WO2017058716A1

WO2017058716A1 - Tricyclic compounds

Info

Publication number: WO2017058716A1
Application number: PCT/US2016/053718
Authority: WO
Inventors: Tracy Tzu-Ling Tang Lin; Andrei W. Konradi; Joseph Vacca; Wang Shen; Craig Coburn
Original assignee: Vivace Therapeutics, Inc.
Priority date: 2015-09-28
Filing date: 2016-09-26
Publication date: 2017-04-06

Abstract

Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers or congenital diseases. Specific cancers and congenital disease includes those that are mediated by YAP/TAZ.

Description

TRICYCLIC COMPOUNDS

CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 62/233,916, filed September 28, 2015, the content of which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE DISCLOSURE

[0002] YAP and TAZ are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Hyperactivation of YAP and TAZ have been implicated in numerous cancers as well as in congenital diseases. Furthermore, mutations in one or more members of the Hippo pathway network have been observed to modulate the activation of YAP and TAZ. Described herein are inhibitors associated with one or more members of the Hippo pathway network, such as YAP/TAZ.

SUMMARY OF THE DISCLOSURE

[0003] Provided herein are substituted tricyclic compounds and pharmaceutical compositions comprising said compounds. In some embodiments, the subject compounds are useful for the treatment of cancer and congenital diseases.

[0004] One embodiment provides a compound of Formula (C) or geometric isomer or a pharmaceutically acceptable salt thereof:

Formula (C)

wherein,

Ai is N, C, or CR₆; A₂ is N, C, or CR₇; A₃ is N, C or CR₈; A₄ is N, C, or CR₉; A₅ is N, C, or

CRio; A₆ is N, C or CR_n; A₇ is N, C or CR_n; A₈ is N, C or CRj₃;

R2 and R3 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C₃-Ciocycloalkyl, substituted or unsubstituted C₃-Ciocycloalkenyl, substituted

or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein any substituted group

of R2 and R3 is substituted with 1-4 R_n;

or R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a

unsubstituted or substituted 4-8 membered ring, containing 0- 1 additional heteroatom selected from N, S, and O; wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R_n;

R4 is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted or

unsubstituted

C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein if R4 is substituted, then R4 is substituted with 1-4 R_J8;

Ri and R14 are each independently H, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Ceheteroalkyl;

R6, R₇, Re, R9, Rio, Rn, R12, and R13 are each independently H, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,

substituted or unsubstituted heteroaryl, halogen, CN, OR₁6, N(Ri₆)₂, SR₁6, SOR₁5, SO₂R₁5,

C0₂R₁₆, CON(R₁₆)₂, S0₂N(R₁₆)₂, or N0₂;

each Ri5 is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted

Ci-Cefiuoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each Ri6 is independently H, substituted or unsubstituted Ci-Cealkyl, substituted or

unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R_½ groups attached to

the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle;

Rn and Ri8 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or

unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, OR₂0, N(R₂o)₂, SR₂0, SOR₁9, SO₂R₁9, CO₂R₂0, CON(R₂₀)₂, SO₂N(R₂₀)₂, NH(C=0)OR_19, or N0₂; wherein any substituted group of R₁₇ is substituted with 1-4 R₂i; wherein any substituted group of Ris is substituted with 1-4 R₂₂ each Rig is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted

Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl,substituted or unsubstituted

C₂

-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,

or substituted or unsubstituted heteroaryl;

each R₂o is independently H, substituted or unsubstituted Ci-Cealkyl, substituted or

unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R₂₀ groups attached to

R₂₁ and R₂₂ are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or

unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, CH₂-CN, CH₂-OR₂₄, OR₂₄, CH₂-N(R₂₄)2, N(R₂₄)₂, SR₂₄, SOR23, SO2R23, C0₂R₂ , CON(R₂₄)₂, S0₂N(R₂₄)₂, NH(C=0)OR₂₃, or N0₂;

each R₂3 is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted

Cr

C₂

or substituted or unsubstituted heteroaryl; and each R₂4 is independently H, substituted or unsubstituted Ci-Cealkyl, substituted or

unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R24 groups attached to

the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle.

[0005] In some embodiments, the compound of Formula (C) is:

[0006] In some embodiments, the compound of Formula (C) is:

[0012] In some embodiments, the compound of Formula (C) is:

[0013] In some embodiments, the compound of Formula (C) is:



[0016] In some embodiments, at least two A_1; A₂, A₃, A₄, A₅, A₆, A₇, A₈, are N. In some embodiments, at least three Ai, A₂, A3, A₄, A5, Ae, A₇, As, are N. In some embodiments, X is a bond. In some embodiments, X is C=N(ORi₄). In some embodiments, R 4 is hydrogen. In some embodiments, R is hydrogen.

[0017] In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional heteroatom selected from N, S, and 0, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 _]7. In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional N heteroatom, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 Rn. In some

embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring containing 0- 1 additional N heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 Rn. In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted piperidinyl or unsubstituted or substituted piperazinyl, and wherein if the piperidinyl or piperazinyl is substituted, then the piperidinyl or piperazinyl is substituted with 1-4 Rn. In some embodiments, R2 and R3 are taken together with the nitrogen atom to which they are attached to form a substituted piperidinyl that is substituted with 1-4 Rn. In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a substituted piperazinyl that is substituted with 1-4 Rn. In some embodiments, each Rn is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, halogen, CO2R20_, OR20, N(R₂o)2_, or NH(C=0)ORi9 _, and wherein any substituted group of Rn is substituted with I-4R21. In some embodiments, R₂₀ is hydrogen. In some embodiments, Rn is substituted or unsubstituted aryl, and wherein any substituted group of Rn is substituted with l-4R₂i. In some embodiments, each R₂₁ is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefiuoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, halogen, CN, CH₂- CN, CH₂-OR₂₄, OR₂₄, CH₂-N(R₂₄)₂, and N(R₂₄)₂. In some embodiments, R₂₄ is hydrogen.In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are

attached to form: ^{R 7} (^Ri7)m ₅

, ΟΓ *^{1 7} (^Ri7)m ₅ wherein each m is 0, 1, 2, or 3 and n is 0, 1, or 2.

[0018] In some embodiments, R₄ is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C₃-Ciocycloalkyl, substituted or unsubstituted C₃_Ciocycloalkenyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein if R₄ is substituted, then R₄ is substituted with 1-4 R_J8 In some embodiments, R₄ is substituted or unsubstituted aryl, and wherein if the aryl is substituted, then the aryl is substituted with 1-4 R_J8. In some embodiments, R₄ is substituted or unsubstituted phenyl, and wherein if the phenyl substituted, then the phenyl is substituted with 1-4 R_J8 In some embodiments, R₄ IS substituted or unsubstituted C₃-Ciocycloalkyl, and wherein if C₃- Ciocycloalkyl is substituted, then the C₃-Ciocycloalkyl is substituted with 1-4 R_J8 In some embodiments, Rj is substituted C₃-Ciocycloalkyl that is substituted with 1-4 R_J8. In some embodiments, Rj is substituted or unsubstituted cyclohexyl, and wherein if the cyclohexyl is substituted, then the cyclohexyl is substituted with 1-4 R_J8. In some embodiments, R₄ is substituted cyclohexyl that is substituted with 1-4 R_J8. In some embodiments, each R_J8 is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted aryl, halogen, or NH(C=0)O substituted group of Ri₈ is substituted with 1-4R₂₂. In some

embodiments,

and o is 0, 1 or 2.

[0019] In some embodiments, the compound of Formula (C) is:

and R₄ IS substituted or unsubstituted C3-Ciocycloalkyl or substituted or unsubstituted aryl, and wherein if R₄ is substituted, then R₄ is substituted with 1-4 R_J8

[0020] In some embodiments, the compound of Formula (C) is:

and R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring, containing 0- 1 additional N heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 R_n.

[0021] In some embodiments, the compound exhibits an IC₅₀ of no more than about 5.000 μΜ.

In some embodiments, the compound exhibits an IC₅₀ of no more than about 10.000 μΜ. In some e



[0022] Another embodiment provides a pharmaceutical composition comprising a

pharmaceutically acceptable excipient and a compound of Formula (C) or geometric pharmaceutically acceptable salt thereof:

Formula (C)

wherein,

CR₁0; A₆ is N, C or CR_n; A₇ is N, C or CRi₂; A₈ is N, C or CR_J3;

R₂ and R3 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted

or unsubstituted C₂-Ci₀heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein any substituted group of R2 and R3 is substituted with 1-4 R_n;

or R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring, containing 0- 1 additional heteroatom selected from N, S, and O; wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R_n;

R4 is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3

-Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted or unsubstituted

C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,

or substituted or unsubstituted heteroaryl; wherein if R4 is substituted, then R₄ is substituted

substituted or unsubstituted heteroaryl, halogen, CN, OR₁6, N(Ri₆)2, SR16, SOR₁5,

S0₂R₁₅, C0₂R₁₆, CON(R₁₆)₂, S0₂N(R₁₆)₂, or N0₂;

each Ri5 is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Cr

Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or

unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle; Rn and Ri8 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or

unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, OR₂0, N(R₂o)₂, SR₂0, SOR₁9, SO₂R₁9, CO₂R₂0, CON(R₂₀)₂, SO₂N(R₂₀)₂, NH(C=0)OR_19, or N0₂; wherein any substituted group of R₁₇ is substituted with 1-4 R₂i; wherein any substituted group of Ris is substituted with 1-4 R₂₂; each Ri9 is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted

Cr

Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or

unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

C₂

unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R24 groups attached to

[0023] Another embodiment provides a method for treating a cancer in a subject comprising administering a therapeutically effective amount of a compound of Formula (C) or geometric isomer or a pharmaceutically acceptable salt thereof, to the subject in need thereof:

Formula (C)

wherein,

Ai is N, C, or CR₆; A₂ is N, C, or CR₇; A₃ is N, C or CRs; A₄ is N, C, or CR₉; A₅ is N, C, or

CR10; A₆ is N, C or CR„; A₇ is N, C or CR_n; A₈ is N, C or CRj₃;

unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein any substituted group

of R2 and R3 is substituted with 1-4 Rn;

R4 is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C₃- Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted or unsubstituted

C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein if R4 is substituted, then R₄ is substituted with 1-4 R_J8;

substituted or unsubstituted heteroaryl, halogen, CN, OR₁6, N(Ri₆)2, SR16, SOR₁5, S0₂R₁₅, C0₂R₁₆, CON(R₁₆)₂, S0₂N(R₁₆)₂, or N0₂;

Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3 -Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R_½ groups attached to

unsubstituted C₃ -Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, OR₂o, N(R₂₀)₂, SR₂o, SOR₁₉, S0₂Ri₉, C0₂R₂o, CON(R₂₀)₂, SO₂N(R₂₀)₂,

or N0₂; wherein any substituted group of R₁₇ is substituted with 1-4 R_2J; wherein any substituted group of Ris is substituted with 1-4 R_22; each Rig is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl,substituted or unsubstituted

C₂

or substituted or unsubstituted heteroaryl;

unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R20 groups attached to

R21 and R22 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or

unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, CH₂-CN, CH₂-OR₂₄, OR₂₄, CH₂-N(R₂₄)2, N(R₂₄)₂, SR₂₄, SOR23, SO2R23, C0₂R₂ , CON(R₂₄)₂, S0₂N(R₂₄)₂, NH(C=0)OR₂₃, or N0₂;

each R23 is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted

Cr

C₂

or substituted or unsubstituted heteroaryl; and

each R₂₄ is independently H, substituted or unsubstituted Ci-Cealkyl, substituted or

unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R2₄ groups attached to

[0024] In some embodiments, the cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP). In some embodiments, the compound is an inhibitor of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compound increases the phosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decreases the

dephosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compound increases the ubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decreases the deubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator

(TAZ/YAP).

[0025] In some embodiments, the cancer is characterized by a mutant Ga-protein. In some embodiments, the mutant Ga-protein is selected from G12, G13, Gq, Gl 1, Gi, Go, and Gs. In some embodiments, the cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, and primary liver cancer. In some embodiments, the cancer is uveal melanoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is primary liver cancer.

[0026] Another embodiment provides a method for treating a congenital disease in a subject comprising administering a therapeutically effective amount of a compound of Formula (C) or geometric isomer or a pharmaceutically acceptable salt thereof, to the subject in need thereof:

Formula (C)

wherein,

CRio; A₆ is N, C or CR_n; A₇ is N, C or CR_n; A₈ is N, C or CRj₃;

or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein any substituted group

of R2 and R3 is substituted with 1-4 R_n;

or R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring, containing 0-1 additional heteroatom selected from N, S, and O; wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R_n;

R4 is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted or unsubstituted

S0₂R₁₅, C0₂R₁₆, CON(R₁₆)₂, S0₂N(R₁₆)₂, or N0₂;

the same N atom are taken together with the N atom to which they are attached to form a

substituted or unsubstituted heterocycle Rn and Ri8 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or

Cr

C₂

or substituted or unsubstituted heteroaryl;

unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, CH₂-CN, CH₂-OR₂₄, OR₂₄, CH₂-N(R₂₄)2, N(R₂₄)₂, SR₂ , SOR23, SO2R23, C0₂R₂₄, CON(R₂₄)₂, S0₂N(R₂₄)₂, NH(C=0)OR₂₃, or N0₂;

Cr

C₂

-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

each R₂4 is independently H, substituted or unsubstituted Ci-Cealkyl, substituted or

[0027] In some embodiments, the congenital disease is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator

(TAZ/YAP). In some embodiments, the compound is an inhibitor of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compound increases the phosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decreases the dephosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compound increases the ubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decreases the deubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator

(TAZ/YAP).

[0028] In some embodiments, the congenital disease is characterized by a mutant Ga-protein. In some embodiments, the mutant Ga-protein is selected from G12, G13, Gq, Gi l, Gi, Go, and Gs.

In some embodiments, the congenital disease is Sturge-Weber Syndrome or Port-Wine stain. In some embodiments, the congenital disease is Sturge-Weber Syndrome. In some embodiments, the congenital disease is Port-Wine stain.

INCORPORATION BY REFERENCE

[0029] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Various aspects of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0031] FIG. 1 illustrates a schematic representation of the Hippo signaling network. Hippo pathway components shaded in dark gray indicate components that inhibit YAP/TAZ activity. Hippo pathway components shaded in light gray indicate components that promote YAP/TAZ activity. Pointed and blunt arrowheads indicate activating and inhibitory interactions,

respectively. Abbreviations: a-CAT (a-Catenin), AJUB (Ajuba), AMOT (Angiomotin), β-TRCP (β-transducing repeat containing protein), CK1 (Casein Kinase 1), CRB (Crumbs), E-CAD (E- cadherin), EX (Expanded), GPCR (G-protein coupled receptor), HIPK (Homeodomain interacting protein kinase), KIBRA (Kidney brain), LATS (Large tumor suppressor), LGL (Lethal giant larvae), MASK (Multiple ankyrin single KH), MER (Merlin), MOB (Mps one binder), MST (Mammalian sterile 20 like), PALS (Protein Associated with Lin-7), PATJ (Palsl- associated tight junction protein), PP2A (Protein phosphatase 2A), PTPN14 (Protein tyrosine phosphatase non-receptor type 14), RASSF (Ras associated factor), SAV (Salvador), SCRIB (Scribble), SIK (Salt inducible kinase), TAO (Thousand and one amino acid protein), TAZ (transcriptional coactivator with PDZ-binding motif), TEAD (TEA domain protein), VGL4 (Vestigial-like 4), WBP2 (WW domain binding protein 2), YAP (Yes associated protein), ZO (Zonula occludens), ZYX (Zyxin).

[0032] FIG. 2 illustrates a schematic representation of the Hippo signaling pathway regulated by G alpha proteins.

DETAILED DESCRIPTION OF THE DISCLOSURE

Certain Terminology

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise.

Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[0034] As used herein, in some embodiments, ranges and amounts are expressed as "about" a particular value or range. About also includes the exact amount. Hence "about 5 μΕ" means "about 5 μ]_," and also "5 μΚ" Generally, the term "about" includes an amount that would be expected to be within experimental error.

[0035] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0036] As used herein, the terms "individual(s)", "subject(s)" and "patient(s)" mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly or a hospice worker).

[0037] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0038] "Amino" refers to the -NH₂ radical.

[0039] "Cyano" refers to the -CN radical.

[0040] "Nitro" refers to the -N0₂ radical.

[0041] "Oxa" refers to the -O- radical.

[0042] "Oxo" refers to the =0 radical.

[0043] "Thioxo" refers to the =S radical.

[0044] "Imino" refers to the =N-H radical.

[0045] "Oximo" refers to the =N-OH radical.

[0046] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C₁-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C₁-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cg alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C₁-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C₁-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C ₁-C₂ alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C_\ alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C₂-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl («-propyl), 1-methylethyl (z^'so-propyl), 1 -butyl («-butyl), 1- methylpropyl (sec-butyl), 2-methylpropyl (/so-butyl), 1, 1 -dime thylethyl (ferf-butyl), 1-pentyl (n- pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -C(0)N(R^a)₂, -N(R^a)C(0)OR^f, -OC(O)- NR^aR^f, -N(R^a)C(0)R^f, -N(R^a)S(0)_tR^f (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tR^f (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R^f is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0047] " Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0048] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,

trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -C(0)N(R^a)₂,

-N(R^a)C(0)OR^f, -OC(O)- NR^aR^f, -N(R^a)C(0)R^f, -N(R^a)S(0)_tR^f (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tR^f (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R^f is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0049] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -C(0)N(R^a)₂, -N(R^a)C(0)OR^f, -OC(O)- NR^aR^f, -N(R^a)C(0)R^f, -N(R^a)S(0)_tR^f (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tR^f (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,

carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R^f is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0050] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, «-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cg alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C₁-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C_\- C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C₁-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C_\ alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C₂-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -C(0)N(R^a)₂, -N(R^a)C(0)OR^f, -OC(O)- NR^aR^f, -N(R^a)C(0)R^f, -N(R^a)S(0)_tR^f (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tR^f (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and each R^f is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

[0051] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i. e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-CN, -R^b-OR^a, -R^b-OC(0)-R^a, -R^b-OC(0)-OR^a, -R^b-OC(0)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)OR^a, -R^b-C(0)N(R^a)₂,

-R^b-0-R^c-C(0)N(R^a)₂, -R^b-N(R^a)C(0)OR^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tOR^a (where t is 1 or 2), -R^b-S(0)_tR^a (where t is 1 or 2) and -R^b-S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl,

cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0052] "Aryloxy" refers to a radical bonded through an oxygen atom of the formula -0-aryl, where aryl is as defined above.

[0053] "Aralkyl" refers to a radical of the formula -R^c-aryl where R^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0054] "Aralkenyl" refers to a radical of the formula -R^d-aryl where R^d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0055] "Aralkynyl" refers to a radical of the formula -R^e-aryl, where R^e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0056] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and in some embodiments, include fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. In some embodiments, the carbocyclyl is saturated, (i. e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as "cycloalkyl. " Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., C3- cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). An unsaturated carbocyclyl is also referred to as "cycloalkenyl. " Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,

cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i. e., bicyclo[2.2. l]heptanyl), norbornenyl, decalinyl,

7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R^b-OR^a, -R^b-OC(0)-R^a, -R^b-OC(0)-OR^a, -R^b-OC(0)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)OR^a, -R^b-C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b-N(R^a)C(0)OR^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tOR^a (where t is 1 or 2), -R^b-S(0)_tR^a (where t is 1 or 2) and -R^b-S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0057] "Carbocyclylalkyl" refers to a radical of the formula -R^c-carbocyclyl where R^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0058] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents. [0059] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0060] "Heterocyclyl" or "heterocycle" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which include fused or bridged ring systems in some embodiments. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. In some embodiments, the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). In some embodiments, the heterocyclyl is saturated, (i.e., containing single bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated heterocyclyl radical is also referred to as "heterocycloalkyl." Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,

2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and

1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R^b-CN , -R^b-OR^a, -R^b-OC(0)-R^a, -R^b-OC(0)-OR^a, -R^b-OC(0)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)OR^a, -R^b-C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b-N(R^a)C(0)OR^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tOR^a (where t is 1 or 2), -R^b-S(0)_tR^a (where t is 1 or 2) and -R^b-S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0061] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g. , oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ceheteroalkyl. In some embodiments, the alkyl part of the heteroalkyl radical is optionally substituted as defined for an alkyl group.

[0062] "Heterocyclylalkyl" refers to a radical of the formula -R^c-heterocyclyl where R^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0063] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula - 0-R^c -heterocyclyl where R^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0064] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, in some embodiments, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, benzo[b][l,4]oxazinyl,

1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl,

5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1 ,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,

5,6,6a,7,8,9,10, 10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,

pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,

5.6.7.8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,

6.7.8.9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,

5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-OC(0)-R^a, -R^b-OC(0)-OR^a, -R^b-OC(0)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a,

-R^b-C(0)OR^a, -R^b-C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b-N(R^a)C(0)OR^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tOR^a (where t is 1 or 2), -R^b-S(0)_tR^a (where t is 1 or 2) and -R^b-S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0065] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals. [0066] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0067] "Heteroaryloxy" refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.

[0068] "Heteroarylalkyl" refers to a radical of the formula -R^c-heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0069] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- R^c -heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a

nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0070] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term

"positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0071] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0072] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0073] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0074] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates,

toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997), which is hereby incorporated by reference in its entirety). In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0075] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, NN-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylgluc amine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al, supra.

[0076] As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By

"therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments. For prophylactic benefit, in some embodiments, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. [0077] "Prodrug" is meant to indicate a compound that is converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism {see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,

Amsterdam).

[0078] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.

[0079] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. In some embodiments, prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

Compounds

[0080] Disclosed herein are tricyclic compounds containing one or more oxime moiety or derivatives thereof. One embodiment provides a compound of Formula (A) or geometric isomer or a pharmaceutically acceptable salt thereof:

Formula (A)

wherein, Ai is N, C, or CR₆; A₂ is N, C, or CR₇; A₃ is N, C or CR₈; A₄ is N, C, or CR₉; A₅ is N, C, or

CRio; A₆ is N, C or CRn; A₇ is N, C, or CRn; A₈ is N, C or CR₁₃, wherein at least one Ai, A₂, A₃, A₄, A₅, A₆, A₇, A₈, is N;

R2 and R₃are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted

or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3- Ciocycloalkenyl,

substituted or unsubstituted d-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein any substituted group of R2 and R₃ is substituted with 1-4 R_n;

or R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring, containing 0-1 additional heteroatom selected from N, S, and O; or R4 and R5 are taken together with the nitrogen atom to which

they are attached to form a unsubstituted or substituted 4-8 membered ring, containing 0-

1

additional heteroatom selecting from N, S, and O; wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R_n;

R₄ and R5 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein any substituted group of R4 and R5 is substituted with 1-4 R_J8;

or R₄ and R5 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring, containing 0-1 additional heteroatom selected from N, S, and O; or R4 and R5 are taken together with the nitrogen atom to which

1

additional heteroatom selecting from N, S, and O; wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R_J8;

Ri and R14 are each independently H, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted Ci-Ceheteroalkyl; R-6, R₇, Re, R9, Rio, Rn, R12, and R13 are each independently H, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted

C2- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,

substituted or unsubstituted heteroaryl, halogen, CN, OR₁6, N(Ri₆)2, SR16, SOR₁5, S0₂R₁₅,

C0₂R₁₆, CON(R₁₆)₂, S0₂N(R₁₆)₂, or N0₂;

each Ri5 is independently substituted or unsubstituted Ci-Cealkyl, substituted or

unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R_½ groups attached to

Rn and Ris are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or

unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, OR20, N(R₂o)2, SR20, SOR19, SO2R19, CO2R20, CON(R₂₀)₂, SO₂N(R₂₀)2, NH(C=0)OR_19, or N0₂; wherein any substituted group of R₁₇ is substituted with 1-4 R₂i; wherein any substituted group of Ris is substituted with 1-4 R₂2; each Rig is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted

C₂

or substituted or unsubstituted heteroaryl; each R₂o is independently H, substituted or unsubstituted Ci-Cealkyl, substituted or

Cr

C₂

or substituted or unsubstituted heteroaryl; and

[0081] In some embodiments, the compound of Formula (A) is:

41

[0084] In some embodiments, the compound of Formula (A) is:

[0085 In some embodiments, the compound of Formula (A) is:

[0086] In some embodiments, the compound of Formula (A) is:

0087] In some embodiments, the compound of Formula (A) is:

[0088] In some embodiments the compound of Formula (A) is:

[0089] In some embodiments, the compound of Formula (A) is:

[0093] In some embodiments, the compound of Formula (A) is:

[0099] In some embodiments, the compound of Formula (A) is:

[00100] In some embodiments, the compound of Formula (A) is:

[00101] In some embodiments, the compound of Formula (A) is:

[00102] In some embodiments, the compound of Formula (A) is:

[00103] In some embodiments, the compound of Formula (A) is:

[00104] In some embodiments, the compound of Formula (A) is:

[00105] In some embodiments the compound of Formula (A) is:

[00106] In some embodiments, the compound of Formula (A) is:

[00107]

[00110] In some embodiments, X is a bond. In some embodiments, X is C=N(ORi₄). In some embodiments, is hydrogen. In some embodiments, R is hydrogen.

[00111] In some embodiments, R₂ and R₃ are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, wherein any substituted group of R₂ and R₃ is substituted with 1- 4 R17. In some embodiments, R₂ is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefiuoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, wherein any substituted group of R₂ is substituted with 1-4 ¾₇. In some embodiments, R₃ is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, wherein any substituted group of R₃ is substituted with 1-4 Rn- In some embodiments, R₂ IS substituted or unsubstituted Ci-Cealkyl, and R₃ is substituted or unsubstituted Ci-Ceheteroalkyl, wherein any substituted group of R₂ and R₃ is substituted with 1-

[00112] In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional heteroatom selected from N, S, and 0, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 Rn. In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional 0 heteroatom, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R₁₇. In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring containing 0- 1 additional 0 heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 Rn. In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional N heteroatom, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 Rn. In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring containing 0-1 additional N heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 Rn. In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted piperidinyl or unsubstituted or substituted piperazinyl, and wherein if the piperidinyl or piperazinyl is substituted, then the piperidinyl or piperazinyl is substituted with 1-4 Rn. In some embodiments, R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a substituted piperidinyl that is substituted with 1-4 Rn. In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a substituted piperazinyl that is substituted with 1-4 Rn. In some embodiments, each Rn is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, halogen, CO₂R₂0_, OR₂0, N(R₂o)_2, or

, and wherein any substituted group of Rn is substituted with l-4R₂i. In some embodiments, R₂₀ is hydrogen. In some embodiments, Rn is substituted or unsubstituted aryl, and wherein any substituted group of Rn is substituted with l-4R₂i. In some embodiments, each R₂i is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefiuoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, halogen, CN, CH₂-CN, CH₂- OR24, OR24, CH₂-N(R₂4)2, and N(R₂4)2. In some embodiments, R24 is hydrogen. In some embodiments, R2 and R3 are taken together with the nitrogen atom to which they are attached to

form: ^Rl7 (^Ri 7>m _;

2, or 3 and n is 0, 1, or 2. In some embodiments, R2 and R3 are taken together with the nitrogen atom to

which they are attached to form:

and wherein n is 0, 1, or

2.

[00113] In some embodiments, R4 and R5 are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, and wherein any substituted group of R4 and R5 is substituted with 1-4 Rig. In some embodiments, R4 is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefiuoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, and wherein any substituted group of R₄ is substituted with 1-4 Ri₈. In some embodiments, R₅ is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, and wherein any substituted group of R5 is substituted with 1-4 Ri₈. In some embodiments, R4 is substituted or unsubstituted C i-Cealkyl, and R5 is substituted or unsubstituted Ci-Ceheteroalkyl, and wherein any substituted group of R4 and R5 is substituted

[00114] In some embodiments, R4 and R5 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional heteroatom selected from N, S, and 0, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R_J8. In some embodiments, R4 and R5 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional 0 heteroatom, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 Ri8. In some embodiments, R4 and R5 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring containing 0- 1 additional 0 heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 R_J8. In some embodiments, R4 and R5 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0- 1 additional N heteroatom, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R_J8. In some embodiments, R₄ and R5 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring containing 0- 1 additional N heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 Ri₈. In some embodiments, R₄ and R5 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted piperidinyl or unsubstituted or substituted piperazinyl, and wherein if the piperidinyl or piperazinyl is substituted, then the piperidinyl or piperazinyl is substituted with 1-4 Ris. In some embodiments, R₄ and R5 are taken together with the nitrogen atom to which they are attached to form a substituted piperidinyl that is substituted with 1-4 Ri₈. In some embodiments, R₄ and R5 are taken together with the nitrogen atom to which they are attached to form a substituted piperazinyl that is substituted with 1-4 Ri₈. In some embodiments, each Ri₈ is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, halogen, CO₂R_20, OR₂₀, N(R₂₀)_2j or NH(C=0)ORi₉ ; and wherein any substituted group of Ris is substituted with 1-4R₂₂. In some embodiments, R₂₀ is hydrogen. In some embodiments, Ri₈ is substituted or unsubstituted aryl, and wherein any substituted group of Ri₈ is substituted with 1-4R₂₂. In some embodiments, each R₂₂ is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefiuoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, halogen, CN, CH₂-CN, CH₂- OR₂4, OR₂4, CH₂-N(R₂4)₂, and N(R₂4)₂. In some embodiments, R₂4 is hydrogen. In some

which they are attached to

in each m is 0, 1, 2, or 3 and n is 0, 1, or 2. In some embodiments, R₄ and R₅ are taken together with the nitrogen atom to

which they are attached to form:

, or ₅ and wherein n is 0, 1, or

2.

