WO2019152731A1

WO2019152731A1 - Androgen receptor antagonists

Info

Publication number: WO2019152731A1
Application number: PCT/US2019/016176
Authority: WO
Inventors: Santhosh N. PATIL; Bugga VNBS SARMA
Original assignee: Alpine Androsciences, Inc.
Priority date: 2018-01-31
Filing date: 2019-01-31
Publication date: 2019-08-08

Abstract

Compounds that inhibit the androgen receptor, pharmaceutical compositions comprising one or more of the compounds, as well as methods of treating cancer using such compounds are described.

Description

ANDROGE RECEPTOR ANTAGONISTS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of Indian Patent Application No.

20181 1003686, filed on January 31, 2018, and U.S. Provisional Application No.

62/649,470, filed March 28, 2018, the entire contents of which are hereby incorporated herein by reference.

FIELD

[0002] The present disclosure relates to compounds that inhibit the androgen receptor and variants thereof, as well as methods of treating cancer using such compounds.

BACKGROUND

[0003] The androgen receptor (AR) is a transcription factor that regulates gene expression of several genes important for development and maintenance of male-specific phenotypes. Recent discoveries have also uncovered a role of AR in regulating genes related to the female reproductive system. AR is activated upon binding to testosterone or dihydrotestosterone (DHT) in the cytoplasm of a cell before dimerizing, translocating to the nucleus, and binding to androgen receptor elements (ARE) promoter sequences of target genes or binding other proteins to regulate gene expression. Genes regulated by AR include the prostate specific antigen (PSA) and the insulin-like growth factor I receptor (IGF-1R).

[0004] The androgen receptor (AR) has been closely associated with prostate cancer, and has been a target for treatment of the disease. Several AR variants (AR-Vs), such as alternative splice variants, have been associated with aggressive forms of prostate cancer, including refractory prostate cancer and castration-resistant prostate cancer. AR is a multi- domain protein, including an N-terminal regulatory domain, a DNA binding domain (DBD) and a ligand binding domain (LBD). Inhibitors have been developed to target the LBD of AR: however certain variants of AR, such as AR-V7, lack the LBD and cannot be inhibited by such inhibitors. Accordingly, there continues to be a need to develop novel AR inhibitors, and in particular inhibitors that can modulate the activity of AR-Vs. BRIEF SUMMARY

[0005] Described herein are compounds that inhibit the androgen receptor and variants thereof, pharmaceutical compositions compri sing one or more of the compounds, as well as methods of treating cancer using such compounds.

[0006] In one aspect, there is provided a compound of formula (I):

or a salt thereof, wherein: X is C(R⁴) or N, wherein when X is N, R³ is other than hydrogen; Y is -O- or -N=CH-; L is C₂-C6 alkenylene wherein L is optionally substituted by L^a; each R¹ is independently halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C8 cycloalkyl, C₆-Ci4 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, -OR⁵, -NR⁶R⁷, cyano, or nitro, wherein each R¹ is independently optionally substituted by halogen, oxo, -OH, or Ci- Ce alkyl; R² is C6-C14 aryl, C₃-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 12- membered heterocyclyl, wherein the Ce-Cu aryl, C₃-C8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R² are each independently optionally substituted by halogen, oxo, -OR⁵, -NR⁶R⁷, -S(=0)R⁵, -S(=O)₂R⁵, -S(=0)₂NR⁶R⁷, cyano, nitro, or Ci-C₆ alkyl optionally substituted by halogen, -OH, or oxo; R³ and R⁴ are each independently hydrogen, halogen, amino, C₁-C₆ alkyl, C₃-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C₆-Ci4 aryl, or 5- to 10-membered heteroaryl, wherein the amino, Ci-C₆ alkyl, C₃-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C₆-Ci4 aryl, and 5- to 10-membered heteroaryl of R³ and R⁴ are each independently optionally substituted by halogen, oxo, cyano, -OR⁵, -NR R⁷, or alkyl optionally substituted by halogen, -oxo, or -OH; m is 0, 1, 2, 3, or 4; L^a is C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, -OR³, cyano, or oxo; R⁵ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C8 cycloalkyl, C₆-Ci4 aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C8 cycloalkyl, Ce-Ci4 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R⁵ are each independently optionally substituted by halogen, -OH, oxo, cyano, or Ci-C₆ alkyl optionally substituted by halogen, -OH, or oxo; and R⁶ and R⁷ are each independently hydrogen, Ci-C₆ alkyl, C₂-Ce alkenyl, C₂-C₆ alkynyl, C₃- Cs cycloalkyl, C₆-Ci4 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, - S(=0)R⁵, or -S(=O)₂R⁵, wherein the Cj-Ce alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃- C₈ cycloalkyl, C -Cu aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R⁶ and R⁷ are independently optionally substituted by halogen, -OR⁵, oxo, cyano, or Ci-C6 alkyl, optionally substituted by halogen, -OH, or oxo; with the proviso that when the compound of formula (I) is a salt, the cation is not a compound of formula (la):

(la).

[0007] In some embodiments, L is C₂ alkenylene optionally substituted by L^a In some embodiments, L is -CH=CH-. In some embodiments, L is C₂ alkenylene substituted by -CN.

[0008] In some embodiments, R² is optionally substituted C₆-C₁₄ aryl. In some

embodiments, R² is phenyl. In some embodiments, R² is optionally substituted C -C₈ cycloalkyl. In some embodiments, R² is cyclopentyl. In some embodiments, R² is cyclohexyl. In some embodiments, R² is optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, R² is optionally substituted 6-membered heterocyclyl. In some embodiments, R² is optionally substituted piperidinyl. In some embodiments, R² is l-methylpiperidin-4-yl. In some embodiments, R² is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R² is optionally substituted 6-memebered heteroaryl. In some embodiments, R² is optionally substituted pyridinyl. In some embodiments, R² is pyridin-3-yl.

[0009] In some embodiments, m is 0, 1, or 2.

[0010] In some embodiments, m is 0.

[0011] In some embodiments, m is 1. In some embodiments, m is 1 and R¹ is halogen. In some embodiments, m is 1 and R¹ is optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, m is 1 and R¹ is optionally substituted piperidinyl or morpholinyl. In some embodiments, m is 1 and R¹ is optionally substituted C₁-C₆ alkyl. In some

embodiments, m is 1 and R¹ is -CF₃. In some embodiments, m is 1 and R¹ is -OR⁵. In some embodiments, m is 1 and R¹ is -OCF₃. In some embodiments, m is 1 and R¹ is -NR⁶R'. In some embodiments, m is 1, R¹ is -NR⁶R⁷, and R⁶ and R⁷ are independently selected from hydrogen, -CH₂CH₂OH, and -CH₂CF₃.

