydrolyzed or oxidized, in a host to form a compound of the present disclosure (e.g., a compound of the present invention) after administration. Typical examples of prodrugs include compounds having biologically labile or cleavable (protecting) groups on a functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using esters or phosphoramidates as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present disclosure are metabolized to produce a compound of the present disclosure or a pharmaceutically acceptable salt thereof. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs", Ed. H. Bundgaard, Elsevier, 1985.

[0362] Example compounds

[0363] In certain embodiments, the present invention relates to compounds having the structure of Formula I:

[0364]

[0365] or a pharmaceutically acceptable salt thereof,

[0366] in:

[0367] A is aryl or heteroaryl;

[0368] B is a bond, aryl or heteroaryl;

[0369] The 5,6-membered bicyclic heteroaryl represented by C and D is selected from:

[0370] in Represents the attachment point, * represents the connection with L 1's attachment point, and ** represents the attachment point to B;

[0371] a1 is CH, N or NH;

[0372] a2 is C(Z 1 ), N or N(Z 2 );

[0373] a3 is C(Z 1 ), N or N(Z 2 ),

[0374] provided that a1, a2 and a3 are selected such that ring D is aromatic;

[0375] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0376] L 2 is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(R X1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0377] W is C(O)OR W1 ,C(O)N(H)S(O)2R W2 ,S(O)2N(H)C(O)R W2 ,S(O)2N(H)R W3 , in Represents the attachment point;

[0378] X is absent, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy or N(R X1 )(R X2 ), wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0379] Y is aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, N(R X1 )(R X2 ) or hydroxy, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0380] Z 1 is H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0381] Z 2 is H, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0382] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0383] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0384] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0385] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0386] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0387] R W2 is C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0388] R W3 is aryl or heteroaryl;

[0389] R W1a is H or C1-C6 alkyl;

[0390] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0391] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0392] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0393] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0394] R X1 and R X2 is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3 Replace; or

[0395] R X1 and R X2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0396] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0397] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0398] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0399] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0400] R X3c and R X3d Together with the nitrogen to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen;

[0401] R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0402] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0403] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0404] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0405] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0406] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0407] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0408] m is 0, 1, 2, or 3;

[0409] n is 0, 1, 2, 3 or 4, provided that in the case where B is a bond n is 0; and

[0410] p is independently 0 or 1 in each instance.

[0411] In certain embodiments, the present invention relates to compounds of formula I, wherein:

[0412] R X3 is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0413] R X3a is independently in each case C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano.

[0414] In certain embodiments, the present invention relates to compounds of formula I, wherein:

[0415] B is aryl or heteroaryl;

[0416] X is aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy or N(R X1 )(R X2 ), wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0417] R X3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halo, amino, nitro or cyano; and

[0418] n is 0, 1, 2, 3 or 4.

[0419] In certain embodiments, the present invention relates to compounds having the structure of Formula II:

[0420]

[0421] or a pharmaceutically acceptable salt thereof,

[0422] in:

[0423] A is aryl or heteroaryl;

[0424] B is a bond, aryl or heteroaryl;

[0425] a1 is CH, N or NH;

[0426] a2 is C(Z 1 ), N or N(Z 2 );

[0427] a3 is C(Z 1 ), N or N(Z 2 );

[0428] a4 is S, O or NH,

[0429] provided that a1, a2 and a3 are selected such that ring D is aromatic;

[0430] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0431] L 2 is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(R X1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0432] X is absent, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy or N(R X1 )(R X2 ), wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0433] Y is aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, N(R X1 )(R X2 ) or hydroxy, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0434] Z 1 is H, halogen, -L2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0435] Z 2 is H, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0436] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0437] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0438] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0439] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0440] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0441] R W1a is H or C1-C6 alkyl;

[0442] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0443] R W2bis independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0444] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0445] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0446] R X1 and R X2 is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, aryl, heteroaryl or heterocyclyl, wherein aryl, heteroaryl or heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3 Replace; or

[0447] R X1 and R X2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0448] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0449] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0450] RX3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0451] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0452] R X3c and R X3d Together with the N to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen.

[0453] R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0454] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0455] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3replace;

[0456] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0457] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0458] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0459] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0460] m is 0, 1, 2, or 3;

[0461] n is 0, 1, 2, 3 or 4, provided that in the case where B is a bond n is 0; and

[0462] p is independently 0 or 1 in each instance.

[0463] In certain embodiments, the present invention relates to compounds of formula II, wherein:

[0464] R X3 is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0465] R X3ais independently in each case C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano.

[0466] In certain embodiments, the present invention relates to compounds of formula II, wherein:

[0467] B is aryl or heteroaryl;

[0468] X is aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy or N(R X1 )(R X2 ), wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0469] R X3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halo, amino, nitro or cyano; and

[0470] n is 0, 1, 2, 3 or 4.

[0471] In certain embodiments, the present invention relates to compounds of formula II, wherein:

[0472] A is an aryl group;

[0473] B is an aryl group;

[0474] a1 is CH;

[0475] a2 is C(H) or N;

[0476] a3 is C(Z 1 );

[0477] a4 is S, O or NH;

[0478] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0479] L 2 is independently a bond or -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -;

[0480] X is an aryl or heteroaryl group, wherein the aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0481] Y is a heterocyclic group, a C1-C6 hydroxyalkyl group, a C1-C6 alkoxy group, N(R X1 )(R X2 ) or hydroxy, wherein the heterocyclic group is optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0482] Z 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0483] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0484] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0485] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0486] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl or heteroaryl, wherein the heterocyclic, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0487] R W1a is H or C1-C6 alkyl;

[0488] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0489] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0490] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0491] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0492] R X1 and R X2 is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence; or

[0493] R X1 and R X2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0494] R X3 is independently aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl and heteroaryl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0495] R X3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0496] R Z1 is independently halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, nitro or cyano, wherein the C1-C6 alkyl, C1-C6 aminoalkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 replace;

[0497] R Z2is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 replace;

[0498] R Z3 is independently aryl, heteroaryl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl and heteroaryl are each optionally substituted with one or more R Z4 replace;

[0499] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0500] m is 0, 1, 2, or 3;

[0501] n is 0, 1, 2, 3, or 4; and

[0502] p is independently 0 or 1 in each instance.

[0503] In certain embodiments, the present invention relates to compounds of formula II, wherein:

[0504] A is an aryl group;

[0505] B is an aryl group;

[0506] a1 is CH;

[0507] a2 is C(Z 1 );

[0508] a3 is C(H);

[0509] a4 is S, O or NH;

[0510] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0511] L 2 is independently a bond or -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -;

[0512] X is an aryl or heteroaryl group, wherein the aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0513] Y is a heterocyclic group, a C1-C6 hydroxyalkyl group, a C1-C6 alkoxy group, N(R X1 )(R X2 ) or hydroxy, wherein the heterocyclic group is optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0514] Z 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0515] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0516] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0517] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0518] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl or heteroaryl, wherein the heterocyclic, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0519] R W1a is H or C1-C6 alkyl;

[0520] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0521] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0522] In R W2a isOC(O)N(R W2b)(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0523] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0524] R X1 and R X2 is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence; or

[0525] R X1 and R X2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R X3 replace;

[0526] R X3 is independently aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl and heteroaryl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0527] R X3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0528] R Z1 is independently halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, nitro or cyano, wherein the C1-C6 alkyl, C1-C6 aminoalkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 replace;

[0529] R Z2 is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 replace;

[0530] R Z3 is independently aryl, heteroaryl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl and heteroaryl are each optionally substituted with one or more R Z4 replace;

[0531] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0532] m is 0, 1, 2, or 3;

[0533] n is 0, 1, 2, 3, or 4; and

[0534] p is independently 0 or 1 in each instance.

[0535] In a preferred embodiment, Z 1 is a bicyclic aryl or a bicyclic heteroaryl. In a more preferred embodiment, the bicyclic heteroaryl is indazolyl, benzimidazolyl, benzimidazolinone, indolyl, pyrrolopyridinyl or isoquinolinyl, wherein indazolyl, benzimidazolyl, benzimidazolinone, indolyl, pyrrolopyridinyl and isoquinolinyl are each optionally substituted with 1, 2 or 3 groups independently selected from C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxyl, halogen, amino, nitro or cyano.

[0536] In certain embodiments, the present invention is directed to compounds of formula I or II, wherein A is phenyl, pyridine, pyridazine, pyrimidine, pyrazine or thiophene.

[0537] In certain embodiments, the present invention is directed to compounds of formula I or II, wherein B is phenyl, pyridine or thiophene.

[0538] In certain embodiments, the present invention relates to compounds of any one of Formula I or II, wherein:

[0539] A is phenyl, pyridine or pyrimidine;

[0540] B is phenyl, pyridine or thiophene;

[0541] L 1 It is O;

[0542] R 1 It is H;

[0543] R 2 is independently C1-C6 alkyl or halogen at each occurrence;

[0544] m is 0; and

[0545] n is 2.

[0546] In certain embodiments, the present invention relates to compounds of formula I or II, wherein:

[0547] Y is in Represents the attachment point;

[0548] R 3 is H or C1-C6 alkyl;

[0549] R 4 Yes-OP(O)(O - )(O - ), -OP(O)(O - )(OR 5 ), -OP(O)(OR 5 )(OR 5 ), -OS(O2)-O - ,-OS(O2)-OR 5 , Cy a ,-OC(O)-R 6 ,-OC(O)-OR 6 or-OC(O)-N(R 6 )(R 6 );

[0550] Cy a is cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0551] R 5 is independently H, C1-C6 alkyl, or aralkyl(C1-C6); and

[0552] R 6 is independently H, C1-C6 alkyl or C1-C6 aminoalkyl in each instance.

[0553] In certain embodiments, the present invention relates to compounds of formula I or II, wherein L 2 is a bond and Y is a hydroxyl group.

[0554] In certain embodiments, the present invention relates to compounds having the structure of Formula III:

[0555]

[0556] or a pharmaceutically acceptable salt thereof,

[0557] in:

[0558] a2 is C(Z 1 ) or N;

[0559] a4 is S, O or NH;

[0560] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0561] L 2 is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(R X1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0562] E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0563] F is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0564] Z 1 is independently H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0565] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0566] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0567] R 2is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0568] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0569] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0570] R W1a is H or C1-C6 alkyl;

[0571] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0572] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0573] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0574] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0575] R X3is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0576] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0577] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0578] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0579] R X3c and R X3d Together with the nitrogen to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen;

[0580] R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0581] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0582] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0583] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0584] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0585] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0586] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0587] m is 0, 1, 2, or 3;

[0588] n is 0, 1, 2, 3, or 4;

[0589] p is independently 0 or 1 at each occurrence; and

[0590] q is independently 0, 1, 2, 3 or 4 at each occurrence, provided that in the absence of E in -(R X3 ) q Here q is 0.

[0591] In certain embodiments, the present invention relates to compounds of formula III, wherein:

[0592] E is aryl, heteroaryl, cycloalkyl or heterocyclyl; and

[0593] q is independently 0, 1, 2, 3 or 4 at each occurrence.

[0594] In certain embodiments, the present invention relates to compounds of formula III, wherein:

[0595] R X3 is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0596] R X3a In each case, is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano. In certain embodiments, the present invention relates to compounds of formula III, wherein:

[0597] a2 is C(H) or N;

[0598] a4 is S, O or NH;

[0599] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0600] L 2 is independently a bond or -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -;

[0601] E is aryl or heteroaryl;

[0602] F is a cycloalkyl group or a heterocyclyl group;

[0603] Z 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0604] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0605] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0606] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0607] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl or heteroaryl, wherein the heterocyclic, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0608] R W1a is H or C1-C6 alkyl;

[0609] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0610] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0611] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0612] RW3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0613] R X3 is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0614] R X3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0615] R Z1 is independently halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, nitro or cyano, wherein the C1-C6 alkyl, C1-C6 aminoalkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 replace;

[0616] R Z2 is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 replace;

[0617] R Z3 is independently at each occurrence aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0618] m is 0, 1, 2, or 3;

[0619] n is 0, 1, 2, 3, or 4;

[0620] p is independently 0 or 1 at each occurrence; and

[0621] q is independently 0, 1, 2, 3 or 4 at each occurrence.

[0622] In certain embodiments, the present invention relates to compounds of any one of Formula I, II, or III, wherein:

[0623] L 1 It is O;

[0624] R 1 It is H;

[0625] R 2 is independently C1-C6 alkyl or halogen at each occurrence;

[0626] m is 0; and

[0627] n is 2.

[0628] In other embodiments, the present invention relates to compounds of any one of Formula I, II or III, wherein:

[0629] R W1 It is H;

[0630] L 1 It is O;

[0631] R 1 It is H;

[0632] R 2 is independently C1-C6 alkyl or halogen at each occurrence;

[0633] m is 0; and

[0634] n is 2.

[0635] In other embodiments, the invention relates to compounds of any of formula I, II or III, wherein a2 is C(H) or N.

[0636] In certain embodiments, the present invention relates to compounds of formula III, wherein Z 1 In each instance, is independently H or halogen, and more particularly, halogen is Br or Cl.

[0637] In other embodiments, the present invention relates to compounds of formula III, wherein Z 1 is independently H at each occurrence, optionally substituted phenyl, optionally substituted pyridine, optionally substituted thiophene, optionally substituted furan, optionally substituted pyrrole, optionally substituted cyclopropyl or optionally substituted cyclobutyl. In a preferred embodiment, Z 1 In some embodiments, the optional substitution is halogen, and more particularly, halogen is F or Cl.

[0638] In certain embodiments, the present invention relates to compounds having the structure of Formula IV:

[0639]

[0640] or a pharmaceutically acceptable salt thereof,

[0641] in:

[0642] a 2a is CH or N;

[0643] a4 is S, O or NH;

[0644] L 1 is independently at each occurrence a bond, CH2, O, NH, S, SO or SO2;

[0645] E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0646] F is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0647] Z 1a is H, halogen, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0648] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0649] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0650] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0651] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0652] R W1a is H or C1-C6 alkyl;

[0653] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0654] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0655] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0656] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0657] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0658] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0659] R X3bis independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0660] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0661] R X3c and R X3d Together with the nitrogen to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen;

[0662] R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0663] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0664] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0665] R Z3 is independently at each occurrence aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0666] m is 0, 1, 2, or 3;

[0667] n is 0, 1, 2, 3, or 4; and

[0668] q is independently 0, 1, 2, 3 or 4 at each occurrence, provided that in the absence of E in -(R X3 ) q Here q is 0.

[0669] In certain embodiments, the present invention relates to compounds of formula IV, wherein:

[0670] E is aryl, heteroaryl, cycloalkyl or heterocyclyl; and

[0671] q is independently 0, 1, 2, 3 or 4 at each occurrence.

[0672] In certain embodiments, the present invention relates to compounds of formula IV, wherein:

[0673] R X3 is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0674] R X3a is independently in each instance C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano.

[0675] In certain embodiments, the present invention relates to compounds of formula III or IV, wherein:

[0676] R 1 It is H;

[0677] R 2 is independently C1-C6 alkyl or halogen at each occurrence;

[0678] m is 0; and

[0679] n is 2.

[0680] In certain embodiments, the present invention relates to compounds of formula IV, wherein Z 1a is halogen, and more particularly, halogen is Br or Cl.

[0681] In other embodiments, the present invention relates to compounds of formula IV, wherein Z 1a is optionally substituted phenyl, optionally substituted pyridine, optionally substituted thiophene, optionally substituted furan, optionally substituted pyrrole, optionally substituted cyclopropyl, or optionally substituted cyclobutyl. In certain embodiments, the optional substitution is C1-C6 alkyl, and more particularly, the C1-C6 alkyl is methyl or ethyl. In certain embodiments, the optional substitution is halogen, and more particularly, the halogen is F or Cl.

[0682] In certain embodiments, the present invention relates to compounds of formula III or IV, wherein:

[0683] E is phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine, furan, thiophene, pyrrole, pyrazole, imidazole or triazole;

[0684] F is pyrrolidine, piperidine, piperazine, tetrahydropyran, morpholine, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl or 2-oxaspiro[3.3]heptyl;

[0685] R X3 is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halo, amino, nitro or cyano; and

[0686] q is independently 0, 1 or 2 in each instance.

[0687] In certain embodiments, the present invention relates to compounds having the structure of Formula V:

[0688]

[0689] or a pharmaceutically acceptable salt thereof,

[0690] in:

[0691] a2 is C(Z 1 ) or N;

[0692] a4 is S, O or NH;

[0693] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0694] L 2is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(R X1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0695] E is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0696] F is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0697] G is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0698] Z 1 is independently H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0699] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0700] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0701] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0702] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0703] R W1is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0704] R W1a is H or C1-C6 alkyl;

[0705] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0706] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0707] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0708] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0709] R X3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0710] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0711] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0712] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0713] R X3c and R X3d Together with the N to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen; R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0714] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3Replace; or

[0715] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0716] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0717] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0718] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0719] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0720] m is 0, 1, 2, or 3;

[0721] n is 0, 1, 2, 3, or 4;

[0722] p is independently 0 or 1 in each instance;

[0723] q is independently at each occurrence 0, 1, 2, 3 or 4; and

[0724] r is 0, 1, 2, 3, or 4.

[0725] In certain embodiments, the present invention relates to compounds having the structure of Formula V, wherein:

[0726] R X3is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0727] R X3a R is independently in each instance C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano.

[0728] In certain embodiments, the present invention relates to compounds having the structure of Formula VI:

[0729]

[0730] or a pharmaceutically acceptable salt thereof,

[0731] in:

[0732] a2 is C(Z 1 ) or N;

[0733] a4 is S, O or NH;

[0734] L 1 is independently at each occurrence a bond, CH2, O, NH, S, SO or SO2;

[0735] E is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0736] F is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0737] G is aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0738] Z 1 is independently H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0739] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0740] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0741] R 2is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0742] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0743] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0744] R W1a is H or C1-C6 alkyl;

[0745] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0746] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0747] In R W2a isOC(O)N(R W2b )(R W2b ) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0748] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0749] R X3is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0750] R X3a is independently heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, -C(O)N(R X3c )(R X3d ), amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein heteroaryl, heterocyclic group, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 hydroxyalkyl are each optionally substituted with 1 or 2 R X3b replace;

[0751] R X3b is independently at each occurrence aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano, wherein aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano;

[0752] R X3c and R X3d Each is independently selected from H, C1-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl; or

[0753] R X3c and R X3d Together with the N to which they are attached, they form a 4-6 membered heterocyclic ring optionally substituted with 1 or 2 groups each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 acyl or halogen; R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0754] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0755] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0756] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0757] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0758] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0759] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0760] m is 0, 1, 2, or 3;

[0761] n is 0, 1, 2, 3, or 4;

[0762] q is independently at each occurrence 0, 1, 2, 3 or 4; and

[0763] r is 0, 1, 2, 3, or 4.

[0764] In certain embodiments, the present invention relates to compounds of formula VI, wherein

[0765] R X3 is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0766] R X3a R is independently in each instance C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano.

[0767] In certain embodiments, the present invention relates to compounds of formula III, IV, V or VI, wherein:

[0768] F is in Represents the attachment point;

[0769] R 3 is H or C1-C6 alkyl;

[0770] R 4 Yes-OP(O)(O - )(O - ), -OP(O)(O - )(OR 5 ), -OP(O)(OR 5 )(OR 5 ), -OS(O2)-O - ,-OS(O2)-OR 5 , Cy a ,-OC(O)-R 6 ,-OC(O)-OR 6 or-OC(O)-N(R 6 )(R 6 );

[0771] R5 is independently H, C1-C6 alkyl or aralkyl(C1-C6);

[0772] R 6 is independently H, C1-C6 alkyl or C1-C6 aminoalkyl at each occurrence; and

[0773] q in F with R X3 In the case of substitution, it is 0.

[0774] In certain embodiments, the present invention relates to compounds having the structure of Formula VII:

[0775]

[0776] or a pharmaceutically acceptable salt thereof,

[0777] in:

[0778] a2 is C(Z 1 ) or N;

[0779] a4 is S, O or NH;

[0780] L 1 is a bond, CH2, O, NH, S, SO or SO2;

[0781] L 2 is independently a bond, optionally substituted C1-C6 alkyl, -(C1-C6 alkyl) p -O-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -N(R X1 )-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S-(C1-C6 alkyl) p -, -(C1-C6 alkyl) p -S(O)-(C1-C6 alkyl) p -or-(C1-C6 alkyl) p -S(O)2-(C1-C6 alkyl) p -;

[0782] E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

[0783] Y a is C1-C6 hydroxyalkyl, C1-C6 alkoxy, N(R X1 )(R X2 ) or hydroxyl;

[0784] Z 1is independently H, halogen, -L 2 -Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0785] Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted with 1, 2, 3 or 4 R Cy1 replace;

[0786] R 1 is H, hydroxy, C1-C3 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl or C1-C2 alkoxy;

[0787] R 2 is independently cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, nitro or N(R 2a )(R 2b );

[0788] R 2a and R 2b Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl;

[0789] R W1 is H, C1-C6 alkyl, CH(R W1a )(R W2a ), heterocyclic, aryl, heteroaryl or in represents a point of attachment, wherein the heterocyclyl, aryl and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0790] R W1a is H or C1-C6 alkyl;

[0791] R W2a It is OC(O)OR W2b , OC(O)N(R W2b )(R W2b ) or OP(O)(OR W2b )2;

[0792] R W2b is independently H, C1-C6 alkyl, cycloalkyl or C1-C6 alkoxy at each occurrence; or

[0793] In R W2a isOC(O)N(R W2b )(R W2b) In the case of two R W2b Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R W3a replace;

[0794] R W3a is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0795] R X3 is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl and heterocyclyl are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0796] R X3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0797] R Z1 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0798] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0799] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0800] RZ3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0801] R Z4 is independently in each instance C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0802] R Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxyl, N(R Cy2 )(R Cy2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano;

[0803] R Cy2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl at each occurrence;

[0804] m is 0, 1, 2, or 3;

[0805] n is 0, 1, 2, 3, or 4;

[0806] p is independently 0 or 1 at each occurrence; and

[0807] q is independently 0, 1, 2, 3 or 4 at each occurrence, provided that in the absence of E in -(R X3 ) q Here q is 0.

[0808] In certain embodiments, the present invention relates to compounds of formula VII, wherein:

[0809] E is phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine, furan, thiophene, pyrrole, pyrazole, imidazole or triazole;

[0810] Y a It is N(R X1 )(R X2 );and

[0811] q is independently 0, 1 or 2 in each instance.

[0812] In certain embodiments, the present invention relates to any of the compounds described herein, wherein the C1-C6 haloalkyl is trifluoromethane or trifluoroethane.

[0813] In other embodiments, the present invention relates to compounds of formula I, II, III, IV, V, VI or VII, wherein R W1 yes

[0814] In certain embodiments, the present invention relates to compounds having the structure of Formula VIII:

[0815]

[0816] or a pharmaceutically acceptable salt thereof,

[0817] in:

[0818] E is heteroaryl;

[0819] L 3 is -CH2- or -CH2CH2-;

[0820] Y b is H, heterocyclyl, -N(CH3)2, -N(CH2CH3)2, -CH2N(CH3)2 or -CH2N(CH2CH3)2; or

[0821] L 3 is not present and Y b It is H;

[0822] Z 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z1 replace;

[0823] R X3 is independently aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, heterocyclyl and C1-C6 alkoxy are each optionally substituted with 1, 2, 3 or 4 R X3a replace;

[0824] R X3a is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

[0825] R Z1is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, oxo, halogen, hydroxy, N(R Z2 )(R Z2 ), C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro or cyano, wherein the aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted with one or more R Z3 replace;

[0826] R Z2 is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 hydroxyalkyl, wherein said aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or more R Z3 Replace; or

[0827] Two R's Z2 Together with the N to which they are attached, they form a heterocyclic or heteroaryl group, wherein the heterocyclic and heteroaryl groups are each optionally substituted with 1, 2, 3 or 4 R Z3 replace;

[0828] R Z3 is independently aryl, heteroaryl, cycloalkyl, heterocyclyl, C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted with one or more R Z4 replace;

[0829] R Z4 is independently at each occurrence C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylamino, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano; and

[0830] q is 0, 1, 2, 3, or 4.

[0831] In certain embodiments, the present invention relates to compounds of formula VIII, wherein:

[0832] E is pyrimidinyl or pyrazolyl;

[0833] L 3 It is -CH2CH2-;

[0834] Yb is a heterocyclic group;

[0835] Z 1 is a cycloalkyl group; and

[0836] q is 0, 1, or 2.

[0837] In other embodiments, the compound of Formula VIII has an MCL1 IC of about 100 nM or less. 50 .

[0838] In other embodiments, the compound of Formula VIII has an average IC of 1 μM or less against drug-sensitive cell lines in Table 3. 50 .

[0839] In other embodiments, the average IC values ​​of the compound of formula VIII against the drug-sensitive cell lines in Table 3 are 50 Comparison Table 3 Average IC of drug-resistant cell lines 50 At least about 10 times more effective.

[0840] In certain embodiments, the present invention relates to compounds having the structure of Formula IX:

[0841]

[0842] or a pharmaceutically acceptable salt thereof,

[0843] in:

[0844] E is pyrimidinyl, pyrazolyl, pyridyl or imidazolyl;

[0845] L 3 is -CH2- or -CH2CH2-;

[0846] Y b Morpholinyl, piperazinyl, piperidinyl, N(CH2CH3)2 or N(CH3)2;

[0847] Z 1 is cyclobutyl, benzyl, pyridyl, pyrazolyl or imidazolyl;

[0848] R X3 benzyl, pyridyl, C1-C3 alkoxy or C1-C4 alkyl;

[0849] R X3a-1 and R X3a-2 are each independently H, C1-C3 alkyl, C1-C2 haloalkyl, amino, cyano or halogen; and

[0850] R Z1 is C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or halogen.

[0851] In certain embodiments, the present invention relates to compounds having the structure of Formula X:

[0852]

[0853] or a pharmaceutically acceptable salt thereof, wherein R X3-2 yes

[0854] in Represents the attachment point.

[0855] In a specific embodiment, R X3-2 yes

[0856] In a preferred embodiment, R X3-2 yes

[0857] In other embodiments, the compound of formula VIII is selected from:

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866] or a pharmaceutically acceptable salt thereof.

[0867] In certain aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874] or a pharmaceutically acceptable salt thereof.

[0875] In certain aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891] or a pharmaceutically acceptable salt thereof.

[0892] In certain aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912] or a pharmaceutically acceptable salt thereof.

[0913] In certain aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0914]

[0915]

[0916]

[0917] or a pharmaceutically acceptable salt thereof.

[0918] In certain aspects, the present invention relates to a compound of formula III having a structure selected from the group consisting of:

[0919] or a pharmaceutically acceptable salt thereof.

[0920] In certain aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928] or a pharmaceutically acceptable salt thereof.

[0929] In certain aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946] or a pharmaceutically acceptable salt thereof.

[0947] In certain aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967] or a pharmaceutically acceptable salt thereof.

[0968] In certain aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0969]

[0970]

[0971]

[0972]

[0973] or a pharmaceutically acceptable salt thereof.

[0974] In certain aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0975]

[0976]

[0977]

[0978] or a pharmaceutically acceptable salt thereof.

[0979] In other aspects, the present invention relates to a compound of formula II having a structure selected from the group consisting of:

[0980]

[0981]

[0982]

[0983] or a pharmaceutically acceptable salt thereof.

[0984] In certain aspects, the present invention relates to a compound of formula III having a structure selected from the group consisting of:

[0985]

[0986] or a pharmaceutically acceptable salt thereof.

[0987] In certain aspects, the compound is selected from: or a pharmaceutically acceptable salt thereof.

[0988] In certain embodiments, the present invention is directed to a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable diluent or excipient.

[0989] Specific embodiments of the present invention include those compounds listed in Table 1. Disclosed in Table 1 are each compound's identification number ("Cmpd"), chemical structure ("Structure"), and example method ("Method") used to synthesize the compound.

[0990] Particular embodiments of the present invention include compounds of formula IX, wherein E, R X3 , R X3a-1 , R X3a-2 , L 3 , Y b , Z 1 and R Z1 In this order as defined in the rows of Table 4.

[0991] Table 1.

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031] Example Methods of Treatment / Use

[1032] The compounds described herein are MCL1 inhibitors and therefore can be used to treat diseases in which the underlying pathology is mediated (at least in part) by deregulation of MCL1 or its normal activity. Such diseases include cancer and other diseases in which there is a disorder of cell proliferation, apoptosis or differentiation.

[1033] In certain embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject an effective amount of any compound described herein or a pharmaceutically acceptable salt thereof. For example, the cancer can be selected from cancer (e.g., endometrial cancer, bladder cancer, breast cancer, or colon cancer (e.g., colorectal cancer such as colon adenocarcinoma and colon adenoma)), sarcoma (e.g., sarcoma such as Kaposi's sarcoma, osteosarcoma, mesenchymal tumors such as fibrosarcoma or rhabdomyosarcoma), renal cancer, epidermal cancer, liver cancer, lung cancer (e.g., adenocarcinoma, small cell lung cancer, and non-small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, and skin cancer (e.g., squamous cell carcinoma), human breast cancer (e.g., primary breast tumor, lymph node-negative breast cancer, invasive ductal adenocarcinoma of the breast, non-endometrioid breast cancer), familial melanoma, and melanoma. Other examples of cancers that can be treated with the compounds of the invention include hematopoietic tumors of the lymphoid lineage (e.g., leukemias, acute lymphocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, B-cell lymphomas (such as diffuse large B-cell lymphoma), T-cell lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkett lymphoma), and hematopoietic tumors of the myeloid lineage, such as acute and chronic myeloid leukemias, myelodysplastic syndromes, and promyelocytic leukemias. Other cancers include tumors of the central or peripheral nervous system, such as astrocytomas, neuroblastomas, gliomas, or schwannomas; seminoma; teratocarcinoma; xeroderma pigmentosum; retinoblastoma; keratoacanthoma; and follicular thyroid carcinoma.