[00115] One embodiment provides a compound of Formula (B) or geometric isomer or a pharmaceutically acceptable salt thereof:

Formula (B)

wherein,

CRio; A₆ is N, C or CR_n; A₇ is N, C or CR_n; A₈ is N, C or CRj₃;

R2 and R3 are each independently substituted or unsubstituted Ci-Cealkyl, substituted or

unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted

or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein if R₂ is substituted, then R₂ is substituted with 1-4 Ri_7j and wherein if R₃ is substituted, then R₃ is substituted

R6, R7, Re, R9, Rio, Rn, R12, and R13 are each independently H, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted

C₂- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,

C0₂R₁₆, CON(R₁₆)₂, S0₂N(R₁₆)₂, or N0₂;

each Ri5 is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl,substituted or unsubstituted C₂- Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or

substituted or unsubstituted heteroaryl;

unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R_½ groups attached to

Rn and Ri₈ are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or

unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, OR₂0, N(R₂o)₂, SR₂0, SOR₁9, SO₂R₁9, CO₂R₂0, CON(R₂₀)₂, SO₂N(R₂₀)₂, NH(C=0)OR_19, or N0₂; wherein any substituted group of R₁₇ is substituted with 1-4 R₂₁; wherein any substituted group of Ris is substituted with 1-4 R₂₂; each Rig is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted

Cr

C₂

or substituted or unsubstituted heteroaryl;

unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R₂0 groups attached to

R₂₁ and R₂₂ are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or

Cr

C₂ -Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl,

or substituted or unsubstituted heteroaryl; and

[00116] In some embodiments, the compound of Formula (B) is:

[00117] In some embodiments, the compound of Formula (B) is:

[00118] In some embodiments, the compound of Formula (B) is:

61

[00123] In some embodiments, the compound of Formula (B) is:

[00124] In some embodiments, the compound of Formula (B) is:

[00125]

63

[00127] In some embodiments, X is a bond. In some embodiments, X is C=N(ORi₄). In some embodiments, R14 is hydrogen. In some embodiments, Ri is hydrogen.

[00128] In some embodiments, R2 is substituted or unsubstituted Ci.Cealkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted or unsubstituted C₂-Ci₀heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein if R₂ is substituted, then R2 is substituted with 1-4 Rn. In some embodiments, R2 IS substituted or unsubstituted Ci-Cealkyl, and wherein if the Ci-Cealkyl is substituted, then the Ci-Cealkyl is substituted with 1-4 Rn. In some embodiments, R2 IS substituted or unsubstituted C3-Ciocycloalkenyl, and wherein if the C3-Ciocycloalkenyl is substituted, then the C3-Ciocycloalkenyl is substituted with 1-4 Rn. In some embodiments, R2 is substituted or unsubstituted C₂-Cioheterocycloalkyl, and wherein if the C₂-Cioheterocycloalkyl is substituted, then the C₂-Cioheterocycloalkyl is substituted with 1-4 Rn. In some embodiments, R2 is substituted or unsubstituted aryl, and wherein if the aryl is substituted, then the aryl is substituted with 1-4 Rn. In some embodiments, R2 is substituted or unsubstituted phenyl, and wherein if the phenyl substituted, then the phenyl is substituted with 1-4 Rn. In some embodiments, R2 IS substituted or unsubstituted C3-Ciocycloalkyl, and wherein if C3- Ciocycloalkyl is substituted, then the C3-Ciocycloalkyl is substituted with 1-4 Rn. In some embodiments, R2 IS substituted C3-Ciocycloalkyl that is substituted with 1-4 Rn. In some embodiments, R2 IS substituted or unsubstituted cyclohexyl, and wherein if the cyclohexyl is substituted, then the cyclohexyl is substituted with 1-4 Rn. In some embodiments, R2 is substituted cyclohexyl that is substituted with 1-4 Rn. In some embodiments, each Rn is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted aryl, halogen, or NH(C=0)ORi₉, and wherein any substituted group of Rn is substituted with l-4R₂i. In some

embodiments, R₂ is

, and o is 0, 1 or 2. In some embodiments, R₂ is

and o is 0, 1 or 2. In some embodiments, R2 IS _; and o is 0, 1, 2, or

3.

[00129] In some embodiments, R3 is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein if R₃ is substituted, then R₃ is substituted with 1-4 R_J8 In some embodiments, R3 is substituted or unsubstituted Ci-Cealkyl, and wherein if the Ci-Cealkyl is substituted, then the Ci-Cealkyl is substituted with 1-4 R_J8. In some embodiments, R3 is substituted or unsubstituted C3-Ciocycloalkenyl, and wherein if the C3-Ciocycloalkenyl is substituted, then the C3-Ciocycloalkenyl is substituted with 1-4 R_J8. In some embodiments, R3 is substituted or unsubstituted C₂-Cioheterocycloalkyl, and wherein if the C₂-Cioheterocycloalkyl is substituted, then the C₂-Cioheterocycloalkyl is substituted with 1-4 R_J8. In some embodiments, R3 is substituted or unsubstituted aryl, and wherein if the aryl is substituted, then the aryl is substituted with 1-4 R_J8. In some embodiments, R3 is substituted or unsubstituted phenyl, and wherein if the phenyl substituted, then the phenyl is substituted with 1-4 R_J8 In some embodiments, R3 is substituted or unsubstituted C3-Ciocycloalkyl, and wherein if C3- Ciocycloalkyl is substituted, then the C3-Ciocycloalkyl is substituted with 1-4 R_J8 In some embodiments, R3 is substituted C3-Ciocycloalkyl that is substituted with 1-4 R_J8. In some embodiments, R3 is substituted or unsubstituted cyclohexyl, and wherein if the cyclohexyl is substituted, then the cyclohexyl is substituted with 1-4 R_J8. In some embodiments, R3 is substituted cyclohexyl that is substituted with 1-4 R_J8. In some embodiments, each R_J8 is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted aryl, halogen, or NH(C=0)ORi₉; and wherein any substituted group of Ri₈ is substituted with 1-4R₂₂. In some

embodiments, R3 is

_; and o is 0, 1 or 2. In some embodiments, R3 is

and o is 0, 1 or 2. In some embodiments, R3 is ₅ and o is 0, 1, 2, or

3.

[00130] One embodiment provides a compound of Formula (C) or geometric isomer or a pharmaceutically acceptable salt thereof:

Formula (C)

wherein,

CR10; A₆ is N, C or CR„; A₇ is N, C or CR_n; A₈ is N, C or CRj₃;

R2 and R3 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-C₆fluoroalkyl, substituted or unsubstituted Ci-C₆heteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted

of R2 and R3 is substituted with 1-4 R_n;

or R2 and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring, containing 0- 1 additional heteroatom selected from N, S, and O; wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R_n;

C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein if R4 is substituted, then R₄ is substituted with 1-4 R_J8; Ri and R14 are each independently H, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted C i-Ceheteroalkyl;

substituted or unsubstituted heteroaryl, halogen, CN, OR₁6, N(Ri₆)2, SR16, SOR₁5, S0₂Ri5, CO2R16, CON(R₁₆)₂, S0₂N(R₁₆)₂, or N0₂;

Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

substituted or unsubstituted heterocycle;

Rn and Ri8 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or

unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, OR20, N(R₂o)2, SR20, SOR19, SO2R19, CO2R20, CON(R₂₀)₂, SO₂N(R₂₀)2, NH(C=0)OR_19, or N0₂; wherein any substituted group of R₁₇ is substituted with 1-4 R21; wherein any substituted group of Ris is substituted with 1-4 R22; each Rig is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted

Cr

C₂

-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

Cr

C₂

or substituted or unsubstituted heteroaryl; and

[00131] In some embodiments, the compound of Formula (C) is:

[00132]

[00133] In some embodiments, the compound of Formula (C) is:

[00134] In some embodiments, the compound of Formula (C) is:

[00135] In some embodiments, the compound of Formula (C) is:

[00138] In some embodiments, the compound of Formula (C) ^'

[00139] In some embodiments, the compound of Formula (C) is: [00140] I

[00141]

[00142] In some embodiments, at least two A_1; A₂, A₃, A₄, A₅, A₆, A₇, A₈, are N. In some embodiments, at least three A_1; A₂, A₃, A₄, A₅, A₆, A₇, A₈, are N. In some embodiments, X is a bond. In some embodiments, X is C=N(ORi₄). In some embodiments, R 4 is hydrogen. In some embodiments, R_\ is hydrogen.

[00143] In some embodiments, R₂ and R3 are each independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, and wherein any substituted group of R₂ and R3 is substituted with 1-4 R17. In some embodiments, R₂ is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefiuoroalkyl, substituted or unsubstituted C i-Ceheteroalkyl, and wherein any substituted group of R₂ is substituted with 1-4 R₁₇. In some embodiments, R3 is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, wherein any substituted group of R3 is substituted with 1-4 R₁₇. In some embodiments, R2 IS substituted or unsubstituted Ci-Cealkyl, and R3 is substituted or unsubstituted Ci-Ceheteroalkyl; and wherein any substituted group of R₂ and R3 is substituted with 1-4 R₁₇.

[00144] In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional heteroatom selected from N, S, and 0, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R₁₇. In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional 0 heteroatom, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R17. In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring containing 0- 1 additional 0 heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 R₁₇. In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional N heteroatom, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R₁₇. In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring containing 0-1 additional N heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 R₁₇. In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted piperidinyl or unsubstituted or substituted piperazinyl, and wherein if the piperidinyl or piperazinyl is substituted, then the piperidinyl or piperazinyl is substituted with 1-4 R₁₇. In some embodiments, R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a substituted piperidinyl that is substituted with 1-4 ₁₇. In some embodiments, R2 and R3 are taken together with the nitrogen atom to which they are attached to form a substituted piperazinyl that is substituted with 1-4 R₁₇. In some embodiments, each Rn is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, halogen, CO2R20, OR20, N(R₂o)2, or NH(C=0)ORi9, and wherein any substituted group of Rn is substituted with l-4R₂i. In some embodiments, R20 is hydrogen. In some embodiments, Rn is substituted or unsubstituted aryl, and wherein any substituted group of Rn is substituted with l-4R₂i. In some embodiments, each R₂i is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefiuoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, halogen, CN, CH2-CN, CH2- OR24, OR24, CH₂-N(R₂4)2, and N(R₂4)2. In some embodiment, R24 is hydrogen. In some embodiments, R2 and R3 are taken together with the nitrogen atom to which they are attached to

, or ₅ wherein each m is 0, 1, 2, or 3 and n is 0, 1, or 2. In some embodiments, R2 and R3 are taken together with the nitrogen atom to

2.

[00145] In some embodiments, R4 is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein if R₄ is substituted, then R₄ is substituted with 1-4 R_J8 In some embodiments, R4 IS substituted or unsubstituted Ci-Cealkyl, and wherein if the Ci-Cealkyl is substituted, then the Ci-Cealkyl is substituted with 1-4 R_J8. In some embodiments, R4 IS substituted or unsubstituted C3-Ciocycloalkenyl, and wherein if the C3-Ciocycloalkenyl is substituted, then the C3-Ciocycloalkenyl is substituted with 1-4 R_J8. In some embodiments, R4 is substituted or unsubstituted C2-Cioheterocycloalkyl, and wherein if the C2-Cioheterocycloalkyl is substituted, then the C2-Cioheterocycloalkyl is substituted with 1-4 R_J8. In some embodiments, R4 is substituted or unsubstituted aryl, and wherein if the aryl is substituted, then the aryl is substituted with 1-4 Ri₈. In some embodiments, R4 is substituted or unsubstituted phenyl, and wherein if the phenyl substituted, then the phenyl is substituted with 1-4 R_J8 In some embodiments, R4 IS substituted or unsubstituted C3-Ciocycloalkyl, and wherein if C3- Ciocycloalkyl is substituted, then the C3-Ciocycloalkyl is substituted with 1-4 R_J8 In some embodiments, R4 IS substituted C3-Ciocycloalkyl that is substituted with 1-4 R_J8. In some embodiments, R4 IS substituted or unsubstituted cyclohexyl, and wherein if the cyclohexyl is substituted, then the cyclohexyl is substituted with 1-4 Ri₈. In some embodiments, R4 is substituted cyclohexyl that is substituted with 1-4 R_J8. In some embodiments, each R_J8 is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted aryl, halogen, =0)ORi substituted group of Ri₈ is substituted with 1-4R₂2. In some

and R4 IS substituted or unsubstituted C3-Ciocycloalkyl or substituted or unsubstituted aryl, and wherein if R₄ is substituted, then R₄ is substituted with 1-4 R_J8

[00147] In some embodim (C) is:

and R2 and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring, containing 0- 1 additional N heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 R₁₇.

[00148] In some embodiments, the compound of Formula (C) is:

and R4 IS substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3- Ciocycloalkenyl, or substituted or unsubstituted aryl, and wherein if R4 is substituted, then R4 is substituted with 1-4 Ri₈.

[00149] In some embodim (C) is:

and R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring, containing 0- 1 additional N heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 R₁₇.

[00150] In some embodiments, the compound disclosed herein has the structure provided in Table 1.

^CN yl)benzonitrile

fluoren-9-one oxime

[00151] In some embodiments, the compound disclosed herein has the structure provided in Table 2.

TABLE 2

In some embodiments, the compound disclosed herein has the structure provided in Table 3.

me embodiments, the compound disclosed herein has the structure provided

me embodiments, the compound disclosed herein has the structure provided

Preparation of the Compounds

[00155] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (W aterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[00156] Methods known to one of ordinary skill in the art are identified through various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-lnterscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618- 5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley- VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471- 19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-lnterscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[00157] In some instances, specific and analogous reactants are identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., is contacted for more details). Chemicals that are known but not commercially available in catalogs are prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[00158] The compounds described herein are prepared by the general synthetic routes described below in Schemes 1-4.

Scheme 1

A-4

[00159] In some embodiments, a compound of formula A-l is treated with neat chlorosulfonic acid under heating (60- 150 °C) to provide a bis-sulfonylchloride compound of formula A-2. In some instances, the crude product of formula A-2 is purified via

recrystallization from an appropriate organic solvent, such as dry THF or dry MeCN. In some instances, the compound of formula A-2 in DCM/pyridine (5/1) is cooled to -20°C, and is treated with 1.0 equivalent of an amine of formula NHR₂R₃ to afford an intermediate of formula A-3. After the mixture is warmed to room temperature and stirred for 12 hours, 1.5 equivalents of an amine of formula NHR₄R₅ is added, and the reaction is stirred for another 12 hours. In some instances, the crude product work-up of the reaction is separated by preparative HPLC to provide a compound of formula A-4. Subsequent treatment of a compound of formula A-4 with hydroxylamine HC1 salt (5 equivalents) in pyridine under suitable conditions, such as at 60 °C for 2 hours, provides a compound of formula A-5.

[00160] In Scheme 2, at least one of A₂, A₄, A₅, and A₇ is N while the rest are

independently C-R, wherein R is each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C₂- Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, OR₁₅, N(R₁₆)₂, SR₁₅, SOR₁₅, S0₂R₁₅, C0₂R₁₅, CON(R₁₆)₂, S0₂N(R₁₆)₂, or N0₂.

[00161] In some embodiments, to a solution of a compound of formula B-l in wet THF

(~2 weight% water) at 0°C is bubbled in ~5-8 equivalents of chlorine gas (reaction flask is weight before and after introduction of gas to calculate amount). The reaction flask is then gradually warmed to room temperature, and maintained at room temperature for 6 hours to provide a compound of formula B-2. In some instances, the crude product of formula B-2 is purified via recrystallization from an appropriate organic solvent, such as dry THF or dry MeCN. In some instances, the transformation of a compound with formula B-2 to the corresponding product of formula B-5 is accomplished using the procedures described in Scheme 1.

Scheme 3

C-5

[00162] For Scheme 3, Z is defined as a halogen. In some embodiments, a compound of formula C-1 is treated with R₂SH (1.0 equivalent) and CS₂CO₃ (1.2 equivalent) under suitable conditions, such as in DMSO at 60-150 C, until LCMS analysis confirms that most of the starting material has been consumed. In some instances, the crude product is purified with silica column chromatography to provide a compound of formula C-2. Alternatively, when Z is I or Br or CI, a compound of formula C-1 is treated with R₂SH (1.0 equivalent), Pd(DBA)₂ (0.0125 equivalent) X-Phos (0.05 equivalent) and K₃PO₄ (2 equivalents) under suitable conditions, such as in toluene at 80-110 C, until most starting material is consumed, to provide a product of formula C-2. In some embodiments, treatment of a compound of formula C-2 with R3SH (2.0 equivalent) and CS₂CO₃ (1.2 equivalent) under suitable conditions, such as in DMSO at 60-150 C, until LCMS analysis confirms that the starting material has been consumed. Alternatively, when Z is I or Br or CI, a compound of formula C-2 is treated with R₃SH (2.0 equivalent), Pd(DBA)₂ (0.0125 equivalent) X-Phos (0.05 equivalent) and K₃PO₄ (3 equivalents) under suitable conditions, such as in toluene at 80-110 C, until most of the starting material is consumed, to provide a compoound of formula C-3. In some embodiments, the crude product is purified from silica column chromatography to give a purified compound of formula C-3. In some instances, a compound of formula C-4 is prepared by oxidizing the compound of formula C-3 under suitable conditions. In some instances, the oxidation is performed with H₂O₂ in a suitable organic acid, such as AcOH; with mCPBA in a suitable organic solvent, such as chloroform; or with tert-butyl peroxide in a suitable organic solvent, such as MeCN. In some embodiments, treatment of a compound of formula C-4 with hydroxylamine HC1 salt (5 equivalents) in pyridine, under suitable conditions, such as at 60 °C for 2 hours, provides the compound of formula C-5. Scheme 4

[00163] In Scheme 4, Z is a halogen. In some instances, a compound of formula D-1 is treated with neat chlorosulfonic acid under heat, such as 60-150 °C, to provide a sulfonylchloride of formula D-2. In some instances, the compound of formula D-2 in DCM is cooled, such as at - 20 °C, and is treated with 1.0 equivalent of an amine of formula NHR₂R₃ and trimethylamine (2.0 equivalents) to afford an intermediate of formula D-3. In some instances, a compound of formula D-3 is treated with R₄SH (2.0 equivalent) and CS₂CO₃ (1.2 equivalent) under suitable conditions, such as in DMSO at 60-150 C, until LCMS analysis confirms that most of the starting material is consumed, to provide a compound of formula D-4. Alternatively, when Z is I or Br or CI, a compound of formula D-3 is treated with R₄SH (2.0 equivalent), Pd(DBA)₂ (0.0125 equivalent) X-Phos (0.05 equivalent) and K₃PO₄ (3 equivalents) under suitable conditions, such as in toluene at 80-110 C, until most of the starting material is consumed, to afford a product of formula D-4. In some instances, a compound of formula D-5 is prepared by the oxidation of a compound of formula D-4. In some instances, the oxidation is performed with H₂O₂ in a suitable organic acid, such as AcOH; with mCPBA in a suitable organic solvent, such as chloroform; or with tert-butyl peroxide in a suitable organic solvent, such as MeCN. Treatment of a compound of formula D-5 with hydroxylamine HC1 salt (5 equivalents) in pyridine under suitable conditions, such as at 60 °C for 2 hours, provides the compound of formula D-6.

Further Forms of Compounds Disclosed Herein

Isomers

[00164] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the

diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.

Labeled compounds

[00165] In some embodiments, the compounds described herein exist in their

isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some

embodiments, the methods disclosed herein include methods of treating diseases by

administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, examples of isotopes that are incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., ³H and carbon- 14, i. e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e. , ²H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.

[00166] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts

[00167] In some embodiments, the compounds described herein exist as their

pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by

administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[00168] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the disclosure, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

Solvates

[00169] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[00170] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with

pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In some embodiments, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Prodrugs

[00171] In some embodiments, the compounds described herein exist in prodrug form. The disclosure provides for methods of treating diseases by administering such prodrugs. The disclosure further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.

[00172] In some embodiments, prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e. g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present disclosure. The amino acid residues include but are not limited to the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine,

gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. In other embodiments, prodrugs include compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e. g., two, three or four) nucleic acid residues is covalently joined to a compound of the present disclosure.

[00173] Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives,

N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, metal salts and sulfonate esters. In some embodiments, compounds having free amino, amido, hydroxy or carboxylic groups are converted into prodrugs. For instance, free carboxyl groups are derivatized as amides or alkyl esters. In certain instances, all of these prodrug moieties incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.

[00174] Hydroxy prodrugs include esters, such as though not limited to, acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonate esters, sulfate esters and disulfide containing esters; ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlined in

Advanced Drug Delivery Reviews 1996, 19, 115.

[00175] Amine derived prodrugs include, but are not limited to the following groups and combinations of groups: N R— N O — N S — N O — N S — N O R— N O O

H H H H H H H

R' S R' S R' O R' S R O R' O

N A OA S — NA OA O ,R— NA OA S ,R— NA SA O ,R— NA SA S ,R— NA SA O ,R

H H H H H H

as well as sulfonamides and phosphonamides.

[00176] In certain instances, sites on any aromatic ring portions are susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, reduce, minimize or eliminate this metabolic pathway.

Metabolites

[00177] In some embodiments, compounds described herein are susceptible to various metabolic reactions. Therefore, in some embodiments, incorporation of appropriate substituents into the structure will reduce, minimize, or eliminate a metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of an aromatic ring to metabolic reactions is, by way of example only, a halogen, or an alkyl group.

[00178] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

Pharmaceutical Compositions

[00179] In certain embodiments, the compound as described herein is administered as a pure chemical. In other embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21^st Ed. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is hereby incorporated herein by reference in its entirety.

[00180] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition. [00181] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (A), or a pharmaceutically acceptable salt thereof.

[00182] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (B), or a pharmaceutically acceptable salt thereof.

[00183] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (C), or a pharmaceutically acceptable salt thereof.

[00184] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (A), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (B), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (C), or a pharmaceutically acceptable salt thereof.

[00185] In certain embodiments, the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

[00186] These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions are formulated as a unit dose, and/or are formulated for oral or subcutaneous administration.

[00187] In some instances, exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. [00188] For preparing solid compositions such as tablets in some instances, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. , conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[00189] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more

pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions also comprise buffering agents in some embodiments. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00190] In some instances, a tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the

pharmaceutical-formulating art. [00191] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms contain optionally inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[00192] Suspensions, in addition to the subject composition, optionally contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00193] In some embodiments, formulations for rectal or vaginal administration are presented as a suppository, which are prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[00194] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component is optionally mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which are required in some embodiments.

[00195] In some embodiments, the ointments, pastes, creams and gels contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[00196] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[00197] Compositions and compounds disclosed herein are alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are used because they minimize exposing the agent to shear, which result in degradation of the compounds contained in the subject compositions in some embodiments. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[00198] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which optionally contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[00199] Examples of suitable aqueous and non-aqueous carriers employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. In some embodiments, proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants

[00200] Also contemplated are enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP),

hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate- methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S 100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

[00201] In some embodiments, the dose of the composition comprising at least one compound as described herein differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose.

[00202] In some instances, pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented) as determined by persons skilled in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

[00203] In some embodiments, oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

The Hippo Signaling Network

[00204] The Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTRl) (FIG. 1). The Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control. In an un-phosphorylated/de-phosphorylated state, YAP, also known as YAPl or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors to upregulate genes that promote proliferation, migration, and inhibit apoptosis. In some instances, unregulated upregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to development of cancer. In some instances, overexpression of YAP/TAZ is associated with cancer.

[00205] Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues οΐΗιρρο/Ηρο in Drosophila), Latsl/2

(homologues of Warts/Wts), and their adaptor proteins Savl (homologue of Salvador/Sav) and Mob (MOBKL1A and MOBKL1B; homologues of Mats), respectively (FIG. 1). In general, MST1/2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl/2 kinase. Latsl/2 is also activated by the scaffold protein Mob. The activated Latsl/2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.

[00206] In some instances, Latsl/2 phosphorylates YAP at the [HXRXXS] consensus motifs. YAP comprises five [HXRXXS] consensus motifs, wherein X denotes any amino acid residue. In some instances, Latsl/2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates YAP at all five of the consensus motifs. In some instances, Lats 1/2 phosphorylate at the S 127 amino acid position. The phosphorylation of YAP S 127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S 127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[00207] Additional phosphorylation occurs at the S381 amino acid position in YAP.

Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK15/E in the degradation motif, which then signals for interaction with the β-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.

[00208] In some instances, Latsl/2 phosphorylates TAZ at the [HXRXXS] consensus motifs. TAZ comprises four [HXRXXS] consensus motifs, wherein X denotes any amino acid residues. In some instances, Latsl/2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Latsl/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[00209] In some embodiments, phosphorylated YAP/TAZ accumulates in the cytoplasm, and undergoes SCF^^^-mediated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skpl, a bridging protein, and RBX1 which contains a small RING Finger domain which interacts with E2-ubiquitin conjugating enzyme. In some cases, the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A

(FBXW1A, PTrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase- associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g. SCP^^TrCP1) interacts with an El ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate. Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBAl, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. In some embodiments, the ubiquitinated YAP/TAZ further undergoes the degradation process through the 26S proteasome.

[00210] In some embodiments, un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus. Within the nucleus, YAP/TAZ interacts with the TEAD family of transcription factors (e.g. TEAD1, TEAD2, TEAD3, or TEAD4) to activate genes involved in anti-apoptosis and proliferation, such as for example CTFG, Cyr61, and FGF1.

[00211] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators (FIG. 1). In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction. YAP/TAZ regulation mediated by G-proteins/GPCRs

[00212] In some embodiments, the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins (FIG. 2). G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs. In some instances, there are two classes of G proteins: monomeric small GTPases; and heterotrimeric G protein complexes. In some instances, the latter class of complexes comprise of alpha (G_a), beta (Gp), and gamma (G_Y) subunits. In some cases, there are several classes of G_a subunits: G_q/na, Gn_/na, Gj_/0a (G inhibitory, G other), and G_sa (G

stimulatory).

[00213] In some instances, G;a (G inhibitory), G₀a (G other), G_q/na, and Gmuo. coupled GPCRs activate YAP/TAZ and promote nuclear translocation. In other instances, G_sa (G stimulatory) coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation.

[00214] In some cases, Gja (G inhibitory), G₀a (G other), G_q/na, and Gn/n , coupled GPCRs activate YAP/TAZ through repression of Latsl/2 activities. In contrast, G_sa, in some embodiments, induces Latsl/2 activity, thereby promoting YAP/TAZ degradation.

G_q Family

[00215] G_qd (also known as G_q/n protein), participates in the inositol trisphosphate (IP₃) signal transduction pathway and calcium (Ca²⁺) release from intracellular storage through the activation of phospholipase C (PLC). The activated PLC hydrolyzes phosphatidylinositol 4,5- bisphosphate (PIP₂) to diacyl glycerol (DAG) and IP₃. In some instances, IP₃ then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca²⁺ channel. In some cases, the binding triggers the opening of the Ca²⁺ channel, and thereby increases the release of Ca²⁺ into the cytoplasm.

[00216] In some embodiments, the GPCRs that interact with G_qa include, but are not limited to, 5 -hydroxy tryptamine receptor (5-HT receptor) types 5-HT₂ and 5-HT₃; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine HI receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M₃, and M₅; and trace amine-associated receptor 1.

[00217] In some instances, there are several types of G_qa: G_q, G_q/n, G_q i4, and G_q i5. The G_q protein is encoded by GNAQ. G_q/n is encoded by GNA11. G^u is encoded by GNA14. G_q 15 is encoded by GNA15.

[00218] In some instances, mutations or modifications of the G_qa genes have been associated with cancer. Indeed, studies have shown that mutations in G_qa promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.

[00219] In some instances, mutations or modifications of the G_qa genes have been associated with congenital diseases. In some instances, mutations of G_qa have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome. In some instances, about 92% of Port-Wine stain cases harbors a mutation in GNAQ. In some instances, about 88% of Sturge-Weber Syndrome harbors a mutation in GNAQ.

G 12/13 Family

[00220] G12/1301 modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g. Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.

[00221] In some embodiments, the GPCRs that interact with G 12/130 include, but are not limited to, purinergic receptors (e.g. P2Yi, P2Y₂, P2Y₄, P2Y₆); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)- 1, PAR-2]; thromboxane (TXA2); sphingosine 1-phosphate (e.g. S 1P₂, S IP₃, S IP₄ and S IP₅);

lysophosphatidic acid (e.g. LPAi, LPA₂, LPA3); angiotensin II (AT I); serotonin (5-HT_2C and 5- HT₄); somatostatin (ssts); endothelin (ETA and ET_B); cholecystokinin (CCKi); Vi_a vasopressin receptors; D₅ dopamine receptors; fMLP formyl peptide receptors; GAL₂ galanin receptors; EP₃ prostanoid receptors; Ai adenosine receptors;

adrenergic receptors; BB₂ bombesin receptors; B₂ bradykinin receptors; calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NKi tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors.

[00222] In some instances, G12/1301 is further subdivided into G12 and G13 types which are encoded by GNA12 and GNA13, respectively.

Gj_/o Family

[00223] Gj/₀a (G inhibitory, G other) (also known as Gi/G₀ or Gi protein) that suppresses the production of 3 ',5 '-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.

[00224] In some embodiments, the GPCRs that interact with G;a include, but are not limited to, 5 -hydroxy tryptamine receptor (5-HT receptor) types 5-HTi and 5-HT₅; muscarinic acetylcholine receptors such as M₂ and M₄; adenosine receptors such as Ai and A₃; adrenergic receptors such as a₂A, <¾Β, and a₂c; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D₂, D₃, and D₄; GABA_B receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8); histamine receptors such as H₃ and H₄ receptors; melatonin receptors such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and melatonin receptor type 3 (MT3); niacin receptors such as NIACRl and NIACR2; opioid receptors such as δ, κ, μ, and nociceptin receptors; prostaglandin receptors such as prostaglandin E receptor 1 (EPi), prostaglandin E receptor 3 (EP₃), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors sstl, sst2, sst3, sst4, and sst5; and trace amine-associated receptor 8.

[00225] In some instances, there are several types of G;a: G;al, G;a2, G;a3, G;a4, G₀a, G_t, Ggust, and G_z. G;al is encoded by GNAI1. G;a2 is encoded by GNAI2. G;a3 is encoded by

GNAI3. G₀a, the a₀ subunit, is encoded by GNAOl. G_t is encoded by GNAT1 and GNAT2. G_gust is encoded by GNAT3. G_z is encoded by GNAZ.

G_s Family

[00226] G_sa (also known as G stimulatory, G_s alpha subunit, or G_s protein) activates the cAMP-dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3',5'-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, the GPCRs that interact with G_sa include, but are not limited to, 5-hydroxytryptamine receptor (5- HT receptor) types 5-HT₄, 5-HT₆, and 5-HT₇; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A_2a and A_2b; arginine vasopressin receptor 2 (AVPR2); β-adrenergic receptors βι, β₂ and β₃; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor Di-like family receptors such as Di and D₅; follicle-stimulating hormone receptor (FSH-receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H₂ receptor; luteinizing hormone/choriogonadotropin receptor; melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D₂ and I₂; secretin receptor; thyrotropin receptor; trace amine-associated receptor 1 ; and box jellyfish opsin.