[0012] In some embodiments, m is 2. In some embodiments, m is 2 and R¹ is independently selected from halogen, perhaloalkyl, and perhaloalkoxy.

[0013] In some embodiments, R³ is selected from -CH₃ and -NH₂.

[0014] In some embodiments, Y is -N=CH- and the compound has the formula (I-A):

(^Rl)m (I-A).

[0015] In some embodiments, Y is -O- and the compound has the formula (I-B):

[0016] In some embodiments, X is N and the compound has the formula (I-C):

[0017] In some embodiments, X is C(R⁴) and the compound has the formula (I-D):

[0018] In some embodiments, X is C(R⁴) and R⁴ is selected from -CH₃ and -NH₂.

[0019] In some embodiments, the compound is selected from the group consisting of Compound Nos. 1-107 in Table 1, or a salt thereof.

[0020] In some embodiments, the salt is a pharmaceutically acceptable salt.

[0021] In another aspect, there is provided a pharmaceutical composition comprising any one of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0022] In another aspect, there is provided a method of treating prostate cancer comprising administering to an individual having prostate cancer a therapeutically effective amount of any one of the compounds described above or a pharmaceutically acceptable salt thereof. In some embodiments, the prostate cancer is metastatic.

[0023] In another aspect, there is provided a method of inhibiting gene promoter activity of androgen receptor or a variant thereof in a cell that expresses said androgen receptor or variant thereof, comprising contacting the cell with any one of the compounds described above or a salt thereof. In some embodiments, the cell is a prostate cancer cell. In some embodiments, the cell is a metastatic prostate cancer cell. In some embodiments, the cell is contacted with the compound or salt thereof in vitro. In some embodiments, the cell is contacted with the compound or salt thereof in vivo.

[0024] In another aspect, there is provided a method of killing a cell that expresses androgen receptor or a variant thereof, comprising contacting the cell with any one of the compounds described above or a salt thereof In some embodiments, the cell is a prostate cancer cell. In some embodiments, the cell is a metastatic prostate cancer cell. In some embodiments, the cell is contacted with the compound or salt thereof in vitro. In some embodiments, the cell is contacted with the compound or salt thereof in vivo.

[0025] In another aspect, there is provided a method of inhibiting proliferation of a cell that expresses androgen receptor or a variant thereof, comprising contacting the cell with any one of the compounds described above or a salt thereof. In some embodiments, the cell is a prostate cancer cell. In some embodiments, the cell is a metastatic prostate cancer cell. In some embodiments, the cell is contacted with the compound or salt thereof in vitro. In some embodiments, the cell is contacted with the compound or salt thereof in vivo.

[0026] In another aspect, there is provided a use of any one of the compounds described above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prostate cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1A shows the effect of certain test compounds on PSA gene expression. FIG. I B shows the effect of certain test compounds on TMPRSS2 gene expression. Error bars in FIGS. 1 A and IB represent the standard error from the mean (SEM). A one way analysis of variance (ANOVA) followed by Bonferroni's Multiple Comparison Test was used to calculate statistical significance of the test compound compared to treatment with 1 nM dihydrotestosterone (DHT). * = P < 0.05, ** = P < 0.01, *** = P < 0.001, and ns = not significant.

[0028] FIG. 2A (LNCaP cells) and FIG. 2B (22Rvl cells) show cell proliferation of LNCaP cells or 22Rvl cells after incubation with test compounds, as measured by DAPI fluorescence signal. For both FIG. 2A and FIG. 2B, bars are presented left to right in the same order as the compounds listed in the key from top to bottom. DETAILED DESCRIPTION OF THE INVENTION

[0029] The invention provides, inter alia, compounds of formula (I), and variations thereof, pharmaceutical compositions compri sing compounds of formula (I), methods of inhibiting androgen receptor and androgen receptor variants, and methods of using such compounds and compositions in treating prostate cancer.

Definitions

[0030] Unless clearly indicated otherwise, use of the terms "a", "an" and the like refers to one or more.

[0031] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X".

[0032] "Alkyl" as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a "CrC₂o alkyl"), having 1 to 10 carbon atoms (a "Cr-Cio alkyl"), having 6 to 10 carbon atoms (a "C -Cw alkyl"), having 1 to 6 carbon atoms (a "Ci-C6 alkyl"), having 2 to 6 carbon atoms (a "C₂-C₆ alkyl"), or having 1 to 4 carbon atoms (a "C]-C₄ alkyl"). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0033] "Alkylene" as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 20 carbon atoms (a "C^C_M alkylene"), having 1 to 10 carbon atoms (a "C -Cto alkylene"), having 6 to 10 carbon atoms (a "C6-C₁₀ alkylene"), having 1 to 6 carbon atoms (a "C Ce alkylene"), 1 to 5 carbon atoms (a "C Cs alkylene"), 1 to 4 carbon atoms (a "C C alkylene") or 1 to 3 carbon atoms (a "CVC₃ alkylene"). Examples of alkylene include, but are not limited to, groups such as methylene (-CH₂-), ethylene (-CH₂CH₂-), propylene (-CH₂CH₂CH₂-), isopropylene (-CH₂CH(CH₃)-), butylene (-CH₂(CH₂)₂CH₂-), isobutylene (-CH₂CH(CH₃)CH₂-), pentylene (-CH₂(CH₂)₃CH₂-), hexylene (-CH₂(CH₂)₄CH₂-), heptylene (-CH₂(CH₂)₅CH₂-), octylene (-CH₂(CH₂)₆CH₂-), and the like.

[0034] "Alkenyl" as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=€) and having the number of carbon atoms designated (i.e., C₂-C₁₀ means two to ten carbon atoms). An alkenyl group may have "cis" or "trans" configurations, or alternatively have Έ" or "Z" configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a "C2-C20 alkenyl"), having 6 to 10 carbon atoms (a "Ce-Cu alkenyl"), having 2 to 8 carbon atoms (a "C₂-C8 alkenyl"), having 2 to 6 carbon atoms (a "C Ce alkenyl"), or having 2 to 4 carbon atoms (a "C₂-C₄ alkenyl"). Examples of alkenyl group include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2- methylbuta-l,3-dienyl, pent-l-enyl, pent-2-enyl, hex-l-enyl, hex-2-enyl, hex-3-enyl, and the like.