[1034] In particular embodiments, the cancer is selected from the group consisting of head and neck cancer, sarcoma, melanoma, myeloma, lymphoma, lung cancer (including non-small cell lung cancer and small cell lung cancer), breast cancer, pancreatic cancer, thyroid cancer, colorectal cancer, ovarian cancer, and acute myeloid leukemia.

[1035] In certain aspects, the subject is a mammal, such as a human.

[1036] Also disclosed herein are methods for inhibiting MCL1 in a cell, comprising contacting the cell with any compound described herein or a pharmaceutically acceptable salt thereof, thereby inhibiting the function of MCL1 in the cell. For example, the cell is a cancer cell. In preferred embodiments, cell proliferation is inhibited or cell death is induced.

[1037] Also disclosed herein are methods for treating a disease treatable by inhibiting MCL1 in a subject, comprising administering to a subject deemed in need of such treatment an effective amount of any compound described herein and / or a pharmaceutically acceptable salt thereof. Diseases treatable by inhibiting MCL1 include, for example, diseases characterized by dysregulation of apoptosis, including hyperproliferative diseases such as cancer. Further exemplary diseases include head and neck cancer, sarcoma, melanoma, myeloma, lymphoma, lung cancer (including non-small cell lung cancer and small cell lung cancer), breast cancer, pancreatic cancer, thyroid cancer, colorectal cancer, ovarian cancer, and acute myeloid leukemia.

[1038] The treatment method comprises administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable salt thereof. Separate embodiments include methods of treating any of the aforementioned disorders or diseases by administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[1039] Certain embodiments include methods for modulating MCL1 activity in a subject, comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof. Additional embodiments provide methods for treating a disorder or disease mediated by MCL1 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof. Other embodiments of the present invention provide methods for treating a disorder or disease mediated by MCL1 in a subject in need thereof, comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, wherein the disorder or disease is selected from a cancer having a genetic aberration that activates MCL1 activity. These include, but are not limited to, cancer.

[1040] Figure 1 Results from a xenograft study of the AMO-1 myeloma cell line using the compound of Formula X and an MCL1 inhibitor tested in humans and available as catalog number HY-112218 (MedChemExpress LLC, New Jersey, USA) on October 2, 2020, were presented. Eight mice were used per group, and mice were administered various concentrations of the compound of Formula X or HY-112218 daily (QD) via intravenous (IV) injection for the first five days of the study. A 10 mg / kg dose of HY-112218 and a 60 mg / kg dose of the compound of Formula X are approximately the maximum tolerated dose in mice and represent theoretical efficacious doses in humans. These results demonstrate unexpectedly prolonged tumor growth inhibition with the compound of Formula X, with tumors treated with HY-112218 resuming growth on or around study day 21. Figure 2 Results from a study of AMO-1 myeloma cell line xenografts show changes in tumor volume over time. Figure 3Figure 2 is a table of daily percent body weight changes in mice from an AMO-1 myeloma cell line xenograft study.

[1041] The present method also provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for treating a disorder or disease mediated by MCL1.

[1042] In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat a disorder or disease mediated by MCL1.

[1043] Other embodiments of the present method provide a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[1044] Other embodiments of the present methods encompass the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disorder or disease mediated by MCL1.

[1045] Equivalent method

[1046] While specific embodiments of the present invention have been discussed, the foregoing description is illustrative and not restrictive. Numerous variations of the present invention will become apparent to those skilled in the art upon reference to this specification and the claims that follow. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification with such variations. Example

[1047] Synthesis scheme

[1048] The compounds disclosed herein can be synthesized via a number of specific methods. The examples below outlining specific synthetic routes and general schemes are intended to provide guidance to the synthetic chemist of ordinary skill, who will readily appreciate that solvents, concentrations, reagents, protecting groups, sequence of synthetic steps, times, temperatures, etc. can all be modified as desired and are well within the skill and judgment of the skilled artisan.

[1049] Example A: Synthesis of Compounds A2 to A9

[1050] Synthesis of compound A2

[1051]

[1052] To a mixture of compound A1 (140 g, 592.1 mmol, 1.00 equiv) in MeOH (554.3 g, 17.3 mol, 700 mL, 29.2 equiv) was added H2SO4 (116.1 g, 1.18 mol, 63.1 mL, 2.00 equiv) at 0°C. The mixture was stirred at 85°C for 12 hours. LCMS (product Rt = 0.867 min, m / z = 252.4 (M+1) + ) showed that compound A1 was consumed and a major peak with the desired MS was formed. The mixture was concentrated under reduced pressure to provide a residue, which was adjusted to pH 8 with aqueous NaHCO 3 . The mixture was extracted with ethyl acetate (1.00 L, 2 times). The combined organic phases were washed with brine (500 mL, 2 times), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to produce compound A2 (106.0 g, 415.15 mmol, 70.1% yield, 98.1% purity), which was a yellow oil and was analyzed by LCMS (compound A2 Rt=0.866 min, m / z=252.4 (M+1)). + The yellow oily compound A2 was used directly in the subsequent step.

[1053] 1 H NMR (400 MHz, CDCl3):

[1054] δ8.60 (s, 1H), 7.65 (s, 1H), 3.95 (s, 3H) ppm.

[1055] Synthesis of compound A3

[1056]

[1057] To a mixture of compound A2 (106.0 g, 423.2 mmol, 1.00 equiv), Pd2(dba)3 (19.38 g, 21.16 mmol, 0.05 equiv), K2CO3 (58.5 g, 423.2 mmol, 1.00 equiv), and Xantphos (24.5 g, 42.3 mmol, 0.10 equiv) in THF / H2O (530 mL / 130 mL) was added dropwise a solution of BnSH (52.6 g, 423.5 mmol, 49.6 mL, 1.00 equiv) in THF (130 mL) at 60° C. under a nitrogen atmosphere, and the mixture was stirred at 60° C. for 1 hour. LCMS (product Rt=1.006 min, m / z=294.5 (M+1) +) showed that compound A2 was consumed and a major peak with the desired MS was formed. The mixture was diluted with brine (300 mL), extracted with ethyl acetate (300 mL, 2 times), and the organic phase was washed with brine (300 mL, 2 times), dried over sodium sulfate and concentrated under reduced pressure to provide a crude product, which was triturated in ethyl acetate / petroleum ether solution (1 / 2, 350 mL) to provide impure compound A3 (85.0 g, crude) as a green solid, which was identified by LC / MS (compound A3 Rt=1.038 minutes, m / z=294.1 (M+1)). + Compound A3 was used without further purification.

[1058] 1 H NMR (400 MHz, CDCl3):

[1059] δ8.29 (s, 1H), 7.68 (s, 1H), 7.34-7.21 (m, 5H), 4.17 (s, 2H), 3.40 (s, 3H) ppm.

[1060] Synthesis of compound A4

[1061]

[1062] To a mixture of compound A3 (85.0 g, 289.3 mmol, 1.00 equiv) in THF (160 mL) and H2O (160 mL) was added NaOH (4 M, 144.67 mL, 2.00 equiv) at 15-20°C, and the mixture was stirred at 15-20°C for 2 hours. LCMS (Compound A4 Rt = 0.898 min, m / z = 280.5 (M+1) + ) showed that compound A3 was consumed and the desired MS was found. The mixture was diluted with ethyl acetate (300.0 mL) and adjusted to pH ~ 5 with 6M HCl aqueous solution. The solid formed was filtered and washed with water (20.0 mL) and dried under reduced pressure to provide a crude product, which was triturated in acetonitrile (250.0 mL) and filtered to provide compound A4 (71.0 g, 252.3 mmol, 87.2% yield, 99.4% purity) as a green solid and was analyzed by LCMS (Compound A4 Rt = 0.898 min, m / z = 280.0 (M + 1) + Compound A4 was used without further purification.

[1063] 1 H NMR (400 MHz, DMSO-d6):

[1064] δ8.51 (s, 1H), 7.74 (s, 1H), 7.28-7.43 (m, 5H), 4.38 (s, 2H) ppm.

[1065] Synthesis of compound A5

[1066]

[1067] To a mixture of Compound A4 (32.0 g, 114.4 mmol, 1.00 equiv) and DMF (418.04 mg, 5.72 mmol, 440.0 μL, 0.05 equiv) in DCM (350 mL) was added (COCl) (29.0 g, 228.8 mmol, 20.0 mL, 2.00 equiv) at 0° C., and the mixture was stirred at 20° C. for 3 hours. A sample was taken and quenched with one drop of lithium (tert-butoxycarbonyl)amide (prepared in THF with n-BuLi at −78° C.), LCMS (Compound A5 Rt=0.996, Compound A5 MS=379.1 (M+1) + ) showed that most of compound A4 was consumed and a major peak with the desired MS was formed. The mixture was concentrated and co-evaporated with DCM (100 mL, 3 times) to provide crude compound A5 (68.2 g, crude) as a green gum. Compound A5 was used directly without further purification.

[1068] Synthesis of compound A6

[1069]

[1070] To a mixture of tert-butyl carbamate (20.0 g, 171.0 mmol, 1.50 equivalents) and TMEDA (19.9 g, 171.0 mmol, 25.8 mL, 1.50 equivalents) in THF (100.0 mL) was added dropwise n-BuLi (2.5 M, 68.4 mL, 1.50 equivalents) at -70 ° C. The resulting mixture was stirred for 1 hour at -70 ° C. Compound A5 (34.0 g, 114.02 mmol, 1.00 equivalents) was dissolved in THF (100.0 mL) at -70 ° C. and added to the previous THF solution. The mixture was stirred for 2 hours at -70 ° C. TLC (petroleum ether / ethyl acetate=5 / 1, reactant 1 Rf=0.1, product Rf=0.3) showed that most of Compound A5 was consumed and formed a major spot. The mixture is stirred at -70 ° C with aqueous NH4Cl (500.0mL) and quenched, extracted with ethyl acetate (500.0mL, 3 times), and the organic phase is then washed with brine (600mL, 2 times), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a crude product. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1~3 / 1) to provide impure product (35.0g), which is a yellow solid, as determined by LCMS (product Rt=0.994 minute, m / z=379.0 (M+1)). + ) was confirmed and purified by reverse phase C18 column chromatography (10% to 75% acetonitrile / water + 0.1% FA). The eluate was concentrated under reduced pressure to remove acetonitrile and filtered, and the solid was dried under reduced pressure to provide compound A6 (11.5 g, 30.4 mmol, 13.3% yield, 100% purity) as a white solid, which was identified by LCMS (product Rt = 0.981 min, m / z = 378.9 (M+1) + ) and HNMR confirmed.

[1071] Compound A6 (8.00 g, 21.12 mmol, 1.00 equiv) was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to provide a purer form (7.50 g, 19.80 mmol, 93.75% yield) as a white solid, which was confirmed by HNMR and TLC (petroleum ether / ethyl acetate = 5 / 1, compound A6 Rf = 0.2).

[1072] 1 H NMR (400 MHz, CDCl3):

[1073] δ8.12 (s, 1H), 8.01 (s, 1H), 7.30 (s, 1H), 7.17-7.20 (m, 3H), 7.08-7.10 (m, 2H), 3.96 (s, 2H), 1.37 (s, 9H) ppm.

[1074] Synthesis of Compound A7

[1075]

[1076] To a mixture of compound A6 (5.00 g, 13.2 mmol, 1.00 equivalent) in THF (130.0 mL) was added dropwise LDA (2 M, 14.5 mL, 2.20 equivalents) at -70 ° C., and the mixture was stirred at -70 ° C. for 1 hour. A solution of I2 (7.37 g, 29.0 mmol, 5.85 mL, 2.20 equivalents) in THF (20.0 mL) was added dropwise, and the mixture was stirred at -70 ° C. for 30 minutes. TLC (petroleum ether: ethyl acetate = 5 / 1, compound A6 Rf = 0.2, compound A7 Rf = 0.25) and LCMS (product Rt = 1.036 minutes, m / z = 505.0 (M + 1) + ) shows that most of compound A6 is consumed and the desired MS is found. The mixture is quenched by aqueous NH4Cl (100.0mL), extracted with ethyl acetate (150.0mL, 2 times), and the organic phase is concentrated under reduced pressure to provide a crude product. The crude product is ground in acetonitrile (35.0mL) to provide a yellow solid confirmed by HPLC (77.1% purity), followed by ethyl acetate / petroleum ether (2 / 1, 26.0mL), then filtered and collected solids to provide the first batch of products. The filtrate is concentrated under reduced pressure to provide a residue, which is ground in ethyl acetate / petroleum ether (2 / 1, 8.00mL) to provide a second batch of products. The two batches are combined and dried under reduced pressure to provide compound A7 (3.50g, 6.64mmol, 50.3% yield, 95.8% purity), which is determined by LCMS (compound A7Rt = 1.031 minutes, m / z = 504.8 (M + 1) + In the pilot reaction, compound A7 was also confirmed by 2D-NMR.

[1077] 1 H NMR (400 MHz, CDCl3):

[1078] δ7.80 (s, 1H), 7.50 (s, 1H), 7.10-6.80 (m, 5H), 3.90 (s, 2H), 1.30 (s, 9H) ppm.

[1079] Synthesis of compound A8

[1080]

[1081] To a mixture of compound A7 (3.50 g, 6.93 mmol, 1.00 equivalent) in DCM (20.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.00 mL, 7.79 equivalents) at 20 ° C, and the mixture was stirred at 20 ° C for 1 hour. TLC (petroleum ether: ethyl acetate=3 / 1, product Rf=0.2) showed that compound A7 was consumed and formed a major spot. The mixture was concentrated under reduced pressure to provide a crude product. Ethyl acetate (100.0 mL) was added to the crude product, NaHCO was used The mixture was adjusted to pH~7, extracted with ethyl acetate (100 mL, 2 times) and concentrated under reduced pressure to provide a yellow solid. The solid was triturated with petroleum ether / ethyl acetate (v / v=1 / 1, 12.0 mL) to provide compound A8 (2.40 g, 5.29 mmol, 76.3% yield, 89.2% purity), which was determined by LCMS (product Rt=0.866 min, m / z=404.7 (M+1) + ) and yellow solid confirmed by HNMR.

[1082] 1 H NMR (400 MHz, DMSO-d6):

[1083] δ8.19 (s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.25-7.33 (m, 5H), 4.28 (s, 2H) ppm.

[1084] Synthesis of compound A9

[1085]

[1086] To a mixture of compound A8 (2.40 g, 5.93 mmol, 1.00 equiv) in DCM (10.0 mL) was added sulfonyl chloride (880.6 mg, 6.52 mmol, 652.3 μL, 1.10 equiv) at 20° C., and the mixture was stirred at 20° C. for 1 hour. LCMS (product Rt=0.777 min, m / z=313.3 (M+1) + ) showed that compound A8 was consumed and a major peak with the desired MS was formed. The mixture was concentrated under reduced pressure to provide a crude product, which was triturated in ethyl acetate (20.0 mL) and dried under reduced pressure to provide compound A9 (1.64 g, 4.75 mmol, 80.0% yield, 90.5% purity), which was determined by LCMS (product Rt = 0.682 min, m / z = 312.9 (M+1) + ), a light yellow solid confirmed by HPLC (94.3% purity) and HNMR.

[1087] 1 H NMR (400 MHz, DMSO-d6):

[1088] δ 9.10 (s, 1H) ppm.

[1089] Example B: Synthesis of Compounds B2 to B6

[1090] Synthesis of compound B2

[1091]

[1092] To a mixture of compound B1 (90.0 g, 433.8 mmol, 1.00 equiv) in DCM (900.0 mL) were added TIPSCl (100.4 g, 520.6 mmol, 111.4 mL, 1.20 equiv) and imidazole (73.8 g, 1.08 mol, 2.50 equiv). The mixture was stirred at 25° C. for 16 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, compound B1 R f =0.9, compound B2 R f =0.9) showed that compound B1 was completely consumed and a new spot was observed. The mixture was washed with brine (50.0 mL, 4 times), the combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to provide crude compound B2 (140.3 g) as a colorless oil, which was confirmed by HNMR. Compound B2 was used in subsequent reactions without further purification.

[1093] 1 H NMR (400 MHz, CDCl3):

[1094] δ1.06 (s, 2H) 7.48 (d, J = 2.4Hz, 1H), 7.21 (dd, J = 8.8, 2.4Hz, 1H), 1.27-1.33 (m, 3H), 6.78 (d, J = 8.8Hz, 1H), 1.12 (d, J = 7.2Hz, 18H) ppm.

[1095] Synthesis of compound B3

[1096]

[1097] To a solution of DIPA (42.0 g, 415.6 mmol, 58.7 mL, 1.20 equiv) in THF (0.5 L) was added n-BuLi (2.50 M, 152.3 mL, 1.10 equiv) at -70 ° C, and the mixture was stirred at -70 ° C for 30 minutes. A solution of compound B2 (126.0 g, 346.3 mmol, 1.00 equiv) in THF (1.50 L) was added dropwise to the mixture, and the mixture was stirred at -70 ° C under a nitrogen atmosphere for 4 hours. CH3I (122.9 g, 865.8 mmol, 53.9 mL, 2.50 equiv) was added dropwise at -70 ° C, and the mixture was slowly warmed to 25 ° C for 12 hours. HPLC (Compound B2 Rt = 2.620 minutes) showed an Rt of the starting material. HPLC (Compound B3 Rt=2.776 minutes, Compound B2 Rt=2.621 minutes) shows the generation of a new peak. The reaction mixture is quenched by adding NH4Cl (1M, 1000.0mL), then extracted with EtOAc (1000.0mL, 2 times). The combined organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue is purified by column chromatography (SiO2, n-hexane, petroleum ether / ethyl acetate=100:1, Compound B3 R f =0.84) to provide compound B3 (121.8 g, 84.4% purity, 83.8% yield) as a colorless oil confirmed by HPLC and HNMR.

[1098] Synthesis of compound B4

[1099]

[1100] To a mixture of compound B3 (121.8 g, 270.8 mmol, 1.00 equiv) in THF (500.0 mL) was added TBAF (1.00 M, 284.3 mL, 1.05 equiv) at 20°C. The mixture was stirred at 20°C for 16 hours. TLC (petroleum ether / ethyl acetate = 3:1, compound B3 R f =0.99, Compound B4 R f =0.6) points out that compound B3 is completely consumed and forms main spot.Saturated brine (500.0mL) and ethyl acetate (500.0mL) are added to the mixture.Aqueous phase is extracted with ethyl acetate (500.0mL, 2 times).The organic layer through merging is at anhydrous Na2SO4 upper drying, filtering, and concentrating under reduced pressure, there is provided crude compound B4.Crude compound B4 is by silica gel chromatography (petroleum ether / ethyl acetate=10:1~4:1; TLC, petroleum ether / ethyl acetate=3:1, R f =0.6) to provide compound B4 (130.0 g, crude) as a yellow oil confirmed by HNMR.

[1101] 1 HNMR (400 MHz, CDCl3):

[1102] δ (d, J=8.8Hz, 1H), 6.80 (d, J=8.8Hz, 1H), 5.55 (br d, J=2.4Hz, 1H), 2.52 (s, 3H)ppm.

[1103] Synthesis of compound B5

[1104]

[1105] To a solution of compound B4 (45.0 g, 203.2 mmol, 1.00 equiv), 2-(4-methylpiperazin-1-yl)ethan-1-ol (44.0 g, 304.8 mmol, 1.50 equiv) and PPh3 (80.0 g, 304.8 mmol, 1.50 equiv) in toluene (550.0 mL) was added DEAD (70.8 g, 406.4 mmol, 73.9 mL, 2.00 equiv) at 20°C under a nitrogen atmosphere. The mixture was heated to 50°C and stirred for 2 hours, and then HCl / MeOH (4.00 M, 270.0 mL, 5.32 equiv) was added to the mixture and stirred at 20°C for 2 hours. LCMS (Compound B5 Rt = 0.772 min, m / z = 349.1 (M+1) + ) shows that compound B4 is completely consumed and the desired mass is detected. The reaction mixture is filtered to obtain a filter cake, which is dissolved with H2O / MeOH (v / v=1 / 1, 800.0mL) and the pH is adjusted to pH 10 with a saturated aqueous solution of Na2CO3. The mixture is concentrated under reduced pressure to remove MeOH, and the solution is extracted with EtOAc (500.0mL, 3 times). The combined organic phases are washed with brine (500.0mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide compound B5, which is a brown oily residue (43.1g, 107.9mmol, 53.1% yield, 87% purity) as determined by HNMR and LCMS (compound B5 Rt=0.761min, m / z=348.9 (M+1)). + Compound B5 was used in the subsequent step without further purification.

[1106] 1 HNMR (400 MHz, CDCl3):

[1107] δ7.34-7.41 (m, 1H), 6.67 (d, J=8.8Hz, 1H), 4.07-4.19 (m, 2H), 2.83-2.89 (m, 2H), 2.66 (br s, 4H), 2.41-2.54 (m, 7H), 2.24-2.31 (m, 3H)ppm.

[1108] Synthesis of compound B6

[1109]

[1110] To a mixture of compound B5 (5.00 g, 14.4 mmol, 1.00 equiv) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.35 g, 28.8 mmol, 5.87 mL, 2.00 equiv) in THF (25.0 mL) was added n-BuLi (2.50 M, 11.5 mL, 2.00 equiv) at -70°C. The mixture was stirred at -70°C for 1 hour. LCMS (Compound B6 Rt = 0.974 min, m / z = 395.5 (M+1) + ) showed that compound B5 was completely consumed and a major peak with the desired MS was detected. The mixture was quenched with aqueous NH4Cl (100.0 mL), extracted with ethyl acetate (150.0 mL, 2 times), and the organic phase was dried over sodium sulfite and concentrated under reduced pressure to provide crude compound B6. Crude compound B6 was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1 to EtOH: ethyl acetate = 1 / 6; TLC-EtOH: ethyl acetate = 1 / 3, compound B6 R f =0.1) to provide compound B6 (3.08 g, 6.87 mmol, 47.8% yield, 88.1% purity), which was determined by LCMS (compound B6 Rt = 0.896 min, m / z = 395.3 (M+1) + ), HPLC (Compound B6 Rt=2.044 min) and HNMR confirmed the yellow solid.

[1111] 1 HNMR (400 MHz, CDCl3):

[1112] δ7.64 (d, J=8.4Hz, 1H), 6.76 (d, J=8.4Hz, 1H), 4.18 (t, J=6.0Hz, 2H), 2.89 (t, J=6.0Hz, 2H), 2.68 (br s, 4H), 2.61 (s, 3H), 2.48 (br s, 4H), 2.30 (s, 3H), 1.34 (s, 12H) ppm.

[1113] Example C: Synthesis of Compounds C2, C3 & C4, & Isolation of C4-A & C4-B

[1114] Synthesis of compound C2

[1115]

[1116] To a mixture of compound C1 (200.0 g, 0.94 mol, 1.00 equiv) and ethyl chloroacetate (144.3 g, 1.18 mol, 125.5 mL, 1.25 equiv) in THF (1000 mL) was added dropwise NaHMDS (1 M, 1.18 L, 1.25 equiv) at -70°C under a nitrogen atmosphere. The reaction was stirred at -70°C for 1 hour and then at 25°C for 16 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R f =0.75) shows that the reaction is complete.Saturated NH is added to the reaction mixture Cl (2000mL) and then extracted with EtOAc (400mL, then 200mL) to obtain an organic phase.Organic phase salt water washing (200mL) and concentrating under reduced pressure.The crude product mixture passes through flash column chromatography (SiO , petroleum ether / ethyl acetate=5 / 1) purifying, there is provided compound C2 (395.0g, 1.32mol, 70.3% yield), it is a yellow oil.

[1117] 1 HNMR (400 MHz, CDCl3):

[1118] δ7.45-7.40 (m, 6H), 7.31 (d, J=4.0Hz, 1H), 7.23-7.22 (m, 2H), 5.17 (s, 2H), 4 .53(d, J=2.0Hz, 1H), 4.37-4.29(m, 2H), 3.49(s, 1H), 1.36-1.32(m, 3H)ppm.

[1119] Synthesis of compound C3

[1120]

[1121] Compound C2 (195.0 g, 654.0 mmol, 1.00 equiv) and then Pd(OH)2 / C (19.0 g, 10% purity, 1.00 equiv) were added to a solution of HOAc (65 mL) and EtOAc (1365 mL). The reaction was stirred at 25°C under 50 Psi of H2 for 3 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, R f=0.3) showed that the reaction was complete. The two reactions were filtered, combined and concentrated to obtain a crude product. The crude product mixture was purified by flash column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1 to 7 / 1) to provide crude compound C3 (207.0 g, 985.0 mmol, 75.3% yield) as a yellow oil.

[1122] Synthesis of compound C4

[1123]

[1124] To a solution of compound C3 (150.0 g, 713.5 mmol, 1.00 equiv) in DMF (1050 mL) were added K2CO3 (197.2 g, 1.43 mol, 2.00 equiv) and PMBCl (100.5 g, 642.0 mmol, 87.4 mL, 0.90 equiv) at 25°C. TLC (petroleum ether / ethyl acetate = 2 / 1, R f =0.4) showed that the reaction was complete. The reaction mixture was quenched in ice water (1000 mL) and extracted into ethyl acetate (1000 mL, then 750 mL). The combined ethyl acetate extracts were washed with brine (500 mL) solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (Phenomenex Synergi C18 100x21.2 mm x 4 μm; mobile phase: [water-ACN]; B%: 35%-57% 35 minutes; 57%-57%, 35 minutes) to provide compound C4 (119.0 g, 340.0 mmol, 47.6% yield, 94.4% purity) as a yellow oil.

[1125] Isolation of compounds C4-A and C4-B

[1126]

[1127] Compound C4 was separated by SFC (column: DAICEL CHIRALPAK AS (250 mm x 50 mm, 10 μm); mobile phase: [Neu-ETOH]; B%: 17%-17%, 4.5 minutes). Compound C4-A (27.5 g) and compound C4-B (26.4 g) both produced light yellow solids upon drying. The absolute configuration of the chiral centers of compounds C4-A and C4-B was assigned using vibrational circular dichroism spectroscopy as described in the Methods section below.

[1128] For compound C4-A:

[1129] 1 HNMR (400 MHz, DMSO-d6):

[1130] δ7.37 (d, J=4.0Hz, 2H), 7.17-7.09 (m, 2H), 7.00 (d, J=4.0Hz, 1H), 6.92 (d, J=4.0Hz, 2H), 6.82 (s, 1H), 5.43 (d, J=4.0Hz, 1H), 5.01 (s, 2H), 4.23 (d, J=4.0Hz, 1H), 3.96 (t, J=4.0Hz, 2H), 3.73 (s, 3H), 2.97 (m, 1H), 2.75 (d, J=4.0Hz, 1H), 1.03 (t, J=4.0Hz, 3H) ppm.

[1131] SFC: ee value is 97.1%

[1132] HPLC: Rt = 3.365 minutes, purity 100.0%

[1133] LCMS: Rt=2.602 min, m / z=348.2 (M+18) +

[1134] For compound C4-B:

[1135] 1 HNMR (400 MHz, DMSO-d6):

[1136] δ7.37 (d, J=4.0Hz, 2H), 7.15-7.10 (m, 2H), 7.00 (d, J=4.0Hz, 1H), 6.92 (d, J=4.0Hz, 2H), 6.82 (s, 1H), 5.43 (d, J=4.0Hz, 1H), 5. 01 (s, 2H), 4.23 (d, J=4.0Hz, 1H), 3.97 (t, J=4.0Hz, 2H), 3.73 (s, 3H), 2.97 (m, 1H), 2.71-2.76 (m, 1H), 1.03 (t, J=4.0Hz, 3H) ppm.

[1137] SFC: ee value is 98.5%

[1138] HPLC: product Rt = 3.352 minutes, purity 98.0%

[1139] LCMS: Product Rt = 2.590 min, m / z = 348.2 (M+18) +

[1140] Example D: Synthesis of Compounds D2, D3 & D5

[1141] Synthesis of compound D2

[1142]

[1143] To a mixture of compound D1 (100.0 g, 482.0 mmol, 1.00 equiv) and K2CO3 (79.9 g, 578.45 mmol, 1.20 equiv) in ACN (500 mL) was added SEMCl (141.3 g, 847.5 mmol, 150.0 mL, 1.76 equiv) at 0°C, and the mixture was stirred at 25°C for 14 hours. TLC (petroleum ether / ethyl acetate = 10 / 1, compound D1 R f =0.03, compound D2 R f =0.6) showed that most of compound D1 was consumed and formed a major spot. The mixture was filtered and washed with ACN (100.0 mL). The filtrate was concentrated under reduced pressure to provide a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1; TLC, petroleum ether / ethyl acetate = 10 / 1, compound D2 R f =0.6) to provide compound D2 (104.0 g, 307.9 mmol, 63.9% yield) as a light yellow oil.

[1144] 1 HNMR (400MHz, CDCl3): δ7.51 (d, J=2.4Hz, 1H), 7.31 (dd, J=2.4, 8.8Hz, 1H), 7.09 (d, J=8.8Hz, 1H), 5.2 9-5.26 (m, 1H), 5.28 (s, 1H), 3.85-3.75 (m, 1H), 3.95-3.70 (m, 1H), 1.07-0.84 (m, 2H), 0.01 (s, 9H)ppm.

