WO2022216945A1

WO2022216945A1 - Macrocyclic mcl1 inhibitors and uses thereof

Info

Publication number: WO2022216945A1
Application number: PCT/US2022/023856
Authority: WO
Inventors: Tristin E. ROSE; Emma L. BAKER-TRIPP; Corey M. REEVES; Brian M. Stoltz; Michael D. Bartberger; Oliver C. LOSON; Martina S. MCDERMOTT; Neil A. O'BRIEN; Dennis Slamon
Original assignee: California Institute Of Technology; 1200 Pharma Llc; The Regents Of The University Of California
Priority date: 2021-04-07
Filing date: 2022-04-07
Publication date: 2022-10-13

Abstract

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

Description

MACROCYCLIC MCL1 INHIBITORS AND USES THEREOF

RELATED APPLICATION

This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/171,902, filed April 7, 2021, the content of which is hereby incorporated by reference.

BACKGROUND

MCL1 (also abbreviated as MC1-1, MCL-1, Mell or Mcl-1) protein is a member of the BCL2 family of proteins. 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 membrane of mitochondria, where they form homo-oligomers. These oligomers cause pore formation in the outer mitochondrial membrane and triggers apoptosis. Other members of the BCL2 family, including BCL2, BCLXL and MCL1, prevent apoptosis (i.e., they are anti-apoptotic).

The pathological mechanisms of certain diseases are known to involve the deregulation of apoptosis. For example, increased apoptosis is implicated in the neurodegenerative diseases Parkinson's disease, Alzheimer's disease and ischemia. In contrast, deficiencies in apoptosis are implicated in the development of cancers and their chemoresistances, in auto-immune diseases, inflammatory diseases and viral infections.

The anti-apoptotic proteins of the BCL2 family are associated with several cancers, such as, for example, colon cancer, breast cancer, non-small-cell lung cancer, small-cell lung cancer, bladder cancer, prostate cancer, lymphoma, myeloma, acute myeloid leukemia (also called acute myelogenous leukemia), chronic lymphocytic leukemia, pancreatic cancer, and ovarian cancer.

Some 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 useful for the treatment of cancers.

Therefore, a welcomed contribution to the art would be small-molecules (i.e., compounds) that inhibit MCL1 activity for treating a broad spectrum of cancers, such as, for example, myeloma, lymphoma, acute myelogenous leukemia, melanoma, sarcoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer.

SUMMARY

In certain embodiments, the invention relates to a compound having:

(a) the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl;

B is aryl or heteroaryl; the 5,6-membered bicyclic heteroaryl represented by C and D is selected from:

represents the points of attachment, * represents the point attaching to L¹, and ** represents the point attaching to B; a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₃ is C(Z¹), N or N(Z²), provided that a₁, 32, and 33 are selected such that ring D is aromatic;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

L² in each instance is independently a bond, optionally substituted C₁-C₆ alkyl, - (C₁-C₆ alkyl)p-O-(C₁-C₆ alkyl)_P-, -(C₁-C₆ alkyl)_P-N(R^xl)-(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-;

L³ in each instance is independently CH₂, C(R^L2)(R^L2a), CH=CH, S, O, N(R^L2), C(O), or S(O)₂, provided that each occurrence of S, O, or N(R^L2) is not adjacent to another occurrence of any one of S, O, or N(R^L2);

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,

represents the point of attachment;

X is absent, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, or N(R^X1)(R^X2), wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one, two, three or four R^X3;

Y is aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, N(R^X1)(R^X2), or hydroxyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one, two, three or four R^X3 _;

Z¹ in each instance is independently H, halogen, -L²-Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1; Z² is H, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^Cyl;

R¹ in each instance is independently H, hydroxy, C₁-C₃ alkyl, C₁-C₂ haloalkyl, C₁- C2 hydroxyalkyl, or C₁-C₂ alkoxy;

R² in each instance is independently cyano, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ aminoalkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, nitro, N(R^2a)(R^2b) or C₃-C₄ cycloalkyl, wherein C₃-C₄ cycloalkyl is optionally substituted with one or two groups each independently selected from halogen, C₁-C₃ alkyl and C₁-C₃ haloalkyl;

R^2a and R^2b are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ hydroxy alkyl;

R^L2 in each instance is independently H, Y, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or two groups each independently selected from Y, oxo, -N(R^L3)₂, -OR^L3, - SR^L3, -S(O)₂N(R^L3)₂, and -S(O)₂-Y; and

R^L2a in each instance is independently Y, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or two groups each independently selected from Y, oxo, -N(R^L3)₂, -OR^L3, - SR^L3, -S(O)₂N(R^L3)₂, and -S(O)₂-Y, or

R^L2 and R^L2a, together with the carbon atom to which they are attached, form a C3-C7 monocyclic cycloalkyl, C4-C7 monocyclic cycloalkenyl, or a 4-7 membered monocyclic heterocycle, wherein each are optionally substituted with one -OR^L4 and 0, 1, 2 or 3 R^L5 groups;

R^L3 in each instance is independently H, Y, C₁-C₆ alkyl or C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl and the C₁-C₆ haloalkyl are optionally substituted with one group selected from Y, -OR^L6, -SR^L6, -S(O)₂R^L6 and -N(R^L6)₂;

R^L4 is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -(C₂-C₆ alkylenyl)-OR^L6 or -(C₂-C₆ alkylenyl)-N(R^L6)₂; R^L5 in each instance is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, -CN, oxo, -NO₂, -P(O)(R^L7)₂, -OC(O)R^L7, -OC(O)N(R^L6)₂, -SR^L6, -S(O)₂R^L7, -S(O)₂N(R^L6)₂, -C(O)R^L6, -C(O)N(R^L6)₂, -N(R^L6)₂, -N(R^L6)C(O)R^L7, -N(R^L6)S(O)₂R^L7, -N(R^L6)C(O)O(R^L7), -N(R^L6)C(O)N(R^L6)₂, -(C₁-C₆ alkylenyl)OR^L6, -(C₁-C₆ alkylenyl)-OC(O)N(R^L6)₂, -(C₁-C₆ alkylenyl)-SR^L6, -(C₁-C₆ alkylenyl)-S(O)₂R^L7, -(C₁-C₆ alkylenyl)-S(O)₂N(R^L6)₂, -(C₁-C₆ alkylenyl)-C(O)R^L6, -(C₁-C₆ alkylenyl)- C(O)N(R^L6)₂, -(C₁-C₆ alkylenyl)-N(R^L6)₂, -(C₁-C₆ alkylenyl)-N(R^L6)C(O)R^L7, -(C₁-C₆ alkylenyl)-N(R^L6)S(O)₂R^L7, -(C₁-C₆ alkylenyl)-N(R^L6)C(O)O(R^L7), -(C₁-C₆ alkylenyl)- N(R^L6)C(O)N(R^L6)₂, or -(C₁-C₆ alkylenyl)-CN;

R^L6 in each instance is independently H, C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R^W1 is H, C₁-C₆ alkyl, CH(R^W1a)(R^W2a), heterocyclyl, aryl, heteroaryl, or

, where

represents the point of attachment, wherein each of said heterocyclyl, aryl and heteroaryl is optionally substituted with one, two, three or four

R^W3a.

R^W2 is C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R^W3 is aryl or heteroaryl;

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^W2b in each instance is independently H, C₁-C₆ alkyl, cycloalkyl or C₁-C₆ alkoxy; or, when R^W2a is OC(O)N(R^W2b)(R^W2b), the two R^W2b, together with the N to which they are connected, form a heterocyclyl or heteroaryl, wherein each of said heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R^W3a;

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

R^X1 and R^X2 are in each instance each independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, aryl, heteroaryl, or heterocyclyl, wherein each of aryl, heteroaryl, or heterocyclyl are optionally substituted with one, two, three or four R^X3; ; oorr

R^X1 and R^X2, together with the N to which they are connected, form a heterocycle or heteroaryl, wherein each of said heterocycle and heteroaryl is optionally substituted with one, two, three or four R^X3;

R^X3 in each instance 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 each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one, two, three or four R^X3a;

R^X3a in each instance 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 each of heteroaryl, heterocyclyl, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and C₁-C₆ hydroxyalkyl is optionally substituted with one or two R^X3b;

R^X3b in each instance is independently 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 each of aryl, heteroaryl and heterocyclyl is optionally substituted with one, two, three or four 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;

R^X3c and R^X3d is each independently selected from H, C₁-C₆ cycloalkyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl; or

R^X3c and R^X3d, together with the N to which they are connected, form a 4 - 6 membered heterocycle optionally substituted with one or two groups each independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl or halogen;

R^Z1 in each instance 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 each of said aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁- C₆ alkoxy, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or more R^Z3;

R^Z2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl, wherein each of said aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more R^Z3; or two R^Z2, together with the N to which they are connected, form a heterocycle or heteroaryl, wherein each of said heterocycle and heteroaryl is optionally substituted with one, two, three or four R^Z3;

R^Z3 in each instance 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 each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z4;

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

R^Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxy, 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;

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and p in each instance is independently 0 or 1; or

(b) the structure of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl;

B is aryl or heteroaryl; a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₃ is C(Z¹), N or N(Z²); a₄ is S, O or NH, provided that a₁, a₂, and a₃ are selected such that ring D is aromatic;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

L² in each instance is independently a bond, optionally substituted C₁-C₆ alkyl, - (C₁-C₆ alkyl)_P-O-(C₁-C₆ alkyl)_P-, -(C₁-C₆ alkyl)_P-N(R^xl)-(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-;

Y is aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, N(R^X1)(R^X2) or hydroxyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one, two, three or four R^X3;

Z¹ in each instance is independently H, halogen, -L²-Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

Z² is H, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

R^L2 and R^L2a, together with the carbon atom to which they are attached, form a C3-C7 monocyclic cycloalkyl, C4-C7 monocyclic cycloalkenyl, or a 4-7 membered monocyclic heterocycle, wherein each are optionally substituted with one -OR^L4 and 0, 1, 2 or 3 R^L5 groups; R^L3 in each instance is independently H, Y, C₁-C₆ alkyl or C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl and the C₁-C₆ haloalkyl are optionally substituted with one group selected from Y, -OR^L6, -SR^L6, -S(O)₂R^L6 and -N(R^L6)₂;

R^L4 is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -(C₂-C₆ alkylenyl)-OR^L6 or -(C₂-C₆ alkylenyl)-N(R^L6)₂;

R^L5 in each instance is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, -CN, oxo, -NO₂, -P(O)(R^L7)₂, -OC(O)R^L7, -OC(O)N(R^L6)₂, -SR^L6, -S(O)₂R^L7, -S(O)₂N(R^L6)₂, -C(O)R^L6, -C(O)N(R^L6)₂, -N(R^L6)₂, -N(R^L6)C(O)R^L7, -N(R^L6)S(O)₂R^L7, -N(R^L6)C(O)O(R^L7), -N(R^L6)C(O)N(R^L6)₂, -(C₁-C₆ alkylenyl)OR^L6, -(C₁-C₆ alkylenyl)-OC(O)N(R^L6)₂, -(C₁-C₆ alkylenyl)-SR^L6, -(C₁-C₆ alkylenyl)-S(O)₂R^L7, -(C₁-C₆ alkylenyl)-S(O)₂N(R^L6)₂, -(C₁-C₆ alkylenyl)-C(O)R^L6, -(C₁-C₆ alkylenyl)- C(O)N(R^L6)₂, -(C₁-C₆ alkylenyl)-N(R^L6)₂, -(C₁-C₆ alkylenyl)-N(R^L6)C(O)R^L7, -(C₁-C₆ alkylenyl)-N(R^L6)S(O)₂R^L7, -(C₁-C₆ alkylenyl)-N(R^L6)C(O)O(R^L7), -(C₁-C₆ alkylenyl)- N(R^L6)C(O)N(R^L6)₂, or -(C₁-C₆ alkylenyl)-CN;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

, where

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^W3a is C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano; R^X1 and R^X2 are in each instance each independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, aryl, heteroaryl, or heterocyclyl, wherein each of aryl, heteroaryl, or heterocyclyl are optionally substituted with one, two, three or four R^X3 ; or

R^X3a in each instance 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 each of heteroaryl, heterocyclyl, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and C₁-C₆ hydroxyalkyl is optionally substituted with one, or two R^X3b;

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; m is 0, 1, 2, or 3; n is 0, 1, 2, 3 or 4; and p in each instance is independently 0 or 1; or (c) the structure of Formula IIa, IIa-1, IIa-2, Ila- 3 or IIa-4:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is a 6 membered aryl or heteroaryl, provided that the carbon attached to bond α and carbon attached to bond β have a meta-relationship to each other; a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₃ is C(Z¹), N or N(Z²); a₄ is S, O or NH, provided that a₁, a₂, and a₃ are selected such that ring D is aromatic;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

Y is aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, N(R^X1)(R^X2) or hydroxyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one, two, three or four R^X3; Z¹ in each instance is independently H, halogen, -L²-Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

R^L3 in each instance is independently H, Y, C₁-C₆ alkyl or C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl and the C₁-C₆ haloalkyl are optionally substituted with one group selected from Y, -OR^L6, -SR^L6, -S(O)₂R^L6 and -N(R^L6)₂; R^L4 is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -(C₂-C₆ alkylenyl)-OR^L6 or -(C₂-C₆ alkylenyl)-N(R^L6)₂;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is 0C(0)0R^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; m is 0, 1, 2, or 3; n is 0, 1, 2, 3 or 4; and p in each instance is independently 0 or 1; or

(d) the structure of Formula IIb, IIb-1, IIb-2, IIb-3 or IIb-4:

or a pharmaceutically acceptable salt thereof, wherein:

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

Y¹ is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^X3;

R² in each instance is independently cyano, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ aminoalkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, nitro, N(R^2a)(R^2b) or C₃-C₄ cycloalkyl, wherein C₃-C₄ cycloalkyl is optionally substituted with one or two groups each independently selected from halogen, C₁-C₃ alkyl and C₁-C₃ haloalkyl; R^2a and R^2b are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ hydroxy alkyl;

R^L2 in each instance is independently H, Y¹, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or two groups each independently selected from Y¹, oxo, -N(R^L3)₂, -OR^L3, - SR^L3, -S(O)₂N(R^L3)₂, and -S(O)₂-Y¹; and

R^L2a in each instance is independently Y¹, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or two groups each independently selected from Y¹, oxo, -N(R^L3)₂, -OR^L3, - SR^L3, -S(O)₂N(R^L3)₂, and -S(O)₂-Y¹, or

R^L3 in each instance is independently H, Y¹, C₁-C₆ alkyl or C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl and the C₁-C₆ haloalkyl are optionally substituted with one group selected from Y¹, -OR^L6, -SR^L6, -S(O)₂R^L6 and -N(R^L6)₂;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl; R^W1 is H, C₁-C₆ alkyl, CH(R^W1a)(R^W2a), heterocyclyl, aryl, heteroaryl, or

, where

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is 0C(0)0R^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^X3b in each instance is independently 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 each of aryl, heteroaryl and heterocyclyl is optionally substituted with one, two, three or four 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; R^X3c and R^X3d is each independently selected from H, C₁-C₆ cycloalkyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl; or

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; m is 0, 1, 2, or 3; n is 0, 1, 2, 3 or 4; p in each instance is independently 0 or 1; and q is 0, 1, 2, 3 or 4, with the proviso that q is 0 when E is absent; or

(e) the structure of Formula III, IIIa, IIIa-1 or IIIa-2:

or a pharmaceutically acceptable salt thereof, wherein: a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₃ is C(Z¹), N or N(Z²); a₄ is S, O or NH, provided that a₁, a₂, and a₃ are selected such that ring D is aromatic; a₅ is C(R^A1) or N;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

L³ in each instance is independently CH₂, C(R^L2)(R^L2a), CH=CH, S, O, N(R^L2), C(0), or S(O)₂, provided that each occurrence of S, O, or N(R^L2) is not adjacent to another occurrence of any one of S, O, or N(R^L2); Y is aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, N(R^X1)(R^X2) or hydroxyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one, two, three or four R^X3;

R^A1 in each instance is independently H, cyano, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ aminoalkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, nitro, N(R^2a)(R^2b) or C₃-C₄ cycloalkyl, wherein C₃-C₄ cycloalkyl is optionally substituted with one or two groups each independently selected from halogen, C₁-C₃ alkyl and C₁-C₃ haloalkyl;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

, where

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂; R^W2b in each instance is independently H, C₁-C₆ alkyl, cycloalkyl or C₁-C₆ alkoxy; or, wwhheenn R R^W2a is OC(O)N(R^W2b)(R^W2b), the two R^W2b, together with the N to which they are connected, form a heterocyclyl or heteroaryl, wherein each of said heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R^W3a;

R^X1 and R^X2 are in each instance each independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, aryl, heteroaryl, or heterocyclyl, wherein each of aryl, heteroaryl, or heterocyclyl are optionally substituted with one, two, three or four R^X3; or

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; n is 0, 1, 2, 3 or 4; and p in each instance is independently 0 or 1; or

(f) the structure of Formula IIIb, IIIb-1 or IIIb-2:

or a pharmaceutically acceptable salt thereof, wherein: a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₄ is S, O or NH; a₅ is C(R^A1) or N;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

Z¹ is H, halogen, -L²-Cy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

Z² is H, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1; Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^Cyl;

R¹ in each instance is independently H, hydroxy, C₁-C₃ alkyl, C₁-C₂ haloalkyl, C₁- C₂ hydroxyalkyl, or C₁-C₂ alkoxy;

R^L3 in each instance is independently H, Y¹, C₁-C₆ alkyl or C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl and the C₁-C₆ haloalkyl are optionally substituted with one group selected from Y¹, -OR^L6, -SR^L6, -S(O)₂R^L6 and -N(R^L6)₂; R^L4 is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, -(C₂-C₆ alkylenyl)-OR^L6 or -(C₂-C₆ alkylenyl)-N(R^L6)₂;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is 0C(0)0R^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; n is 0, 1, 2, 3 or 4; p in each instance is independently 0 or 1; and q is 0, 1, 2, 3 or 4, with the proviso that q is 0 when E is absent; or

(g) the structure of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

G¹ is O or CH₂;

G³ is N or C(CN);

Y^1-1 is optionally substituted heterocyclyl, aminoalkyl, haloalky 1 or oxyalkyl;

B¹ is phenyl optionally substituted with 1, 2, 3 or 4 B^la groups each independently selected from methyl, fluoro and chloro, where * represents the point attaching to the ether, and ** represents the point attaching to the pyridine;

Z¹ is aryl or heteroaryl optionally substituted with 1 or 2 groups each independenly selected from fluoro, chloro, methoxy, ethoxy, methyl, ethyl, isopropyl, isobutyl, tert-butyl and cyano; and

R^X3 is aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl, wherein each of said aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl and C₁-C₆ hydroxyalkyl is optionally substituted with one, two, three or four R^X3a;

R^X3a in each instance 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 each of heteroaryl, heterocyclyl, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and C₁-C₆ hydroxyalkyl is optionally substituted with one, two or three R^X3b;

R^X3b in each instance is independently heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano; and R^X3c and R^X3d is each independently selected from H, C₁-C₆ cycloalkyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl or C₁-C₆ acyl; or

R^X3c and R^X3d, together with the N to which they are connected, form a 4 - 6 membered heterocycle optionally substituted with one or two groups each independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl or halogen; or

(h) the structure of F ormula V :

or a pharmaceutically acceptable salt thereof, wherein:

G¹ is bond or CH₂;

G³ is N or C(CN);

B¹ is phenyl optionally substituted with 1, 2, 3 or 4 B^la groups each independently selected from methyl, fluoro and chloro, where * represents the point attaching to the methylene, and ** represents the point attaching to the pyridine;

R^X3b in each instance is independently heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano; and

R^X3c and R^X3d is each independently selected from H, C₁-C₆ cycloalkyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl or C₁-C₆ acyl; or R^X3c and R^X3d, together with the N to which they are connected, form a 4 - 6 membered heterocycle optionally substituted with one or two groups each independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl or halogen.

DETAILED DESCRIPTION

Definitions

Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, 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.

The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g., Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al, “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al, “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000). Chemistry 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, C.A. (1985).

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

A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc?), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

“Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount. “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and/or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 10 carbon atoms, preferably from 1 to about 6 unless otherwise defined. Examples of straight chained and branched alkyl groups include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C₁-C₆ straight chained or branched alkyl group is also referred to as a “lower alkyl” group. Alternatively, when an alkyl group is between or conjugating two groups, it is considered an alkylene.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen (e.g., fluoro), a hydroxyl, an oxo, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halogen, amino, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

The term “alkylene” or “alkylenyl,” as used herein, refers to a divalent radical derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms (C₁-C₆ alkylenyl) or of 1 to 4 carbon atoms (C₁- C₄ alkylenyl) or of 1 to 3 carbon atoms (C₁-C₃ alkylenyl) or of 2 to 6 carbon atoms (C₂- C₆ alkylenyl). Examples of alkylenyl include, but are not limited to, -CH₂- , -CH₂CH₂-, -C((CH₃)₂)CH₂CH₂CH₂-, -C((CH₃)₂)CH₂CH₂, -CH₂CH₂CH₂CH₂- and -CH₂CH(CH₃)CH₂-.

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 carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds.

Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term “alkynyl,” as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both “unsubstituted alkynyls” and “substituted alkynyls,” the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term “alkylamino,” as used herein, refers to an amino group substituted with at least one alkyl group.

The term “alkylthio,” as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

The term “C_x-C_y,” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain 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-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups. Preferred haloalkyl groups include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C₂-C_y alkenyl” and “C₂-C_y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, tert-butoxy and the like.

The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by

wherein each R^A independently represents a hydrogen or a hydrocarbyl group, or two R^A are taken together with the N atom to which they are attached to complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “aminoalkyl,” as used herein, refers to an alkyl group substituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring 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 cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, aniline, and the like.

The term “carbocycle” refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkyl and cycloalkenyl rings. “Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. 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 decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3- to about 10-carbon atoms, from 3- to 8-carbon atoms, or more typically from 3- to 6-carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings (e.g., fused bicyclic compounds, bridged bicyclic compounds, and spirocyclic compounds).

The term “fused bicyclic compound” refers to a bicyclic molecule in which 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., a-thujene and decalin). For example, in a fused cycloalkyl each of the rings shares two adjacent atoms with the other ring, and the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.

The term “spirocyclic compound” or “spirocycle” refers to a bicyclic molecule or group in which the two rings have only one single atom, the spiro atom, in common.

The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single 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 one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, quinoline, quinoxaline, naphthyridine, and the like.

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

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, in some instances, most preferably a 5-membered ring, in other instances, most preferably a 6- membered ring, which ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which one, two or more carbons (e.g., fused heterobicyclic compounds, bridged heterobicyclic compounds, and heterospirocyclic compounds) are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. The terms “heterocyclyl” and “heterocyclic” further include spirocycles, wherein at least one of the rings is heterocyclic, e.g., the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, and/or heterocyclyl. Heterocyclyl groups include, for example, pyrrolidine, piperidine, piperazine, pyrrolidine, tetrahydropyran, tetrahydrofuran, morpholine, lactones, lactams, oxazolines, imidazolines and the like.

The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

The term “haloalkyl,” as used herein, refers to an alkyl group substituted with one or more halo.

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 typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae

wherein each R^A independently represents hydrogen or hydrocarbyl, such as alkyl, or both R^A taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “sulfoxide” is art-recognized and refers to the group -S(O)-R^A, wherein R^A represents a hydrocarbyl.

The term “sulfonyl” is art-recognized and refers to the group -S(0)₂-R^A, wherein R^A represents a hydrocarbyl.

The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or

“substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Substitutions can be one or more and the same or different for appropriate organic compounds.

The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt that is suitable for or compatible with the treatment of patients.

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

The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds of the invention, or any of their intermediates. Illustrative inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.

Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixtures and separate individual isomers.

Some of the 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.

This disclosure contemplates all rotational isomers and atropisomers of the compounds and the salts, drugs, prodrugs, or mixtures thereof (including all possible mixtures of rotational isomers). Structures shown without stereochemistry are intended to cover one, the other, or a mixture of both rotational isomers or atropisomers.

“Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of the invention). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate 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 this disclosure are metabolized to produce a compound of the invention, 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. Example Compounds

In certain embodiments, the invention relates to a compound having the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl;

represents the points

of attachment, * represents the point attaching to L¹, and ** represents the point attaching to B; a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₃ is C(Z¹), N or N(Z²), provided that a₁, a₂, and a₃ are selected such that ring D is aromatic;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

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, represents the point of attachment;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

represents the point of attachment, wherein each of said heterocyclyl, aryl and heteroaryl is optionally substituted with one, two, three or four _R ^W3a.

R^W2 is C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

_RW3 is aryl or heteroaryl;

R^W1a is H or C₁-C₆ alkyl;

R^W2a is 0C(0)0R^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^X1 and R^X2 are in each instance each independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, aryl, heteroaryl, or heterocyclyl, wherein each of aryl, heteroaryl, or heterocyclyl are optionally substituted with one, two, three or four R^X3; or R^X1 and R^X2, together with the N to which they are connected, form a heterocycle or heteroaryl, wherein each of said heterocycle and heteroaryl is optionally substituted with one, two, three or four R^X3;

R^Z1 in each instance 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 each of said aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁- C₆ alkoxy, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or more R^Z3; R^Z2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl, wherein each of said aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more R^Z3; or two R^Z2, together with the N to which they are connected, form a heterocycle or heteroaryl, wherein each of said heterocycle and heteroaryl is optionally substituted with one, two, three or four R^Z3;

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and p in each instance is independently 0 or 1.