[0035] "Alkenylene" as used herein refers to the same residues as alkenyl, but having bivalency. Particular alkenylene groups are those having 2 to 20 carbon atoms (a "C₂-C₂o alkenylene"), having 2 to 10 carbon atoms (a "C₂-C_lo alkenylene"), having 6 to 10 carbon atoms (a "Ce-Cio alkenylene"), having 2 to 6 carbon atoms (a "C₂-Ce alkenylene"), 2 to 4 carbon atoms (a "C₂-C₄ alkenylene") or 2 to 3 carbon atoms (a "C₂-C₃ alkenylene").

Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH₂-), 1,4-but-l-enylene (-CH=CH-CH₂CH₂-), l,4-but-2-enylene (-CH₂CH=CHCH₂-), 1,6-hex-l-enylene (-CH=CH-(CH₂)₃CH₂-), and the like.

[0036] "Alkynyl" as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C₂-C_lo means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a "C₂- C₂o alkynyl"), having 6 to 10 carbon atoms (a "Ce-Cio alkynyl"), having 2 to 8 carbon atoms (a "C₂-Cs alkynyl"), having 2 to 6 carbon atoms (a "C₂-C6 alkynyl"), or having 2 to 4 carbon atoms (a "C₂-C₄ alkynyl"). Examples of alkynyl group include, but are not limited to, groups such as ethynyl (or acetyl enyl), prop-l-ynyl, prop-2-ynyl (or propargyl), but-l-ynyl, but-2- ynyl, but-3-ynyl, and the like.

[0037] "Alkynylene" as used herein refers to the same residues as alkynyl, but having bivalency. Particular alkynylene groups are those having 2 to 20 carbon atoms (a "C₂-C₂o alkynylene"), having 2 to 10 carbon atoms (a "C₂-C]o alkynylene"), having 6 to 10 carbon atoms (a "Ce-Cto alkynylene"), having 2 to 6 carbon atoms (a "C₂-C6 alkynylene"), 2 to 4 carbon atoms (a "C2-C4 alkynylene") or 2 to 3 carbon atoms (a "C2-C₃ alkynylene").

Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C≡C-), propynylene (-C≡CCH₂-), and the like.

[0038] "Cycloalkyl" as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C^-C^ means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C₃-C8 cycloalkyl"), having 3 to 6 annular carbon atoms (a "C₃-C₆ cycloalkyl"), or having from 3 to 4 annular carbon atoms (a "C₃-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomyl, and the like.

[0039] "Cycloalkylene" as used herein refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C₃-C_S cycloalkylene"), having 3 to 6 carbon atoms (a "C₃-C6 cycloalkylene"), or having from 3 to 4 annular carbon atoms (a "C₃-C4 cycloalkylene"). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. A cycloalkylene may attach to the remaining structures via the same ring carbon atom or different ring carbon atoms. When a cycloalkylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis- or trans- to each other. For example, cyclopropylene may include 1,1 -cyclopropylene and 1,2-cyclopropylene (e.g., cis- 1,2- cyclopropylene or trans-l,2-cyclopropylene), or a mixture thereof.

[0040] "Cycloalkenyl" refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C 0 means two to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C₃-C8 cycloalkenyl"). Examples of cycloalkenyl groups include, but are not limited to,

cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

[0041] "Cycloalkenylene" as used herein refers to the same residues as cycloalkenyl, but having bi valency.

[0042] "Aryl" or "Ar" as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryi) which condensed rings may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a "Ce-Cu aryl"). An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

[0043] "Arylene" as used herein refers to the same residues as aryl, but having bivalency. Particular arylene groups are those having from 6 to 14 annular carbon atoms (a "Ce-Cw arylene").

[0044] "Heteroaryi" as used herein refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryi group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. Particular heteroaryi groups are 5 to 14- membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, particular heteroaryi groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, particular heteroaryi groups are poly cyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. A heteroaryi group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryi group having more than one ring where at least one ring is non- aromatic is connected to the parent structure at an aromatic ring position. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0045] "Heteroarylene" as used herein refers to the same residues as heteroaryl, but having bivalency.

[0046] "Heterocycle", "heterocyclic", or "heterocyclyl" as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl, aryl or heteroaryl. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein. Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12- membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6- membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms

independently selected from nitrogen, oxygen and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0047] "Heterocyclylene" as used herein refers to the same residues as heterocyclyl, but having bivalency.

[0048] "Halo" or "halogen" refers to elements of the Group 17 seri es having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3- fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a "perhaloalkyl." A preferred perhaloalkyl group is trifluoroalkyl (-CF₃). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF₃).

[0049] "Oxo" refers to the moiety =0.

[0050] "Optionally substituted" unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted.

[0051] Unless clearly indicated otherwise, "an individual" as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human.

[0052] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. The methods of the invention contemplate any one or more of these aspects of treatment.

[0053] As used herein, the term "effective amount" intends such amount of a compound of the invention which should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e. , a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0054] A "therapeutically effective amount" refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome.

[0055] As used herein, "unit dosage form" refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.

[0056] As used herein, the term "controlled release" refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a "controlled release" formulation, administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g. , pH- dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g. , coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).

[0057] As used herein, by "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.

Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0058] "Pharmaceutically acceptable salts" are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0059] The term "excipient" as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.;

suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc. [0060] Unless otherwise stated, "substantially pure" intends a composition that contains no more than 15% impurity, such as a composition comprising less than 12%, 10%, 8%, 5%, 3%, 1% impurity. For example, a composition comprising substantially pure 6-position regioisomer contains less than 5% of the 7-position regioisomer.

Compounds

[0061] In one aspect, provided is a compound of formula (I)

or a salt thereof, wherein:

X is C(R⁴) or N wherein when X is N, R³ is other than hydrogen; Y is -O- or -N=CH-;

L is C₂-C6 alkenylene wherein L is optionally substituted by L^a; each R¹ is independently halogen, C\-Ce alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃- Cs cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, - OR⁵, -NR⁶R⁷, cyano, or nitro, wherein each R¹ is independently optionally substituted by halogen, oxo, -OH, or C]-Ce alkyl;

R² is Ce-C₁₄ aryl, C₃-Cg cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C^-Cn aryl, C₃-C8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R² are each independently optionally substituted by halogen, oxo, -OR⁵, -NR R⁷, -S(=0)R⁵, -S(=O)₂R⁵, -S(=0)₂NR R⁷, cyano, nitro, or C C₆ alkyl optionally substituted by halogen, -OH, or oxo;

R³ and R⁴ are each independently hydrogen, halogen, amino, C₁-C₆ alkyl, C₃-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C₁₄ aryl, or 5- to 10-membered heteroaryl, wherein the amino, C₁-C₆ alkyl, C₃-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C₆-C₁₄ aryl, and 5- to 10-membered heteroaryl of R³ and R⁴ are each independently optionally substituted by halogen, oxo, cyano, -OR⁵, -NR⁶R⁷, or alkyl optionally substituted by halogen, -oxo, or -OH; m is 0, 1, 2, 3, or 4; L^a is C C₆ alkyl, d-Cehaloalkyl, halogen, -OR³, cyano, or oxo;