[00227] In some instances, there are two types of G_sa: G_s and G₀i_£ G_s is encoded by GNAS. G₀i_f is encoded by GNAL. Additional Regulators of the Hippo signaling network

[00228] In some embodiments, the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some instances, the Crumbs complex comprise transmembrane CRB proteins which assembles multi-protein complexes that functions in cell polarity. In some instances, CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components. In some instances, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.

[00229] In some instances, the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1.

[00230] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity. In some embodiments, E- cad associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm. In other instances, Ajuba protein family members interact with Latsl/2 kinase activity, thereby prevents inactivation of YAP/TAZ.

[00231] In some embodiments, additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK 1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB 1, Ajuba, and ZOl/2.

[00232] In some embodiments, the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator

(TAZ/YAP). In some embodiments, the compounds increase the ubiquitination of

transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/ Yes- associated protein transcriptional coactivator (TAZ/YAP).

[00233] In some embodiments, the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by or related to the Hippo pathway. In some instances, the one or more proteins comprise a protein shown in Figs. 1 and/or 2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of the G_qa family proteins such as G_q, Gq n, Gq/i4, and G_q/is; the Gn_/na family of proteins such as Go and G13 ; or the G;a family of proteins such as G;al, G;a2, G;a3, G;a4, G₀a, G_t, Ggust, and G_z. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G_q. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G_q/n. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/14. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/15. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gu. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G;al . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G;a2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gid3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gi(x4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G₀a. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G_t. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggu_St. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G_z.

[00234] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Savl. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TEAD.

[00235] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g. 26S proteasome).

[00236] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42.

[00237] Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.

[00238] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease. USP47 is a member of the ubiquitin-specific protease (USP UBP) superfamily of cysteine proteases. In some embodiments, the compounds disclosed herein are inhibitors of USP47.

[00239] Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above.

Diseases

Cancer

[00240] In some embodiments, the compounds disclosed herein are useful for treating cancer. In some embodiments, the cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP). In some embodiments, the cancer is characterized by a mutant Ga-protein. In some embodiments, the mutant Ga-protein is selected from G12, G13, Gq, Gl 1, Gi, Go, and Gs. In some embodiments, the mutant Ga-protein is G12. In some embodiments, the mutant Ga-protein is G13. In some embodiments, the mutant Ga-protein is Gq. In some embodiments, the mutant Ga-protein is Gi l . In some embodiments, the mutant Ga-protein is Gi. In some embodiments, the mutant Ga- protein is Go. In some embodiments, the mutant Ga-protein is Gs.

[00241] In some embodiments, the cancer is a solid tumor. In some instances, the cancer is a hematologic malignancy. In some instances, the solid tumor is a sarcoma or carcinoma. In some instances, the solid tumor is a sarcoma. In some instances, the solid tumor is a carcinoma.

[00242] Exemplary sarcoma includes, but is not limited to, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid

hemangioendothelioma, epithelioid sarcoma, esthesioneuroblastoma, Ewing sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma,

fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Kaposi sarcoma, leiomyosarcoma of bone, liposarcoma, liposarcoma of bone, malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma (MFH) of bone, malignant mesenchymoma, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoid liposarcoma, myxoinflammatory fibroblastic sarcoma, neoplasms with perivascular epitheioid cell differentiation, osteosarcoma, parosteal osteosarcoma, neoplasm with perivascular epitheioid cell differentiation, periosteal

osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET/extraskeletal Ewing tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, telangiectatic osteosarcoma.

[00243] Exemplary carcinoma includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, or vulvar cancer. In some instances, the liver cancer is primary liver cancer.

[00244] In some instances, the cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neack cancer, prostate cancer, or meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neack cancer, prostate cancer, or meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the cancer is uveal melanoma. In some cases, the cancer is mesothelioma. In some cases, the cancer is esophageal cancer. In some cases, the cancer is liver cancer. In some cases, the cancer is primary liver cancer.

[00245] In some instances, the cancer is a hematologic malignancy. In some embodiments, a hematologic malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some instances, a hematologic malignancy is a T-cell malignancy. Exemplary T-cell malignancy includes, but is not limited to, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, or treatment-related T-cell lymphomas.

[00246] In some instances, a hematologic malignancy is a B-cell malignancy. Exemplary

B-cell malignancy includes, but is not limited to, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[00247] In some instances, the cancer is a relapsed or refractory cancer. In some embodiments, the relapsed or refractory cancer is a relapsed or refractory solid tumor. In some embodiments, the relapsed or refractory solid tumor is a relapsed or refractory sarcoma or a relapsed or refractory carcinoma. In some embodiments, the relapsed or refractory carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[00248] In some instances, the relapsed or refractory cancer is selected from relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neack cancer, prostate cancer, or meningioma. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neack cancer, prostate cancer, or meningioma. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma. In some cases, the relapsed or refractory cancer is relapsed or refractory mesothelioma. In some cases, the relapsed or refractory cancer is relapsed or refractory esophageal cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory liver cancer. In some cases, the relapsed or refractory cancer is relapsed or refractory primary liver cancer.

[00249] In some instances, the relapsed or refractory cancer is a relapsed or refractory hematologic malignancy. In some embodiments, a relapsed or refractory hematologic malignancy is a relapsed or refractory leukemia, a relapsed or refractory lymphoma, a relapsed or refractory myeloma, a relapsed or refractory non-Hodgkin's lymphoma, a relapsed or refractory Hodgkin's lymphoma, a relapsed or refractory T-cell malignancy, or a relapsed or refractory B-cell malignancy. In some instances, a relapsed or refractory hematologic malignancy is a relapsed or refractory T-cell malignancy. In some instances, a relapsed or refractory hematologic malignancy is a relapsed or refractory B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid

granulomatosis.

[00250] In some instances, the cancer is a metastasized cancer. In some instances, the metastasized cancer is a metastasized solid tumor. In some instances, the metastasized solid tumor is a metastasized sarcoma or a metastasized carcinoma. In some embodiments, the metastasized carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[00251] In some instances, the metastasized cancer is selected from metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neack cancer, prostate cancer, or meningioma. In some cases, the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neack cancer, prostate cancer, or meningioma. In some cases, the metastasized cancer is metastasized uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the metastasized cancer is metastasized uveal melanoma. In some cases, the metastasized cancer is metastasized mesothelioma. In some cases, the metastasized cancer is metastasized esophageal cancer. In some cases, the metastasized cancer is metastasized liver cancer. In some cases, the metastasized cancer is metastasized primary liver cancer.

[00252] In some instances, the metastasized cancer is a metastasized hematologic malignancy. In some embodiments, the metastasized hematologic malignancy is a metastasized leukemia, a metastasized lymphoma, a metastasized myeloma, a metastasized non-Hodgkin's lymphoma, a metastasized Hodgkin's lymphoma, a metastasized T-cell malignancy, or a metastasized B-cell malignancy. In some instances, a metastasized hematologic malignancy is a metastasized T-cell malignancy. In some instances, a metastasized hematologic malignancy is a metastasized B-cell malignancy, such as for example, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

Congenital Diseases [00253] In some embodiments, the compounds disclosed herein are useful for treating a congenital disease. In some embodiments, the congenital disease is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes- associated protein transcription coactivator (TAZ/YAP). In some embodiments, the congenital disease is characterized by a mutant Ga-protein. In some embodiments, the mutant Ga-protein is selected from G12, G13, Gq, Gl 1, Gi, Go, and Gs. In some embodiments, the mutant Ga-protein is G12. In some embodiments, the mutant Ga-protein is G13. In some embodiments, the mutant Ga-protein is Gq. In some embodiments, the mutant Ga-protein is Gl 1. In some embodiments, the mutant Ga-protein is Gi. In some embodiments, the mutant Ga-protein is Go. In some embodiments, the mutant Ga-protein is Gs.

[00254] In some embodiments, the congenital disease is the result of a genetic abnormality, an intrauterine environment, errors related to morphogenesis, infection, or epigenetic modifications on a parental germline, or a chromosomal abnormality. Exemplary congenital diseases include, but are not limited to, Sturge-Weber Syndrome, Port- Wine stain, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart defects, congenital hypothyroidism, congenital muscular dystrophy, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Friedreich's ataxia, galactosemia, hemoglobinopathies, Krabbe disease, limb-girdle muscular dystrophy, medium chain acyl-CoA dehydrogenase definiency, myasthenia gravis, neural tube defects, phenylketonuria, Pompe disease, severe combined immunie deficiency (SCID), Stickler syndrome (or hereditary progressive arthro-ophthalmopathy), spinal muscular atrophy, and trisomy 18. In some embodiments, the congenital disease is Sturge-Weber Syndrome or Port- Wine stain. In some embodiments, the congenital disease is Sturge-Weber Syndrome. In some embodiments, the congenital disease is Port-Wine stain.

EXAMPLES

[00255] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

List of abbreviations

[00256] As used above, and throughout the disclosure, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN acetonitrile

Bn benzyl

BOC or Boc ferf-butyl carbamate

t-Bu tert-butyl

Cy cyclohexyl

DBA dibenzylideneacetone

DCE dichloroethane (C1CH₂CH₂C1)

DCM dichloromethane (CH₂CI₂)

DIPEA or DIEA diisopropylethylamine

DMAP 4-(N,N-dimethylamino)pyridine

DMF dimethylformamide

DMA NN-dimethylacetamide

DMSO dimethylsulfoxide

Dppf or dppf 1 , l'-bis(diphenylphospliino)ferrocene

eq equivalent(s)

Et ethyl

Et₂0 diethyl ether

EtOH ethanol

EtOAc ethyl acetate

HPLC high performance liquid chromatography

LAH lithium aluminum anhydride

LCMS liquid chromatography mass spectrometry

Me methyl

MeOH methanol

MS mass spectroscopy

NMM N-methyl-morpholine

NMP N-methyl-pyrrolidin-2-one

NMR nuclear magnetic resonance

RP-HPLC reverse phase-high pressure liquid chromatography

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography I. Chemical Synthesis

[00257] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times were approximate and were not optimized. Column chromatography and thin layer

chromatography (TLC) were performed on silica gel unless otherwise noted.

Example Al : 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-(l-phenylethyl)piperazin-l- yl)sulfonyl)-9H-fluoren-9-

Pr

Step 1 : (l-bromoethyl)benzene

[00258] To a mixture of Al-1 (1.0 g, 8.2 mmol, 990 uL, 1.00 eq) and CBr₄ (3.5 g, 10.6 mmol, 1.30 eq) in DCM (15 mL), was added ΡΡ1¾ (2.8 g, 10.7 mmol, 1.30 eq) by portions at 0 °C. The resulted mixture was stirred at 0 °C for 0.5 h, 20 °C for 2 h. LCMS showed there's no desired compound. TLC showed the starting material was consumed completed, and a new spot with lower polarity formed. The mixture was concentrated in vacuum. The residue was purified by silica gel chromatography eluted with PE. Compound Al-2 (1.5 g, 8.1 mmol, 99% yield) was obtained as colorless oil, which was checked by ¾ NMR. ¾ NMR (400 MHz,

CHLOROFORM-i δ 7.89 (d, J = 7.3 Hz, 2 H), 7.82 - 7.76 (m, 2 H), 7.76 - 7.69 (m, 1 H), 5.66 (q, J = 6.9 Hz, 1 H), 2.50 (d, J = 7.1 Hz, 3 H).

Step 2: tert-butyl 4-(l-phenylethyl)piperazine-l-carboxylate [00259] To a mixture of Al-3 (845.4 mg, 4.5 mmol, 1.05 eq) and K₂C0₃ (896.2 mg, 6.5 mmol, 1.50 eq) in DMF (10 mL), was added Al-2 (800 mg, 4.3 mmol, 1.00 eq). The resulted mixture was stirred at 50 °C for 17 h. LCMS showed there's desired compound. The mixture was diluted with EA (80 mL), washed with brine (80 mL *4). The organic layer was dried over anhydrous Na₂S0₄, concentrated in vacuum. The residue was diluted with PE (5 mL) and DCM (3 mL). The mixture was filtered. The filtrate was concentrated in vacuum. The residue (the filtrate) was purified by silica gel chromatography eluted with PE/EA = 0-20%. Compound Al-4 (400 mg, 1.2 mmol, 28.4% yield, 89% purity) was obtained as light yellow oil, which was confirmed by ¾ NMR. ¾ NMR (400 MHz, CHLOROFORM- ) δ 7.33 - 7.28 (m, 4 H), 7.27 - 7.22 (m, 1 H) 3.43 - 3.38 (m, 5 H), 2.48 - 2.40 (m, 2 H), 2.38 - 2.30 (m, 2 H), 1.44 (s, 9 H), 1.38 (d, J = 6.8 Hz, 3 H).

Step 3: l-(l-phenylethyl)piperazine

[00260] A mixture of Al-4 (100 mg, 344 umol, 1.00 eq) in HCl/dioxane (12 M, 3 mL,

104.54 eq) was stirred at 20 °C for 0.5 h. LCMS showed the starting material was consumed completely. The mixture was concentrated in vacuum. Compound Al-5 (80 mg, crude, HC1) was obtained as white solid.

Step 4: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-(l-phenylethyl)piperazin-l-yl)sulfonyl)- 9H-fluoren-9-one

[00261] To a mixture of Al-5 (50 mg, 221 umol, 3.33 eq, HC1) and TEA (34 mg, 331 umol, 46 uL, 5.00 eq) in DCM (6 mL), was added Al-6 (30 mg, 66 umol, 1.00 eq). The resulted mixture was stirred at 20 °C for 1 h. LCMS showed the reaction was completed. The mixture was concentrated in vacuum. Compound Al-7 (50 mg, crude) was obtained as light yellow solid. Step 5: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-(l-phenylethyl)piperazin-l-yl)sulfonyl)- 9H-fluoren-9-one oxime

[00262] To a mixture of Al-7 (50 mg, 82 umol, 1.00 eq) in pyridine (5 mL), was added

NH₂OH.HCl (12 mg, 0.17 mmol, 2.00 eq). The resulted mixture was stirred at 40 °C for 1 h. LCMS showed the reaction was completed. The mixture was concentrated in vacuum. The residue was purified by pre-HPLC (basic condition). Compound 1 (19.95 mg, 31.76 umol, 38.5% yield, and 99% purity) was obtained as off-white solid, which was confirmed by LCMS and ¾ NMR. LCMS (ESI): RT = 0.721 min, mass calcd. for C₃₃H₃₉N₃O₅S₂ 621.23, m/z found 622.1 [M+H]⁺. ¾ NMR (400 MHz, DMSO-i/₆) 513.44 (s, 1H), 8.76 (s, 0.5H), 8.63 (s, 0.5H), 8.50 - 8.40 (m, 2H), 8.15 - 8.06 (m, 1H), 8.00 (dd, J = 8.1, 1.7 Hz, 0.5H), 7.97 - 7.91 (m, 1H), 7.85 (dd, J = 7.9, 1.5 Hz, 0.5H), 7.26 - 7.20 (m, 2H), 7. 19 - 7.15 (m, 2H), 7.15 - 7.10 (m, 1H), 3.34 - 3.20 (m, 2H), 2.92 (s, 4H), 2.43 (s, 2H), 2.38 - 2.30 (m, 2H), 1.78 - 1.69 (m, 2H), 1.58 - 1.48 (m, 2H), 1.47 - 1.38 (m, 2H), 1.23 - 1.13 (m, 5H), 0.84 (s, 3H), 0.79 (s, 3H). Example A2: 2-[4-[3-[(dimethylamino)methyl]-2,4-difluoro-phenyl]piperazin-l-yl]sulfonyl- 7-(4,4-dimethylcyclohexyl d 2)

Prep

Step 1 : tert-butyl 4-(2,4-difluoro-3-formyl-phenyl)piperazine-l-carboxylate

[00263] To a mixture of A2-3 (300 mg, 0.955 mmol, 1.00 eq) in THF (10 mL) was added n-BuLi (2.5 M, 0.76 mL, 2.00 eq) in one portion at -78 °C under N₂.The mixture was stirred at -78 °C for 2 h, then added a solution of ethyl formate (248 mg, 3.34 mmol, 0.27 mL, 3.50 eq) and stirred at -78 °C for 1 h, and then warmed to 20 °C and stirred at 20 °C for 3 h. LCMS showed 8.6% of the starting material remained. Several new peaks were shown on LCMS and 56.4% of desired compound was detected. The reaction mixture was quenched by addition water (15 mL) at 20°C, and then extracted with DCM (20 mL * 4). The combined organic layers were dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to give A2-4 (160 mg, 0.412 mmol, 43.1% yield, 84% purity) as the light yellow solid. LCMS (ESI): RT = 0.773 min, mass calcd. For C₁₆H₂₀F₂N₂O₃, 326.14, m/z found 270.9 [M+H-56]⁺ and 226.9 [M+H- 100]⁺.

Step 2: tert-butyl 4-[3-[(dimethylamino)methyl]-2,4-difluoro-phenyl]piperazine-l- carboxylate [00264] To a mixture of Et₃N (248 mg, 2.45 mmol, 0.40 mL, 5.00 eq) in EtOH (8 mL) was added N-methylmethanamine (120 mg, 1.47 mmol, 0. 14 mL, 3.00 eq, HC1) and A2-4 (160 mg, 490 mmol, 1.00 eq) and tetraisopropoxytitanium (278 mg, 0.981 mmol, 0.29 mL, 2.00 eq) in one portion at 45 °C. The mixture was stirred at 45 °C for 16 h. And then themixture was added NaBH₄ (93 mg, 2.45 mmol, 5.00 eq) and stirred at 25 °C for 2 h. LCMS showed the compound A2-4 was consumed completely and one main peak with desired MS was detected. The reaction mixture was quenched by addition Sat. NH₄C1 (10 mL) at 20°C and filtered and washed with DCM (10 mL). The filtrate was extracted with DCM (10 mL*3).The combined organic phase was dried with anhydrous Na₂SC , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ethergradient @ 20 mL/min) to give A2-5 (60 mg, 0.167 mmol, 34.1% yield, and 99% purity) as colorless oil

Step 3: l-(2,6-difluoro-3-piperazin-l-yl-phenyl)-N,N-dimethyl-methanamine

[00265] To a mixture of A2-5 (30 mg, 84 umol, 1.00 eq) in HCl/MeOH (4 M, 2 mL, 94.78 eq) was stirred at 25 °C for 1 h under N₂. LCMS showed the compound A2-5 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product A2-1 A (25 mg, crude, HC1) was used into the next step without further purification.

Step 4 : 2- [4- [3- [(dimethylamino)methyl] -2,4-difluoro-phenyl] piper azin-1 -yl] sulf onyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one

[00266] To a mixture of A2-1A (25 mg, 86 umol, 1.00 eq, HC1) and Et₃N (52 mg, 0.514 mmol, 71 uL, 6.00 eq) in DCM (6 mL) was added A2-1 (40 mg, 88 umol, 1.03 eq) in one portion at 20 °C .The mixture was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The yellow solid was main contained A2-2 (57 mg, crude) and it was used next step without further purification.

Step 5 : 2- [4- [3- [(dimethylamino)methyl] -2,4-difluoro-phenyl] piper azin-1 -yl] sulf onyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime

[00267] To a mixture of hydroxylamine (41 mg, 0.594 mmol, 7.00 eq, HC1) in pyridine (5 mL) was added A2-2 (57 mg, 85 umol, 1.00 eq) in one portion at 40 °C under N₂.The mixture was stirred at 40 °C for 1 h. LCMS showed starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (basic condition) to give Compound 2 (18.79 mg, 27. 1 1 umol, 31.96% yield, and 99. 1% purity) as white solid. LCMS (ESI): RT = 1.554 min, mass calcd. For C₃₄H₄₀F₂N₄O₅S₂, 686.24 m/z found 687. 1 [Μ+Η]⁺. ΤΤ NMR (400 MHz, DMSO-i/₆) δ 13.44 (br s, IH), 8.80 - 8.65 (m, IH), 8.60- 8.50 (m, 2H), 8.15 -

7.89 (m, 3H), 7.08 - 6.91 (m, 2H), 3.42 (s, 2H), 3.30 - 3.24 (m, IH), 3.01 - 3. 17 (m, 8H), 2.08 (s, 6 H), 1.90 - 1.70 (m, 2H), 1.54 - 1.35 (m, 4H), 1.23 - 1. 14 (m, 2H), 0.91 - 0.73 (m, 6H).

Example A3: 2-((4-Benzylpiperazin-l-yl)sulfonyl)-7-((4,4-dimethylcyclohexyl)sulfonyl)-9H- fluoren-9-one oxime (Compound 3)

Pr

Step 1 : tert-Butyl 4-benzylpiperazine-l-carboxylate

[00268] To a solution of compound A3-1 (20.0 g, 107 mmol, 1.0 eq) and

bromomethylbenzene (22.0 g, 129 mmol, 1.2 eq) in CH₃CN (300 mL) was added K₂CO₃ (14.8 g, 107 mmol, 1.0 eq). The reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (50 mL) and the resultant mixture was extracted with EA (80 mL * 2). The combined organic layers were dried over NaiSO/t, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether: ethyl acetate = 1 :0 to 5: 1) to afford the title compound (16.8 g, 57% yield) as a white solid. 'HNMR (400MHZ, CDCl₃-i/) δ 7.34 - 7.23 (m, 5H), 3.50 (s, 2H), 3.46 - 3.38 (m, 4H), 2.43 - 2.33 (m, 4H), 1.45 (s, 9H)

Step 2: 1-Benzylpiperazine hydrochloride

[00269] To a solution of compound A3-2 (16.8 g, 60.8 mmol, l .O eq) in Dioxane-HCI (100 mL) was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (12.5 g, 97% yield) as a white solid. Step 3: 2-((4-Benzylpiperazin-l-yl)sulfonyl)-7-((4,4-dimethylcyclohexyl)sulfonyl)-9H- fluoren-9-one

[00270] Compound A3-3 (14 mg, 66 umol, 1.0 eq, HC1) and TEA (20 mg, 0.20 mmol, 3.0 eq) in DCM (4 mL) was added compound A3-4 (30 mg, 66 umol, 1.0 e ). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with DCM (30 mL * 3). The combined organic layers were dried over Na₂SC , filtered and concentrated to dryness under reduced pressure to obtain the title compound (35 mg, 89% yield) as a yellow solid. LCMS (ESI): RT = 0.867 min, mass calcd. for C₃₂H₃₆N₂O₅S₂ 592.21, m/z found 593.1 [M+H]⁺.

Step 4: 2-((4-Benzylpiperazin-l-yl)sulfonyl)-7-((4,4-dimethylcyclohexyl)sulfonyl)-9H- fluoren-9-one oxime

[00271] To a solution of compound A3-5 (35 mg, 59 umol, 1.0 eq) and hydroxylamine (12 mg, 0.18 mmol, 3.0 eq, HC1) in pyridine (5 mL) was stirred at 30 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography over Phenomenex Synergi C18 150*30mm*4um (eluent: water ((0.05%HC1)-ACN) 34/64, v/v). The pure fractions were collected and the volatiles were removed under vacuum. The residue was re-suspended in water (6 mL) and the resulting mixture was lyophilized to dryness to remove the solvent residue completely. The title compound (12.75 mg, 34% yield) was obtained as a white solid. LCMS (ESI): RT = 3.192 min, mass calcd. for C₃₂H₃₇N₃O₅S₂ 607.22, m/z found 608.0 [M+H]⁺, ¾ NMR (400MHz, DMSO-i/₆) δ 13.53 - 13.48 (m, 1H), 8.79 - 8.64 (m, 1H), 8.44 - 8.33 (m, 2H), 8.15 - 8.08 (m, 1H), 8.04 - 7.90 (m, 2H), 7.54 - 7.35 (m, 5H), 4.52 - 4.06 (m, 2H), 4.05 - 3.62 (s, 2H), 3.31 - 3.01 (m, 5H), 2.88 - 2.71 (m, 2H), 1.75 (d, J = 11.0 Hz, 2H), 1.59 - 1.48 (m, 2H), 1.43 (d, J = 12.8 Hz, 2H), 1.25 - 1. 15 (m, 2H), 0.86 (s, 3H), 0.81 (s, 3H).

Example A4: 2-(4,4-dimethylcyclohexyl)sulfonyl-7-[4-(2-phenylethyl)piperazin-l- yl]sulfonyl-fluoren-9-one

P

Step 1 : 2-phenylethyl 4-methylbenzenesulfonate

[00272] To a solution of A4-3 (200.0 mg, 1.64 mmol, 0.20 mL, 1.00 eq) in pyridine (20.0 mL) was added 4-methylbenzenesulfonyl chloride (359.6 mg, 1.89 mmol, 1. 15 eq). The reaction mixture was stirred at 25°C for 16 hrs. LCMS showed that the desired product was detected. The reaction mixture was poured into 30mL H₂0, extracted with EtOAc (3*20mL). The combined organic layers were washed with brine (3* 15 mL), dried over Na₂S0₄ and filtered. The filtrate was concentrated under reduced pressure. A4-4 (200.0 mg, 0.72 mmol, 44.1% yield) was used to next step without purification as colorless oil.

Step 2: tert-butyl 4-(2-phenylethyl)piperazine-l-carboxylate

[00273] To a solution of tert-butyl piperazine- l-carboxylate (202.2 mg, 1.09 mmol, 1.50 eq) in MeCN (5.0mL) was added K₂C0₃ (200.0 mg, 1.45 mmol, 2.00 eq) and A4-4 (200.0 mg, 0.72 mmol, 1.00 eq). The reaction mixture was stirred at 70°C for 16 hrs. LCMS showed that the A4-4 was consumed completely and the desired product was detected. The reaction mixture was filtered immediately, and the filtration cake was washed with MeCN (30 mL). The organic layers were evaporated under reduced pressure. A4-5 (232.0 mg, crude) was used to next step without purification as light yellow oil.

Step 3: l-(2-phenylethyl)piperazine

[00274] To a solution of A4-5 (232.0 mg, 0.80 mmol, 1.00 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (8.0 mmol, 4.0 mL). The reaction mixture was stirred at 25°C for 0.5 hr. LCMS (ES3730-340-P 1A) showed that the desired product was detected. The reaction mixture was evaporated under reduced pressure. A4-1A (195.0 mg, crude) was used to next step without purification as light yellow solid.

Step 4: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(2-phenylethyl)piperazin-l-yl]sulfonyl- fluoren-9-one

[00275] To a solution of A4-1A (50.0 mg, 0.22 mmol, 50.1 uL, 2.00 eq, HC1) in DCM (5.0 mL) was added TEA (44.7 mg, 0.44 mmol, 61.2 uL, 4.00 eq) and A4-1 (50.0 mg, 0. 11 mmol, 1.00 eq). The reaction mixture was stirred at 25°C for 2 hrs. LCMS showed that the A4-1 was consumed completely and the desired product was detected. The reaction mixture was diluted with H₂0 (30 mL), extracted with DCM (3* 15mL). The combined organic layers were washed with brine (3* lOmL), dried over Na₂S0₄ and filtered. The filtrate was concentrated under reduced pressure. A4-2 (135.0 mg, crude) was used to next step without purification as light yellow solid.

Step 5: 2-(4,4-dimethylcyclohexyl)sulfonyl-7-[4-(2-phenylethyl)piperazin-l-yl]sulfonyl- fluoren-9-one oxime

[00276] To a solution of A4-2 (130.0 mg, 0.21mmol, 1.00 eq) in pyridine (10.0 mL) was added NH₂OH.HCl (29.8 mg, 0.43 mmol, 2.00 eq). The reaction was stirred at 25°C for 1 hr. LCMS showed that the desired product was detected. The reaction mixture was evaporated under reduced pressure, a residue was formed. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*30 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 60%-90%, lmin) to obtain Compound 4 (8.03 mg, 12.91 umol, 6.03% yield) as white solid. LCMS (ESI): RT =2.504 min, mass cal.cd for C₃₃H₃₉N₃O₅S₂ 621.23, m/z found 622.2 [M+H]⁺. ¾ NMR (400 MHz, DMSO-i¾ 58.77 - 8.65 (m, lH), 8.40-8.33 (dd, J = 4.0, 7.9 Hz, 1H), 8.32-8.25 (dd, J = 2.9, 7.9 Hz, 1H), 8.13 - 8.06 (m, 1H), 8.02 - 7.95 (m, 1H), 7.85-7.75 (dd, J = 1.4, 8.0 Hz, 1H), 7.24 - 7.18 (m, 2H), 7. 17 - 7.09 (m, 3H), 3.40 - 3.35 (m, 4H), 3.28 - 3.23 (m, 2H), 3.01 - 2.91 (m, 4H), 2.69 - 2.60 (m, 2H), 1.79 - 1.69 (m, 2H), 1.58 - 1.48 (m, 2H), 1.46 - 1.38 (m, 2H), 1.26 - 1.14 (m, 3H), 0.85 (s, 3H), 0.80 (s, 3H).

Example A5: 2- [4- [2,4-difluoro-3-(hydroxymethyl)phenyl] piperazin-l-yl] sulf onyl-7-(4,4- dimethylcyclohexyl)sulfo

Preparation of Compound 5:

Step 1 : tert-butyl 4-(2,4-difluoro-3-formyl-phenyl)piperazine-l-carboxylate

[00277] To a mixture of A5-3 (440 mg, 1.31 mmol, 1.00 eq) in THF (8 mL) was added n-

BuLi (2.5 M, 1.05 mL, 2.00 eq) in one portion at -78 °C under N₂.The mixture was stirred at -78

°C for 2 h, then added a solution of N-methyl-N-phenyl-formamide (182 mg, 1.35 mmol, 166 uL,

1.03 eq) in THF (1 mL) and stirred at -78 °C for 30 min, and then stirred at 20 °C for 2 h. LCMS showed 21% of the reactant remained and TLC showed new spots were formed. The reaction mixture was quenched by addition water (15 mL) at 20°C, and then extracted with DCM

(20 mL * 4). The water phase was lyophilized to give compound A5-4 (100 mg, 0.306 mmol) as white solid, which was confirmed by ¾ NMR. ¾ NMR (400 MHz, DMSO-i/₆) 58.48 (s, 2H ,

3.60 - 3.40 (m, 4H), 2.84 (t, J = 4.8 Hz, 4H), 1.41 (s, 9H).