In certain embodiments, the invention relates to a compound of Formula I, wherein when L² is a bond, then X is presentln certain embodiments, the invention relates to a compound of Formula I, wherein:

R^X3 in each instance is independently aryl, heteroaryl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein each of said aryl, heteroaryl, and heterocyclyl is optionally substituted with one, two, three or four R^X3a; R^X3a in each instance is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl, or cyano, wherein each of C₁-C₆ alkyl, C₁-C₆ alkoxy and C₁-C₆ hydroxyalkyl is optionally substituted with one, two, three or four groups each independently selected from halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano.

In certain embodiments, the invention relates to a compound of Formula I, wherein:

B is aryl or heteroaryl;

X is aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, or N(R^X1)(R^X2), wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one, two, three or four R^X3;

R^X3a in each instance is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro, or cyano; m is 0 or 1; and n is 0, 1 or 2.

In certain embodiments, the invention relates to a compound having the structure of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl;

B is aryl or heteroaryl; a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₃ is C(Z³), N or N(Z²); a₄ is S, O or NH, provided that a₁, a₂, and a₃ are selected such that ring D is aromatic;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

R^L6 in each instance is independently H, C₁-C₆ alkyl or C₁-C₆ haloalkyl; R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R^W1 is H, C₁-C₆ alkyl, CH(R^W1a)(R^W2a), heterocyclyl, aryl, heteroaryl, or represents the point of attachment, wherein each of said

heterocyclyl, aryl and heteroaryl is optionally substituted with one, two, three or four

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; m is 0, 1, 2, or 3; n is 0, 1, 2, 3 or 4; and p in each instance is independently 0 or 1.

In certain embodiments, the invention relates to a compound of Formula n, wherein:

R^X3 in each instance is independently aryl, heteroaryl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein each of said aryl, heteroaryl, and heterocyclyl is optionally substituted with one, two, three or four R^X3a;

R^X3a in each instance is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl, or cyano, wherein each of C₁-C₆ alkyl, C₁-C₆ alkoxy and C₁-C₆ hydroxyalkyl is optionally substituted with one, two, three or four groups each independently selected from halogen, amino, nitro, sulfonamide, sulfoxide, sulfonyl or cyano.

B is aryl or heteroaryl;

X is aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, or N(R^X1)(R^X2), wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one, two, three or four R^X3; R^X3a in each instance is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro, or cyano; m is 0 or 1; and n is 0, 1 or 2.

In some embodiments, the invention relates to a compound of Formula n, wherein:

A is aryl;

B is aryl; a₁ is CH; a₂ is C(H); a₃ is C(Z³); a₄ is S, O or NH;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

L² is a bond or -(C₁-C₆ alkyl)_p-O-(C₁-C6 alkyl)_p-;

X is aryl or heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one, two, three or four R^X3;

Y is heterocyclyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, N(R^X1)(R^X2), or hydroxyl, wherein heterocyclyl is optionally substituted with one, two, three or four R^X3;

Z¹ is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

R² in each instance 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);

R^W1 is H, C₁-C₆ alkyl, CH(R^W1a)(R^W2a), heterocyclyl, aryl, or heteroaryl, wherein each of said heterocyclyl, aryl and heteroaryl is optionally substituted with one, two, three or four R^W3a;

R^W1a is H or C₁-C₆ alkyl; R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^W2b in each instance is independently H, C₁-C₆ alkyl, cycloalkyl or C₁-C₆ alkoxy; or, wwhheenn R R^W2a is OC(O)N(R^W2b)(R^W2b), the two R^W2b, together with the N to which they are connected, form a heterocyclyl or heteroaryl, wherein each of said heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R^W3a;

R^X1 and R^X2 are in each instance each independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; or

R^X3 in each instance is independently aryl, heteroaryl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein each of said aryl and heteroaryl is optionally substituted with one, two, three or four R^X3a;

R^X3a in each instance is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

R^Z1 in each instance 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 each of said C₁-C₆ alkyl, C₁-C₆ aminoalkyl and C₁-C₆ alkoxy is optionally substituted with one or more R^Z3;

R^Z2 in each instance is independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl, wherein each of said C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more R^Z3;

R^Z3 in each instance 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 each of said aryl and heteroaryl is optionally substituted with one or more R^Z4; R^Z4 in each instance is independently C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylamino, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano; m is 0, 1 or 2; n is 0, 1 or 2; and p in each instance is independently 0 or 1.

In preferred embodiments, R² in each instance is independently cyano, fluoride, chloride, 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).In preferred embodiments, Z¹ is an optionally substituted monocyclic aryl, optionally substituted monocyclic heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl. In more preferred embodiments, the monocyclic cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl.

In some embodiments, the invention relates to a compound of Formula I or n, wherein A is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or thiophenyl. In other embodiments, A¹ is phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, most preferably phenyl or pyridinyl.

In some embodiments, the invention relates to a compound of Formula I or n, wherein B is phenyl, pyridinyl or thiophenyl.

In other embodiments, the invention relates to a compound of Formula I or II, wherein:

A is aryl, preferably phenyl;

B is aryl, preferably phenyl; a₂ is C(H); a₃ is C(Z¹); a₄ is S;

W is C(O)OR^W1;

L¹ is O;

L² is a bond or -(C₁-C₆ alkyl)p-O-(C₁-C₆ alkyl)_P-; each instance of R¹ is H;

R^W1 is H;

R² is methyl, chloro or fluoro; e is 3, 4 or 5; m is 0 or 1; n is 0, 1 or 2; and p in each instance is independently 0 or 1.

In some embodiments, the invention relates to a compound of any of Formulas I or II, wherein:

A is phenyl, pyridine or pyrimidine;

B is phenyl, pyridine or thiophene;

L¹ is O;

R¹ in each instance is H;

R² in each instance is independently C₁-C₆ alkyl or halogen; e is 3, 4 or 5; m is 0; and n is 2, 3 or 4, and n is most preferably 2 or 4.

In certain embodiments, the invention relates to a compound of Formula II having the structure of Formula IIa, IIa-1, IIa-2, IIa-3 or IIa-4:

or a pharmaceutically acceptable salt thereof, wherein:

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂; L² in each instance is independently a bond, optionally substituted C₁-C₆ alkyl, - (C₁-C₆ alkyl)_P-O-(C₁-C₆ alkyl)_P-, -(C₁-C₆ alkyl)_P-N(R^xl)-(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-;

R^2a and R^2b are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ hydroxy alkyl; R^L2 in each instance is independently H, Y, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or two groups each independently selected from Y, oxo, -N(R^L3)₂, -OR^L3, - SR^L3, -S(O)₂N(R^L3)₂, and -S(O)₂-Y; and

, where

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is 0C(0)0R^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^X3a in each instance 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 each of heteroaryl, heterocyclyl, amino, nitro, sulfonamide, sulfoxide, sulfonyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and C₁-C₆ hydroxyalkyl is optionally substituted with one, or two R^X3b; R^X3b in each instance is independently 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 each of aryl, heteroaryl and heterocyclyl is optionally substituted with one, two, three or four 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;

R^Z3 in each instance 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 each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z4; R^Z4 in each instance is independently C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylamino, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

In certain embodiments, the invention relates to a compound of Formula II having the structure of Formula IIb, IIb-1, IIb-2, IIb- 3 or IIb-4:

or a pharmaceutically acceptable salt thereof, wherein:

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

, where

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; m is 0, 1, 2, or 3; n is 0, 1, 2, 3 or 4; p in each instance is independently 0 or 1; and q is 0, 1, 2, 3 or 4, with the proviso that q is 0 when E is absent. In certain embodiments, the invention relates to a compound having the structure of Formula IIb-7, IIb-8, IIb-11 or IIb-12:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is a 6 membered aryl or heteroaryl, provided that the carbon attached to bond α and carbon attached to bond β have a meta-relationship to each other;

G¹ is a O or CH₂;

G² is a O or CH₂;

Y^1-1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^X3, or Y^1-1 is or

, wherein R³ is H or C₁-C₆ alkyl; R⁴ is -O-P(O)(O-)(O-), -O-P(O)(O- )(0R⁵), -O-P(O)(OR⁵)(OR⁵), -0-S(0₂)-0-, -O-S(O₂)-OR⁵, Cy^a, -O-C(O)-R⁶, -O-C(O)- OR⁶, or -O-C(O)-N(R⁶)(R⁶); Cy^a is cycloalkyl, heterocyclyl, aryl or heteroaryl; R⁵ in each instance is independently H, C₁-C₆ alkyl, or aralkyl(C₁-C₆); and R⁶ in each instance is independently H, C₁-C₆ alkyl, or C₁-C₆ aminoalkyl;

Z¹ in each instance is independently aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

R^L2a is Y^1-1, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or two groups each independently selected from Y^1-1, oxo, -N(R^L3)₂, -OR^L3, - SR^L3, -S(O)₂N(R^L3)₂, and -S(O)₂-Y^1-1;

R^L2a-1 is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl;

R^L3 in each instance is independently H, Y^1-1, C₁-C₆ alkyl or C₁-C₆ haloalkyl, wherein C₁-C₆ alkyl and C₁-C₆ haloalkyl are optionally substituted with one group selected from Y^1-1, -OR^L6, -SR^L6, -S(O)₂R^L6 and -N(R^L6)₂;

R^X3 is aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein each of said aryl, heteroaryl, cycloalkyl, heterocyclyl C₁-C₆ alkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkyl is optionally substituted with one, two, three or four R^X3a;

R^Z4 in each instance is independently C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylamino, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano; m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4.

In certain embodiments of the above Formula IIb-8 and Formula IIb-12, Y^1-1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^X3.In certain embodiments, the invention relates to a compound having the structure of Formula IIb-9, IIb-10, IIb- 13 or IIb-14:

or a pharmaceutically acceptable salt thereof, wherein: A¹ is a 6 membered aryl or heteroaryl, provided that the carbon attached to bond α and carbon attached to bond β have a meta-relationship to each other;

G¹ is a bond or CH₂;

Y^1-1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^X3, or Y^1-1 is

, wherein R³ is H or C₁-C₆ alkyl; R⁴ is -O-P(O)(O-)(O-), -O-P(O)(O- )(OR⁵), -O-P(O)(OR⁵)(OR⁵), -O-S(O₂)-O-, -O-S(O₂)-OR⁵, Cy^a, -O-C(O)-R⁶, -O-C(O)- OR⁶, or -O-C(O)-N(R⁶)(R⁶); Cy^a is cycloalkyl, heterocyclyl, aryl or heteroaryl; R⁵ in each instance is independently H, C₁-C₆ alkyl, or aralkyl(C₁-C₆); and R⁶ in each instance is independently H, C₁-C₆ alkyl, or C₁-C₆ aminoalkyl;

R^L2a-1 is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl; R^L3 in each instance is independently H, Y^1-1, C₁-C₆ alkyl or C₁-C₆ haloalkyl, wherein C₁-C₆ alkyl and C₁-C₆ haloalkyl are optionally substituted with one group selected from Y^1-1, -0R^L6, -SR^L6, -S(O)₂R^L6 and -N(R^L6)₂;

In certain embodiments of the above Formula IIb-10 and Formula IIb-14, Y^1-1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^X3.In particular embodiments, the compound of Formula IIb- 8 has the structure of Formula IIb-8a or IIb-8b:

In particular embodiments, the compound of Formula IIb-10 has the structure of

Formula IIb-1 Oa:

In particular embodiments, the compound of Formula IIb- 12 has the structure of Formula IIb-12a or IIb-12b:

In particular embodiments, the compound of Formula IIb- 14 has the structure of

Formula IIb-14a:

In certain embodiments, the invention relates to a compound having the structure of Formula III, IIIa, IIIa-1 or IIIa-2:

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; n is 0, 1, 2, 3 or 4; and p in each instance is independently 0 or 1.

In certain embodiments, the invention relates to a compound of Formula HI having the structure of Formula IIIb, IIIb-1 IIIb-2, IIIb-3, or IIIb-8:

or a pharmaceutically acceptable salt thereof, wherein: a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₄ is S, 0 or NH; a₅ is C(R^A1) or N;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl;

R^L5 in each instance is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, -CN, oxo, -NO₂, -P(O)(R^L7)₂, -OC(O)R^L7, -OC(O)N(R^L6)₂, -SR^L6, -S(O)₂R^L7, -S(O)₂N(R^L6)₂, -C(O)R^L6, -C(O)N(R^L6)₂, -N(R^L6)₂, -N(R^L6)C(O)R^L7, -N(R^L6)S(O)₂R^L7, -N(R^L6)C(O)O(R^L7), -N(R^L6)C(O)N(R^L6)₂, -(C₁-C₆ alkylenyl)OR^L6, -(C₁-C₆ alkylenyl)-OC(O)N(R^L6)₂, -(C₁-C₆ alkylenyl)-SR^L6, -(C₁-C₆ alkylenyl)-S(O)₂R^L7, -(C₁-C₆ alkylenyl)-S(O)₂N(R^L6)₂, -(C₁-C₆ alkylenyl)-C(O)R^L6, -(C₁-C₆ alkylenyl)- C(O)N(R^L6)₂, -(C₁-C₆ alkylenyl)-N(R^L6)₂, -(C₁-C₆ alkylenyl)-N(R^L6)C(O)R^L7, -(C₁-C₆ alkylenyl)-N(R^L6)S(O)₂R^L7, -(C₁-C₆ alkylenyl)-N(R^L6)C(O)O(R^L7), -(C₁-C₆ alkylenyl)- N(R^L6)C(O)N(R^L6)₂, or -(C₁-C₆ alkylenyl)-CN; R^L6 in each instance is independently H, C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

, where

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^Cy2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; n is 0, 1, 2, 3 or 4; p in each instance is independently 0 or 1; and q is 0, 1, 2, 3 or 4, with the proviso that q is 0 when E is absent.

In certain embodiments, the invention relates to a compound having the structure of Formula IIIb-4, IIIb-5, IIIb-9 or IIIb- 10:

or a pharmaceutically acceptable salt thereof, wherein:

G¹ is a O or CH₂;

G² is a O or CH₂;

, wherein R³ is H or C₁-C₆ alkyl; R⁴ is -O-P(O)(O-)(O-), -O-P(O)(O- )(OR⁵), -O-P(O)(OR⁵)(OR⁵), -O-S(O₂)-O-, -O-S(O₂)-OR⁵, Cy^a, -O-C(O)-R⁶, -O-C(O)- OR⁶, or -O-C(O)-N(R⁶)(R⁶); Cy^a is cycloalkyl, heterocyclyl, aryl or heteroaryl; R⁵ in each instance is independently H, C₁-C₆ alkyl, or aralkyl(C₁-C₆); and R⁶ in each instance is independently H, C₁-C₆ alkyl, or C₁-C₆ aminoalkyl; Z¹ in each instance is independently aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

_RX3= and R^X3d is each independently selected from H, C₁-C₆ cycloalkyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl; or

R^Z4 in each instance is independently 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 n is 0, 1, 2, 3 or 4. In certain embodiments of the above Formula IIIb-5 and Formula IIIb-10, Y^1-1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^X3.

In certain embodiments, the invention relates to a compound having the structure of Formula IIIb-6, IIIb-7, IIIb-11, or IIIb-12:

or a pharmaceutically acceptable salt thereof, wherein:

G¹ is a bond or CH₂;

or

R^2a and R^2b are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ hydroxy alkyl; R^L2a is Y^1-1, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or two groups each independently selected from Y^1-1, oxo, -N(R^L3)₂, -OR^L3, - SR^L3, -S(O)₂N(R^L3)₂, and -S(O)₂-Y^1-1;

R^X3c and R^X3d, together with the N to which they are connected, form a 4 - 6 membered heterocycle optionally substituted with one or two groups each independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl or halogen; R^Z1 in each instance 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 each of said aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁- C₆ alkoxy, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or more R^Z3;

R^Z4 in each instance is independently 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 n is 0, 1, 2, 3 or 4.

In certain embodiments of the above Formula IIIb-7 and Formula IIIb-12, Y^1-1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^X3.In particular embodiments, the compound of Formula IIIb- 5 has the structure of Formula IIIb-5a or IIIb-5b:

In particular embodiments, the compound of Formula IIIb-7 has the structure of

Formula IIIb-7a:

In particular embodiments, the compound of Formula IIIb- 10 has the structure of

Formula IIIb- 10a or IIIb- 10b:

In particular embodiments, the compound of Formula IIIb- 12 has the structure of

Formula IIIb-12a:

In certain embodiments, the invention relates to a compound of Formula IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein:

E is aryl, heteroaryl, cycloalkyl or heterocyclyl; and q is 0, 1, 2, 3 or 4, and most preferably is 2, 3 or 4. In some embodiments, the invention relates to a compound of Formula III, IIIa, IIIa-1, IIIa-2, IIIb, IIIb-1, IIIb-2 or IIIb-3 wherein:

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

In some embodiments, the invention relates to a compound of Formula III, IIIa or IIIb, wherein: a₂ is C(H) or N; a₄ is S, O or NH;

L¹ is a O;

L² is a bond or -(C₁-C₆ alkyl)_p-O-(C₁-C6 alkyl)_p-;

L³ in each instance is independently CH₂, C(R^L2)(R^L2a), O, N(R^L2) or C(O);

E is aryl or heteroaryl, preferably heteroaryl;

Y or Y¹ is cycloalkyl or heterocyclyl, optionally substituted with one, two, three or four R^X3;

R¹ in each instance is H;

R² in each instance is independently cyano, Cl, F, Br, hydroxy, C₁-C₆ alkyl (preferably methyl or ethyl), C₁-C₆ alkylamino, C₁-C₆ aminoalkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, nitro or N(R^2a)(R^2b);

R^W1 is H; e is 3, 4 or 5; n is 0, 1 or 2; and p in each instance is independently 0 or 1. In some embodiments, the invention relates to a compound of any of Formulas I, II or III, wherein:

R^W1 is H;

L¹ is O;

R¹ in each instance is H;

R² in each instance is independently C₁-C₆ alkyl (preferably methyl or ethyl) or halogen (preferably Cl or F); e is 3, 4 or 5; m is 0; and n is 2, 3 or 4, and more preferably is 2 or 4.

In other embodiments, the invention relates to a compound of any of Formula I, II or III, wherein a₂ is C(H) or N.

In some embodiments, the invention relates to a compound of Formula III, wherein Z¹ in each instance is independently H, fluoro substituted aryl, fluoro substituted heteroaryl, or halogen, and more particularly, the halogen is Br or Cl.

In other embodiments, the invention relates to a compound of Formula III, wherein Z¹ in each instance is independently H, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted thiophenyl, optionally substituted furanyl, optionally substituted pyrrolyl, optionally substituted cyclopropyl, or optionally substituted cyclobutyl. In preferred embodiments, Z¹ is cycloalkyl, and more preferably, cyclobutyl. In some embodiments, the optional substitution is Ci-Ce alkyl, and more particularly, the Ci-Ce alkyl is methyl or ethyl. In some embodiments, the optional substitution is halogen, and more particularly, the halogen is F or Cl.In some embodiments, the invention relates to a compound of Formula IIa-2, IIa-3, IIa-4, IIb-2, IIb-3, IIb-4, IIb-5, IIb-6, IIb-7, IIb-8, IIb-9, IIb-10, IIb-11, IIb-12, IIb-13, IIb-14, IIIa-1, IIIa-2, IIIb-1 IIIb-2, IIIb-3, IIIb-4, IIIb-5, IIIb-6, IIIb-7, IIIb-8, IIIb-9, IIIb-10, IIIb-11 or IIIb- 12, wherein Z¹ is optionally substituted phenyl or optionally substituted cycloalkyl. In preferred embodiments, Z¹ is cycloalkyl, and more preferably, cyclobutyl.

In some embodiments, Z¹ is cycloalkyl, and more preferably, cyclobutyl, and is substituted with one or two R^Z1 groups, wherein in each instance R^Z1 is independently 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. In specific embodiments, R^Z1 in each instance is independently C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl. In preferred embodiments, R^Z1 in each instance is C₁-C₆ alkyl. In other preferred embodiments, R^Z1 occurs twice. In more preferred embodiments, R^Z1 occurs once.

In other preferred embodiments, Z¹ is optionally substituted phenyl, and the optional substitution is halogen, and more particularly, the halogen is F or Cl.

In some embodiments, the optional substitution is C₁-C₆ alkyl, and more particularly, the C₁-C₆ alkyl is methyl or ethyl.

In some embodiments, the invention relates to a compound of Formula IIb-8, IIb- 10, IIb-12, IIb-14, IIIb-5, IIIb- 7, IIIb- 10, or IIIb- 12, or a pharmaceutically acceptable salt thereof, wherein:

Y^1-1 is represents the

point of attachment.

In some embodiments, the invention relates to a compound of Formula IIIb, Hlb-l or IIIb-2, wherein:

E is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl or triazolyl;

Y is pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, oxetanyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2- azaspiro[3.3]heptanyl, or 2-oxaspiro[3.3]heptanyl;

R^X3 in each instance is independently 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, and more preferably is 2 or 4.

In some embodiments, the invention relates to a compound of Formula I, n, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, III, IIIa, nia-1, IIIa-2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein: at least one instance of L³ is C(R^L2)(R^L2a) or N(R^L2);

R^L2 or R^L2a is Y or Y¹; Y or Y¹ is represents

the point of attachment;

R³ is H or C₁-C₆ alkyl;

R⁴ is -O-P(O)(O )(O ), -O-P(O)(O )(OR⁵), -O-P(O)(OR⁵)(OR⁵), -O-S(O₂)-O-, -O-S(O₂)-OR⁵, Cy^a, -O-C(O)-R⁶, -O-C(O)-OR⁶, or -O-C(O)-N(R⁶)(R⁶);

Cy^a is cycloalkyl, heterocyclyl, aryl or heteroaryl;

R⁵ in each instance is independently H, C₁-C₆ alkyl, or aralkyl(C₁-C₆); and

R⁶ in each instance is independently H, C₁-C₆ alkyl, or C₁-C₆ aminoalkyl.

In some embodiments, the invention relates to a compound of Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, III, IIIa, IIIa-1, IIIa-2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein (L³)_e comprises C(O)N(R^L2) and/or N(R^L2)C(O).

In some embodiments, the invention relates to a compound of Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, III, IIIa, nia-1, IIIa-2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein e is 1. In other embodiments, e is 2. In other embodiments, e is 3. In other embodiments, e is 4. In other embodiments, e is 5. In other embodiments, e is 6. In other embodiments, e is 7. In other embodiments, e is 8.

In some embodiments, the invention relates to a compound of Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, III, IIIa, nia-1, IIIa-2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein e is 1, 2, 3 or 4.

In some embodiments, the invention relates to a compound of Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, III, IIIa, nia-1, IIIa-2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein L³ in each instance is independently CH₂, C(R^L2)(R^L2a), O, N(R^L2) or C(O); and e is 3, 4 or 5.

In some embodiments, the invention relates to a compound of Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, III, IIIa, nia-1, IIIa-2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein L³ in each instance is independently CH₂, C(H)(R^L2a), or O; and e is 3, 4 or 5. In some embodiments, the invention relates to a compound of Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, III, IIIa, IIIa-1, IIIa-2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein L³ in each instance is independently CH₂, C(H)(R^L2a), N(R^L2), or C(O); and e is 3, 4 or 5.

In some embodiments, the invention relates to a compound of Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, III, IIIa, nia-1, IIIa-2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein L³ in each instance is independently CH₂, C(H)(R^L2a), or N(R^L2); and e is 3, 4 or 5.

In preferred embodiments, the invention relates to a compound of Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, IH, IIIa, nia-1, nia-2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein L³ is selected from:

represents the points of attachment, * represents the point attaching to A, A¹ or A², and ** represents the point attaching to B or B¹.

In preferred embodiments, L³ is selected from:

In other preferred embodiments, the invention relates to a compound of Formula

1, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, III, IIIa, IIIa-1, IIIa-

2, IIIb, IIIb, -1, IIIb, -2 or IIIb, -3, wherein:

L³ in each instance is independently CH₂, C(R^L2)(R^L2a), O, N(R^L2), or C(O), provided that one and only one occurrence of L³ is C(R^L2)(R^L2a);

Y is heterocyclyl or N(R^X1)(R^X2), wherein heterocyclyl is optionally substituted with one, two, three or four R^X3 _;

Z¹ in each instance is independently halogen, aryl, heteroaryl or cycloalkyl, wherein each of said aryl, heteroaryl and cycloalkyl is optionally substituted with one or more R^Z1, and halogen is preferably Cl or Br;

R^X1 and R^X2, together with the N to which they are connected, form a heterocycle that is optionally substituted with one, two, three or four R^X3;

R^X3a in each instance is independently 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; R^X3c and R^X3d is each independently selected from H, C₁-C₆ cycloalkyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl or C₁-C₆ acyl; or

R^L2 in each instance is H;

R^L2a in each instance is independently C₁-C₆ alkyl or C₂-C₆ alkenyl, wherein each of C₁-C₆ alkyl and C₂-C₆ alkenyl is optionally substituted with Y, -N(R^L3)₂, -OR^L3, - SR^L3, -S(O)₂N(R^L3)₂ or -S(O)₂-Y;

R^L3 in each instance is independently H, Y or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with Y, -OR^L6, -SR^L6, -S(O)₂R^L6 or -N(R^L6)₂;

R^L6 in each instance is independently H, C₁-C₆ alkyl or C₁-C₆ haloalkyl; and e is 3, 4 or 5.