R⁵ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-Ce alkynyl, Cj-Cg cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C8 cycloalkyl, C6-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R⁵ are each independently optionally substituted by halogen, -OH, oxo, cyano, or C₁-C₆ alkyl optionally substituted by halogen, - OH, or oxo; and

R⁶ and R⁷ are each independently hydrogen, C4-C6 alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃- Cg cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, - S(=0)R⁵, or -S(=O)₂R⁵, wherein the Cj-Ce alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃- Cg cycloalkyl, C -Cu aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R⁶ and R⁷ are independently optionally substituted by halogen, -OR⁵, oxo, cyano, or C₁-C₆ alkyl, optionally substituted by halogen, -OH, or oxo, or

R⁶ and R⁷ are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally containing an additional heteroatom and optionally substituted by halogen, oxo, cyano, or C₁-C₆ alkyl optionally substituted by halogen, -OH, or oxo; with the proviso that when the compound of formula (I) is a salt, the cation is not a compound of formula (la):

(la).

[0062] In the descriptions herein, it is understood that every description, variation, embodiment or aspect of a moiety may be combined every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment or aspect provided herein with respect to R¹ of formula (I) may be combined with every description, variation, embodiment or aspect of Y, L, X, R², R³ and/or m the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to any of formulae I-A, I-B, I-C, I-D, II-A, II-B, II-C, II-D, III- A, III-B, and III-C detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae.

[0063] In some embodiments of the compound of formula (I), wherein Y is -N=CH-, the compound is of the formula (I-A):

(^Rl)m (I-A)

or a salt thereof, wherein L, X, R¹, R², R³, and m are as defined for formula (I).

[0064] In some embodiments of the compound of formula (I), wherein Y is -<

compound is of the formula (I-B):

[0065] In some embodiments of the compound of formula (I), wherein X is N, the compound is of the formula (I-C):

or a salt thereof, wherein L, Y, R¹, R², R³, and m are as defined for formula (I).

[0066] In some embodiments of the compound of formula (I), wherein X is C(R⁴), the compound is of the formula (I-D):

or a salt thereof, wherein L, Y, R¹, R², R³, R⁴, and m are as defined for formula (I). [0067] In some embodiments of the compound of formula (I), wherein Y is -N=CH- and X is N, the compound is of the formula (II-A):

I

(R¹)m (II-A)

or a salt thereof, wherein L, R¹, R², R³, and m are as defined for formula (I).

[0068] In some embodiments of the compound of formula (I), wherein Y is -N=CH- and X is C(R⁴), the compound is of the formula (II-B):

,R⁴

R²

(R¹)m (II-Β)

or a salt thereof, wherein L, R¹, R², R³, R⁴, and m are as defined for formula (I).

[0069] In some embodiments of the compound of formula (I), wherein Y is -O- and X is N, the compound is of the formula (II-C):

R³ (II-C)

[0070] In some embodiments of the compound of formula (I), wherein Y is -O- and X is

C(R⁴), the compound is of the formula (II-D):

R³ (II-D)

[0071] In some embodiments of the compound of formula (I-A), wherein m is 1, the compound is a compound of the formula (III- A):

^{R1 7 R} (ΙII-Α)

or a salt thereof, wherein L, X, R¹, R², and R³ are as defined for formula (I). In one embodiment, a compound of formula (III- A) is provided, wherein R¹ is at the 6-position of the quinoxaline ring. In one embodiment, a compound of formula (III-A) is provided, wherein R¹ is at the 7-position of the quinoxaline ring. In another embodiment, a composition comprising a compound of formula (III- A) is provided, such as a composition comprising a mixture of regioisomers. In one embodiment is provided a composition comprising a mixture of 6- and 7-position regioisomers of a compound of formula (III- A), in which the composition comprises a mixture of a compound of formula (III-A) wherein R¹ is at the 7- position of the quinoxaline ring and a compound of formula (III-A) wherein R¹ is at the 6- position of the quinoxaline ring. Compositions comprising a mixture of regioisomers may contain the compounds in any ratio, including a 50:50 mixture of two regioisomers, such as a 50:50 mixture of 6- and 7-position regioisomers of a compound of formula (III-A). In some embodiments, the mixture of regioisomers consist of the regioisomer wherein R¹ is in the 6- position of the quinoxaline core and the regioisomer wherein R¹ is in the 7-position of the quinoxaline core.

[0072] In some embodiments of the compound of formula (I -A), wherein m is 1, the compound is a single regioisomer wherein R¹ is in the 6-position of the quinoxaline core and is represented by the formula (III-B):

or a salt thereof, wherein L, X, R¹, R², and R³ are as defined for formula (I). In one variation is provided a composition comprising substantially pure 6-position regioisomer. In another variation, a composition comprising substantially pure 6-position regioisomer is provided wherein no more than 5% of the 7-position regioisomer is present.

[0073] In some embodiments of the compound of formula (I-A), wherein m is 1, the compound is a single regioisomer wherein R¹ is in the 7-position of the quinoxaline core and is represented by the formula (III-C):