Step 2.: tert-butyl 4-[2,4-difluoro-3-(hydroxymethyl)phenyl]piperazine-l-carboxylate

[00278] To a mixture of compound A5-4 (100 mg, 0.306 mmol, 1.00 eq) in THF (10 mL) was added BH₃-Me₂S (10 M, 0.46 mL, 15.00 eq) in one portion at 0 °C under N₂. The mixture was stirred at 0 °C for 5 min, then heated to 62 °C and stirred for 2 h. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was quenched by addition MeOH (8 mL) at 0°C, and then concentrated under reduced pressure to give a residue. ¾ NMR confirmed the residue was contained desired product. TLC showed one main spot was formed. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ethergradient @ 20 mL/min) to give compound A5-5 (20 mg, 60 umol, 19.6% yield, and 98.8% purity) as colorless oil. LCMS (ESI): RT = 0.817 min, mass calcd. For C₁₆H₂₂F₂N₂O₃, 328.16 m/z found 272.9[M+H-56]⁺ and 228.9[M+H- 100]⁺.¹H NMR (400 MHz, CHLOROFORM-i δ 6.96 - 6.78 (m, 2H), 4.80 (d, J = 6.6 Hz, 2H) 3.60 (t, J = 4.8 Hz, 4H), 2.97 (t, J = 4.8 Hz, 4H), 1.49 (s, 9H).

Step 3: (2,6-difluoro-3-piperazin-l-yl-phenyl)methanol [00279] To a mixture of compound A5-5 (20 mg, 60 umol, 1.00 eq) in HCl/dioxane (4 M,

4 mL, 262.68 eq) was stirred at 20 °C for 40 min. LCMS indicated the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give compound A5-1A (17 mg, HC1 salt) as white solid, which was used next step without further purification.

Step 4: 2-[4-[2,4-difluoro-3-(hydroxymethyl)phenyl]piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one

[00280] To a mixture of compound A5-1A (17 mg, 64 umol, 1.00 eq, HC1) and Et₃N (39 mg, 0.385 mmol, 53 uL, 6.00 eq) in DCM (6 mL) was added compound A5-1 (30 mg, 66 umol, 1.03 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give A5-2 (40 mg, crude), which was used next step without further purification.

Step 5: 2-[4-[2,4-difluoro-3-(hydroxymethyl)phenyl]piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime

[00281] To a mixture of NH₂OH.HCl (26 mg, 0.372 mmol, 6.00 eq) in pyridine (5 mL) was added A5-2 (40 mg, 62 umol, 1.00 eq) in one portion at 20 °C. The mixture was stirred at 35 °C for 1 h. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (basic condition) to give Compound 5 (14.41 mg, 21.8 umol, 35.2% yield, and 100% purity) as white solid. LCMS (ESI): RT = 1.812 min, mass calcd. For C₃₂H₃₅F₂N₃O₆S₂, 659.19 m/z found 660.1 [M+H]⁺. ¾ NMR (400 MHz, DMSO-i/e) δ 13.42 (br s, 1H), 8.76 (s, 0.5H), 8.71 (s, 0.5H), 8.50 - 8.40 (m, 2H), 8.15 - 7.92 (m, 3H), 7.08 - 6.91 (m, 2H), 5.16 (t, J = 5.6 Hz, 1H), 4.42 (d, J = 5.2 Hz, 2H), 3.24 - 3.20 (m, 1H), 3.18 - 2.96 (m, 8H), 1.90 - 1.80 (m, 2H), 1.57 - 1.40 (m, 4H), 1.20-1.05 (m, 2H), 0.89 - 0.78 (m, 6H).

Example A6: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-((4-fluorophenyl)amino)piperidin- l-yl)sulfonyl)-9H-fluoren-9-one (Compound 6)

P

Step 1 : tert-butyl 4-((4-fluorophenyl)amino)piperidine-l-carboxylate

[00282] To the solution of compound A6-1 (279 mg, 2.5 mmol, 240 uL, 1.0 eq) in DCE (5 mL) was added fert-butyl 4-oxopiperidine- l-carboxylate (500 mg, 2.51 mmol, 1.0 eq) and HOAc (301 mg, 5.0 mmol, 287 uL, 2.0 eq). The mixture was stirred at 15 °C for 10 min. Then

NaBH(OAc)3 (798 mg, 3.8 mmol, 1.5 eq) was added to the mixture. The solution was stirred at 15 °C for another 2 hr. The reaction was monitored by TLC. NaOH aqueous (2M, 10 mL) was added to the mixture. The solution was stirred for 5 min. Then the mixture was extracted with DCM (10 mL *4). The combined organic layers were dried with NaiSC and concentrated under reduced pressure to give compound A6-2 (830 mg, crude) as a yellow solid.

Step 2: N-(4-fluorophenyl)piperidin-4-amine

[00283] The solution of compound A6-2 (830 mg, 2.8 mmol, 1.0 eq) in HCl/dioxane (4 M,

10 mL, 14.2 eq) was stirred at 20 °C for 0.5 hr. The reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure to give compound A6-1A (748 mg, crude, HCI) as a yellow solid.

Step 3: 2-((4-(4-fluoro-2-methoxyphenyl)piperazin-l-yl)sulfonyl)-7-((4-fluorophenyl)thio)- 9H-fluoren-9-one

[00284] To the solution of compound A6-1A (15 mg, 66 umol, 1.5 eq, HCI) in DCM (5 mL) was added TEA (22 mg, 0.2 mmol, 31 uL, 5.0 eq). The mixture was stirred at 20 °C for 10 min. Then compound A6-3 (20 mg, 44 umol, 1.0 eq) was added to the mixture. The solution was stirred for another 50 min at 20 °C The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give compound A6-4 (40 mg, crude) as a yellow solid.

Step 4: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-((4-fluorophenyl)amino)piperidin-l- yl)sulfonyl)-9H-fluoren-9-one [00285] To the solution of compound A6-4 (40 mg, 65 umol, 1.0 eq) in pyridine (4 mL) was added hydroxylamine (9 mg, 0. 1 mmol, 2.0 eq, HC1). The mixture was stirred at 60 °C for 0.5 hr. The reaction solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Mobile phase A : water with 0.05% ammonia solution; Mobile phase B : MeCN; column temperature: 30 °C Gradient: 60 - 90% B 10 min) to give Compound 6 (5.68 mg, 9.0 umol, 13.7% yield, 99% purity) as a light yellow solid. LCMS (ESI): RT = 2.615 min, mass calcd. for C₃₂H₃₆FN₃O₅S₂ 625.21, m/z found 626. 1 [M+H]⁺, ¾ NMR (400MHz, DMSO- d₆) δ 13.42 (br s, 1H), 8.77 - 8.66 (m, 1H), 8.41 - 8.29 (m, 2H), 8.15 - 8.06 (m, 1H), 8.03 - 7.96 (m, 1.5H), 7.91 (dd, J = 1.5, 7.9 Hz, 0.5H), 6.87 - 6.78 (m, 2H), 6.49 (dd, J = 8.9, 4.5 Hz, 2H), 5.37 (d, J = 8.2 Hz, 1H), 3.58 (s, 2H), 3. 17 (s, 2H), 1.96 - 1.91 (m, 2H), 1.76 - 1.71 (m, 2H), 1.60 - 1.30 (m, 6H), 1.26 - 1.1 1 (m, 3H), 0.89 - 0.75 (m, 6H).

Example A7: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-(4-fluoro-2-hydroxyphenyl)-4- hydroxypiperidin-l-yl)sulfonyl)-9H-fluoren-9-one oxime (Compound 7)

P

Step 1 : l-benzyl-4-(2-(benzyloxy)-4-fluorophenyl)piperidin-4-ol

[00286] To a solution of A7-1 (250 mg, 889.3 umol, 1.00 eq) in THF (8 mL) was added n-

BuLi (2.5 M, 400 uL, 1.12 eq) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 min, then A7-2 (252.5 mg, 1.33 mmol, 248 uL, 1.50 eq) in THF (2 mL) was added dropwise. The mixture was stirred at -78 °C for 0.5 h, 20 °C for 3 h. LCMS showed the reaction was completed. The mixture was quenched with saturated NH₄C1 aqueous (15 mL), extracted with EA (20 mL *2). The organic layer was dried over anhydrous NaiSO/_t, concentrated in vacuum. The residue was purified by silica gel chromatography eluted with PE/EA = 0-30%. Compound A7-3 (120 mg, 306.5 umol, 34.5% yield) was obtained as light yellow oil, which was confirmed by ¾ NMR. ¾ NMR (400 MHz, CHLOROFORM-i/) 57.34 - 7.43 (m, 5H), 7.23 - 7.33 (m, 5H , 6.73 (d, J = 10.8 Hz, 1H), 6.60-6.50 (m, 1H), 5.11 (s, 2 H), 3.55 (s, 2 H), 2.80-2.60 (m, 2 H), 2.51 (t, J = 11.1 Hz, 2H), 2.14 (td, J = 12.6, 4.0 Hz, 2H), 1.96 - 2.03 (m, 2H).

Step 2: 4-(4-fluoro-2-hydroxyphenyl)piperidin-4-ol

[00287] To a mixture of A7-3 (120 mg, 0.31 mmol, 1.00 eq) in Me OH (10 mL), was added

Pd(OH)₂ (21.5 mg, 30.7 umol, 20% purity, 0.10 eq). The mixture was degassed under vacuum and purged with H₂ for 3 times. The resulted mixture was stirred at 20 °C under H₂ (15 Psi) for 18 h. LCMS showed the starting material was consumed completed, and the desired MS was observed. The mixture was filtered, and the filtrate was concentrated in vacuum. Compound A7- 4 (70 mg, crude) was obtained as light brown solid.

Step 3: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-(4-fluoro-2-hydroxyphenyl)-4- hydroxypiperidin-l-yl)sulfonyl)-9H-fluoren-9-one

[00288] To a mixture of A7-4 (40 mg, 0.19 mmol, 4.29 eq) and TEA (40.2 mg, 0.4 mmol,

55 uL, 9.00 eq) in DCM (2.5 mL), was added A7-5 (20 mg, 44.2 umol, 1.00 eq). The resulted mixture was stirred at 20 °C for 1.5 h. LCMS showed the reaction was completed. The mixture was combined with previous batch, concentrated in vacuum. Compound A7-6 (40 mg, crude) was obtained as yellow solid, which was used in next step without further purification.

Step 4: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-(4-fluoro-2-hydroxyphenyl)-4- hydroxypiperidin-l-yl)sulfonyl)-9H-fluoren-9-one oxime

[00289] To a mixture of A7-6 (40 mg, 63.7 umol, 1.00 eq) in pyridine (3 mL) was added

NH₂OH.HCl (8.9 mg, 0.13 mmol, 2.00 eq). The resulted mixture was stirred at 40 °C for 1 h. LCMS showed the reaction was completed. The mixture was concentrated in vacuum. The residue was checked by HPLC. The residue was purified by pre-HPLC (basic condition).

Compound 7 (6.47 mg, 9.66 umol, 15.2% yield, and 96% purity) was obtained as off-white solid, which was confirmed by LCMS and ¾ NMR. LCMS (ESI): RT = 0.857 min, mass calcd. for C₃₂H₃₅FN₂O₇S₂ 642.19, m/z found 624.9 [M-H₂0+H]⁺. ¾ NMR (400 MHz, DMSO-i/₆) δ ppm 13.44 (s, 1H), 10.09 (d, J = 3.8 Hz, 1H), 8.63 - 8.81 (m, 1H), 8.38 (dd, J = 8.1, 2.3 Hz, 1H), 8.33 (dd, J = 7.9, 2.9 Hz, 1H), 8.06 - 8.13 (m, 1H), 7.98 - 8.03 (m, 1.5 H) 7.93 (dd, J = 7.9, 1.5 Hz, 0.5H), 7.36 (t, J = 8.2 Hz, 1H), 6.52 - 6.60 (m, 2H), 5.18 (s, 1H), 3.53 - 3.62 (m, 2H), 3.19 - 3.30 (m, 1H), 2.57 - 2.65 (m, 2H), 2.54 (s, 2H), 1.74 (d, J = 11.5 Hz, 2H), 1.46 - 1.58 (m, 4H), 1.42 (d, J = 13.2 Hz, 2H), 1.14 - 1.25 (m, 2H), 0.85 (s, 3H), 0.80 (s, 3H). Example A8: 2-((4-(4-fluoro-2-methoxyphenyl)piperazin-l-yl)sulfonyl)-7-((4- fluorophenyl)sulfonyl -9H-fluoren-9-one oxime (Compound 8)

P

Step 1 : tert-butyl 4-(4-fluoro-2-methoxyphenyl)piperazine-l-carboxylate

[00290] To the solution of A8-1 (200 mg, 1.0 mmol, 1.0 eq) in toluene (5 mL) was added

Pd₂(dba)₃ (45 mg, 49 umol, 0.05 eq), BINAP (61 mg, 98 umol, 0.1 eq), f-BuONa (187 mg, 2.0 mmol, 2.0 eq), iert-butyl piperazine-l-carboxylate (273 mg, 1.5 mmol, 1.5 eq). The mixture was stirred at 110 °C for 16 hr under N₂ atmosphere. The reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 10: 1 to 3: 1) to give A8-2 (273 mg, 0.8 mmol, 90% yield) as a brown oil.

Step 2: l-(4-fluoro-2-methoxyphenyl)piperazine

[00291] To the solution of A8-2 (273 mg, 0.9 mmol, 1.0 eq) in EtOAc (4 mL) was added

HCl/EtOAc (4 M, 4 mL, 18.2 eq). The mixture was stirred at 15 °C for 0.5 hr. The reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure to give compound A8-1A (285 mg, crude, HC1) as a yellow solid.

Step 3: 2-fluoro-7-((4-(4-fluoro-2-methoxyphenyl)piperazin-l-yl)sulfonyl)-9H-fluoren-9-one

[00292] To the solution of A8-1A (284 mg, 1.15 mmol, \Meq, HC1) in DCM (5 mL) was added TEA (341 mg, 3.4 mmol, 467 uL, 5.0 eq). The mixture was stirred at 15 °C for 5min. Then compound A8-3 (200 mg, 0.7 mmol, 1.0 eq) was added to the mixture. The solution was stirred for another 25 min at 15 °C. The reaction was monitored by LCMS. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 10: 1 to 0: 1, PE: DCM = 3 :2) to give A8-4 (235 mg, 0.5 mmol, 74% yield) as a yellow solid.

Step 4: 2-((4-(4-fluoro-2-methoxyphenyl)piperazin-l-yl)sulfonyl)-7-((4-fluorophenyl)thio)- 9H-fluoren-9-one

[00293] To the solution of A8-4 (100 mg, 0.2 mmol, l.O eq) in DMF (4 mL) was added compound A8-4A (33 mg, 0.3 mmol, 27 uL, 1.2 eq) and K₂CO₃ (59 mg, 0.4 mmol, 2.0 eq). The mixture was stirred at 100 °C for 1 hr under microwave. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, Petroleum ether/DCM = 1 :0 to 0: 1) to give A8-5 (80mg, 0. 1 mmol, 65% yield) as a yellow solid.

Step 5: 2-((4-(4-fluoro-2-methoxyphenyl)piperazin-l-yl)sulfonyl)-7-((4- fluorophenyl)sulfonyl)-9H-fluoren-9-one

[00294] To the solution of A8-5 (80 mg, 0.1 mmol, l.O eq) in DCM (5 mL) was added m-

CPBA (112 mg, 0.6 mmol, 4.0 eq). The mixture was stirred at 15 °C for 16 hr. The reaction was monitored by LCMS. Sat. Na₂S0₃ aqueous (5 mL) was added to the solution. The mixture was stirred for 5 min. The mixture was extracted with DCM (20 mL*3). The combined organic layers were dried with Na₂SC)₄ and concentrated under reduced pressure to give A8-6 (124 mg, crude) as a yellow solid.

Step 6: 2-((4-(4-fluoro-2-methoxyphenyl)piperazin-l-yl)sulfonyl)-7-((4- fluorophenyl)sulfonyl)-9H-fluoren-9-one oxime

[00295] To the solution of A8-6 (124 mg, 0.2 mmol, 1.0 eq) in pyridine (5.00 mL) was added hydroxylamine (28 mg, 0.4 mmol, 2.0 eq, HC1). The mixture was stirred at 60 °C for 1.5 hr. The reaction solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Mobile phase A : water with 0.05% ammonia solution; Mobile phase B : MeCN; column temperature: 30°C Gradient: 60 - 80% B 10 min) to give Compound 8 (35.20 mg, 53 umol, 27% yield, 93.8% purity) as a light yellow solid. LCMS (ESI): RT = 2.752 min, mass calcd. for C₃₀H_25F2N₃O₆S₂ 625.12, m/z found 626.1 [M+H]⁺, ¾ NMR (400MHz, DMSO-i/₆) δ 8.84 (d, J=1.5 Hz, 0.5H), 8.67 (d, J=l . 1 Hz, 0.5H), 8.37 - 8.28 (m, 2H), 8.24 - 8.20 (m, 1H), 8. 16 - 8.07 (m, 2.5H), 8.02 - 7.97 (m, 1H), 7.90 (dd, J=1.5, 8.2 Hz, 0.5H), 7.48 (dt, J=2.0, 8.8 Hz, 2H), 6.91 - 6.76 (m, 2H), 6.64 (dt, J=2.6, 8.5 Hz, 1H), 3.67 (s, 3H), 3.08 - 2.93 (m, 8H).

Example A9: 2-(4,4-dimethylcyclohexyl)sulfonyl-7-[4-[2-fluoro-3- (hydroxymethyl)phenyl]piperazin-l-yl]sulfonyl-fluoren-9-one oxime (Compound 9)

P

Step 1 : l-(benzyloxymethyl)-3-bromo-2-fluoro-benzene

[00296] To a solution of A9-1 (1.0 g, 4.88 mmol, 1.0 eq) in DMF (20 mL) was added NaH

(390 mg, 9.76 mmol, 60% purity in mineral oil, 2.0 eq) at 0°C and stirred 30 min at the temperature. BnBr (918 mg, 5.37 mmol, 1. 1 eq) was added into the mixture and stirred at 20°C for 3 hr. TLC (Petroleum ether: Ethyl acetate=10/l) showed the starting material was consumed completely. The reaction mixture was poured into cold water (40 ml) and then extracted by ethyl acetate (3 X 40 mL). The combined organic layers were washed with brine (40 mL*2) dried over NaiSO/t, concentrated under reduced pressure to give A9-2 (1.4 g, 4.74 mmol, 97% yield) as light yellow oil, which was directly used without further purification. ¾ NMR (400 MHz,

CHLOROFORM - d) δ 7.46 - 7.51 (m, IH), 7.40 - 7.45 (m, IH), 7.36 - 7.39 (m, 3H), 7.29 - 7.34 (m, IH), 7.04 (t, J = 7.78 Hz, IH), 4.64 (s, 2H), 4.61 (s, 2H).

Step 2:tert-butyl 4-[3-(benzyloxymethyl)-2-fluoro-phenyl]piperazine-l-carboxylate

[00297] To a solution of A9-2 (500 mg, 1.69 mmol, 1.0 eq), tert-butyl piperazine- 1- carboxylate (346 mg, 1.86 mmol, 1. 1 eq) and f-BuONa (325 mg, 3.38 mmol, 2.0 eq) in toluene (10 mL) was added Pd₂(dba)₃ (62 mg, 0.068 mmol, 0.04 eq) and BINAP (84 mg, 0. 135 mmol, 0.08 eq). The resulted mixture was stirred at 100°C under N₂ for 3hr. LCMS showed 30% desired compound was found and the starting material was remained. The reaction mixture was concentrated to afford the crude product. The crude product was purified by column chromatography over silica gel eluted with petroleum ether/ethyl acetate= l/0 to 10/1 to give compound A9-3 (560 mg, 1.40 mmol, 83% yield) as yellow oil. LCMS (ESI): RT = 0.928 min, mass calc. for C23H29FN2O3 400.22, m/z found 401.0 [M+H]⁺.

Step 3: tert-butyl 4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazine-l-carboxylate

[00298] To a solution of A9-3 (560 mg, 1.40 mmol, 1.0 eq) in MeOH (15 mL) was added

Pd(OH)₂ (49.15 mg, 0.350 mmol, 0.25 eq) under N₂. The suspension was degassed under vacuum and purged with ¾ several times. The mixture was stirred under ¾ (15 psi) at 20°C for 48 hr. LCMS showed 93% desired compound was found and the starting material was consumed completely. The reaction mixture was filtered and concentrated to give A9-4 (450 mg, 1.35 mmol, 96 % yield, and 93% purity). LCMS (ESI): RT = 0.822 min, mass calc. for C₁₆H₂₃FN₂O₃ 3 10.17, m/z found 254.9 [M+H-56]⁺.

Step 4: 2-(l ,4-dioxaspiro [4.5] decan-8-ylthio)-7-fluoro-9H-fluoren-9-one

[00299] A9-4 (450 mg, 1.35 mmol, 1.0 eq) was dissolved HCl/EtOAc (10 mL, 4M) and the reaction mixture was stirred at 25°C for 2 hr. LCMS showed the starting material was consumed completely. The reaction mixture was concentrated to give A9-5 (300.00 mg, 1.22 mmol, 90% yield, HC1) as light yellow solid, which was directly used without further purification. LCMS (ESI): RT = 0.631 min, mass calc. for CnHi₅FN₂0 210. 12, m/z found 211.0[M+H]⁺; ¾ NMR (400 MHz, METHANOL-^) δ 7.19 - 7.09 (m, 2H), 7.07 - 7.01 (m, 1H), 4.65 (d, J = 1.37 Hz, 2H), 3.42 - 3.36 (m, 4H), 3.34 - 3.31 (m, 4H).

Step 5: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-[2-fluoro-3- (hydroxymethyl)phenyl]piperazin-l-yl] sulfonyl-fluoren-9-one

[00300] To a solution of A9-5 (26 mg, 0.106 mmol, 1.2 eq, HC1) and TEA (35.74 mg,

0.353 mmol, 4.0 eq) in DCM (3 mL) was added A9-6 (40 mg, 0.088 mmol, 1.0 eq). The resulted mixture was stirred at 25°C for 2 hr. LCMS showed 88% desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give A9-7 (70 mg, crude) as yellow solid which was directly used without further purification. LCMS (ESI): RT = 0.849 min, mass calc. for C₃₂H₃₅FN₂O₆S₂ 626.19, m/z found 627. 1 [M+H]⁺.

Step 6: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-[2-fluoro-3- (hydroxymethyl)phenyl]piperazin-l-yl]sulfonyl-fluoren-9-one oxime

[00301] A mixture of A9-7 (70 mg, 0.112 mmol, 1.0 eq) and NH₂OH.HCl (23 mg, 0.335 mmol, 3.0 eq) in pyridine (2. mL) was stirred at 50°C for 1 h. LCMS showed 80% desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre- HPLC (Condition: water (0.05% ammonia hydroxide v/v)-ACN. Column: Gemini 150*25 5u.) to give Compound 9 (27 mg, 0.042 mmol, 38 % yield) as light yellow solid. LCMS (ESI): RT = 1.835 min, mass calc. for C₃₂H₃₆FN₃O₆S₂641.2, m/z found 642.1 [M+H]⁺; ¾ NMR (400 MHz, DMSO- d₆) δ 8.74 (s, 0.5H), 8.69 (s, 0.5H), 8.37 (dd, J = 8.16, 3.09 Hz, 1H), 8.32 (dd, J = 7.94,

4.19 Hz, 1H), 8.12 - 8.04 (m, 1H), 8.03 - 7.96 (m, 1.5H), 7.92 (dd, J = 7.94, 1.54 Hz, 0.5H), 7.07 - 7.00 (m, 2H), 6.94 - 6.87 (m, 1H), 5.15 (t, J = 5.73 Hz, 1H), 4.44 (d, J = 5.51 Hz, 2H), 3.40 -

3.20 (m, 1H), 3.20 - 3.00 (m, 8H), 1.75 - 1.70 (m, 2H), 1.60-1.40 (m, 2H), 1.40 - 1.30 (m, 2H), 1.23 - 1.11 (m, 2H), 0.86 - 0.75 (m, 6H).

Example A10: 2-(4,4-dimethylcyclohexyl)sulfonyl-7-[4-[2-(2- methoxyethyl)phenyl]pip (Compound 10)

Preparation of Compound 10:

Step 1 : 3-bromo-2-fluoro-N,N-dimethyl-benzamide

[00302] To a solution of Al 0-3 (700.0 mg, 3.20 mmol, 1.0 e ) in DCM (20 mL) was added CDl (570.8 mg, 3.52 mmol, 1.1 eq) portionwise at 0°C. The reaction mixture was stirred at 45°C for 1 hr. Then, the reaction mixture was cooled to 25°C and added TEA (485.7 mg, 4.80 mmol, 0.67 mL, 1.5 eq), A10-3A (313.11 mg, 3.84 mmol, 1.2 eq, HCI). The reaction was stirred at 25°C for 16 hrs. LCMS showed that the AlO-3 was consumed and the desired product was detected. The reaction mixture was diluted with DCM (30 mL) and washed with citric acid (30 mL). Then the combined organic layers were washed with satNaHCC^ (50 mL), dried over Na₂S0₄ and filtered. The filtrated was concentrated under reduced pressure to give A10-4 (727.7 mg, 2.96 mmol, 92.4% yield) as an orange oil, which was used to next step without purification. Step 2: tert-butyl 4-[3-(dimethylcarbamoyl)-2-fluoro-phenyl]piperazine-l-carboxylate

[00303] To a solution of A10-4A (455.4 mg, 2.45 mmol, 1.5 eq), f-BuONa (313.3 mg,

3.26 mmol, 2.0 eq), BINAP ( 101.5 mg, 0. 16mmol, 0. 1 eq) in toluene (15.0 mL) was added A10-4 (400.0 mg, 1.63 mmol, 1.0 eq) and Pd₂(dba)₃ (46.9 mg, 81.50 umol, 0.05 eq). The reaction mixture was stirred at 100°C for 16 hours. LCMS showed that the A10-4 was consumed completely and the desired product was detected. The reaction mixture was evaporated. The residue was purified by column chromatography (Si0₂, Petroleum ether/Ethyl acetate=l/0 to 5 : 1) to give A10-5 (354.7 mg, 1.01 mmol, 61.9% yield) as light yellow oil.

Step 3: 2-fluoro-N,N-dimethyl-3-piperazin-l-yl-benzamide

[00304] To a solution of A10-5 (354.7 mg, 1.01 mmol, 1.0 eq) in EtOAc (4.0 mL) was added HCl/EtOAc (16.0 mmol, 9.0 mL, 15.84 eq). The reaction mixture was stirred at 25°C for 0.5 hr. LCMS showed that the desired product was detected. The reaction mixture was evaporated to give A10-6 (290.6 mg, 1.01 mmol, 99.9% yield, HC1) as light yellow solid,which was used to next step without purification.

Step 4: l-(2-fluoro-3-piperazin-l-yl-phenyl)-N,N-dimethyl-methanamine

[00305] To a solution of Al 0-6 ( 160.0 mg, 0.56 mmol, 1.0 eq, HC1) in THF (5.0 mL) was added BH₃-Me₂S (422.4 mg, 5.56 mmol, 10.0 eq). The reaction mixture was stirred at 60°C for 3 hrs. LCMS showed that the A10-6 was consumed completely and the desired product was detected. The reaction was diluted with MeOH (20 mL) and evaporated to give A10-1A (234.2 mg, crude) as light yellow oil, which was used to next step without purification.

Step 5 : 2- [4- [3- [(dimethylamino)methyl] -2-fluoro-phenyl] piper azin- 1-yl] sulf onyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one

[00306] To a solution of A10-1A (27.5 mg, 0. 12 mmol, 1.5 eq) in DCM (5.0 mL) was added TEA (23.5 mg, 0.23 mmol, 32. 1 uL, 3.0 eq) and AlO-l (35.0 mg, 77.3 umol, 1.0 eq). The reaction mixture was stirred at 25°C for 3 hours. LCMS showed that the AlO-l was consumed completely and desired product was detected. The reaction was diluted with H₂0 (30 mL), extracted with DCM (50 mL). The combined organic layers were washed with brine (15 mL), dried over Na₂S0₄ and filtered. The filtrate was concentrated under reduced pressure. A10-2 (158.5 mg, crude) was used to next step without purification as light yellow solid.

Step 6: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-[2-(2-methoxyethyl)phenyl]piperazin-l- yl]sulfonyl-fluoren-9-one oxime

[00307] To a solution of A10-2 (50.5 mg, 77.3 umol, 1.0 eq) in pyridine (5.0 mL) was added hydroxylamine (5. 1 mg, 0. 15 mmol, 2.0 eq). The reaction mixture was stirred at 25 °C for 2 hrs. LCMS showed that the A10-2 was consumed completely and the desired product was detected. The reaction mixture was evaporated under reduced pressure, a residue was formed. The residue was purified by prep-HPLC (column: Xtimate C 18 150*25mm*5um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 69%-71%, lOmin) to obtain

Compound 10 (12.54 mg, 18.75 umol, 24.3% yield, 100% purity) as white solid. LCMS (ESI): RT = 1.605 min, mass cal.cd for C₃₄H₄₁FN₄O₅S₂ 668.25, m/z found 669. 1 [M+H]⁺. ¾ NMR (400 MHz, DMSO-i ) δ 8.77 - 8.70 (m, 1H), 8.40 - 8.32 (m, 2H), 8. 13 - 7.91 (m, 3H), 7.09 - 6.95 (m, 3H), 3.78 - 3.48 (m, 2H), 3. 15-3.04 (m, 8H), 2.25-2.05 (br. s, 6H), 1.77 - 1.70 (m, 2H), 1.55- 1.49 (br. s, 2H), 1.48 - 1.38 (m, 2H), 1.25 - 1.14 (m, 3H), 0.85 (s, 3H), 0.79 (s, 3H).

Example All : 3- [4- [(9Z)-7-(4,4-dimethylcyclohexyl)sulfonyl-9-hydroxyimino-fluoren-2- yl]sulfonylpiperazin-l-yl -2-fluorobenzonitrile (Compound 11)

Preparation of Compound 11 :

Step 1 : tert-butyl 4-(3-cyano-2-fluoro-phenyl)piperazine-l-carboxylate

[00308] To a solution of Al l-1 (200 mg, 1.0 mmol, 1.0 eq), tert-butyl piperazine-1- carboxylate (205 mg, 1. 1 mmol, 1. 1 eq) and f-BuONa (192 mg, 2.0 mmol, 2.0 eq) in toluene (10 mL) was added Pd₂(dba)₃ (37 mg, 0.040 mmol, 0.04 eq) and BINAP (50 mg, 0.080 mmol, 0.08 eq). The resulted mixture was stirred at 100°C under Ni for 5 hour. LCMS showed 24% desired compound was found and the starting material was remained. The reaction mixture was concentrated. The residue crude product was dissolved with CH₂CI₂ (15 ml) and washed with water (2 ^χ 15 mL). After drying over anhydrous NaiSC , the solvent was removed under reduced pressure to afford the crude product. The crude product was purified by column chromatography over silica gel eluted with petroleum ether/ethyl acetate=l/0 to 10/1 to give All-2 (83 mg, 0.236 mmol, 24% yield, and 87% purity) as a yellow solid. LCMS (ESI): RT = 0.804 min, mass calc. for C₁₆H₂₀FN₃O₂ 305.15, m/z found 249.9 [M+H-56]⁺.