[1145] Synthetic compound D3

[1146]

[1147] To a solution of DIPA (15.7 g, 155.7 mmol, 22.0 mL, 1.50 equiv) in THF (140.0 mL) was added n-BuLi (2.5 M, 45.6 mL, 1.10 equiv) at -70°C. The mixture was stirred at -70°C for 30 minutes. A solution of compound D2 (35.0 g, 103.6 mmol, 1.00 equiv) in THF (350.0 mL) was added to the mixture at -70°C. The mixture was stirred at -70°C for 4 hours. MeI (17.6 g, 124.3 mmol, 7.74 mL, 1.20 equiv) was added to the mixture at -70°C and stirred at 25°C for 12 hours. HPLC (compound D3, Rt = 2.985 minutes) showed that compound D2 was completely consumed and a major peak of a new compound was detected. HPLC showed a peak of substance. The reaction mixture was quenched by adding saturated NH4Cl (400.0 mL) at 0°C for 30 minutes and then extracted with EtOAc (400.0 mL, 2 times). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. Compound D3 (35.0 g, 92.6 mmol, 89.4% yield, 93.1% purity) was obtained as a yellow oil.

[1148] 1 HNMR (400MHz, CDCl3): δ7.39 (d, J=8.8Hz, 1H), 6.96 (d, J=8.8Hz, 1H), 5.31-5.25 ( m, 2H), 3.82-3.77 (m, 2H), 2.53 (s, 3H), 0.99-0.92 (m, 2H), 0.02-0.00 (m, 9H)ppm.

[1149] Synthesis of compound D5

[1150] Compound D4

[1151]

[1152] To a mixture of compound D3 (35.0 g, 92.6 mmol, 1.00 equiv) and compound D4 (35.00 g, 188.1 mmol, 38.4 mL, 2.03 equiv) in THF (175.0 mL) was added n-BuLi (2.5 M, 77.0 mL, 2.08 equiv) at -60 ° C. The mixture was stirred at -60 ° C for 1 hour. HPLC showed that compound D3 was completely consumed and a major peak of a new compound was detected. The reaction mixture was quenched by adding saturated NH4Cl solution (300.0 mL) at 0 ° C for 20 minutes, stirred at 20 ° C for 30 minutes, and extracted with ethyl acetate (200.0 mL, 2 times). The combined organic layers were washed with brine (300.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 500 / 1 to 50 / 1, petroleum ether / ethyl acetate = 50 / 1, R f =0.6), affording compound D5 (15.34 g, 37.0 mmol, 39.9% yield, 96.2% purity) as a yellow oil.

[1153] 1 HNMR (400MHz, CDCl3): δ7.64 (d, J=8.4Hz, 1H), 7.03 (d, J=8.4Hz, 1H), 5.32 (s, 2H), 3.86-3.74(m, 2H), 2.63(s, 3H), 1.35(s, 12H), 0.98-0.93(m, 2H), 0.01(s, 9H)ppm.

[1154] Example 1: Synthesis of Intermediates 1-1, 1-2, 1-3, 1-4, 1-5, Compounds 1-6, Compounds 1 to 30, and Compounds 52 and 91

[1155] Synthesis of compounds 1-6

[1156] Synthetic intermediate 1-1

[1157]

[1158] A solution of compound C4-A (2.0 g, 6.05 mmol) and imidazole (1.24 g, 18.2 mmol) in dichloromethane (20 mL) was cooled to 0° C. To this cooled solution was added tert-butyldimethylsilyl chloride (1.4 g, 9.08 mmol) in one portion. The reaction was removed from the cooling bath and stirred at ambient temperature for 12 hours, at which time TLC analysis showed complete conversion to the desired product.

[1159] The reaction was stopped and poured into a separatory funnel containing water (20 mL). The organic phase was separated and the aqueous phase was washed with dichloromethane (20 mL, 2 times). The combined organic extracts were concentrated onto silica gel. Silica gel chromatography (0-30% ethyl acetate / hexane) was performed. The product fractions were collected and concentrated to produce intermediate 1-1, which was a transparent oil (2.8 g, >99% yield).

[1160] 1 HNMR (500 MHz, CDCl3):

[1161] δ7.42-7.36 (m, 2H), 7.24-7.13 (m, 2H), 6.95-6.88 (m, 3H), 6.87 (td, J=7 .4, 1.1Hz, 1H), 5.03 (s, 2H), 4.49 (dd, J=9.0, 4.8Hz, 1H), 4.13 (q, J=7.2H z, 2H), 3.82 (s, 3H), 3.23 (dd, J=13.0, 4.7Hz, 1H), 2.85 (dd, J=13.0, 9.0Hz, 1H), 1.20 (t, J=7.1Hz, 3H), 0.75 (s, 9H), -0.17 (s, 3H), -0.28 (s, 3H).

[1162] Synthetic intermediate 1-2

[1163]

[1164] To a round-bottom flask was added intermediate 1-1 (1.0 g, 2.25 mmol), dichloromethane (200 mL) and deionized water (23 mL) to produce a clear solution. The reaction was stirred and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.0 g, 8.78 mmol) was added in one portion and allowed to stir under nitrogen at ambient temperature for 12 hours, at which time TLC analysis showed complete conversion to the desired product.

[1165] The reaction was stopped and poured into a separatory funnel containing saturated aqueous sodium bicarbonate solution (50 mL). The organic phase was separated and the aqueous phase was washed with ethyl acetate (50 mL, 2 times). The combined organic matter was concentrated onto silica gel. Silica gel chromatography (0-30% ethyl acetate / hexane) was performed. The product fractions were collected and concentrated to produce intermediate 1-2 as a white solid (0.569 g, 78% yield).

[1166] 1 H NMR (500 MHz, CDCl3):

[1167] δ7.59 (s, 1H), 7.14 (td, J=7.6, 1.7Hz, 1H), 7.02 (dd, J=7.5, 1.7Hz, 1H), 6.90 (dd, J=8.0, 1.2Hz, 1H), 6.81 (td, J=7.4, 1.2Hz, 1H), 4.52 (dd, J=6.7, 3.8Hz, 1H), 4.16-4.07 (m, 2H), 3.15-3.04 (m, 2H), 1.19 (t, J=7.2Hz, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.01 (s, 3H).

[1168] Synthetic intermediates 1-3

[1169]

[1170] To a cooled suspension of Intermediate 1-2 (2.0 g, 6.16 mmol), (1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methanol (2.0 g, 11.1 mmol) and triphenylphosphine (3.2 g, 12.32 mmol) in tetrahydrofuran (50 mL) was added di-tert-butyl azodicarboxylate (2.8 g, 12.32 mmol) in tetrahydrofuran (12 mL) dropwise via cannula. The reaction was removed from the cooling bath and stirred at ambient temperature for 12 hours, at which time LC / MS analysis indicated conversion to the desired product.

[1171] The reaction was concentrated onto silica gel. Silica gel chromatography (0-10% methanol / dichloromethane) was performed with refractive index detection. Product fractions were pooled and concentrated to yield Intermediate 1-3 as a clear oil (1.6 g, 56% yield).

[1172] 1 H NMR (300 MHz, CDCl3):

[1173] δ7.58 (d, J=1.8Hz, 1H), 7.29-7.15 (m, 2H), 7.00-6.89 (m, 2H), 6.42 (d, J=1 .8Hz, 1H), 5.14 (s, 2H), 4.90 (q, J=8.5Hz, 2H), 4.33 (dd, J=9.1, 4.5Hz, 1H) , 4.12 (q, J=7.1Hz, 2H), 3.13 (dd, J=13.2, 4.5Hz, 1H), 2.81 (dd, J=13.2, 9. 1Hz, 1H), 1.20 (t, J=7.1Hz, 3H), 0.74 (s, 9H), -0.18 (s, 3H), -0.29 (s, 3H).

[1174] Synthetic intermediates 1-4

[1175]

[1176] To a round-bottom flask was added intermediate 1-3 (1.69 g, 3.47 mmol) and dissolved in tetrahydrofuran (29 mL) to produce a clear solution. The reaction was stirred under nitrogen and tetra-n-butylammonium fluoride (4.2 mL, 1.0 M in tetrahydrofuran) was added dropwise to the stirred solution, which was allowed to stir at ambient temperature for 1 hour, at which time TLC analysis showed complete conversion to the desired product.

[1177] The reaction was stopped and poured into a separatory funnel containing saturated aqueous ammonium chloride solution (20 mL). The organic phase was separated and the aqueous phase was washed with ethyl acetate (50 mL, 2 times). The combined organic matter was concentrated onto silica gel. Silica gel chromatography (0-30% acetone / hexane) was performed. The product fractions were collected and concentrated to produce intermediate 1-4 as a white solid (0.929 g, 72% yield).

[1178] 1 H NMR (300 MHz, CDCl3):

[1179] δ7.58 (d, J=1.8Hz, 1H), 7.31-7.18 (m, 2H), 7.04-6.91 (m, 2H), 6.41 (d, J=1.8Hz, 1H), 5.13 (s, 2H), 4.90 (q, J=8.4Hz, 2H), 4.45-4.31 (m, 1H), 4.28-4.05 (m, 2H), 3.17 (dd, J=13.8, 4.5Hz, 1H), 2.89 (dd, J=13.8, 8.0Hz, 1H), 1.22 (t, J=7.1Hz, 3H).

[1180] Synthetic intermediates 1-5

[1181]

[1182] To a cooled suspension of compound A9 (700 mg, 2.24 mmol), intermediate 1-4 (876 mg, 2.4 mmol) and triphenylphosphine (881 mg, 3.36 mmol) in tetrahydrofuran (15 mL) was added di-tert-butyl azodicarboxylate (774 mg, 3.36 mmol) in tetrahydrofuran (7 mL) via cannula. The reaction was removed from the cooling bath and stirred at ambient temperature for 4 hours, at which time LC / MS analysis showed complete conversion to the desired product.

[1183] The reaction was concentrated onto silica gel. Silica gel chromatography (0-40% ethyl acetate / hexanes) was performed with refractive index detection. Product fractions were pooled and concentrated to yield Intermediate 1-5 as an off-white solid (650 mg, 44% yield).

[1184] 1 H NMR (500 MHz, CDCl3):

[1185] δ8.77 (s, 1H), 7.55 (d, J=1.9Hz, 1H), 7.39 (dd, J=7.7, 1.7Hz, 1H), 7.30-7. 25 (m, 1H), 7.00-6.93 (m, 2H), 6.40 (d, J = 1.8Hz, 1H), 5.69 (dd, J = 8.7, 4.8Hz , 1H), 5.18-5.07(m, 2H), 4.97-4.81(m, 2H), 4.14(q, J=7.1Hz, 2H), 3.46(d d, J=14.0, 4.8Hz, 1H), 3.32 (dd, J=14.0, 8.7Hz, 1H), 1.14 (t, J=7.1Hz, 3H).

[1186] Synthesis of compounds 1-6

[1187]

[1188] To a flask containing intermediate 1-5 (350 mg, 0.526 mmol) was added compound B6 (250 mg, 0.633 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (19 mg, 0.027 mmol) and tribasic potassium phosphate (335 mg, 1.58 mmol). The solid was dissolved in degassed 1,4-dioxane (1.75 mL) and deionized water (0.88 mL). The reaction was stirred at 60 ° C for 12 hours, allowed to cool and poured into a separatory funnel containing water (3 mL). The organic phase was separated and the aqueous phase was washed with dichloromethane (5 mL, 2 times). The combined organic extracts were concentrated onto silica gel. Silica gel chromatography (0-20% methanol / dichloromethane) was performed. The product fractions were pooled and concentrated to produce compound 1-6, which was a yellow solid and a mixture of diastereomers (274 mg, 65% yield).

[1189] 1 H NMR (500 MHz, methanol-d4):

[1190] δ9.06 (s, 0.2H), 9.05 (s, 0.8H), 7.58 (d, J=1.9Hz, 0.8H), 7.57 (d, J=1.9 Hz, 0.2H), 7.25-7.10 (m, 3H), 7.07-7.03 (m, 1H), 6.92-6.85 (m, 1H), 6.5 6 (d, J=1.9Hz, 1H), 6.45 (dd, J=7.4, 1.7, 1H), 5.35 (dd, J=9.7, 3.7Hz, 0.8H), 5.30 (dd, J=8.7, 5.1Hz, 0.2H), 5.24-5.17 (m, 2H), 5.03 (q, J=8.6, 2 H), 4.37-4.14 (m, 2H), 4.26 (td, J=5.6, 2.0Hz, 2H), 4.19-4.08 (m, 2H), 4 .11-4.02(m, 2H), 3.09(dd, J=13.8, 3.7, 1H), 2.96-2.87(m, 2H), 2.57(s , 0.5H), 2.29(s, 0.5H), 2.25(s, 3H), 2.18(s, 0.5H), 2.00(s, 3H), 1.90( s, 0.5H), 1.34 (s, 3H), 1.10 (t, J=7.1Hz, 2.4H), 1.04 (t, J=7.1Hz, 0.6H).

[1191] Synthesis of compounds 1 and 2

[1192]

[1193] Compound 1-6 (80.7 mg, 0.0999 mmol), substituted boronate (68 μL, 0.300 mmol), X-Phos-Pd-G3 (8.5 mg, 0.0099 mmol) and potassium phosphate (63.4 mg, 0.300 mmol) were added to a vial. Under an argon atmosphere, a solution of dioxane and water (2: 1; 0.4 M) was degassed with argon bubbling. The solvent was transferred to a reaction flask, which was sealed and heated to 111 ° C for a period of 15 hours. After cooling, the reaction was stirred with QuadraPure TU (Sigma-Aldrich, 200 mg) for 30 minutes. The reaction was diluted with dichloromethane / methanol and filtered through a Celite pad. Volatiles were removed under reduced pressure and the resulting solid was used directly in the saponification step.

[1194] The crude product obtained above was dissolved in a mixture of dioxane and water (2: 1, 2 mL). Lithium hydroxide aqueous solution (1 mL, 1 N) was injected under nitrogen and the reaction was stirred at ambient temperature for four hours. After neutralization with acetic acid, the mixture was filtered and purified by reverse phase HPLC (20 mm C18 column, 25 mL / min, 25-60% acetonitrile / water + 0.25% TFA in 20 minutes). Two fractions were collected, frozen and concentrated to dryness on a freeze dryer. The resulting oily solid was converted into its HCl salt via freeze-dried dilute hydrochloric acid aqueous solution. The corresponding atropisomer fractions 1 (compound 1, 4.01 mg) and 2 (compound 2, 7.38 mg) were analyzed by LC / MS and proton NMR, and the results were shown to be the expected products.

[1195] For compound 1:

[1196] 1 H NMR (400 MHz, DMSO-d6):

[1197] δ9.37 (s, 1H), 7.57 (d, J=1.8Hz, 1H), 7.22-7.16 (m, 2H), 7.10-7.02 (m, 2H) , 6.81 (t, J=7.4Hz, 1H), 6.54 (dd, J=7.2, 2.1Hz, 2H), 6.34 (d, J=7.4Hz, 1H), 5.99 (t, J=4.0Hz, 1H), 5.31-5.05 (m, 5H), 3.50-3.20 (width, m, 8H), 3.15-3.07 ( m, 1H), 2.75 (s, 3H), 2.29-2.21 (m, 1H), 2.16 (s, 3H), 1.93-1.88 (m, 1H)ppm.

[1198] LC / MS: m / z=845.3[M+H] + amu.

[1199] For compound 2:

[1200] 1 H NMR (400MHz, DMSO-d6): δ9.37 (s, 1H), 7.56 (d, J=1.8Hz, 1H), 7.36-7.05 (m, 3H), 6.88-6.78 (m, 1H), 6.60-6.38 (m, 3H), 5.97 (t, J=4.0 Hz, 1H), 5.32-5.01 (m, 5H), 3.50-3.25 (width, m, 8H), 3.06 (dd, J=13.9, 3.6Hz, 1H), 2.76 (s, 2H), 2.35-2.16 (m, 2H), 1.96-1.86 (m, 1H)ppm.

[1201] LC / MS: m / z=845.3[M+H] + amu.

[1202] Synthesis of compounds 3 and 4

[1203]

[1204] Two peaks of recovered compounds 1-6 saponified to the corresponding acids were also isolated during the synthesis of compounds 1 and 2 and analyzed and shown to be the expected products by LC / MS and proton NMR.

[1205] For compound 3:

[1206] 1 H NMR (400 MHz, DMSO-d6):

[1207] δ9.28 (s, 1H), 7.56 (d, J=1.8Hz, 1H), 7.28-7.13 (m, 2H), 7.08 (t, J=7.2Hz, 2H), 6.79 (t, J=7.4Hz, 1H), 6.52 (d, J=1.8Hz, 1H), 6.22 (d, J=7. 4Hz, 1H), 5.28-5.08 (m, 5H), 3.50-3.30 (width, m, 8H), 3.20-3.06 (m, 1H), 2.76 (s, 4H), 2.30-2.21 (m, 2H), 2.13 (s, 3H), 1.94-1.88 (m, 1H)ppm.

[1208] LC / MS: m / z=797.3[M+H] + amu.

[1209] For compound 4:

[1210] 1 H NMR (400 MHz, DMSO-d6):

[1211] δ9.28 (s, 1H), 7.57 (d, J=1.8Hz, 1H), 7.28-7.16 (m, 3H), 7.08 (d, J=8.3Hz, 1H), 6.88-6.73 (m, 1H), 6.53 (d, J=1.8Hz, 1H), 6.27 (dd, J=7 .5, 1.7Hz, 1H), 5.31-5.09 (m, 5H), 4.47 (s, 2H), 3.35-3.25 (width, m, 8H), 3.12 (dd, J=13.8, 3.1Hz, 1H), 2.79 (s, 3H), 2.36-2.20 (m, 2H)ppm.

[1212] LC / MS: m / z=797.3[M+H] + amu.

[1213] Synthesis of compounds 5 and 6

[1214]

[1215] Compound 1-6 (75.8 mg, 0.0938 mmol), substituted boronate (26.3 mg, 0.188 mmol), X-Phos-Pd-G3 (7.9 mg, 0.0094 mmol) and potassium phosphate (60.0 mg, 0.282 mmol) were added to a vial. Under an argon atmosphere, a solution of dioxane and water (2:1; 0.4 M) was degassed with argon bubbling. The solvent was transferred to a reaction flask, which was sealed and heated to 111 ° C for 15 hours. After cooling, the reaction was stirred with QuadraPure TU (Sigma-Aldrich, 200 mg) for 30 minutes. The reaction was diluted with dichloromethane / methanol and filtered through a Celite pad. Volatiles were removed under reduced pressure and the resulting solid was used directly in the saponification step.

[1216] The crude product obtained above was dissolved in a mixture of dioxane and water (2: 1, 4 mL). Under a nitrogen atmosphere, an aqueous lithium hydroxide solution (2 mL, 1 N) was injected and the reaction was stirred at ambient temperature for four hours. After neutralization with acetic acid, the mixture was filtered and purified by reverse phase HPLC (20 mm C18 column, 25 mL / min, 25-50% acetonitrile / water + 0.25% TFA in 20 minutes). Two fractions were collected, frozen and concentrated to dryness on a freeze dryer. The resulting oily solid was converted into its HCl salt via freeze-dried dilute hydrochloric acid aqueous solution. The corresponding atropisomer fractions 1 (compound 5, 2.1 mg) and 2 (compound 6, 11.1 mg) were analyzed by LC / MS and proton NMR and were shown to be the expected products.

[1217] Compound 5:

[1218] 1 H NMR (400 MHz, DMSO-d6):

[1219] 6 .65-6.53 (m, 1H), 6.35-6.30 (s, 1H), 5.38-5.30 (m, 1H), 5.10-4.90 (m, 4H), 4.20-4.00 (m, 2H), 3.70-3.40 (m, 10H), 3.27 (s, 3H)ppm.

[1220] LC / MS: m / z=839.2[M+H] + amu.

[1221] Compound 6:

[1222] 1 H NMR (400MHz, DMSO-d6): δ9.49 (s, 1H), 7.57 (d, J=1.8Hz, 1H), 7.40-7.23 (m, 3H), 7.22-7.13 (m, 2H), 7.11-7.05 (m, 3H), 6.79-6.65 (m, 1H), 6.53 (d, J=1.8Hz, 1H), 6.29-6.15 (m, 1H), 5.30-5.04 (m, 5H), 3.50-3.40 (width, m, 8H), 3.08 (dd, J=13.8, 3.5Hz, 1H), 2.75 (s, 2H)ppm.

[1223] LC / MS: m / z=839.2[M+H] + amu.

[1224] Synthesis of compound 7

[1225]

[1226] To a microwave vial containing compound 1-6 (20 mg, 0.025 mmol) was added X-Phos-Pd-G3 (4 mg, 0.005 mmol), 1-naphthyl substituted boronic acid (17 mg, 0.099 mmol) and tribasic potassium phosphate (18 mg, 0.085 mmol). The vial was capped and the solid was dissolved in degassed dioxane (0.333 mL, 0.08 M) and water (0.167 mL, 0.15 M) after 3 nitrogen / vacuum cycles. The reaction was stirred at 80 ° C for 12 hours and allowed to cool to room temperature. The reaction was quenched with water (1.0 mL) and transferred to a separatory funnel containing dichloromethane (2 mL). The aqueous layer was extracted with dichloromethane (2 mL, 3 times). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure.

[1227] Then dioxane (0.600mL, 0.04M) and lithium hydroxide aqueous solution (2M solution, 0.600mL) are added to the crude reaction mixture. Allow the reaction to stir at room temperature for 12 hours. The reaction is quenched with 2N hydrochloric acid (0.300mL), diluted with water, and transferred to a separatory funnel containing a chloroform / isopropanol (5: 1) mixture. The water layer is extracted (10mL, 3 times) with chloroform / isopropanol (5: 1). The combined organic matter is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude reaction is purified by reverse phase chromatography (0.25% TFA / water / 20-70% acetonitrile). Product fractions are collected and concentrated to produce compound 7, which is an off-white amorphous solid (6.7mg, 31% yield).

[1228] 1 H NMR (500 MHz, methanol-d4): δ 9.36 (s, 1H), 7.89-7.82 (m, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.50-7.38 (m, 2H), 7.38-7.12 (m, 2H), 7.12-7.00 (m, 1H), 6.99-6.70 (m, 1H), 6.56 (d, J = 2.5, 1 5.17 (m, 2H), 5.05 (qd, J = 8.6, 3.2 Hz, 2H), 3.27-2.90 (m, 4H), 2.8 (s, 3H), 2.56-2.21 (m, 1H), 2.19-1.84 (m, 1H), 1.82-1.48 (m, 1H), 1.29 (s, 1H) (27 of 42 protons observed) ppm. LC / MS: m / z = 871.3 [M+H] + amu.

[1229] Synthesis of compound 8

[1230] Compound 8 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic acid ester to obtain compound 8 as an off-white solid.

[1231] LCMS: m / z = 877.2 [M+H] + amu.

[1232] Synthesis of compound 9

[1233] Compound 9 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic acid ester to obtain compound 9 as an off-white solid.

[1234] 1H NMR (500MHz, methanol-d4): δ9.35 (d, J=11.9Hz, 1H), 8.25-8.18 (m, 1H), 8.16-8.11 (m, 1H), 8.08 (dt, J=7.8, 1.0Hz, 3H), 7.90-7 .87 (m, 1H), 7.57 (dd, J=13.2, 1.9Hz, 1H), 7.42-7.39 (m, 1H), 7.32-7.24 (m, 1H), 7.19 (ddd, J=8.0, 7.1, 1.1Hz, 2H), 7.14-7 .09 (m, 1H), 7.01-6.98 (m, 1H), 6.79-6.67 (m, 2H), 6.56 (dd, J=27.7, 2.0Hz, 1H), 6.49-6.41 (m, 2H), 5.42-5.31 (m, 1H), 5.3 0-5.22 (m, 2H), 5.17-5.05 (m, 2H), 3.80-3.73 (m, 1H), 3.07-2.74 (m, 8H), 2.63 (d, J = 2.4Hz, 3H), 2.24 (d, J = 5.4Hz, 3H) ppm.

[1235] LCMS: m / z = 927.2 [M+H] + amu.

[1236] Synthesis of compound 10

[1237] Compound 10 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic ester or acid to obtain compound 10 as an off-white solid.

[1238] LCMS: m / z = 874.3 [M+H] + amu.

[1239] Synthesis of compound 11

[1240] Compound 11 was synthesized by following the general procedure for compound 7 and using the corresponding aryl-substituted boronate or acid to obtain compound 11 as an off-white solid.

[1241] LCMS: m / z = 834.3 [M+H] + amu.

[1242] Synthesis of compound 12

[1243] Compound 12 was synthesized by following the general procedure for compound 7 and using the corresponding heterocyclic group to replace the boronic ester or acid. Compound 12 was obtained as an off-white solid.

[1244] 1H NMR (500MHz, methanol-d4): δ9.39 (s, 1H), 9.34 (s, 1H), 7.63 (s, 1H), 7.50 (m, 2H), 7.27 (d, J = 8.8Hz, 2H), 7.10 (m, 1H), 6.98 (s, 1H), 6.8 5 (s, 1H), 6.61 (s, 1H), 6.37 (m, 1H), 5.29 (s, 1H), 5.13 (m, 2H), 3.33-3.03 (m, 4H), 2.91-2.84 (m, 7H), 2.72 (s, 3H), 2.1 (s, 3H)ppm.

[1245] LCMS: m / z = 876.3 [M+H] + amu.

[1246] Synthesis of compound 13

[1247] Compound 13 was synthesized by following the general procedure for compound 7 and using the corresponding cycloalkyl-substituted boronate or acid to obtain compound 13 as an off-white solid.

[1248] 1 H NMR (500MHz, methanol-d4): δ9.34 (s, 1H), 7.63 (d, J=1.9Hz, 1H), 7.34 (d, J=8.5Hz, 1H), 7.27-7.16 (m, 2H), 7.08 (dd, J=18. 9, 8.4Hz, 2H), 6.97 (t, J = 7.5Hz, 1H), 6.87 (td, J = 7.4, 1.0Hz, 1H), 6.81 (d, J = 7.4Hz, 1H), 6.61 (d, J = 1.9Hz, 1H), 6.45 ( dd, J=7.5, 1.7Hz, 1H), 5.47 (dd, J=9.8, 3.6Hz, 1H), 5.29 (d, J=3.4Hz, 2H), 5.15-5.04 (m, 3H), 4.39-4.28 (m, 2H), 3.3 2-3.07 (m, 5H), 2.96 (t, J=7.1Hz, 3H), 2.88 (s, 3H), 2.45 (dd, J=13.9, 9.7Hz, 1H), 2.14-1.97 (m, 2H), 1.85 (s, 3H)ppm. LCMS: m / z=861.2[M+H] + amu.

[1249] Synthesis of compound 14

[1250] Compound 14 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic acid ester to obtain compound 14 as an off-white solid.

[1251] 1 H NMR (500MHz, methanol-d4): δ9.39 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 7.63 (d, J=1.9Hz, 1H), 7.35 (d, J=8.5Hz, 1H), 7. 28-7.07 (m, 2H), 6.99 (d, J=8.6Hz, 1H), 6.96-6.88 (m, 2H), 6.85 (td, J=7.5, 1.0Hz, 1H), 6.44 (dd, J=7.5, 1.7Hz, 1H), 5.48 (dd, J=9.6, 3.6Hz, 1H), 5.33-5.20 (m, 2H), 5.10 (qd, J=8.5, 2.4Hz, 2H), 4.32 (s, 2H), 3.72 (s, 3H), 3.3 7 (p, J=1.6Hz, 5H), 3.22 (t, J=3.9Hz, 1H), 2.90 (d, J=1.1Hz, 3H), 2.49 (dd, J=13.9, 9.6Hz, 1H), 1.82 (s, 3H)ppm.

[1252] LCMS: m / z = 879.3 [M+H] + amu.

[1253] Synthesis of compound 15

[1254] Compound 15 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic acid ester to obtain compound 15 as an off-white solid.

[1255] 1 H NMR (300MHz, methanol-d4): δ9.35 (s, 1H), 9.05 (s, 1H), 7.57 (t, J=2.0Hz, 2H), 7.32 (dd, J=8.4, 4. 8Hz, 2H), 7.25-7.12 (m, 2H), 7.01 (dd, J=22.6, 8.8Hz, 2H), 6.95-6.85 (m, 1H), 6.75 (dd, J=1 3.6, 7.4Hz, 1H), 6.54 (d, J=8.3Hz, 1H), 6.40 (d, J=7.5Hz, 1H), 5.43-5.31 (m, 1H), 5.22 (d, J =5.9Hz, 3H), 5.08-5.01 (m, 2H), 3.81 (d, J = 2.5Hz, 2H), 3.20-3.01 (m, 8H), 2.99 (s, 3H)ppm.

[1256] LCMS: m / z = 874.3 [M+H] + amu.

[1257] Synthesis of compound 16

[1258] Compound 16 was synthesized by following the general procedure for compound 7 and using the corresponding heterocyclic group to replace the boronic ester or acid. Compound 16 was obtained as an off-white solid.

[1259] 1 H NMR (300 MHz, methanol-d4) δ 9.35 (s, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 21.8, 8.4 Hz, 2H), 7.21-7.12 (m, 1H), 7.11-6.91 (m, 2H), 6.86-6.68 (m, 3H), 6.56 (d, J = 1.9 Hz , 1H), 6.37 (d, J=6.2Hz, 1H), 5.41 (dd, J=9.8, 3.7Hz, 2H), 5.23 (s, 2H), 5.11-5.0 0 (m, 2H), 4.24 (t, J=4.8Hz, 2H), 3.26-2.94 (m, 8H), 2.81 (s, 3H), 1.70 (s, 3H)ppm.