In preferred embodiments, the hetereocyclyl of Y is selected from pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, oxetanyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2- azaspiro[3.3]heptanyl, or 2-oxaspiro[3.3]heptanyl, the C₁-C₆ alkyl of R^X3 in each instance is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertbutyl, and the C₁-C₆ alkyl of R^L2a is selected from methyl, ethyl, propyl or butyl.

In further preferred embodiments, R^L2a is C₁-C₆ alkyl substituted with Y. In other preferred embodiments, R^L2a is C₁-C₂ alkyl substituted with an unsubstituted Y.

In further preferred embodiments, R^L2a is C₁-C₆ alkyl substituted with Y. In other preferred embodiments, R^L2a is C₁-C₂ alkyl substituted with a substituted Y, wherein the Y is substituted with one R^X3.

In further preferred embodiments, R^L2a is C₁-C₂ alkyl- Y-R^X3.

In further preferred embodiments, R^L2a i

where represents the point of attachment to the C of C(R^L2)(R^L2a). In further preferred embodiments, R^L2a i

In other preferred embodiments, the invention relates to a compound of Formula

2, IIIb, IIIb-1, IIIb-2 or IIIb-3, wherein e is 2, 3 or 4, preferably 3 or 4, and more preferably 4. In other aspects, e is 3, 4 or 5.

In certain embodiments, the invention relates to a compound having the structure of Formula IV, IVa or IVb:

or a pharmaceutically acceptable salt thereof, wherein:

G¹ is O or CH₂;

G₃ is N or C(CN);

Y^1-1 is C₁-C₂ alkyl- Y^1-2 or Y^1-2, or Y^1-1 is

wherein R³ is H or C₁-C₆ alkyl; R⁴ is -O-P(O)(O )(O ), -O-P(O)(O-)(OR⁵), - O-P(O)(OR⁵)(OR⁵), -O-S(O₂)-O-, -O-S(O₂)-OR⁵, Cy^a, -O-C(O)-R⁶, -O-C(O)-OR⁶, or -O- C(O)-N(R⁶)(R⁶); Cy^a is cycloalkyl, heterocyclyl, aryl or heteroaryl; R⁵ in each instance is independently H, C₁-C₆ alkyl, or aralkyl(C₁-C₆); and R⁶ in each instance is independently H, C₁-C₆ alkyl, or C₁-C₆ aminoalkyl;

Y^1-2 is optionally substituted heterocyclyl, aminoalkyl, haloalky 1 or oxyalkyl;

Z¹ is cycloalkyl, aryl or heteroaryl, wherein said cycloalkyl, aryl and heteroaryl are each optionally substituted with 1 or 2 groups each independenly selected from fluoro, chloro, methoxy, ethoxy, methyl, ethyl, isopropyl, isobutyl, tert-butyl and cyano;

R^X3c and R^X3d is each independently selected from H, C₁-C₆ cycloalkyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl or C₁-C₆ acyl; or

R^X3c and R^X3d, together with the N to which they are connected, form a 4 - 6 membered heterocycle optionally substituted with one or two groups each independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl or halogen.

In certain embodiments, the invention relates to a compound having the structure of Formula IV, IVa or IVb, wherein Y^1-1 is C₁-C₂ alkyl- Y^1-2 or Y^1-2; and Z¹ is aryl or heteroaryl optionally substituted with 1 or 2 groups each independenly selected from fluoro, chloro, methoxy, ethoxy, methyl, ethyl, isopropyl, isobutyl, tert-butyl and cyano.

In some embodiments, the compound of Formula IV has the structure of Formula IVa-1, IVa-2, IVa-3, IVa-4, IVb-1, IVb-2, IVb-3 or IVb-4:

or a pharmaceutically acceptable salt thereof.

In other embodiments, the compound of Formula IV has the structure of Formula IVa-1 or IVb-1. In other embodiments, the compound of Formula IV has the structure of Formula IVa-1. In other embodiments, the compound of Formula IV has the structure of Formula IVa-2. In other embodiments, the compound of Formula IV has the structure of Formula IVa-3. In other embodiments, the compound of Formula IV has the structure of Formula IVa-4. In yet other embodiments, the compound of Formula IV has the structure of Formula IVb-1. In yet other embodiments, the compound of Formula IV has the structure of Formula IVb-2. In yet other embodiments, the compound of Formula IV has the structure of Formula IVb-3. In yet other embodiments, the compound of Formula IV has the structure of Formula IVb-4.

In certain embodiments, the invention relates to a compound having the structure of Formula V or Va:

or a pharmaceutically acceptable salt thereof, wherein:

G¹ is bond or CH₂;

G₃ is N or C(CN); Y^1-1 is C₁-C₂ alkyl- Y^1-2 or Y^1-2, or Y^1-1 is

wherein R³ is H or C₁-C₆ alkyl; R⁴ is -O-P(O)(O )(O ), -O-P(O)(O )(OR⁵), - O-P(O)(OR⁵)(OR⁵), -O-S(O₂)-O-, -O-S(O₂)-OR⁵, Cy^a, -O-C(O)-R⁶, -O-C(O)-OR⁶, or -O- C(O)-N(R⁶)(R⁶); Cy^a is cycloalkyl, heterocyclyl, aryl or heteroaryl; R⁵ in each instance is independently H, C₁-C₆ alkyl, or aralkyl(C₁-C₆); and R⁶ in each instance is independently H, C₁-C₆ alkyl, or C₁-C₆ aminoalkyl;

In certain embodiments, the invention relates to a compound having the structure of Formula V or Va, wherein Y^1-1 is C₁-C₂ alkyl- Y^1-2 or Y^1-2; and Z¹ is aryl or heteroaryl optionally substituted with 1 or 2 groups each independenly selected from fluoro, chloro, methoxy, ethoxy, methyl, ethyl, isopropyl, isobutyl, tert-butyl and cyano.

In some embodiments, the compound of Formula IV has the structure of Formula Va-1, Va-2, Va-3 or Va-4:

or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of Formula V has the structure of Formula Va-1. In other embodiments, the compound of Formula V has the structure of Formula Va-2. In yet other embodiments, the compound of Formula V has the structure of Formula Va-3. In yet other embodiments, the compound of Formula V has the structure of Formula Va-4.

In other embodiments, the compound of Formula IIIb-3 has an MCL1 K_d of about 300 nM or lower.

In other embodiments, the compound of Formula IIIb-3 has an average IC₅₀ for the drug sensitive cell lines of Table 3 of 1 μM or lower.

In yet other embodiments, the compound of Formula IIIb-3 has an average IC₅₀ for the drug-sensitive cell lines of Table 3 that is at least about 10-fold more potent than the average IC₅₀ for the drug-resistant cell lines of Table 3.

In certain embodiments, the invention relates to a compound having the structure of Formula IIIb-4, IIIb-5, IIIb-5a, IIIb-5b, IIIb-6, IIIb-7, IIIb-7a, IIIb-8, IIIb-9, IIIb-10 IIIb-lOa, IIIb-10b, IIIb-11, IIIb-12, IIIb-12a, IV, IVa, IVa-1, IVa-2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3, IVb-4, V, Va, Va-1, Va-2, Va-3 or Va-4, or a pharmaceutically acceptable salt thereof, wherein R^X3 is

represents the point of attachment.

where represents the point of attachment. In specific embodiments, R^X3 is

In preferred embodiments, R^X3 is

In more preferred embodiments, R^X3 is

In certain embodiments, the invention relates to a compound having the structure of Formula IV, IVa, IVa-1, IVa-2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3, IVb-4, V, Va, Va-1, Va-2, Va-3 or Va-4, or a pharmaceutically acceptable salt thereof, wherein Y^1-1 i iss

represents the point of attachment. In preferred embodiments, Y^1-1 iiss

In certain embodiments, the invention relates to a compound having the structure of Formula IV, IVa, IVa-1, IVa-2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3, IVb-4, V, Va, Va-1, Va-2, Va-3 or Va-4, or a pharmaceutically acceptable salt thereof, wherein:

Y^1-1 is represents the

point of attachment.

In certain embodiments, the invention relates to a compound having the structure of Formula IV, IVa, IVa-1, IVa-2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3, IVb-4, V, Va, Va-1, Va-2, Va-3 or Va-4, or a pharmaceutically acceptable salt thereof, wherein B¹ is phenyl optionally substituted with 1 or 2 B^la groups. In other embodiments, B¹ is phenyl optionally substituted with 2 B^la groups. In other embodiments, B¹ is phenyl optionally substituted with 2 or 3 B^la groups. In other embodiments, B¹ is phenyl optionally substituted with 3 B^la groups.

In certain embodiments, the invention relates to a compound having the structure of Formula IV, IVa, IVa-1, IVa-2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3, IVb-4, V, Va, Va-1, Va-2, Va-3 or Va-4, or a pharmaceutically acceptable salt thereof, wherein Z¹ is optionally substituted cycloalkyl or optionally substituted phenyl. In specific embodiments, Z¹ is cycloalkyl optionally substituted with one or two substituents independenly selected from fluoro, chloro, methoxy, ethoxy, methyl, ethyl, isopropyl, isobutyl, tert-butyl and cyano. In preferred embodiments, the one or two substituents are independently selected from methyl, ethyl, isopropyl, isobutyl and tert-butyl. In other preferred embodiments, there is one substituent. In yet other preferred embodiments, there are two substituents.

In specific embodiments, Z¹ is

represents the point of attachment.

In some aspects, the invention relates to a compound of Formula in having a structure selected from:

a pharmaceutically acceptable salt thereof. In some aspects, the invention relates to a compound of Formula III having a structure selected from:

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt

thereof.

or a pharmaceutically acceptable salt thereof.

, or a pharmaceutically acceptable salt

thereof. In some aspects, the invention relates to a compound of Formula in having a structure selected from:

or a pharmaceutically acceptable salt

thereof.

or a pharmaceutically acceptable salt

or a pharmaceutically acceptable salt thereof.

In some aspects, the invention relates to a compound of Formula m having a structure selected from:

or a pharmaceutically acceptable salt

thereof.

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt

thereof.

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt

thereof.

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable diluent or excipient.

Specific embodiments of the invention include those compounds listed in Table 1. The identifying number (“Cmpd”), the chemical structure (“Structure”), and the example method used to synthesize the compound (“Method”) are disclosed in Table 1 for each compound.

Specific embodiments of the invention include those compounds listed in Table 1- A. The identifying number (“Cmpd”), the chemical structure (“Structure”), and the example method that is used to synthesize the compound (“Method”) are disclosed in Table 1-A for each compound.

Specific embodiments of the invention include compounds of Formula IVa-1, IVa-2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3, IVb-4, Va-1, Va-2, Va-3 or Va-4, wherein R^X3, Y^1-1, B¹ and Z¹ are defined, in that order, as listed in each row of Table 1-B, and wherein Table 1-C specifies the chemical structures of the groups specified in Table 1-B.

In other embodiments, the invention relates to compounds of Formula IVa-1, IVa- 2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3 or IVb-4, wherein:

R^X3 is RX3-1, RX3-2, RX3-3, RX3-4, RX3-5, RX3-6, RX3-7, RX3-8, RX3-9,

RX3-10, RX3-11 or RX3-12, where represents the point of attachment; Y^1-1 is Yl-1-1, Yl-1-2, Yl-1-3, Yl-1-4, Yl-1-5, Yl-1-6, Yl-1-7, Yl-1-8, Yl-1-

9, Yl-1-10, Yl-1-11 or Yl-1-12, where

represents the point of attachment;

B¹ is Bl-1, Bl-2, Bl-3, Bl-4, Bl-5, Bl-6, Bl-7, Bl-8, Bl-9 or Bl-10, where

represents the points of attachment, * represents the point attaching to the ether, and ** represents the point attaching to the pyridine;

Z¹ is Zl-1, Zl-2, Zl-3, Zl-4, Zl-5, Zl-6 or Zl-7, where

represents the point of attachment; and wherein the chemical structures of RX3-1, RX3-2, RX3-3, RX3-4, RX3-5, RX3- 6, RX3-7, RX3-8, RX3-9, RX3-10, RX3-11, RX3-12, Yl-1-1, Yl-1-2, Yl-1-3, Yl-1-4, Yl-1-5, Yl-1-6, Yl-1-7, Yl-1-8, Yl-1-9, Yl-1-10, Yl-1-11, Yl-1-12, Bl-1, Bl-2, Bl-3, Bl-4, Bl-5, Bl-6, Bl-7, Bl-8, Bl-9, Bl-10, Zl-1, Zl-2, Zl-3, Zl-4, Zl-5, Zl-6 and Zl- 7 are depicted in Table 1-C.

In some embodiments, the compounds are of Formula IVa-1. In some embodiments, the compounds are of Formula IVa-2. In other embodiments, the compounds are of Formula IVa-3. In other embodiments, the compounds are of Formula IVa-4. In yet other embodiments, the compounds are of Formula IVb. In yet other embodiments, the compounds are of Formula IVb-1. In yet other embodiments, the compounds are of Formula IVb-2. In specific embodiments, the compounds are of Formula IVb-3. In specific embodiments, the compounds are of Formula IVb-4.

In other embodiments, the invention relates to compounds of Formula Va-1, Va-2, Va-3 or Va-4, wherein:

R^X3 is RX3-1, RX3-2, RX3-3, RX3-4, RX3-5, RX3-6, RX3-7, RX3-8, RX3-9, RX3-10, RX3-11 or RX3-12, where

represents the point of attachment;

Y^1-1 is Yl-1-1, Yl-1-2, Yl-1-3, Yl-1-4, Yl-1-5, Yl-1-6, Yl-1-7, Yl-1-8, Yl-1-

9, Yl-1-10, Yl-1-11 or Yl-1-12, where

represents the point of attachment;

B¹ is Bl-1, Bl-2, Bl-3, Bl-4, Bl-5, Bl-6, Bl-7, Bl-8, Bl-9 or Bl-10, where

represents the points of attachment, * represents the point attaching to the methylene, and ** represents the point attaching to the pyridine; Z¹ is Zl-1, Zl-2, Zl-3, Zl-4, Zl-5, Zl-6 or Zl-7, where represents the point of attachment; and wherein the chemical structures of RX3-1, RX3-2, RX3-3, RX3-4, RX3-5, RX3- 6, RX3-7, RX3-8, RX3-9, RX3-10, RX3-11, RX3-12, Yl-1-1, Yl-1-2, Yl-1-3, Yl-1-4, Yl-1-5, Yl-1-6, Yl-1-7, Yl-1-8, Yl-1-9, Yl-1-10, Yl-1-11, Yl-1-12, Bl-1, Bl-2, Bl-3, Bl-4, Bl-5, Bl-6, Bl-7, Bl-8, Bl-9, Bl-10, Zl-1, Zl-2, Zl-3, Zl-4, Zl-5, Zl-6 and Zl- 7 are depicted in Table 1-C.

In some embodiments, the compounds are of Formula Va-1. In some embodiments, the compounds are of Formula Va-2. In other embodiments, the compounds are of Formula Va-3. In other embodiments, the compounds are of Formula Va-4.

Specific embodiments of the invention include compounds of Formula IVa-1, IVa-2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3, IVb-4, Va-1, Va-2, Va-3 or Va-4, wherein R^X3, Y^1-1, B¹ and Z¹ are defined, in that order, as listed in each row of Table 2-B, and wherein Table 1-C ’ specifies the chemical structures of the groups specified in Table 2-B. In certain embodiments, the compounds are of Formula IVa-1. In certain embodiments, the compounds are of Formula IVa-2. In certain embodiments, the compounds are of Formula IVa-3. In other certain embodiments, the compounds are of Formula IVa-4. In certain embodiments, the compounds are of Formula IVb. In other certain embodiments, the compounds are of Formula IVb-1. In other certain embodiments, the compounds are of Formula IVb-2. In other certain embodiments, the compounds are of Formula IVb-3. In other certain embodiments, the compounds are of Formula IVb-4. In yet other certain embodiments, the compounds are of Formula Va-1. In yet other certain embodiments, the compounds are of Formula Va-2. In yet other certain embodiments, the compounds are of Formula Va-3. In yet other certain embodiments, the compounds are of Formula Va-4. Specific embodiments of the invention include compounds of Formula IVa-1, IVa-2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3, IVb-4, Va-1, Va-2, Va-3 or Va-4, wherein R^X3, Y^1-1, B¹ and Z¹ are defined, in that order, as listed in each row of Table 3-B, and wherein Table 1-C ’ specifies the chemical structures of the groups specified in Table 3-B. In certain embodiments, the compounds are of Formula IVa-1. In certain embodiments, the compounds are of Formula IVa-2. In certain embodiments, the compounds are of Formula IVa-3. In other certain embodiments, the compounds are of Formula IVa-4. In certain embodiments, the compounds are of Formula IVb. In other certain embodiments, the compounds are of Formula IVb-1. In other certain embodiments, the compounds are of Formula IVb-2. In other certain embodiments, the compounds are of Formula IVb-3. In other certain embodiments, the compounds are of Formula IVb-4. In yet other certain embodiments, the compounds are of Formula Va-1. In yet other certain embodiments, the compounds are of Formula Va-2. In yet other certain embodiments, the compounds are of Formula Va-3. In yet other certain embodiments, the compounds are of Formula Va-4.

In certain embodiments, the invention relates to compounds of Formula IVa-1, IVa-2, IVa-3, IVa-4, IVb, IVb-1, IVb-2, IVb-3 or IVb-4, wherein:

R^X3 is RX3-1, RX3-2, RX3-3, RX3-4, RX3-5, RX3-6, RX3-7, RX3-8, RX3-9, RX3-10, RX3-11, RX3-12, RX3-13, RX3-14, RX3-15, RX3-16, RX3-17, RX3-18, RX3-

19 or RX3-20, where

represents the point of attachment;

Y^1-1 is Yl-1-1, Yl-1-2, Yl-1-3, Yl-1-4, Yl-1-5, Yl-1-6, Yl-1-7, Yl-1-8, Yl-1-

9, Yl-1-10, Yl-1-11 or Y1 - 1 - 12, where

represents the point of attachment;

B¹ is Bl-1, Bl-2, Bl-3, Bl-4, Bl-5, Bl-6, Bl-7, Bl-8, Bl-9, Bl-10 or Bl-11, where represents the points of attachment, * represents the point attaching to the ether, and ** represents the point attaching to the pyridine;

Z¹ is Zl-1, Zl-2, Zl-3, Zl-4, Zl-5, Zl-6 or Zl-7, where

represents the point of attachment; and wherein the chemical structures of RX3-1, RX3-2, RX3-3, RX3-4, RX3-5, RX3- 6, RX3-7, RX3-8, RX3-9, RX3-10, RX3-11, RX3-12, RX3-13, RX3-14, RX3-15, RX3- 16, RX3-17, RX3-18, RX3-19, RX3-20, Yl-1-1, Yl-1-2, Yl-1-3, Yl-1-4, Yl-1-5, Yl-1- 6, Yl-1-7, Yl-1-8, Yl-1-9, Yl-1-10, Yl-1-11, Yl-1-12, Bl-1, Bl-2, Bl-3, Bl-4, Bl-5, Bl-6, Bl-7, Bl-8, Bl-9, Bl-10, Bl-11, Zl-1, Zl-2, Zl-3, Zl-4, Zl-5, Zl-6 and Zl-7 are depicted in Table 1-C’.

In certain embodiments, the invention relates to compounds of Formula Va-1, Va- 2, Va-3 or Va-4, wherein:

R^X3 is RX3-1, RX3-2, RX3-3, RX3-4, RX3-5, RX3-6, RX3-7, RX3-8, RX3-9,

RX3-10, RX3-11 or RX3-12, where

represents the point of attachment;

Y^1-1 is Yl-1-1, Yl-1-2, Yl-1-3, Yl-1-4, Yl-1-5, Yl-1-6, Yl-1-7, Yl-1-8, Yl-1-

9, Yl-1-10, Yl-1-11 or Yl-1-12, where

represents the point of attachment;

B¹ is Bl-1, Bl-2, Bl-3, Bl-4, Bl-5, Bl-6, Bl-7, Bl-8, Bl-9 or Bl-10, where

represents the points of attachment, * represents the point attaching to the methylene, and ** represents the point attaching to the pyridine;

Z¹ is Zl-1, Zl-2, Zl-3, Zl-4, Zl-5, Zl-6 or Zl-7, where

represents the point of attachment; and wherein the chemical structures of RX3-1, RX3-2, RX3-3, RX3-4, RX3-5, RX3- 6, RX3-7, RX3-8, RX3-9, RX3-10, RX3-11, RX3-12, Yl-1-1, Yl-1-2, Yl-1-3, Yl-1-4, Yl-1-5, Yl-1-6, Yl-1-7, Yl-1-8, Yl-1-9, Yl-1-10, Yl-1-11, Yl-1-12, Bl-1, Bl-2, Bl-3, Bl-4, Bl-5, Bl-6, Bl-7, Bl-8, Bl-9, Bl-10, Zl-1, Zl-2, Zl-3, Zl-4, Zl-5, Zl-6 and Zl- 7 are depicted in Table 1-C’.

Table 1.

Table 1-A.

Table 1-B.

Table 2-B.

Table 1-C.

Table 1-C’.

Example Methods of Treatment/Use

The compounds described herein are inhibitors of MCL1 and therefore may be useful for treating diseases wherein the underlying pathology is (at least in part) mediated by MCL1 or the dysregulation of its normal activity. Such diseases include cancer and other diseases in which there is a disorder of cell proliferation, apoptosis, or differentiation.

In certain embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject an effective amount of any of the compounds described herein, or a pharmaceutically acceptable salt thereof For example, the cancer may be selected from carcinoma (e.g., a carcinoma of the endometrium, bladder, breast, or colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma)), sarcoma (e.g., a sarcoma such as Kaposi’s, osteosarcoma, tumor of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma), kidney, epidermis, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), esophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, nose, head and neck, prostate, and skin (e.g., squamous cell carcinoma), human breast cancers (e.g., primary breast tumors, node-negative breast cancer, invasive duct adenocarcinomas of the breast, non- endometrioid breast cancers), familial melanoma, and melanoma. Other examples of cancers that may be treated with a compound of the invention include hematopoietic tumors of lymphoid lineage (e.g. leukemia, acute lymphocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, B-cell lymphoma (such as diffuse large B cell lymphoma), T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett’s lymphoma), and hematopoietic tumors of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia. Other cancers include a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; seminoma; teratocarcinoma; xeroderma pigmentosum; retinoblastoma; keratoctanthoma; and thyroid follicular cancer.

In particular embodiments, the cancer is selected from 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 myelogenous leukemia.

In some aspects, the subject is a mammal, for example, a human.

Further disclosed herein are methods of inhibiting MCL1 in a cell comprising contacting said cell with any of the compounds described herein, or a pharmaceutically acceptable salt thereof, such that the function of MCL1 is inhibited in said cell. For example, the cell is a cancer cell. In preferred embodiments, proliferation of the cell is inhibited or cell death is induced.

Further disclosed herein is a method of treating a disease treatable by inhibition of MCL1 in a subject, comprising administering to the subject in recognized need of such treatment, an effective amount of any of the compounds described herein and/or a pharmaceutically acceptable salt thereof Diseases treatable by inhibition of 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 myelogenous leukemia.

The methods of treatment comprise administering a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. Individual embodiments include methods of treating any one of the above-mentioned disorders or diseases by administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

Certain embodiments include a method of 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 a method for the treatment of a disorder or a disease mediated by MCL1 in a subject in need thereof, comprising administering to the subject an effective amount of the compound of Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, IIb-6, IIb-7, IIb-8, IIB-8a, IIb-8b, IIb-9, IIb-10, IIb-10a, IIb-11, IIb-12, IIb-12a, IIb-12b, IIb-13, IIb-14, III, IIIa, IIIa-1, IIIa-2, IIIb, IIIb-1, IIIb-2, IIIb-3, IIIb-4, IIIb-5, IIIb-5a, IIIb-5b, IIIb-6, IIIb-7, IIIb-7a, IIIb-8, IIIb-9, IIIb-10, IIIb-10a, IIIb-10b, IIIb-11, IIIb-12, IIIb-12a, IV, IVa, IVb, IVa-1, IVb-l, IVa-2, IVb-2, IVa-3, IVb-3, IVa-4, IVb-4, V, Va, Va-1, Va-2, Va-3, or Va- 4 or a pharmaceutically acceptable salt thereof. Other embodiments of the invention provide a method of treating a disorder or a disease mediated by MCL1, in a subject in need of treatment thereof comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein the disorder or the disease is selected from carcinomas with genetic aberrations that activate MCL1 activity. These include, but are not limited to, cancers.

The present method also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disorder or disease mediated by MCL1.

In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, is used for the treatment of a disorder or a disease mediated by MCL1.

Yet other embodiments of the present method provide a compound according to Formula I, II, IIa, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, IIb-6, IIb- 7, IIb-8, IIB-8a, IIb-8b, IIb-9, IIb-10, IIb-lOa, IIb-11, IIb-12, IIb-12a, IIb-12b, IIb-13, IIb- 14, III, IIIa, IIIa-1, IIIa-2, IIIb, IIIb-1, IIIb-2, IIIb-3, IIIb-4, IIIb-5, IIIb-5a, IIIb-5b, IIIb-6, IIIb-7, IIIb-7a, IIIb-8, IIIb-9, IIIb-10, IIIb-lOa, IIIb-lOb, IIIb-11, IIIb-12, IIIb-12a, IV, IVa, IVb, IVa-1, IVb-l, IVa-2, IVb-2, IVa-3, IVb-3, IVa-4, IVb-4, V, Va, Va-1, Va-2, Va-3, or Va-43, or a pharmaceutically acceptable salt thereof, for use as a medicament.