Step 2: 2-fluoro-3-piperazin-l-yl-benzonitrile

[00309] All-2 (87 mg, 0.248 mmol, 1.0 eq) was dissolved HCl/EtOAc (3 mL, 4M) and the reaction mixture was stirred at 25°C for 2 hr. LCMS showed 82% desired compound was found and the starting material was consumed completely. The reaction mixture was

concentrated to give the crude All-3 (70 mg, 0.237 mmol, 96% yield, 82% purity, HC1) as light yellow solid, which was directly used without further purification.. LCMS (ESI): RT = 0.791 min, mass calc. for C11H12FN3 205.10, m/z found 205.8 [M+H]⁺.

Step 3: 3-[4-[7-(4,4-dimethylcyclohexyl)sulfonyl-9-oxo-fluoren-2-yl]sulfonylpiperazin-l-yl]- 2-fluoro-benzonitrile

[00310] To a solution of All-3 (26 mg, 0.106 mmol, 1.2 eq, HC1) and TEA (36 mg, 0.353 mmol, 4.0 eq) in DCM (3 mL) was added All-4 (40mg, 0.088 mmol, 1.0 eq). The resulted mixture was stirred at 25°C for 2 hours. LCMS showed 61% desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give the All-5 (70 mg, crude) as yellow solid, which was directly used without further purification. LCMS (ESI): RT = 0.921 min, mass calc. for C₃₂H₃₂FN₃O₅S₂ 621.18, m/z found 621.9 [M+l]⁺. Step 4: 3-[4-[(9Z)-7-(4,4-dimethylcyclohexyl)sulfonyl-9-hydroxyimino-fluoren-2- yl]sulfonylpiperazin-l-yl]-2-fluorobenzonitrile

[00311] A mixture of All-5 (70 mg, 0.113 mmol, 1.0 eq) and NH₂OH.HCl (39 mg, 0.563 mmol, 5.0 eq) in pyridine (2 mL) was stirred at 50°C for 1 hour. LCMS showed 85% desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre- HPLC (Condition: water (0.05% ammonia hydroxide v/v)-ACN. Column: Phenomenex Gemini 150*25mm* lOum.) to give Compound 11 (25 mg, 0.039 mmol, 35% yield, 99.5% purity) as light yellow solid. LCMS (ESI): RT = 1.937 min, mass calc. for C₃₂H₃₃FN₄O₅S₂ 636.19, m/z found 649.2 [M+13]⁺; MS: 637.1813, [M+H]⁺; ¾ NMR (400 MHz, DMSO- d₆) δ 8.85 - 8.66 (m, 1H), 8.50 - 8.40 (m, 2H), 8.25 - 7.95 (m, 3H), 7.55 - 7.35 (m, 2H), 7.35 - 7.20 (m, 1 H), 3.29 - 3.27 (m, 2H), 3.26 - 3.24 (m, 1H), 3.20 - 3.16 (m, 6H), 1.80 - 1.70 (m, 2H), 1.60 - 1.37 (m, 4H), 1.35 - 1.20 (m, 2H), 0.91 - 0.74 (m, 6H). Example A12: 2-[4-(4-chloro-2-hydroxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime (Compound 12)

P

Step 1 : 5-chloro-2-piperazin-l-yl-phenol

[00312] To a mixture of A12-3 (70 mg, 0.214 mmol, 1.00 eq) in DCM (6 mL) was added BBr₃ (910 mg, 3.63 mmol, 0.35 mL, 16.96 eq) in one portion at 0 °C under N₂.The mixture was stirred at 0 °C for 3 min, then heated to 15 °C and stirred for 1.5 h. LCMS showed A12-3 was consumed completely and one small peak with desired MS was detected. The reaction mixture was continued stirred for 16 h. LCMS indicated the desired product was increased, but the intermediate was not consumed completely. The reaction was continued stirred for 20 h. LCMS showed about 74 % of desired compound was detected. The reaction mixture was quenched by MeOH (8 mL) dropwise and concentrated under reduced pressure to give A12-1A (46 mg, crude) as the yellow solid, which was used next step without further purification.

Step2: 2-[4-(4-chloro-2-hydroxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one

[00313] To a solution of A12-1A (20 mg, 0.07 mmol, 1.00 eq) in DCM (6 mL) was added Εΐ₃Ν (42 mg, 0.418 mmol, 0.058 mL, 6.00 eq). The reaction mixture was stirred at 20 °C for 1 min. The reaction mixture was added A12-l(20 mg, 0.044 mmol, 0.63 eq) and stirred at 20 °C for 45 min. LCMS showed A12-1 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give A12-2 (45 mg, crude) as the yellow solid, which was used next step without further purification. Step 3: 2-[4-(4-chloro-2-hydroxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime

[00314] To a mixture of NH₂OH.HCl (25 mg, 0.358 mmol, 5.00 eq) in pyridine (5 mL) was added A12-2 (45 mg, 0.072 mmol, 1.00 eq) in one portion at 40 °C for 1 h. LCMS showed A12-2 was remained and no desired MS was detected. The reaction mixture was added NH₂OH.HCl (50 mg, 0.715 mmol, 10.00 eq) and continued stirred 1 h. LCMS showed A12-2 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by Prep-HPLC (basic condition) to give Compound 12 (4.78 mg, 7.3 umol, 10.2% yield, and 98.7% purity). LCMS (ESI): RT = 0.882 min, mass calcd. For C₃₁H₃₄CIN₃O₆S₂, 643. 16 m/z found 644.0[M+H]⁺.¹H NMR (400 MHz, CHLOROFORM- ) S 8.93 - 8.84 (m, 1H , 8.36 - 8.22 (m, 1H), 8. 1 1 - 7.88 (m, 4H), 7.05 (d, J = 8.8 Hz, 1H), 6.94 - 6.88 (m, 2H), 3.40 - 3.20 (m, 4H), 3.05 - 2.97 (m, 5H), 2.00 - 1.80 (m, 2H), 1.80 - 1.60 (m, 2H), 1.60 - 1.40 (m, 2H), 1.23 - 1.23 (m, 2H), 0.81 - 1.00 (m, 6H).

Example A13: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(3-fluoro-2-methoxy- phenyl)piperazin-l-yl]sul )

Step 1 : 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(3-fluoro-2-methoxy-phenyl)piperazin-l- yl] sulf onyl-fluoren-9-one

[00315] To a solution of A13-1 (80 mg, 0.119 mmol, 1.0 eq) in THF (5 mL) was added

NaH ( 14 mg, 0.356 mmol, 60% purity in mineral oil, 3.0 eq) at 0°C and the mixture was stirred for 30 minutes. A solution of CH₃I (25 mg, 0.178 mmol, 1.5 eq) in THF (1 mL) was added slowly at 0°C to the reaction mixture and the temperature was raised to 30°C. The mixture was stirred at this temperature for 16 hr. LCMS and TLC showed 72% desired compound was found and the starting material was consumed completely (Petroleum ether: Ethyl acetate= 1/1, RF= 0.4). To the reaction mixture ice cold water (15 mL) and ethyl acetate (20 mL) was added and the mixture was stirred for 10 minutes. The organic phase was separated and the aqueous layer was extracted with ethyl acetate (10 mL*2). The organic layer was dried over anhydrous Na₂S0₄, concentrated in vacuum to give A13-2 (100 mg, 0. 115 mmol, 97% yield, 72% purity) as light yellow solid, which was directly used without further purification.

Step 2: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(3-fluoro-2-methoxy-phenyl)piperazin-l- yl]sulfonyl-fluoren-9-one oxime

[00316] A mixture of A13-2 (100 mg, 0. 115 mmol, 1.0 eq) and NH₂OH.HCl (40 mg, 0.574 mmol, 5.0 eq) in pyridine (2 mL) was stirred at 50°C for 1 h. LCMS showed 57% desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre- HPLC (Condition: water (0.05% ammonia hydroxide v/v)-ACN. Column: Gemini 150*25 5u.) to give Compound 13 (40 mg, 0.062 mmol, 54 % yield, and 100% purity) as a white solid. LCMS (ESI): RT = 2.057 min, mass calc. for C₃₂H₃₆FN₃O₆S₂ 641.20, m/z found 642.0 [M+H]⁺; ¾ NMR (400 MHz, DMSO- d₆) δ 8.80 - 8.60 (m, 1H), 8.45 - 8.30 (m, 2H), 8.14 - 8.07 (m, 1H), 8.06 - 8.02 (m, 1H), 7.90-7.80 (m, 1H), 7.04 - 6.96 (m, 1H), 6.87 (t, J = 9.2 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 3.66 (s, 3H), 3.22 - 3.20 (m, 1H), 3. 17 - 3. 14 (m, 4H), 3. 14-3.05 (m, 4H), 1.90- 1.70 (m, 2H), 1.60- 1.50 (m, 2H), 1.40- 1.25 (m, 2H), 1.25 - 1. 14 (m, 2H), 0.88 (s, 3H), 0.86 (s, 3H).

Example A14: 2-(4,4-dimethylcyclohexyl)sulfonyl-7-[4-[3-(hydroxymethyl)-2-methyl- phenyl]piperazin-l-yl] sulfonyl-fluoren-9-one oxime (Compound 14)

P

Step 1 : l-(benzyloxymethyl)-3-bromo-2-methyl-benzene

[00317] To a mixture of A14-3 (150 mg, 0.746 mmol, 1.00 eq) in DMF (6 mL) was added NaH (60 mg, 1.49 mmol, 60% purity, 2.00 eq) in one portion at 0 °C. The mixture was stirred at 15 °C for 30 min and then it was cooled in ice and to it was added

bromomethylbenzene (144 mg, 0.825 mmol, 100 uL, 1. 11 eq) and stirred at 15 °C for 1.5 h. LCMS showed no desired MS was detected.TLC indicated A14-3 was consumed completely. TLC showed one new spot was found. The reaction mixture was quenched by addition water (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (40 mL ), dried with anhydrous NaiSC , filtered and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 40/1 to 30: 1). ¾ NMR confirmed the colorless oil was A14-4 (190 mg, 0.653 mmol, 87.8% yield). ^!H NMR (400 MHz, CHLOROFORM-i δ 7.52 (d, J = 8.03Hz, 1H), 7.45-7.25 (m, 4H), 7.20 - 7. 15 (m, 2H), 7.05 (t, J = 8.0 Hz, 1H), 4.58 (s, 2H), 4.57 (s, 2H), 2.41 (s, 3H).

Step 2: tert-butyl 4-[3-(benzyloxymethyl)-2-methyl-phenyl]piperazine-l-carboxylate

[00318] To a mixture of A14-5 (146 mg, 0.783 mmol, 1.20 eq) and A14-4 (190 mg, 0.653 mmol, 1.00 eq) in toluene (10 mL) was added Pdi(dba)3 (30 mg, 33 umol, 0.05 eq) and f-BuONa (188 mg, 1.96 mmol, 3.00 eq) and X-phos (31 mg, 65 umol, 0. 10 eq) in one portion under N₂.The mixture was stirred at 110 °C and stirred for 16 h. LCMS showed one peak with desired MS was detected.TLC indicated A14-4 was consumed completely. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL*2), dried with anhydrous NaiSO/t, filtered and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 20/1 to 10: 1).LCMS confirmed the light yellow oil was A14-6 (170 mg, 0.418 mmol, 64. 1% yield, 97.5% purity). LCMS (ESI): RT = 1.057 min, mass calcd. For C₂₄H₃₂N₂O₃, 396.24 m/z found 397.1 [M+H]⁺.

Step 3: tert-butyl 4-[3-(hydroxymethyl)-2-methyl-phenyl]piperazine-l-carboxylate

[00319] To a solution of A14-6 (80 mg, 0. 197 mmol, 1.00 eq) in MeOH (30 mL) was added Pd/C (100 mg, wet, 10%) under Ar. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (50 psi) at 45 °C for 16 h.

LCMS showed the A14-6 was consumed completely and one main peak with desired MS was detected. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 5/1 to 1 : 1) to give A14-7 (30 mg, 98 umol, 49.8% yield, and 100% purity) as colorless oil. LCMS (ESI): RT = 0.827 min, mass calcd. For C17H26N2O3, 306.19 m/z found 307.0 [M+H]⁺ and 250.9.0 [M+H-56]⁺ and 207.0 [M+H- 100]⁺.

Step 4: (2-methyl-3-piperazin-l-yl-phenyl)methanol

[00320] To a mixture of A14-7 (30 mg, 98 umol, 1.00 eq) in HCl/dioxane (4 M, 4 mL,

163.42 eq) was stirred at 10 °C for 30 min. TLC showed the A14-7 was consumed completely. The reaction mixture was concentrated under reduced pressure to give A14-1A (27 mg, crude, 2HC1) as white solid, which was used next step without further purification.

Step 5: 2-(4,4-dimethylcyclohexyl)sulfonyl-7-[4-[3-(hydroxymethyl)-2-methyl- phenyl] piperazin-1 -yl] sulfonyl-fluoren-9-one

[00321] To a solution of A14-1A (22 mg, 79.5 umol, 1.20 eq, 2HC1) in DCM (6 mL) was added Et₃N (34 mg, 0.331 mmol, 46 uL, 5.00 e ). The reaction mixture was stirred at 15 °C for 1 min. The reaction mixture was added A14-1 (30 mg, 66 umol, 1.00 eq) and stirred at 15 °C for 1 h. LCMS showed the A14-1 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The light yellow solid was A14-2 (55 mg, crude) and it was used next step without

further purification.

Step 6 : 2-(4,4-dimethylcyclohexyl)sulf onyl-7- [4- [3-(hydr oxymethyl)-2-methyl- phenyl] piperazin-1 -yl] sulfonyl-fluoren-9-one oxime

[00322] To a solution of hydroxylamine (12 mg, 0.176 mmol, 2.00 eq, HC1) in pyridine (6 mL) was added A14-2 (55 mg, 88.3 umol, 1.00 eq). The reaction mixture was stirred at 40 °C for 2 h. LCMS showed the A14-2 was remained and one peak with desired MS was detected. The reaction mixture was added hydroxylamine (12 mg, 0.176 mmol, 2.00 eq, HC1) and continued stirred 3 h. LCMS showed the A14-2 was consumed completely and one peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (HC1 condition). LCMS and ¾ NMR confirmed the light yellow solid was Compound 14 (6.75 mg, 10.0 umol, 11.3% yield, 100% purity, HC1). LCMS (ESI): RT = 1.850 min, mass calcd. For C₃₃H₃₉N₃O₆S₂, 637.23 m/z found 638.1

[M+H]⁺. ¾ NMR (400 MHz, DMSO-i/₆) δ 13.48 (br. s., 1H), 8.80-8.65 (m, 1H), 8.38 - 8.32 (m, 2H), 8.12 - 8.01 (m, 3H), 7.11 - 7.05 (m, 2H), 6.96 (d, J = 2.4 Hz, 1H), 4.44 (s, 2H), 3.46 - 3.12 (m, 5H), 3.00 - 2.80 (m, 4H), 2.01 (s, 3H), 1.76 - 1.71 (m, 2H), 1.56 - 1.39 (m, 4H), 1.21 - 1. 17 (m, 2H), 0.83 - 0.78 (m, 6H).

Example A15: 2-[4-(2-chloro-6-hydroxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime (Compound 15)

Step 1 : l-benzyloxy-2-bromo-3-chloro-benzene

[00323] To a solution of A15-1 (200 mg, 0.96 mmol, 1 eq) and A15-2 (164.9 mg, 0.96 mmol, 0. 11 mL, 1 eq) in DMF (5 mL) was added K₂CO₃ (267 mg, 1.9 mmol, 2 e ). The resulted mixture was stirred at 80 °C for 2 hour. TLC (Petroleum ether: Ethyl acetate= 10/l) showed desired compound was found and the starting material was consumed completely. The mixture was diluted with water (10 mL) carefully and extracted with EtOAc (15 mL x 2). The combined organic layers were concentrated to give A15-3 (250 mg, 0.84 mmol, 87. 1% yield) as a yellow solid, which was directly used without further purification.

Step 2: tert-butyl 4-(2-benzyloxy-6-chloro-phenyl)piperazine-l-carboxylate

[00324] To a solution of A15-4 (156.5 mg, 0.84 mmol, leq), A15-3 (250 mg, 0.84 mmol,

1 eq) and f-BuONa (161.47 mg, 1.68 mmol, 2.00 eq) in toluene (5 mL) was added BINAP (41.8 mg, 67.2 umol, 0.08 eq) and Pdi(dba)3 (30.8 mg, 33.6 umol, 0.04 eq). The resulted mixture was stirred at 100 °C under N₂ for 15 hour. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated. The residue was dissolved with CH₂CI₂ (15 ml) and washed with water (2 ^χ 15 mL). After drying over anhydrous NaiSC , the solvent was removed under reduced pressure to afford the crude product. The crude product was purified by column chromatography over silica gel eluted with petroleum ether/ethyl acetate=l/0 to 20/1 to give compound A15-5 (180 mg, 0.42 mmol, 49.7% yield, 93.4% purity) as a light yellow oil. LCMS (ESI): RT = 1.073 min, mass calc. for

C22H27CIN2O3 402.17, m/z found 403.0 [M+H]⁺.

Step 3: 3-chloro-2-piperazin-l-yl-phenol

[00325] To a solution of A15-5 (90 mg, 0.22 mmol, 1 eq) in DCM (10 mL) was added

BBr₃ (112 mg, 0.45 mmol, 43.1 uL, 2 eq). The resulted mixture was stirred at 20 °C for 1 hour. LCMS showed desired compound was found and the starting material was consumed completely. The reaction was quenched with MeOH (5 mL) and concentrated under reduced pressure to give A15-6 (40 mg, 0. 19 mmol, 84.2% yield) as a yellow solid, which was directly used without further purification.

Step 4: tert-butyl 4-(2-chloro-6-hydroxy-phenyl)piperazine-l-carboxylate

[00326] To a solution of A15-6 (40 mg, 0.19 mmol, 1 eq) and NaOH (7.5 mg, 0. 19 mmol,

1 eq) in THF (5 mL) was added A15-7 (82.1 mg, 0.38 mmol, 86.4 uL, 2 e ). The resulted mixture was stirred at 20 °C for 2 hour. LCMS showed desired compound was found and the starting material was consumed completely. The reaction was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography over silica gel eluted with Petroleum ether/ethyl acetate= l/0 to 10/1 to give A15-8 (50 mg, 0.16 mmol, 85% yield) as a yellow solid. LCMS (ESI): RT = 0.940 min, mass calc. for C₁₅H₂₁CIN₂O₃ 312. 12, m/z found 212.8 [M+H- 100]⁺, 256.8 [M+H-56]⁺.

Step 5: 3-chloro-2-piperazin-l-yl-phenol

[00327] A mixture of A15-8 (50 mg, 0. 16 mmol, 1.00 eq) in HCl/MeOH (4 M, 1.2 mL,

29.6 eq) stirred at 20 °C fori hour. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give A15-9 (20.00 mg, 80.28 umol, 50.2% yield, HC1) as gray solid, which was directly used without further purification.

Step 6: 2-[4-(2-chloro-6-hydroxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one

[00328] To a solution of A15-9 (19.8 mg, 79.5 umol, 1.2 eq, HC1) and TEA (26.8 mg, 0.26 mmol, 36.7 uL, 4 eq) in DCM (5 mL) was added A15-10 (30 mg, 66.2 umol, 1 eq). The resulted mixture was stirred at 20 °C for 1 hour. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give A15-11 (30.0 mg, 47.68 umol, 72% yield) as a yellow solid, which was directly used without further purification. LCMS (ESI): RT = 1.040 min, mass calc. for

C₃iH₃₃ClN₂0₆S2 628.15, m/z found 629.1 [M+H]⁺. Step 7: 2-[4-(2-chloro-6-hydroxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime

[00329] A mixture of A15-11 (30 mg, 47.9 umol, 1 eq) and NH₂OH.HCl (33 mg, 0.48 mmol, 10 eq) in pyridine (2 mL) stirred at 50 °C for 1 hour. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition:water (0.05% ammonia hydroxide v/v)-ACN. Column: Xtimate C 18

150*25mm*5um.) to give Compound 15 (21. 11 mg, 32.77 umol, 68.7% yield, and 100% purity) as a white solid. LCMS (ESI): RT = 1.019 min, mass calc. for C₃₁H₃₄CIN₃O₆S₂ 643.16, m/z found 644.0 [M+H]⁺; ^JH NMR (400 MHz, DMSO-i/₆) 513.41 (br s, 1H), 9.41 (br s, 1H), 8.77 (s, 0.5H), 8.71 (s, 0.5H), 8.39 (dd, J = 8.38, 3.97 Hz, 1H), 8.35 (dd, J = 7.94, 4.85 Hz, 1H), 8. 14 - 8.07 (m, 1H), 8.05 - 7.99 (m, 1.5H), 8.00 -7.90 (m, 0.5H), 6.98 - 6.92 (m, 1H), 6.80 - 6.73 (m, 2H), 3.50-3.30 (m, 1H), 3.20-3.00 (m, 4H), 2.57 - 2.54 (m, 2H), 2.50 - 2.40 (m, 2 H), 1.80 - 1.60 (m, 2H), 1.58 - 1.50 (m, 2H), 1.50 - 1.35 (m, 2H), 1.30 - 1.20 (m, 2H), 0.91 - 0.76 (m, 6H).

Example A16: 2-[4-(4,5-difluoro-2-hydroxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime (Compound 16)

Step 1 : l-benzyloxy-2-bromo-4,5-difluoro-benzene

[00330] To a solution of A16-1 (500 mg, 2.39 mmol, 1 eq) and K₂C0₃ (661 mg, 4.78 mmol, 2 eq) in DMF (15 mL) was added bromomethylbenzene (450 mg, 2.63 mmol, 1. 1 eq). The resulted mixture was stirred at 80°C for 3 hr. LCMS showed the starting material was consumed completely. The reaction mixture was poured into cold water (30 ml) and then extracted by ethyl acetate (3 x30 mL). The combined organic layers were washed with brine (40 mL*2) dried over NaiSO/t, concentrated in vacuo to give a light yellow solid. The solid was directly used without further purification. A16-2 (650 mg, 2.13 mmol, 89 % yield, 98% purity) was obtained as a light yellow oil.'H NMR (400 MHz, CHLOROFORM-t/) δ 7.31 - 7.48 (m, 5H), 7.25 (s, 1H), 6.71 - 6.84 (m, 1H), 5.09 (s, 2H).

Step 2: tert-butyl 4-(2-benzyloxy-4,5-difluoro-phenyl)piperazine-l-carboxylate

[00331] To a solution of A16-2 (300 mg, 1 mmol, 1 eq), compound A16-3 (205 mg, 1.1 mmol, 1.1 eq) and f-BuONa (192 mg, 2.0 mmol, 2 eq) in toluene (10 mL) was added Pdi(dba)3 (37 mg, 0.040 mmol, 0.04 eq) and BINAP (50 mg, 0.080 mmol, 0.08 eq). The resulted mixture was stirred at 100°C under N₂ for 2 hr. LCMS showed desired compound was found and the starting material was remained. The reaction mixture was concentrated. The residue crude product was dissolved with CH₂CI₂ (15 ml) and washed with water (2 x 15 mL), respectively. After drying over anhydrous NaiSC , the solvent was removed under reduced pressure to afford the crude product. The crude product was purified by column chromatography over silica gel eluted with petroleum ether/ethyl acetate= l/0 to 10/1 to give a yellow oil. A16-4 (345 mg, 0.842 mmol, 84 % yield, 99% purity) was obtained as a yellow solid. LCMS (ESI): RT = 0.904 min, mass calc. for C₂₂H₂₆F₂N₂O₃ 404.19, m/z found 405.1 [M+H]⁺.

Step 3: tert-butyl 4-(4,5-difluoro-2-hydroxy-phenyl)piperazine-l-carboxylate

[00332] To a solution of A16-4 (340 mg, 0.841 mmol, 1 eq) in MeOH (15 mL) was added

Pd/C (80 mg, 10% purity) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under ¾ (15 psi) at 20°C for 2 hr. LCMS showed 85% desired compound was found and the starting material was consumed completely. The reaction mixture was filtered and concentrated to give the product as a red solid. A16-5 (250 mg, 0.676 mmol, 80% yield, 85% purity) was obtained as a red solid. LCMS (ESI): RT = 0.751 min, mass calc. for C₁₅H₂₀F₂N₂O₃ 314.14, m/z found 314.9 [M+H]⁺.

Step 4: 4,5-difluoro-2-piperazin-l-yl-phenol

[00333] A16-5 (250 mg, 0.676 mmol, 1 eq) was dissolved HCl/EtOAc (8 mL) and the reaction mixture was stirred at 15°C for 2 hr. LCMS showed 95% desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give the crude product. The residue was directly used without further purification. A16-6 (175 mg, 0.660 mmol, 98% yield, 95% purity, HC1) was obtained as yellow solid. LCMS (ESI): RT = 0.566 min, mass calc. for C₁₀H₁₂F₂N₂O 214.09, m/z found 214.8 [M+H]⁺. Step 5: 2-[4-(4,5-difluoro-2-hydroxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one

[00334] To a solution of A16-6 (47 mg, 0.177 mmol, 2 eq, HC1) and TEA (36 mg, 0.353 mmol, 4 eq) in DCM (3 mL) was added A16-7 (40 mg, 0.088 mmol, 1 eq). The resulted mixture was stirred at 25°C for 2 hr. LCMS showed 25.8 % desired product was found and the starting material was consumed completely. The reaction mixture was concentrated to give the crude product. The residue was directly used without further purification. A16-8 (70 mg, crude) was obtained as brown solid. LCMS (ESI): RT = 0.882 min, mass calc. for C₃₁H₃₂F₂N₂O₆S₂ 630.17, m/z found 631.1 [M+l]⁺.

Step 6: 2-[4-(4,5-difluoro-2-hydroxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime

[00335] A mixture of A16-8 (70 mg, 0.111 umol, 1.00 eq) and NH₂OH.HCl (39 mg, 0.555 mmol, 5 eq) in pyridine (2 mL) was stirred at 50°C for 1 h. LCMS showed 35% desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by pre- HPLC (Condition: water (0.05% ammonia hydroxide v/v)-ACN. Column: Phenomenex Gemini 150*25mm* lOum.) to give the product as a solid. Compound 16 (15.0 mg, 0.023 mmol, 21 % yield, 100% purity) was obtained as light yellow solid. LCMS (ESI): RT = 1.915 min, mass calc. for C₃₁H₃₃F₂N₃O₆S₂645.18, m/z found 646.0 [M+H] +; ¾ NMR (400 MHz, DMSO- d6) δ 8.76 - 8.79 (m, 0.5H), 8.70 - 8.73 (m, 0.5H), 8.38 - 8.43 (m, 1H), 8.32 - 8.38 (m, 1H), 8.12 - 8.15 (m, 0.5H), 8.07 - 8.11 (m, 0.5H), 7.99 - 8.07 (m, 1.5H), 7.92 - 7.97 (m, 0.5H), 6.93 - 7.02 (m, 1H), 6.72 - 6.80 (m, 1H), 3.10 (br. s., 4H), 2.98 (br. s., 4H), 1.68 - 1.80 (m, 2H), 1.48 - 1.59 (m, 2H), 1.39 - 1.47 (m, 2H), 1.15 - 1.25 (m, 2H), 0.76 - 0.89 (m, 6H).

Example A17: 2-(4,4-dimethylcyclohexyl)sulfonyl-7-[4-(4-fluoro-2,5-dimethoxy- phenyl)piperazin-l-yl]sulfonyl-fluoren-9-one oxime (Compound 17)

Preparation of Compound 17:

Step 1 : 2-bromo-5-fluoro-4-methoxy-phenol

[00336] A17-3 (500 mg, 3.52 mmol, 1.00 eq) is dissolved in dry DCM ( 10 mL). The well stirred reaction mixture is cooled to - 15°C (ice/salt). A solution of molecular bromine (619 mg, 3.87 mmol, 2 mL, 1. 10 eq) in dry DCM (5 mL) is slowly dropped into the reaction mixture, after complete addition stirring is at 10 °C for 1 h. TLC showed trace of A17-3 was remained and two new spots were found. Water (10 ml) containing NaiSC (488 mg, 3.87 mmol, 1. 10 eq) is added and the reaction mixture was stirred at ambient temperature for 30 min. The organic layer is separated, washed with water (10 ml) and dried over anhydrous NaiSC . After filtration, the solvent is completely removed under reduced pressure. TLC showed only one spot was found.¹ H NMR confirmed the light brown solid was A17-4 (700 mg, 3. 17 mmol, 90. 1% yield). ¾ NMR (400 MHz, DMSO-i/e) δ 10.09 (br. s, 1H) 7.28 (d, J = 9.2 Hz, 1H) 6.81 (d, J = 12.8 Hz, 1H) 3.80 (s, 3H).

Step 2: l-bromo-4-fluoro-2,5-dimethoxy-benzene

[00337] To a mixture of A17-4 (400 mg, 1.81 mmol, 1.00 eq) in DMF ( 10 mL) was added NaH (144.8 mg, 3.62 mmol, 60% purity in mineral oil, 2.00 eq) in one portion at 0 °C. The mixture was stirred at 10 °C for 20 min, then added CH₃I (770 mg, 5.42 mmol, 0.34 mL, 3.00 eq) at 10 °C and stirred for 2 h. TLC showed the A17-4 was consumed completely. The reaction mixture was quenched by addition water (40 mL) at 0 °C, filtered and concentrated under reduced pressure to give a white solid. ¾ NMR confirmed the white solid was A17-5 (310 mg, 1.32 mmol, 72.9% yield). ¾ NMR (400 MHz, DMSO-i/₆) δ 7.40 (d, J = 9.2 Hz, 1H) 7.16 (d, J = 13.2 Hz, 1H) 3.80 (s, 3H), 3.79 (s, 3H).