or a salt thereof, wherein L, X, R¹, R², and R³ are as defined for formula (I). In one variation is provided a composition comprising substantially pure 7-position regioisomer. In another variation, a composition comprising substantially pure 7-position regioisomer is provided wherein no more than 5% of the 6-position regioisomer is present. [0074] In some embodiments of the compound of formula (I-A), (I-B), (1-C), (I-D), (II- A), (II-B), (II-C), (II-D), (III-A), (III-B), or (ΙII-C), or a salt thereof, L is C₂ alkenylene optionally substituted by L^a In a particular embodiment, L is unsubstituted C₂ alkenylene. In some embodiments of the compound of formula (I-A), (I-B), (I-C), (I-D), (II-Α), (II-B), (II-C), (II- D), (III-A), (III-B), or (III-C), or a salt thereof, R² is phenyl, C₅-C₆ cycloalkyl, 6-membered heterocyclyl, or 6-membered heteroaryl, wherein the phenyl, C5-C6 cycloalkyl, 6-membered heterocyclyl, and 6-membered heteroaryl of R² are each independently optionally substituted by halogen, oxo, -OR⁵, -NR⁶R⁷, -S(=0)R⁵, -S(=O)₂R⁵, -S(=0)₂NR R⁷, cyano, nitro, or C₁-C₆ alkyl optionally substituted by halogen, -OH, or oxo. In some embodiments of the compound of formula (I-A), (I-B), (I-C), (I-D), (II-Α), (H-B), (II-C), or (II-D), or a salt thereof, m is 0, 1 or 2. In some embodiments of the compound of formula (I-A), (I-B), (I-C), (I-D), (II-A), (II- B), (II-C), (II-D), (III-A), (III-B), or (III-C), or a salt thereof, R¹ is independently selected from halogen, perhaloalkyl, C₃ cycloalkyl, 4- to 6-membered heterocyclyl, -OR⁵ , and - NR⁶R⁷, wherein the C₃ cycloalkyl and 4- to 6-membered heterocyclyl of R¹ are each independently optionally substituted by halogen, oxo, -OH, or C]-Ce alkyl, R³ is Cj-Ce alkyl optionally substituted by halogen, and R⁶ and R' are independently selected from hydrogen, - S(=O)₂R⁵, and C₁-C₆ alkyl optionally substituted by halogen or -OR⁵. In some embodiments of the compound of formula (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), or (III-C), or a salt thereof, R' is -CH₃ or -NH₂. In some embodiments of the compound of formula (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-C), (II-D), (ffl-A), (III-B), or (III-C), or a salt thereof, L is C₂ alkenylene optionally substituted by L^a; R² is phenyl, C5- C₆ cycloalkyl, 6-membered heterocyclyl, or 6-membered heteroaryl, wherein the phenyl, C5- C₆ cycloalkyl, 6-membered heterocyclyl, and 6-membered heteroaryl of R² are each independently optionally substituted by halogen, oxo, -OR⁵, -NR⁶R⁷, -S(=0)R⁵, -S(=O)₂R⁵, - S(=0)₂NR⁶R⁷, cyano, nitro, or C C₆ alkyl optionally substituted by halogen, -OH, or oxo; m is 0; and R^J is -CH₃ or -NH₂. In some embodiments of the compound of formula (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), or (ffl-C), or a salt thereof, L is C₂ alkenylene optionally substituted by L^a; R² is phenyl, Cj-Ce cycloalkyl, 6-membered heterocyclyl, or 6-membered heteroaryl, wherein the phenyl, Cs-Ce cycloalkyl, 6-membered heterocyclyl, and 6-membered heteroaryl of R² are each independently optionally substituted by halogen, oxo, -OR⁵, -NR⁶R⁷, -S(=0)R⁵, -S(=O)₂R⁵, -S(=0)₂NR⁶R⁷, cyano, nitro, or d-C₆ alkyl optionally substituted by halogen, -OH, or oxo; m is 1; R¹ is halogen, C₃ cycloalkyl, 4- to 6-membered heterocyclyl, -OR⁵, or -NR⁶R⁷, wherein the C₃ cycloalkyl and 4- to 6- membered heterocyclyl of R¹ are each independently optionally substituted by halogen, oxo, - OH, or C4-C6 alkyl, R⁵ is Ci-Cf, alkyl optionally substituted by halogen, and R⁶ and R⁷ are independently selected from hydrogen, -S(=O)₂R⁵, and C₁-C₆ alkyl optionally substituted by halogen or -OR⁵; and R³ is -CH₃ or -NH₂. In some embodiments of the compound of formula (I-A), (I-B), (I-C), (1-D), (11-A), (1I-B), (II-C), (II-D), (III-A), (III-B), or (III-C), or a salt thereof, L is C₂ alkenylene optionally substituted by L^a; R² is phenyl, C5-C6 cycloalkyl, 6- membered heterocyclyl, or 6-membered heteroaryl, wherein the phenyl, Cs-C₆ cycloalkyl, 6- membered heterocyclyl, and 6-membered heteroaryl of R² are each independently optionally substituted by halogen, oxo, -OR⁵, -NR⁶R⁷, -S(=0)R⁵, -S(=O)₂R⁵, -S(=0)₂NR⁶R⁷, cyano, nitro, or C₁-C₆ alkyl optionally substituted by halogen, -OH, or oxo; m is 2; R¹ is

independently selected from halogen, perhaloalkyl, perhaloalkoxy, and optionally substituted 3- to 12-membered heterocyclyl; and R³ is -CH₃ or -NH₂.

[0075] In some embodiments of the compound of formula (I-A), (I-B), (I-C), (I-D), (II- A), (II-B), (II-C), (II-D), (III-A), (III-B), or (ffl-C), or a salt thereof, where applicable, the compound has one or more of the following structural features:

(i) L is C9-C₃ alkenylene optionally substituted by L^a,

such as:

(i-a) L is C₂ alkenylene substituted by L^a (e.g., -CN) or

(i-b) L is unsubstituted C alkenylene

(ii) R² is phenyl, C5-C6 cycloalkyl, 6-membered heterocyclyl, or 6-membered heteroaryl, wherein the phenyl, C5-C6 cycloalkyl, 6-membered heterocyclyl, and 6-membered heteroaryl of R² are each independently optionally substituted by halogen, oxo, -OR⁵, -NR⁶R⁷, -S(=0)R⁵, -S(=O)₂R⁵, - S(=0)₂NR⁶R⁷, cyano, nitro, or C₁-C₆ alkyl optionally substituted by halogen, - OH, or oxo,

such as:

(ii-a) R² is unsubstituted phenyl

(ii-b) R² is phenyl substituted by halogen, perhaloalkyl, -CN, or S(=0)₂NR R⁷

(ii-c) R² is unsubstituted cyclopentyl or cyclohexyl

(ii-d) R² is cyclopentyl or cyclohexyl substituted by halogen, oxo, -OR⁵, - NR⁶R⁷, -S(=0)R⁵, -S(=O)₂R⁵, -S(=0)₂NR⁶R⁷, cyano, nitro, or d-C₆ alkyl optionally substituted by halogen, -OH, or oxo (ii-e) R² is unsubstituted 6-membered heterocyclyl

(ii-f) R² is 6-membered heterocyclyl substituted by C₁-C₆ alkyl (e.g., N- methylpiperidinyl)

(ii-g) R² is unsubstituted 6-membered heteroaryl (e.g., pyridinyl) or

(ii-h) R² is 6-membered heteroaryl substituted by C₁-C₆ alkyl (e.g.,

methylpyridinyl)

(iii) m is 0, 1 or 2

(iv) R¹ is independently selected from halogen, perhaloalkyl, C₃ cycloalkyl, 4- to 6-membered heterocyclyl, -OR⁵ , and -NR⁶R⁷, wherein the C₃ cycloalkyl and 4- to 6-membered heterocyclyl of R¹ are each independently optionally substituted by halogen, oxo, -OH, or C₁-C₆ alkyl, R is C₁-C₆ alkyl optionally substituted by halogen, and R⁶ and R ' are independently selected from hydrogen, -S(=O)₂R⁵, and C₁-C₆ alkyl optionally substituted by halogen or - OR⁵,

such as:

(iv-a) R¹ is fluoro, chloro, or bromo

(iv-b) R¹ is peril uoromethyl

(iv-c) R¹ is unsubstituted cyclopropyl

(iv-d) R¹ is cyclopropyl optionally substituted by halogen, oxo, -OH, or C₁-C₆ alkyl

(iv-e) R¹ is unsubstituted 4- to 6-membered heterocyclyl (e.g., pyrrolidinyl, piperidinyl, morpholinyl, or 1,2,3,6-tetrahydropyridinyl)

(iv-f) R¹ is 4- to 6-membered heterocyclyl substituted by halogen, oxo, -OH, or C₁-C₆ alkyl (e.g., difluoroazetidinyl, pyrrolidinonyl,

difluoropiperidinyl, methylpiperazinyl, or methylmorpholinyl)

(iv-g) R¹ is alkoxy (e.g, -OCH₃) or perhaloalkoxy (e.g., -OCF₃)

(iv-h) R¹ is -NR⁶R⁷, wherein R⁶ and R⁷ are independently selected from

hydrogen, -S(=O)₂R⁵, and C₁-C₆ alkyl optionally substituted by halogen or -OR⁵ (e.g., -N(CH₃)₂, -NH(CH₂)₂OH, -NH(CH₂)₂OCH₃, - N((CH₂)₂OH)CH₂CF₃, or -NH(=0)₂CH₃; and

(v) R³ is -CH₃ or -NH₂.

[0076] In one aspect, a compound of formula (I-A), (I-B), (I-C), (I-D), (II-Α), (II-B), (II-C), (II-D), (III-A), (III-B), or (III-C), or a salt thereof, is provided, wherein the compound has two of the structural features (i)-(v), such as (i) and any one of (ii)-(v): (ii) and any one of (i) or (iii)-(v); (iii) and any one of (i), (ii), (iv), or (v); (iv) and any one of (i)-(iii) or (v); or (v) and any one of (i)-(iv). In one aspect, a compound of formula (I-A), (I-B), (I-C), (I-D), (II-A), (II-B), (II-C), (II-D), (ΙII-Α), (III-B), or (ffl-C), or a salt thereof, is provided, wherein the compound has three of the structural features (i)-(v), such as (i) and any two of (ii)-(v); (ii) and any of two of (i) or (iii)-(v); (iii) and any two of (i), (ii), (iv), or (v); (iv) and any two of (i)-(iii) or (v); or (v) and any two of (i)-(iv). In one aspect, a compound of formula (I-A), (I- B), (I-C), (I-D), (II-Α), (II-B), (II-C), (II-D), (M-A), (III-B), or (M-C), or a salt thereof, is provided, wherein the compound has four of the structural features (i)-(v), such as (i) and any three of (ii)-(v); (ii) and any of three of (i) or (iii)-(v); (iii) and any three of (i), (ii), (iv), or (v); (iv) and any three of (i)-(iii) or (v); or (v) and any three of (i)-(iv). In one aspect, a compound of formula (I-A), (I-B), (1-C), (I-D), (II-A), (II-B), (II-C), (II-D), (1II-A), (III-B), or (III-C), or a salt thereof, is provided, wherein the compound has all of the structural features (i)-(v).

[0077] In some embodiments, X is C(R⁴) and R⁴ is selected from optionally substituted C]- C₆ alkyl and optionally substituted amino. In some embodiments, R⁴ is optionally substituted Ci alkyl. In some embodiments, R⁴ is -CH₃. In some embodiments, R⁴ is -NH₂.

[0078] In some embodiments, L is C₂ alkenylene optionally substituted by L^a. In a particular variation, L is -CH=CH-. In another particular variation, L is C₂ alkenylene substituted by -CN (e.g., -C(CN)=CH- or -CH=C(CN)-).

[0079] In some embodiments, R² is optionally substituted Ce-Cu aryl. In some

embodiments, R² is optionally substituted phenyl. In some embodiments, R² is unsubstituted phenyl. In some embodiments, R² is phenyl substituted with halogen (e.g., fluoro or chloro), C₁-C₆ alkyl optionally substituted by halogen (e.g., -CF₃), cyano, or -S(=0)₂NR⁶R⁷ (e.g., - S(=0)₂NH₂).

[0080] In some embodiments, R² is optionally substituted C₃-C₈ cycloalkyl. In some embodiments, R² is optionally substituted Cs-C₆ cycloalkyl. In some embodiments, R² is optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some

embodiments, R² is unsubstituted cyclopentyl or unsubstituted cyclohexyl.

[0081] In some embodiments, R² is optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, R² is optionally substituted 6-membered heterocyclyl. In some embodiments, R² is optionally substituted piperidinyl. In some embodiments, R² is 1- methylpiperidinyl. In some embodiments, R² is 1-methylpiperidinyl and attached to the rest of the molecule at the C4 position (i.e., R² is l-methylpiperidin-4-yl).

[0082] In some embodiments, R² is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R² is optionally substituted 6-membered heteroaryl. In some embodiments, R² is optionally substituted pyridinyl. In some embodiments, R² is unsubstituted pyridinyl. In some embodiments, R² is unsubstituted pyridinyl and attached to the rest of the molecule at the C3 position (i.e., R² is pyridin-3-yl). In some embodiments, R² is substituted pyridinyl. In some embodiments, R² is 3-methylpyridinyl and attached to the rest of the molecule at the C2 position (i.e., R² is 3-methylpyridin-2-yl).