Still other embodiments of the present method encompass the use of a compound of Formula I, H, Ila, IIa-1, IIa-2, IIa-3, IIa-4, IIb, IIb-1, IIb-2, IIb-3, IIb-4, IIb-5, IIb-6, IIb-7, IIb-8, HB-8a, IIb-8b, IIb-9, IIb-10, IIb-lOa, IIb-11, IIb-12, IIb-12a, IIb-12b, IIb-13, IIb-14, III, IIIa, IIIa-1, IIIa-2, IIIb, IIIb-1, IIIb-2, IIIb-3, IIIb-4, IIIb-5, IIIb-5a, IIIb-5b, IIIb-6, IIIb-7, IIIb-7a, IIIb-8, IIIb-9, IIIb-10, IIIb-lOa, IIIb-lOb, IIIb-11, IIIb-12, IIIb-12a, IV, IVa, IVb, IVa-1, IVb-1, IVa-2, IVb-2, IVa-3, IVb-3, IVa-4, IVb-4, V, Va, Va-1, Va- 2, Va-3, or Va-4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease mediated by MCL1. EQUIVALENTS

While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

EXEMPLIFICATION

Synthetic Protocols

Compounds as disclosed herein can be synthesized via a number of specific methods. The examples which outline specific synthetic routes, and the generic schemes below are meant to provide guidance to the ordinarily skilled synthetic chemist, who will readily appreciate that the solvent, concentration, reagent, protecting group, order of synthetic steps, time, temperature, and the like can be modified as necessary, well within the skill and judgment of the ordinarily skilled artisan.

Example A: Synthesis of Compounds A2 through A9

Scheme 1. Synthesis of Compound A2

To a mixture of compound Al (140 g, 592.1 mmol, 1.00 eq) in MeOH (554.3 g, 17.3 mol, 700 mL, 29.2 eq) was added H₂SO₄ (116.1 g, 1.18 mol, 63.1 mL, 2.00 eq) at 0 °C. The mixture was stirred at 85 °C for 12 hours. LCMS (product Rt = 0.867 min, m/z = 252.4 (M+l)⁺) showed compound Al was consumed and a main peak with desired MS was formed. The mixture was concentrated under vacuum to give residue which was adjusted to pH 8 by aqueous NaHCO₃. The mixture was extracted with ethyl acetate (1.00 L, 2 times). The combined organic phase was washed with brine (500 mL, 2 times), dried with Na₂SO₄, filtered and concentrated under reduced pressure to yield compound A2 (106.0 g, 415.15 mmol, 70.1% yield, 98.1% purity) as a yellow oil, and was confirmed by LCMS (compound A2 Rt = 0.866 min, m/z = 252.4 (M+l)⁺) and HNMR Compound A2 in its yellow oil state was used directly for the next step.

¹H NMR (400 MHz, CDCl₃):

5 8.60 (s, 1H), 7.65 (s, 1H), 3.95 (s, 3H) ppm.

Scheme 2. Synthesis of Compound A3

To a mixture of compound A2 (106.0 g, 423.2 mmol, 1.00 eq) , Pd2(dba)3 (19.38 g, 21.16 mmol, 0.05 eq), K₂CO₃ (58.5 g, 423.2 mmol, 1.00 eq), and Xantphos (24.5 g, 42.3 mmol, 0.10 eq) in THF/H₂O (530 mL/130 mL) was added drop-wise a solution of BnSH (52.6 g, 423.5 mmol, 49.6 mL, 1.00 eq) in THF (130 mL) at 60 °C under nitrogen atmosphere, and the mixture was stirred at 60 °C for 1 hour. LCMS (product Rt = 1.006 min, m/z = 294.5 ( M+l)⁺) showed compound A2 was consumed and a main peak with 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 vacuum to give a crude product, which was triturated in a solution of ethyl acetate/petroleum ether (1/2, 350 mL) to give impure compound A3 (85.0 g, crude) as green solid, which was confirmed by LC/MS (compound A3 Rt = 1.038 min, m/z = 294.1 (M+l)⁺) and HNMR. Compound A3 was used without further purification.

¹H NMR (400 MHz, CDCl₃):

5 8.29 (s, 1H), 7.68 (s, 1H), 7.34 - 7.21 (m, 5H), 4.17 (s, 2H), 3.40 (s, 3H) ppm. Scheme 3. Synthesis of Compound A4

To a mixture of compound A3 (85.0 g, 289.3 mmol, 1.00 eq) in THF (160 mL) and H₂O (160 mL) was added NaOH (4 M, 144.67 mL, 2.00 eq) 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+l)⁺) showed compound A3 was consumed and the desired MS was found. The mixture was diluted with ethyl acetate (300.0 mL), adjusted to pH~5 with aqueous 6 M HC1. The formed solid was filtered and washed with water (20.0 mL) and dried under vacuum to give crude product, which was triturated in acetonitrile (250.0 mL) and filtered to give compound A4 (71.0 g, 252.3 mmol, 87.2% yield, 99.4% purity) as green solid and confirmed by LCMS (compound A4 Rt = 0.898 min, m/z = 280.0 (M+l)⁺) and HNMR Compound A4 was used without further purification.

¹H NMR (400 MHz, DMSO-d₆):

5 8.51 (s, 1H), 7.74 (s, 1H), 7.28-7.43 (m, 5H), 4.38 (s, 2H) ppm.

Scheme 4. Synthesis of Compound AS

To a mixture of compound A4 (32.0 g, 114.4 mmol, 1.00 eq) and DMF (418.04 mg, 5.72 mmol, 440.0 μL, 0.05 eq) in DCM (350 mL) was added (COC1)₂ (29.0 g, 228.8 mmol, 20.0 mL, 2.00 eq) at 0 °C, and the mixture was stirred at 20 °C for 3 hours. A sample was taken and quenched with a drop of lithium (tert-butoxycarbonyl) amide (prepared THF solution with n-BuLi at -78 °C) and LCMS (compound A5 Rt = 0.996, compound A5 MS = 379.1 (M+l)⁺) showed that most of compound A4 was consumed and a main peak with the desired MS was formed. The mixture was concentrated and coevaporated with DCM (100 mL, 3 times) to give crude compound A5 (68.2 g, crude) as green gum. Compound A5 was used directly without further purification.

Scheme 5. Synthesis of Compound A6

To a mixture of tert-butyl carbamate (20.0 g, 171.0 mmol, 1.50 eq) and TMEDA (19.9 g, 171.0 mmol, 25.8 mL, 1.50 eq) in THF (100.0 mL) was added n-BuLi (2.5 M, 68.4 mL, 1.50 eq) drop- wise at -70 °C, and the formed mixture was stirred at -70 °C for

1 hour. Compound A5 (34.0 g, 114.02 mmol, 1.00 eq) was dissolved in THF (100.0 mL) and added to the previous THF solution at -70 °C. The mixture was stirred at -70 °C for

2 hours. TLC (petroleum ether/ethyl acetate = 5/1, reactant 1 Rf = 0.1, product Rf = 0.3) showed a majority of compound A5 was consumed and a main spot was formed. The mixture was quenched with aqueous NH₄CI (500.0 mL) at -70 °C while stirring, extracted with ethyl acetate (500.0 mL, 3 times), and the organic phase was then washed with brine (600 mL, 2 times), dried over sodium sulfate, filtered and concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1- 3/1) to give impure product (35.0 g) as a yellow solid, which was confirmed by LCMS (product Rt = 0.994 min, m/z = 379.0 (M+l)⁺) and was purified by reversed C18 column chromatography (10%~75% acetonitrile in water +0.1% FA). The eluent was concentrated under vacuum to remove acetonitrile and filtered, and the solid was dried under vacuum to give compound A6 (11.5 g, 30.4 mmol, 13.3% yield, 100% purity) as a white solid, which was confirmed by LCMS (product Rt = 0.981 min, m/z = 378.9 (M+l)⁺) and HNMR.

Compound A6 (8.00 g, 21.12 mmol, 1.00 eq) was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate = 5/1-0/1) to give 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).

NMR (400MHZ, CDCl₃): δ 8.12 (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.

Scheme 6. Synthesis of Compound A7

To a mixture of compound A6 (5.00 g, 13.2 mmol, 1.00 eq) in THF (130.0 mL) was added drop-wise LDA (2 M, 14.5 mL, 2.20 eq) 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 eq) in THF (20.0 mL) was added drop-wise 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 min, m/z = 505.0 (M+l)⁺) showed most of compound A6 was consumed and the desired MS was found. The mixture was quenched by aqueous NH₄CI (100.0 mL), extracted with ethyl acetate (150.0 mL, 2 times) and the organic phase was concentrated under vacuum to give crude product. The crude product was triturated in acetonitrile (35.0 mL) to give a yellow solid confirmed by HPLC (77.1% purity), followed in ethyl acetate/petroleum ether (2/1, 26.0 mL), then filtered and the solid was collected to give 1^st batch of product. The filtrate was concentrated under vacuum to give a residue, which was triturated in ethyl acetate/petroleum ether (2/1, 8.00 mL) to give 2^nd batch of product. The two batches were combined and dried under vacuum to give compound A7 (3.50 g, 6.64 mmol, 50.3% yield, 95.8% purity) as a light yellow solid confirmed by LCMS (compound A7 Rt = 1.031 min, m/z = 504.8 (M+l)⁺) and HNMR. Compound A7 was also confirmed by 2D-NMR in a pilot reaction.

¹H NMR (400 MHz, CDCl₃):

57.80 (s, 1H), 7.50 (s, 1H), 7.10-6.80 (m, 5H), 3.90 (s, 2H), 1.30 (s, 9H) ppm. Scheme 7. Synthesis of Compound A8

To a mixture of compound A7 (3.50 g, 6.93 mmol, 1.00 eq) in DCM (20.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.00 mL, 7.79 eq) at 20 °C and the mixture was stirred at 20 °C for 1 h. TLC (petroleum ether: ethyl acetate = 3/1, product Rf = 0.2) showed compound A7 was consumed and one main spot was formed. The mixture was concentrated under vacuum to give crude product. To the crude product was added ethyl acetate (100.0 mL) and the mixture was adjusted to pH~7 with NaHCO₃, which was extracted with ethyl acetate (100 mL, 2 times) and concentrated under vacuum to give a yellow solid. The solid was triturated with petroleum ether/ethyl acetate (v/v = 1/1, 12.0 mL) to give compound A8 (2.40 g, 5.29 mmol, 76.3% yield, 89.2% purity) as a yellow solid confirmed by LCMS (product Rt = 0.866 min, m/z = 404.7 (M+l)⁺) and HNMR

¹H NMR (400 MHz, DMSO-d₆):

5 8.19 (s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.25-7.33 (m, 5H), 4.28 (s, 2H) ppm.

Scheme 8. Synthesis of Compound A9

To a mixture of compound A8 (2.40 g, 5.93 mmol, 1.00 eq) in DCM (10.0 mL) was added sulfuryl chloride (880.6 mg, 6.52 mmol, 652.3 μL, 1.10 eq) 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+l)⁺) showed compound A8 was consumed and a main peak with the desired MS was formed. The mixture was concentrated under vacuum to give crude product, which was triturated in ethyl acetate (20.0 mL) and dried under vacuum to give compound A9 (1.64 g, 4.75 mmol, 80.0% yield, 90.5% purity) as a light yellow solid confirmed by LCMS (product Rt = 0.682 min, m/z = 312.9 (M+l)⁺), HPLC (94.3% purity) and HNMR

NMR (400 MHz, DMSO-d₆):

59.10 (s, 1H) ppm.

Example D: Synthesis of Compounds D2 through D9

Scheme 27. Synthesis of Compound D2

To a solution of Compound D1 (100 g, 356.0 mmol, 1.0 eq) in THF (900 mL) and MeOH (300 mL) was added trimethylsilyldiazomethane (2 M in hexanes, 195.8 mL, 1.1 eq) drop-wise at 20 °C. The mixture was then stirred at 20 °C for 1 h. Another addition of trimethylsilyldiazomethane (2 M in hexanes, 35.60 mL, 0.2 eq) was added drop-wise and the mixture was stirred at 20 °C for an additional 10 h. The mixture was quenched with water (200 mL) and then adjusted to pH = 9 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (3 x 800 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude yellow oil. The crude product was purified by silica gel chromatography with petroleum ether: ethyl acetate from 50:1 to 10:1 to give Compound D2 (71.0 g, 240.7 mmol, 67.6% yield) as yellow oil.

Scheme 28. Synthesis of Compound D3

To a solution of compound D2 (71 g, 240.74 mmol, 1.0 eq) in dichloromethane (400 mL) was added m-chloroperoxybenzoic acid (78.2 g, 385.2 mmol, 85% purity, 1.6 eq) in portions. The mixture was then stirred at 20 °C for 10 h. The mixture was quenched with saturated sodium bicarbonate and the organic layer was washed with aqueous sodium bicarbonate solution and brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude yellow oil. The crude product was triturated with MTBE (800 mL) to give Compound D3 (65.0 g, 209.1 mmol, 86.8% yield) as white solid.

Scheme 29. Synthesis of Compound D4

Compound. D3 (112.0 g, 360.2 mmol, 1.0 eq) was dissolved in phosphoryl chloride (830.9 g, 5.42 mol, 503.6 mL, 15.0 eq) and heated to 90°C and left to stir for 2 hours. The reaction mixture was concentrated to give a residue. The residue poured into aqueous sodium bicarbonate solution (1000 mL) and stirred at 0 °C for 30 minutes. The aqueous phase was extracted with ethyl acetate (3 x 1000 mL). The combined organic phase was washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 15/1 to 10/1, TLC: petroleum ether/ethyl acetate = 15/1, Rf =0.5) to give Compound D4 (92.0 g, 279.3 mmol, 77.5% yield) as a colorless oil.

Scheme 30. Synthesis of Compound D5

To a mixture of Compound D4 (42.0 g, 127.5 mmol, 1.0 eq), Pd2(dba)3 (5.84 g, 6.38 mmol, 0.05 eq), Xantphos (7.38 g, 12.75 mmol, 0.1 eq), DIEA (16.5 g, 127.5 mmol, 22.2 mL, 1.0 eq) in toluene (150 mL) was added benzyl mercaptan (17.4 g, 140.3 mmol, 16.4 mL, 1.1 eq) in toluene (50 mL) drop-wise at 100°C under nitrogen. The reaction was stirred at 100 °C for 5 hours. The crude mixture was filtered through a pad of celite and the cake was washed with ethyl acetate and the organics were concentrated in vacuo. The crude product was purified by reversed-phase HPLC to give Compound. D5 (20.1 g, 53.9 mmol, 42.3% yield) as a yellow oil.

Scheme 31. Synthesis of Compound D6

To a solution of Compound D5 (20.1 g, 53.9 mmol, 1.0 eq) in pyridine (400 mL) was added lithium iodide (28.9 g, 215.7 mmol, 8.27 mL, 4.0 eq). The reaction was stirred at 120 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was diluted with aqueous HC1 (1.0 M, 1000 mL) and extracted with ethyl acetate (3 x100O mL). The combined organic layers were washed with brine (1000 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude residue. The crude product was triturated with ethyl acetate (2 N) at 50 °C for 30 min to give Compound D6 (10.6 g, 29.6 mmol, 54.8% yield) as an off-white solid.

Scheme 32. Synthesis of Compound D7

To a solution of Compound D6 (10.6 g, 29.56 mmol, 1.0 eq) and dimethylformamide (216.0 mg, 2.96 mmol, 227.4 uL, 0.1 eq) in dichloromethane (150 mL) was added oxalyl chloride (7.50 g, 59.1 mmol, 5.17 mL, 2.0 eq) at 0 °C. The reaction was stirred at 15 °C for 2 hours. The reaction mixture was concentrated in vacuo to remove dichloromethane to give Compound D7 (10.2 g, 27.1 mmol, 91.5% yield) as a brown oil and was used in next step directly. Scheme 33. Synthesis of Compound D8

Ammonia (460.67 mg, 27.05 mmol, 1 eq) was bubbled into THF (500 mL) at 10 °C for 30 minutes. Compound D7 (10.2 g, 27.1 mmol, 1.0 eq) was added to the ammonia solution at 15 °C. The reaction was stirred at 15 °C for 1 hour. The reaction mixture was concentrated in vacuo to remove THF. The residue was diluted with water (500 mL) and extracted with dichloromethane (2 x 500 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give Compound D8 (8.5 g, 23.8 mmol, 87.9% yield) as a brown solid was used to next step directly.

Scheme 34. Synthesis of Compound D9

To a solution of Compound D8 (8.5 g, 23.8 mmol, 1.0 eq) in dichloromethane (150 mL) was added sulfuryl chloride (3.53 g, 26.1 mmol, 2.61 mL, 1.1 eq) was stirred at 15 °C for 1 hour. The product was collected by filtration and the cake was washed with dichloromethane (100 mL) and dried under high vacuum to give Compound D9 (5.5 g, 20.7 mmol, 87.2% yield) as a yellow solid.

LC/MS: m/z = 264.9 [M+H]⁺ amu.

¾ NMR (400 MHz, DMSO) δ 9.15 (s, 1H).

Uses for Compound D9 as Intermediate

Compound D9 can be used in place of Compound A9 in reactions detailed herein, particularly in those reactions that are part of the synthesis of compounds of the invention (e.g., Step 1 of Scheme 20. Synthesis of Compound 1; Step 1 of Scheme 22. Synthesis of Compound 7; Step 5 of Scheme 23. Synthesis of Compound 8; Step 3 of Scheme 25. Synthesis of Compound 10; and Step 3 of Scheme 26. Synthesis of Compound 11\ A person of ordinary skill in the art would readily understand that the same or similar reactions conditions can be used with Compound D9 as those used with Compound A9, and furthermore, if desired, the person of ordinary skill in the art would readily understand how to optimize said reaction conditions to better obtain the desired product of reactions using Compound D9.

Example B: Synthesis of Compound Bl

Scheme 9. Synthesis of Compound Bl

Step 1: Synthesis of (S)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 4- methylbenzenesulfonate

(R)-(2,2-dimethyl- 1 ,3 -dioxolan-4-yl)methanol

(10.1g, 76.4mmol) was dissolved in anhydrous DCM (125 mL) and treated with Et₃N (16.mL, 115mmol) and DMAP (932mg, 7.63mmol), then the mixture was cooled to 0°C and tosyl chloride (16.76g, 87.9mmol) was added portionwise. After lOmin, the mixture was allowed to warm to rt and stirred for 90min. The mixture was diluted with a little hexanes and filtered. The filtrate was adsorbed onto silica and eluted with 0, 5 then 20% EtOAc in hexanes. The product-containing fractions were pooled and filtered through a thin pad of silica gel rinsing with 7:3 hexanes: EtOAc to give the title compound (20.81g, 95%) as a colorless light oil.

Rf = 0.54 (6:4 hexanes: EtOAc)

LC/MS, ESI [M+H]⁺ = 287.1 m/z

¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, J= 8.0 Hz, 2H), 7.35 (d, J= 8.1 Hz, 2H), 4.30 - 4.23 (m, 1H), 4.00 (ddq, J= 20.1, 10.1, 5.5, 4.9 Hz, 3H), 3.76 (dd, J= 8.3, 5.3 Hz, 1H), 2.45 (s, 3H), 1.33 (s, 3H), 1.30 (s, 3H)

Step 2: Synthesis of (S)-2,3-Dihydroxypropyl 4-methylbenzenesulfonate (S)-(2,2-Dimethyl-l ,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (7.63g, 26.63 mmol) was treated with acetone (13.5mL) and IN HC1 (13.5mL) and warmed to 60 °C. After 40min, the mixture was concentrated by rotary evaporation and the oily residue was taken up in DCM and dried over MgSO₄, filtered, and concentrated to give the title compound (6.92g, quant.) as a colorless oil which crystallized upon standing.

LC/MS, ESI [M+H]⁺ = 247.1 m/z

Step 3: Synthesis of (S)-3-(bis(4-Methoxyphenyl)(phenyl)methoxy)-2-hydroxypropyl 4- methylbenzenesulfonate

(S)-2,3-dihydroxypropyl 4-methylbenzenesulfonate (6.56g, 26.6mmol) was dissolved in anhydrous DCM (90mL) and treated with 4,4'-dimethoxytrityl chloride (9.48g, 28.0mmol), and the mixture was cooled to 0°C, then anhydrous iPr₂EtN (4.6mL, 40mmol) was added dropwise. After lOmin, additional iPr₂EtN (ImL) was added, and stirring was continued for Ihr. The mixture was washed with sat NH₄CI (75mL) and the organic phase was collected and the aqueous extracted once with DCM. The combined extract was dried over MgSO₄, filtered through a thin pad of silica gel rinsing with 1 : 1 hexanes: EtOAc, and concentrated. The residue was dissolved in DCM and purified by flash column chromatography on silica gel eluted with 0→ 25;25→ 60% EtOAc in hexanes to give the title compound (16.16g, >100%) as a yellow colored, vitreous oil. Rf= 0.33 (1:1 hexanes: EtOAc)

¹H NMR (400 MHz, DMSO-d₆): δ 7.78 - 7.73 (m, 2H), 7.48 - 7.42 (m, 2H), 7.32 - 7.26 (m, 4H), 7.25 - 7.18 (m, 2H), 7.15 (dd, J= 9.0, 1.2 Hz, 4H), 6.90 - 6.84 (m, 4H), 4.09 - 3.92 (m, 2H), 3.74 (s, 7H), 2.94 (dd, J= 9.2, 5.2 Hz, 1H), 2.84 (dd, J= 9.3, 6.8 Hz, 1H), 2.39 (s, 3H)

¹³C NMR (101 MHZ, DMSO-d₆): δ 158.06, 144.88, 144.79, 135.49, 132.07, 130.12, 129.61, 127.78, 127.64, 127.57, 126.63, 113.12, 85.34, 71.78, 67.15, 63.49, 55.03, 21.10

Step 4: Synthesis of (R)-3-(bis(4-Methoxyphenyl)(phenyl)methoxy)-2-(4-bromo-2,6- dichlorophenoxylpropyl 4-methylbenzenesulfonate

(S)-3 -(bis(4-methoxypheny l)(phenyl)methoxy)-2-hydroxypropyl 4- methylbenzenesulfonate (2.13g, 3.88mmol), 4-bromo-2,6-dichlorophenol (1.41g, 5.83mmol), and PPh₃ (1.53g, 5.83mmol) were co-evaporated from anhydrous THF, further dried in vacuo, then reconstituted in anhydrous THF (16 mL). DBAD (1.34g, 5.82 mmol) was then added dropwise as a solution in anhydrous THF (10 mL) over a period of approximately lOmin and the mixture was warmed to 45 °C for 5hrs then cooled to rt. The mixture was diluted with Et2O and washed with 5% K₂CO₃ (x3), brine, dried over Na₂SO₄, filtered, and concentrated. The residue was dissolved in hexanes/DCM and purified by flash column chromatography on silica gel eluted with 0→ 25% EtOAc in hexanes to give the title compound (4.016g, >100%) as a white semi-solid residue which remained contaminated by di-tert-butyl hydrazine- 1,2-dicarboxy late.

LC/MS, ESI [M+H]⁺ = 795.0 m/z Rf = 0.49 (7:3 hexanes: EtOAc) NMR (400 MHz, CDCl₃) δ 7.79 - 7.64 (m, 2H), 7.39 - 7.13 (m, 13H), 6.86 - 6.72 (m, 4H), 4.56 - 4.33 (m, 3H), 4.01 - 3.83 (m, 1H), 3.79 (s, 6H), 3.52 - 3.36 (m, 1H), 2.44 (d, J = 10.4 Hz, 3H)

Step 5: Synthesis of Compound Bl ((R)-3-(bis(4-Methoxyphenyl)(phenyl)methoxy)-2-

(2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl 4- methylbenzenesulfonate)

In a sealed vial, (R)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)-2-(4-bromo-2,6- dichlorophenoxy)propyl 4-methylbenzenesulfonate (508mg, 0.658mmol) was treated with bis(pinacolato)diboron (200mg, 0.789mmol), NaOAc (81 mg, 0.99mmol), Pd(dppf)Cl₂ (15mg, 0.021mmol), and 2-methyl-THF (3.5mL). The mixture was cooled to -78 °C and degassed by three freeze-pump-thaw cycles then heated to 80 °C. After 17hr, the reaction was cooled to rt, amended with additional NaOAc (81 mg, 0.99mmol), bis(pinacolato)diboron (200mg, 0.789mmol), and Pd(dppf)Cl₂ (30mg, 0.042mmol), sparged with N₂ for 10min, then heated to 100 °C for 24hr. The mixture was cooled to rt, diluted with EtOAc, filtered through Celite, and concentrated. The residue was dissolved in hexanes:DCM and purified by flash column chromatography on silica gel, and eluted with 0→ 40% EtOAc in hexanes to give the title compound (431 mg, 80%) as an off-white semi-solid residue.

Rf = 0.36 (7:3 hexanes: EtOAc)

LC/MS, ESI [M+Na]⁺ = 841.1 m/z

Synthesis of Compound. Bl Analogs

Additional compounds are prepared using the methods disclosed herein by replacing the phenol (i.e. 4-bromo-2,6-dichlorophenol) in Scheme 9 with an alternative phenol to produce the analog of intermediate compound Bl required to prepare additional macrocyclic compounds.