Step 3: tert-butyl 4-(4-fluoro-2,5-dimethoxy-phenyl)piperazine-l-carboxylate

[00338] To a mixture of A17-5 (200 mg, 0.851 mmol, 1.00 eq) and tert-butyl piperazine- 1- carboxylate (190 mg, 1.02 mmol, 1.20 eq) in toluene (15 mL) was added Pdi(dba)3 (39 mg, 0.043 mmol, 0.05 eq) and f-BuONa (205 mg, 2. 13 mmol, 2.50 eq) and X-phos (41 mg, 0.085 mmol, 0.10 eq) in one portion under N₂. The mixture was stirred at 1 15 °C and stirred for 16 h. LCMS showed no desired MS was detected. TLC indicated A17-5 was consumed completely. TLC showed two new spots were found. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried with anhydrous NaiSC , filtered and concentrated in vacuum. The residue was purified by column chromatography (PE / EA = 10: 1 to 5: 1). LCMS showed the yellow oil was A17-6 (150 mg, 0.375 mmol, 44.0% yield, and 85% purity). LCMS (ESI): RT = 0.745 min, mass calcd. For C17H25FN2O4, 340.18 m/z found 340.9 [M+H]⁺ and 284.9 [M+H-56]⁺ and 240.9 [M+H- 100]⁺.

Step 4: l-(4-fluoro-2,5-dimethoxy-phenyl)piperazine

[00339] To a mixture of A17-6 (100 mg, 0.294 mmol, 1.00 eq) in HCl/dioxane (4 M, 3 mL, 40.85 eq) was stirred at 10 °C for 30 min. TLC showed A17-6 was consumed completely. The reaction mixture was concentrated under reduced pressure to give A17-1A (80 mg, crude, 2 HC1) as the yellow solid, which was used next step without further purification.

Step 5: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluoro-2,5-dimethoxy-phenyl)piperazin- 1 -yl] sulfonyl-fluoren-9-one

[00340] To a solution of Al 7-1 A (19.1 mg, 0.061 mmol, 0.92 eq, 2 HC1) in DCM (6 mL) was added Et₃N (33 mg, 0.335 mmol, 46 uL, 5.00 eq). The reaction mixture was added A17-1 (30 mg, 66 umol, 1.00 eq) and stirred at 15 °C for 1 h. LCMS showed A17-1 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give A17-2 (80 mg, crude) as yellow solid.

Step 6: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluoro-2,5-dimethoxy-phenyl)piperazin- l-yl]sulfonyl-fluoren-9-one oxime

[00341] To a mixture of hydroxylamine (17 mg, 0.244 mmol, 2.00 eq, HC1) in pyridine

(5.00 mL) was added A17-2 (80 mg, 0.122 mmol, 1.00 eq) in one portion. The mixture was stirred at 40 °C for 2 h. LCMS showed A17-2 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (basic condition). LCMS and ¾ NMR confirmed the white solid was Compound 17 (10.77 mg, 16.1 umol, 13.2% yield, and 100% purity). LCMS (ESI): RT = 0.881min, mass calcd. For C₃₃H₃₈FN₃O₇S₂, 671.21 m/z found 671.9 [M+H]⁺. ¾ NMR (400 MHz, DMSO-i/₆) δ 13.42 (br. s, 1H), 8.77 - 8.69 (m, 1H), 8.42 - 8.31 (m, 2H), 8.14 - 7.93 (m, 3H), 6.87 (d, J = 13.2 Hz, 1H), 6.70 (d, J = 9.2 Hz, 1H), 3.76 (s, 3H), 3.63 (s, 3H), 3.28 - 3.21 (m, 1H) 3.20 - 3.09 (m, 8H), 1.78 - 1.69 (m, 2H), 1.57 - 1.39 (m, 4H), 1.24 - 1.14 (m, 2H), 0.89 - 0.75 (m, 6H). Example 18A: 2-((4-(2-chloro-4-fluorophenyl)piperazin-l-yl)sulfonyl)-7-((4,4- dimethylcyclohexyl)sulfonyl)-9H-fluoren-9-one oxime (Compound 18)

Preparation of Compound 18:

Step 1 : tert-butyl 4-(2-chloro-4-fluorophenyl)piperazine-l-carboxylate

[00342] To the solution of A18-1 (200 mg, 1 mmol, 1.0 eq), Pd₂(dba)₃ (44 mg, 48 umol,

0.05 eq), BINAP (60 mg, 0. 1 mmol, 0. 1 eq), f-BuONa (184 mg, 1.9 mmol, 2.0 eq) in toluene (5 mL) was added fert-butyl piperazine- l-carboxylate (267 mg, 1.4 mmol, 1.5 eq). The mixture was stirred at 1 10 °C for 16 hr. The reaction was monitored by TLC. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=20: 1) to give the A18-2 (187 mg, 0.6 mmol, 62.2% yield) as a yellow oil. Step 2: l-(2-chloro-4-fluorophenyl)piperazine

[00343] The solution of A18-2 (187 mg, 0.6 mmol, 1.0 eq) in HCl/EtOAc (5 mL, 4

M) was stirred at 15°C for 0.5 hr. The reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure to give the A18-1A (108 mg, 0.4 mmol, 72.4% yield, HC1) as a brown solid.

Step 3: 2-((4-(2-chloro-4-fluorophenyl)piperazin-l-yl)sulfonyl)-7-((4,4- dimethylcyclohexyl)sulfonyl)-9H-fluoren-9-one

[00344] To the solution of A18-1A (21 mg, 0.08 mmol, 1.5 eq, HC1) in DCM (3 mL) was added TEA (17 mg, 0. 165 mmol, 0.023 mL, 3.0 eq). The mixture was stirred at 15°C for 5 min. Then A18-3 (25 mg, 0.056 mmol, 1.0 eq) was added to the mixture. The mixture was stirred at 15°C for 25 min. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give the A18-4 (52 mg, crude) as a red solid.

Step 4: 2-((4-(2-chloro-4-fluorophenyl)piperazin-l-yl)sulfonyl)-7-((4,4- dimethylcyclohexyl)sulfonyl)-9H-fluoren-9-one oxime

[00345] To the solution of A18-4 (52 mg, 0.082 mmol, 1.0 eq) in pyridine (3 mL) was added hydroxylamine (11 mg, 0.2 mmol, 2.0 eq, HC1). The mixture was allowed to stir at 60°C for 1 hr. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Mobile phase A : water (lOmM NH₄HC0₃)-ACN; Mobile phase B : MeCN; column temperature: 30 °C Gradient: 57-87% B 2.5 min) to give Compound 18 (2.07 mg, 3.1 umol, 3.7% yield, 95.4% purity) as a light yellow solid. LCMS (ESI): RT = 2.596 min, mass calcd. for C₃₁H₃₃CIFN₃O₅S₂ 645.15, m/z found 646.0 [M+H]⁺, ¾ NMR (400MHz, CHLOROFORM-d) δ 8.93 - 8.82 (m, 1H), 8.50 (d, J = 12.3 Hz, 1H), 8.34 - 8.21 (m, 1H), 8.09 - 7.93 (m, 3H), 7.13 - 7.07 (m, 1H), 7.03 - 6.95 (m, 2H), 3.28 (m, 1H), 3.09 (m, 1H), 2.96 - 2.86 (m, 1H), 1.95 - 1.89 (m, 2H), 1.80 - 1.50 (m, 2H), 1.32 - 1.11 (m, 3H), 0.91 - 0.87 (m, 6H).

Example A19: 2-((4-(2,5-Difluorophenyl)piperazin-l-yl)sulfonyl)-7-((4,4- dimethylcyclohexyl)sul 9)

Preparation of Compound 19:

Step 1 : tert-Butyi 4-(2,5-difluorophenyl)piperazine-l-carboxylate

[00346] To a solution of A19-1 (500 mg, 2.59 mmol, 1.0 eq), A19-1A (579 mg, 3.11 mmol, 1.2 eq), BINAP (161 mg, 0.259 mmol, 0.1 eq), f-BuONa (498 mg, 5. 18 mmol, 2.0 eq) and Pdi(dba)3 (119 mg, 0.130 mmol, 0.05 eq) in toluene (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with DCM (30 mL * 3). The combined organic layers were dried over NaiSOzt, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether: ethyl acetate = 1 : 0 to 10: 1) to afford the title compound (400 mg, 52% yield) as a yellow solid. ¾ NMR (400MHz, COC -d) δ 7.01 - 6.90 (m, 1H), 6.66 - 6.56 (m, 2H), 3.65 - 3.53 (m, 4H), 3.07 - 2.93 (m, 4H), 1.48 (s, 9H).

Step 2: l-(2,5-Difluorophenyl)piperazine hydrochloride

[00347] To a solution of A19-2 (400 mg, 1.34 mmol, 1.0 eq) in HCl-MeOH (5 mL, 4M) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound A19-3 (300 mg, 95% yield) as a yellow solid.

Step 3: 2-((4-(2,5-Difluorophenyl)piperazin-l-yl)sulfonyl)-7-((4,4- dimethylcyclohexyl)sulfonyl)-9H-fluoren-9-one

[00348] A19-3 (15.5 mg, 66.2 umol, 1.0 eq, HC1) and TEA (20 mg, 0.20 mmol, 3.0 eq) in DCM (5 mL) was added A19-4 (30 mg, 66.2 umol, 1.0 e ). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (38 mg, crude) as a red solid. LCMS (ESI): RT = 0.909 min, mass calcd. for C₃₁H₃₂F₂N₂O₅S₂ 614.17, m/z found 615.0 [M+H]⁺.

Step 4: 2-((4-(2,5-Difluorophenyl)piperazin-l-yl)sulfonyl)-7-((4,4- dimethylcyclohexyl)sulfonyl)-9H-fluoren-9-one oxime

[00349] To a solution of A19-5 (38 mg, 62 umol, 1.00 eq) and hydroxylamine (8.6 mg,

0.124 mmol, 2.00 eq, HQ) in pyridine (5 mL) was stirred at 30 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography over Phenomenex Synergi C 18 250*21.2mm*4um (eluent: water (0.05% ammonia hydroxide) - 74/84, v/v). The pure fractions were collected and the volatiles were removed under vacuum. The residue was re-suspended in water (6 mL) and the resulting mixture was lyophilized to dryness to remove the solvent residue completely. The title compound (9.65 mg, 24% yield) was obtained as a white solid. LCMS (ESI): RT = 1.997 min, mass calcd. for C3₁H33F₂N3O5S₂ 629.18, m/z found 630. 1 [M+H]⁺, ¾ NMR (400MHz, DMSO- d₆) 813.35 (br. s., 1H), 8.76 - 8.67 (m, 1H), 8.38 - 8.28 (m, 2H), 8. 12 - 8.04 (m, 1H), 8.02 - 7.89 (m, 2H), 7. 15 - 7.06 (m, 1H), 6.90 - 6.81 (m, 1H), 6.78 - 6.70 (m, 1H), 3.23 - 3. 17 (m, 1H), 3.20 - 2.90 (m, 8H), 1.80 - 1.60 (m, 2H), 1.60 - 1.40 (m, 2H), 1.40-1.25 (m, 2H), 1.21 - 1.12 (m, 2H), 0.83 (s, 3H), 0.77 (s, 3H).

Example A20: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4- [4-fluoro-2- (trifluoromethyl)phenyl]piperazin-l-yl]sulfonyl-fluoren-9-one (Compound 20)

Preparation of Compound 20:

Step 1 : tert-butyl 4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine-l-carboxylate

[00350] To a solution of A20-2 (200 mg, 1.07 mmol, 1 eq) , A20-1 (260 mg, 1.07 mmol,

1.00 eq) and f-BuONa (206 mg, 2.14 mmol, 2 eq) in toluene (5 mL) was added BINAP (53 mg, 0.09 mmol, 0.08 eq) and Pdi(dba (39 mg, 0.04 mmol, 0.04 eq). The resulted mixture was stirred at 100°C under N₂ for 16 hr. LCMS and TLC (Petroleum ether: Ethyl acetate=10/l) showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated. The residue crude product was dissolved with CH₂CI₂ (15 ml) and washed with water (2 15 mL). After drying over anhydrous Na₂SC , the solvent was removed under reduced pressure to afford the crude product. The crude product was purified by column chromatography over silica gel eluted with petroleum ether/ethyl acetate=l/0 to 10/1 to give A20-3 (310 mg, 0.89 mmol, 83% yield) as light yellow oil. ¾ NMR (400 MHz,

CHLOROFORM-i δ 7.40 - 7.25 (m, 2H), 7.25 - 7.20 (m, lH), 3.60 - 3.45 (m, 4H), 2.82 (t, J = 4.4 Hz, 4H), 1.49 (s, 9H).

Step 2: l-[4-fluoro-2-(trifluoromethyl)phenyl] piper azine

[00351] A20-3 (310 mg, 0.9 mmol, 1 eq) was dissolved HCl/MeOH (5 mL) and the reaction mixture was stirred at 15°C for 2 hr. LCMS showed 93.8% desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give the crude product. The residue was directly used without further purification. A20-4 (230 mg, 0.8 mmol, 85% yield, 93.8% purity, HC1) was obtained as yellow solid. LCMS (ESI): RT = 0.591 min, mass calc. for C₁₁H₁₂F₄N₂ 248.09, m/z found 249.0 [M+H]⁺.

Step 3: 2-(4,4-dimethylcyclohexyl)sulfonyl-7-[4-[4-fluoro-2- (trifluoromethyl)phenyl]piperazin-l-yl]sulfonyl-fluoren-9-one

[00352] To a solution of A20-4 (28 mg, 0.10 mmol, 1.5 eq, HC1) and TEA (27 mg, 0.27 mmol, 4 eq) in DCM (3 mL) was added A20-5 (30 mg, 0.07 mmol, 1 eq). The resulted mixture was stirred at 25°C for 2 hr. LCMS showed the starting material was consumed completely. The reaction mixture was concentrated to give the A20-6 (40 mg, crude) as brown solid. The residue was directly used without further purification.

Step 4: 2-(4,4-dimethylcyclohexyl)sulfonyl-7-[4-[4-fluoro-2-

(trifluoromethyl)phenyl]piperazin-l-yl]sulfonyl-fluoren-9-one

[00353] A mixture of A20-6 (40 mg, 0.06 mmol, 1 eq) and NH₂OH.HCl (21 mg, 0.30 mmol, 5 eq) in pyridine (2 mL) was stirred at 50°C for 1 h. LCMS showed 58% desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep- HPLC (Condition: water (0.05% ammonia hydroxide v/v)-ACN. Column: Phenomenex Gemini 150*25mm* 10um.). Compound 20 (18 mg, 0.03 mmol, 44% yield) was obtained as light yellow solid. LCMS (ESI): RT = 0.925 min, mass calc. for C₃₂H₃₃F₄N₃O₅S₂ 679.18, m/z found 679.6 [M+H]⁺; ¾ NMR (400 MHz, DMSO- d₆) δ 8.78 (s, 0.5H), 8.72 (s, 0.5H), 8.44 - 8.33 (m, 2H), 8.16 - 8.12 (m, 0.5H), 8.12 - 8.08 (m, 0.5H), 8.06 - 7.99 (m, 1.5H), 7.97 - 7.92 (m, 0.5H), 7.76 - 7.70 (m, 1H), 7.53 (s, 2H), 3.61 (t, J= 6.65 Hz, 2H), 3.02 - 3.14 (m, 3H), 2.95 (br. s., 4H), 1.77 (s, 2H), 1.48 - 1.60 (m, 2H), 1.39 - 1.47 (m, 2H), 1.13 - 1.26 (m, 2H), 0.90-0.80 (m, 6H).

Example A21 : 2-[4-(2,5-difluoro-4-methoxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sul

Preparation of Compound 21 :

Step 1 : tert-butyl 4-(2,5-difluoro-4-methoxy-phenyl)piperazine-l-carboxylate

[00354] To a solution of A21-3A (187.9 mg, 1.01 mmol, 1.50 eq), BINAP (83.8 mg,

0.13mmol, 0.20 eq), f-BuONa (129.3 mg, 1.35 mmol, 2.00 eq) in toluene (5 mL) was added A21- 3 (150.0 mg, 672.6 umol, 1.00 eq) and Pdi(dba)3 (61.6 mg, 67.3 umol, 0.10 eq) . The reaction mixture was stirred at 100°C for 16 hrs. The reaction mixture was monitored by LCMS. LCMS showed that the desired product was detected. TLC (Si0₂, PE/EA=3/1) showed that the A21-3 was consumed completely and a new spot was formed. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography (S1O₂, Petroleum ether/Ethyl acetate = 1 :0 to 20: 1) to give A21-4 (376.5 mg, crude) as light yellow solid.

Step 2: l-(2,5-difluoro-4-methoxy-phenyl)piperazine

[00355] To a solution of A21-4 (220.8 mg, 0.67 umol, 1.00 eq) in EtOAc (5 mL) was added HCl/EtOAc (20.0 mmol, 9 mL, 29.74 eq). The reaction mixture was stirred at 25°C for 2 hrs. The reaction was monitored by LCMS. LCMS showed that the A21-4 was consumed completely and the desired product was detected. The reaction mixture was evaporated under reduced pressure to give A21-1A (350.3 mg, crude, HC1) as a bright red solid, which was used to next step without purification.

Step 3: 2- [4-(2,5-difluoro-4-methoxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one

[00356] To a solution of A21-1A (26.3 mg, 99.4 umol, 1.50 eq, HC1) in DCM (5 mL) was added TEA (26.8 mg, 0.26 mmol, 36.7 uL, 4.00 eq) and A21-1 (30.0 mg, 66.2 umol, 1.00 eq). The reaction mixture was stirred at 25°C for 1 hr. The reaction was monitored by LCMS. LCMS showed that the desired product was detected. The reaction mixture was evaporated under reduced pressure to give A21-2 (102.7 mg, crude) as black brown solid, which was used to next step without purification.

Step 4: 2- [4-(2,5-difluoro-4-methoxy-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime [00357] To a solution of A21-2 (42.7 mg, 66.2 umol, 1.00 eq) in pyridine (5 mL) was added NH₂OH.HCl (9.2 mg, 0. 13 umol, 2.00 eq). The reaction mixture was stirred at 25°C for 16 hrs. The reaction was monitored by LCMS. LCMS showed that the A21-2 was consumed completely and the desired product was detected. The reaction mixture was evaporated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C 18 150*30 5u;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN] ;B%: 65%- 95%, 10min) to give Compound 21 (6.07 mg, 9.2 umol, 13.9% yield, 100% purity) as light pink solid. LCMS (ESI): RT = 1.689 min, mass calcd. for C₃₂H₃₅F₂N₃O₆S₂ 659. 19, m/z found 660.1 [M+H]⁺. ¾ NMR (400 MHz, DMSO-i¾ 58.76 - 8.69 (m, lH), 8.41 - 8.32 (m, 2H), 8.13 - 8.06 (m, 1H), 8.04 - 7.97 (m, 2H), 7.95-7.85 (m, 1H), 7.12-7.03 (m, 1H), 7.02-6.90 (m, 1H), 3.75 (s, 3H), 3. 15-3.05 (m, 4H), 3.04-2.90 (m, 4H), 1.80 - 1.65 (m, 2H), 1.58 - 1.49 (m, 2H), 1.45- 1.35 (m, 2H), 1.26 - 1. 13 (m, 3H), 0.85 (s, 3H), 0.80 (s, 3H).

Example A22: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(2,4-dimethylphenyl)piperazin-l- yl]

Pr

Step 1 : tert-butyl 4-(2,4-dimethylphenyl)piperazine-l-carboxylate

[00358] To a mixture of A22-4 (397 mg, 2. 13 mmol, 1. 10 eq) and A22-3 (449 mg, 1.94 mmol, 1.00 eq) in toluene (15 mL) was added Pdi(dba)3 (89 mg, 97 umol, 0.05 eq) and f-BuONa (373 mg, 3.88 mmol, 2.00 eq) and X-phos (92 mg, 0.194 mmol, 0. 10 eq) in one portion under N₂.The mixture was stirred atl lO °C and stirred for 16 h. LCMS showed one peak with desired MS was detected. TLC indicated the compound A22-3 was consumed completely. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried with anhydrous NaiSO/_t, filtered and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 25/1 to 5: 1) to give A22-5 (340 mg, 1.11 mmol, 57.3% yield, 95% purity) as the light yellow oil. LCMS (ESI): RT = 0.966 min, mass calcd. For C17H26N2O2, 290.20 m/z found 290.9 [M+H]⁺ and 234.9 [M+H-56]⁺ and 191.0 [M+H-100]⁺.

Step 2: l-(2,4-dimethylphenyl)piperazine

[00359] To a mixture of A22-5 (340 mg, 1.11 mmol, 1.00 eq) in HCl/EtOAc (4 M, 4 mL,

14.49 eq) was stirred at 10°C for 30 min. TLC indicated the A22-5 was consumed completely. The reaction mixture was concentrated under reduced pressure to give A22-1A (300 mg, crude, 2HC1) as a white solid.

Step 3: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(2,4-dimethylphenyl)piperazin-l- yl] sulf onyl-fluoren-9-one

[00360] To a solution of A22-1A (21 mg, 80 umol, 1.45 eq, 2HC1) in DCM (6 mL) was added Et₃N (28 mg, 0.276 mmol, 38 uL, 5.00 eq). The reaction mixture was added A22-1 (25 mg, 55 umol, 1.00 eq) and stirred at 10 °C for 2 h. LCMS showed the A22-1 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give A22-2 (75 mg, crude) as a yellow solid, which was used next step without further purification.

Step 4: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(2,4-dimethylphenyl)piperazin-l- yl]sulfonyl-fluoren-9-one oxime

[00361] To a solution of NH₂OH.HCl (34 mg, 0.494 mmol, 4.00 eq) in pyridine (5 mL) was added A22-2 (75 mg, 0.124 mmol, 1.00 eq).T e reaction mixture was stirred at 40 °C for 2 h. LCMS showed the A22-2 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by Prep-HPLC (basic condition). LCMS and ¾ NMR confirmed the light yellow solid was Compound 22 (5.56 mg, 8.9 umol, 7.2% yield, and 100% purity). LCMS (ESI): RT = 1.075 min, mass calcd. For C₃₃H₃₉N₃O₅S₂, 621.23 m/z found 622.1[M+H]⁺. ¾ NMR (400 MHz, CHLOROFORM- ) δ 9.69 (br. s., 0.5H), 9.52 (br. s., 0.5H), 8.90 - 8.76 (m, 1H), 8.31 - 8.18 (m, 1H), 8.05 - 7.86 (m, 3H), 7.06 - 6.85 (m, 3H), 3.50 - 3.20 (m, 4H), 3.10 - 2.80 (m, 5H), 2.26 (s, 3H), 2.14 (s, 3H), 2.00 - 1.80 (m, 2H), 1.80 - 1.60 (m, 2H), 1.60 - 1.40 (m, 2H), 1.30 - 1.10 (m, 2H), 1.00 - 0.80 (m, 6H). Example A23: 2-[4-(2-bromo-4-fluoro-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfo

P

Step 1 : tert-butyl 4-(2-bromo-4-fluoro-phenyl)piperazine-l-carboxylate

[00362] A mixture of A23-1C (200 mg, 0.66 mmol, 1.0 eq), tert-butyl piperazine- 1- carboxylate (148.6 mg, 0.8 mmol, 1.2 eq), Pd₂(dba)₃ (60.9 mg, 66.5 umol, 0.1 eq), BINAP (82.8 mg, 0. 13 mmol, 0.2 eq) and f-BuONa (95.8 mg, 1 mmol, 1.5 eq) in toluene (5 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hour under N₂ atmosphere, to give a black solution. TLC showed A23-1C was consumed completely and one main new spot was detected. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate= 1 :0-8: 1) to give A23-1B (40 mg, 1 1 1.3 umol, 16.7% yield) as a yellow gum. ¾ NMR (400 MHz, CDC1₃) δ 7.36 - 7.32 (m, 1H), 7.01 - 6.99 (m, 2H), 3.70-3.50 (m 4H), 2.92 (t, J = 4.8 Hz, 4H), 1.49 (s, 9H). Step 2: l-(2-bromo-4-fluoro-phenyl)piperazine

[00363] To a solution of A23-1B (40 mg, 0. 1 1 mmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (3.0 mL) .The mixture was stirred at 5- 15 °C for 3 hour to give a brown suspension. LCMS showed A23-1B was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated to give A23-1A (40 mg, crude, HC1) as a brown solid, which was used in next step directly without further purification. LCMS (ESI): RT = 0.961 min, mass calc. for Ci₀Hi₂BrFN₂ 258.02, m/z found 258.7 [M+H]⁺. Step 3: 2-[4-(2-bromo-4-fluoro-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one

[00364] To a solution of A23-1A (30 mg, 0.12 mmol, 1.7 eq) and TEA ( 13.4 mg, 0.13 mmol, 18.4 uL, 2.0 eq) in DCM (3 mL) was added A23-1 (30.0 mg, 66.2 umol, 1.0 eq) at 0°C. The mixture was stirred at 0- 15 °C for 1 hr to give a brown solution. LCMS showed A23-1 was consumed completely and no desired MS was detected. The residue was concentrated to give A23-2 (40.0 mg, crude) as a black brown solid, which was used in next step directly without further purification.

Step 4: 2-[4-(2-bromo-4-fluoro-phenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime

[00365] To a solution of A23-2 (40.0 mg, 59.2 umol, 1.0 eq) in pyridine (2 mL) was added

NH₂OH.HCl (16.5 mg, 0.24 mmol, 4.0 eq). The mixture was stirred at 5- 15°C for 16 hour. LCMS showed A23-2 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated to give a residue. The residue was purified by Prep-HPLC (basic) to give compound Compound 23 (11.18 mg, 16.2 umol, 27.3% yield) as a light yellow solid. LCMS (ESI): RT = 2.661 min, mass calc. for C₃iH₃₃BrFN₃05S2 689. 10, m/z found 690.0 and 692.0 [M+H]⁺; ¾ NMR (400 MHz, DMSO-i¾) δ8.77 (s, 0.5H), 8.72 (s, 0.5H), 8.41 - 8.34 (m, 2H), 8. 14 - 7.96 (m, 3H), 7.52 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 6.0 Hz, 2H), 3.40-3. 10(m, 5H), 3.10-2.90 (m, 4H), 1.76- 1.72 (m, 2H), 1.57- 1.41 (m, 4H), 1.23- 1.16 (m, 2H), 0.85 (s, 3H), 0.80 (s, 3H).

Example A24: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(2,3,4-trifluorophenyl)piperazin-l- yl]sulfonyl-fluoren-9-one

Preparation of Compound 24:

Step 1 : tert-butyl 4-(2,3,4-trifluorophenyl)piperazine-l-carboxylate

[00366] A mixture of A24-1C (200 mg, 0.95 mmol, 1 12.4 uL, 1.0 eq), A24-1D (21 1.9 mg,

1.1 mmol, 1.2 eq), Pd₂(dba)₃ (86.8 mg, 94.8 umol, 0.1 eq), BINAP (118. 1 mg, 0. 19 mmol, 0.2 eq) and f-BuONa (136.7 mg, 1.4 mmol, 1.5 eq) in toluene (5 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100 °C for 16 hour under N₂ atmosphere. TLC showed Reactant A24-1C was consumed completely and one main new spot was detected. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate= 1 :0-8: 1) to give compound A24-1B (250 mg, 790.3 umol, 83.4% yield) as a yellow oil. ¾ NMR (400 MHz, CDC1₃) δ 6.82 - 6.79 (m, 1H), 6.57 - 6.53 (m, 1H), 3.52 (t, J = 4.8 Hz, 4H), 2.91 (t, J = 4.8 Hz, 4H), 1.41 (s, 9H).

Step 2: l-(2,3,4-trifluorophenyl)piperazine

[00367] To a solution of A24-1B (250 mg, 0.79 mmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (3 mL, 4M). The mixture was stirred at 5- 15 °C for 4 hour to give a yellow suspension. LCMS showed starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated to give compound (200 mg, crude, HC1) as a brown solid, which was used in next step directly without further purification. LCMS (ESI): RT = 0.855 min, mass calc. for CioH„F₃N₂ 216.09, m/z found 216.8 [M+H]⁺. Step 3: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(2,3,4-trifluorophenyl)piperazin-l- yl] sulf onyl-fluoren-9-one

[00368] To a solution of A24-1A (30 mg, 0. 14 mmol, 2. 1 eq) and TEA (13.4 mg, 0.13 mmol, 18.4 uL, 2.0 eq) in DCM (3 mL) was added A24-1 (30.0 mg, 66.2 umol, 1.0 eq) at 0°C. The mixture was stirred at 0- 15 °C for 1 hr to give a brown solution. LCMS showed A24-1 was consumed completely. The reaction was concentrated to give compound (40 mg, crude) as a black brown solid, which was used in next step directly without further purification.

Step 4: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(2,3,4-trifluorophenyl)piperazin-l- yl]sulfonyl-fluoren-9-one oxime [00369] To a solution of A24-2 (40 mg, 63.2 umol, 1.0 eq) in pyridine (2.0 mL) was added

NH₂OH.HCl (17.6 mg, 0.25 mmol, 4.0 eq). The mixture was stirred at 5- 15 °C for 16 hour. LCMS showed A24-2 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (basic) to give the title compound (3.93 mg, 6. 1 umol, 9.6% yield) as a light yellow solid. LCMS (ESI): RT = 2.531 min, mass calc. for C₃₁H₃₂F₃N₃O₅S₂ 647. 17, m/z found 648. 1 [M+H]⁺; ¾ NMR (400 MHz, DMSO-i¾ δ 8.76 (s, 0.5H), 8.70 (s, 0.5H), 8.38 - 8.32 (m, 2H), 8.12 - 7.98 (m, 3H), 7.22 - 7. 17 (m, 1H), 6.90 - 6.75 (m, 1H), 3.25-2.95 (m, 9H), 1.73- 1.70 (m, 2H) 1.54- 1.38 (m, 4H), 1.21- 1. 14 (m, 2H), 0.83 (s, 3H), 0.77 (s, 3H).

Example A25: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-(2,4,6-trifluorophenyl)piperazin- l-yl)sulfonyl)-9H-fluoren-9-one oxime (Compound 25)

Preparation of Compound 25:

Step 1 : tert-butyl 4-(2,4,6-trifluorophenyl)piperazine-l-carboxylate

[00370] To the solution of A25-1 (200.0 mg, 0.95 mmol, 111.73 uL, 1.00 eq), fert-butyl piperazine- l-carboxylate (264.8 mg, 1.42 mmol, 1.50 eq), Pd₂(dba)₃ (43.4 mg, 0.047 mmol, 0.05 eq), BINAP (59.0 mg, 0.095 mmol, 0. 10 eq) in toluene (10 mL) was added f-BuONa (364.4 mg, 3.79 mmol, 4.00 eq). The mixture was allowed to stir at 110 °C for 16 hr. The reaction was monitored by LCMS. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=20: l) to give the A25- 2 (170.00 mg, 0.54 mmol, 56.7% yield) as a yellow solid.