[1260] LCMS: m / z = 928.3 [M+H] + amu.

[1261] Synthesis of compound 17

[1262] Compound 17 was synthesized by following the general procedure for compound 7 and using the corresponding heterocyclic group to replace the boronic ester or acid. Compound 17 was obtained as an off-white solid.

[1263] 1H NMR (500MHz, methanol-d4): δ9.39 (s, 1H), 7.73 (d, J=2.3Hz, 1H), 7.63 (d, J=1.9Hz, 1H), 7.35 (d, J=8.5Hz, 1H), 7.23 (ddd, J=9 .2, 7.6, 1.8Hz, 1H), 7.16 (dd, J=8.3, 5.1Hz, 1H), 7.11-7.07 (m, 1H), 6.99 (d, J=8.6Hz, 1H), 6.95-6.89 (m, 1H), 6.85 (td , J=7.5, 1.0Hz, 1H), 6.61 (d, J=1.9Hz, 1H), 6.44 (dd, J=7.5, 1.7Hz, 1H), 5.48 (dd, J=9.6, 3.6Hz, 1H), 5.29 (d, J=4.0Hz, 2H), 5.10 (qd, J=8.5, 2.4Hz, 2H), 4.32 (s, 2H), 3.72 (s, 3H), 3.35-3.13 (m, 8H), 2.90 (d, J=1.1Hz, 3H), 1.82 (s, 3H)ppm.

[1264] LCMS: m / z = 874.3 [M+H] + amu.

[1265] Synthesis of compound 18

[1266] Compound 18 was synthesized by following the general procedure for compound 7 and using the corresponding heterocyclic group to replace the boronic ester or acid. Compound 18 was obtained as an off-white solid.

[1267] 1 H NMR (500MHz, methanol-d4): δ9.38 (s, 1H), 8.03 (s, 1H), 7.63 (d, J=1.9Hz, 1H), 7.53 (dd, J=7.8, 1.1Hz, 1H), 7.41 (d, J =8.5Hz, 1H), 7.28 (d, J = 3.2Hz, 1H), 7.21 (d, J = 8.6Hz, 1H), 7.06 (dd, J = 23.5, 8.4Hz, 1H), 6.88-6.79 (m, 1H), 6.7 7-6.69 (m, 1H), 6.62 (d, J = 1.9Hz, 1H), 6.52 (d, J = 3.2Hz, 1H), 6.41 (d, J = 6.8Hz, 1H), 5.46 (dd, J = 9.9, 3.4Hz, 1H) , 5.34-5.24 (m, 2H), 5.16-5.06 (m, 2H), 3.31-3.21 (m, 8H), 3.08 (s, 2H), 3.05 (d, J=0.5Hz, 3H), 1.72 (s, 3H)ppm.

[1268] LCMS: m / z = 860.3 [M+H] + amu.

[1269] Synthesis of compound 19

[1270] Compound 19 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic acid ester to obtain compound 19 as an off-white solid.

[1271] 1 H NMR (300MHz, methanol-d4): δ9.35 (s, 1H), 7.89-7.83 (m, 1H), 7.76 (dd, J=6.7, 2.5Hz, 1H), 7.57 (d, J=1 .9Hz, 1H), 7.38-7.31 (m, 3H), 7.20-7.12 (m, 1H), 7.10 (s, 1H), 7.03 (dd, J=8.4, 4.0Hz, 2H), 6.78 (t, J=7.5Hz, 1H), 6.56 (d, J=1.9Hz, 1H), 6.40-6.31 (m, 1H), 5.41 (dd, J=9.9, 3.3Hz, 1H), 5.23 (s , 2H), 5.11-5.01 (m, 2H), 4.28 (d, J=4.8Hz, 2H), 3.28-2.94 (m, 8H), 2.81 (s, 3H), 1.69 (s, 3H)ppm.

[1272] LCMS: m / z = 877.3 [M+H] + amu.

[1273] Synthesis of compound 20

[1274] Compound 20 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic acid ester. Compound 20 was obtained as an off-white solid.

[1275] 1H NMR (300MHz, methanol-d4): δ9.46 (s, 1H), 7.77 (d, J=8.0Hz, 1H), 7.57 (dd, J=3.4, 1.9Hz, 1H), 7.43 (dd , J=12.1, 8.4Hz, 2H), 7.30-7.11 (m, 3H), 7.10-6.99 (m, 1H), 6.91-6.78 (m, 1H), 6.76 (d, J=9.9Hz, 1H), 6.56 (d, J=2.0Hz, 1H), 6.36 (dd, J=7.5, 1.7Hz, 1H), 5.43 (dd, J=10.0, 3.2Hz, 1H), 5.23 (s, 2H ), 5.12-5.00(m, 2H), 4.51-4.40(m, 2H), 3.69(s, 3H), 3.42(s, 8H), 2.88(s, 3H), 1.72(s, 3H)ppm.

[1276] LCMS: m / z = 874.3 [M+H] + amu.

[1277] Synthesis of compound 21

[1278] Compound 21 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic ester or acid. Compound 21 was obtained as an off-white amorphous solid (10.0 mg, 31% yield).

[1279] 1 H NMR (400MHz, methanol-d4): δ9.34 (s, 1H), 7.64 (d, J=2.2Hz, 1H), 7.60-7.51 (m, 2H), 7.30 (d, J=8.6Hz, 1H), 7.25-7. 07 (m, 3H), 7.07-7.01 (m, 1H), 6.91 (d, J=8.6Hz, 1H), 6.84-6.75 (m, 2H), 6.56 (d, J=1.9Hz, 1H), 6.39 (dd, J=7. 5, 1.7 Hz, 1H), 5.42 (dd, J = 9.6, 3.7 Hz, 1H), 5.30-5.18 (m, 2H), 5.05 (qd, J = 8.7, 1.5 Hz, 2H), 4.23 (t, J = 4.9 Hz, 2H), 3.29-3.17 (m, 5H), 3.17-2.93 (m, 7H), 2.82 (s, 3H), 2.48-2.36 (m, 1H), 1.76 (s, 3H) ppm (40 of 40 protons observed).

[1280] LC / MS: m / z = 861.2 [M+H] + amu.

[1281] Synthesis of compound 22

[1282] Compound 22 was synthesized by following the general procedure for compound 7 and using the corresponding aryl-substituted boronate or acid. Compound 22 was obtained as an off-white amorphous solid (6.7 mg, 20% yield).

[1283] 1 H NMR (400 MHz, methanol-d4): δ 9.33 (s, 1H), 7.65-7.60 (m, 1H), 7.60-7.52 (m, 2H), 7.52-7.34 (m, 3H), 7.22-7.09 (m, 2H), 7.07-7.00 (m, 1H), 6.87-6.70 (m, 1H), 6.56 (d, J = 1.9 Hz, 1H), 6.33 (dd, J = 7.5, 1.7 Hz, 1H), 5.41 (dd, J = 10.0, 3.3 Hz, 1H), 5.29-5.19 (m, 2H), 5.10-5.00 (m, 2H), 4.39-4.27 (m, 2H), 3.30-3.15 (m, 6H), 3.15-2.86 (m, 5H), 2.84 (s, 3H), 2.45-2.32 (m, 1H), 1.69 (s, 3H) ppm (39 of 39 protons observed).

[1284] LC / MS: m / z = 889.2 [M+H] + amu.

[1285] Synthesis of compound 23

[1286] Compound 23 was synthesized by following the general procedure for compound 7 and using the corresponding aryl-substituted boronate or acid to obtain compound 23 as an off-white solid.

[1287] 1H NMR (500MHz, methanol-d4): δ9.10 (s, 1H), 7.62 (d, J=1.9Hz, 1H), 7.31-7.23 (m, 4H), 7.21 (d, J=8.6Hz, 1H), 7.15 (m, 3H), 7.11 (dd, J=8.3, 1.1Hz, 1H), 6.93 (td, J=7.4, 1.0Hz, 1H), 6.61 (d, J=1.9Hz, 1H), 6.45 (dd, J=7.4, 1 .7Hz, 1H), 5.44 (dd, J=10.2, 3.0Hz, 1H), 5.33-5.25 (m, 2H), 5.09 (td, J=8.7, 2.6Hz, 2H), 4.46 (t, J=4.9Hz , 2H), 4.10(s, 3H), 3.47-3.38(m, 4H), 3.34-3.12(m, 4H), 2.93(s, 3H), 2.44-2.32(m, 1H), 2.06(s, 3H)ppm.

[1288] LCMS: m / z = 851.2 [M+H] + amu.

[1289] Synthesis of compound 24

[1290] Compound 24 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronate or acid. Compound 24 was obtained as an off-white amorphous solid (12.4 mg, 38% yield).

[1291] 1 H NMR (500MHz, methanol-d4): δ9.34 (s, 1H), 7.75 (dd, J=7.9, 1.1Hz, 1H), 7.60-7.54 (m, 2H), 7.39 (d, J=5.5Hz, 1H), 7.33 (d, J=8. 6Hz, 1H), 7.22-7.09 (m, 2H), 7.07-7.00 (m, 1H), 7.00-6.91 (m, 2H), 6.79 (td, J=7.4, 1.1Hz, 1H), 6.56 (d, J=1.9Hz, 1H), 6 .40 (dd, J = 7.5, 1.7 Hz, 1H), 5.43 (dd, J = 9.7, 3.6 Hz, 1H), 5.29-5.18 (m, 2H), 5.05 (qd, J = 8.6, 1.4 Hz, 2H), 4.31-4.21 (m, 2H), 3.31-3.19 (m, 4H), 3.20-2.99 (m, 6H), 2.82 (s, 3H), 2.41 (dd, J = 14.0, 9.7 Hz, 1H), 1.69 (s, 3H) ppm (38 of 40 protons observed).

[1292] LC / MS: m / z=877.2[M+H] + amu.

[1293] Synthesis of compound 25

[1294] Compound 25 was synthesized by following the general procedure for compound 7 and using the corresponding cycloalkyl-substituted boronate or acid. Compound 25 was obtained as an off-white amorphous solid (6.2 mg, 19% yield).

[1295] 1 H NMR (400 MHz, methanol-d4): δ 9.31 (s, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.41-7.14 (m, 1H), 7.14-6.68 (m, 6H), 6.68-6.35 (m, 2H), 5.55-5.33 (m, 1H), 5.33-5.15 (m, 2H), 5.04 (qd, J = 8.6, 2.4 Hz, 2H), 4.43-4.11 (m, 2H), 3.30-2.93 (m, 11H), 2.93-2.68 (m, 5H), 2.66 (s, 1H), 2.60-2.11 (m, 1H), 2.09-1.85 (m, 1H), 1.85-1.64 (m, 3H) ppm (40 of 46 protons observed).

[1296] LC / MS: m / z=875.3[M+H] + amu.

[1297] Synthesis of compound 26

[1298] Compound 26 was synthesized by following the general procedure for compound 7 and using the corresponding aryl-substituted boronate or acid. Compound 26 was obtained as an off-white amorphous solid (10.5 mg, 34% yield).

[1299] 1H NMR (400MHz, methanol-d4): δ9.30 (s, 1H), 7.57 (d, J=1.9Hz, 1H), 7.38 (d, J=8.5Hz, 1H), 7.30-7.21 (m, 1H), 7.2 1-7.14 (m, 1H), 7.14-7.07 (m, 2H), 7.07-6.90 (m, 3H), 6.80 (td, J=7.5, 1.1Hz, 1H), 6.56 (d, J=1.9Hz, 1H), 6.37 (dd, J = 7.5, 1.8 Hz, 1H), 5.41 (dd, J = 9.9, 3.4 Hz, 1H), 5.26-5.20 (m, 2H), 5.05 (qd, J = 8.7, 1.7 Hz, 2H), 4.44-4.30 (m, 2H), 3.28-3.07 (m, 7H), 2.85 (s, 3H), 2.45-2.35 (m, 1H), 1.74 (s, 3H) ppm (34 of 39 protons observed).

[1300] LC / MS: m / z=839.2[M+H] + amu.

[1301] Synthesis of compound 27

[1302] Compound 27 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic ester or acid to obtain compound 27 as an off-white amorphous solid.

[1303] 1 H NMR (500MHz, acetonitrile-d3): δ9.15 (s, 1H), 7.50 (s, 1H), 7.30 (d, J=8.2Hz, 1H), 7.20 (dd, J=4.9, 3.1Hz, 1H), 7.1 3-7.03 (m, 4H), 7.00 (d, J = 8.5Hz, 1H), 6.91 (d, J = 8.2Hz, 1H), 6.73 (t, J = 7.4Hz, 1H), 6.52 (s, 1H), 6.43 (s , 1H), 5.22 (d, J=9.3Hz, 1H), 5.16-4.93 (m, 4H), 4.29-4.14 (m, 2H), 3.73-3.69 (m, 2H), 3.68-3.64 (m, 2H) , 3.61-3.57(m, 2H), 3.53-3.50(m, 2H), 3.23-3.11(m, 1H), 2.88(s, width, 2H), 2.35(s, 3H), 1.79(s, 3H)ppm.

[1304] LC / MS: m / z=827.2[M+H] + amu.

[1305] Synthesis of compound 28

[1306] Compound 28 was synthesized by following the general procedure for compound 7 and using the corresponding heteroaryl-substituted boronic ester or acid to obtain compound 28 as an off-white amorphous solid.

[1307] 1 H NMR (400 MHz, methanol-d4): δ 9.19 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 2H), 7.05 (d, J = 8.2 Hz, 1H), 6.90-6.80 (m, 3H), 6.55 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 7.3 Hz, 2H). z, 1H), 5.40 (dd, J=9.7, 3.2Hz, 1H), 5.23 (s, 2H), 5.04 (q, J=8.5Hz, 2H), 4.38 (dt, J=7.6, 5.0Hz, 2 H), 3.81 (s, 3H), 3.23-2.98 (m, 10H), 2.83 (s, 3H), 2.33 (dd, J=13.8, 9.9Hz, 1H), 1.80 (s, 3H)ppm.

[1308] LC / MS: m / z = 825.2 [M+H] + amu.

[1309] Synthesis of compound 29

[1310]

[1311] To a microwave vial containing compound 1-6 (30 mg, 0.037 mmol) was added X-Phos-Pd-G3 (3 mg, 0.004 mmol). The vial was capped and the solid was dissolved in degassed THF (0.124 mL, 0.3 M) after 3 nitrogen / vacuum cycles. Cyclobutylzinc bromide (0.5 M in THF, 0.297 mL, 0.149 mmol) was then added to the stirred solution. The reaction was stirred at 60 ° C for 12 hours and allowed to cool to room temperature. Dioxane (0.600 mL, 0.04 M) and lithium hydroxide aqueous solution (2 M solution, 0.600 mL) were then added to the crude reaction mixture. The reaction was allowed to stir at room temperature for 12 hours. The reaction was quenched with acetic acid (0.100 mL), diluted with DMSO and purified by reverse phase chromatography (0.25% TFA / water / 20-70% acetonitrile). Product fractions were pooled and concentrated to give compound 29 as an off-white amorphous solid (10.9 mg, 56% yield).

[1312] 1 H NMR (500MHz, methanol-d4): δ9.25 (s, 1H), 7.56 (d, J=1.9Hz, 1H), 7.20 (td, J=5.8, 1.0Hz, 1H), 7.16-7.10 (m, 2H), 7.07-7.03 (m, 1H), 6.88 (td, J=6.4, 1.0Hz, 1H), 6.55 (d, J=1.8Hz, 1H) 6.51 (dd, J=10.0, 2.0Hz, 1H), 5.39 (dd, J=9.7, 3.5Hz, 1H), 5.28-5. 19 (m, 2H), 5.04 (qd, J = 8.8, 2.9 Hz, 2H), 4.43-4.33 (m, 2H), 3.56-3.47 (m, 1H), 3.23-3.08 (m, 6H), 2.85 (s, 3H), 2.51 (quintet, J = 9 Hz, 1H), 2.42-2.28 (m, 2H), 2.12-2.03 (m, 1H), 2.01-1.89 (m, 2H), 1.88 (s, 3H), 1.87-1.79 (m, 1H) ppm (36 of 42 protons observed).

[1313] LC / MS: m / z = 799.3 [M+H] + amu.

[1314] Synthesis of compound 30

[1315] Compound 30 was synthesized by following the general procedure for compound 29 and using cyclopropylzinc bromide. Compound 30 was obtained as an off-white amorphous solid (9.0 mg, 47% yield).

[1316] 1H NMR (500MHz, methanol-d4): δ9.01 (s, 1H), 7.56 (d, J=1.9Hz, 1H), 7.29-7.23 (m, 1H), 7.23-7.17 (m, 1H), 7.16-7.11 (m, 1H), 7.07-7.02 (m, 1H), 6.89 (td, J=7.5, 1.0Hz, 1H), 6.56 (d, J=1.9Hz, 1H), 6.44 (dd, J=7.4, 1.7Hz, 1H), 5.36 (dd, J=10.0 , 3.2Hz, 1H), 5.26-5.23 (m, 2H), 5.10-4.99 (m, 3H), 4.36 (t, J=5.0Hz, 2H), 3.27-2.90 (m, 10H), 2.83 (s, 3H), 2.33 (dd , J=13.9, 10.0Hz, 1H), 2.01 (s, 3H), 1.78-1.61 (m, 1H), 1.37-1.25 (m, 1H), 1.14-0.97 (m, 2H), 0.97-0.76 (m, 2H)ppm.

[1317] LC / MS: m / z=785.2[M+H] + amu.

[1318] Synthesis of compound 52

[1319] Compound 52 was synthesized by following the general procedure for compound 29 and using 2-pyridylzinc bromide to obtain compound 52 as a brown solid.

[1320] 1 H NMR (400MHz, methanol-d4): δ9.50 (s, 1H), 8.85-8.73 (m, 1H), 8.22-8.08 (m, 1H), 7.83-7.74 (m, 1H), 7.44-7.34 (m, 2H), 7. 26-7.14 (m, 2H), 7.11-7.03 (m, 2H), 6.83 (td, J=7.5, 0.9Hz, 1H), 6.56 (d, J=1.9Hz, 1H), 6.45 (dd, J=7.5, 1.7Hz, 1H), **5.46 (dd, J = 9.7, 3.8 Hz, 1H), 5.24 (s, 2H), 5.20-5.12 (m, 1H), 5.12-4.99 (m, 2H), 5.11-4.99 (m, 2H), 4.37 (t, J = 4.9 Hz, 2H), 3.93-3.84 (m, 1H), 2.84 (s, 4H), 2.66 (s, 5H), 2.63 (s, 1H), 2.18 (s, 2H), 1.82 (s, 3H) ppm (39 of 39 protons observed).

[1321] LC / MS: m / z=822.2[M+H] + amu.

[1322] Synthesis of compound 91

[1323]

[1324] Compound 1-6 (30 mg, 0.037 mmol), 2-oxa-6-azaspiro[3.3]heptane hydrochloric acid (11 mg, 0.111 mmol), XantPhos-Pd-G3 (3.9 mg, 0.005 mmol) and cesium carbonate (12 mg, 0.037 mmol) were added to a vial. Under a nitrogen atmosphere, a solution of dioxane and water (2: 1; 0.4 M) was degassed with nitrogen bubbling. The solvent was transferred to a reaction flask, which was sealed and heated to 90 ° C for a period of 12 hours. After cooling, the reaction was diluted with deionized water and transferred to a separatory funnel containing dichloromethane. The aqueous layer was extracted with dichloromethane, the combined organics were dried over sodium sulfate, filtered, and volatiles were removed under reduced pressure. The resulting oil was used directly in the saponification step.

[1325] The above crude product is dissolved in a mixture of dioxane, 2N LiOH and methanol (4:1:1, 2mL), allowed to stir at room temperature 2 hours. After neutralization with acetic acid, filtered mixture and purified by reversed-phase HPLC (20mm C18 post, 25mL / min, 25-60% acetonitrile.water+0.25% TFA in 22 minutes). Pooled fractions containing the desired product and concentrated to dryness on a freeze dryer, obtained compound 91, is a white solid (4.6mg product, 15% yield), which is analyzed and displayed as the expected product by LC / MS and proton NMR.

[1326] 1H NMR (400 MHz, methanol-d4): δ 8.72 (s, 1H), 7.58-7.54 (m, 1H), 7.40-7.32 (m, 1H), 7.19 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 7.13-7.00 (m, 2H), 6.84 (td, J = 7.5, 1.1 Hz, 1H), 6.58-6.52 (m, 1H), 6.40-6.31 (m, 1H), 5.32 (dd, J = 9.9, 3.4 Hz, 1H), 5.28-5.17 (m, 2H), 5.09-4 .98 (m, 2H), 4.66 (s, 3H), 4.42-4.29 (m, 2H), 3.83-3.66 (m, 2H), 3.64-3.52 (m, 1H), 3.48-3.34 (m, 1H), 3.27-3.20 (m, 1H), 3.20-3.10 (m, 2H), 3.10-3.02 (m, 2H), 2.86-2.79 (m, 3H), 2.41-2.30 (m, 1H), 2.06-2.01 (m, 1H), 1.99 (s, 2H) ppm (35 of 43 protons observed).

[1327] LC / MS: m / z=842.3[M+H] + amu.

[1328] Example 2: Synthesis of Compound 31

[1329] Synthetic intermediate 2-1

[1330]

[1331] To a cooled suspension of compound A9 (108 mg, 0.344 mmol), compound C-4A (147 mg, 0.45 mmol) and triphenylphosphine (135 mg, 0.52 mmol) in tetrahydrofuran (15 mL) was added dropwise via cannula di-tert-butyl azodicarboxylate (119 mg, 0.52 mmol) in tetrahydrofuran (3.5 mL). The reaction was removed from the cooling bath and stirred at ambient temperature for 4 hours, at which time LC / MS analysis showed complete conversion to the desired product.

[1332] The reaction was concentrated onto silica gel. Silica gel chromatography (0-40% ethyl acetate / hexanes) was performed with refractive index detection. Product fractions were pooled and concentrated to yield Intermediate 2-1 as a yellow oil (259 mg, quantitative yield, some impurities present).

[1333] Synthetic intermediate 2-2

[1334]

[1335]

[1336] To a flask containing intermediate 2-1 (257 mg, 0.344 mmol) was added compound B6 (250 mg, 0.633 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (12.2 mg, 0.017 mmol) and cesium carbonate (336 mg, 1.03 mmol). The solid was dissolved in degassed 1,4-dioxane (1.6 mL) and deionized water (0.75 mL). The reaction was stirred at 60°C for 12 hours, allowed to cool and poured into a separatory funnel containing water (10 mL). The organic phase was separated and the aqueous phase was washed with dichloromethane (10 mL, 3 times). The combined organic extracts were concentrated onto silica gel. Silica gel chromatography (0-20% methanol / dichloromethane) was performed. The product fractions were pooled and concentrated to produce intermediate 2-2 as a mixture of diastereomers (175 mg, 56% yield).

[1337] Synthesis of compound 31

[1338]

[1339] To a solution of n-BuLi (1 mL, 2.4 mmol) cooled to -78°C was added THF (1 mL) followed by 4-fluoro-bromobenzene (0.27 mL, 2.4 mmol). The reaction was stirred for 30 minutes and a solution of zinc chloride in THF (4.8 mL, 0.5 M, 2.4 mmol) was injected. The resulting Negishi reagent was allowed to warm to ambient temperature. To a second reaction vessel were added intermediate 2-2 (45 mg, 0.059 mmol) and X-Phos-Pd-G3 (4.9 mg, 0.0058 mmol). After 3 argon / vacuum cycles, Negishi reagent (0.34 M, 3 equivalents) was injected and the reaction was warmed to 60°C for 24 hours. The reaction was poured into an aqueous ammonium chloride solution and diluted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated to dryness.

[1340] The crude material was dissolved in dioxane (2 mL) and treated with aqueous lithium hydroxide (1 M, 200 μL). After 20 hours, the reaction was acidified with acetic acid (20 μL), filtered and purified by reverse phase HPLC (30-70% acetonitrile / water + 0.25% TFA). The active fractions were pooled, frozen on a lyophilizer and concentrated to dryness (2.8 mg).

[1341] 1H NMR (400MHz, DMSO-d6): δ9.22 (s, 1H), 7.35-7.25 (m, 4H), 7.13-7.06 (m, 1H), 6.94 -6.75 (m, 7H), 6.70 (td, J=7.4, 1.1Hz, 1H), 6.54 (d, J=8.5Hz, 1H), 5.69 (dd, J=7.6, 5.5Hz, 1H), 4.91 (s, 2H), 4.40 (d, J=9.7Hz, 2H), 3.76 (s, 3H), 3.53 (d, J=10.8Hz, 2 H), 3.34-3.15 (m, 3H), 3.05 (dd, J=13.9, 7.6Hz, 1H), 2.61 (s, 3H), 1.95 (s, 3H)ppm.

[1342] LC / MS: m / z=797.2[M+H] + amu.

[1343] Example 3: Synthesis of Compounds 3-2, 3-3, Compounds 32 to 39, Compounds 53 to 54, Compounds 75 to 80, Compounds 82 to 90, and Compound 103

[1344] Synthesis of compound 3-2

[1345]

[1346] To a solution of compound 3-1 (1.25 g, 3.07 mmol), PPh (1.10 g, 2.88 mmol), EtN (1.28 mL, 9.18 mmol) and compound A9 (0.60 g, 1.92 mmol) in THF (19.2 mL) was added DBAD (0.755 g, 2.88 mmol) in one batch. The mixture was then stirred for 12 hours. The resulting solution was adsorbed on silica gel and purified by chromatography. The isolated product (compound 3-2; 1.3 g, 1.85 mmol, 96% yield) was a yellow oil.

[1347] LC / MS: m / z = 675.0 [M+H] + amu.

[1348] Alternative synthesis of compound 3-2

[1349] To a solution of compound 3-1 (4.0 g, 9.79 mmol), PPh (3.34 g, 12.73 mmol), EtN (4.1 mL, 29.38 mmol) and compound A9 (3.67 g, 11.75 mmol) in THF (48.966 mL) was added dropwise DBAD (2.93 g, 12.73 mmol) (10 mL) as a THF solution. The mixture was then stirred for 12 hours. The resulting solution was adsorbed on silica gel and purified by chromatography. The isolated product (compound 3-2; 3.5 g, 4.979 mmol, 50.84% ​​yield) was a yellow oil.

[1350] LC / MS: m / z = 675.0 [M+H] + amu.

[1351] Synthesis of compound 3-3

[1352]

[1353] A round-bottom flask containing compound 3-2 (3.5 g, 4.98 mmol), Pd (amphos) Cl 2 (176.28 mg, 0.2500 mmol), compound B6 (2.36 g, 5.97 mmol) and K 3 PO 4 (3.17 g, 14.94 mmol) was evacuated and back-filled with nitrogen three times before adding fresh degassed dioxane (16 mL) and water (8 mL). The mixture was then heated to 80° C. for 12 hours. The solution was cooled to ambient temperature, diluted with ethyl acetate, partitioned with saturated ammonium chloride and extracted three times with ethyl acetate. The combined organic washes were dried over MgSO 4 , concentrated, and purified via flash chromatography (0-25% DCM / MeOH). Compound 3-3 (3.78 g, 4.4796 mmol, 89.97% yield) was isolated as a light yellow solid.

[1354] LC / MS: m / z=815.1[M+H] + amu.

[1355] Synthesis of compound 32

[1356] Compound 32 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic acid ester, and following the general procedure used to synthesize compound 7. Compound 32 was obtained as an off-white solid.

[1357] 1H NMR (300MHz, methanol-d4): δ9.35 (s, 1H), 8.89 (d, J=5.5Hz, 1H), 7.96 (dd, J=18.6, 5.3Hz, 2H), 7.81 (d, J=7.6H z, 1H), 7.61-7.50 (m, 1H), 7.41 (d, J=8.5Hz, 1H), 7.30-7.08 (m, 4H), 7.00 (d, J=7.9Hz, 1H), 6.96-6.80 (m , 3H), 6.43 (d, J=7.5Hz, 1H), 5.57 (td, J=10.2, 2.8Hz, 1H), 5.33 (d, J=5.6Hz, 2H), 4.44-4.32 (m, 2H), 4.3 0-4.12 (m, 2H), 3.92 (d, J=1.2Hz, 3H), 3.17 (s, 8H), 2.85 (d, J=4.9Hz, 3H), 1.80 (s, 2H), 1.35 (s, 3H)ppm.

[1358] LC / MS: m / z = 902.3 [M+H] + amu.

[1359] Synthesis of compound 33

[1360] Compound 33 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic acid ester, and the general procedure used to synthesize compound 7. Compound 33 was obtained as an off-white solid.

[1361] 1 H NMR (300MHz, methanol-d4): δ9.34 (d, J=3.1Hz, 1H), 8.93 (d, J=5.6Hz, 1H), 8.08-7.82 (m, 2H), 7.5 9 (t, J=7.3Hz, 1H), 7.43 (d, J=8.6Hz, 1H), 7.31-7.08 (m, 4H), 7.03-6.75 (m, 4H), 6.42 (d, J=7 .3Hz, 1H), 5.67-5.49 (m, 1H), 5.38 (d, J=5.8Hz, 2H), 4.32 (m, 2H), 3.97 (d, J=1.5Hz, 3H), 3.8 8 (d, J=1.9Hz, 3H), 3.43 (d, J=21.4Hz, 8H), 2.65 (s, 3H), 2.58-2.43 (m, 1H), 1.80 (s, 3H)ppm.