Examples of alternative phenols that are used include, but are not limited to: 4- bromophenol, 4-bromo-2,6-difluoro-3-methylphenol, 4-bromo-2,6-dichloro-3- methylphenol, 4-bromo-2,6-dichlorophenol, 4-bromo-2-chloro-3 -methylphenol, 4- bromo-2-fluoro-3 -methylphenol, 4-bromo-2,3-difluorophenol, 4-bromo-2-fluoro-5- methylphenol, 4-bromo-2,3-dimethylphenol, 4-bromo-3-methylphenol, 4-bromo-2- chloro-5-methylphenol, 4-bromo-2,6-dichlorophenol, 4-bromo-2,6-difluorophenol, 4- bromo-6-chloro-2-fluoro-3-methylphenol, 4-bromo-3,5-dimethylphenol, 4-bromo-2- chloro-6-fluoro-3 -methylphenol and 4-bromo-2,6-dichloro-3,5-dimethylphenol.

Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired phenols, or obtain them from chemical vendors.

Synthesis of Compound. Bl Enantiomer

The enantiomer of Compound Bl is synthesized using (S)-(2,2-dimethyl-l,3- dioxolan-4-yl)methanol in step 1 of Scheme 9 instead of (R)-(2,2-dimethyl-l,3-dioxolan- 4-yl)methanol. The enantiomer of of Compound Bl is also used to prepare additional macrocyclic compounds.

The skilled artisan could use procedures established by the art to synthesize or prepare (S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol, or obtain it from a chemical vendor. Enantiomers of Compound Bl analogs are prepared in the same way.

Scheme 10. Synthesis of Compound B2

Step 1: Synthesis of (S)-2-Hydroxy-3-((2-(trimethylsilyl)ethoxy)methoxy)propyl 4- methylbenzenesulfonate

(S)-2,3-Dihydroxypropyl 4-methylbenzenesulfonate (3.09g, 12.6mmol) was dissolved in anhydrous DCM (31.4mL) and cooled to 0 °C then treated with anhydrous iPr₂EtN (1.8mL, 15.5mmol) followed by dropwise addition of SEM-CI (2.3mL, 13 mmol). After 75min, additional iPr₂EtN (900uL) and SEM-CI (l.lmL) was added. After 3hrs, the mixture was diluted with DCM and washed with half-saturated NaHCO₃. The aqueous was extracted once with DCM and the combined extract was dried over Na₂SO₄, filtered, and concentrated. Purification by flash column chromatography on silica gel eluted with 0→ 50% EtOAc in hexanes afforded the title compound (2.229g, 47.1%) as a colorless oil. Rf = 0.47 (6:4 hexanes:EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J= 7.9 Hz, 2H), 7.34 (d, J= 7.9 Hz, 2H), 4.63 (s, 2H), 4.11 - 4.00 (m, 2H), 4.00 - 3.91 (m, 1H), 3.68 - 3.55 (m, 4H), 2.44 (s, 3H), 0.92 (t, J= 8.5 Hz, 2H), 0.01 (s, 9H).

Step 2: Synthesis of Compound B2 ((R)-2-(2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methoxy)propyl 4- methylbenzenesulfonate)

(S)-2-Hydroxy-3-((2-(trimethylsilyl)ethoxy)methoxy)propyl 4- methylbenzenesulfonate (1.16g, 3.07mmol), 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenol (989mg, 3.68mmol), and PPh₃ (1.21g, 4.61mmol) were dissolved in anhydrous THF (7mL) and cooled to 0 °C. Separately, DBAD (1.06g, 4.6mmol) was dissolved in anhydrous THF (6mL) then added drop wise via syringe pump over a period of 30min. After an additional 30min, the mixture was allowed to warm to rt and stirred overnight. Additional PPh3 (403mg, 1.54mmol) and DBAD (353mg, 1.53 mmol) was added and the mixture was heated to 45C for 2hrs. The mixture was cooled to rt, diluted with Et2O, and washed with 5% K₂CO₃ (x3), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel eluted with 0→ 30% EtOAc in hexanes to give the title compound (922.5mg, 47.9%) a₅ a faintly yellow, viscous oil. Rf = 0.51 (7:3 hexanes: EtOAc)

¹H NMR (400 MHz, CDCl₃): δ 7.78 - 7.71 (m, 2H), 7.57 (d, J= 8.3 Hz, 1H), 7.30 - 7.23 (m, 2H), 6.73 (d, J= 8.4 Hz, 1H), 4.63 (d, J= 11.9 Hz, 3H), 4.33 (dd, J= 10.7, 4.6 Hz, 1H), 4.29 - 4.24 (m, 1H), 3.76 (d, J= 5.1 Hz, 2H), 3.58 (dd, J= 9.6, 7.3 Hz, 2H), 2.57 (s, 3H), 2.41 (s, 3H), 1.34 (s, 12H), 0.90 (t, J= 8.4 Hz, 2H), -0.00 (s, 9H) Synthesis of Compound. B2 Analogs

Additional compounds are prepared using the methods disclosed herein by replacing the boronate ester (i.e. 2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenol) in Scheme 10 with an alternative boronate ester to produce the analog of intermediate compound B2 required to prepare additional macrocyclic compounds.

Examples of alternative boronate esters that are used include, but are not limited to: 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol, 2,6-difluoro-3-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol, 2,6-dichloro-3-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenol, 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenol, 2-chloro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenol, 2-chloro-6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)phenol, 6-chloro-2-fluoro-3-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)phenol, 2-fluoro-3-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan- 2-yl)phenol, 2,3-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol, 2,3- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol, 3-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenol, 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenol, 2,6-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenol, 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol and 2,6- dichloro-3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol.

Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired boronate esters, or obtain them from chemical vendors.

Synthesis of Compound B2 Enantiomer

The enantiomer of Compound B2 is synthesized using (R)-2,3-dihydroxypropyl 4- methylbenzenesulfonate in step 1 of Schme 10 instead of (S)-2,3-dihydroxypropyl 4- methylbenzenesulfonate. (R)-2, 3 -dihydroxypropyl 4-methylbenzenesulfonate is prepared following the first two steps of the procedure to synthesize Compound Bl and using (S)- (2,2-dimethyl-l,3-dioxolan-4-yl)methanol a₅ the starting material. Alternatively, (R)-2,3- dihydroxypropyl 4-methylbenzenesulfonate may be obtained from a chemical vendor. Enantiomers of Compound B2 analogs are prepared in the same way. The enantiomer of of Compound B2 is also used to prepare additional compounds.

Scheme 11. Synthesis of Compound. B3 and B3 Analogs

Compound B3 is prepared using the method described in Scheme 11.

Additional compounds are prepared using the methods disclosed herein by replacing the aldehyde (i.e. 4-bromo-2-chlorobenzaldehyde) in Scheme 11 with an alternative aldehyde to produce the analog of intermediate compound B3 required to prepare additional macrocyclic compounds.

Examples of alternative aldehydes that are used include, but are not limited to: 4- bromo-2,6-dichlorobenzaldehyde, 4-bromo-2-fluorobenzaldehyde, 4-bromo-2,3- difluorobenzaldehyde, 4-bromobenzaldehyde, 4-bromo-2,6-difluorobenzaldehyde, 4- bromo-3 -methylbenzaldehyde, 4-bromo-2,6-dichloro-3-methylbenzaldehyde, 4-bromo-2- chloro-5-methylbenzaldehyde, 4-bromo-2,6-difluoro-3-methylbenzaldehyde, 4-bromo-2- fluoro-5-methylbenzaldehyde, 4-bromo-2, 3 -dimethylbenzaldehyde and 4-bromo-3,5- dimethylbenzaldehyde. It is readily apparent to the skilled artisan that aldehydes such a₅ 4-bromo-3 -methylbenzaldehyde, 4-bromo-2, 3 -dimethylbenzaldehyde and 4-bromo-3,5- dimethylbenzaldehyde would not require step 2. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired aldehydes, or obtain them from chemical vendors. Scheme 12. Synthesis of Compound. B4 and B4 Analogs

Compound B4 is prepared using the methods described in Scheme 12.

Additional compounds are prepared using the methods disclosed herein by replacing the phenol (i.e. 4-bromo-2-chlorophenol) in Scheme 12 with an alternative phenol to produce the analog of intermediate compound B4 required to prepare additional macrocyclic compounds.

Examples of alternative phenols that are used include but are not limited to: 4- bromophenol, 4-bromo-2-chloro-3-methylphenol, 4-bromo-2-fluoro-3-methylphenol, 4- bromo-2,3-difluorophenol, 4-bromo-2,3-dimethylphenol, 4-bromo-3 -methylphenol, 4- bromo-2,6-dichlorophenol, 4-bromo-2,6-difluorophenol, 4-bromo-3,5-dimethylphenol and 4-bromo-2,6-dichloro-3,5-dimethylphenol. It is readily apparent to the skilled artisan that phenols such a₅ 4-bromo-2-chloro-3 -methylphenol, 4-bromo-2-fluoro-3- methylphenol, 4-bromo-2,3-dimethylphenol, 4-bromo-3-methylphenol, 4-bromo-3,5- dimethylphenol and 4-bromo-2,6-dichloro-3,5-dimethylphenol would not require step 2. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired phenols, or obtain them from chemical vendors.

Scheme 13. Synthesis of Compound B5 and B5 Analogs

Compound B5 is prepared using the methods described in Scheme 13. The corresponding analogs of Compound B5 are synthesized using analogs of

Compound B4.

Scheme 14. Synthesis of Compound. B6 and B6 Analogs

Compound B6 is prepared using the methods described in Scheme 14.

Additional compounds are prepared using the methods disclosed herein by replacing the 1,3-dioxane (i.e. 2-(4-bromo-2-chloro-3-methylphenyl)-l,3-dioxane) in

Scheme 14 with an alternative 1,3-dioxane to produce the analog of intermediate compound B6 required to prepare additional macrocyclic compounds.

Scheme 15. Synthesis of Compound B7 and B7 Analogs

Compound B7 is prepared using the methods described in Scheme 15. Additional compounds are prepared using the methods disclosed herein by replacing the aniline (i.e. 2-chloro-3-methylaniline) in Scheme 15 with an alternative aniline to produce the analog of intermediate compound B7required to prepare additional macrocyclic compounds.

Examples of alternative anilines that are used include, but are not limited to: aniline, 2,6-dichloroaniline, 2, 6-dichloro-3 -methylaniline, 2-fluoroaniline, 2,3- difluoroaniline, aniline, 2,6-difluoroaniline, 2,6-difluoro-3-methylaniline, zn-toluidine, 2,3-dimethylaniline, 3, 5 -dimethylaniline, 2-chloro-5-methylaniline and 2-fluoro-5- methylaniline. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired anilines, or obtain them from chemical vendors.

Example C: Synthesis of Compound Cl, Compound Cl’, Compound C2,

Compound C2’, Compound C3 and Compound C4

Scheme 16. Synthesis of Compound. Cl

Step 1 : Synthesis of ethyl 2-acetoxy-2-(diethoxyphosphoryl)acetate

To a solution of ethyl 2-oxoacetate (200g, 980mmol) in toluene (1.0L) wa₅ added diethyl phosphonate (135g, 980mmol, 126 mL) at 0 °C in portions. Et₃N (297g, 2.94mol) wa₅ added to the mixture at 0 °C and the resulting mixture wa₅ stirred at 25 °C for 1 hr. Acetic anhydride (91.7mL, 980 mmol) wa₅ added to the mixture at 0 °C and the resulting mixture wa₅ stirred at 25 °C for 11 hours. The pH of the mixture wa₅ adjusted to 6 with 2 N HC1 and the resulting solution wa₅ extracted with EtO Ac (500 mL x 3). The combined extract wa₅ dried over Na₂SO₄ and concentrated to give the title compound (230g, 83.2%) as a brown oil, which was used in the next step without purification.

Rr = 0.3 (1:1 heptane: EtO Ac) LC/MS, ESI [M+H]⁺ = 283.1 m/z

¹H NMR (400 MHz, CDCl₃) δ 5.37-5.42 (m, 1H), 4.13-4.26 (m, 1H), 2.19 (s, 3H), 1.33 (dt, J = 6.8, 2.4 Hz, 6H), 1.28 (t, J = 7.6 Hz, 3H)

Step 2: Synthesis of 2-(benzyloxy)-5-hydroxybenzaldehyde

To a mixture of 2,5-dihydroxybenzaldehyde (150 g, 1.09 mol) and K₂CO₃ (375 g, 2.72 mol) in DMF (750 mL) was added BnBr (223 g, 1.30 mol) dropwise at a rate sufficient to maintain an internal temperature of 15-20 °C. The mixture was stirred at 20 °C for 12 hrs then poured into water (1.0L) and extracted with MTBE (500 mL x 3). The combined extract was washed with NaOH (1 M, 300 mL). The pH of the aqueous layer was adjusted to 2-3 with HC1 (2 M) and extracted with MTBE (300 mL x 3). The combined extract was dried over Na₂SO₄ and concentrated to give the crude product (120 g, 45.4%) as a brown solid, which was used directly without purification.

Rf = 0.4 (2:1 heptane: EtO Ac)

NMR (400 MHz, CDCl₃): δ 10.48 (s, 1H), 7.36-7.42 (m, 6H), 7.11 (dd, J= 8.8, 3.2 Hz, 1H), 6.98 (d, J= 8.8 Hz, 1H), 5.15 (s, 2H)

Step 3: Synthesis of 2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)benzaldehyde

To a solution of 2-(benzyloxy)-5-hydroxybenzaldehyde (110 g, 482 mmol) and imidazole (65.6 g, 964 mmol) in DCM (550 mL) was added TBSC1 (87.2 g, 578 mmol) in portions at a rate sufficient to maintain an internal temperature of 5-10 °C. The mixture was then stirred at 20 °C for 12 hours. The mixture was filtered and the filter cake was washed with EtOAc (300 mL). The filtrate was washed with water (300 mL) and the aqueous layer was extracted with EtOAc (300 mL x 2). The combined extract was dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel (n-heptane/EtOAc = 8:1 → 3:1) to give the title compound (153 g, 93%) as a yellow oil.

Rf = 0.6 (4:1 heptane: EtOAc)

LC/MS, ESI [M+Na]⁺ = 365.1 m/z

NMR (400 MHz, CDCl₃): δ 10.50 (s, 1H), 7.39-7.45 (m, 5H), 7.30 (d, J= 3.2 Hz, 1H), 7.03 (dd, J= 8.8, 3.2 Hz, 1H), 6.95 (d, J= 8.8 Hz, 1H), 5.15 (s, 2H), 0.98 (s, 9H), 0.19 (s, 6H)

Step 4: Synthesis of ethyl 2-acetoxy-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acrylate

To a solution of 2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)benzaldehyde (190 g, 674 mmol) in THF (500 mL) was added CS₂CO₃ (314 g, 963 mmol) at 20 °C under N₂. Ethyl 2-acetoxy-2-(diethoxyphosphoryl)acetate (165 g, 482 mmol) in THF (350 mL) was added to the mixture at 0-5 °C under N₂. The mixture was stirred at 20 °C for 12 hours then the mixture washed with brine (400 mL) and the aqueous layer was extracted with EtOAc (500 mL x 2). The combined extract was dried over Na₂SO₄, concentrated, and purified by column chromatography on silica gel (n-heptane/EtOAc = 10: 1 → 3: 1) to give the product (130 g, 56.9%, 2.2: 1 E/Z) as a yellow oil.

Rf = 0.45 (4:1 heptane:EtOAc)

¹H NMR (400 MHz, CDCl₃) δ δ 7.81 (s, 1H), 7.33-7.45 (m, 5H), 6.82-6.91 (m, 1H), 6.77-6.81 (m, 1H), 5.03-5.08 (m, 2H), 4.11-4.34 (m, 2H), 2.25-2.32 (m, 3H), 1.14-1.38 (m, 3H), 0.95-0.97 (m, 9H), 0.15-0.17 (m, 6H)

Step 5: Synthesis of

Ethyl 2-acetoxy-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)propanoate

Three reactions were carried out in parallel. To a solution of ethyl 2-acetoxy-3-(2- (benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acrylate (15.0 g, 31.9 mmol) in MeOH (75.0 mL) was added Rh/C (3.00 g, 50% purity, 5%) under N₂ at 20 °C. The mixture was degassed and purged with H₂ (45 psi) three times. The resulting mixture was heated to 25 °C and stirred for 1 hour. The reaction mixtures were filtered and the combined filtrate was concentrated. The residue was purified by column chromatography on silica gel (n-heptane:EtOAc 8:1 → 3:1) to give the title compound (30.0 g, 66.4%) as a yellow colored heavy oil.

Rf = 0.5 (4:1 heptane: EtOAc)

NMR (400 MHz, CDCl₃) δ 7.32-7.47 (m, 5H), 6.77-6.80 (m, 1H), 6.68-6.70 (m, 2H), 5.29 (dd, J= 9.6, 4.4 Hz, 1H), 5.03-5.06 (m, 2H), 4.14-4.20 (m, 2H), 3.33 (dd, J= 13.6, 4.4 Hz, 1H), 2.96 (dd, J= 14.0, 9.6 Hz, 1H), 2.05 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H), 0.98 (s, 9H), 0.17 (s, 6H)

Step 6: Synthesis of

Ethyl 3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)-2-hydroxypropanoate

To a solution of Ethyl 2-acetoxy-3-(2-(benzyloxy)-5-((tert- butyldimethylsilyl)oxy)phenyl)propanoate (30.0 g, 63.5 mmol) in EtOH (150 mL) was added K₂CO₃ (35.1 g, 254 mmol) in one portion and the mixture was stirred at 20 °C for 2 hrs. The suspension was filtered and the filter cake was washed with EtOAc (50.0 mL x 2). The filtrate was concentrated and purified by column chromatography on silica gel (n-heptane:EtOAc 10:1 3:1) to give the title compound (23.0 g, 84.2%) as a yellow oil.

Rf = 0.3 (4:1 heptane: EtOAc)

NMR (400 MHz, CDCl₃) δ 7.37-7.45 (m, 5H), 6.79 (d, J= 8.8 Hz, 1H), 6.72 (d, J = 3.2 Hz, 1H), 6.68 (dd, J= 8.4, 2.8 Hz, 1H), 5.04-5.08 (m, 2H), 4.47-4.48 (m, 1H), 4.10- 4.19 (m, 2H), 3.19 (dd, J= 13.6, 4.4 Hz, 1H), 2.88-2.97 (m, 2H), 1.21 (t, J= 6.8 Hz, 3H), 0.98 (s, 9H), 0.18 (s, 6H)

Step 7: Resolution of

Ethyl (R)-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)-2-hydroxypropanoate

Ethyl 3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)-2- hydroxypropanoate (63.0g, 144.4mmol) was resolved by SFC (ChiralPak AS, CO₂/:iPrOH + 0.05% Et2NH, 100bar) to give the title compound (17.9 g, 28.4% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.45 (m, 5H), 6.79 (d, J= 8.8 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 6.68 (dd, J= 8.8, 3.2 Hz, 1H), 5.04-5.08 (m, 2H), 4.48-4.49 (m, 1H), 4.10- 4.21 (m, 2H), 3.19 (dd, J= 13.6, 4.4 Hz, 1H), 2.90-2.97 (m, 2H), 1.22 (t, J= 6.8 Hz, 3H), 0.98 (s, 9H), 0.18 (s, 6H)

Step 8: Resolution of Compound Cl (Ethyl (S)-3-(2-(benzyloxy)-5-((tert- butyldimethylsilyl)oxy)phenyl)-2-hydroxypropanoate)

The title compound (19.5 g, 31.0%) was obtained as a yellow oil by SFC resolution of the racemate as described for the R -enantiomer.

Synthesis of Compound. Cl ’

Scheme 16’. Synthesis of Compound Cl ’

Synthesis of Compound Cl ’ (ethyl (S)-2-acetoxy-3-(2-(benzyloxy)-5-((tert- butyldimethylsilyl)oxy)phenyl)propanoate)

To a mixture of ethyl 2-acetoxy-3-(2-(benzyloxy)-5-((tert- butyldimethylsilyl)oxy)phenyl)acrylate (35.0 g, 74.4 mmol, 1.00 eq) in MeOH (175 mL) was added Et(R,R)DUPHOS-Rh (1.77 g, 2.45 mmol, 0.033 eq) under Ar at 20 °C. The mixture was degassed and purged with H₂ three times. The result mixture was heated to 50 °C and stirred under H₂ (50 psi) for 12 h. The reaction mixture was filtered and the filter cake was washed with MeOH (2 x 60 mL). The filtrate was concentrated in vacuo at 45 °C to give the title compound (crude 34.0 g, 71.94 mmol) as a yellow oil.

NMR (400 MHz CDCl₃) δ 7.33-7.48 (m, 6H), 6.79 (d, J= 8.0 Hz, 1H), 6.68-6.71 (m, 2H), 5.30 (q, J= 5.2 Hz, 1H), 5.05 (d, J= 5.2 Hz , 2H), 4.13-4.20 (m, 2H), 3.33 (dd, J = 13.6, 4.4 Hz, 1H), 2.94-3.00 (m, 1H), 2.05 (s, 3H), 1.21 (t, J= 7.2 Hz, 3H), 0.99 (s , 9H), 0.18 (s , 6H).

LC/MS: m/z = 495.1 [M+Na]⁺ amu.

Scheme 17. Synthesis of Compound. C2

Step 1: Synthesis of (R)-3-(2-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)-l- ethoxy-l-oxopropan-2-yl benzoate

To a solution of ethyl (S)-3-(2-(benzyloxy)-5-((tert- butyldimethylsilyl)oxy)phenyl)-2-hydroxypropanoate (10 g, 23 mmol) in THF (500 mL) was added benzoic acid (3.40 g, 27.9 mmol) and PPh₃ (9.14 g, 34.8 mmol), and the resulting mixture was stirred for 5 minutes at ambient temperature then DBAD (8.02 g, 34.83 mmol) was added as a solid in a single portion. The resulting mixture was stirred at 25°C 3hrs. The mixture was partitioned between EtOAc (200 mL) and water (200 mL) and the aqueous layer was extracted with EtOAc (100 mL). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:EtOAc 20:1→ 10:1) to give the title compound (10.8 g, 87.0%) as a colorless oil.

Rf = 0.63 (4:1 petroleum ether:EtOAc)

NMR (500 MHz, CDCl₃): δ 8.04 - 7.99 (m, 2H), 7.57 - 7.51 (m, 1H), 7.48 - 7.44 (m, 2H), 7.38 (q, J= 7.8 Hz, 4H), 7.32 - 7.28 (m, 1H), 6.81 - 6.75 (m, 2H), 6.66 (dd, J= 8.7, 2.9 Hz, 1H), 5.52 (dd, J= 9.5, 4.3 Hz, 1H), 5.10 - 5.01 (m, 2H), 4.26 - 4.09 (m, 2H), 3.46 (dd, J= 13.9, 4.3 Hz, 1H), 3.15 (dd, J= 13.9, 9.5 Hz, 1H), 1.23 (t, J= 7.1 Hz, 3H), 0.95 (s, 9H), 0.12 (d, J= 3.0 Hz, 6H)

Step 2: Synthesis of (R)-3-(5-((tert-Butyldimethylsilyl)oxy)-2-hydroxyphenyl)-l-ethoxy- l-oxopropan-2-yl benzoate

(R)-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)- 1 -ethoxy- 1 - oxopropan-2-yl benzoate (10.8 g, 20.2 mmol) was dissolved in EtOH (108 mL) and Pd/C (1.1 g, 10% purity) was added. The vessel was evacuated and backfilled with N₂ x3, then evacuated and backfilled with H₂ x3, fitted with balloon of H₂, and stirred at 25°C for 12 hours. The mixture was filtered through Celite and concentrated to give the title compound (8.70 g, 96.9%) as a colorless oil.

Rf = 0.45 (5:1 petroleum ether:EtOAc).

LC/MS: m/z = 445.2 [M+H]⁺ amu

Step 3: Synthesis of (R)-3-(5-((tert-Butyldimethylsilyl)oxy)-2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-l -ethoxy- 1 -oxopropan-2-yl benzoate

To a solution of (R)-3-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)-l- ethoxy-l-oxopropan-2-yl benzoate (6.60 g, 14.9 mmol) in THF (360 mL) was added (2- (2-methoxyphenyl)pyrimidin-4-yl)methanol (3.53 g, 16.3 mmol) and PPh₃ (5.84 g, 22.3 mmol) and the resulting mixture was stirred for 5min at room temperature, then DBAD (5.13 g, 22.3 mmol) was added in a single portion as a solid. The resulting mixture was stirred at 25°C for 16 hrs. The mixture was partitioned between EtOAc (200 mL) and water (200 mL), and the aqueous layer was extracted with EtOAc (3x200ml). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc 10:1→ 5:1) to give the title compound (5.8 g, 60.8%) as a yellow oil.