Step 2: l-(2,4,6-trifluorophenyl)piperazine

[00371] To the solution of A25-2 (170.0 mg, 0.54 mmol, 1.00 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 0.135 mL, 1.00 eq). The mixture was allowed to stir at 15 °C for 2 hr. The reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure to give the product A25-1A (147.00 mg, crude, HC1) as an off-white solid.

Step 3: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-(2,4,6-trifluorophenyl)piperazin-l- yl)sulfonyl)-9H-fluoren-9-one

[00372] To the solution of A25-1A (29.3 mg, 0.12 mmol, 1.50 eq, HC1) in DCM (3.0 mL) was added TEA (23.5 mg, 0.23 mmol, 0.03 mL, 3.00 eq). The mixture was allowed to stir at 15 °C for 10 min. Then A25-3 (35.0 mg, 0.077 mmol, 1.00 eq) was added to the mixture. The solution was stirred at 15 °C for 50 min. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give the A25-4 (86.0 mg, crude) as a red solid.

Step 4: 2-((4,4-dimethylcyclohexyl)sulfonyl)-7-((4-(2,4,6-trifluorophenyl)piperazin-l- yl)sulfonyl)-9H-fluoren-9-one oxime

[00373] To the solution of A25-4 (86.0 mg, 0.13 mmol, 1.00 eq) in pyridine (5 mL) was added hydroxylamine (18.9 mg, 0.27 mmol, 2.00 eq, HQ). The mixture was allowed to stir at 60 °C for 0.5 hr. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Mobile phase A : water with 0.05% ammonia solution; Mobile phase B : MeCN; column temperature: 30 °C Gradient : 61- 91% B 10 min) to give Compound 25 (6.4 mg, 9.9 umol, 7.3% yield, 100% purity) as a light yellow solid. LCMS (ESI): RT = 0.937 min, mass calcd. for C31H32F3N3O5S2 647. 17, m/z found 648.0 [M+H]⁺, ¾ NMR (400MHz, DMSO-i/₆) δ 8.77 - 8.65 (m, 1H), 8.50-8.30 (m, 2H), 8.13 - 7.88 (m, 3H), 7.11 (t, J = 9.2 Hz, 2H), 3.15 - 3.00 (m, 8H), 2.58 (m, 1H), 1.74 - 1.71 (m, 2H), 1.57 - 1.37 (m, 4H), 1.21 - 1.12 (m, 2H), 0.86 - 0.76 (m, 6H).

Example A26: 2-(4-((7-((4,4-dimethylcyclohexyl)sulfonyl)-9-(hydroxyimino)-9H-fluoren-2- yl)sulfonyl)piperazin-l-yl)benzonitrile (Compound 26)

Preparation of Compound 26:

Step 1 : tert-butyl 4-(2-cyanophenyl)piperazine-l-carboxylate

[00374] To the solution of A26-1 (500.00 mg, 2.75 mmol, 1.00 eq), Pd₂(dba)₃ (125.91 mg,

0.14 mmol, 0.05 eq), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (131. 10 mg, 0.28 mmol, 0. 10 eq), f-BuONa (1.06 g, 11.00 mmol, 4.00 eq) in toluene (5 mL) was added tert- butyl piperazine- l-carboxylate (768 mg, 4. 13 mmol, 1.50 eq). The mixture was stirred at 110°C for 16 hr. The reaction was monitored by TLC. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=6: 1) to give the A26-2 (420.00 mg, 1.46 mmol, 53.15% yield) as a yellow oil.

Step 2: 2-(piperazin-l-yl)benzonitrile

[00375] To the solution of HCl/dioxane (4 M, 4 mL, 10.96 eq) was added A26-2 (420.00 mg, 1.46 mmol, 1.00 eq). The mixture was allowed to stir at 15°C for 0.5 hr. The reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure to give the A26-1A (269.00 mg, 1.20 mmol, 82.36% yield, HCI) as a yellow solid.

Step 3: 2-(4-((7-((4,4-dimethylcyclohexyl)sulfonyl)-9-oxo-9H-fluoren-2- yl)sulfonyl)piperazin-l-yl)benzonitrile

[00376] To the solution of A26-1A (34.57 mg, 0. 15 mmol, 0.03 mL, 2.00 eq, HCI) in

DCM (3 mL) was added TEA (39.09 mg, 0.38 mmol, 0.054 mL, 5.00 eq). The mixture was allowed to stir at 15 °C for 5 min. Then A26-3 (35.00 mg, 0.077 mmol, 1.00 eq) was added to the solution. The mixture was allowed to stir at 15°C for 30 min. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give the A26-4 (179.00 mg, crude) as a yellow solid.

Step 4: 2-(4-((7-((4,4-dimethylcyclohexyl)sulfonyl)-9-(hydroxyimino)-9H-fluoren-2- yl)sulfonyl)piperazin-l-yl)benzonitrile

[00377] To the solution of A26-4 (179.00 mg, 0.296 mmol, 1.00 eq) in pyridine (5 mL) was added hydroxylamine (41.20 mg, 0.593 mmol, 2.00 eq, HCI). The mixture was allowed to stir at 60 °C for 1 hr. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Mobile phase A : water with 0.05% ammonia solution; Mobile phase B : MeCN; column temperature: 30 °C Gradient: 58-88% B 10 min) to give Compound 26 (7.44 mg, 11.46 umol, 3.86% yield, 95.3% purity) as a light yellow solid. LCMS (ESI): RT = 2.287 min, mass calcd. for C₃₂H₃₄N₄O₅S₂ 618.20, m/z found 619.1 [M+H]⁺, ¾ NMR (400MHz, DMSO-i/₆) δ 8.76 - 8.68 (m, 1H), 8.40- 8.25 (m, 2H), 8.12 - 7.90 (m, 3H), 7.67 (d, J= 8.0 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 3.40 - 3.30 (m, 1H), 3.30 - 3.05 (m, 8H), 1.74 - 1.70 (m, 2H), 1.57 - 1.35 (m, 4H), 1.24 - 1.12 (m, 2H), 0.87 - 0.74 (m, 6H).

Example A27: 2-((4-(2,4-difluorophenyl)piperazin-l-yl)sulfonyl)-7-((4,4- dimethylcyclohexyl)sulfonyl)-9H-fluoren-9-one oxime (Compound 27)

Preparation of Compound 27:

Step 1 : terf-butyl 4-(2,4-difluorophenyl)piperazine-l-carboxylate

[00378] To the solution of A27-1 (500.00 mg, 2.59 mmol, 0.29 mL, 1.00 eq) , Pd₂(dba)₃

(118.59 mg, 0.13 mmol, 0.05 eq), Xphos (123.47 mg, 0.26 mmol, 0.10 eq), f-BuONa (995.60 mg, 10.36 mmol, 4.00 eq) in toluene (5 mL) was added iert-butyl piperazine- l-carboxylate (723.58 mg, 3.89 mmol, 1.50 eq). The mixture was allowed to stir at 110°C for 16 hr. The reaction was monitored by TLC. The reaction was concentrated under reduced pressure. The residue was purified byPrep-HPLC (Mobile phase A : water with 0.05% ammonia solution; Mobile phase B : MeCN; column temperature: 30 °C Gradient: 65-95% B 10 min) to give the A27-2 (195.00 mg, 653.64 umol, 25.24% yield) as a light yellow solid. Step 2: l-(2,4-difluorophenyl)piperazine

[00379] The solution of A27-2 (195.00 mg, 653.64 umol, 1.00 eq) in HCl/dioxane (4 M,

6.00 mL) was allowed to stir at 15 °C for 0.5 hr. The reaction was monitored by TLC. The reaction solution was concentrated under reduced pressure to give the A27-1A (176.00 mg, crude, HC1) as a yellow solid.

Step 3: 2-((4-(2,4-difluorophenyl)piperazin-l-yl)sulfonyl)-7-((4,4- dimethylcyclohexyl)sulfonyl)-9H-fluoren-9-one

[00380] To the solution of A27-1A (27.20 mg, 0.12 mmol, 1.50 eq, HC1) in DCM (3 mL) was added TEA (23.46 mg, 0.23 mmol, 0.03 mL, 3.00 eq). The mixture was allowed to stir at 15°C for 5 min. Then A27-3 (35.00 mg, 0.078 mmol, 1.00 eq) was added to the mixture. The mixture was stirred at 15°C for another 55 min. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give the A27-4 (97.00 mg, crude) as a red solid.

Step 4: 2-((4-(2,4-difluorophenyl)piperazin-l-yl)sulfonyl)-7-((4,4- dimethylcyclohexyl)sulfonyl)-9H-fluoren-9-one oxime

[00381] To the solution of A27-4 (97.00 mg, 0.16 mmol, 1.00 eq) in pyridine (3 mL) was added hydroxylamine (21.93 mg, 0.32 mmol, 2.00 eq, HC1). The mixture was allowed to stir at 60°C for 0.5 hr. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Mobile phase A : water with 0.05% ammonia solution; Mobile phase B : MeCN; column temperature: 30 °C Gradient: 60- 90% B 10 min) to give Compound 27 (3.96 mg, 6.14 umol, 3.89% yield, 97.57% purity) as a light yellow solid. LCMS (ESI): RT = 2.482 min, mass calcd. for C₃₁H₃₃F₂N₃O₅S₂ 629.18, m/z found 630.1 [M+H]⁺, ¾ NMR (400MHz, DMSO-i/₆) δ 8.76 - 8.65 (m, 1H), 8.39 - 8.27 (m, 2H), 8.13 - 7.86 (m, 3H), 7.20 - 7.10 (m, 1H), 7.09 - 6.92 (m, 1H), 3.23 - 3.19 (m, 1H), 3.15 - 2.96 (m, 8H), 1.80-1.60 (m, 2H), 1.53 - 1.37 (m, 3H), 1.24 - 1.10 (m, 3H), 0.85 - 0.76 (m, 6H).

Example A28: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluoro-2-methoxy- phenyl)piperazin-l-yl]sul

Preparation of Compound 28:

Step 1 : tert-butyl 4-(4-fluoro-2-methoxy-phenyl)piperazine-l-carboxylate

[00382] To a solution of A28-3 (200.00 mg, 0.98 mmol, 1.00 eq), tert-butyl piperazine- 1- carboxylate (908.45 mg, 4.88 mmol, 5.00 eq), BINAP (121.48 mg, 0. 195 mmol, 0.20 eq), Pd₂(dba)₃ (89.33 mg, 0.098 mmol, 0. 10 eq) in toluene (20 mL) was added f-BuONa (140.62 mg, 1.46 mmol, 1.50 eq) . The reaction mixture was stirred at 100°C for 20hrs. TLC (S1O₂,

PE/EA=3 : 1) showed that the A28-3 was consumed completely and a new spot was formed. The reaction mixture was evaporated under reduced pressure, a residue was formed. The residue was purified by column chromatography (S1O₂, Petroleum ether/Ethyl acetate = 0 to 15 : 1) to give A28-4 (310.50 mg, 0.9 mmol, 94.49% yield, 92. 13% purity) as a light yellow oil.

Step 2: l-(4-fluoro-2-methoxy-phenyl)piperazine

[00383] To a solution of A28-4 (310.50 mg, 1.00 mmol, 1.00 eq) in MeOH (4 mL) was added HCl/MeOH (16.00 mmol, 9 mL, 16.00 eq). The reaction mixture was stirred at 25°C for 3 hrs. LCMS showed that the A28-4 was consumed completely and the desired product was detected. The reaction mixture was evaporated under reduced pressure to give A28-1A (413.70 mg, crude, HC1) as a light yellow solid.

Step 3: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluoro-2-methoxy-phenyl)piperazin-l- yl] sulf onyl-fluoren-9-one

[00384] To a solution of A28-1A (24.51 mg, 0.099 mmol, 1.50 eq, HC1) in DCM (5 mL) was added TEA (33.51 mg, 0.33 mmol, 0.046 mL, 5.00 eq) and A28-1 (30.00 mg, 0.066 mmol, 1.00 eq) at 0°C. The reaction mixture was stirred at 25°C for 3hrs. LCMS showed that the A28- 1 A was consumed completely and the desired product was detected. The reaction mixture was quenched with H₂0 (5 mL), extracted with DCM (45 mL). The organic layer was washed with brine (15 mL), dried over Na₂S0₄ and filtered. The filtrate was concentrated under reduced pressure. A28-2 (122.40 mg, crude) as a black brown solid was used to next step without purification. Step 4: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluoro-2-methoxy-phenyl)piperazin-l- yl]sulfonl-fluoren-9-one oxime

[00385] To a solution of A28-2 (41.51 mg, 0.066 mmol, 1.00 eq) in pyridine (5 mL) was added hydroxylamine (23.01 mg, 0.33 mmol, 5.00 eq, HC1). The reaction mixture was stirred under 25°C for 2 hrs. LCMS showed that the A28-2 was consumed completely and the desired product was detected. The reaction mixture was evaporated under reduced pressure. The residue was purified by Prep-HPLC (column: Xtimate C 18 150*25mm*5um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN] ; B%: 58%-88%, lOmin) to obtain Compound 28 (2.38 mg, 3.71 umol, 5.60% yield) as an off-white solid. LCMS (ESI): RT = 1.963 min, mass calcd for C₃₂H₃₆FN₃O₆S₂ 641.20, m/z found 642. 1 [M+H]⁺. ^!H NMR (400 MHz, DMSO-i¾) 513.40 (s, 1H), 8.80 - 8.66 (m, 1H), 8.39-8.34 (d, J = 7.9 Hz, 1H), 8.33 - 8.28 (m, 1H), 8.10 - 8.03 (m, 1H), 8.01 - 7.95 (m, 1H), 7.95 - 7.80 (m, 1H), 6.90 - 6.80 (m, 1H), 6.80 - 6.70 (m, 1H), 6.69 - 6.50 (m, 1H), 3.67 (s, 3H), 3. 10 - 3.00 (m, 4H), 2.99 - 2.80 (m, 4H), 1.75 - 1.60 (m, 2H), 1.55 - 1.46 (m, 2H), 1.45 - 1.30 (m, 2H), 1.23 - 1. 10 (m, 3H), 0.85 - 0.65 (m, 6H).

Example A29: Methyl l-((7-((4,4-dimethylcyclohexyl)sulfonyl)-9-(hydroxyimino)-9H- fluoren-2-yl)sulfonyl)-4-(4-fluorophenyl)piperazine-2-carboxylate (Compound 29)

Preparation of Compound 29:

Step 1 : 1-tert-Butyl 2-methyl 4-(4-fluorophenyl)piperazine-l,2-dicarboxylate

[00386] To a solution of A29-1 (200.00 mg, 0.819 mmol, 1.00 eq) in DCM (5 mL) were added A29-1A (229. 11 mg, 1.64 mmol, 2.00 eq), Cu(OAc)₂ (148.70 mg, 0.819 mmol, 1.00 eq), 4A MS (50 mg) and pyridine (0. 13 mL, 1.64 mmol, 2.00 eq). The reaction mixture was stirred at 25 °C for 16 hours under oxygen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether: ethyl acetate = 1 :0 to 10: 1) to afford the title compound (250 mg, 90% yield). LCMS (ESI): RT = 0.800 min, mass calcd. for C₁₇H₂₃FN₂O₄ 338.16, m/z found 338.9 [M+H] , ¾ NMR (400MHz, COCh-d) δ 7.00 - 6.93 (m, 2H), 6.91 - 6.84 (m, 2H), 4.92 - 4.85 (m, 0.5H), 4.73 - 4.66 (m, 0.5H), 4.09 - 3.88 (m, 2H), 3.78 (s, 3H), 3.40 - 3.18 (m, 2H), 2.94 - 2.83 (m, 1H), 2.79 - 2.66 (m, 1H), 1.49 (d, J=16.8 Hz, 9H).

Step 2: Methyl 4-(4-fluorophenyl)piperazine-2-carboxylate hydrochloride

[00387] To a solution of A29-2 (150 mg, 0.44 mmol, 1.00 eq) in 1,4-dioxane (2 mL) was added 1,4-dioxane-HCl (5 mL) at 0 °C. The reaction mixture was allowed to warm up to 25 °C and stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (110 mg, 90% yield) as white oil. LCMS (ESI): RT = 0.496 min, mass calcd. for Ci₂Hi₅FN₂0₂ 238.11, m/z found 238.8 [M+H]⁺.

Step 3: Methyl l-((7-((4,4-dimethylcyclohexyl)sulfonyl)-9-oxo-9H-fluoren-2-yl)sulfonyl)-4- (4- fluorophenyl)piperazine-2-carboxylate

[00388] A29-4 (30 mg, 0.066 mmol, 1.00 eq), A29-3 (18.2 mg, 0.066 mmol, 1.00 eq,

HC1) and DMAP (0.81 mg, 6.62 umol, 0.10 eq) were taken up into a microwave tube in pyridine (4 mL) .The sealed tube was heated at 70 °C for 1 hour under microwave. The reaction mixture was concentrated under reduced pressure to obtain the title A29-5 (35 mg, crude) as yellow oil. LCMS (ESI): RT = 0.900 min, mass calcd. for C₃₃H₃₅FN₂O₇S₂ 654.19, m/z found 655.0 [M+H]⁺. Step 4: Methyl l-((7-((4,4-dimethylcyclohexyl)sulfonyl)-9-(hydroxyimino)-9H-fluoren-2- yl)sul

fonyl)-4-(4-fluorophenyl)piperazine-2-carboxylate

[00389] To a solution of A29-5 (60 mg, 0.092 mmol, 1.00 eq) in pyridine (4 mL) was added hydroxylamine (12.74 mg, 0.18 mmol, 2.00 eq, HC1). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography over Xtimate C 18

150*25mm*5um (eluent: CH₃CN in H₂0 (0.05% NH₃.H₂0) 64/94, v/v). The pure fractions were collected and the volatiles were removed under vacuum. The residue was re-suspended in water (lOmL) and the resulting mixture was lyophilized to dryness to remove the solvent residue completely. The title compound (8.33 mg, 14% yield) was obtained as a white solid. LCMS (ESI): RT = 1.972 min, mass calcd. for C₃₃H₃₆FN₃O₇S₂ 669.20, m/z found 670. 1 [M+H]⁺, ¾ NMR (400MHz, COC\ -d) δ 9.31 - 9.08 (m, 1H), 8.83 (d, J = 2.6 Hz, 1H), 8.23 (d, J = 5.7 Hz, 1H), 8.00 (t, J = 7.9 Hz, 1H), 7.95 - 7.81 (m, 3H), 6.98 - 6.90 (m, 2H), 6.85 - 6.78 (m, 2H), 4.89 - 4.81 (m, 1H), 3.99 (d, J = 11.9 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.60 (d, J = 3.5 Hz, 3H), 3.54 - 3.49 (m, 1H), 3.37 - 3.29 (m, 1H), 3.05 - 2.96 (m, 1H), 2.94 - 2.80 (m, 2H), 1.93 - 1.85 (m, 2H), 1.78 - 1.66 (m, 2H), 1.51 (d, J = 13.7 Hz, 2H), 1.21 - 1.10 (m, 2H), 0.96 - 0.82 (m, 6H). Example A30: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluoro-2-hydroxy- p

P

Step 1 : tert-butyl 4-(2-benzyloxy-4-fluoro-phenyl)piperazine-l-carboxylate

[00390] A mixture of A30-2G (1.0 g, 3.6 mmol, 1.0 eq), A30-4E (795.0 mg, 4.3 mmol, 1.2 eq) , Pd₂(dba)₃ (325.7 mg, 355.7 umol, 0. 1 eq) , BINAP (443.0 mg, 0.711 mmol, 0.2 eq) and t- BuONa (512.8 mg, 5.3 mmol, 1.5 eq) in toluene (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hour under N₂ atmosphere, to give a black solution. TLC-MS showed A30-2G was consumed completely and one main new spot was formed. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate= 1 :0-8: 1). A30-3G (1.2 g, 3. 1 mmol, 87.2% yield) was obtained as a yellow solid. ¾ NMR (400 MHz, CDC1₃) δ7.46 - 7.35 (m, 5H), 6.84 (d, J = 5.6 Hz, 1H), 6.71 - 6.63 (m, 2H), 5. 10 (s, 2H), 3.56 (t, J = 4.8 Hz, 4H), 2.99 (t, J = 4.8 Hz, 4H), 1.48 (s, 9H).

Step 2: tert-butyl 4-(4-fluoro-2-hydroxy-phenyl)piperazine-l-carboxylate

[00391] To a solution of A30-3G (1.2 g, 3. 1 mmol, 1.0 eq) in Me OH (30 mL) was added

Pd-C (10%, 0. 1 g) under N₂. The suspension was degassed under vacuum and purged with ¾ several times. The mixture was stirred under H₂ (15 psi) at 5- 15 °C for 5 hours. LCMS showed A30-3G was consumed completely and one main peak with desired MS was detected. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to give a residue. The residue was used in next step directly without further purification. A30-4G (910 mg, 3.1 mmol, 98.7% yield) was obtained as gray oil. LCMS (ESI): RT = 0.730 min, mass calcd. for C₁₅H₂₁FN₂O₃ 296.15, m/z found 296.8 [M+H]⁺

Step 3: 5-fluoro-2-piperazin-l-yl-phenol [00392] To a solution of A30-4G (910.0 mg, 3.1 mmol, 1.0 eq) in MeOH (10 mL) was added HCl/MeOH (10 mL). The mixture was stirred at 5- 15 °C for 1 hr to give a brown solution. LCMS showed A30-4G was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated to give A30-5G (750 mg, crude, HC1) as a gray solid which was used in next step directly without further purification. LCMS (ESI): RT = 0.557 min, mass calcd. for Ci₀Hi₃FN₂O 196.10, m/z found 196.8 [M+H]⁺

Step 4: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluoro-2-hydroxy-phenyl)piperazin-l- yl] sulf onyl-fluoren-9-one

[00393] To a solution of A30-5G (123.3 mg, 0.53 mmol, 1.2 eq, HC1) and TEA (0.18 mL,

1.3 mmol, 3.0 eq) in DCM (5.0 mL) was added and A30-1 (200.0 mg, 0.44 mmol, 1.00 eq) at 0 °C. The mixture was stirred at 0- 15 °C for 2 hour to give a brown solution. LCMS showed A30- 1 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated to give A30-2 (280.0 mg, crude) as a brown solid, which was used in next step directly without further purification. LCMS (ESI): RT = 0.918 min, mass calcd. for C₃₁H₃₃FN₂O₆S₂ 612.18, m/z found 612.9 [M+H]⁺

Step 5: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluoro-2-hydroxy-phenyl)piperazin-l- yl]sulfonyl-fluoren-9-one oxime

[00394] To a solution of A30-2 (280.0 mg, 0.46 mmol, l.O eq) in pyridine (5 mL) was added NH₂OH.HCl (95.3 mg, 1.4 mmol, 3.0 eq). The mixture was stirred at 5- 15 °C for 2 hr to give a brown solution. LCMS showed A30-2 was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated to give a residue. The residue was purified by Prep-HPLC (basic) to give Compound 30 (173. 17 mg, 0.28 mmol, 60.4% yield) as a light yellow solid. LCMS (ESI): RT = 2. 185 min, mass calcd. for C₃₁H₃₄FN₃O₆S₂ 627.19, m/z found 628.1 [M+H]⁺ _; ¾ NMR (400 MHz, DMSO-ik) δ 13.46 ( s, 1H), 9.28 (s, 1H), 8.77 (s, 0.6H), 8.71 (s, 0.5H), 8.41 - 8.34 (m, 2H), 8. 14 - 8.02 (m, 3H), 6.93 (t, J= 7.2 Hz, 1H), 6.58 - 6.53 (m, 2H), 3.33 - 3.26(m, 1H), 3. 11 (s, 4H), 2.94 (s, 4H), 1.76 - 1.73 (m, 2H), 1.54 - 1.42 (m, 4H), 1.24 - 1.20 (m, 2H), 0.86 (s, 3H), 0.80 (s, 3H).

Example A31 : 2-[4-(2,5-dimethoxyphenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime (Compound 31)

Preparation of Compound 31 :

Step 1 : tert-butyl 4-(2,5-dimethoxyphenyl)piperazine-l-carboxylate

[00395] To a solution of A31-2 (200.00 mg, 1.07 mmol, 1.00 eq) , A31-1 (232.25 mg, 1.07 mmol, 1.00 eq) and f-BuOK (240.13 mg, 2.14 mmol, 2.00 eq) in toluene (5 mL) was added BINAP (53.30 mg, 0.086 mmol, 0.08 eq) and Pd₂(dba)₃ (39.19 mg, 0.043 mmol, 0.04 eq) . The resulted mixture was stirred at 100 °C under N₂ for 16 hours. LCMS and TLC (Petroleum ether: Ethyl acetate=3/l) showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated. The residue crude product was dissolved with CH₂CI₂ (15 ml) and washed with water (2 x 15 mL), respectively. After drying over anhydrous NaiSC , the solvent was removed under reduced pressure to afford the crude product. The crude product was purified by column chromatography over silica gel eluted with petroleum ether/ethyl acetate= l/0 to 15/1 to give compound A31-3 (345.00 mg, 1.04 mmol, 97.01% yield, 97% purity) as a yellow oil. LCMS (ESI): RT = 0.709 min, mass calc. for C₁₇H₂₆N₂O₄ 322.19, m/z found 322.9 [M+H]⁺.

Step 2: l-(2,5-dimethoxyphenyl)piperazine

[00396] A31-3 (340.00 mg, 1.02 mmol, 1.00 eq) was dissolved HCI/MeOH (4 M, 5 mL,

19.61 eq) and the reaction mixture was stirred at 15°C for 2 hours. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give the crude product. The residue was directly used without further purification. A31-4 (250.00 mg, 0.95 mmol, 92.83% yield, 98% purity, HC1) was obtained as yellow solid. LCMS (ESI): RT = 0.880 min, mass calc. for ^Ηι₈Ν₂0₂ 222.14, m/z found 222.9 [M+H]⁺.

Step 3: 2-[4-(2,5-dimethoxyphenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one

[00397] To a solution of A31-4 (42.84 mg, 0.17 mmol, 1.50 eq, HC1) and TEA (44.68 mg,

0.44 mmol, 61.21 uL, 4.00 eq) in DCM (3.00 mL) was added A31-5 (50.00 mg, 0.11 mmol, 1.00 eq). The resulted mixture was stirred at 25 °C for 2 hours. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give the crude A31-6 (70.00 mg, 0.11 mmol, 99.28% yield) as brown solid, which was directly used without further purification. LCMS (ESI): RT = 0.895 min, mass calc. for C33H38N2O7S2 638.21, m/z found 639.0 [M+H]⁺.

[00398] Step 4: 2-[4-(2,5-dimethoxyphenyl)piperazin-l-yl]sulfonyl-7-(4,4- dimethylcyclohexyl)sulfonyl-fluoren-9-one oxime

[00399] A mixture of A31-6 (70.00 mg, 0.11 mmol, 1.00 eq) and NH₂OH.HCl (22.84 mg,

0.33 mmol, 3.00 eq) in pyridine (2 mL) was stirred at 50 °C for 1 hour. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep- HPLC (Condition: water (0.05% ammonia hydroxide v/v)-ACN. Column: Gemini 150*25 5u) to give the Compound 31 (16.00 mg, 0.023 mmol, 20.54% yield, and 91.96% purity) was obtained as brown solid. LCMS (ESI): RT = 1.955 min, mass calc. for C33H39N3O7S2 653.22, m/z found 654.1 [M+H]⁺; ¾ NMR (400 MHz, DMSO- d6) δ 13.40 (s, 1 H), 8.76 - 8.72 (m, 0.5H), 8.70 - 8.67 (m, 0.5H), 8.39 - 8.35 (m, 1H), 8.35 - 8.30 (m, 1H), 8.13 - 8.09 (m, 0.5H), 8.09 - 8.05 (m,0.5H), 8.03 - 7.96 (m, 1.5H), 7.94 - 7.89 (m, 0.5H), 6.78 (d, J = 8.8 Hz, 1H), 6.47 (dd, J = 8.8 Hz, 2.65 Hz, 1H), 6.44 - 6.39 (m, 1H), 3.64 (s, 3H), 3.60 (s, 3H), 3.25 - 3.20 (m, 1H), 3.13 - 2.96 (m, 8H), 1.75 - 1.69 (m, 2H), 1.56 - 1.47 (m, 2H), 1.44 - 1.37 (m, 2H), 1.22 - 1.13 (m, 2H), 0.89 - 0.73 (m, 6H).

Example A32: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluorophenyl)-3,3-dimethyl- piperazin-l-yl]sulfony -fluoren-9-one oxime (Compound 32)

P

Step 1 : tert-butyl 4-(4-fluorophenyl)-3,3-dimethyl-piperazine-l-carboxylate [00400] A32-1 (200.0 mg, 0.933 mmol, 1.00 eq), A32-2 (310.8 mg, 1.40 mmol, 0. 16 mL,

1.50 eq), f-BuONa (179.4 mg, 1.87 mmol, 2.00 eq) and bis(tri-tertbutylphosphine) Palladium(O) (47.69 mg, 0.093 mmol, 0. 10 eq) were taken up into toluene (6.00 mL). The reaction mixture was stirred at 1 10 °C for 2 hour under N₂. LCMS and TLC (Petroleum ether: Ethyl acetate=10/l) showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give a crude product. The residue was purified by Prep- TLC (Petroleum ether: Ethyl acetate= 10/1) to give the A32-3 (260.0 mg, 0.776 mmol, 83. 1 1% yield, 92% purity) as a yellow oil. LCMS (ESI): RT =0.630 min, mass calcd. for C₁₇H₂₅FN₂O₂ 308.19, m/z found 308.9 [M+H]⁺

Step 2: l-(4-fluorophenyl)-2,2-dimethyl-piperazine

[00401] A32-3 (260.0 mg, 0.776 mmol, 1.00 eq) was dissolved ethyl acetate (3 mL).