[1362] LC / MS: m / z = 888.3 [M+H] + amu.

[1363] Synthesis of compound 34

[1364] Compound 34 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 34 was obtained as an off-white amorphous solid (4.2 mg, 17% yield).

[1365] 1 H NMR (400MHz, methanol-d4): δ9.30 (s, 1H), 8.88 (d, J=5.4Hz, 1H), 7.90 (d, J=5.4Hz, 1H), 7.75 (dd, J=7.7, 1.8Hz, 1H), 7.59-7.49 (m, 2H), 7.41 (d, J=8.5Hz, 1H), 7.26-7.06 (m, 6H), 7.02-6.95 (m, 1H), 6.93-6.86 (m, 2H), 6.83 (td, J=7.4, 1.0Hz, 1H), 6.39 (dd, J=7.5, 1.7Hz, 1H), 6.33 (d, J =2.2 Hz, 1H), 5.58 (dd, J=10.2, 3.1 Hz, 1H), 5.38-5.24 (m, 2H), 5.02 (s, 2H), 4.42-4.28 (m, 2H), 3.89 (d, J=3.9 Hz, 6H), 3.44 (dd, J=13.9, 3.1 Hz, 1H), 3.29-3.17 (m, 4H), 3.17-2.94 (m, 5H), 2.83 (s, 3H), 2.66 (s, 2H), 2.50 (dd, J=14.0, 10.2 Hz, 1H), 1.73 (s, 3H) ppm (51 of 51 protons observed). LC / MS: m / z = 967.4 [M+H] + amu.

[1366] Synthesis of compound 35

[1367] Compound 35 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 35 was obtained as an off-white amorphous solid (56 mg, 54% yield).

[1368] 1H NMR (400MHz, methanol-d4): δ9.30 (s, 1H), 8.85 (d, J=5.3Hz, 1H), 7.83 (d, J=5.3Hz, 1H), 7.62 (dd, J=7.5, 1.8Hz, 1H), 7.52-7.45 (ddd, J=8.9, 7.4, 1.8Hz, 1H), 7.43 (d, J=8.5Hz, 1H), 7.29-7.20 (m, 1H), 7.20-7.04 (m, 5H), 7.04-6.92 (m, 3H), 6.81 (t, J= 7.4 Hz, 1H), 6.42 (dd, J = 7.4, 1.6 Hz, 1H), 5.56 (dd, J = 10.1, 3.1 Hz, 1H), 5.33-5.19 (m, 2H), 4.38-4.21 (m, 2H), 3.84 (s, 3H), 3.50-3.37 (m, 1H), 2.99 (t, J = 4.9 Hz, 2H), 2.79 (s, 3H), 2.52 (dd, J = 14.0, 10.1 Hz, 1H), 1.73 (s, 3H) ppm (35 of 44 protons observed). LC / MS: m / z = 875.3 [M+H] + amu.

[1369] Synthesis of compound 36

[1370] Compound 36 was synthesized using compound 3-3, cyclobutylzinc bromide, and the general procedure used to synthesize compound 29. Compound 36 was obtained as an off-white solid.

[1371] 1 H NMR (400 MHz, methanol-d4): δ 9.07 (s, 1H), 8.75 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 5.2 Hz, 1H), 7.52 (dd, J = 7.5, 1.8 Hz, 1H), 7.43-7.27 (m, 2H), 7.17 (d, J = 8.5 Hz, 1H), 7.09-6.95 (m, 5H), 6.81 (d, J = 8.3 Hz, 1H), 6.77-6.70 (m, 1H) , 6.46 (dd, J=7.5, 1.7Hz, 1H), 5.35 (dd, J=10.2, 2.9Hz, 1H), 5.22-5.10 (m, 2H), 4.19 (t, J=5.1Hz, 2H), 3.74 (s, 3H), 3.44-3.35 (m, 2H), 2.83-2.70 (m, 10H), 2.50-2.35 (m, 5H), 2.26 (q, J=9.2Hz, 1H), 1.71 (s, 5H)ppm.

[1372] LC / MS: m / z=835.3[M+H] + amu.

[1373] Synthesis of compound 103

[1374] Compound 103 was synthesized by using compound 3-3, cyclobutylzinc bromide, and the first step used to synthesize compound 29 without the second step to obtain compound 103 as an off-white solid.

[1375] 1 H NMR (400MHz, acetonitrile-d3): δ9.57-9.42 (m, 1H), 9.00 (d, J=5.5Hz, 1H), 8.43-8.28 (m, 1H), 7.99 (t, J=5.2Hz, 1H), 7.73 (ddq, J=8.6, 7.3, 1.5Hz , 1H), 7.36-7.30(m, 1H), 7.28-7.18(m, 2H), 7.17-7.08(m, 2H), 7.00-6.91(m, 2H), 6.71(dd, J=7.4, 1.7Hz, 1H), 5.50(dd, J=9.0, 4.6Hz, 1H), 5.45 (d, J=2.0Hz, 2H), 4.69 (t, J=4.7Hz, 2H), 4.14 (d, J=3.4Hz, 2H), 4.05 (qd, J=7.1, 1.3Hz, 2H), 3.94-3.76 (m, 3H), 3.71-3.44 (m, 5H), 3.23 (dd, J=14.2, 4.6Hz, 1H), 2.76 (s, 3H), 2.74-2.53 (m, 2H), 2.22-2.02 (m, 1H), 1.97 (d, J=1.9Hz, 4H), 1.06 (t, J=7.1Hz, 3H)ppm.

[1376] LC / MS: m / z=862.3[M+H] + amu.

[1377] Synthesis of compound 37

[1378] Compound 37 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 37 was obtained as an off-white solid.

[1379] 1H NMR (300MHz, methanol-d4): δ9.30 (s, 1H), 8.90 (d, J=5.5Hz, 1H), 7.95 (d, J=5.6Hz, 1H), 7.83 (dd, J=7.7, 1.8 Hz, 1H), 7.60-7.50 (m, 1H), 7.43 (d, J=8.5Hz, 1H), 7.26-7.06 (m, 3H), 7.03-6.88 (m, 4H), 6.83 (t, J=7. 4Hz, 1H), 6.39 (d, J=6.8Hz, 1H), 5.58 (dd, J=10.2, 2.9Hz, 1H), 5.40-5.24 (m, 2H), 4.38 (t, J=4.8Hz, 2H ), 3.92 (s, 3H), 3.23 (q, J=6.3, 5.0Hz, 8H), 2.86 (d, J=3.7Hz, 3H), 2.62-2.38 (m, 1H), 1.76 (s, 3H)ppm.

[1380] LC / MS: m / z = 905.3 [M+H] + amu.

[1381] Synthesis of compound 38

[1382] Compound 38 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic acid ester, and the general procedure used to synthesize compound 7. Compound 38 was obtained as an off-white solid.

[1383] 1 H NMR (300MHz, methanol-d4): δ9.21 (s, 1H), 8.89 (d, J = 5.6Hz, 1H), 7.94 (d, J = 5.5Hz, 1H), 7.80 (d, J = 7.8Hz, 1H), 7.55 (t, J = 8.4Hz, 1H), 7.41-7.31 (m, 2H), 7.24 (dd, J=14.1, 8.4Hz, 2H), 7.11 (d, J=7.9Hz, 2H), 7.00 (d, J=8.1Hz, 1H), 6.89 (t, J=7.3Hz, 1H), 6.46 (d, J =7.3Hz, 1H), 5.58 (d, J = 8.5Hz, 1H), 5.44-5.25 (m, 2H), 4.42 (s, 2H), 3.91 (s, 3H), 3.83 (d, J = 8.5Hz, 1H), 3.46 (d, J = 13.8Hz, 1H) , 3.19 (s, 7H), 2.85 (s, 3H), 2.45 (dd, J=14.1, 10.4Hz, 1H), 2.04 (dd, J=12.9, 5.9Hz, 1H), 1.81 (s, 3H), 0.83 (t, J=6.5Hz, 5H)ppm.

[1384] LC / MS: m / z = 903.3 [M+H] + amu.

[1385] Synthesis of compound 39

[1386] Compound 39 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 39 was obtained as an off-white solid.

[1387] 1 H NMR (500MHz, methanol-d4): δ9.38 (s, 1H), 8.97 (d, J=5.6Hz, 1H), 8.05 (d, J=5.7Hz, 1H), 7.94 (dt, J=5.9, 1.7Hz, 1 H), 7.63 (ddd, J=9.0, 7.4, 1.8Hz, 1H), 7.48 (d, J=8.6Hz, 1H), 7.32-7.12 (m, 5H), 7.05 (d, J=8.1Hz, 1H), 6.9 8-6.81 (m, 4H), 6.45 (dd, J=7.5, 1.7Hz, 1H), 5.64 (dd, J=10.2, 3.0Hz, 1H), 5.42 (q, J=15.7Hz, 2H), 4.46 (t, J=4.9Hz, 2H), 4.01 (s, 3H), 3.71 (s, 3H), 3.56-3.40 (m, 7H), 2.93 (s, 3H), 2.56 (dd, J=14.0, 10.2Hz, 1H) ppm.

[1388] LC / MS: m / z = 887.3 [M+H] + amu.

[1389] Synthesis of compound 40

[1390] Compound 40 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 40 was obtained as an off-white solid.

[1391] 1H NMR (500MHz, methanol-d4): δ9.38 (d, J=2.2Hz, 1H), 9.00 (d, J=5.8Hz, 1H), 8.11 (d, J=5.7Hz, 1H), 8.04 (dq, J=6.1, 1.9Hz, 1H ), 7.73-7.59 (m, 2H), 7.50 (d, J=8.5Hz, 1H), 7.41-7.29 (m, 3H), 7.28-7.15 (m, 3H), 7.05 (td, J=8.6, 2.3Hz, 3H), 6.89 ( t, J=7.4Hz, 1H), 6.42 (dd, J=7.5, 1.7Hz, 1H), 5.64 (dd, J=10.3, 2.8Hz, 1H), 5.45 (q, J=16.0Hz, 2H), 4.52 (t, J=4.9Hz, 2H), 4.05 (d, J=3.0Hz, 3H), 3.62-3.42 (m, 7H), 2.97 (d, J=3.1Hz, 3H), 2.55 (dd, J=14.0, 10.3Hz, 1H), 1.81 (s, 3H)ppm.

[1392] LC / MS: m / z=876.4[M+H] + amu.

[1393] Synthesis of compound 53

[1394] Compound 53 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 53 was obtained as a brown solid.

[1395] 1H NMR (400MHz, methanol-d4): δ9.44 (s, 1H), 8.86 (d, J=5.3Hz, 1H), 7.82 (d, J=5.3Hz, 1H), 7.80-7.75 (m, 1H), 7.66 (dd, J=7.6, 1.7Hz, 1H), 7.51 ( ddd, J=8.4, 7.4, 1.8Hz, 1H), 7.46 (d, J=8.5Hz, 1H), 7.23-7.14 (m, 3H), 7.08 (td, J=7.5, 1.0Hz, 1H), 6.99 (d, J=8.1Hz, 1H), 6.83 (t, J=7. 3 Hz, 1H), 6.44 (dd, J = 6.8, 2H), 5.61 (dd, J = 10.0, 3.2, 1H), 5.35-5.22 (m, 3H), 4.33 (t, J = 4.9 Hz, 2H), 3.93-3.87 (m, 2H), 3.86 (s, 3H), 3.09-3.01 (m, 5H), 2.81 (s, 3H), 2.66 (s, 1H), 2.61-2.39 (m, 2H), 2.38-2.24 (m, 1H), 2.07-1.90 (m, 3H), 1.78 (s, 3H) ppm (44 of 44 protons observed).

[1396] LC / MS: m / z=858.3[M+H] + amu.

[1397] Synthesis of compound 54

[1398] Compound 54 was synthesized using compound 3-3, the corresponding heterocyclic substituted boronic acid ester, and following the general procedure used to synthesize compound 7. Compound 54 was obtained as an off-white oil.

[1399] 1H NMR (400 MHz, methanol-d4): δ 9.22 (s, 1H), 8.86 (d, J = 5.4 Hz, 1H), 7.86 (d, J = 5.4 Hz, 1H), 7.72 (dd, J = 7.7, 1.8 Hz, 1H), 7.52 (ddd, J = 9.0, 7.4, 1.8 Hz, 1H), 7.30 (d, J = 8.5Hz, 1H), 7.25-7.17(m, 2H), 7.17-7.03(m, 2H), 7.03-6.95(m, 1H), 6.89(td , J=7.5, 1.0Hz, 1H), 6.51 (dd, J=7.5, 1.7Hz, 1H), 5.74-7.68 (m, 1H), 5.57 (dd, J =9.9, 3.4Hz, 1H), 5.37-3.24(m, 2H), 4.42-4.28(m, 2H), 4.14-3.98(m, 2H), 3. 88 (s, 3H), 3.71 (t, J=5.6Hz, 2H), 3.38 (dd, J=14.0, 3.4Hz, 1H), 3.27 (s, 3H), 3 .10 (t, J = 4.9 Hz, 3H), 2.83 (s, 3H), 2.53 (dd, J = 14.0, 9.9 Hz, 1H), 2.36-2.26 (m, 1H), 2.23-2.07 (m, 1H), 1.96 (s, 3H), 1.36-1.20 (m, 5H) ppm (47 of 47 protons observed).

[1400] LC / MS: m / z = 863.2 [M+H] + amu.

[1401] Synthesis of compound 75

[1402] Compound 75 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic acid ester, and the general procedure used to synthesize compound 7. Compound 75 was obtained as an amorphous off-white solid.

[1403] 1H NMR (300MHz, methanol-d4): δ9.22 (s, 1H), 8.93 (dd, J=5.7, 3.5Hz, 1H), 8.06 (d, J=5.8Hz, 1H), 8.03-7.91 (m, 1H), 7.65-7.51 (m , 2H), 7.38 (d, J=8.5Hz, 1H), 7.32-7.08 (m, 4H), 7.02 (d, J=8.2Hz, 1H), 6.97-6.83 (m, 2H), 6.48 (dd, J=7.4, 1.7Hz, 1H), 5 .59 (dd, J=10.3, 2.7Hz, 1H), 5.49-5.28 (m, 2H), 4.52 (t, J=4.9Hz, 2H), 4.38-4.27 (m, 1H), 4.21-4.05 (m, 3H), 3.98 (s, 2H ), 3.44 (s, 11H), 2.91 (s, 3H), 2.46 (dd, J=14.0, 10.3Hz, 1H), 2.33 (t, J=7.3Hz, 1H), 2.06-2.02 (m, 2H), 1.83 (s, 2H)ppm.

[1404] LC / MS: m / z=875.3[M+H] + amu.

[1405] Synthesis of compound 76

[1406] Compound 76 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic acid ester, and the general procedure used to synthesize compound 7. Compound 76 was obtained as an amorphous off-white solid.

[1407] 1H NMR (300MHz, methanol-d4): δ9.43 (s, 1H), 8.93 (d, J=5.7Hz, 1H), 8.01 (d, J=5.7Hz, 1H), 7.91 (dd, J=7.8, 1.8Hz, 1H), 7.63-7.48 (m, 2H), 7 .38 (d, J=8.5Hz, 1H), 7.27-7.16 (m, 3H), 7.11 (td, J=7.6, 1.0Hz, 1H), 7.01 (d, J=8.2Hz, 1H), 6.89 (dd, J=7.9, 6.9Hz, 1H), 6.50 (dd, J =7.4, 1.7Hz, 1H), 5.63 (dd, J=10.3, 2.8Hz, 1H), 5.54 (d, J=2.4Hz, 1H), 5.46-5.29 (m, 2H), 4.51 (t, J=4.8Hz, 2H), 4.21 (q, J=7.3Hz, 2H), 3.95 (s, 3H), 3.56-3.37 (m, 10H), 2.90 (s, 3H), 2.47 (dd, J=14.1, 10.4Hz, 1H), 1.86 (d, J=3.1Hz, 4H), 1.44 (t, J=7.3Hz, 3H)ppm.

[1408] LC / MS: m / z=875.3[M+H] + amu.

[1409] Synthesis of compound 77

[1410] Compound 77 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic acid ester, and the general procedure used to synthesize compound 7. Compound 77 was obtained as an amorphous off-white solid.

[1411] 1H NMR (300MHz, methanol-d4): δ9.29 (s, 1H), 8.93 (dd, J=5.8, 3.2Hz, 1H), 8.04 (d, J=5.8Hz, 1H), 7.96 (dd, J=7.8, 1.8Hz, 1H) , 7.60 (ddd, J=8.4, 7.4, 1.8Hz, 1H), 7.33-7.18 (m, 5H), 7.16-7.08 (m, 1H), 7.03 (d, J=8.0Hz, 1H), 6.97-6.86 (m, 1H) , 6.54 (dd, J=7.3, 1.7Hz, 1H), 6.08 (s, 1H), 5.62 (dd, J=10.2, 2.8Hz, 1H), 5.37 (dd, J=16.2, 5.5Hz, 3H), 4.55-4.39 ( m, 3H), 3.97 (d, J=1.0Hz, 5H), 3.41 (t, J=7.0Hz, 20H), 2.90 (d, J=1.6Hz, 5H), 2.44 (s, 3H), 1.89 (d, J=5.4Hz, 3H) ppm.

[1412] LC / MS: m / z=862.3[M+H] + amu.

[1413] Synthesis of compound 78

[1414] Compound 78 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic acid ester, and the general procedure used to synthesize compound 7. Compound 78 was obtained as an amorphous off-white solid.

[1415] 1 H NMR (300MHz, methanol-d4): δ9.27 (s, 1H), 8.90 (d, J=5.5Hz, 1H), 7.96 (d, J=5.7Hz, 1H), 7.83 (dd, J=7.7, 1.8Hz, 1H) , 7.62-7.52 (m, 1H), 7.31-7.17 (m, 5H), 7.10 (t, J=7.6Hz, 1H), 7.02 (dd, J=8.3, 3.9Hz, 1H), 6.95-6.88 (m, 1H) , 6.57 (d, J=7.7Hz, 1H), 5.61 (dd, J=10.3, 3.0Hz, 1H), 5.49 (s, 1H), 5.39-5.30 (m, 2H), 4.46-4.36 (m, 2H), 3.9 2 (s, 4H), 3.25-2.97 (m, 3H), 2.85 (s, 4H), 2.45 (dd, J=14.1, 10.2Hz, 1H), 2.06-1.99 (m, 3H), 1.88 (s, 3H)ppm.

[1416] LC / MS: m / z = 888.3 [M+H] + amu.

[1417] Synthesis of compound 79

[1418] Compound 79 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic acid ester, and the general procedure used to synthesize compound 7. Compound 79 was obtained as an amorphous off-white solid.

[1419] LC / MS: m / z = 903.3 [M+H] + amu.

[1420] Synthesis of compound 80

[1421] Compound 80 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 80 was obtained as an amorphous off-white solid.

[1422] 1 H NMR (300MHz, methanol-d4): δ9.34 (d, J=0.4Hz, 1H), 8.91 (d, J=5.6Hz, 1H), 7.98 (d, J=5.6Hz, 1H), 7.88 (dd, J=7 .7, 1.7Hz, 1H), 7.78-7.54 (m, 3H), 7.54-7.41 (m, 4H), 7.30-7.05 (m, 4H), 6.99 (d, J=8.2Hz, 1H), 6.34 (d, J =7.5Hz, 1H), 5.58 (dd, J = 10.4, 2.9Hz, 1H), 5.42-5.25 (m, 2H), 4.39 (d, J = 5.2Hz, 2H), 3.95 (d, J = 1.4Hz, 3H ), 3.53-3.42 (m, 1H), 3.19 (s, 9H), 2.86 (d, J=1.7Hz, 3H), 2.50 (dd, J=13.9, 10.4Hz, 1H), 1.69 (s, 3H)ppm.

[1423] LC / MS: m / z = 882.3 [M+H] + amu.

[1424] Synthesis of compound 82

[1425] Compound 82 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 82 was obtained as an amorphous off-white solid.

[1426] 1H NMR (300MHz, methanol-d4): δ9.31 (s, 1H), 8.88 (d, J=5.4Hz, 1H), 7.90 (d, J=5.4Hz, 1H), 7.77 (d, J=7 .5Hz, 1H), 7.54 (t, J=7.8Hz, 1H), 7.30 (d, J=8.3Hz, 2H), 7.21 (q, J=7.1Hz, 2H), 7.14-6.91 (m, 4H), 6.85 (t, J=7.5Hz, 1H), 6.45 (d, J=7.4Hz, 1H), 5.64-5.55 (m, 1H), 5.41-5.25 (m, 2H), 4.28 (s, 2H), 3.90 (s, 3H), 3.09 (s, 4H), 2.82 (s, 3H), 2.53 (dd, J=14.0, 9.8Hz, 1H), 1.83 (s, 3H)ppm.

[1427] LC / MS: m / z=875.3[M+H] + amu.

[1428] Synthesis of compound 83

[1429] Compound 83 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 83 was obtained as an amorphous off-white solid.

[1430] 1 H NMR (300MHz, methanol-d4): δ9.33 (s, 1H), 8.90 (d, J=5.5Hz, 1H), 7.94 (d, J=5.6Hz, 1H), 7.83 (dd, J=7.7, 1.7H z, 1H), 7.61-7.46 (m, 1H), 7.31-7.15 (m, 5H), 7.11 (td, J=7.5, 1.0Hz, 1H), 7.06-6.92 (m, 5H), 6.87 (t, J =7.4Hz, 1H), 6.50 (d, J = 7.4Hz, 1H), 5.61 (dd, J = 9.8, 3.3Hz, 1H), 5.43-5.24 (m, 2H), 4.29 (t, J = 4.8Hz, 2 H), 3.31 (s, 3H), 3.17 (s, 6H), 2.84 (s, 3H), 2.52 (dd, J=14.0, 9.9Hz, 1H), 2.13 (s, 3H), 1.88 (s, 3H)ppm.

[1431] LC / MS: m / z=871.3[M+H] + amu.

[1432] Synthesis of compound 84

[1433] Compound 84 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 84 was obtained as an amorphous off-white solid.

[1434] 1 H NMR (300MHz, methanol-d4): δ9.31 (s, 1H), 8.88 (d, J=5.5Hz, 1H), 7.90 (d, J=5.4Hz, 1H), 7.75 (dd, J =7.7, 1.8Hz, 1H), 7.58-7.48(m, 1H), 7.44(d, J=8.5Hz, 1H), 7.24-7.13(m, 3H), 7.13-6.94(m , 4H), 6.83 (t, J=7.7Hz, 1H), 6.40 (d, J=5.9Hz, 1H), 5.58 (dd, J=10.3, 3.0Hz, 1H), 5.37-5.15 (m, 2H), 3.89 (s, 3H), 3.54-3.32 (m, 1H), 3.10 (t, J=4.9Hz, 3H), 2.83 (s, 3H), 1.76 (s, 3H)ppm.

[1435] LC / MS: m / z = 911.3 [M+H] + amu.

[1436] Synthesis of compound 85

[1437] Compound 85 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 85 was obtained as an amorphous off-white solid.

[1438] 1H NMR (300MHz, methanol-d4): δ9.30 (s, 1H), 8.90 (d, J = 5.5Hz, 1H), 7.95 (d, J = 5.5Hz, 1H), 7.82 (d, J = 7.6Hz, 1H), 7.56 (t, J=7.9Hz, 1H), 7.43 (d, J=8.5Hz, 1H), 7.29-7.04 (m, 5H), 6.99 (d, J=8.2Hz, 1H), 6.83 (t, J=7.6Hz , 1H), 6.38 (d, J=7.4Hz, 1H), 5.57 (dd, J=10.2, 2.8Hz, 1H), 5.42-5.25 (m, 2H), 4.37 (s, 2H), 3.92 (s, 3H), 3.64-3.33 (m, 1H), 3.11 (d, J=26.2Hz, 4H), 2.84 (s, 3H), 2.50 (dd, J=13.9, 10.3Hz, 1H), 1.75 (s, 3H)ppm.

[1439] LC / MS: m / z=893.3[M+H] + amu.

[1440] Synthesis of compound 86

[1441] Compound 86 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 86 was obtained as an amorphous off-white solid.

[1442] 1 H NMR (300MHz, methanol-d4): δ9.31 (d, J=0.8Hz, 1H), 8.89 (d, J=5.5Hz, 1H), 7.92 (d, J=5.4Hz, 1H), 7.83-7.7 5 (m, 1H), 7.72-7.46 (m, 2H), 7.30-7.14 (m, 2H), 7.10 (t, J=7.5Hz, 1H), 7.06-6.83 (m, 5H), 6.75 (d, J=8 .5Hz, 1H), 6.49 (d, J=7.7Hz, 1H), 5.60 (dd, J=9.8, 3.4Hz, 1H), 5.41-5.23 (m, 2H), 4.31 (d, J=5.3Hz, 2 H), 3.91 (d, J=1.7Hz, 3H), 3.24 (s, 0H), 3.20-3.15 (m, 7H), 2.85 (s, 3H), 2.14 (s, 3H), 1.87 (s, 3H)ppm.

[1443] LC / MS: m / z = 889.3 [M+H] + amu.

[1444] Synthesis of compound 87

[1445] Compound 87 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 87 was obtained as an amorphous off-white solid.

[1446] 1 H NMR (300MHz, methanol-d4): δ9.34 (s, 1H), 8.93 (d, J=5.7Hz, 1H), 8.03 (d, J=5.7Hz, 1H), 7.95 (dd, J=7.8, 1.7Hz, 1H), 7 .69-7.51 (m, 1H), 7.42 (d, J=8.6Hz, 1H), 7.28-7.07 (m, 5H), 7.04-6.96 (m, 1H), 6.90-6.79 (m, 4H), 6.40 (dd, J=7 .4, 1.7Hz, 1H), 5.59 (dd, J=10.2, 2.8Hz, 1H), 5.48-5.28 (m, 2H), 4.42 (t, J=4.8Hz, 2H), 3.97 (s, 3H), 3.92-3.72 (m, 2H), 3.50-3.33 (m, 12H), 2.88 (s, 3H), 2.49 (dd, J=14.0, 10.3Hz, 1H), 1.78 (s, 3H), 1.32 (t, J=7.0Hz, 3H) ppm.

[1447] LC / MS: m / z = 901.3 [M+H] + amu.

[1448] Synthesis of compound 88

[1449] Compound 88 was synthesized using compound 3-3, the corresponding aryl-substituted boronate or acid, and following the general procedure used to synthesize compound 7. Compound 88 was obtained as an off-white solid.

[1450] 1H NMR (400MHz, methanol-d4): δ9.30 (s, 1H), 8.84 (d, J=5.3Hz, 1H), 7.81 (d, J=5.3Hz, 1H), 7.64 (dd, J=7.7, 1.8Hz, 1H), 7.54-7.45 (m, 1H) , 7.44-7.36 (m, 2H), 7.29-7.04 (m, 6H), 6.98 (d, J=8.2Hz, 1H), 6.82 (t, J=7.5Hz, 1H), 6.41 (d, J=7.1Hz, 1H), 5.58 (dd, J=10.1, 3. 1 Hz, 1H), 5.35-5.18 (m, 2H), 4.37-4.25 (m, 2H), 3.85 (s, 3H), 3.50-3.46 (m, 1H), 3.41 (dd, J=14.4, 2.8 Hz, 1H), 3.15-3.10 (m, 1H), 3.00 (t, J=4.9 Hz, 2H), 2.80 (s, 3H), 2.52 (dd, J=14.0, 10.1 Hz, 1H), 1.99 (s, 1H), 1.73 (s, 3H), 1.29 (s, 1H) ppm (38 of 43 protons observed).

[1451] LC / MS: m / z = 909.3 [M+H] + amu.

[1452] Synthesis of compound 89

[1453] Compound 89 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic acid ester, and the general procedure used to synthesize compound 7. Compound 89 was obtained as an off-white solid.

[1454] 1H NMR (400MHz, methanol-d4): δ9.21 (s, 1H), 8.87 (d, J=5.4Hz, 1H), 7.90 (d, J=5.4Hz, 1H), 7.74 (dd, J=7.6, 1.8Hz, 1H), 7.58-7.48 (m, 1H), 7.40-7.31 (m, 2H ), 7.30-7.24 (m, 1H), 7.25-7.16 (m, 3H), 7.10 (td, J=7.5, 1.0Hz, 1H), 7.0 4-6.97 (m, 1H), 6.90 (td, J=7.4, 1.0Hz, 1H), 6.51 (dd, J=7.5, 1.7Hz, 1H), 5 .60 (dd, J = 10.3, 2.9 Hz, 1H), 5.38-5.21 (m, 2H), 4.40 (t, J = 4.9 Hz, 2H), 4.02-3.91 (m, 1H), 3.87-3.80 (m, 1H), 3.45 (dd, J = 13.9, 3.0 Hz, 1H), 3.22-2.97 (m, 5H), 2.84 (s, 3H), 2.48 (dd, J = 14.0, 10.3 Hz, 1H), 1.82 (s, 3H), 1.23-1.08 (m, 1H), 0.65-0.52 (m, 2H), 0.35-0.23 (m, 2H) ppm (40 of 49 protons observed).

[1455] LC / MS: m / z = 901.3 [M+H] + amu.

[1456] Synthesis of compound 90

[1457] Compound 90 was synthesized using compound 3-3, the corresponding heteroaryl-substituted boronic ester or acid, and following the general procedure used to synthesize compound 7. Compound 90 was obtained as an off-white solid.