Rf = 0.53 (5:1 petroleum ether:EtOAc)

NMR (400 MHz, CDCl₃): δ 8.05 - 7.97 (m, 2H), 7.97 - 7.89 (m, 1H), 7.89 - 7.78 (m, 1H), 7.59 - 7.48 (m, 2H), 7.45 - 7.36 (m, 2H), 7.16 - 7.06 (m, 2H), 6.83 (d, J= 2.7 Hz, 1H), 6.76 - 6.65 (m, 2H), 5.59 (dd, J= 9.4, 4.3 Hz, 1H), 5.25 (s, 2H), 4.25 (qd, J= 7.1, 1.0 Hz, 2H), 4.12 (q, J= 7.1 Hz, 2H), 3.55 (dd, J= 13.9, 4.4 Hz, 1H), 3.21 (dd, J= 13.9, 9.4 Hz, 1H), 2.04 (s, 3H), 1.27 (t, J= 7.1 Hz, 3H), 0.94 (s, 9H), 0.1 (d, J= 3.2 Hz, 6H) LC/MS: m/z = 643.3 [M+H]⁺ amu

Step 4: Synthesis of Compound C2 (Methyl (R)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2- (2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-2-hydroxypropanoate)

(R)-3-(5-((tert-Butyldimethylsilyl)oxy)-2-((2-(2-methoxyphenyl)pyrimidin-4- yl)methoxy)phenyl)-l -ethoxy- l-oxopropan-2-yl benzoate (2 g, 3.11 mmol) was taken up in MeOH (10 mL) and cooled to 0 °C, then treated with NaOMe (168 mg, 3.11 mmol). After 15 minutes the mixture was treated with AcOH (187 μL, 3.27 mmol), and the mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc 4: 1→ 1 : 1) to give the title compound (3.3 g, 67%) as a yellow oil.

Rf = 0.38 (1:1 petroleum ether:EtOAc)

¹H NMR (400 MHz, CDCl₃): δ 7.84 - 7.72 (m, 1H), 7.61 (d, J= 5.3 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.17 - 6.97 (m, 2H), 6.86 - 6.55 (m, 3H), 5.27 - 5.13 (m, 2H), 4.55 (dd, J= 7.8, 4.6 Hz, 1H), 3.92 (s, 3H), 3.76 (s, 3H), 3.28 (dd, J= 13.7, 4.6 Hz, 1H), 3.00 (dd, J= 13.8, 7.8 Hz, 1H), 0.97 (s, 9H), 0.17 (s, 6H) LC/MS: m/z = 525.2 [M+H]⁺ amu Scheme 17'. Synthesis of Compound. C2’

Step 1: Synthesis of (S)-3-(2-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)-l- ethoxy- l-oxopropan-2-yl benzoate

To a solution of ethyl (S)-3-(2-(benzyloxy)-5-((tert- butyldimethylsilyl)oxy)phenyl)-2-hydroxypropanoate (13.5 g, 31.4 mmol) in dichloromethane (140 mL) was added triethylamine (5.24 mL, 37.6 mmol) and benzoyl chloride (3.64 mL, 31.4 mmol). The resulting mixture was stirred at 25 ºC for 12 hours. The mixture was partitioned between EtO Ac (200 mL) and water (200 mL) and the aqueous layer was extracted with EtO Ac (3 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (13.5 g, 81% yield) as a yellow oil.

Step 2: Synthesis of (S)-3-(5-((tert-Butyldimethylsilyl)oxy)-2-hydroxyphenyl)-l-ethoxy- l-oxopropan-2-yl benzoate

(S)-3-(2-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)- 1 -ethoxy- 1 - oxopropan-2-yl benzoate (13.5 g, 25.2 mmol) was dissolved in ethanol (120 mL) and Pd/C (1.9 g, 10% purity) was added. The vessel was evacuated and backfilled with N₂ 3x, then evacuated and backfilled with H₂ 3x, fitted with a balloon of H₂, and stirred at 25 ºC for 12 hours. The mixture was filtered through Celite and concentrated to give the title compound (10.8 g, 96% yield) as a colorless oil.

Step 3: Synthesis of (S)-3-(5-((tert-Butyldimethylsilyl)oxy)-2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-l -ethoxy- 1 -oxopropan-2-yl benzoate

To a solution of (S)-3-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)-l- ethoxy-l-oxopropan-2-yl benzoate (5.0 g, 11.2 mmol) in THF (110 mL) was added (2-(2- methoxyphenyl)pyrimidin-4-yl)methanol (3.0 g, 13.9 mmol) and PPh₃ (4.5 g, 17.2 mmol) and the resulting mixture was stirred for 5 minutes at 25 ºC, then DBAD (3.9 g, 16.9 mmol) was added in a single portion as a solid. The resulting solution was stirred at 25 ºC for 16 hours. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography to give the title compound (2.15 g, 30% yield) as an off-white foam.

Step 4: Synthesis of Compound C2’ (methyl (S)-3-(5-((tert-Butyldimethylsilyl)oxy)-2-

((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-2-hydroxypropanoate)

(S)-3-(5-((tert-Butyldimethylsilyl)oxy)-2-((2-(2-methoxyphenyl)pyrimidin-4- yl)methoxy)phenyl)-l -ethoxy- l-oxopropan-2-yl benzoate (3.2 g, 4.98 mmol) was dissolved in methanol (17 mL) and cooled to 0ºC, then treated with NaOMe (20 mL, 10.0 mmol, 0.5 M in methanol). After 15 minutes the mixture was quenched with AcOH (570 uL, 10.0 mmol) and the mixture was concentrated. The residue was purified by silica gel chromatography to give the title compound (1.8 g, 69% yield) as an off-white foam. ¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J = 5.2 Hz, 1H), 7.71 (dd, J = 7.5, 1.8 Hz, 1H), 7.56 (d, J= 5.2 Hz, 1H), 7.45 (ddd, J= 8.3, 7.4, 1.8 Hz, 1H), 7.16 - 7.01 (m, 2H), 6.78 - 6.65 (m, 3H), 5.27 - 5.08 (m, 2H), 4.55 (s, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.28 (dd, J = 13.8, 4.6 Hz, 1H), 3.01 (dd, J= 13.7, 7.8 Hz, 1H), 0.98 (s, 9H), 0.18 (s, 6H) (35 of 36 protons observed).

LC/MS: m/z = 525.1 [M+H]⁺ amu. Synthesis of Compound. C2 and Compound C2’ Analogs

Additional compounds are prepared using the methods disclosed herein by replacing the alcohol (i.e. (2-(2-methoxyphenyl)pyrimidin-4-yl)methanol) in Scheme 17 with an alternative alcohol to produce the analog of intermediate compound C2 or compound C2’ required to arrive at the additional compounds.

Examples of alternative alcohols that are used include, but are not limited to: (2- (2-methoxyphenyl)pyrimidin-4-yl)methanol, (2-(3,3,3-trifluoropropoxy)pyrimidin-4- yl)methanol, (2-(2,2-difluoroethoxy)pyrimidin-4-yl)methanol, (2-(2- (methoxymethyl)phenyl)pyrimidin-4-yl)methanol, (2-(2- (difluoromethoxy)phenyl)pyrimidin-4-y l)methanol, (2-(5 -fluoro-2- methoxyphenyl)pyrimidin-4-yl)methanol, (2-(2,2,2-trifluoroethoxy)pyrimidin-4- yl)methanol, (2-(pyridin-4-yl)pyrimidin-4-yl)methanol, (2-(4,4- difluorocyclohexyl)pyrimidin-4-yl)methanol, (2-(tetrahydro-2//-pyran-4-yl)pyrimidin-4- yl)methanol, (2-(3-morpholinophenyl)pyrimidin-4-yl)methanol, 4-(4- (hydroxymethy l)pyrimidin-2-yl)-3 -methylbenzonitrile, 1 -(4-(4-(4- (hydroxymethyl)pyrimidin-2-yl)phenyl)piperazin- 1 -yl)ethan- 1 -one, azetidin- 1 -yl(4-(4- (hydroxymethyl)pyrimidin-2-yl)phenyl)methanone, (2-(4-morpholinophenyl)pyrimidin- 4-yl)methanol, (2-(3-(l-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-4-yl)methanol, (2-(3- ( 1 -methyl- 1H-pyrazol-4-yl)phenyl)pyrimidin-4-yl)methanol, (2-(3 -( 1 -methyl- 1H- pyrazol-5-yl)phenyl)pyrimidin-4-yl)methanol, l-(4-(6-(4-(hydroxymethyl)pyrimidin-2- yl)pyridin-3-yl)piperazin-l -yl)ethan-l -one, (2-(4-(2- morpholinoethoxy)phenyl)pyrimidin-4-yl)methanol, 4-(4-(hydroxymethyl)pyrimidin-2- yl)-3-methoxybenzonitrile, 3-fluoro-4-(4-(hydroxymethyl)pyrimidin-2-yl)benzonitrile, (2-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)pyrimidin-4-yl)methanol, (2-(3-fluoro-4- morpholinophenyl)pyrimidin-4-yl)methanol, (2-(4-(morpholinomethyl)phenyl)pyrimidin- 4-yl)methanol and (2-(6-morpholinopyridin-3-yl)pyrimidin-4-yl)methanol. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired alcohols, or obtain them from chemical vendors. Synthesis of Compound. C2 Enantiomer

The enantiomer of Compound C2 is synthesized using ethyl (R)-3-(2- (benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)-2-hydroxypropanoate in step 1 of Scheme 17 instead of ethyl (S)-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)- 2-hydroxypropanoate. The enantiomer of Compound C2 is also used to prepare additional macrocyclic compounds.

Scheme 18. Synthesis of Compound C3 and C3 Analogs

Compound C3 is prepared using the methods described in Scheme 18.

Additional compounds are prepared using the methods disclosed herein by replacing the benzonitrile (i.e. 2-methoxybenzonitrile) in Scheme 18 with an alternative benzonitrile to produce the analog of intermediate compound C3 required to prepare additional macrocyclic compounds.

Examples of alternative benzonitriles that are used include, but are not limited to: 2-(methoxymethyl)benzonitrile, 5-fluoro-2-methoxybenzonitrile, 2- (difluoromethoxy)benzonitrile, 5-fluoro-2-methoxybenzonitrile and isonicotinonitrile. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired benzonitrile, or obtain them from chemical vendors. Scheme 19. Synthesis of Compound. C4 and C4 Analogs

Compound C4 is prepared using the methods described in Scheme 19.

Additional compounds are prepared using the methods disclosed herein by replacing Compound C2 in Scheme 19 with an alternative alcohol to produce the analog of intermediate compound C2 required to prepare additional macrocyclic compounds. Examples of alternative alcohols that are used include, but are not limited to: (2- (2-methoxyphenyl)pyrimidin-4-yl)methanol, (2-(3,3,3-trifluoropropoxy)pyrimidin-4- yl)methanol, (2-(2,2-difluoroethoxy)pyrimidin-4-yl)methanol, (2-(2- (methoxymethyl)phenyl)pyrimidin-4-yl)methanol, (2-(2- (difluoromethoxy)phenyl)pyrimidin-4-y l)methanol, (2-(5 -fluoro-2- methoxyphenyl)pyrimidin-4-yl)methanol, (2-(2,2,2-trifluoroethoxy)pyrimidin-4- yl)methanol, (2-(pyridin-4-yl)pyrimidin-4-yl)methanol, (2-(4,4- difluorocyclohexyl)pyrimidin-4-yl)methanol, (2-(tetrahydro- 2H-pyran-4-yl)pyrimidin-4- yl)methanol, (2-(3-morpholinophenyl)pyrimidin-4-yl)methanol, 4-(4- (hydroxymethy l)pyrimidin-2-yl)-3 -methylbenzonitrile, 1 -(4-(4-(4- (hydroxymethyl)pyrimidin-2-yl)phenyl)piperazin- 1 -yl)ethan- 1 -one, azetidin- 1 -yl(4-(4- (hydroxymethyl)pyrimidin-2-yl)phenyl)methanone, (2-(4-morpholinophenyl)pyrimidin- 4-yl)methanol, (2-(3-(l-methyl-1H-pyrazol-3-yl)phenyl)pyrimidin-4-yl)methanol, (2-(3- ( 1 -methyl- 1H-pyrazol-4-yl)phenyl)pyrimidin-4-yl)methanol, (2-(3 -( 1 -methyl- 1H- pyrazol-5-yl)phenyl)pyrimidin-4-yl)methanol, l-(4-(6-(4-(hydroxymethyl)pyrimidin-2- yl)pyridin-3-yl)piperazin-l -yl)ethan-l -one, (2-(4-(2- morpholinoethoxy)phenyl)pyrimidin-4-yl)methanol, 4-(4-(hydroxymethyl)pyrimidin-2- yl)-3-methoxybenzonitrile, 3-fluoro-4-(4-(hydroxymethyl)pyrimidin-2-yl)benzonitrile, (2-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)pyrimidin-4-yl)methanol, (2-(3-fluoro-4- morpholinophenyl)pyrimidin-4-yl)methanol, (2-(4-(morpholinomethyl)phenyl)pyrimidin- 4-yl)methanol and (2-(6-morpholinopyridin-3-yl)pyrimidin-4-yl)methanol. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired alcohols, or obtain them from chemical vendors.

Example 1: Synthesis of Compound 1

Scheme 20. Synthesis of Compound. 1

Step 1: Synthesis of Methyl (S)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-2-((5-chloro-4-iodoisothiazolo[5,4- c1pyridin-3-yl)oxy)propanoate

To a flask containing 5-chloro-4-iodo-isothiazolo[5,4-c]pyridin-3-one (100mg, 0.32mmol) was added DBAD (126 mg, 0.48mmol) and Compound C2 (methyl (R)-3-(5- ((tert-butyldimethylsilyl)oxy)-2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)- 2-hydroxypropanoate; 193mg, 0.37mmol). The solids were dissolved in THF (3.2mL) and triphenylphosphine (179mg, 0.48mmol) was added at rt. After 20min, the mixture was concentrated on to silica gel and purified by flash column chromatography on silica gel eluted with 0→ 40% EtOAc in hexanes to give the title compound (165mg, 63%) as a yellow solid.

LC/MS, ESI [M+H]⁺ = 819.1 m/z

NMR (400 MHz, Methanol-d₄): δ 8.91 (s, 1H), 8.86 - 8.80 (m, 1H), 7.69 (dt, J= 5.3, 0.9 Hz, 1H), 7.59 (dd, J= 7.6, 1.8 Hz, 1H), 7.46 (ddd, J= 8.4, 7.4, 1.8 Hz, 1H), 7.14 (dd, J= 8.4, 1.1 Hz, 1H), 7.05 (td, J= 7.5, 1.0 Hz, 1H), 6.94 (d, J = 2.9 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.70 (dd, J= 8.7, 3.0 Hz, 1H), 5.94 (dd, J= 8.9, 4.4 Hz, 1H), 5.25 - 5.19 (m, 2H), 3.84 (s, 3H), 3.75 (s, 3H), 3.71 - 3.62 (m, 1H), 3.36 (dd, J= 14.0, 8.9 Hz, 1H), 0.92 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H)

Step 2: Synthesis of Methyl (S)-2-((4-(4-(((R)-l-(bis(4- methoxyphenyl)(phenyl)methoxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichlorophenyl)-5- chloroisothiazolo[5,4-clpyridin-3-yl)oxy)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)propanoate

A microwave vial was charged with Compound Bl ((R)-3-(bis(4- methoxyphenyl)(phenyl)methoxy)-2-(2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy)propyl 4-methylbenzenesulfonate; 343mg, 0.419mmol), methyl (S)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-2-((5-chloro-4-iodoisothiazolo[5,4- c]pyridin-3-yl)oxy)propanoate (229mg, 0.280mmol), PEPPSI-iPr (lOmg, 0.015mmol), and K₃PO₄ (92.mg, 0.433mmol) and evacuated and backfilled with N₂ (x3) then amended with degassed dioxane:H₂O (2: 1) (1.9mL) and warmed to 70 °C. After 16hrs, the mixture was diluted with EtOAc and washed with H₂O (x2), brine, filtered through a thin pad of silica gel, and concentrated. The residue was dissolved in hexanes :DCM and purified by flash column chromatography on silica gel eluted with 0→ 60% Me₂CO in hexanes to give the title compound (265mg, 68.5%) as a pale yellow foam.

Step 3: Synthesis of Methyl (S)-2-((4-(4-(((R)-l-(bis(4- methoxyphenyl)(phenyl)methoxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichlorophenyl)-5- chloroisothiazolo[5,4-c]pyridin-3-yl)oxy)-3-(5-hydroxy-2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)propanoate

Methyl (S)-2-((4-(4-(((R)-l-(bis(4-methoxyphenyl)(phenyl)methoxy)-3- (tosyloxy)propan-2-yl)oxy)-3,5-dichlorophenyl)-5-chloroisothiazolo[5,4-c]pyridin-3- yl)oxy)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2-methoxyphenyl)pyrimidin-4- yl)methoxy)phenyl)propanoate (261 mg, 0.189mmol) was dissolved in THF (2mL), cooled to 0 °C, and treated with TBAF, IM in THF (187uL, 0.187mmol). After 20min, the mixture was diluted with EtOAc and washed with sat. NH₄CI, brine, filtered through a thin pad of silica gel, and concentrated. TLC anlaysis showed a major spot. The residue was dissolved in hexanes:DCM and purified by flash column chromatography on silica gel eluted with 0→ 80% Me₂CO in hexanes to give the title compound (232.2mg, 97%) as a pale yellow foam.

Rf= 0.51 (1:1 hexanes:Me₂CO)

Step 4: Synthesis of Methyl (11S,20S)-20-[[bis(4-methoxyphenyl)-phenyl- methoxy] methyl] -3 ,23 ,26-trichloro- 14-[[2-(2-methoxyphenyl)pyrimidin-4-yllmethoxyl -

10,18,21-trioxa-7-thia-4,8-diazapentacyclo[20.2.2.12,6.113, 17.09,28]octacosa-

1 (25),2(28),3,5,8, 13(27), 14, 16,22(26),23 -decaene- 11 -carboxylate

Methyl (S)-2-((4-(4-(((R)-l-(bis(4-methoxyphenyl)(phenyl)methoxy)-3- (tosyloxy)propan-2-yl)oxy)-3,5-dichlorophenyl)-5-chloroisothiazolo[5,4-c]pyridin-3- yl)oxy)-3-(5-hydroxy-2-((2-(2-methoxyphenyl)pyrimidin-4- yl)methoxy)phenyl)propanoate (219mg, 0.172mmol) was dissolved in anhydrous DMF (17.3mL) and treated with K₂CO₃ (562mg, 1.72mmol) and the mixture was stirred at 40 °C for 36hrs. The mixture was diluted with EtOAc and washed with H₂O (x3), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, and concentrated. The residue was dissolved in hexanes:DCM and purified by flash column chromatography on silica gel and eluted with 0→ 60% Me₂CO to give the title compound (74.8mg, 39.5%) as a glassy residue.

Rf = 0.33 (6:4 hexanes:Me₂CO) Step 5: Synthesis of Methyl (11S,20R)-3,23,26-trichloro-20-(hydroxymethyl)-14-[[2-(2- methoxyphenyl)pyrimidin-4-yllmethoxyl-l 0, 18,21 -trioxa-7-thia-4,8- diazapentacyclo[20.2.2.12,6.113, 17.09,28]octacosa-

1 (25),2(28),3,5,8, 13(27), 14, 16,22(26),23 -decaene- 11 -carboxylate

Methyl (11 S,20S)-20-[[bis(4-methoxyphenyl)-phenyl-methoxy]methyl]-3,23,26- trichloro- 14- [ [2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy ] - 10, 18,21 -trioxa-7-thia-4, 8- diazapentacyclo[20.2.2.12,6.113, 17.09, 28]octacosa-

1 (25), 2(28), 3, 5, 8, 13(27), 14, 16, 22(26), 23 -decaene- 11 -carboxylate (74.8mg, 0.0681mmol) was treated with DCM:MeOH:HCO₂H (1:1:1) (450uL) at rt. After 75min, the mixture was quenched by careful addition of sat NaHCO₃ then partitioned between sat NaHCO₃ and EtOAc. The organic phase was collected and washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was dissolved in DCM:hexanes and purified by flash column chromatography on silica gel eluted with 0 → 60% Me₂CO in hexanes to give the title compound (48.0mg, 88.5%) as a white foam.

Rf = 0.26 (6:4 hexanes:Me₂CO)

LC/MS, ESI [M+H]⁺ = 795.0/797.0 m/z (1:1)

NMR (600 MHz, CDCl₃): δ 8.93 (s, 1H), 8.88 (d, J= 5.1 Hz, 1H), 7.67 (dd, J= 7.6, 1.8 Hz, 1H), 7.57 (d, J = 5.1 Hz, 1H), 7.48 (d, J= 2.2 Hz, 1H), 7.41 (ddd, J= 8.3, 7.3, 1.8 Hz, 1H), 7.31 (d, J= 2.2 Hz, 1H), 7.08 - 7.00 (m, 2H), 6.75 - 6.66 (m, 2H), 6.10 - 6.05 (m, 2H), 5.25 - 5.20 (m, 1H), 5.17 (d, J= 15.3 Hz, 1H), 5.14 (d, J= 15.0 Hz, 1H), 4.45 (dd, J= 12.2, 8.1 Hz, 1H), 4.27 (dd, J= 12.2, 2.6 Hz, 1H), 4.05 (dd, J= 11.9, 3.7 Hz, 1H), 3.96 (dd, J= 11.9, 5.2 Hz, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 3.43 (dd, J= 15.7, 6.9 Hz, 1H), 3.25 (dd, J= 15.7, 3.1 Hz, 1H), 2.70 (s, 1H)

Step 6: Synthesis of Methyl (11S,20S)-3,23,26-trichloro-14-[[2-(2- methoxyphenyl)pyrimidin-4-yl1methoxy1-20-(p-tolylsulfonyloxymethyl)- 10, 18,21 -trioxa-

7-thia-4,8-diazapentacyclo[20.2.2.12,6.113,17.09,281octacosa-

1 (25),2(28),3,5,8, 13(27), 14, 16,22(26),23 -decaene- 11 -carboxylate

Methyl (1 lS,20R)-3,23,26-trichloro-20-(hydroxymethyl)-14-[[2-(2- methoxyphenyl)pyrimidin-4-yl]methoxy]-l 0, 18,21-trioxa-7-thia-4,8- diazapentacyclo[20.2.2.12,6.113, 17.09, 28]octacosa- 1 (25), 2(28), 3, 5, 8, 13(27), 14, 16, 22(26), 23 -decaene- 11 -carboxylate (48mg,

0.060mmol) was dissolved in anhydrous DCM (250μL) and treated with DMAP (7.4mg, 0.060mmol), Et₃N (34μL, 0.24mmol), and tosyl chloride (115mg, 0.603mmol), and the mixture was heated to 50 °C in a sealed vial for 14hr. The mixture was cooled to rt and amended with half-saturated NaHCO₃ (500μL) and stirred vigorously at rt for 50min. The mixture was diluted with EtOAc and washed with dilute NaHCO₃ (x2), brine, dried over Na₂SO₄, filtered, and concentrated. The material was dissolved in DCM:hexanes (~1 : 1) and purified by flash column chromatography on silica gel (12g) eluted with 0→ 70% Me₂CO in hexanes to give the title compound (42.5mg, 74.2%) as a faintly yellow foamy residue.

Rf = 0.29 (6:4 hexanes:Me₂CO)

LC/MS, ESI [M+H]⁺ = 949.0/951.0 m/z (1:1)

Step 7: Synthesis of Methyl (11S,20R)-3,23,26-trichloro-14-[[2-(2- methoxyphenyl)pyrimidin-4- yllmethoxy] -20-[(4-methylpiperazin- 1 - yl)methyll - 10, 18,21 - trioxa-7 -thia-4, 8-diazapentacyclo[20.2.2.12,6.113,17.09,281 octacosa-

1 (25),2(28),3,5,8, 13(27), 14, 16,22(26),23 -decaene- 11 -carboxylate

Methyl (11 S,20S)-3,23,26-trichloro-14-[[2-(2-methoxyphenyl)pyrimidin-4- yl] methoxy] -20-(p-tolylsulfonyloxymethyl)- 10,18,21 -trioxa-7 -thia-4, 8- diazapentacyclo[20.2.2.12,6.113, 17.09, 28]octacosa-

1 (25), 2(28), 3, 5, 8, 13(27), 14, 16, 22(26), 23 -decaene- 11 -carboxylate (42.5mg, 0.0447mmol) was dissolved in anhydrous DMF (200μL) and treated with 1- methylpiperazine (250μL, 2.25mmol) and heated to 60 °C for 10.5hrs. The mixture was cooled to rt, diluted with EtOAc, and washed with 5% K₂CO₃ (x2), brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (42.1 mg, >100%) as an amber colored foam.

LC/MS, ESI [M+H]⁺ = 877.1/879.1 m/z (1:1)

Step 8: Synthesis of Methyl (11S,20R)-23,26-dichloro-3-(4-fluorophenyl)-14-[[2-(2- methoxyphenyl)pyrimidin-4- yllmethoxyl -20-[(4-methylpiperazin- 1 - yl)methyll - 10, 18,21- trioxa-7 -thia-4, 8-diazapentacyclo[20.2.2.12,6.113,17.09,28] octacosa-

1 (25),2(28),3,5,8, 13(27), 14, 16,22(26),23 -decaene- 11 -carboxylate

A vial was charged with methyl (1 lS,20R)-3,23,26-trichloro-14-[[2-(2- methoxypheny l)pyrimidin-4-yl]methoxy ] -20- [(4-methylpiperazin- 1 -yl)methyl] - 10, 18,21 - trioxa-7 -thia-4, 8-diazapentacy clo[20.2.2.12,6.113,17.09,28]octacosa- l(25),2(28),3,5,8,13(27),14,16,22(26),23-decaene-ll-carboxylate (39.3mg, 0.0447mmol), (4-fluorophenyl)boronic acid (25mg, 0.179mmol), K₂CO₃ (24mg, 0.174mmol), and XPhos Pd G3 (5.7mg, 0.0067mmol). The vial was evacuated and backfilled with N₂ (x3), then degassed 1,4-dioxane (300μL) and H₂O (150μL) were added and the mixture was degassed by three freeze-pump thaw cycles and heated to 85 °C for 8.5hr. Ammonium pyrrolidinedithiocarbamate (15mg, 0.091 mmol) was added and stirring continued at rt for 15min. The mixture was then diluted with EtOAc, washed with 5% K₂CO₃ (x2), brine, dried over Na₂SO₄, filtered, and concentrated. The residue was dissolved in DCM: hexanes (~1 : 1) and purified by flash column chromatography on silica gel eluted with 0→ 8% MeOH in DCM + 2% Et₃N to give the title compound (26.8mg, 63.9%) as a pale yellow foamy residue.