HCl/EtOAc (4 M, 3 mL, 15.47 eq) was added and the reaction mixture was stirred at 20°C for 3 hours. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give the A32-4 (210.00 mg, crude, HC1) as light yellow solid, which was directly used without further purification. LCMS (ESI): RT =0.540 min, mass calcd. for Ci₂Hi₇FN₂ 208.28, m/z found 208.8 [M+H]+

Step 3: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluorophenyl)-3,3-dimethyl-piperazin-l- yl] sulf onyl-fluoren-9-one

[00402] To a solution of A32-4 (54 mg, 0.221 mmol, 2.00 eq, HC1) and TEA (44.68 mg,

0.442 mmol, 0.06 mL, 4.00 eq) in DCM (3 mL) was added A32-5 (50 mg, 0. 1 1 mmol, 1.00 eq). The resulted mixture was stirred at 20°C for 2 hours. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was

concentrated to give the A32-6 (100.00 mg, 0.086 mmol, 78.30% yield, 54% purity) as brown solid product, which was directly used without further purification. LCMS (ESI): RT =0.914 min, mass calcd. For C₃₃H₃₇FN₂O₅S 624.21, m/z found 625.2 [M+H]⁺.

Step 4: 2-(4,4-dimethylcyclohexyl)sulfonyl-7- [4-(4-fluorophenyl)-3,3-dimethyl-piperazin-l- yl]sulfonyl-fluoren-9-one oxime

[00403] A mixture of A32-6 (100 mg, 0.086 mmol, 1.00 eq) and NH₂OH.HCl (18 mg,

0.26 mmol, 3.00 eq) in pyridine (2 mL) was stirred at 25 °C for 2 hours. LCMS showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep- HPLC (Condition: water (0.05% ammonia hydroxide v/v)-ACN. Column: Gemini 150*25 5u.) to give the Compound 32 (18 mg, 0.028 mmol, 32.55% yield, 100% purity) as white solid .LCMS (ESI): RT =1.985 min, mass calcd. For C₃₃H₃₈FN₃O₅S₂ 639.22, m/z found 640. 1 [M+H]⁺ ¾ NMR (400 MHz, DMSO-i/6) 613.41 (s, 1 H), 8.76 (s, 0.5 H), 8.68 (s, 0.5 H), 8.37 - 8.41 (m, 1 H), 8.31 - 8.36 (m, 1 H), 8.11 - 8.14 (m, 0.5 H), 8.07 - 8.11 (m, 0.5 H), 8.00 - 8.03 (m, 1 H), 7.97 - 8.00 (m, 0.5 H), 7.89 - 7.94 (m, 0.5 H), 7.20-7.00 (m, 4 H), 3.21 - 3.27 (m, 1 H), 3.08 - 3.16 (m, 2 H), 2.99 - 3.08 (m, 2 H), 2.90 - 2.70 (m, 2 H), 1.68 - 1.80 (m, 2 H), 1.48 - 1.59 (m, 2 H), 1.37 - 1.47 (m, 2 H), 1.13 - 1.26 (m, 2 H), 0.98 (s, 6 H), 0.85 (s, 3 H), 0.80 (s, 3 H).

Example Bl:

Example B1

Step 1

[00404] Compound Bl-1 (20 mmol, reference Zhao, Jian-Feng et al., Tetrahedron, 67(10),

1977-1982; 2011) is dissolved in chlorosulfonic acid (100 mL) and heated to reflux until LCMS analysis indicates that no starting material remains. The reaction mixture is cooled to room temperature and is slowly poured to ice (500 g). The solid is collected and dried under high vacuum for 12 hours to afford compound Bl-2.

Step 2

[00405] To a solution of Bl-2 (0.1 mmol) in DCM (2 mL) is added piperidine (0.3 mmole) and DIEA (0.3 mmol). The reaction is stirred at room temperature over 12 h. After

concentration of the solvent, the mixture is purified with silica column chromatography to afford compound Bl-3.

Step 3

[00406] Compound Bl-3 is dissolved pyridine (1 mL) and is added to hydroxylamine hydrochloride salt (NH₂OH-HCl, 100 mg). The mixture is heated at 80 °C for 2 hours. The reaction is concentrated, and the residue is purified with silica gel column chromatography to yield Example Bl.

Examples B2-B5:

Preparation of Examples B2-B5:

[00407] The compounds of Examples B2-B5 are prepared according to the procedures as described in Example Bl .

Step 1

[00408] To a solution of Bl-2 (0.1 mmol) in DCM (2 mL) at 0 °C, a solution of 4- phenylpiperazine (0. 1 mmole) and DIEA (0.3 mmol) in DCM (3 mL) is added in a dropwise manner. After the reaction is stirred at room temperature for 6 hours, piperidine (0.2 mmol) is added to the reaction mixture. The resulting solution is stirred at room temperature for 15 hours. After concentration of the solvent, the mixture is purified with silica column chromatography to provide compound B6-1, along with symmetric bis-sulphonamide byproducts.

Step 2

[00409] Compound B6-1 is dissolved pyridine (1 mL), and is added to hydroxylamine hydrochloride salt (NH₂OH-HCl, 100 mg). The mixture is heated at 80 °C for 2 hours. The reaction is concentrated, and residue is purified with silica gel column chromatography to provide Example B6.

Examples B7-B1

Preparation of Examples B7-B10:

[00410] The compounds of Examples B7-B10 are prepared according to the procedures as described in Example B6.

B11-1 B11 -2 B11 -3

Step 1

[00411] Compound Bll-1 (20 mmol) is heated with H₂0₂ (30%, 10 equivalents) in

AcOH/toluene (1 : 1, 50 mL) at 80 °C for 16 hours. The reaction is concentrated, and water is added to the residue. The solid is collected and dried under high vacuum 15 h to afford compound Bl l-2.

Step 2

[00412] Compound Bll-2 (15 mmol) is dissolved in POCI₃ (30 mL) and is heated to reflux for 30 min. The excess POCI₃ is removed by vacuum concentration, and the residue is poured into ice. The solid is collected and dried under vacuum to provide compound Bll-3. Step 3

[00413] To compound Bll-3 (10 mmol) in DMF (20 mL), potassium carbonate (20 mmol) and benzylthiol (22 mmol) are added. The reaction mixture is then heated to 80 °C for 16 hours. Water (10 mL) is slowly added to the reaction, and solid is collected via filtration and washed with water. The compound Bl l-4 is dried under high vacuum for 15 hours.

Step 4

[00414] Chlorine gas is slowly bubbled through a suspension of compound Bll-4 (5 mmol) in AcOH (12 ml) and water (8 ml) for 5-6 h at 0 °C. The mixture is extracted with DCM (50 mL x 2) and the combined organic phase is washed with sodium meta-bisulphate, water and brine, dried

and concentrated in vacuo to afford compound Bll-5, which was used in the next step without further purification.

Step 5 [00415] To a solution of compound Bll-5 (0.1 mmol) in DCM (2 mL), piperidine (0.3 mmol) and DIEA (0.3 mmol) are added. Reaction is stirred at room temperature over 12 h. After concentration of the solvent, the mixture is purified with silica column chromatography to afford compound Bll-6.

Step 6

[00416] Compound Bll-6 (50 mg) is dissolved pyridine (1 mL), and is then added to hydroxylamine hydrochloride salt (NH₂OH-HCl, 100 mg). The mixture is heated at 80 °C for 2 hours. The reaction is concentrated, and residue is purified with silica gel column

chromatography to provide Example Bll.

Examples B12-

Preparation of Examples B12-B15:

[00417] The compounds of Examples B12-B15 are prepared according to the procedures as described in Example Bll.

Example B16:

B11-5 B16-1 Example B16

Step 1

[00418] To a solution of Bl 1-5 (0.1 mmol) in DCM (2 mL) at 0 °C is added a solution of

4-phenylpiperazine (0.1 mmole) and DIEA (0.3 mmol) in DCM (3 mL) in a dropwise manner. After the reaction is stirred at room temperature for 6 hours, piperidine (0.2 mmol) is added to the reaction mixture. The resulting solution is stirred at room temperature for 15 hours. After concentration of the solvent, the mixture is purified with silica column chromatography to afford compound B16-1, along with symmetric bis-sulphonamide as byproducts.

Step 2

[00419] Compound B16-1 is dissolved pyridine (1 mL), and is added to hydroxylamine hydrochloride salt (NH₂OH-HCl, 100 mg). The mixture is heated at 80 °C for 2 hours. The reaction is concentrated, and residue is purified with silica gel column chromatography to provide Example B16. Examples B17-

Preparation of Examples B17-B20:

[00420] The compounds of Examples B17-B20 are prepared according to the procedures as described in Example B16.

Preparation of Example B21 :

Step 1

[00421] To a solution of 3-bromo-5-methoxypyridine (B21-1, 50 mmol) in THF (200 mL) at -78 °C is added LDA (2.0 M in THF, 26 mL). After the reaction is maintained at -78 °C for 1 hour, DMF (10 mmol) is added to the reaction mixture. The reaction is gradually warmed to room temperature over 5 hours. The reaction mixture is diluted with ethyl acetate (100 mL), washed with water (50 mL), dried over MgSO/_t, filtered and concentrated. The residue is purified with silica column chromatography to provide compound B21-2

Step 2

[00422] To a solution of compound B21-2 (50 mmol) in DCM (200 mL) at 0 °C is added

PCC (30 mmol). The reaction is allowed to warm to room temperature slowly. After the starting material is completely consumed, the reaction mixture is filtered through silica and concentrated. The residue is purified with silica column chromatography to provide compound B21-3.

Step 3

[00423] Copper powder (200 mmol), compound B21-3 (40 mmol), and sand (100 g) are thoroughly mixed together and heated at 200 °C until starting material is consumed. The mixture is cooled to room temperature, stirred with DCM (500 mL), filtered. The filtrate is filtered through silica, rinsed with DCM, and concentrated. The residue is purified by silica column chromatography to afford compound B21-4.

Step 4

[00424] To a solution of compound B21-4 (20 mmol) in DCM (50 mL) at 0 °C is added boron trichloride (50 mmol). The reaction is stirred at room temperature until the starting material is mostly converted to diol. The reaction mixture is concentrated, and dissolved in DCM, neutralized with aqueous saturated sodium bicarbonate to about pH 8. The mixture is separated, and aqueous layer is extracted with DCM (50 mL x 2). The combined organic phases are dried over MgSC , filtered and concentrated. The residue is purified by column

chromatography to afford compound B21-5.

Step 5

[00425] Compound B21-5 (15 mmol) is dissolved in POCI₃ (30 mL) and is heated to reflux for 30 min. The excess POCI₃ is removed by vacuum concentration, and the residue is poured into ice. The solid is collected and dried under vacuum to yield compound B21-6.

Step 6

[00426] To compound B21-6 (10 mmol) in DMF (20 mL) is added potassium carbonate

(20 mmol) and benzylthiol. The reaction mixture is then heated to 80 °C for 16 hours. After the reaction is cooled to room temperature, water (10 mL) is slowly added to the reaction, and solid is collected via filtration, and washed with water. The obtained compound B21-7 is dried under high vacuum for 15 hours.

Step 7

[00427] Chlorine gas is slowly bubbled through a suspension of B21-7 (5 mmol) in AcOH

(12 ml) and water (8 ml) for 5-6 h at 0 °C. The mixture is extracted with DCM (50 mL x 2) and the combined organic phase is washed with sodium meta-bisulphate, water and brine, dried (NaiSO/_t) and concentrated in vacuo to provide compound B21-8 which was used in the next step without further purification.

Step 8

[00428] To a solution of B21-8 (0.1 mmol) in DCM (2 mL) is added piperidine (0.3 mmole) and DIEA (0.3 mmol). Reaction is stirred at room temperature over 12 h. After concentration of the solvent, the mixture is purified with silica column chromatography to afford compound B21-9.

Step 9

[00429] Compound B21-9 (50 mg) is dissolved pyridine (1 mL), and is added to hydroxylamine hydrochloride salt (NH₂OH-HCl, 100 mg). The mixture is heated at 80 °C for 2 hours. The reaction is concentrated, and residue is purified with silica gel column

chromatography to afford Example B21

Examples B22-

Preparation of Examples B22-B25:

[00430] The compounds of Examples B22-B25 are prepared according to the procedures as described in Example B21.

Step 1

[00431] To a solution of B21-8 (0.1 mmol) in DCM (2 mL) at 0 °C is added a solution of

4-phenylpiperazine (0.1 mmole) and DIEA (0.3 mmol) in DCM (3 mL) in a dropwise manner. After the reaction is stirred at room temperature for 6 hours, piperidine (0.2 mmol) is added to the reaction mixture. The resulting solution is stirred at room temperature for 15 hours. After concentration of the solvent, the mixture is purified with silica column chromatography to provide compound B26-1, along with symmetric bis-sulphonamide as byproducts.

Step 2

[00432] Compound B26-1 is dissolved pyridine (1 mL), and hydroxylamine hydrochloride salt (NH₂OH-HCl, 100 mg) is added. The mixture is heated at 80 °C for 2 hours. The reaction is concentrated, and residue is purified with silica gel column chromatography to provide Example B26

Examples B27-

Preparation of Examples B27- B30:

[00433] The compounds of Examples B27- B30 are prepared according to the procedures as described in Example B26.

Example B31 :

Preparation of Example B31 :

Step 1

[00434] To a solution of B31-1 (20 mmol) in isopropyl alcohol (100 mL) at room temperature is added a solution of cyclohexyl thiol (19 mmol) and DIEA (20 mmol) in isopropyl alcohol (100 mL) over 1 hour. After the reaction is stirred at room temperature, the solvent is evaporated, and residue is purified with silica gel column chromatography, the product is further recrystallized to afford compound B31-2.

Step 2

[00435] To a solution of B31-2 (1.0 mmol) in isopropyl alcohol (40 mL) at room temperature is added 3,5-dimethylphenylthiol (1.2 mmol) and DIEA (1.5 mmol). The reaction is heated at 80 °C until all starting material is consumed. The solvent is evaporated, and residue is purified with silica gel column chromatography to provide compound B31-3.

Step 3

[00436] To a solution of B31-3 (0.2 mmol) in acetonitrile (2 mL) and acetic acid (0.5 mL) is added hydrogen peroxide (30% aqueous, 0.5 mL). The reaction is stirred at room temperature until the conversion is complete. The reaction mixture is partitioned between ethyl acetate (50 mL) and water (10 mL), and the organic phase is washed twice with water, then dried and concentrated. The residue is purified with silica column chromatography to afford compound B31-4

Step 4

[00437] Compound B31-4 is dissolved pyridine (1 mL), and hydroxylamine hydrochloride salt (NH₂OH-HCl, 100 mg) is added. The mixture is heated at 80 °C for 2 hours. The reaction is concentrated, and residue is purified with silica gel column chromatography to provide Example B31 Examples B32-

Preparation of Examples B32-B40:

[00438] The compounds of Examples B32-B40 are prepared according to the procedures as described in Example B31.

Example B41 :

Preparation of Example B41 :

Step 1

[00439] Compound B41-1 (prepared according to Org. Lett 2014, 3216, 20 g) is treated with chlorosulfonic acid (80 mL) at 110 C until starting material has been consumed. After the reaction mixture is cooled to room temperature, it is carefully poured onto ice (500 g). The precipitate is collected via filtration, rinsed with cold water, and dried under high vacuum for 15 hours. The obtained compound B41-2 is used without further purification.

Step 2

[00440] Compound B41-2 (0.2 mmol) is dissolved in DCM, and to it is added DIEA (0.5 mmol) and 4-phenylpiperazine (0.30 mmol). The reaction mixture is stirred at room temperature over 15 hours, and concentrated. The residue is purified with silica column chromatography to afford compound B41-3.

Step 3

[00441] To compound B41-3 (0.2 mmol) in DMF (2 mL) is added K₂C0₃ (0.5 mmol) and cyclohexylthiol (0.3 mmol). The reaction mixture is heated at 100 C until starting material disappeared. The reaction is poured into water (10 mL), and solid is collected via filtration and is rinsed with water. The crude product is dried under high vacuum to provide compound B41-4, which is used without further purification.

Step 4

[00442] To a solution of compound B41-4 (0.2 mmol) in acetonitrile (2 mL) and acetic acid (0.5 mL) is added hydrogen peroxide (30% aqueous, 0.5 mL). The reaction is stirred at room temperature until the conversion is complete. The reaction mixture is partitioned between ethyl acetate (50 mL) and water (10 mL), and the organic phase is washed twice with water, then dried and concentrated. The residue is purified with silica column chromatography to afford compound B41-5.

Step 5

[00443] Compound B41-5 is dissolved pyridine (1 mL), and to it was added

hydroxylamine hydrochloride salt (NH₂OH-HCl, 100 mg). The mixture is heated at 80 °C for 2 hours. The reaction is concentrated, and residue is purified with silica gel column

chromatography to provide Example B41.

Examples B42-B60:

Preparation of Examples B42-B60:

[00444] The compounds of Examples B42-B60 are prepared according to the procedures as described in Example B41.

Example B61 :

B61 -3 Example B61

Step 1

[00445] To a solution of bis-sulfonyl chloride B61-1 (2.0 mmol) in DCM (10 mL) at 0 °C is added a solution of DIEA (3.0 mmol) and cis-3,5-dimethylpiperidine (2.0 mmol) in DCM (10 mmol) in a dropwise manner. The reaction mixture is stirred at room temperature over 15 hours, and concentrated. The residue is purified with silica column chromatography to afford compound B61-2.

Step 2

[00446] A mixture of 3-chlorophenylboronic acid (1.5 mmol), B61-2 (1 mmol), ₂CO (2 mmol), and palladium chloride (0.05 mmol) in acetone/water (3/1, 10 ml) at 0 °C under nitrogen atmosphere is stirred at room temperature until starting material is consumed. After completion of the reaction, the reaction mixture is partitioned between ethyl acetate (60 mL) and water (20 mL), and the organic phase is with water (2 x 10 ml). The residue after concentration of organic phase is purified by silica column chromatography to afford compound B61-3.

Step 3

[00447] Compound B61-3 (100 mg) is dissolved pyridine (1 mL), and hydroxylamine hydrochloride salt (NH₂OH-HCl, 100 mg) is added. The mixture is heated at 80 °C for 2 hours. The reaction is concentrated, and residue is purified with silica column chromatography to provide Example B61. Examples B62

Preparation of Examples B62- B65:

[00448] The compounds of Examples B62- B65 are prepared according to the procedures as described in Example B61.

II. Biological Evaluation

Example CI : YAP Reporter Assay

[00449] HEK293T cells stably transfected with 8XTBD luciferase reporter and pRLTK in

384-well plates were treated with the test compounds, starting from 3μΜ (final concentration in assay plate), 1 :3 dilution, and 10 points in quadruplicates. Post 24-hr incubation with compounds at 37°C and 5% C02, cells were lysed and 8XTBD-driven firefly luciferase and control TK- driven renilla luciferase activities were measured using Promega Dual-Luciferase Reporter Assay System. [00450] Reagents: The reagents used for this study are: DMEM: Invitrogen# 11960077 ,

Dual-Glo Luciferase Assay System: Promega-E2980, Puromycin Dihydrochloride: Invitrogen- Al 113803, 384-well plate: PerkinElmer-6007480, L-GLUTAMINE: Invitrogen-25030164, Hygromycin B: Invitrogen- 10687010 , and Penicillin-Streptomycin: Merk-TMS-AB2-C

[00451] Mediums: The mediums used for this assay were: Culture Medium: DMEM+ lug/mL puromycin + 200 ug/mL hygromycin (with 10% FBS + ImM L-glutamine); and Assay Medium: DMEM (with 10% FBS + ImM L-glutamine + lx P/S).

[00452] Cell Plating: The appropriate media was warmed at 37°C by water bath: Culture Medium, Assay Medium, 1* D-PBS, 0.05% trypsin-EDTA. The cells were trypsinized after removing all media, then washed with 1* sterile D-PBS and then with 2 ml 0.05% trypsin- EDTA. The cells were then incubated at RT for one minute. Then 10 ml/75cm2 flask Assay Medium was added to each flask. Using a 10 ml pipette, the cells were then gently resuspended in the media, until the clumps completely disappeared. The cells were then transferred into 50 ml centrifuge tubes and were centrifuged at 800 rpm for 5 mins. The medium was removed and the cells were resuspended with Assay Medium. An aliquot of cells was used to count the cell density (cells/ml). The cell suspension was then diluted with Assay Medium to a concentration of 6x104 cells/ml. 50ul cells suspension was then plated to 384-well plate (PerkinElmer- 6007480), 3x103 cells/well and the cells were incubated in an incubator at 37°C, 5% C02.

[00453] Compound Treatment: In the afternoon (incubation of the plate with 3-4 hrs), the test compounds were added by Echo, starting from 3uM (final concentration in the assay plate), 1 :3 dilution, 10 points, quadruplicates. The plate was placed at 37°C, 5% C02 incubator for 24hrs.

[00454] Detection: The Dual-Glo Luciferase Reagent was prepared by transferring the contents of one bottle of Dual-Glo Luciferase Buffer to one bottle of Dual-Glo Luciferase Substrate to create the Dual-Glo Luciferase Reagent. Mixing was performed by inversion until the substrate was thoroughly dissolved. After mixing, the reagent was aliquoted into 15 ml tubes. In the afternoon (24hrs post compound treatment), the DMEM+ medium in the 384 well plates were aspirated by Microplate Washer.

[00455] Measuring firefly luciferase activity: 20ul Dual-Glo Luciferase Reagent was added to the 384-well plates. The plates were protected from light to prevent interference with the assay. The plates were shaken for lmin followed centrifuging plates at lOOOrpm for 30 seconds. After waiting at least 10 minutes, the firefly luminescence was measured by Envision.

[00456] Measuring renilla luciferase activity: 20ul Stop-Glo Reagent was added to the 384-well plates. The plates were shaken for lmin and then centrifuged at lOOOrpm for 30 seconds. After waiting at least 10 minutes, the renilla luminescence was measured by Envision. [00457] Compound IC₅₀ and maximum inhibition on the firefly luciferase and renilla luciferase activities were reported separately and are shown in the table below.

fluorc )-2,5-dimethoxy-phenyl)pipera2 dn- 1-

(hydroxyimino)-9H-fluoren-2-

Note: Biochemical assay IC₅₀ data are designated within the following ranges:

A: < 0.100 μΜ

B: > 0.100 μΜ to < 1.000 μΜ

C: > 1.000 μΜ to < 5.000 μΜ

D: > 5.000 μΜ

[00458] The compounds disclosed herein are tested to assess their YAP/TAZ activity using the following in vitro and in vivo assays.

Example C2: Cell-based Luciferase Screening [00459] The procedures described herein for the cell-based luciferase screening is as described in PCT/US2013/043752 (WO 2013/188138). For the luciferase reporter assay, BOCs are seeded in 15 cm dish. 5X UAS -luciferase reporter, YAP and TEAD4 plasmids are co- transfected. The cells are split into 384 well plates at the density of 10,000 cells per well with a Multidrop (Thermo) cell dispenser 16 hours after transfection. After allowing the cells to attach overnight, 10 μΜ of any one of the compounds disclosed herein is added using the Biomek FXP Laboratory Automation Workstation (Beckman Coulter). Luciferase activity is assayed using the Dual-glo assay kit (Promega), and reporter activity is detected and quantified with plate reader at 560 nm.

Example C3: Tumor Suppression Assay

[00460] The procedures described herein for the tumor suppression assay is as described in PCT/US2013/043752 (WO 2013/188138). Mouse procedures are performed according to the guidelines of approved animal protocol and based on the methods. After the cells are grown to 90%> confluence, these cells are harvested by trypsinization, washed in phosphate-buffered saline (PBS), and resuspended in PBS supplemented with 50% matrigel (BD Biosciences). An appropriate amount of cells is prepared for administration, such as 200 uL per injection site. Nude mice (Nu-foxnlnu, Charles Rivers Laboratories) are injected on both flanks of the dorsolateral sites subcutaneously. Any one of the compounds described herein is formulated accordingly, such as in in 10% DMSO and 40% propylene glycol, and is then administered at a suitable dose, such as 100 mg/kg daily, via tail-vein injection. Control mice received vehicle alone. The average tumor diameter (two perpendicular axes of the tumor are measured) are recorded. The data are expressed in tumor volume estimated by ([width]2 x length/2). Paired, two-tailed Student's t-test is performed to access the statistical significance.

[00461] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (C) or geometric isomer or a pharmaceutically acceptable salt thereof:

Formula (C)

wherein,

CRio; A₆ is N, C or CR_n; A₇ is N, C or CRi₂; A₈ is N, C or CR_J3;

R₂ and R3 are each independently H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C₃-Ciocycloalkyl, substituted or unsubstituted C₃-Ciocycloalkenyl, substituted

or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or

unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein any substituted group of R₂ and R3 is substituted with 1-4 Rn;

or R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring, containing 0- 1 additional heteroatom selected from N, S, and O; wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R_n;

R4 is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-C₆heteroalkyl, substituted or unsubstituted C₃-

Ciocycloalkyl, substituted or unsubstituted C₃-Ciocycloalkenyl, substituted or unsubstituted

C₂-Cioheterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein if R₄ is substituted, then R₄ is substituted withl-4 R_J8;

Ri and R14 are each independently H, substituted or unsubstituted Ci-Cealkyl, or substituted or unsubstituted C i-Ceheteroalkyl;

substituted or unsubstituted heteroaryl, halogen, CN, OR16, N(Ri6)2, SR16, SOR15, SO2R15,

C0₂R₁₆, CON(R₁₆)₂, S0₂N(R₁₆)₂, or N0₂;

the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle;.

Cr

C₂

Cr

C₂

or substituted or unsubstituted heteroaryl; and

2. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 1, wherein the compound of Formula (C) is:

214

The compound, geometric isomer or pharmaceutically acceptable salt thereof, of or 2, wherein the comp

5. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, and 4, wherein the compound of Formula (C) is:

6. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, or 4, wherein the compound of Formula (C) is:

7. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, 4, and 6, wherein the compound of Formula (C) is:

8. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, 4, 6 and 7, wherein the compound of Formula (C) is:

9. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1-8 wherein X is a bond.

10. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1-4 and 6-7, wherein X is

11. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 10, wherein R_J4 is hydrogen.

12. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1-11, wherein Ri is hydrogen.

13. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1-12, wherein R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional heteroatom selected from N, S, and 0, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 _]7.

14. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 13, wherein R₂ and R3 are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 4-8 membered ring containing 0-1 additional N heteroatom, and wherein if the 4-8 membered ring is substituted, then the 4-8 membered ring is substituted with 1-4 R₁₇.

15. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claims 13 or 14, wherein R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted 6 membered ring containing 0- 1 additional N heteroatom, and wherein if the 6 membered ring is substituted, then the 6 membered ring is substituted with 1-4 R₁₇.

16. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 15, wherein R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a unsubstituted or substituted piperidinyl or unsubstituted or substituted piperazinyl, and wherein if the piperidinyl or piperazinyl is substituted, then the piperidinyl or piperazinyl is substituted with 1-4 R₁₇.

17. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 16, wherein R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a substituted piperidinyl that is substituted with 1-4 R₁₇.

18. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 16, wherein R₂ and R₃ are taken together with the nitrogen atom to which they are attached to form a substituted piperazinyl that is substituted with 1-4 R₁₇.

19. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 13- 18, wherein each R₁₇ is independently substituted or unsubstituted C i-Cealkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, halogen, C0₂R₂o_, OR₂o, N(R₂o)¾

and wherein any substituted group of Rn is substituted with l-4R₂i.

20. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 19, wherein R₂₀ is hydrogen.

21. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 19, wherein R₁₇ is substituted or unsubstituted aryl, and wherein any substituted group of Rn is substituted with l-4R₂i.

22. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claims 19 or 21, wherein each R_2\ is independently selected from substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted C i-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, halogen, CN, CH₂-CN, CH₂-OR₂₄, OR₂₄, CH₂-N(R₂₄)₂, and N(R₂₄)₂.

23. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 22, wherein R₂ is hydrogen.

24. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of atom to which they are attached

, wherein each m is 0, 1, 2, or 3 and n is 0, 1, or 2.

25. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1-24, wherein R is substituted or unsubstituted Ci.Cealkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C3-Ciocycloalkenyl, substituted or unsubstituted C₂-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein if R is substituted, then R is substituted with 1-4 Ri_8.

26. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 25, wherein R_t is substituted or unsubstituted aryl, and if the aryl is substituted, then the aryl is substituted with 1-4 Ri₈.

27. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 26, wherein R_t is substituted or unsubstituted phenyl, and wherein if the phenyl substituted, then the phenyl is substituted with 1-4 Ri_8.

28. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 25, wherein R_t is substituted or unsubstituted C3-Ciocycloalkyl, and wherein if C3- Ciocycloalkyl is substituted, then the C3-Ciocycloalkyl is substituted with 1-4 Ris_.

29. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 28, wherein R_t is substituted C3-Ciocycloalkyl that is substituted with 1-4 Ri₈.

30. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 29, wherein R4 is substituted or unsubstituted cyclohexyl, and wherein if the cyclohexyl is substituted, then the cyclohexyl is substituted with 1-4 Ri_8.

31. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of claim 30, wherein R4 is substituted cyclohexyl that is substituted with 1-4 Ri₈.

32. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 25-31, wherein each Ris is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted aryl, halogen, or NH(C=0)ORi₉, and wherein any substituted group of Ri8 is substituted with 1-4R₂2.

33. The comp omer or pharmaceutically acceptable salt thereof, of

claim 28, wherein R4

and o is 0, 1 or 2.

34. The compound, geometric isomer or pharmaceutically acceptable salt thereof of claim 1, wherein the compound of Formula (C) is:

and R4 IS substituted or unsubstituted C3-Ciocycloalkyl or substituted or unsubstituted aryl, and wherein if R₄ is substituted, then R₄ is substituted with 1-4 Ri_8.

35. The compound, geometric isomer or pharmaceutically acceptable salt thereof of claim 1, wherein the compound of Formula (C) is:

36. The compound, geometric isomer or pharmaceutically acceptable salt thereof of claim, whe

222

223

37. The compound, geometric isomer or pharmaceutically acceptable salt thereof, of any one of claims 1-36, wherein the compound exhibits an IC50 of no more than about 5.000 μΜ.

38. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of claims 1-37, a geometric isomer, or a pharmaceutically acceptable salt thereof.

39. A method for treating a cancer in a subject comprising administering a therapeutically effective amount of a compound of any one of claims 1-37, a geometric isomer, or a

pharmaceutically acceptable salt thereof.

40. A method for treating a congenital disease in a subject comprising administering a therapeutically effective amount of the compound of any one of claims 1-37, a geometric isomer, or a pharmaceutically acceptable salt thereof.