[1458] 1H NMR (400MHz, methanol-d4): δ9.20 (s, 1H), 8.88 (d, J=5.5Hz, 1H), 7.92 (d, J=5.5Hz, 1H), 7.78 (dd, J=7.7, 1.8Hz, 1H), 7.58-7.49 (m, 1H), 7.41-7.16 (m, 5H) ,7.16-7.12(m,1H),7.10(td,J=7.2,1,1H),7.03-6.96(m,1H),6.89(td, J=7.4, 1.0Hz, 1H), 6.49 (dd, J=7.5, 1.7Hz, 1H), 5.59 (dd, J=10.3, 2.9Hz, 1 Hz, 1H), 5.43-5.22 (m, 2H), 4.42 (t, J = 4.9 Hz, 2H), 4.11-3.96 (m, 2H), 3.90 (s, 3H), 3.45 (dd, J = 14.1, 3.0 Hz, 1H), 3.35 (s, 1H), 3.27-3.06 (m, 8H), 2.85 (s, 3H), 2.78-2.62 (m, 1H), 2.46 (dd, J = 14.0, 10.3 Hz, 1H), 2.06-1.91 (m, 3H), 1.91-1.82 (m, 2H), 1.80 (s, 3H), 1.77-1.64 (m, 2H) ppm (50 of 51 protons observed).

[1459] LC / MS: m / z = 915.4 [M+H] + amu.

[1460] Example 4: Synthesis of Compounds 4-1, 4-2, 4-3, Compounds 41 to 51, and Compounds 81, 102, 105 to 108 and 120

[1461] Synthesis of compound 4-1

[1462]

[1463] To a vial was added compound 3-2 (660.69 mg, 1.6 mmol), Pd(amphos)Cl2 (37.77 mg, 0.0500 mmol) and potassium phosphate (679.53 mg, 3.2 mmol). Degassed 1,4-dioxane and water (5.2 mL, 2:1, 0.2 M) were injected and the reaction was warmed to 60°C under a nitrogen atmosphere. After 6.5 hours, an equal portion of compound D5 was added and the reaction was heated at 45°C overnight. The reaction was then allowed to cool and diluted with water and washed three times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Flash chromatography (0-100% hexane / EtOAc) and the active fractions were pooled and concentrated to dryness to produce compound 4-1 (490 mg, 54% yield) as a yellow oil. Compound 4-1 was isolated as a mixture of atropisomers in an approximate 4:1 ratio, and the major component is reported.

[1464] 1 H NMR (400 MHz, chloroform-d): δ 8.92-8.88 (m, 2H), 7.72-7.67 (m, 2H), 7.44 (ddd, J = 8.9, 7.1, 1.6 Hz, 1H), 7.29 (s, 1H), 7.19 (dd, J = 15.1, 8.2 Hz, 1H), 7.12-7.03 (m, 2H), 6.94 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.38-6.33 (m, 1H), 5.53 (dd, J = 10.6, 2.7 Hz, 1H), 5.46 (d, J=7.0Hz, 1H), 5.38 (d, J=7.2Hz, 1H), 5.29-5.16 (m, 2H), 4.22 (q, J=7.1Hz, 2H), 3.88 (s, 3H), 3.86-3.79 (m, 1H), 3.40 (dd, J=1 3.8, 2.8Hz, 1H), 2.45 (dd, J=13.9, 10.5Hz, 1H), 2.09 (s, 3H), 1.24 (s, 3H), 0.92 (ddd, J=16.6, 9.8, 7.2Hz, 1H), -0.07 (s, 9H)ppm.

[1465] LC / MS: m / z=847.2[M+H] + amu.

[1466] Synthesis of compound 4-2

[1467]

[1468] To a 40 mL reaction vial was added potassium phosphate (369.13 mg, 1.74 mmol), Pd-X-Phos-G3 (31 mg, 0.0400 mmol), compound 4-1 (492.1 mg, 0.5800 mmol) and 3-methoxy-phenyl-boronic acid (165 mg, 1.09 mmol). Degassed aqueous 1,4-dioxane / water (4.5 mL, 2:1 dioxane) was injected under nitrogen and the reaction was heated to 80°C for a period of 5 hours. The crude material was diluted with water and ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated. Flash chromatography (20-60% hexane / EtOAc) separated the product (compound 4-2; 250 mg, 47% yield) from some remaining starting material (83 mg, 17% yield). Compound 4-2 was isolated as a mixture of atropisomers in an approximate 4:1 ratio, and the major component is reported.

[1469] 1 H NMR (400MHz, chloroform-d): δ9.27 (d, J=0.6Hz, 1H), 8.97 (d, J=5.2Hz, 1H), 7.80-7.73 (m, 2H), 7.56-7.45 (m, 2H), 7.32 (d, J=8.8Hz, 1H), 7.27- 7.10 (m, 5H), 7.03-6.85 (m, 5H), 6.40 (dd, J=7.5, 1.7Hz, 1H), 5.62 (dd, J=10.3, 3.1Hz, 1H), 5.49 (d, J=7.0Hz, 1H), 5.41 (d, J=7.0Hz, 1H) , 5.34-5.25 (m, 2H), 4.37-4.27 (m, 2H), 3.95 (d, J=1.1Hz, 3H), 3.86 (dt, J=10.2, 6.3Hz, 2H), 3.72 (s, 3H), 3.44 (dd, J=13.7, 3.2Hz, 1H) , 2.60 (dd, J=13.7, 10.4Hz, 1H), 1.86 (s, 2H), 1.64 (s, 3H), 1.34 (t, J=7.1Hz, 3H), 0.96 (tdt, J=13.8, 10.5, 6.8Hz, 2H), 0.00 (s, 9H)ppm.

[1470] LC / MS: m / z = 919.3 [M+H] + amu.

[1471] Synthesis of compound 4-3

[1472]

[1473] A solution of compound 4-2 (250 mg, 0.2700 mmol) in DCM (20 mL) was treated with 2,2,2-trifluoroacetic acid (2 mL, 24.56 mmol) (10% volume). The reaction was monitored by TLC (1:1 hexane / EtOAc) and concentrated to dryness once complete (30 minutes). The resulting TFA salt was dissolved in acetonitrile / water, frozen and lyophilized under reduced pressure to produce compound 4-3 as a yellow powder (250 mg, quantitative). Compound 4-3 was sufficiently pure to be used for alkylation without further purification.

[1474] 1 H NMR (400 MHz, chloroform-d): δ 9.51 (s, 1H), 9.27 (s, 1H), 8.27 (dd, J = 7.9, 1.7 Hz, 1H), 8.07 (s, 1H), 7.71-7.61 (m, 1H), 7.15 (td, J = 9.7, 8.8, 3.1 Hz, 4H), 7.02-6.95 (m, 2H), 6.92-6.71 (m, 5H), 6.60-6.53 (m , 1H), 5.61 (dd, J=10.3, 3.6Hz, 1H), 5.34 (s, 2H), 4.25-4.14 (m, 2H), 4.03 (s, 3H), 3.63 (s, 3H), 3. 31 (dd, J=14.6, 3.4Hz, 1H), 2.63 (dd, J=14.6, 10.1Hz, 1H), 1.70 (s, 3H), 1.18 (t, J=7.1Hz, 3H) ppm.

[1475] LC / MS: m / z = 919.3 [M+H] + amu.

[1476] Synthesis of compound 41

[1477] Compound 41 was synthesized by subjecting compound 4-3 to saponification conditions and separating the atropisomers using reverse phase chromatography, following the general procedure for compound 7. Compound 41 was obtained as an off-white solid.

[1478] 1H NMR (400MHz, methanol-d4): δ9.11 (s, 1H), 8.75 (d, J=5.3Hz, 1H), 7.81 (d, J=5.2Hz, 1H), 7.51 (dd, J=7.6, 1.8 Hz, 1H), 7.38 (ddd, J=8.3, 7.4, 1.8Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 7.11-6.94 (m, 4H), 6.88-6.76 (m, 3H) , 6.75-6.63 (m, 3H), 6.32 (dd, J=7.5, 1.7Hz, 1H), 5.42 (dd, J=10.7, 2.6Hz, 1H), 5.15 (d, J=2.9Hz, 2H), 3 .74 (s, 3H), 3.52 (s, 3H), 3.37 (dd, J=14.1, 2.6Hz, 1H), 2.45 (dd, J=14.3, 10.6Hz, 1H), 1.52 (s, 3H)ppm.

[1479] LC / MS: m / z=761.2[M+H] + amu.

[1480] Synthesis of compound 42

[1481]

[1482] A solution of 2-morpholinoethanol (11 uL, 0.0900 mmol) in THF (150 uL / 5 mL) was prepared and transferred into a vial containing compound 4-3 (16 mg, 0.0200 mmol). A solution of (trimethylphosphoranylidene)acetonitrile (354.25 uL, 0.1800 mmol) was injected and the reaction was stirred at 65°C for 2 hours. Once cooled, the reaction was treated with 300 uL of 2N LiOH. The reaction was stirred overnight to allow complete saponification to form the acid. The reaction was diluted with DMSO (1 mL), neutralized with acetic acid (0.08 mL, 1.33 mmol), filtered and purified by reverse phase HPLC (10-50% water / acetonitrile + 0.25% AcOH buffer). Two peaks were collected: the first of which was the minor diastereomer (2R)-2-[4-[3-chloro-2-methyl-4-(2-morpholinoethoxy)phenyl]-5-(3-methoxyphenyl)isothiazolo[5,4-c]pyridin-3-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid (2.03 mg, 0.0023 mmol, 13% yield) , while the second was the major diastereomer (2R)-2-[4-[3-chloro-2-methyl-4-(2-morpholinoethoxy)phenyl]-5-(3-methoxyphenyl)isothiazolo[5,4-c]pyridin-3-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid (compound 42; 5.81 mg, 0.0066 mmol, 38% yield).

[1483] 1 H NMR (400 MHz, methanol-d4): δ 9.12 (s, 1H), 8.76 (d, J = 5.1 Hz, 1H), 7.82 (d, J = 5.1 Hz, 1H), 7.55-7.34 (m, 3H), 7.08-6.93 (m, 5H), 6.84-6.61 (m, 5H), 6.27 (d, J = 7.4 Hz, 1H), 5.35 (d, J=10.2Hz, 1H), 5.21-5.09 (m, 2H), 4.16 (t, J=5.2Hz, 2H), 3.76-3.72 (m, 4 H), 3.57-3.48 (m, 7H), 2.73 (t, J=5.2Hz, 2H), 2.55-2.50 (m, 5H), 1.54 (s, 3H)ppm.

[1484] LC / MS: m / z=874.3[M+H] + amu.

[1485] Synthesis of compound 43

[1486] Compound 43 was synthesized as follows: Following the general procedure for compound 42 and using the corresponding alcohol, compound 43 was obtained as an off-white amorphous solid.

[1487] 1 H NMR (400 MHz, methanol-d4): δ 9.12 (s, 1H), 8.76 (d, J = 5.3 Hz, 1H), 7.85 (d, J = 5.3 Hz, 1H), 7.54-7.46 (m, 2H), 7.38 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.08-6.95 (m, 5H), 6.83-6.76 (m, 2H), 6.73-6.60 (m, 3H), 6.26 (dd, J = 7.4, 1.8 Hz, 1H), 5.34 (dd, J = 10.5, 2.6Hz, 1H), 5.15 (d, J=4.1Hz, 2H), 4.55-4.45 (s, 2H), 4.17 (d, J=6.3Hz, 2H), 3.74 (s, 3H), 3.51 (s, 3H), 3.38 (dt, J=4.2, 2.1Hz, 1H), 2.77 (t, J=5.3Hz, 2H), 2.60-2.50 (m, 4H), 2.45 (dd, 1H, J=14.4, 10.4Hz), 1.79 (s, 3H), 1.50-1.40 (m, 4H)ppm.

[1488] LC / MS: m / z=872.3[M+H] + amu.

[1489] Synthesis of compound 44

[1490] Compound 44 was synthesized as follows: Following the general procedure for compound 42 and using the corresponding alcohol, compound 44 was obtained as an off-white amorphous solid.

[1491] 1H NMR (400MHz, methanol-d4): δ9.12 (s, 1H), 8.75 (d, J=5.3Hz, 1H), 7.79 (d, J=5.3Hz, 1H), 7.50 (dt, J=7.5, 1.6Hz, 1H ), 7.38 (ddd, J=8.4, 7.4, 1.8Hz, 1H), 7.07-6.95 (m, 4H), 6.82-6.75 (m, 2H), 6.68-6.56 (m, 3H), 6.46 (d, J=8.4 Hz, 1H), 6.37 (t, J=8.5Hz, 1H), 5.29 (dd, J=10.6, 2.5Hz, 1H), 5.16 (q, J=15.3Hz, 2H), 3.96-3.86 (m, 2H), 3.7 4 (s, 3H), 3.64-3.57 (m, 2H), 3.51 (s, 3H), 3.32-3.27 (m, 5H), 2.62 (dd, J=15.4, 10.6Hz, 1H), 1.81 (s, 3H)ppm.

[1492] LC / MS: m / z=819.2[M+H] + amu.

[1493] Synthesis of compound 45

[1494] Compound 45 was synthesized as follows: Following the general procedure for compound 42 and using the corresponding alcohol, compound 45 was obtained as an off-white amorphous solid.

[1495] 1 H NMR (400 MHz, methanol-d4): δ 9.12 (s, 1H), 8.77 (d, J = 5.3 Hz, 1H), 7.86 (d, J = 5.3 Hz, 1H), 7.54-7.45 (m, 2H), 7.41-7.35 (m, 1H), 7.09-6.95 (m, 5H), 6.84-6.77 (m, 2H), 6.73-6.62 (m, 3H), 6.24 (dd, J = 7.6, 1.7 Hz, 1 H), 5.33 (dd, J=10.5, 2.6Hz, 1H), 5.20-5.09 (m, 2H), 4.49 (s, 2H), 4.07 (d, J=6.1Hz, 2H), 3.74 (s, 3H) , 3.51 (s, 3H), 3.40-3.31 (m, 2H), 3.08-2.81 (m, 4H), 2.47-2.27 (m, 5H), 1.80 (s, 3H), 1.55 (s, 3H)ppm.

[1496] LC / MS: m / z = 886.3 [M+H] + amu.

[1497] Synthesis of compound 46

[1498] To the microwave bottle containing compound 4-3 (20mg, 0.025mmol), tetrahydrofuran (0.253mL, 0.1M) was added. To the stirred solution, 2-(dimethylamino)ethanol (0.010mL, 0.101mmol) and cyanomethylenetrimethylphosphorane (0.5M in THF, 0.506mL, 0.253mmol) were added. The reaction was stirred at 65°C for 12 hours and then allowed to cool to room temperature. Lithium hydroxide / water (1N, 0.200mL) was added to the crude reaction mixture and allowed to stir at room temperature for 12 hours. The reaction was quenched with acetic acid (0.200mL) and diluted with DMSO and purified by reverse phase chromatography (0.25% AcOH / water / 20-70% acetonitrile). The product fractions were collected and concentrated to produce compound 46, which was an off-white amorphous solid (5.4mg, 26% yield).

[1499] 1 H NMR (400 MHz, methanol-d4): δ 9.22 (s, 1H), 8.85 (d, J = 5.3 Hz, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.69-7.54 (m, 2H), 7.48 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.26-6.95 (m, 5H), 6.95-6.84 (m, 2H), 6.84-6.65 (m, 3H), 6.35 (dd, J = 7.5, 1.7 Hz, 1H), 5. 45 (dd, J = 10.6, 2.5 Hz, 1H), 5.34-5.14 (m, 2H), 4.68-4.49 (m, 1H), 4.29 (t, J = 5.2 Hz, 2H), 3.84 (s, 3H), 3.62 (s, 3H), 3.55-3.40 (m, 1H), 3.10-2.93 (m, J = 5.1 Hz, 2H), 2.66 (s, 1H), 2.52 (s, 6H), 1.91 (s, 3H) ppm (42 of 42 protons observed).

[1500] LC / MS: m / z=832.3[M+H] + amu.

[1501] Synthesis of compound 47

[1502] Compound 47 was synthesized as follows: Following the general procedure for compound 42 and using the corresponding alcohol, compound 47 was obtained as an off-white amorphous solid.

[1503] 1H NMR (400 MHz, methanol-d4): δ 9.12 (s, 1H), 8.77 (d, J = 5.2 Hz, 1H), 7.85 (d, J = 5.2 Hz, 1H), 7.51 (dd, J = 7.6, 1.8 Hz, 1H), 7.44-7.31 (m, 2H), 7.13-6.93 (m, 5H), 6.84-6.77 (m, 2H), 6.75-6.60 (m, 3H), 6.34 (dd, J = 7.6, 1.7 Hz, 1H), 5.38 (dd, J=10.0, 3.1Hz, 1H), 5.23-5.06 (m, 2H), 4.10 (dq, J=11.4, 5.9, 5.2Hz, 2H), 3.74 (s, 3H), 3.5 2 (s, 3H), 3.40-3.30 (m, 1H), 2.86 (t, J=7.6Hz, 2H), 2.55-2.40 (m, 7H), 2.09-1.94 (m, 2H), 1.81 (s, 3H)ppm.

[1504] LC / MS: m / z=846.3[M+H] + amu.

[1505] Synthesis of compound 48

[1506] Compound 48 was synthesized as follows: Following the general procedure for compound 42 and using the corresponding alcohol, compound 48 was obtained as an off-white amorphous solid.

[1507] 1 H NMR (400 MHz, methanol-d4): δ 9.12 (s, 1H), 8.76 (dd, J = 5.3, 3.1 Hz, 1H), 7.85 (t, J = 4.8 Hz, 1H), 7.55-7.45 (m, 2H), 7.38 (ddd, J = 8.9, 7.4, 1.8 Hz, 1H), 7.10-6.93 (m, 5H), 6.85-6.75 (m, 2H), 6.73-6.62 (m, 3H), 6.25 (dd, J=9.6, 7.4Hz, 1H), 5.40-5.30(m, 1H), 5.18-5.10(m, 2H), 4.49(s, 1H), 4.23-4.07(m, 1H), 3.74(s , 3H), 3.52 (d, J=3.5Hz, 3H), 3.42-3.34 (m, 1H), 2.73-2.27 (m, 5H), 1.80 (s, 5H), 1.62-1.42 (m, 4H)ppm.

[1508] LC / MS: m / z=858.3[M+H] + amu.

[1509] Synthesis of compound 49

[1510] Compound 49 was synthesized as follows: Following the general procedure for compound 42 and using the corresponding alcohol, compound 49 was obtained as an off-white amorphous solid.

[1511] 1 H NMR (400 MHz, methanol-d4): δ 9.12 (s, 1H), 8.77 (dd, J = 5.3, 1.2 Hz, 1H), 7.84 (dd, J = 15.1, 5.3 Hz, 1H), 7.57-7.49 (m, 2H), 7.47-7.35 (m, 2H), 7.09-6.93 (m, 5H), 6.84-6.76 (m, 2H), 6.73-6.62 (m, 3 H), 6.30-6.25(m, 1H), 5.44-5.29(m, 1H), 5.15(s, 2H), 4.51(s, 1H), 4.13-3.85(m, 1H), 3.74( s, 3H), 3.51 (s, 3H), 3.42-3.34 (m, 1H), 2.73-2.27 (m, 5H), 1.80 (s, 5H), 1.62-1.42 (m, 4H)ppm.

[1512] LC / MS: m / z=858.3[M+H] + amu.

[1513] Synthesis of compound 50

[1514] Compound 50 was synthesized as follows: Following the general procedure for compound 42 and using the corresponding alcohol, compound 50 was obtained as an off-white amorphous solid.

[1515] 1H NMR (400 MHz, methanol-d4): δ 9.13 (s, 1H), 8.69 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 5.2 Hz, 1H), 7.60-7.45 (m, 2H), 7.38 (ddd, J = 8.4, 7.4, 1.8 Hz, 1H), 7.13-6.87 (m, 5H), 6.83-6.66 (m, 4H), 6.64-6.57 (m, 1H), 6.19 (dd, J = 7.5, 1.7 Hz, 1H). z, 1H), 5.28 (dd, J=10.3, 2.7Hz, 1H), 5.18-4.95 (m, 2H), 4.33 (t, J=5.1Hz, 2H), 3.74 (s, 3H), 3.52 (s, 3H), 3. 46-3.38 (m, 2H), 3.35-3.28 (m, 1H), 3.20 (s, 4H), 2.45-2.29 (m, 1H), 1.88 (t, J=4.5Hz, 4H), 1.60 (s, 3H)ppm.

[1516] LC / MS: m / z=858.3[M+H] + amu.

[1517] Synthesis of compound 51

[1518] Compound 51 was synthesized as follows: Following the general procedure for compound 42 and using the corresponding alcohol, compound 51 was obtained as an off-white amorphous solid.

[1519] 1 H NMR (400 MHz, methanol-d4): δ 9.15 (s, 1H), 8.75 (d, J = 5.3 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.51 (dd, J = 7.6, 1.8 Hz, 1H), 7.44-7.32 (m, 2H), 7.16-6.94 (m, 5H), 6.88-6.79 (m, 2H), 6.78-6.65 (m, 3H), 6.31 (dd, J=7.6, 1.7Hz, 1H), 5.46 (dd, J=10.4, 2.8Hz, 1H), 5.16 (d, J=4.7Hz, 2H), 3.80 (s, 3H) , 3.74 (s, 3H), 3.52 (s, 3H), 3.43-3.27 (m, 2H), 2.43 (dd, J=14.3, 10.4Hz, 1H), 1.58 (s, 3H)ppm.

[1520] LC / MS: m / z = 775.2 [M+H] + amu.

[1521] Synthesis of compound 81

[1522] Compound 81 was synthesized by following the general procedure for compound 42 using the corresponding aryl-substituted boronate or acid in performing the procedure for compound 4-2 and using the corresponding alcohol in the final step to obtain compound 81 as an off-white amorphous solid.

[1523] 1 H NMR (400MHz, methanol-d4): δ9.12 (s, 1H), 8.77 (d, J = 5.2Hz, 1H), 7.86 (d, J = 5.2Hz, 1H), 7.53-7.47 (m, 2H), 7.42-7.35 (m, 1H), 7.20 (d d, J=8.8, 5.4Hz, 2H), 7.06 (d, J=8.4Hz, 1H), 7.02-6.95 (m, 4H), 6.86 (t, J=8.8Hz, 2H), 6.78 (d, J=8.2Hz, 1H), 6.65 (t, J=7.4Hz, 1H), 6.21 (d, J=6.9Hz, 1H), 5.32 (dd, J=10.6, 2.6Hz, 1H), 5.23-5.09 (m, 2H), 4.49 (s, 5H), 4.09 (d, J=5.0Hz, 2H), 3.74 (s, 4H), 3 .44-3.33 (m, 3H), 3.03 (p, J=1.6Hz, 2H), 2.39 (dd, J=14.3, 10.5Hz, 1H), 2.30 (s, 2H), 1.80 (s, 6H), 1.64 (s, 2H), 1.53 (s, 3H)ppm.

[1524] LC / MS: m / z=874.3[M+H] + amu.

[1525] Synthesis of compound 102

[1526] Compound 102 was synthesized by following the general procedure for compound 42 using the corresponding aryl-substituted boronic ester or acid in performing the procedure for compound 4-2 and using the corresponding alcohol in the final step to obtain compound 102 as an off-white amorphous solid.

[1527] 1H NMR (400MHz, methanol-d4): δ9.20 (s, 1H), 8.75 (d, J=5.3Hz, 1H), 8.02-7.90 (m, 1H), 7.72 (d, J=5.3Hz, 1H), 7.53 ( dd, J=7.6, 1.7Hz, 1H), 7.47-7.20 (m, 3H), 7.20-6.83 (m, 11H), 6.73 (t, J=7.4Hz, 1H), 6.30 (d, J=7.6Hz, 1H), 5.45 (dd, J=10.1, 3.2Hz, 1H), 5.26-5.06 (m, 2H), 4.12 (dt, J=10.8, 5.9Hz, 2H), 3.75 (s, 3H), 3.38 (p, J=1.7H z, 1H), 3.03 (p, J=1.6Hz, 1H), 2.91 (d, J=11.4Hz, 1H), 2.85-2.63 (m, 5H), 2.41 (dd, J=14.0, 10.1Hz, 1H) ppm.

[1528] LC / MS: m / z=874.3[M+H] + amu.

[1529] Synthesis of compound 107

[1530] Compound 107 was synthesized by first deprotecting compound 4-1 following the general procedure for compound 4-3, then using the resulting product and the corresponding alcohol to follow the first step (i.e., step "i") for synthesizing compound 42, and finally using this product and cyclobutylzinc bromide to follow the general procedure for synthesizing compound 29. Compound 107 was obtained as an off-white solid.

[1531] LC / MS: m / z = 723.2 [M+H] + amu.

[1532] Synthesis of compound 108

[1533] Compound 108 was synthesized as follows: first, deprotection of compound 4-1 was performed following the general procedure for compound 4-3, then the resulting product and the corresponding alcohol were used to follow the first step (i.e., step "i") of synthesizing compound 42, and finally, the product and cyclobutylzinc bromide were used to follow the general procedure for synthesizing compound 29. Compound 108 was obtained as an off-white solid.

[1534] LC / MS: m / z = 822.3 [M+H] + amu.

[1535] Synthesis of compound 105

[1536]

[1537] To a vial containing compound 108 (46.0 mg, 0.060 mmol) was added cesium carbonate (36.5 mg, 0.110 mmol). The solid was dissolved in dimethylformamide (2.24 mL). To the stirred solution was added 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (14.1 mg, 0.100 mmol). The capping reaction was heated to 50 ° C for 1 hour, allowed to cool to room temperature and poured into a separatory funnel containing water (1 mL). The organic phase was separated, and the aqueous phase was washed with dichloromethane (2 mL, 2 times), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0 to 20% methanol / dichloromethane). The product fractions were collected and concentrated to produce compound 105, which was an off-white oil.

[1538] 1 H NMR (400MHz, methanol-d4): δ9.23 (s, 1H), 8.86 (d, J=5.2Hz, 1H), 7.68 (d, J=5.2Hz, 1H), 7.62 (dd, J=7.6, 1.8Hz, 1H), 7.47 (ddd, J=8.3, 7.4, 1.8Hz, 1H), 7.20 (ddd , J=8.2, 7.4, 1.7Hz, 1H), 7.15 (dd, J=8.5, 1.0Hz, 1H), 7.12-7.08 (m, 2H), 7.0 6(td, J=7.5, 0.9Hz, 1H), 6.98 (dd, J=8.4, 1.1Hz, 1H), 6.88 (td, J=7.5, 1.1Hz, 1H), 6.61 (dd, J=7.5, 1.7Hz, 1H), 5.56 (dd, J=9.0, 4.8Hz, 1H), 5.34-5.14 (m, 2H), 4.35-4.21(m, 2H), 3.83(s, 3H), 3.69-3.60(m, 4H), 3.60-3.50(m, 1H), 3. 12 (dd, J = 13.9, 4.8 Hz, 1H), 2.96-2.79 (m, 2H), 2.75-2.60 (m, 5H), 2.56-2.35 (m, 2H), 2.15 (s, 2H), 2.08-1.97 (s, 5H), 1.95-1.73 (m, 5H) (48 of 48 protons observed).

[1539] LC / MS: m / z = 934.3 [M+H] + amu.

[1540] Synthesis of compound 106

[1541]

[1542] To a vial containing compound 107 (75.0 mg, 0.10 mmol) was added cesium carbonate (67.6 mg, 0.210 mmol). The solid was dissolved in dimethylformamide (4.18 mL). To the stirred solution was added 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (26.2 mg, 0.18 mmol). The capping reaction was heated to 50 ° C for 1 hour, allowed to cool and poured into a separatory funnel containing water (1 mL). The organic phase was separated and the aqueous phase was washed with dichloromethane (2 mL, 2 times). The organic phase was separated and the aqueous phase was washed with dichloromethane (2 mL, 2 times), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0 to 20% methanol / dichloromethane). The product fractions were collected and concentrated to produce compound 106, which was an off-white oil.

[1543] 1 H NMR (500MHz, methanol-d4): δ9.23 (s, 1H), 8.86 (d, J=5.2Hz, 1H), 7.97 (s, 4H), 7.69 (d, J=5.2Hz, 1H), 7.61 (dd, J=7.5, 1.8Hz, 1H), 7.56-7.4 5 (m, 1H), 7.23-7.13 (m, 2H), 7.11-7.03 (m, 3H), 6.97 (d, J=8.2Hz, 1H), 6.88 (t, J=7.5Hz, 1H), 6.60 (dd, J=7.3, 1.7Hz, 1H), 5.59 (dd, J =9.2, 4.5 Hz, 1H), 5.32-5.18 (m, 2H), 4.95 (d, J=14.0 Hz, 1H), 4.85 (d, J=14.0 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.54 (p, J=8.7 Hz, 1H), 3.14 (dd, J=13.8, 4.7 Hz, 1H), 2.74-2.64 (m, 1H), 2.55-2.34 (m, 2H), 2.16 (s, 1H), 2.06 (s, 3H), 2.04-1.96 (m, 2H) (39 of 39 protons observed).

[1544] LC / MS: m / z=835.2[M+H] + amu.

[1545] Synthesis of compound 120

[1546]

[1547] To a vial containing compound 36 (60.0 mg, 0.072 mmol) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (19.3 mg, 0.110 mmol), 1-hydroxybenzotriazole hydrate (13.6 mg, 0.100 mmol), and 4-(dimethylamino)pyridine (12.3 mg, 0.100 mmol). The solid was dissolved in dimethylformamide (0.720 mL). To the stirred solution was added 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (14.0 mg, 0.108 mmol). The reaction was capped and stirred at 23 ° C for 1 hour. After the reaction was complete, the reaction was poured into a separatory funnel containing water (1 mL). The organic phase was separated and the aqueous phase was washed with dichloromethane (2 mL, 2 times). The combined organic extracts were concentrated to dryness. The crude reaction mixture was purified via reverse phase chromatography (0-60% acetonitrile / water containing 0.025% AcOH).Product fractions were pooled and concentrated to yield compound 120 as a white solid.