Rf = 0.35 (7:3 Me₂CO:hexanes +2% Et₃N) LC/MS, ESI [M+H]⁺ = 937.1/939.1 m/z

Step 9: Synthesis of Compound 1 ((11S,20R)-23,26-dichloro-3-(4-fluorophenyl)-14-[[2-

(2-methoxyphenyl)pyrimidin-4-yllmethoxyl -20- [(4-methylpiperazin- 1 -yl)methyl] -

10,18,21-trioxa-7-thia-4,8-diazapentacyclo[20.2.2.12,6.113, 17.09,28]octacosa-

1 (25),2(28),3,5,8, 13(27), 14, 16,22(26),23 -decaene- 11 -carboxylic acid)

Methyl (11S,20R)-23,26-dichloro-3-(4-fluorophenyl)- 14-[[2-(2- methoxypheny l)pyrimidin-4-yl]methoxy ] -20- [(4-methylpiperazin- 1 -yl)methyl] - 10, 18,21 - trioxa-7 -thia-4, 8-diazapentacy clo[20.2.2.12,6.113,17.09,28] octacosa-

1 (25), 2(28), 3, 5, 8, 13(27), 14, 16, 22(26), 23 -decaene- 11 -carboxylate (26.8mg, 0.0286mmol) was dissolved in THF:H₂O (3:1) (1 ,2mL) and treated with IM LiOH (200μL), and approximately 200μL additional H₂O and THF was added to reach homogeneity. After 7hrs, the reaction was halted by addition of AcOH (96 μL) and diluted with aqueous 0.25% TFA, filtered, and purified by preparative HPLC (20x250mm Cl 8, 5μ, 20mL/min) eluted with 5→ 20(2min);20→ 70%(20min) ACN to give the title compound (22.7mg, 69%) as a pale, yellow glassy residue.

LC/MS, ESI [M+H]⁺ = 923.1/925.1 m/z

NMR (600 MHz, Acetonitrile-d₃): δ 9.31 (s, 1H), 8.85 (d, J= 5.0 Hz, 1H), 7.64 (dd, J = 7.6, 1.9 Hz, 1H), 7.62 (d, J = 5.1 Hz, 1H), 7.48 (ddd, J= 9.1, 7.4, 1.8 Hz, 1H), 7.43 (d, J= 2.2 Hz, 1H), 7.24 - 7.19 (m, 2H), 7.13 (d, J = 8.3 Hz, 1H), 7.11 (d, J= 2.2 Hz, 1H), 7.07 (td, J= 7.4, 1.0 Hz, 1H), 7.03 - 6.96 (m, 2H), 6.86 (d, J= 8.9 Hz, 1H), 6.70 (dd, J = 8.8, 2.9 Hz, 1H), 6.15 (d, J= 5.0 Hz, 1H), 6.12 (d, J= 3.1 Hz, 1H), 5.20 (d, J = 6.0 Hz, 1H), 5.16 (d, J= 15.1 Hz, 1H), 5.11 (d, J= 15.1 Hz, 1H), 4.33 (dd, J= 12.1, 2.3 Hz, 1H), 4.25 (dd, J= 12.2, 8.1 Hz, 1H), 3.82 (s, 3H), 3.60 (dd, J= 15.9, 5.8 Hz, 1H), 3.49 - 3.37 (m, 3H), 3.30 - 3.22 (m, 2H), 3.18 (dd, J= 16.0, 3.7 Hz, 1H), 3.13 - 3.02 (m, 3H), 2.98 (dd, J= 13.8, 6.1 Hz, 1H), 2.89 (dd, J= 13.8, 5.1 Hz, 1H), 2.77 (s, 3H)

Scheme 21. Synthesis of Compound. 2

Step 1: Synthesis of Methyl (2S)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-2-((5-chloro-4-(3-chloro-2-methyl-4-

(((R)-l-(tosyloxy)-3-((2-(trimethylsilyl)ethoxy)methoxy)propan-2- yl)oxy)phenyl)isothiazolo[5,4-c]pyridin-3-yl)oxy)propanoate

A vial was charged with Compound B2 ((R)-2-(2-chloro-3-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-((2-

(trimethylsilyl)ethoxy)methoxy)propyl 4-methylbenzenesulfonate; 50.2mg,

O.OSOlmmol), Compound C2 (methyl (S)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-2-hydroxypropanoate; 54.63mg, 0.0667mmol), K₃PO₄ (21mg, 0.099 mmol), and PEPPSI-iPr (2.3mg, 0.0034mmol), and evacuated and backfilled with N₂ (x3). Dioxane:H₂O (2:1) (450μL) was added and the mixture was heated to 80 °C for 19hrs. The mixture was diluted with EtOAc and washed with H₂O (x2), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→ 70% EtOAc in hexanes to give the title compound (44.3mg, 55.7%) as a faintly yellow glassy residue.

Rf = 0.28 (1:1 hexanes: EtOAc)

Step 2: Synthesis of Methyl (2S)-2-((5-chloro-4-(3-chloro-2-methyl-4-(((R)-l-(tosyloxy)- 3-((2-(trimethylsilyl)ethoxy)methoxy)propan-2-yl)oxy)phenyl)isothiazolo[5,4-clpyridin- 3-yl)oxy)-3-(5-hydroxy-2-((2-(2-methoxyphenyl)pyrimidin-4- yl)methoxy'lphenyl)propanoate

Methyl (2S)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)-2-((5-chloro-4-(3-chloro-2-methyl-4- (((R)-l-(tosyloxy)-3-((2-(trimethylsilyl)ethoxy)methoxy)propan-2- yl)oxy)phenyl)isothiazolo[5,4-c]pyridin-3-yl)oxy)propanoate (132mg, 0.110mmol) was dissolved in THF (1.1 mL), cooled to 0 °C, and treated with TBAF, IM in THF (110μL, 0.110mmol). After 30min, the mixture was diluted with EtOAc and washed with sat NH₄CI, brine, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel eluted with 0→ 60% EtOAc in hexanes to give the title compound (103.3mg, 86.8%) as a faintly yellow residue. Rf = 0.37 (6:4 hexanes:Me₂CO)

LC/MS, ESI [M+2H]⁺ = 539.2/539.8/540.2 m/z

Step 3: Synthesis of Methyl (11S,20S)-3,23-dichloro-14-[[2-(2- methoxyphenyl)pyrimidin-4-yllmethoxyl-24-methyl-20-(2- trimethylsilylethoxymethoxymethyl)- 10, 18,21 -trioxa-7-thia-4,8- diazapentacyclo[20.2.2.12,6.113,17.09,281octacosa-l(24),2(28),3,5,8,13(27),14,16,22,25- decaene-11 -carboxylate

Methyl (2S)-2-((5-chloro-4-(3-chloro-2-methyl-4-(((R)-l-(tosyloxy)-3-((2- (trimethylsilyl)ethoxy)methoxy)propan-2-yl)oxy)phenyl)isothiazolo[5,4-c]pyridin-3- yl)oxy)-3-(5-hydroxy-2-((2-(2-methoxyphenyl)pyrimidin-4- yl)methoxy)phenyl)propanoate (103.3mg, 0.0958mmol) was dissolved in anhydrous DMF (9.6mL) and treated with K₂CO₃ (132.mg, 0.956mmol) and the mixture was heated to 40 °C for 16hr.The mixture was diluted with EtOAc and washed with H₂O, brine, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel eluted with 0→ 70% Me₂CO in hexanes to give the title compound (72.3 mg, 83%) as a colorless film.

(6:4 hexanes:Me₂CO) Rf = 0.33

LC/MS, ESI [M+H]⁺ = 905.2/907.2 m/z (1:1)

Step 4: Synthesis of Methyl (llR,20S)-3,23-dichloro-20-(hydroxymethyl)-14-[[2-(2- methoxyphenyl)pyrimidin-4-yllmethoxyl -24-methyl- 10, 18,21 -trioxa-7 -thia-4, 8- diazapentacyclo[20.2.2.12,6.113,17.09,281octacosa-l(24),2(28),3,5,8,13(27),14,16,22,25- decaene-11 -carboxylate

Methyl ( 11 S,20S)-3 ,23 -dichloro- 14- [ [2-(2-methoxyphenyl)pyrimidin-4- yl] methoxy] -24-methyl-20-(2-trimethylsilylethoxymethoxymethyl)- 10, 18,21 -trioxa-7 - thia-4, 8-diazapentacyclo[20.2.2.12,6.113,17.09,28]octacosa- l(24),2(28),3,5,8,13(27),14,16,22,25-decaene-l l-carboxylate (72.3mg, 0.0798mmol) was treated with TFA:DCM (2:1) (1 ,5mL) at 0 °C. After 25min, the volume was reduced to approximately 100uL by rotary evaporation then carefully quenched with sat NaHCO₃ and partitioned between sat NaHCO₃ and EtOAc. The organic phase was washed with brine, dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→ 70% Me₂CO in hexane to give the title compound (34.9mg, 56.3%) as a colorless film.

Rf = 0.15 (6:4 hexanes:Me₂CO)

LC/MS, ESI [M+H]+ = 775.1/777.1 m/z ¹H NMR (600 MHz, CDCl₃): δ 8.94 (d, J = 2.5 Hz, 1H), 8.86 (d, J = 5.1 Hz, 1H), 7.67 (dd, J= 7.6, 1.9 Hz, 1H), 7.46 (d, J= 5.1 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.16 (d, J= 8.6 Hz, 1H), 7.09 - 7.01 (m, 3H), 6.69 (d, J= 2.8 Hz, 2H), 6.02 (dd, J= 5.1, 3.4 Hz, 1H), 5.93 (d, J= 2.6 Hz, 1H), 5.13 (s, 2H), 5.03 - 4.97 (m, 1H), 4.42 (dd, J= 11.6, 2.0 Hz, 1H), 4.22 (dd, J= 11.6, 8.9 Hz, 1H), 3.92 (qd, J= 11.8, 4.8 Hz, 2H), 3.85 (s, 3H), 3.74 (dd, J= 16.5, 5.1 Hz, 1H), 3.52 (s, 3H), 2.97 (dd, J= 16.6, 3.4 Hz, 1H), 2.62 (s, 1H), 2.09 (s, 3H)

Step 5: Synthesis of Methyl (11S,20S)-3,23-dichloro-14-[[2-(2- methoxyphenyl)pyrimidin-4-yllmethoxyl-24-methyl-20-(p-tolylsulfonyloxymethyl)-

10,18,21-trioxa-7-thia-4,8-diazapentacyclo[20.2.2.12,6, 113, 17.09,281octacosa-

1 (24),2(28),3,5,8, 13(27), 14, 16,22,25 -decaene- 11 -carboxylate

Methyl (1 lR,20S)-3,23-dichloro-20-(hydroxymethyl)-14-[[2-(2- methoxyphenyl)pyrimidin-4-yl] methoxy] -24-methyl- 10, 18,21-trioxa-7-thia-4,8- diazapentacyclo[20.2.2.12, 6.113, 17.09, 28]octacosa-l(24), 2(28), 3, 5, 8, 13(27), 14, 16, 22,25- decaene-11 -carboxylate (34.9mg, 0.045mmol) and DMAP (5.5mg, 0.045mmol) were dissolved in anhydrous DCM (180μL) and treated with iPr₂EtN (32uL, 0.181mmol) followed by tosyl chloride (86mg, 0.451 mmol) and the mixture was warmed to 40 °C for 7hr then cooled to rt and stirring continued for an additional 23hr. The mixture was diluted with EtOAc and washed with dilute NaHCO₃ (x2), brine, dried over Na₂SO₄, filtered, and concentrated. TLC analysis showed a major spot. The residue was dissolved in DCM: hexanes (~1 : 1) and purified by flash column chromatography on silica gel eluted with 0→ 70% Me₂CO in hexanes to give the title compound (36.0mg, 86%) as a colorless residue.

Rf = 0.41 (6:4 hexanes:Me₂CO)

LC/MS, ESI [M+H]⁺ = 929.0/931.1 m/z (1:1)

Step 6: Synthesis of Methyl (11S,20R)-3,23-dichloro-14-[[2-(2- methoxyphenyl)pyrimidin-4-yllmethoxyl -24-methyl-20- [(4-methylpiperazin- 1 - yl)methyll - 10, 18,21 -trioxa-7-thia-4, 8- diazapentacyclo[20.2.2.12,6.113,17.09,281octacosa-l(24),2(28),3,5,8,13(27),14,16,22,25- decaene-11 -carboxylate

Methyl ( 11 S,20S)-3 ,23 -dichloro- 14- [ [2-(2-methoxyphenyl)pyrimidin-4- yl] methoxy] -24-methyl-20-(p-tolylsulfony loxymethyl)- 10, 18,21 -trioxa-7 -thia-4, 8- diazapentacyclo[20.2.2.12, 6.113, 17.09, 28]octacosa-l(24), 2(28), 3, 5, 8, 13(27), 14, 16, 22,25- decaene-11 -carboxylate (36mg, 0.0387mmol) was dissolved in anhydrous DMF (175μL) and treated with 1 -methylpiperazine (215μL, 1.94mmol) and the mixture was warmed to 60 °C for 18hr. The mixture was diluted with EtOAc and washed with 5% K₂CO₃ (x2), brine, dried over Na₂SO₄, filtered, and concentrated. The residue was taken up in CHCl₃, filtered, and concentrated to give the title compound (64.6mg, »100%) as an amber colored residue which was taken forward without purification.

LC/MS, ESI [M+H]⁺ = 857.2/859.2 m/z (1:1)

Step 7: Synthesis of Methyl (11S,20R)-23-chloro-3-(4-fluorophenyl)-14-[[2-(2- methoxyphenyl)pyrimidin-4-yllmethoxyl -24-methyl-20- [(4-methylpiperazin- 1 - yl)methyl] - 10, 18,21 -trioxa-7-thia-4, 8- diazapentacyclo[20.2.2.12,6.113, 17.09,28]octacosa-

1 (25),2(28),3,5,8, 13(27), 14, 16,22(26),23 -decaene- 11 -carboxylate

A vial was charged with methyl (1 lS,20R)-3,23-dichloro-14-[[2-(2- methoxyphenyl)pyrimidin-4-yl]methoxy]-24-methyl-20-[(4-methylpiperazin-l- yl)methy 1] - 10, 18,21 -trioxa-7-thia-4, 8- diazapentacyclo[20.2.2.12, 6.113, 17.09, 28]octacosa-l(24), 2(28), 3, 5, 8, 13(27), 14, 16, 22,25- decaene-11 -carboxylate (crude, 0.0387mmol), (4-fluorophenyl)boronic acid (21.7mg, 0.155mmol), K₂CO₃ (21.4mg, 0.155mmol), and XPhos Pd G3 (4.9mg, 0.0058mmol) then evacuated and backfilled with N₂ (x3). Dioxane:H₂O (2:1) (390μL) was added and the mixture was degassed by three freeze-pump-thaw cycles then heated to 85 °C for 15hr. The mixture was cooled, diluted with EtOAc, and washed with 5% K₂CO₃ (x2), brine, dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→ 10% MeOH in DCM+2% Et₃N. The title compound (18.8mg, 53%) was obtained as a yellow film.

Rf = 0.13 (7:3 Me₂CO:hexanes + 2% Et₃N) LC/MS, ESI [M+H]⁺ = 917.2 m/z

Step 8: Synthesis of Compound 2 ((1 lS,20R)-23-Chloro-3-(4-fluorophenyl)-14-[[2-(2- methoxyphenyl)pyrimidin-4-yl1methoxy1 -24-methyl-20- [ (4-methylpiperazin- 1 - yl)methyll - 10, 18,21 -trioxa-7-thia-4, 8- diazapentacyclo[20.2.2.12,6.113, 17.09,281octacosa-

1 (25),2(28),3,5,8, 13(27), 14, 16,22(26),23 -decaene- 11 -carboxylic acid)

Methyl (1 lS,20R)-23-chloro-3-(4-fluorophenyl)-14-[[2-(2- methoxyphenyl)pyrimidin-4-yl]methoxy]-24-methyl-20-[(4-methylpiperazin-l- yl)methy 1] - 10, 18,21 -trioxa-7-thia-4, 8- diazapentacyclo[20.2.2.12,6.113, 17.09, 28]octacosa-

1 (25), 2(28), 3, 5, 8, 13(27), 14, 16, 22(26), 23 -decaene- 11 -carboxylate (18.5mg, 0.0202mmol) was dissolved in THF:H₂O (3:1) (880μL) and treated with IMLiOH (141μL, 0.141mmol). After 4hr, the reaction was halted by the addition of AcOH (200μL). The mixture was filtered and purified by preparative HPLC (Cl 8, 21x250mm, 5u, 20mL/min 10→ 30; 30→ 85% ACN in aqueous 0.25% TFA over 25min). The volatiles were removed by rotary evaporation and the remainder lyophilized to the title compound (2.3mg, 10%) as a colorless residue.

LC/MS, ESI [M+H]⁺ = 903.2 m/z

¹H NMR (600 MHz, ACN-d₃): δ 9.32 (s, 1H), 8.83 (d, J = 5.1 Hz, 1H), 7.61 (dd, J = 7.6,

1.8 Hz, 1H), 7.52 (d, J = 5.3 Hz, 1H), 7.49 (td, J = 8.9, 8.2, 1.8 Hz, 1H), 7.25 - 7.19 (m, 2H), 7.14 (d, J = 8.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 7.01 - 6.93 (m, 3H), 6.83 (t, J =

8.8 Hz, 2H), 6.74 (dd, J = 8.8, 3.1 Hz, 1H), 5.99 (dd, J = 5.0, 3.4 Hz, 1H), 5.90 (d, J = 3.1 Hz, 1H), 5.15 (d, J = 14.8 Hz, 1H), 5.10 (d, J = 14.9 Hz, 1H), 5.04 (d, J = 2.3 Hz, 1H), 4.43 (dd, J = 11.4, 2.2 Hz, 1H), 4.03 (s, 1H), 3.85 - 3.78 (m, 4H), 3.48 - 3.23 (m, 6H), 3.11 - 3.01 (m, 2H), 2.98 (dd, J = 17.1, 3.6 Hz, 1H), 2.91 (dd, J = 13.6, 6.3 Hz, 1H), 2.81 (dd, J = 13.6, 4.2 Hz, 1H), 2.75 (s, 3H), 2.18 (s, 3H)

Synthesis of Compound. 3

Compound 3 was made following the general procedures used to synthesize

Compound 1, except that Compound C2’ was used instead of Compound C2, (R)-2-(2, 6- dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-((2- (trimethylsilyl)ethoxy)methoxy)propyl 4-methylbenzenesulfonate was used instead of Compound Bl in Step 2, and p-toluenesulfonic anhydride was used instead of TsCl in Step 6.

LC/MS, ESI [M+H]⁺ m/z = 922.9 m/z

¹H NMR (400 MHz, DMSO): δ 9.53 (s, 1H), 8.88 (d, J= 5.1 Hz, 1H), 7.63 - 7.51 (m, 3H), 7.46 (ddd, J= 8.9, 7.3, 1.8 Hz, 1H), 7.32 - 7.19 (m, 3H), 7.19 - 7.09 (m, 4H), 7.06 - 7.01 (m, 1H), 6.93 - 6.74 (m, 2H), 5.93 (s, 2H), 5.29 - 5.05 (m, 2H), 4.92 - 4.67 (m, 1H), 4.67 - 4.24 (m, 2H), 3.77 (s, 3H), 3.74 - 3.69 (m, 1H), 3.05 (d, J= 16.1 Hz, 1H), 2.70 - 2.56 (m, 2H), 2.54 (s, 5H), 2.38 - 2.25 (m, 2H), 2.13 (s, 4H) (41 of 41 protons observed)

Synthesis of Compound 4

Compound 4 was made following the general procedures used to synthesize Compound 2, except that Compound C2’ was used instead of Compound C2, and p- toluenesulfonic anhydride was used instead of TsCl in Step 5.

LC/MS, ESI [M+H]⁺ m/z = 903.3 m/z

NMR (400 MHz, MeOD): δ 9.36 (s, 1H), 8.86 (d, J= 5.3 Hz, 1H), 7.73 - 7.63 (m, 3H), 7.52 (ddd, J= 8.3, 7.4, 1.8 Hz, 1H), 7.23 - 7.06 (m, 6H), 7.00 - 6.90 (m, 3H), 6.92 - 6.87 (m, 1H), 6.87 - 6.78 (m, 2H), 6.02 - 5.96 (m, 1H), 5.85 - 5.79 (m, 1H), 5.26 - 5.13 (m, 2H), 4.72 - 4.63 (m, 1H), 4.48 - 4.34 (m, 2H), 3.99 (dd, J = 16.4, 5.3 Hz, 1H), 3.86 (s, 3H), 2.96 (dd, J= 16.6, 3.0 Hz, 1H), 2.87 (s, 3H), 2.85 - 2.73 (m, 2H), 2.24 (s, 3H) (38 of 44 protons observed)

Synthesis of Compound. 5

Compound 5 is made following the general procedures used to synthesize Compound 1 and using the enantiomer of Compound C2 and the enantiomer of Compound Bl. Synthesis of Compound 6

Compound 5 is made following the general procedures used to synthesize

Compound 2 and using the enantiomer of Compound C2 and the enantiomer of

Compound B2.

Example 2: Synthesis of Compound 7

Scheme 22. Synthesis of Compound. 7

Compound 7 is prepared using the methods described in Scheme 22.

Example 3: Synthesis of Compound 8

Scheme 23. Synthesis of Compound. 8

Compound 8 is prepared using the methods described in Scheme 23.

Example 4; Synthesis of Compound 9

Scheme 24. Synthesis of Compound. 9

Compound 9 is prepared using the methods described in Scheme 24.

Example 5: Synthesis of Compound 10

Scheme 25. Synthesis of Compound. 10 o

Compound 10 is prepared using the methods described in Scheme 25.

Example 6: Synthesis of Compound 11

Scheme 26. Synthesis of Compound 11

Compound 11 is prepared using the methods described in Scheme 26.

Synthesis of Analogs

Alternative Penultimate Step Synthesis Procedures

It is readily apparent to a person of ordinary skill in the art that other boronic acids can be used instead of the (4-fluorophenyl)boronic acid used in the penultimate step of the syntheses of the above compounds in Schemes 22-26.

Examples of alternative boronic acids that are used include, but are not limited to: (5-fluorothiophen-2-yl)boronic acid, (2-ethoxypyridin-4-yl)boronic acid, (2- methoxypyridin-4-yl)boronic acid, (4-((l -methyl- 1H-pyrazol-3- yl)methoxy)phenyl)boronic acid, (3-fluorophenyl)boronic acid, (1 -isobutyl- 1H-pyrazol- 3-yl)boronic acid, (3-methoxyphenyl)boronic acid, (3-cyanophenyl)boronic acid, (2- fluorophenyl)boronic acid, (3,4,5-trifluorophenyl)boronic acid, (3,4- difluorophenyl)boronic acid, (3-ethoxyphenyl)boronic acid and (3-chloro-4- fluorophenyl)boronic acid. It is also readily apparent to the skilled artisan that the corresponding boronate esters of these exemplary boronic acids may be used, or boronate esters may be used to install groups for which boronic acids are not available or practical. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired boronate esters or boronic acids, or obtain them from chemical vendors.

Alternative reaction conditions and Negishi reagents are used in the penultimate step of the syntheses of the above compounds in Schemes 22-26 as exemplified by the following synthetic scheme:

Examples of Negishi reagents that are used include, but are not limited to: cyclopropylzinc bromide, cyclobutylzinc bromide, cycloheptylzinc bromide and cyclohexylzinc bromide. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired Negishi reagents, or obtain them from chemical vendors.

Use of Compound. Bl, B2, B3, B5, B6 or B7 Analogs

Analogs of Compound Bl, B2, B3, B5, B6 or B7 as the case may be are used in the synthesis of the above compounds such that analogs of those compounds are made.

Use of Compound C2 or C4 Analogs

Analogs of Compound C2 or C4, as the case may be, are used in the synthesis of the above compounds such that analogs of those compounds are made. Use of Alternative Heterocycles

Alternative Step 7 of Compounds 1, 3 and 5 Syntheses (Scheme 20)

Analogs of Compounds 1, 3 and 5 are made by using alternative heterocycles in step 7. Examples of such alternative heterocycles that are used include, but are not limited to: morpholine, piperidine, 4,4-dimethylpiperidine and 4,4-difluoropiperidine.

Alternative Step 6 of Compounds 2, 4 and 6 Syntheses (Scheme 21)

Analogs of Compounds 2, 4 and 6 are made by using alternative heterocycles in step 6. Examples of such alternative heterocycles that are used include, but are not limited to: morpholine, piperidine, 4,4-dimethylpiperidine and 4,4-difluoropiperidine.

Alternative Step 4 of Compound 7 Synthesis (Scheme 22)

Analogs of Compound 7 are made by using alternative amines in step 4.