[0083] Also provided is a compound of formula (I), or a salt thereof, wherein R² is

selected from the group consisting of

D^~cn hCH°2^{N H}2 h

D^~CF3 HO KD

N—

[0084] Also provided is a compound of formula (I), or a salt thereof, wherein R² is selected from the group consisting of v— y , , \— / , NH _; and

[0085] Also provided is a compound of formula (I), or a salt thereof, wherein R² is selected from the group consisting of > " _m an_dd >

[0086] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0087] In some embodiments, m is 1 and R¹ is halogen (e.g., fluoro, chloro, and bromo). In some embodiments, m is 1 and R¹ is optionally substituted C3-C8 cycloalkyl. In some embodiments, m is 1 and R¹ is optionally substituted C₃ cycloalkyl (e.g., cyclopropyl). In some embodiments, m is 1 and R¹ is optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, m is 1 and R¹ is optionally substituted 4-membered heterocyclyl. In some embodiments, m is 1 and R¹ is optionally substituted azetidinyl (e.g., azetidin-l-yl, azetidin-2-yl, or azetidin-3-yl). In some embodiments, m is 1 and R¹ is azetidinyl optionally substituted by halogen (e.g., 3,3-difluoroazetidin-l-yl). In some embodiments, m is 1 and R¹ is optionally substituted 5-membered heterocyclyl. In some embodiments, m is 1 and R¹ is optionally substituted pyrrolidinyl. In some embodiments, m is 1 and R¹ is pyrrolidin-l-yl or pyrrolidin-2-on-l -yl. In some embodiments, m is 1 and R¹ is optionally substituted 6- membered heterocyclyl. In some embodiments, m is 1 and R¹ is optionally substituted piperidinyl, piperazinyl, morpholinyl, or tetrahydropyridinyl. In some embodiments, m is 1 and R¹ is unsubstituted piperidinyl (e.g., piperidin-l-yl) or piperidinyl substituted by halogen (e.g., 4,4-difluoropiperidin-l-yl). In some embodiments, m is 1 and R¹ is piperazinyl optionally substituted by Cj-Ce alkyl (e.g., 4-methyl-piperazin-l-yl). In some embodiments, m is 1 and R¹ is unsubstituted morpholinyl (e.g., morpholin-4-yl) or morpholinyl substituted by C₁-C₆ alkyl (e.g., (5)-3-methylmorpholin-4-yl or (i?)-3-methylmorpholin-4-yl). In some embodiments, m is 1 and R¹ is optionally substituted tetrahydropyridinyl (e.g., 1,2,3,6- tetrahydropyridin-4-yl). In some embodiments, m is 1 and R¹ is -OR⁵. In some embodiments, m is 1 and R¹ is -OR⁵, wherein R⁵ is C₁-C₆ alkyl optionally substituted by halogen. In some embodiments, m is 1 and R¹ is -OR⁵, wherein R⁵ is unsubstituted Ci alkyl (i.e., -CH3) or Ci alkyl substituted by halogen (e.g., -CF3). In some embodiments, m is 1 and R¹ is -NR R^;. In some embodiments, m is 1 and R¹ is -NR⁶R⁷, wherein R⁶ and R⁷ are independently selected from hydrogen, -S(=O)₂R⁵, and Cr-Ce alkyl optionally substituted by halogen or -OR⁵. In some embodiments, m is 1 and R¹ is -NR⁶R⁷, wherein R⁶ is hydrogen or C₁-C₆ alkyl substituted by halogen. In some embodiments, m is 1 and R¹ is -NR R', wherein R⁷ is independently selected from -S(=O)₂R⁵ (e.g., -S(=0)₂CH₃) and C -C6 alkyl substituted by - OR⁵ (e.g., -CH₂CH₂OH or -CH₂CH₂OCH₃). In some embodiments, m is 1 and R¹ is -NR⁶R⁷, wherein R⁶ is hydrogen and R⁷ is independently selected from -S(=O)₂R⁵ (e.g., -S(=0)₂CH3) and C4-C6 alkyl substituted by -OR³ (e.g., -CH₂CH₂OH, wherein R⁵ is hydrogen, or - CH₂CH₂OCH3, wherein R⁵ is -CH3). In some embodiments, m is 1 and R¹ is -NR⁶R⁷, wherein R⁶ is C₁-C₆ alkyl substituted by halogen (e.g. , -CH₂CF3) and R' is C C₆ alkyl substituted by - OR⁵ (e.g., -CH₂CH₂OH). In some embodiments, m is 1 and R¹ is -NR⁶R⁷, wherein R⁶ and R⁷ are optionally substituted C] alkyl (e.g., -CH3).

[0088] In some embodiments, m is 2 and R¹ is independently selected from halogen, perhaloalkyl, perhaloalkoxy, and optionally substituted 3- to 12-membered heterocyclyl. In some embodiments, m is 2 and one R¹ is fluoro. In some embodiments, m is 2 and one R¹ is chloro. In some embodiments, m is 2 and one R¹ is perhaloalkyl. In some embodiments, m is 2 and one R¹ is -CF₃. In some embodiments, m is 2 and one R¹ is perhaloalkoxy. In some embodiments, m is 2 and one R¹ is -OCF3. In some embodiments, m is 2 and one R¹ is optionally substituted 6-membered heterocyclyl. In some embodiments, m is 2 and one R¹ is morpholinyl. In some embodiments, m is 2, the first R¹ is fluoro, and the second R¹ is selected from halogen, perhaloalkyl, perhaloalkoxy, and optionally substituted 3- to 12- membered heterocyclyl. In some embodiments, m is 2, one R¹ is fluoro, and the other R¹ is selected from fluoro, chloro, -CF₃, -OCF₃, and morpholinyl. In some embodiments, m is 2 and each R¹ is fluoro. In some embodiments, m is 2, one R¹ is fluoro, and the other R¹ is chloro. In some embodiments, m is 2, one R¹ is fluoro, and the other R¹ is -CF3. In some embodiments, m is 2, one R¹ is fluoro, and the other R¹ is -OCF3. In some embodiments, m is 2, one R¹ is fluoro, and the other R¹ is morpholinyl.

[0089] Also provided is a compound of formula (I), or a salt thereof, wherein R¹ is selected

from the group consisting of fluoro, chloro, bromo,

[0090] Also provided is a compound of formula (I), or a salt thereof, wherein R¹ is selected

F

F₃C ,Ny F₃COy

from the group consisting of fluoro y

F₃C

H

Hor^ . ^ Hor^ .

[0091] Also provided is a compound of formula (I), or a salt thereof, wherein R¹ is selected

from the group consisting of fluoro, ' , and '

(R¹)_n

[0092] In some embodimen ts, the O ^^^{^}HN moiety of the compound of formula

(I) is selected from the group consisting of R¹

moiety of the compound of formula

R , wherein each R¹ is independently as defined for formula (I).

[0094] In some embodiments, R³ is selected from optionally substituted C₁-C₆ alkyl and optionally substituted amino. In some embodiments, R³ is optionally substituted Ci alkyl. In some embodiments, R³ is -CH₃. In some embodiments, R³ is -NH₂.

3

[0095] In some embodiments, the R y moiety of the compound of formula (I) is

N- selected from the group consisting of \

' . and

^ ¹

y

[0096] In some embodiments, the R^J moiety of the compound of formula (I) is

NH₂ selected from the group consisting of

H

y

[0097] In some embodiments, the R^J moiety of the compound of formula (I) is

[0098] When a moiety is contemplated, it is understood that the moiety can be attached to the parent structure at all available positions. For example, azetidinyl may be attached to the parent molecule at the 1 , 2, or 3 position (i.e., azetindin-l-yl, azetindin-2-yl, or azetindin-3- yl, respectively).