[1548] 1 H NMR (400MHz, methanol-d4): δ9.24 (s, 1H), 8.87 (d, J=5.2Hz, 1H), 7.69 (d, J=5.2Hz, 1H), 7.62 (dd, J=7.5, 1.8Hz, 1H), 7.55-7.39 (m, 1H), 7.25-7.18 (m, 1H), 7.18-7.14 (m, 1H), 7.13-7.03 (m, 3H), 7.03-6.96 (m, 1H), 6.89 (td, J=7.4, 1.0Hz, 1H), 6.62 (dd, J=7.5, 1.7Hz, 1H), 5.56 (dd, J = 9.0, 4.8 Hz, 1H), 5.37-5.15 (m, 3H), 4.59 (s, 2H), 4.30 (qt, J = 10.4, 5.0 Hz, 3H), 3.84 (s, 4H), 3.59-3.45 (m, 1H), 3.18-3.06 (m, 2H), 2.93 (t, J = 5.2 Hz, 3H), 2.87-2.54 (m, 8H), 2.54-2.31 (m, 6H), 2.05 (s, 3H), 1.97-1.91 (m, 2H) (51 of 51 protons observed).

[1549] LC / MS: m / z = 947.3 [M+H] + amu.

[1550] Example 5: Synthesis of Intermediate 5-1, Compound 5-1, and Compounds 55 and 56

[1551] Synthetic intermediate 5-1

[1552]

[1553] To a mixture of 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 g, 3.72 mmol), triphenylphosphine (1.4 g, 5.59 mmol) and 2-(dimethylamino)ethanol (0.45 mL, 4.47 mmol) in toluene (12 mL) was added di-tert-butyl azodicarboxylate (1.3 g, 5.59 mmol) in toluene (6 mL) dropwise to the stirred reaction solution. The reaction was stirred at 23° C. for 2 hours, at which time LC / MS analysis showed complete conversion to the desired product (LC / MS: m / z=340.1 [M+H] + amu).

[1554] The reaction was stopped and concentrated onto silica gel. Silica gel chromatography (0-15% methanol / dichloromethane) was performed. Product fractions were pooled and concentrated to give Intermediate 5-1 as a clear oil (0.555 g, 44% yield).

[1555] Synthesis of compound 5-1

[1556]

[1557] To a flask containing compound 3-2 (0.400 mg, 0.57 mmol) was added intermediate 5-1 (0.203 g, 0.60 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (20 mg, 0.029 mmol) and tribasic potassium phosphate (0.362 g, 1.71 mmol). The solid was dissolved in degassed 1,4-dioxane (1.75 mL) and deionized water (0.88 mL). The reaction was stirred at 60°C for 12 hours, allowed to cool and poured into a separatory funnel containing water (3 mL). The organic phase was separated and the aqueous phase was washed with dichloromethane (5 mL, 2 times). The combined organic extracts were concentrated onto silica gel. Silica gel chromatography (0-20% methanol / dichloromethane) was performed. The product fractions were pooled and concentrated to give compound 5-1 as a yellow solid and a mixture of diastereomers (LC / MS: m / z=788.2 [M+H] + amu).

[1558] Synthesis of compound 55

[1559] Compound 55 was synthesized by following the general procedure for compound 7, using compound 5-1 and the corresponding aryl-substituted boronate or acid as starting materials to obtain compound 55 as an off-white solid.

[1560] 1H NMR (400 MHz, methanol-d4): δ 9.24 (s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 5.2 Hz, 1H), 7.68-7.54 (m, 2H), 7.48 (ddd, J = 9.0, 7.5, 1.8 Hz, 1H), 7.26-7.11 (m, 3H), 7.11-7.02 (m, 2H), 7.02-6.93 (m, 3H), 6.80 (d, J = 8.1 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H). , 1H), 6.24 (dd, J = 7.5, 1.6 Hz, 1H), 5.38 (dd, J = 10.4, 2.4 Hz, 1H), 5.22-5.04 (m, 2H), 4.47-4.36 (m, 2H), 3.84 (s, 3H), 3.39 (d, J = 13.9 Hz, 1H), 2.76 (s, 6H), 2.44 (dd, J = 14.1, 10.5 Hz, 1H), 1.93 (s, 3H), 1.66 (s, 3H) ppm (39 of 39 protons observed).

[1561] LC / MS: m / z=820.3[M+H] + amu.

[1562] Synthesis of compound 56

[1563] Compound 56 was synthesized by using compound 5-1 and cyclopropylzinc bromide as starting materials and following the general procedure for synthesizing compound 29. Compound 56 was obtained as an off-white solid.

[1564] 1H NMR (500MHz, methanol-d4): δ9.03 (s, 1H), 8.82 (d, J=5.3Hz, 1H), 7.84 (d, J=5.3Hz, 1H), 7.64 (dd, J=7.5, 1.8Hz, 1H), 7.57-7.47 (m, 1H), 7.34 ( d, J=8.5Hz, 1H), 7.28-7.22 (m, 1H), 7.20-7.15 (m, 2H), 7.08 (t, J=7.5Hz, 1H), 6.99 (d, J=8.2Hz, 1H), 6.91 (t, J=7.4Hz, 1H), 6.48 (dd, J= 7.6, 1.7 Hz, 1H), 5.56 (dd, J = 10.2, 2.9 Hz, 1H), 5.28 (q, J = 15.0 Hz, 2H), 4.58-4.50 (m, 2H), 3.85 (s, 3H), 3.74-5.68 (m, 3H), 3.48-3.39 (m, 1H), 3.08 (m, 4H), 2.44 (dd, J = 13.9, 10.2 Hz, 1H), 2.06 (s, 3H), 1.77-1.62 (m, 1H), 1.29 (s, 2H), 1.16-0.74 (m, 4H) ppm (40 of 40 protons observed).

[1565] LC / MS: m / z = 766.2 [M+H] + amu.

[1566] Example 6: Synthesis of Intermediate 6-1, Compound 6-1, Compound 6-2, Compounds 57 to 63 and Compound 104

[1567] Synthetic intermediate 6-1

[1568]

[1569] Step 1

[1570] 2-chloropyrimidine-4-carboxylic acid methyl ester (5.g, 28.97mmol) and methanol (100mL) were added to a 250mL flask dried in a stove. The resulting mixture was cooled to 0°C and subsequently LiBH (16.mL, 32mmol) was added dropwise via an addition funnel. The reaction was allowed to warm to ambient temperature and continued for one hour. The mixture was quenched with water (2mL) and the solvent was removed under reduced pressure. The resulting residue was distributed between EtOAc (80mL) and water (40mL). The aqueous layer was extracted with 20% iPrOH / CHCl (2x40mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography to provide the desired product, which was a yellow solid.

[1571] 1H NMR (300MHz, CDCl3): δ8.63 (dd, J=5.1, 0.6Hz, 1H), 7.39 (dt, J=5.1, 0.7Hz, 1H), 4.81 (d, J=0.8Hz, 2H) ppm.

[1572] LC / MS: m / z = 145.3 [M+H] + amu.

[1573] Step 2

[1574] To a 250 mL flask containing (2-chloropyrimidin-4-yl)methanol (2.6 g, 17.99 mmol) was added carbon tetrabromide (8.95 g, 26.98 mmol) and DCM (104 mL). The resulting mixture was cooled to 0°C. Triphenylphosphine (9.43 g, 35.97 mmol) in DCM (15 mL) was added to the mixture. The ice bath was removed; the reaction mixture was allowed to warm to ambient temperature. After 45 minutes, the mixture was adsorbed onto silica and purified by silica gel chromatography to provide the desired product as a light brown liquid.

[1575] 1 H NMR (300MHz, CDCl3): δ8.67 (d, J=5.0Hz, 1H), 7.58-7.37 (m, 1H), 4.44 (s, 2H)ppm.

[1576] LC / MS: m / z = 207.2 [M+H] + amu.

[1577] Step 3

[1578] To a mixture of (2S)-2-[tert-butyl(dimethyl)silyl]oxy-3-(2-hydroxyphenyl)propanoate (3.91 g, 12.05 mmol) and KCO (3.33 g, 24.1 mmol) in DMF (60 mL) was added 4-(bromomethyl)-2-chloro-pyrimidine (2.5 g, 12.05 mmol) / DMF (20 mL). The resulting mixture was stirred at ambient temperature under an inert atmosphere for 12 hours, at which point the mixture was distributed between EtOAc (70 mL) and water (30 mL). The organic layer was washed with water (2x20 mL), brine (10 mL), dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography to provide the desired product as a white solid.

[1579] 1H NMR (300MHz, CDCl3) δ8.71 (d, J=5.1Hz, 1H), 7.77 (dt, J=5.1, 0.9Hz, 1H), 7.24 (ddd, J=6.8, 5.3, 1.8Hz, 2H), 6.98 (td, J=7.5, 1.1Hz, 1H), 6.84 (d, J=8.3Hz, 1H), 5.18 (t, J=1.1Hz, 2H), 4 .51 (dd, J=9.6, 3.7Hz, 1H), 4.23 (qd, J=7.1, 2.6Hz, 2H), 3.36 (dd, J=13.2, 3.7Hz, 1H), 2.92 ( dd, J=13.2, 9.6Hz, 1H), 1.31 (t, J=7.1Hz, 3H), 0.77 (s, 9H), -0.14 (s, 3H), -0.26 (s, 3H)ppm.

[1580] LC / MS: m / z = 451.2 [M+H] + amu.

[1581] Step 4

[1582] To a solution of ethyl (2S)-2-[tert-butyl(dimethyl)silyl]oxy-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]propanoate (120 mg, 0.2700 mmol) in MeCN (2 mL) was added 2,2-difluoroethanol (0.5 mL, 7.11 mmol) and KCO (73.54 mg, 0.5300 mmol). The resulting mixture was heated at 60° C. under an inert atmosphere for 17 hours. The mixture was cooled to ambient temperature, quenched with water (5 mL), partitioned between EtOAc (40 mL) and water (20 mL), and extracted with EtOAc (20 mL). The combined organic layers were dried over MgSO , filtered, and concentrated under reduced pressure and used without further purification.

[1583] 1H NMR (300MHz, CDCl3): δ8.58 (d, J=5.0Hz, 1H), 7.43 (d, J=5.0Hz, 1H), 7.27-7.18 (m, 2H), 6.96 ( dd, J=8.1, 7.1Hz, 1H), 6.84 (d, J=8.3Hz, 1H), 5.12 (s, 2H), 4.64 (t, J=6.7Hz, 2H), 4.53 (dd, J=9 .5, 3.9Hz, 1H), 4.28-4.18 (m, 2H), 3.37 (dd, J=13.1, 3.9Hz, 1H), 2.92 (dd, J=13.1, 9.5Hz, 1H) , 2.80-2.63 (m, 2H), 1.34-1.26 (m, 3H), 0.77 (d, J=0.4Hz, 9H), -0.14 (s, 3H), -0.26 (s, 3H)ppm.

[1584] 19 F NMR (282MHz, CDCl3): δ-62.99--66.90(m).

[1585] LC / MS: m / z=529.1[M+H] + amu.

[1586] Step 5

[1587] To a solution of ethyl (2S)-2-[tert-butyl(dimethyl)silyl]oxy-3-[2-[[2-(3,3,3-trifluoropropoxy)pyrimidin-4-yl]methoxy]phenyl]propanoate (110 mg, 0.2100 mmol) in THF (2 mL) was added tert-butylammonium fluoride solution (1 M in THF, 0.33 mL, 0.3300 mmol). The resulting mixture was stirred at ambient temperature. The reaction mixture was then purified by silica gel chromatography to provide intermediate 6-1 as a white foam.

[1588] 1H NMR (300MHz, CDCl3): δ8.56 (d, J=5.0Hz, 1H), 7.33 (dd, J=5.0, 0.7Hz, 1H), 7.25 (t, J=7.0Hz, 2H), 6.99 (t, J=7.4Hz, 1H), 6.84 (d, J=8.5Hz, 1H), 5.14 (s, 2H), 4.69-4.61 (m, 2H), 4.56 (dd, J=8.2, 4.7Hz, 1H), 4.32-4.15 (m, 2H), 3.33 (dd, J=13.7, 4.7Hz, 1H ), 3.04 (dd, J=13.7, 8.2Hz, 1H), 2.80-2.57 (m, 2H), 1.28 (td, J=7.2, 0.6Hz, 3H) ppm.

[1589] 19 F NMR (282MHz, CDCl3): δ-64.80 (t, J=10.6Hz).

[1590] LC / MS: m / z = 415.1 [M+H] + amu.

[1591] Synthesis of compound 57

[1592]

[1593]

[1594] Compound 6-1 was synthesized as follows: using compound A9, intermediate 6-1, and following the general procedure for synthesizing compound 3-2. Then, compound 6-2 was synthesized as follows: using compound B-6, compound 6-1, and following the general procedure for synthesizing compound 3-3. Compound 57 was synthesized as follows: using compound 6-2 and following the general procedure for synthesizing compound 39.

[1595] 1H NMR (300MHz, methanol-d4): δ9.33 (s, 1H), 8.62 (d, J = 5.1Hz, 1H), 7.53 (d, J = 5.1Hz, 1H), 7.44 (d, J = 8.5Hz, 1H), 7.24-7.13 (m, 3H ), 6.95 (dd, J=9.8, 8.3Hz, 2H), 6.90-6.78 (m, 3H), 6.41 (d, J=6.2Hz, 1H), 5.59 (dd, J=10.2, 3.1Hz, 1H), 5.19 (d, J=6.3Hz, 2 H), 4.98 (ddtd, J=4.0, 1.6, 0.8, 0.4Hz, 2H), 4.93-4.87 (m, 1H), 4.67 (t, J=6.2Hz, 2H), 4.35 (t, J=5.0Hz, 2H), 3.68 (s, 3H) , 3.44-3.38 (m, 3H), 3.33-3.21 (m, 3H), 3.10 (t, J=4.7Hz, 3H), 2.86 (s, 3H), 2.77 (dt, J=10.9, 6.1Hz, 2H), 1.78 (s, 3H)ppm.

[1596] 19 F NMR (282 MHz, methanol-d4): δ -66.31 (t, J = 10.9 Hz), -77.37.

[1597] LC / MS: m / z=893.1[M+H] + amu.

[1598] Synthesis of compound 58

[1599] Compound 58 was synthesized by following the general procedure for intermediate 6-1 using the corresponding fluorinated alcohol and then following the general procedure for compound 57. Compound 58 was obtained as an amorphous off-white solid.

[1600] 1H NMR (300MHz, methanol-d4): δ9.31 (s, 1H), 8.62 (d, J = 5.1Hz, 1H), 7.55 (d, J = 5.1Hz, 1H), 7.41 (d, J = 8.5Hz, 1H), 7.22-7.11(m, 3H), 6.98-6.88(m, 2H), 6.87-6.78(m, 3H), 6.44-6.02(m, 4H), 5.56(dd, J=10.2, 3.0Hz, 1H ), 5.18 (d, J = 6.2Hz, 2H), 4.64 (td, J = 14.0, 3.9Hz, 2H), 4.32 (t, J = 4.6Hz, 2H), 3.66 (s, 3H), 3.46-3.33 (m , 4H), 3.29-3.18 (m, 3H), 3.11-3.01 (m, 3H), 2.84 (s, 3H), 2.48 (dd, J=13.9, 10.2Hz, 2H), 1.76 (s, 3H)ppm.

[1601] 19 F NMR (282 MHz, methanol-d4): δ -77.34.

[1602] LC / MS: m / z = 860.3 [M+H] + amu.

[1603] Synthesis of compound 59

[1604] Compound 59 was synthesized by following the general procedure for intermediate 6-1 using the corresponding fluorinated alcohol and then following the general procedure for compound 57. Compound 59 was obtained as an amorphous off-white solid.

[1605] 1H NMR (300MHz, methanol-d4): δ9.30 (s, 1H), 8.57 (d, J = 5.1Hz, 1H), 7.47 (d, J = 5.1Hz, 1H), 7.41 (d, J = 8.5Hz, 1H), 7.22-7.10 (m, 3H), 6 .92 (t, J=8.3Hz, 2H), 6.84 (d, J=9.6Hz, 2H), 6.39 (d, J=6.8Hz, 1H), 5.56 (dd, J=10.1, 3.0Hz, 1H), 5.29-5.21 (m, 1H), 5.15 (d, J =6.0Hz, 1H), 4.89-4.84 (m, 1H), 4.47 (t, J = 6.2Hz, 2H), 4.36-4.29 (m, 3H), 4.17 (ddd, J = 12.0, 6.1, 1.9Hz, 2H), 3.66 (s, 2H), 3 .04 (t, J=5.1Hz, 2H), 2.83 (s, 2H), 2.35 (t, J=7.3Hz, 3H), 2.08-2.04 (m, 4H), 2.03 (s, 2H), 1.53 (s, 3H), 0.94-0.88 (m, 3H)ppm.

[1606] 19 F NMR (282 MHz, methanol-d4): δ -68.00 (t, J = 11.1 Hz).

[1607] LC / MS: m / z = 906.3 [M+H] + amu.

[1608] Synthesis of compound 60

[1609] Compound 60 was synthesized by following the general procedure for intermediate 6-1 using the corresponding electrophile, and then following the general procedure for compound 57. Compound 60 was obtained as an amorphous off-white solid.

[1610] 1H NMR (300MHz, methanol-d4): δ9.30 (s, 1H), 8.32 (d, J = 5.1Hz, 1H), 7.39 (d, J = 8.6Hz, 1H), 7.21-7.08 (m, 3H), 6.94 (d, J = 5.1Hz, 1H), 6.92 -6.86 (m, 2H), 6.85-6.73 (m, 3H), 6.41-6.32 (m, 1H), 5.56 (dd, J=10.1, 3.2Hz, 1H), 5.02 (t, J=3.9Hz, 2H), 4.84 (d, J=5.2Hz, 1H), 4.33 (t, J=4.8Hz, 2H), 3.99-3.89 (m, 3H), 3.64 (s, 3H), 3.39-3.32 (m, 2H), 3.25 (d, J=8.0Hz, 3H), 3.10 (q, J=8.4, 6.8Hz, 3H), 2.8 3 (s, 3H), 2.44 (dd, J=13.8, 10.2Hz, 1H), 2.25-2.14 (m, 1H), 2.06-1.84 (m, 4H), 1.74 (s, 3H), 1.51-1.44 (m, 1H), 1.29 (s, 2H)ppm.

[1611] 19 F NMR (282 MHz, methanol-d4): δ -77.42.

[1612] LC / MS: m / z = 900.2 [M+H] + amu.

[1613] Synthesis of compound 61

[1614] Compound 61 was synthesized by following the general procedure for intermediate 6-1 using the corresponding electrophile, and then following the general procedure for compound 57. Compound 61 was obtained as an amorphous off-white solid.

[1615] 1H NMR (300MHz, methanol-d4): δ9.32 (s, 1H), 8.31 (d, J = 5.1Hz, 1H), 7.39 (d, J = 8.6Hz, 1H), 7.22-7.07 (m, 3H), 6.95 (d, J = 5.1H) z, 1H), 6.89 (d, J=7.9Hz, 2H), 6.86-6.74 (m, 3H), 6.42-6.34 (m, 1H), 5.56 (dd, J=10.0, 3.3Hz, 1H), 5.03 (d, J=3.4Hz, 2H), 4.35 (t, J=4.7Hz, 2H), 4.08 (t, J=11.9Hz, 2H), 3.97 (s, 1H), 3.85 (t, J=5.5Hz, 2H), 3.65 (s, 3H), 3.39-3.33 (m, 2 H), 3.18 (d, J=5.2Hz, 5H), 2.84 (s, 3H), 2.52-2.45 (m, 1H), 2.18-1.97 (m, 3H), 1.75 (s, 5H), 1.29 (d, J=2.4Hz, 2H) ppm.

[1616] 19 F NMR (282 MHz, methanol-d4): δ -77.53 (s).

[1617] LC / MS: m / z = 900.3 [M+H] + amu.

[1618] Synthesis of compound 62

[1619] Compound 62 was synthesized by following the general procedure for intermediate 6-1 using the corresponding electrophile, and then following the general procedure for compound 57. Compound 62 was obtained as an amorphous off-white solid.

[1620] 1H NMR (300MHz, methanol-d4): δ9.29 (s, 1H), 8.23 ​​(dd, J=5.7, 3.2Hz, 1H), 7.27-7.07 (m, 3H), 6.98 (d, J=5.7Hz, 1H), 6.93-6.83 (m, 3H), 6.80-6.69 (m, 3 H), 6.34 (dd, J=7.4, 1.7Hz, 1H), 5.46 (dd, J=9.6, 3.5Hz, 1H), 5.13-5.01 (m, 2H), 4.46-4.36 (m, 1H), 4.33-4.16 (m, 2H), 3.76 (t, J=5.0Hz, 2H), 3.66 (s, 2H), 3.57-3.46 (m, 2H), 3.44-3.32 (m, 2H), 3.28 (dd, J=0.4Hz, 3H), 3.09 (q, J=4.3, 3.8Hz, 3H), 2.84 (d, J=4.3Hz, 3H), 2.65 (s, 2H), 2. 50 (dd, J=14.1, 9.6Hz, 1H), 2.37 (s, 2H), 2.05-1.94 (m, 1H), 1.65 (q, J=5.9Hz, 2H), 1.53-1.44 (m, 2H), 1.29 (s, 3H), 0.90 (d, J=8.1Hz, 5H) ppm.

[1621] LC / MS: m / z = 892.3 [M+H] + amu.

[1622] Synthesis of compound 63

[1623] Compound 63 was synthesized by following the general procedure for intermediate 6-1 using the corresponding electrophile, and then following the general procedure for compound 57. Compound 63 was obtained as an amorphous off-white solid.

[1624] 1H NMR (300MHz, methanol-d4): δ9.33 (s, 1H), 8.30 (d, J=5.2Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.22-7.09 (m, 3H), 6.97 (d, J=5.3Hz , 1H), 6.93-6.86 (m, 2H), 6.85-6.72 (m, 3H), 6.47 (s, 1H), 6.37 (d, J=7.5Hz, 1H), 6.22 (s, 1H), 5.58 (dd, J=10.2, 3.3Hz, 1H), 5.07 (d, J=3.8Hz, 2H), 4.42 (d, J=3.9Hz, 1H), 4.35 (t, J=4.8Hz, 2H), 4.14 (d, J=10.8Hz, 3H), 3.66 (s, 3H), 3.59 (t , J=11.9Hz, 3H), 3.36 (s, 3H), 3.13 (s, 5H), 2.85 (s, 3H), 2.54-2.40 (m, 1H), 1.95 (s, 3H), 1.76 (s, 3H), 1.69 (s, 2H)ppm.

[1625] 19 F NMR (282 MHz, methanol-d4): δ -77.56 (s).

[1626] LC / MS: m / z = 930.3 [M+H] + amu.

[1627] Synthesis of compound 104

[1628] Compound 104 was synthesized using the general procedure for compound 57, except that cyclobutylzinc bromide and the general procedure for compound 29 were used instead of the fluorinated alcohol and the procedure for the synthesis of intermediate 6-1 in step 4 of the synthesis of intermediate 6-1, and cyclobutylzinc bromide and the general procedure for the synthesis of compound 29 were used in the final step of the synthesis of compound 104. Compound 104 was obtained as an off-white solid.

[1629] 1H NMR (400MHz, methanol-d4): δ9.26 (s, 1H), 8.69 (d, J=5.2Hz, 1H), 7.67 (d, J=5.3Hz, 1H), 7.27-7.10 (m, 3H), 7 .01-6.95 (m, 1H), 6.90 (td, J=7.4, 1.0Hz, 1H), 6.54 (dd, J=7.5, 1.7Hz, 1H), 5.55 (dd, J=10.0, 3.3Hz, 1H ), 5.33-5.09 (m, 2H), 4.45-4.27 (m, 2H), 3.90-3.72 (m, 1H), 3.59-3.44 (m, 1H), 3.38-3.32 (m, 1H), 3.28-2.96 (m, 6H), 2.84 (s, 3H), 2.59-2.30 (m, 8H), 2.19-2.02 (m, 2H), 2.01-1.81 (m, 8H) (44 of 47 protons observed).

[1630] LC / MS: m / z=783.3[M+H] + amu.

[1631] Example 7: Synthesis of Intermediate 7-1, Compound 7-1, Compound 7-2, Compound 7-3, Compound 7-4, Compounds 64 to 68, Compounds 71 ​​to 74, Compounds 112 to 116, Compound 119, and Compounds 121, 122, and 124 to 126

[1632] Synthetic intermediate 7-1

[1633]

[1634] To a solution of ethyl (2S)-2-[tert-butyl(dimethyl)silyl]oxy-3-[2-[(2-chloropyrimidin-4-yl)methoxy]phenyl]propanoate (85 mg, 0.1900 mmol; see procedure step 1-3 for the synthesis of Intermediate 6-1) in 1,4-dioxane (6 mL) was added (2-methoxy-3-pyridyl)boronic acid (57.65 mg, 0.3800 mmol), Pd(dppf)Cl2 (13.79 mg, 0.0200 mmol), Cs2CO3 (122.8 mg, 0.3800 mmol), and water (1.5 mL). The resulting mixture was heated at 80°C under an inert atmosphere. After 2 hours, the mixture was cooled to ambient temperature and then partitioned between EtOAc (40 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (20 mL), the combined organic layers were dried over MgSO 4 , filtered and concentrated, and the crude residue was purified by silica gel chromatography to provide intermediate 7-1 as a light brown solid.

[1635] 1 H NMR (300MHz, CDCl3): δ8.95 (d, J=5.1Hz, 1H), 8.33 (dd, J=5.0, 2.0Hz, 1H), 8.15 (dd, J=7.4, 2.0Hz, 1H), 7.73 (d, J =5.0Hz, 1H), 7.25 (ddd, J=7.6, 6.1, 1.7Hz, 2H), 7.07 (dd, J=7.4, 5.0Hz, 1H), 7.01-6.94 (m, 1H), 6.91 (d, J=8.2Hz, 1H), 5.27 (d, J=1.4Hz, 2H), 4.57 (dd, J=9.6, 3.8Hz, 1H), 4.25 (qd, J=7.1, 2.1Hz, 2H), 4.07 (s, 3H), 3.42 (dd, J=13 .2, 3.8Hz, 1H), 2.93 (dd, J=13.1, 9.6Hz, 1H), 1.32 (t, J=7.1Hz, 3H), 0.78 (s, 9H), -0.13 (s, 3H), -0.25 (s, 3H)ppm.

[1636] LC / MS: m / z=524.1[M+H] + amu.

[1637] Synthesis of compound 64

[1638]

[1639]

[1640] Intermediate 7-2 was synthesized as follows: using intermediate 7-1 and following the general procedure for synthesizing intermediate 6-1, step 5. Compound 7-1 was synthesized as follows: using compound A9, intermediate 7-2, and following the general procedure for synthesizing compound 3-2. Then, compound 7-2 was synthesized as follows: using compound B-6, compound 7-1, and following the general procedure for synthesizing compound 3-3. Compound 64 was synthesized as follows: using compound 7-2 and following the general procedure for synthesizing compound 35.

[1641] 1H NMR (300MHz, methanol-d4): δ9.30 (s, 1H), 8.86 (d, J=5.3Hz, 1H), 8.28 (dd, J=5.0, 2.0Hz, 1H), 8.11 (dd, J=7.4, 2.0Hz, 1H), 7.81 (d, J=5.3Hz, 1H), 7.31-6.94 (m, 10H), 6.86 (d, J=8.5Hz, 1H), 6.77 (dt, J=7 .5, 3.3Hz, 3H), 6.40 (d, J=6.8Hz, 1H), 5.54-5.41 (m, 1H), 5.27 (d, J=2.3Hz, 3H), 4.25 (d, J=5.4Hz , 3H), 3.98 (s, 5H), 3.46-3.32 (m, 10H), 3.26-2.96 (m, 3H), 2.85 (d, J=5.6Hz, 5H), 2.37 (s, 4H)ppm.

[1642] LC / MS: m / z=876.2[M+H] + amu.

[1643] Synthesis of compound 65

[1644] Compound 65 was synthesized by following the general procedure for compound 64, using the corresponding aryl-substituted boronate or acid when performing the general procedure for intermediate 7-1, and using the corresponding aryl-substituted boronate or acid when performing the general procedure for compound 35. Compound 65 was obtained as an amorphous off-white solid.

[1645] 1 H NMR (300MHz, methanol-d4): δ9.31 (s, 1H), 8.87 (d, J = 5.1Hz, 1H), 7.85 (d, J = 7.3Hz, 1H), 7.77 (d, J = 5.2Hz, 1H ), 7.58 (d, J = 7.4Hz, 1H), 7.54-7.33 (m, 3H), 7.25-7.07 (m, 3H), 6.98 (d, J = 8.2Hz, 1H), 6.93-6.74 (m, 4 H), 6.41 (d, J = 7.4Hz, 1H), 5.61-5.52 (m, 1H), 5.34-5.16 (m, 2H), 4.82 (s, 3H), 4.33 (d, J = 5.2Hz, 2H), 3 .64 (s, 3H), 3.41 (d, J = 14.5Hz, 1H), 3.23 (s, 3H), 3.17 (d, J = 5.8Hz, 5H), 2.83 (s, 3H), 1.75 (s, 3H) ppm.