Examples of such alternative amines that are used include, but are not limited to: (4- methylpiperazin- 1 -y l)methanamine morpholinomethanamine, 2-morpholinoethan- 1 - amine, (4,4-dimethylpiperidin- 1 -yl)methanamine, 2-(4,4-dimethylpiperidin- 1 -yl)ethan- 1 - amine, (4,4-difluoropiperidin-l-yl)methanamine and 2-(4,4-difluoropiperidin-l-yl)ethan- 1 -amine.

Alternative Step 10 of Compound 8 Synthesis (Scheme 23)

Analogs of Compound 8 are made by using alternative heterocycles in step 10. Examples of such alternative heterocycles that are used include, but are not limited to: morpholine, piperidine, 4,4-dimethylpiperidine and 4,4-difluoropiperidine.

Alternative Step 8 of Compound 9 Synthesis (Scheme 24)

Analogs of Compound 9 are made by using alternative heterocycles in step 8. Examples of such alternative heterocycles that are used include, but are not limited to: morpholine, piperidine, 4,4-dimethylpiperidine and 4,4-difluoropiperidine. Alternative Step 6 of Compound 11 Synthesis (Scheme 25)

Analogs of Compound 11 are made by using alternative heterocycles in step 6.

Examples of such alternative heterocycles that are used include, but are not limited to: 4- (bromomethyl)morpholine, 4-(2-bromoethyl)morpholine, tert-butyl 4- (bromomethyl)piperazine- 1 -carboxylate, 1 -(bromomethyl)-4,4-dimethylpiperidine, 1 -(2- bromoethyl)-4,4-dimethylpiperidine, l-(bromomethyl)-4,4-difluoropiperidine and l-(2- bromoethyl)-4,4-difluoropiperidine.

Assignment of Absolute Chemical Configuration by Vibrational Circular Dichroism

Experimental Protocol for Vibrational Circular Dichroism

A 50 mg/mL CDCl₃ solution of the chiral test compound is subjected to absolute configuration determination via vibrational circular dichroism (VCD) using a ChiralIR-2X spectrometer (BioTools, Inc) set to to 4 cm^-1 resolution and optimized at 1400 cm^-1. A sample of test compound in CDCl₃ is loaded into an SL-4 cell (International Crystal Laboratories) with BaF₂ windows and 100 μm path length, and infrared (IR) and VCD spectra acquired in 24 one-hour blocks, which are averaged at the completion of the run. A 15-minute acquisition of neat (+)-α-pinene control is also acquired to yield a VCD spectrum in agreement with literature spectra. IR and VCD spectra were background- corrected using a 5 -minute block acquisition of the empty instrument chamber. IR spectra are solvent corrected utilizing a one-hour block acquisition of CDCl₃. For enantiomeric pairs of compounds, final VCD spectra used for assignment are processed via enantiomer subtraction (half-difference).

Computational Protocol

An arbitrarily chosen, but known, enantiomer of the compound in question is subjected to an exhaustive initial molecular mechanics-based conformational search (MMFF94 force field, 0.08 Å geometric RMSD cutoff, and 30 kcal/mol energy window) as implemented in MOE (Chemical Computing Group, Montreal, CA). The resultant conformers are checked to ensure the input chirality is retained. All MMFF94 conformers are then subjected to geometry optimization, harmonic frequency calculation, and VCD rotational strength evaluation with density functional theory. All final quantum mechanical calculations utilize the B3PW91 functional, cc-pVTZ basis (def2-TZVP basis for iodine-containing compounds) and the implicit IEFPCM chloroform solvation model as implemented in the Gaussian 16 program system (Rev. B.01; Frisch et al., Gaussian, Inc., Wallingford, CT). Resultant harmonic frequencies are scaled by 0.98. All structurally unique conformers are Boltzmann weighted by relative free energy at 298.15 K. The predicted IR and VCD frequencies and intensities are convolved using Lorentzian line shapes (γ = 4 cm^-1) and summed using the respective Boltzmann weights to yield the final predicted IR and VCD spectra of the input enantiomer. The predicted VCD of the opposite corresponding enantiomer is easily generated by inversion of sign. From the generally excellent agreement between the predicted and measured IR and VCD spectra of the test article, the absolute configuration of the test article can generally be established in an unambiguous fashion.

Biological Experiments

MCL1, BCL2 and BCLXL Affinity Assays

Recombinant MCL1, BCL2 and BCXL proteins were prepared in either an E. coli host derived from the BL21 strain or in HEK-293 cells. The recombinant proteins were subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated for 30 minutes at room temperature with the respective biotinylated peptide ligands for each recombinant protein to generate affinity resins for the assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding. Binding reactions were assembled by combining recombinant protein, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 11 IX stocks in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The recombinant protein concentration in the eluates was measured by qPCR. K_ds were determined using an 11- point 3-fold compound dilution series with three DMSO control points. Measurements were obtained for Compounds 1 and 2 and are presented in Table 2. “A” represents a K_d of 500 nM or less, “B” represents a K_d of 501 nM to 1,500 nM, and “C” represents a K_d of greater than 1,500 nM. Measurements for Compounds 3 - 11 are obtained using these same procedures.

Cell Line Growth Retardation Assay

Cells were seeded at densities of 1,000-5,000 cells per well in 48-well tissue culture plates. After a 24 h rest period, cells were treated with compound at 10 μM, 1 μM, 0.4 μM, 0.08 μM, 0.016 μM, and 0.0032 μM. A group of cells were treated with the vehicle in which the compound was prepared and served as a control. Prior to treatment, cells were counted and this count was used as a baseline for the calculation of growth inhibition. The cells were grown in the presence of compounds for 6 days and were counted on day 6. All cell counting was performed using a Synentec Cellavista plate imager. Growth inhibition was calculated as a ratio of cell population doublings in the presence of compound versus the absence of compound. If treatment resulted in a net loss of cells from baseline, percent lethality was defined as the decrease in cell numbers in treated wells compared with counts on day 1 of non-treated wells post-seeding. IC₅₀ values for each compound were calculated by fitting curves to data points from each dose-response assay using the Proc NLIN function in SAS for Windows version 9.2 (SAS Institute, Inc.).

Designation of Sensitive and Resistant Cohorts and Calculation of Average IC₅₀

Values

Human cancer cell lines were grouped as “sensitive” or “resistant” to MCL1 inhibition based on whether their growth was retarded by AMG-176 (i.e.,

(1 'S, 11R, 12S, 14E, 16S, 16aR, 18aR)-6'-Chloro-3',4', 12, 13, 16, 16a, 17, 18, 18a, 19-decahydro- 16-methoxy- 11,12-dimethyl-,Spiro[5,7-etheno- 1 H, 11 H-cyclobut[i] [ 1 ,4]oxazepino[3,4- f] [ 1 ,2,7]thiadiazacyclohexadecine-2(3H), 1 '(2'H)-naphthalen] -8(9H)-one 10, 10-dioxide) or MIK665 (i.e., (R)-2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazin-l- yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-((2-(2- methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)propanoic acid) (data not shown; see Table 3). These sensitive and resistant cohorts were interrogated for response to each compound, and IC₅₀s were calculated for each cell line using the same technique described above. Average IC₅₀S for the sensitive (“AvgSen IC₅₀”) and resistant (“AvgRes IC₅₀”) cohorts were calculated as arithmetic means of the group, and fold differences (“Fold Diff ’) between the resistant and sensitive cohorts were calculated by dividing the average IC₅₀ for the resistant cohort by the average IC₅₀ for the sensitive cohort. Measurements were obtained for Compounds 1 and 2 and are presented in Table 2. “A’ represents an IC₅₀ of 1 μM or less, “B” represents an IC₅₀ of greater than 1 μM to 5 μM, “C” represents an IC₅₀ of greater than 5 μM, “+” represents a fold difference of 10 or more, and represents a fold difference less than 10. Measurements for Compounds 5 - 11 are obtained using these same procedures.

Caco-2 Assay (P_app A to B)

The degree of bi-directional human intestinal permeability for compounds was estimated using a Caco-2 cell permeability assay. Caco-2 cells were seeded onto polyethylene membranes in 96-well plates. The growth medium was refreshed every 4 to 5 days until cells formed a confluent cell monolayer. HBSS with 10 mM HEPES at pH 7.4 was used as the transport buffer. Compounds were tested at 2 μM bi-directionally in duplicate. Digoxin, nadolol and metoprolol were included as standards. Digoxin was tested at 10 μM bi-directionally in duplicate, while nadolol and metoprolol were tested at 2 μM in the A to B direction in duplicate. The final DMSO concentration was adjusted to less than 1% for all experiments. The plate was incubated for 2 hours in a CO₂ incubator at 37°C, with 5% CO2 at saturated humidity. After incubation, all wells were mixed with acetonitrile containing an internal standard, and the plate was centrifuged at 4,000 rpm for 10 minutes. 100 μL supernatant was collected from each well and diluted with 100 μL distilled water for LC/MS/MS analysis. Concentrations of test and control compounds in starting solution, donor solution, and receiver solution were quantified by LC/MS/MS, using peak area ratio of analyte to internal standard. The apparent permeability coefficient P_app (cm/s) was calculated using the equation: P_app = (dC_r/dt) X V_r / (A X C₀), where dCr/dt is the cumulative concentration of compound in the receiver chamber as a function of time (μM/s); Vr is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport, which is 0.0804 cm² for the area of the monolayer; and Co is the initial concentration in the donor chamber (μM).

The efflux ratio was calculated using the equation:

Efflux Ratio = P_app (BA) / P_app (AB)

Percent recovery was calculated using the equation:

% Recovery = 100 x [(V_r x C_r) + (V_d x C_d)] / (V_dx C₀), where Vd is the volume in the donor chambers, which are 0.075 mL on the apical side and 0.25 mL on the basolateral side; and Cd and Cr are the final concentrations of transport compound in donor and receiver chambers, respectively.

Measurement of Compound Metabolic Stability

The metabolic stability of compounds was determined in hepatocytes from human, mice and rats. Compounds were diluted to 5 μM in Williams' Medium E from 10 mM stock solutions. 10 μL of each compound was aliquoted into a well of a 96-well plate and reactions were started by aliquoting 40 μL of a 625,000 cells/mL suspension into each well. The plate was incubated at 37°C with 5% CO₂. At each corresponding time point, the reaction was stopped by quenching with ACN containing internal standards (IS) at a 1 :3. Plates were shaken at 500 rpm for 10 min, and then centrifuged at 3,220 x g for 20 minutes. Supernatants were transferred to another 96-well plate containing a dilution solution. Supernatants were analyzed by LC/MS/MS.

The remaining percent of compound after incubation was calculated using the following equation:

% Remaining Compound =

Peak Area Ratios of Tested Compound vs. Internal Standard at End Point

Peak Area Ratios of Tested Compound vs. Internal Standard at Start Point Compound half-life and CL_int were calculated using the following equations:

Ct = C₀*e^-k*t (first order kinetics); when Ct = ½C₀, t_½ = ln2/k = 0.693/k; and CL_int = k/(l,000,000 cells/mL)

Rodent Xenograft Models

Xenograft models of human cancer cell lines were established in six- week-old CD-I athymic nude mice by subcutaneous injection of 1.0-3.0 x 10⁷ cells with or without 50% matrigel. When tumors reached an average size of 150-400 mm³, mice (n=8) were randomized into treatment groups. Tumor xenografts were measured with calipers three times per week, and tumor volume (in mm³) was determined by multiplying height x width x length. Statistical differences between treatment arms at specific time points were performed using a two-tailed paired Student t-test. Differences between groups were considered statistically significant at p <0.05.

Activity-Guided Selection of Inhibitors

Subgenera of MCL1 inhibitors having desirable properties were identified using a combination of in vitro data. In particular, the results from the assays described above (e.g., Cell Line Growth Retardation Assay, MCL1, BCL2 and BCLXL Affinity Assays, Caco-2 Assay (P_app A to B), Measurement of Compound Metabolic Stability, and Designation of Sensitivity and Resistant Cohorts and Calculation of Average IC50 Values) were used to select compounds having structural and functional features defined in the subgenera of Formula (IIIb-3).

In particular, a desirable property of compounds examined in MCL1 affinity assays, as described above, is having a K_d of about 300 nM or less.

In particular, a desirable property of compounds examined in sensitive and resistant cell lines, as described above, is having an average IC₅₀ for the drug-sensitive cell lines of Table 3 of about 1 μM or lower and having an average IC₅₀ for the drugresistant cell lines of Table 3 of greater than 1 μM.

The skilled artisan would readily recognize that the results of additional in vitro assays (e.g., CYP enzymatic inhibition, hERG inhibition, compound solubility, targetspecificity analysis), as well as the results of in vivo assays (e.g., rodent xenograft studies, rodent pharmacokinetic and single-dose saturation studies, rodent maximum tolerated dose studies, and oral bioavailability) could be used to identify other subgenera of MCL1 inhibitors, or to narrow subgenera determined using other results, for example, the subgenera of Formula (IIIb-3).

Table 2.

Table 3.

Cell Line Name Cohort

Claims

CLAIMS We claim:

1. A compound having the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl;

represents the points

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

L³ in each instance is independently CH₂, C(R^L2)(R^L2a), CH=CH, S, O, N(R^L2), C(O), C(O)N(R^L2), N(R^L2)C(O) or S(O)₂, provided that each occurrence of S, O, or N(R^L2) is not adjacent to another occurrence of any one of S, O, or N(R^L2);

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

heterocyclyl, aryl and heteroaryl is optionally substituted with one, two, three or four _R ^W3a.

R^W2 is C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

_RW3 is aryl or heteroaryl;

R^W1a is H or C₁-C₆ alkyl;

R^W2a is 0C(0)0R^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^Z1 in each instance is independently aryl, heteroa,r cyylcloalkyl, 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 each of said aryl, heteroa,r cyylcloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or more R^Z3; R^Z2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁- C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl, wherein each of said aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more R^Z3; or two R^Z2, together with the N to which they are connected, form a heterocycle or heteroaryi, wherein each of said heterocycle and heteroaryi is optionally substituted with one, two, three or four R^Z3;

R^Z3 in each instance is independently aryl, heteroaryi, 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 each of said aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z4;

R^Cy1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, hydroxy, 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;

2. The compound of claim 1 having the structure of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₃ is C(Z¹), N or N(Z²); a₄ is S, 0 or NH, provided that a₁, a₂, and a₃ are selected such that ring D is aromatic;

Z² is H, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroa,r cyylcloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂; R^W2b in each instance is independently H, C₁-C₆ alkyl, cycloalkyl or C₁-C₆ alkoxy; or, wwhheenn R R^W2a is OC(O)N(R^W2b)(R^W2b), the two R^W2b, together with the N to which they are connected, form a heterocyclyl or heteroaryl, wherein each of said heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R^W3a; and

R^W3a is C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano.

3. The compound of claim 2, wherein:

R^X3 in each instance is independently aryl, heteroaryl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein each of said aryl, heteroaryl, and heterocyclyl is optionally substituted with one, two, three or four R^X3a; and

4. The compound of claim 2, wherein:

B is aryl or heteroaryl;

5. The compound of claim 2, wherein:

A is aryl; B is aryl; a₁ is CH; a₂ is C(H); a₃ is C(Z¹); a₄ is S, O or NH;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

L² is a bond or -(C₁-C₆ alkyl)p-O-(C₁-C₆ alkyl)_P-;

Z¹ is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryi, cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z1;

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^W2b in each instance is independently H, C₁-C₆ alkyl, cycloalkyl or C₁-C₆ alkoxy; or, when R^W2a is OC(O)N(R^W2b)(R^W2b), the two R^W2b, together with the N to which they are connected, form a heterocyclyl or heteroaryl, wherein each of said heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R^W3a; R^W3a is C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano;

R^Z3 in each instance is independently aryl, heteroa,r Cyl₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylamino, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano, wherein each of said aryl and heteroaryl is optionally substituted with one or more R^Z4;

R^Z4 in each instance is independently C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkylamino, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, hydroxy, halogen, amino, nitro or cyano; m is 0, 1 or 2; n is 0, 1 or 2; and p in each instance is independently 0 or 1.

6. The compound of any one of claims 2-5, wherein Z¹ is cyclopropyl, cyclobutyl or cyclopentyl.

7. The compound of any one of claims 2-4, wherein a₃ is C(Z¹); and Z₁ is

8. The compound of claim 5, wherein Z¹ is

9. The compound of any one of claims 2-4, wherein a₃ is C(Z¹); and Z₁ is

10. The compound of claim 5, wherein Z¹ is

11. The compound of any one of claims 1-10, wherein A is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or thiophenyl.

12. The compound of any one of claims 1-11, wherein B is phenyl, pyridinyl or thiophenyl.

13. The compound of any one of claims 1-12, wherein:

A is phenyl, pyridine or pyrimidine;

B is phenyl, pyridine or thiophene;

L¹ is O;

R¹ in each instance is H;

14. The compound of claim 2 having the structure of Formula IIa, IIa-1, IIa-2, IIa-3 or IIa-4:

or a pharmaceutically acceptable salt thereof, wherein A¹ is a 6 membered aryl or heteroaryl.

15. The compound of claim 2 having the structure of Formula IIb, IIb-1, IIb-2, IIb-3 or IIb-4:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is a 6 membered aryl or heteroaryl;

E is absent, aryl, heteroaryl, cycloalkyl or heterocyclyl; Y¹ is aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each is optionally substituted with one, two, three or four R^X3;

R^L2 and R^L2a, together with the carbon atom to which they are attached, form a C₃-C₇ monocyclic cycloalkyl, C₄-C₇ monocyclic cycloalkenyl, or a 4-7 membered monocyclic heterocycle, wherein each are optionally substituted with one -OR^L4 and 0, 1, 2 or 3 R^L5 groups;

R^L3 in each instance is independently H, Y¹, C₁-C₆ alkyl or C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl and the C₁-C₆ haloalkyl are optionally substituted with one group selected from Y¹, -OR^L6, -SR^L6, -S(O)₂R^L6 and -N(R^L6)₂; and q is 0, 1, 2, 3 or 4, with the proviso that q is 0 when E is absent.

16. A compound having the structure of Formula III, IIIa, IIIa-1 or IIIa-2:

or a pharmaceutically acceptable salt thereof, wherein: a₁ is CH, N or NH; a₂ is C(Z¹), N or N(Z²); a₃ is C(Z¹), N or N(Z²); a₄ is S, 0 or NH, provided that a₁, a₂, and a₃ are selected such that ring D is aromatic; a₅ is C(R^A1) or N;

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

, where

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^Z1 in each instance is independently aryl, heteroa,r cyylcloalkyl, 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 each of said aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or more R^Z3;

R^Z2 in each instance is independently H, aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁- C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl, wherein each of said aryl, heteroaryl, cycloalkyl, heterocyclyl, C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more R^Z3; or two R^Z2, together with the N to which they are connected, form a heterocycle or heteroaryi, wherein each of said heterocycle and heteroaryi is optionally substituted with one, two, three or four R^Z3;

17. A compound having the structure:

L¹ is a bond, CH₂, O, NH, S, SO, or SO₂;

R^L2a in each instance is independently Y¹, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each of C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or two groups each independently selected from Y¹, oxo, -N(R^L3)₂, -OR^L3, - SR^L3, -S(O)₂N(R^L3)₂, and -S(O)₂-Y¹, or R^L2 and R^L2a, together with the carbon atom to which they are attached, form a C3-C7 monocyclic cycloalkyl, C4-C7 monocyclic cycloalkenyl, or a 4-7 membered monocyclic heterocycle, wherein each are optionally substituted with one -OR^L4 and 0, 1, 2 or 3 R^L5 groups;

R^L7 in each instance is independently C₁-C₆ alkyl or C₁-C₆ haloalkyl;

, where

R^W3a.

R^W1a is H or C₁-C₆ alkyl;

R^W2a is OC(O)OR^W2b, OC(O)N(R^W2b)(R^W2b) or OP(O)(OR^W2b)₂;

R^X3c and R^X3d is each independently selected from H, C₁-C₆ cycloalkyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl; or R^X3c and R^X3d, together with the N to which they are connected, form a 4 - 6 membered heterocycle optionally substituted with one or two groups each independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ acyl or halogen;

R^Z1 in each instance is independently aryl, heteroa,r cyylcloalkyl, 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 each of said aryl, heteroa,r cyylcloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl and C₂-C₆ alkynyl is optionally substituted with one or more R^Z3;

R^Z2 in each instance is independently H, aryl, heteroa,r cyylcloalkyl, heterocyclyl, C₁- C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl, wherein each of said aryl, heteroa,r cyylcloalkyl, heterocyclyl, C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one or more R^Z3; or two R^Z2, together with the N to which they are connected, form a heterocycle or heteroaryl, wherein each of said heterocycle and heteroaryl is optionally substituted with one, two, three or four R^Z3;

R^Z3 in each instance is independently aryl, heteroa,r cyylcloalkyl, 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 each of said aryl, heteroa,ryl cycloalkyl and heterocyclyl is optionally substituted with one or more R^Z4;

R^Cy1 is aryl, heteroa,r cyylcloalkyl, heterocyclyl, halogen, hydroxy, 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;

R^Cy2 in each instance is independently H, aryl, heteroa,r cyylcloalkyl, heterocyclyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ hydroxyalkyl; e is 1, 2, 3, 4, 5, 6, 7 or 8; n is 0, 1, 2, 3 or 4; p in each instance is independently 0 or 1; and q is 0, 1, 2, 3 or 4, with the proviso that q is 0 when E is absent.

18. The compound of claim 16 or 17, wherein a₃ is C(Z¹); and Z₁ is

19. The compound of claim 16 or 17, wherein a₃ is C(Z¹); and Z₁ is

20. The compound of any one of claims 1-19, wherein L³ in each instance is independently CH₂, C(R^L2)(R^L2a), O, N(R^L2) or C(O); and e is 3, 4 or 5.

21. The compound of any one of claims 1-20, wherein L³ in each instance is independently CH₂, C(H)(R^L2a), or O; and e is 3, 4 or 5.

22. The compound of any one of claims 1-20, wherein L³ in each instance is independently CH₂, C(H)(R^L2a), N(R^L2), or C(O); and e is 3, 4 or 5.

23. The compound of any one of claims 1-20, wherein L³ in each instance is independently CH₂, C(H)(R^L2a), or N(R^L2); and e is 3, 4 or 5.

24. The compound of any one of claims 20-23, wherein L³ is

or represents the points of attachment, * represents the point

attaching to A, A¹ or A², and ** represents the point attaching to B or B¹.

25. The compound of any one of claims 20-23, wherein L³ is

26. The compound of any one of claims 20-23, wherein L^;

where represents the points of attachment, * represents the point attaching to A, A¹ or

A², and ** represents the point attaching to B or B¹.

27. The compound of claim 24 or 25, wherein R^L2a in each instance is C₁-C₆ alkyl substituted with Y.

28. The compound of claim 26, wherein R^L2 in each instance is C₁-C₆ alkyl substituted with Y.

29. The compound of claim 27 or 28, wherein Y is pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, oxetanyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2- azaspiro[3.3]heptanyl, or 2-oxaspiro[3.3]heptanyl.

30. The compound of claim 29, wherein Y is N-methylpiperazinyl.

31. The compound of claim 30, wherein R^L2 or R^L2a i

32. The compound of claim 26, wherein R^L2 in each instance is H.

33. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

35. A compound selected from the compounds described in Table 1, Table 1-A, Table 1-B, and Table 1-C.

36. A pharmaceutical composition comprising a compound of any one of claims 1-35 and a pharmaceutically acceptable diluent or excipient.

37. A method of treating a patient afflicted with a disease comprising administering an effective amount of the compound of any one of claims 1-35 or the pharmaceutical composition of claim 36 to the patient so as to thereby treat the disease, wherein the underlying pathology of the disease is mediated by MCL1.

38. The method of claim 37, wherein the disease is a cancer.

39. The method of claim 38, wherein the cancer is selected from a carcinoma, a sarcoma, kidney cancer, epidermis cancer, liver cancer, lung cancer, esophagus cancer, gall bladder cancer, ovary cancer, pancreatic cancer, stomach cancer, cervix cancer, thyroid cancer, nose cancer, head and neck cancer, prostate cancer, skin cancer, breast cancer, familial melanoma, and melanoma.

40. The method of claim 39, wherein the carcinoma is a carcinoma of the endometrium, bladder, breast, or colon; the sarcoma is Kaposi’s sarcoma, osteosarcoma, tumor of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; the lung cancer is adenocarcinoma, small cell lung cancer or non-small cell lung carcinomas; the pancreatic cancer is exocrine pancreatic carcinoma; the skin cancer is squamous cell carcinoma; and the breast cancer is a primary breast tumor, node-negative breast cancer, invasive duct adenocarcinomas of the breast or non-endometrioid breast cancer.

41. The method of claim 40, wherein the cancer is selected from leukemia, acute lymphocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, B-cell lymphoma, diffuse large B cell lymphoma, T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett’s lymphoma, acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia.

42. The method of claim 39, wherein the cancer is selected from astrocytoma, neuroblastoma, glioma, schwannoma, seminoma, teratocarcinoma, xeroderma pigmentosum, retinoblastoma, keratoctanthoma, and thyroid follicular cancer.

43. The method of claim 39, wherein the cancer is selected from head and neck cancer, sarcoma, melanoma, myeloma, lymphoma, lung cancer, breast cancer, pancreatic cancer, thyroid cancer, colorectal cancer, ovarian cancer and acute myelogenous leukemia.