[1646] LC / MS: m / z = 901.2 [M+H] +amu.

[1647] Synthesis of compound 66

[1648] Compound 66 was synthesized by following the general procedure for compound 64, using the corresponding aryl-substituted boronate or acid when performing the general procedure for intermediate 7-1, and using the corresponding aryl-substituted boronate or acid when performing the general procedure for compound 35. Compound 66 was obtained as an amorphous off-white solid.

[1649] 1 H NMR (300MHz, methanol-d4): δ9.31 (s, 1H), 8.88 (d, J=5.2Hz, 1H), 7.88 (dd, J=7.7, 1.8Hz, 1H), 7.82 (d, J=5 .2Hz, 1H), 7.56 (td, J=7.8, 1.8Hz, 1H), 7.47-7.29 (m, 3H), 7.23-7.04 (m, 3H), 7.00-6.77 (m, 6H), 6. 41 (dd, J=7.5, 1.7Hz, 1H), 5.58 (dd, J=10.1, 3.2Hz, 1H), 5.33-5.19 (m, 2H), 4.33 (t, J=4.7Hz, 2H), 3 .65 (s, 3H), 3.41 (dd, J=14.0, 3.2Hz, 1H), 3.12 (q, J=6.3, 5.6Hz, 3H), 2.83 (s, 3H), 1.75 (s, 3H)ppm.

[1650] LC / MS: m / z = 923.3 [M+H] + amu.

[1651] Synthesis of compound 67

[1652] Compound 67 was synthesized by following the general procedure for compound 64, using the corresponding aryl-substituted boronate or acid when performing the general procedure for intermediate 7-1, and using the corresponding aryl-substituted boronate or acid when performing the general procedure for compound 35. Compound 67 was obtained as an amorphous off-white solid.

[1653] 1H NMR (300MHz, methanol-d4): δ9.31 (s, 1H), 8.87 (d, J=5.3Hz, 1H), 7.87 (d, J=5.3Hz, 1H), 7.69-7.51 (m, 2 H), 7.49-7.36 (m, 2H), 7.31-7.08 (m, 6H), 6.98 (d, J=8.2Hz, 1H), 6.93-6.75 (m, 4H), 6.44-6.37 (m, 1H), 5.57 (dd, J=10.2, 3.0Hz, 1H), 5.36-5.19 (m, 3H), 4.34 (t, J=4.8Hz, 2H), 3.85 (s, 3H), 3.65 (s , 3H), 3.42 (dd, J=14.1, 3.2Hz, 1H), 3.21-2.99 (m, 3H), 2.84 (s, 4H), 2.65 (s, 4H), 1.76 (s, 3H)ppm.

[1654] LC / MS: m / z = 905.3 [M+H] + amu.

[1655] Synthesis of compound 68

[1656] Compound 68 was synthesized by following the general procedure for compound 64, using the corresponding aryl-substituted boronate or acid when performing the general procedure for intermediate 7-1, and using the corresponding aryl-substituted boronate or acid when performing the general procedure for compound 35. Compound 68 was obtained as an amorphous off-white solid.

[1657] 1 H NMR (300MHz, methanol-d4) δ9.34 (s, 1H), 8.90 (d, J = 5.2Hz, 1H), 8.18 (d, J = 7.6Hz, 1H), 7.90-7.73 (m, 4H), 7.38 (d, J=8.5Hz, 1H), 7.23-7.07 (m, 3H), 6.97 (d, J=8.2Hz, 1H), 6.92-6.78 (m, 5H), 6.45 (d, J=6.2H z, 1H), 5.58 (dd, J=9.9, 3.3Hz, 1H), 5.34-5.20 (m, 2H), 4.34 (t, J=4.7Hz, 2H), 3.65 (s, 3H), 3.52 (s, 3H), 3.45-3.34(m, 1H), 3.28-3.07(m, 3H), 2.84(s, 3H), 2.53(dd, J=14.0, 10.0Hz, 1H), 1.77(s, 3H).

[1658] LC / MS: m / z = 935.3 [M+H] + amu.

[1659] Synthesis of compound 71

[1660] Compound 71 was synthesized by following the general procedure for compound 64, using the corresponding heteroaryl-substituted boronic acid ester or acid in carrying out the general procedure for intermediate 7-1, and using the corresponding aryl-substituted boronic acid ester or acid in carrying out the general procedure for compound 35. Compound 71 was obtained as an off-white solid.

[1661] 1 H NMR (400 MHz, methanol-d4): δ 9.30 (s, 1H), 8.91 (d, J = 5.1 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.94 (dd, J = 5.4, 1.4 Hz, 1H), 7.85-7.78 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.30-7.21 (m, 1H), 7.21-7.07 (m, 3H), 7.01 (ddd, J = 8.4, 4.7, 2.6 Hz, 3H), 6.82 (t, J = 7.4 Hz, 1H), 6.40 (dd, J = 7.4, 1.7 Hz, 1H), 5.59 (dd, J = 10.1, 3.1 Hz, 1H), 5.39-5.23 (m, 2H), 4.42-4.28 (m, 2H), 3.99 (s, 3H), 3.42 (dd, J = 13.8, 3.1 Hz, 2H), 3.20-3.05 (m, 8H), 2.85 (s, 3H), 2.49 (dd, J = 13.9, 10.2 Hz, 1H), 1.75 (s, 3H), 1.32-1.27 (m, 2H) ppm (43 of 43 protons observed).

[1662] LC / MS: m / z=876.3[M+H] + amu.

[1663] Synthesis of compound 72

[1664] Compound 72 was synthesized by following the general procedure for compound 64, using the corresponding heteroaryl-substituted boronic acid ester or acid in carrying out the general procedure for intermediate 7-1, and using the corresponding aryl-substituted boronic acid ester or acid in carrying out the general procedure for compound 35. Compound 72 was obtained as an off-white solid.

[1665] 1H NMR (500MHz, methanol-d4): δ9.29 (s, 1H), 9.05 (d, J=5.1Hz, 1H), 8.95 (s, 4H), 7.98 (d, J=5.0Hz, 1H), 7.43 (d, J=8.5Hz , 1H), 7.30-7.22 (m, 1H), 7.22-7.14 (m, 2H), 7.10 (d, J=7.8Hz, 1H), 7.05-6.98 (m, 3H), 6.83 (t, J=7.4Hz, 1H), 6. 36 (dd, J = 7.5, 1.7 Hz, 1H), 5.60 (dd, J = 10.3, 2.9 Hz, 1H), 5.45-5.25 (m, 2H), 4.45-4.35 (m, 2H), 3.46 (dd, J = 13.7, 3.0 Hz, 1H), 3.25-3.12 (m, 5H), 2.86 (s, 3H), 2.47 (dd, J = 13.8, 10.3 Hz, 1H), 1.75 (s, 3H) ppm (35 of 41 protons observed).

[1666] LC / MS: m / z=846.3[M+H] + amu.

[1667] Synthesis of compound 112

[1668] Compound 112 was synthesized by following the general procedure for compound 64, except that the corresponding aryl-substituted boronate or acid was used when carrying out the general procedure for the synthesis of intermediate 7-1, and cyclobutylzinc bromide and the general procedure for the synthesis of compound 29 were used in the final step of the synthesis of compound 112. Compound 112 was obtained as an off-white solid.

[1669] 1H NMR (400MHz, methanol-d4) δ9.35-9.21 (m, 1H), 8.82 (d, J = 5.1Hz, 1H), 8.12-8.08 (m, 1H), 8.01-7.94 (m, 1H), 7.70 (d, J = 5.1Hz, 1H), 7 .45-7.35 (m, 1H), 7.35-7.09 (m, 5H), 7.06-7.00 (m, 1H), 6.91 (td, J=7.4, 1.0Hz, 1H), 6.57 (dd, J=7.5, 1.7Hz, 1H), 5.58 (dd, J=9 .9, 3.4 Hz, 1H), 5.47-5.05 (m, 2H), 4.41-4.24 (m, 2H), 4.08-3.76 (m, 5H), 3.62-3.44 (m, 1H), 3.36 (dd, J = 14.0, 3.4 Hz, 2H), 3.29-3.18 (m, 10H), 3.18-2.96 (m, 6H), 2.83 (s, 3H), 2.55-2.43 (m, J = 19.1, 12.2, 9.5 Hz, 2H), 2.19-2.02 (m, 2H) (50 of 52 protons observed).

[1670] LC / MS: m / z=890.4[M+H] + amu.

[1671] Synthesis of compound 113

[1672] Compound 113 was synthesized by following the general procedure for compound 64, except that the corresponding aryl-substituted boronate or acid was used when carrying out the general procedure for the synthesis of intermediate 7-1, and cyclobutylzinc bromide and the general procedure for the synthesis of compound 29 were used in the final step of the synthesis of compound 113. Compound 113 was obtained as an off-white solid.

[1673] 1H NMR (400 MHz, methanol-d4): δ 9.12-8.99 (m, 1H), 8.75-8.61 (m, 1H), 8.55-8.45 (m, 1H), 7.59-7.47 (m, 1H), 7.39-7.33 (m, 2H), 7.32-7.25 (m, 2H), 7.24-7.19 (m, 1H), 7.15-6.98 (m, 2H), 6.95-6.78 (m, 3H), 6.78-6.60 (m, 3H). ), 6.52-6.42 (m, 1H), 5.41-5.28 (m, 3H), 5.22-5.06 (m, 2H), 4.57-4.40 (m, 2H), 4.18-4.03 (m, 2H), 3.05-2.74 (m, 9H), 2.66-2.50 (m, 5H), 2.12-2.03 (m, 3H), 1.90-1.85 (m, 1H), 1.82-1.67 (m, 2H) (47 of 50 protons observed).

[1674] LC / MS: m / z = 912.3 [M+H] + amu.

[1675] Synthesis of compound 114

[1676] Compound 114 was synthesized by following the general procedure for compound 64, except that the corresponding aryl-substituted boronate or acid was used when carrying out the general procedure for the synthesis of intermediate 7-1, and cyclobutylzinc bromide and the general procedure for the synthesis of compound 29 were used in the final step of the synthesis of compound 114. Compound 114 was obtained as an off-white solid.

[1677] 1H NMR (400 MHz, methanol-d4): δ 9.23 (s, 1H), 9.20-9.10 (m, 1H), 8.92-8.79 (m, 1H), 8.75 (dd, J = 8.7, 2.4 Hz, 1H), 7.69 (d, J = 5.1 Hz, 1H), 7.50-7.26 (m, 2H), 7.26-7.05 (m, 4H), 7.05-6.96 (m, 2H), 6.96-6.79 (m, 3H), 6.79-6.65 ( m, 2H), 6.55 (dd, J = 7.4, 1.7 Hz, 1H), 5.57 (dd, J = 10.0, 3.2 Hz, 1H), 5.32-5.23 (m, 3H), 4.34 (q, J = 5.6, 5.0 Hz, 1H), 3.81 (s, 4H), 3.13-2.94 (m, 1H), 2.82 (s, 4H), 2.68-2.21 (m, 4H), 2.20-1.74 (m, 8H) (44 of 50 protons observed).

[1678] LC / MS: m / z = 928.3 [M+H] + amu.

[1679] Synthesis of compound 115

[1680] Compound 115 was synthesized by following the general procedure for compound 64, except that the corresponding aryl-substituted boronate or acid was used when carrying out the general procedure for the synthesis of intermediate 7-1, and cyclobutylzinc bromide and the general procedure for the synthesis of compound 29 were used in the final step of the synthesis of compound 115. Compound 115 was obtained as an off-white solid.

[1681] 1 H NMR (400MHz, methanol-d4): δ9.23 (s, 1H), 8.88 (dd, J=5.1, 4.1Hz, 1H), 8.54-8.42 (m, 1H), 8.42-8.27 (m, 1H), 7.93 (d, J=8.3Hz, 1H), 7.7 5 (d, J=5.1Hz, 1H), 7.28-7.18 (m, 1H), 7.18-7.10 (m, 2H), 7.04-6.98 (m, 1H), 6.91 (td, J=7.4, 1.0Hz, 1H), 6.56 (dd, J=7.5, 1.7Hz, 1H), 5.58 (dd, J = 10.0, 3.3 Hz, 1H), 5.42-5.22 (m, 3H), 4.43-4.13 (m, 3H), 3.56-3.46 (m, 2H), 3.37 (d, J = 3.3 Hz, 2H), 3.13 (q, J = 1.8 Hz, 2H), 3.10-2.94 (m, 4H), 2.82 (s, 4H), 2.72 (s, 3H), 2.58-2.31 (m, 3H), 2.13-2.05 (m, 1H), 1.99-1.87 (m, 9H) (49 of 54 protons observed).

[1682] LC / MS: m / z = 952.4 [M+H] + amu.

[1683] Synthesis of compound 116

[1684] Compound 116 was synthesized by following the general procedure for compound 64, except that the corresponding aryl-substituted boronate or acid was used when carrying out the general procedure for the synthesis of intermediate 7-1, and cyclobutylzinc bromide and the general procedure for the synthesis of compound 29 were used in the final step of the synthesis of compound 116. Compound 116 was obtained as an off-white solid.

[1685] 1H NMR (400 MHz, methanol-d4): δ 9.30-9.19 (m, 1H), 8.89-8.81 (m, 1H), 7.97-7.87 (m, 1H), 7.86-7.76 (m, 1H), 7.71-7.58 (m, 2H), 7.29-7.11 (m, 3H), 7.08-6.86 (m, 2H), 6.71-6.37 (m, 1H ), 5.70-5.43 (m, 1H), 5.43-5.19 (m, 2H), 4.46-4.16 (m, 2H), 3.67-3.45 (m, 4H), 3.19-3.00 (m, 8H), 2.89-2.76 (m, 5H), 2.62-2.32 (m, 7H), 2.16-1.93 (m, 3H) (44 of 46 protons observed).

[1686] LC / MS: m / z=844.3[M+H] + amu.

[1687] Synthesis of compound 119

[1688] Compound 119 was synthesized by following the general procedure for compound 64, except that the corresponding aryl-substituted boronate or acid was used when carrying out the general procedure for the synthesis of intermediate 7-1, and cyclobutylzinc bromide and the general procedure for the synthesis of compound 29 were used in the final step of the synthesis of compound 119. Compound 119 was obtained as a yellow solid.

[1689] 1 H NMR (400MHz, methanol-d4): δ9.22 (s, 1H), 8.72 (d, J = 5.1Hz, 1H), 8.29 (d, J = 8.8Hz, 2H), 7.56 (d, J = 5.1Hz, 1H), 7.26-7.17 (m, 1H), 7.17-7.08 (m, 2H), 7.08-6.91 (m, 4H), 6.89 (dt, J=8.0, 1.0Hz, 1H), 6.58 (dd, J=7.5, 1.7Hz, 1H), 5.58 (dd, J=9.9, 3.4Hz, 2H) , 5.36-5.05 (m, 4H), 4.32 (ddt, J = 14.7, 10.5, 5.2 Hz, 4H), 3.74 (dt, J = 14.1, 5.4 Hz, 5H), 3.50-3.45 (m, 1H), 3.13 (q, J = 1.6 Hz, 2H), 3.02 (t, J = 5.2 Hz, 4H), 2.81 (s, 5H), 2.64-2.22 (m, 3H), 2.17 (s, 3H), 2.00 (s, 2H), 1.95-1.83 (m, 6H) (50 of 55 protons observed).

[1690] LC / MS: m / z = 931.4 [M+H] + amu.

[1691] Synthesis of compound 121

[1692] Compound 121 was synthesized by following the general procedure for compound 64, except that the corresponding aryl-substituted boronate or acid was used when carrying out the general procedure for the synthesis of intermediate 7-1, and cyclobutylzinc bromide and the general procedure for the synthesis of compound 29 were used in the final step of the synthesis of compound 121. Compound 121 was obtained as a white solid.

[1693] 1 H NMR (400MHz, methanol-d4): δ9.23 (s, 1H), 8.89-8.87 (m, 1H), 8.86 (d, J=5.2Hz, 1H) , 8.39 (ddd, J=7.8, 1.8, 1.2Hz, 1H), 7.92 (ddd, J=7.7, 1.9, 1.2Hz, 1H), 7.72 ( d, J=5.1Hz, 1H), 7.66 (d, J=2.3Hz, 1H), 7.61-7.51 (m, 1H), 7.30-7.19 (m, 1H) , 7.13 (q, J=8.5Hz, 2H), 7.05 (dd, J=8.3, 1.1Hz, 1H), 6.91 (td, J=7.4, 1.0Hz, 1H), 6.72 (d, J=2.3Hz, 1H), 6.59 (dd, J=7.5, 1.7Hz, 1H), 5.58 (dd, J=10.0, 3. 4Hz, 1H), 5.44-5.20(m, 3H), 4.45-4.11(m, 3H), 3.97(s, 3H), 3.55-3.46(m, 1 H), 3.39-3.33 (m, 2H), 3.13 (q, J = 1.6 Hz, 1H), 3.03-2.95 (m, 5H), 2.80 (s, 4H), 2.67-2.29 (m, 4H), 2.11-1.94 (m, 3H), 1.94-1.83 (m, 4H) (49 of 49 protons observed).

[1694] LC / MS: m / z = 885.3 [M+H] + amu.

[1695] Synthesis of compound 122

[1696] Compound 122 was synthesized by following the general procedure for compound 64, except that the corresponding aryl-substituted boronate or acid was used when carrying out the general procedure for the synthesis of intermediate 7-1, and cyclobutylzinc bromide and the general procedure for the synthesis of compound 29 were used in the final step of the synthesis of compound 122. Compound 122 was obtained as a white solid.

[1697] 1 H NMR (400MHz, methanol-d4): δ9.22 (s, 1H), 8.87 (d, J = 5.2Hz, 1H), 8.52 (d, J = 8.8Hz, 2H), 7.76-7.67 (m, 3H), 7.26-7.18 (m, 1H), 7 .18-7.08 (m, 2H), 7.02 (d, J=8.2Hz, 1H), 6.91 (dt, J=7.2, Hz, 1H), 6.57 (dd, J=7.5, 1.7Hz, 1H), 5.59 (dd, J=10.0, 3.3Hz, 1H ), 5.50-5.19 (m, 1H), 4.42 (t, J = 7.7 Hz, 2H), 4.38-4.27 (m, 2H), 4.23 (t, J = 8.0 Hz, 2H), 3.54-3.45 (m, 4H), 3.13 (q, J = 1.6 Hz, 1H), 3.04-2.97 (m, 2H), 2.82 (s, 3H), 2.56-2.34 (m, 5H), 2.12-2.01 (m, 1H), 1.99 (s, 3H), 1.88 (s, 6H) (46 of 50 protons observed).

[1698] LC / MS: m / z = 888.4 [M+H] + amu.

[1699] Synthesis of compound 73

[1700]

[1701] Intermediate 7-3 was synthesized as follows: first follow the general procedure used to synthesize intermediate 7-1 and use the corresponding aryl-substituted boronate or acid, then follow step 5 of the general procedure used to synthesize intermediate 6-1. Compound 7-3 was synthesized as follows: using compound A9, intermediate 7-3, and following the general procedure used to synthesize compound 3-2. Then, compound 7-4 was synthesized as follows: using compound B-6, compound 7-3, and following the general procedure used to synthesize compound 3-3. Compound 73 was synthesized as follows: using compound 7-4 and following the general procedure used to synthesize compound 29.

[1702] 1H NMR (400MHz, methanol-d4): δ9.26 (s, 1H), 8.86 (s, 1H), 7.81 (d, J=5.2Hz, 1H), 7.43-7.36 (m, 1H), 7.33-7.11 (m, 5H), 7.11-7.02 (m, 2H), 5.34 -5.19 (m, 2H), 4.43-4.28 (m, 2H), 3.84 (s, 3H), 3.67-3.53 (m, 1H), 3.37 (dd, J=14.1, 3.8 Hz, 1H), 3.24-3.14 (m, 4H), 2.85 (s, 4H), 2.72-2.64 (m, 1H), 2.59-2.43 (m, 2H), 2.43-2.24 (m, 2H), 2.18 (s, 3H), 2.16-1.97 (m, 2H), 1.97-1.78 (m, 3H) ppm (46 of 46 protons observed).

[1703] LC / MS: m / z=853.3[M+H] + amu.

[1704] Synthesis of compound 74

[1705] Compound 74 was synthesized by following the general procedure used to synthesize compound 73 and using the corresponding heteroaryl-substituted boronic acid ester when carrying out the general procedure used to synthesize intermediate 7-1. Compound 74 was obtained as an off-white solid.

[1706] 1H NMR (400MHz, methanol-d4): δ9.24 (s, 1H), 9.04 (d, J=5.1Hz, 1H), 8.94 (s, 4H), 7.98 (d, J=5.2, 1H), 7.27-7.1 8 (m, 1H), 7.17 (s, 2H), 7.06-7.01 (m, 1H), 6.93 (td, J=7.4, 1.0Hz, 1H), 6.53 (dd, J=7.5, 1.7Hz, 1H), 5.6 0 (dd, J = 10.2, 3.0 Hz, 1H), 5.45-5.31 (m, 2H), 4.46-4.35 (m, 2H), 3.57-3.45 (m, 1H), 3.40 (dd, J = 13.8, 3.0 Hz, 1H), 3.21-3.10 (m, 4H), 2.86 (s, 3H), 2.59-2.28 (m, 3H), 1.99-1.82 (m, 5H) ppm (35 of 44 protons observed).

[1707] LC / MS: m / z = 806.3 [M+H] + amu.

[1708] Synthetic intermediate 7-4

[1709] ...

Claims

1. A compound having the structure of formula IV: or a pharmaceutically acceptable salt thereof, in: a 2a is CH or N; a4 is S; L 1 It is O; E is absent, 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group; F is 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group; Z 1a is H, halogen, 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 The cycloalkyl group and the 3-10 membered heterocyclic group are each optionally substituted with one or more R Z1 replace; R Z1 is independently halogen, oxo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 The cycloalkyl groups are each optionally substituted with one or more R Z3 replace; R Z3 is independently in each instance a 5-7 membered heteroaryl, C3-C 10 Cycloalkyl, or C1-C6 alkyl; R 1 It is H; R 2 is independently in each instance halogen, hydroxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, or C1-C6 alkoxy; R X3 is independently 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl; wherein the 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 The cycloalkyl group and the 3-10 membered heterocyclic group are each optionally substituted with 1, 2, 3 or 4 R X3a replace; R X3a is independently 6-10 membered aryl, 5-7 membered heteroaryl, 3-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -C(O)N(R X3c )(R X3d ), sulfonamido, sulfonyl, cyano, or halogen, wherein the 6-10 membered aryl, 5-7 membered heteroaryl, 3-10 membered heterocyclyl, C1-C6 alkyl, and C1-C6 alkoxy are each optionally substituted with 1 or 2 R X3b replace; R X3b is independently in each instance 6-10 membered aryl, 5-7 membered heteroaryl, 3-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 acyl, halogen, sulfonamido, sulfonyl or cyano; R X3c and R X3d Each independently selected from H, C6 cycloalkyl; or R X3c and R X3d Together with the N to which they are attached, they form a 4-membered heterocyclic ring; R W1 is H, C1-C6 alkyl, or in Represents the attachment point; m is 0, 1, 2, or 3; n is 1, 2, 3, or 4; and q is independently 0, 1, 2, 3 or 4 at each occurrence, provided that in the absence of E in -(R X3 ) q Here q is 0.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: E is a 6-10 membered aryl, a 5-7 membered heteroaryl, a C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group; Z 1a is H, halogen, 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 The cycloalkyl group and the 3-10 membered heterocyclic group are each optionally substituted with one or more R Z1 Replacement; and R W1 It is H or C1-C6 alkyl.

3. The compound of claim 1, wherein: R 2 is independently C1-C6 alkyl or halogen in each occurrence; m is 0; and n is 2.

4. The compound of claim 1, wherein Z 1a It's a halogen.

5. The compound of claim 4, wherein the halogen is Br or Cl.

6. The compound of claim 1, wherein: Z 1a is phenyl, pyridine, thiophene, furan, pyrrole, cyclopropyl or cyclobutyl, wherein each of them is optionally substituted with 1 or 2 R Z1 Replacement; and R Z1 is independently in each instance halogen or C1-C6 alkyl.

7. The compound of claim 6, wherein R Z1 is independently in each instance methyl, ethyl, F or Cl.

8. The compound of claim 1 having the structure of formula V: or a pharmaceutically acceptable salt thereof, wherein: a2 is CH or N; E is a 6-10 membered aryl, a 5-7 membered heteroaryl, a C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group; G is a 6-10 membered aryl, a 5-7 membered heteroaryl, a C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group; Z 1 is H, halogen, 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 The cycloalkyl group and the 3-10 membered heterocyclic group are each optionally substituted with one or more R Z1 Replacement; and r is 0, 1, 2, 3 or 4.

9. The compound of claim 1 having the structure of formula VI: or a pharmaceutically acceptable salt thereof, in: E is a 6-10 membered aryl, a 5-7 membered heteroaryl, a C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group; G is a 6-10 membered aryl, a 5-7 membered heteroaryl, a C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group; and r is 0, 1, 2, 3 or 4.

10. The compound of claim 1, wherein the C1-C6 haloalkyl group is trifluoromethane or trifluoroethane.

11. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

12. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

13. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

14. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

15. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

16. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

17. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

18. A compound having the structure of formula VIII: or a pharmaceutically acceptable salt thereof, in: E is a 5-7 membered heteroaryl group; L 3 is -CH2- or -CH2CH2-; and Y b is H, 3-10 membered heterocyclyl, -N(CH3)2, -N(CH2CH3)2, -CH2N(CH3)2 or -CH2N(CH2CH3)2; or L 3 is not present; and Y b is H; and Z 1 is a 6-10 membered aryl, a 5-7 membered heteroaryl, a C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the 6-10 membered aryl, 5-7 membered heteroaryl, C3-C 10 The cycloalkyl group and the 3-10 membered heterocyclic group are each optionally substituted with one or more R Z1 replace; R Z1 is independently halogen, oxo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, or C3-C 10 Cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 The cycloalkyl groups are each optionally substituted with one or more R Z3 replace; R Z3 is independently in each instance a 5-7 membered heteroaryl, C3-C 10 Cycloalkyl, or C1-C6 alkyl; R X3 is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano; and q is 0, 1, 2, 3 or 4.

19. Use of the compound of claim 18 for the preparation of a medicament for inhibiting MCL1, wherein the compound has an MCL1 IC of 100 nM or less. 50 .

20. The compound of claim 18 for use in the preparation of a pharmaceutical composition for use with an average IC of 1 μM or less 50 Use of drugs that inhibit the following drug-sensitive cell lines: Cell line name cohort 。 21. Use of the compound of claim 18 for preparing a medicament for inhibiting the following drug-sensitive cell lines, wherein the compound is sensitive to the following drug: Cell line name cohort The average IC 50 Compare the drug-resistant cell lines in the table below: Cell line name cohort The average IC 50 At least 10 times more effective.

22. The compound of claim 18, wherein: E is pyrimidinyl or pyrazolyl; L 3 is -CH2CH2-; Y b is a 3-10 membered heterocyclic group; Z 1 It is C3-C 10 Cycloalkyl; and q is 0, 1, or 2.

23. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 or 8 having the structure of formula X: or a pharmaceutically acceptable salt thereof, wherein R X3-2 yes in Represents the attachment point.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and 22 to 24 and a pharmaceutically acceptable diluent or excipient.

26. Use of a compound according to any one of claims 1 to 18 and 22 to 24 for the preparation of a medicament for the treatment of a disease wherein the underlying pathology of the disease is mediated by MCL1.

27. The use according to claim 26, wherein the disease is cancer.

28. The method of claim 27, wherein the cancer is selected from the group consisting of carcinoma, sarcoma, renal cancer, epidermal cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, skin cancer and breast cancer.

29. The use of claim 28, wherein the carcinoma is a carcinoma of the endometrium, bladder, breast or colon; the sarcoma is Kaposi's sarcoma, osteosarcoma, a tumor of mesenchymal origin; the lung cancer is adenocarcinoma, small cell lung cancer or non-small cell lung cancer; the pancreatic cancer is exocrine pancreatic cancer; the skin cancer is melanoma or squamous cell carcinoma; and the breast cancer is a primary breast tumor, lymph node-negative breast cancer, invasive ductal adenocarcinoma of the breast or non-endometrioid breast cancer.

30. The use of claim 28, wherein the skin cancer is familial melanoma.

31. The use of claim 28, wherein the sarcoma is a fibrosarcoma or a rhabdomyosarcoma.

32. The use of claim 27, wherein the cancer is selected from the group consisting of leukemia, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma, hairy cell lymphoma, Burkett's lymphoma, and myelodysplastic syndrome.

33. The use of claim 32, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute and chronic myeloid leukemia, and promyelocytic leukemia.

34. The use of claim 32, wherein the B-cell lymphoma is selected from the group consisting of Hodgkin's lymphoma and non-Hodgkin's lymphoma.

35. The use of claim 34, wherein the non-Hodgkin's lymphoma is selected from diffuse large B-cell lymphoma and chronic lymphocytic leukemia.

36. The use of claim 27, wherein the cancer is selected from the group consisting of astrocytoma, neuroblastoma, glioma, schwannoma, seminoma, teratoma, xeroderma pigmentosum, retinoblastoma, keratoacanthoma, and follicular thyroid carcinoma.

37. The use of claim 27, wherein the cancer is selected from the group consisting of head and neck cancer, sarcoma, melanoma, myeloma, lymphoma, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, colorectal cancer, ovarian cancer, and acute myeloid leukemia.

Images