[0099] Representative compounds are listed in Table 1.

Table 1

[0100] In some embodiments, provided herein is a compound described in Table 1 , or a tautomer thereof, or a salt of any of the foregoing, and uses thereof. In some embodiments, provided herein is a compound described in Table 1 or a pharmaceutically acceptable salt thereof.

[0101] The compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.

[0102] Where tautomeric forms may be present for any of th e compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.

[0103] The present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described, such as the compounds of Table 1. The structure or name is intended to embrace all possible

stereoisomers of a compound depicted. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.

[0104] The invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element. Exemplar)' isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as ²H, ³H, ⁿC, ¹³C, ¹⁴C ¹³N, ¹⁵0, ¹⁷0, ³²P, ⁵S, ¹⁸F, ⁱ⁶Cl. Certain isotope labeled compounds (e.g. ¾ and ¹⁴C) is useful in compound or substrate tissue distribution studies. Incorporation of heavier isotopes such as deuterium (²H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.

[0105] Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically- labeled reagents in place of the corresponding non-labeled reagent.

[0106] Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like. [0107] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration.

[0108] One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.

Pharmaceutical Compositions and Formulations

[0109] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

[0110] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as

compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.

[0111] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

[0112] A compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0113] One or several compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re- wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington 's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20^th ed. (2000), which is incorporated herein by reference.

[0114] Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0115] Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary' medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.

Methods of Use and Uses

[0116] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.

[0117] In certain embodiments, a compound of formula (I) is an androgen receptor (AR) inhibitor that targets the DNA binding domain of the androgen receptor (DBD-AR). The androgen receptor (AR) may be a wild-type (or full length) androgen receptor (AR-FL) or may be a variant of the androgen receptor (AR-V). The variant androgen receptor may be a splice variant or a truncation variant, which may exclude some or all of the ligand binding domain (LBD) of the androgen receptor, or may include one or more point mutations. For example, the AR-V7 splice variant of the androgen receptor is a known variant found in certain populations of metastatic prostate cancer cells. Androgen receptor is a transcription factor associated with prostate cancer, and an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a patient with prostate cancer for treatment. In some embodiments, the prostate cancer (or prostate cancer cells) includes AR-FL or AR- V, or a combination thereof.

[0118] In some embodiments, the compound inhibits the androgen receptor or a variant thereof. In some embodiments, the androgen receptor is a full length androgen receptor (AR-FL). In some embodiments, the androgen receptor variant (AR-V) is a splice variant. In some embodiments, the androgen receptor variant lacks the ligand binding domain (LBD). In some embodiments, the androgen receptor variant is AR-Vl, AR-V2, AR-V3, AR-V4, AR- V5, AR-V6, AR-V7, AR-V8, AR-V9, AR-V10, AR-Vl 1 , or AR-V12. Certain cells, such as certain prostate cancer cells, express one or more androgen receptor variants, which can collectively be referred to as AR-Vs.

[0119] In some embodiments, the compound has an IC50 to the androgen receptor or a variant thereof of about 1 nM or more (such as about 1.5 nM or more, about 2.5 nM or more, about 5 nM or more, about 10 nM or more, about 25 nM or more, about 50 nM or more. about 100 nM or more, about 250 nM or more, about 500 nM or more, or about 1000 nM or more). In some embodiments, the compound has an IC50 to the androgen receptor or a variant thereof of about 1000 nM or less (such as about 500 nM or less, about 250 nM or less, about 100 nM or less, about 50 nM or less, about 25 nM or less, about 10 nM or less, about 5 nM or less, about 2.5 nM or less, about 1.5 nM or less, or about 1 nM or less). ICso can be determined using, for example, a cell-based luciferase expression assay, wherein luciferase expression is under control of a prostate specific antigen (PSA) promoter, or a qPCR assay.

[0120] In some embodiments, there is a method of inhibiting androgen receptor or variant thereof in vitro, for example by contacting the compound with a cell expressing the androgen receptor or a variant thereof. In some embodiments, there is a method of inhibiting androgen receptor or a variant thereof in vitro, for example by administering the compound to an individual.

[0121] In some embodiments, the compound inhibits androgen receptor gene promoter activity and/or androgen receptor variant gene promoter activity. In some embodiments, the compound is provided at a concentration that inhibits at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60% at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of androgen receptor gene promoter activity and/or androgen receptor variant gene promoter activity. In some embodiments, the compound is provided at a concentration of about 0.1 μΜ or more, about 0.5 μΜ or more, about 1 μΜ or more, about 5 μΜ or more, or about 10 μΜ or more. Gene promoter acti vity can be determined, for example, using a cell-based luciferase expression assay, wherein luciferase expression is under control of a prostate specific antigen (PSA) promoter, or a qPCR assay. In some embodiments, the promoter activity is determined using a cell-based PSA expression assay or a TMPRSS2 expression assay.

[0122] In some embodiments, there is provided a method of killing a cell that expresses androgen receptor or an androgen receptor variant comprising contacting the cell with a compound of formula (I). In some embodiments, the cell is a cancer cell, such as a prostate cancer cell. In some embodiments, the cell is a metastatic cancer cell, such as a metastatic prostate cancer cell.

[0123] In some embodiments, there is a method of inhibiting proliferation of a cell that expresses an androgen receptor or an androgen receptor variant comprising contacting the cell with a compound of formula (I). In some embodiments, the cell is a cancer cell, such as a prostate cancer cell. In some embodiments, the cell is a metastatic cancer cell, such as a metastatic prostate cancer cell.

[0124] In some embodiments, there is a method of treating cancer, such as prostate cancer, in an individual with the cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a metastatic cancer, such as a metastatic prostate cancer.

[0125] In some embodiments, there is a use of a compound of formula (I) or a

pharmaceutically acceptable salt thereof in the treatment of cancer, such as prostate cancer. In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, such as prostate cancer. In some embodiments, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, such as prostate cancer.

Dosing and Method of Administration

[0126] The dose of a compound administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount.

[0127] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject's health status, condition, and weight.

[0128] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.

[0129] A compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a 'drug holiday' (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.

Articles of Manufacture and Kits

[0130] The present disclosure further provides articles of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed.

[0131] The present disclosure further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer.

[0132] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.

[0133] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0134] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to an individual.

General Synthetic Methods

[0135] The compounds of the in vention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

[0136] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.

[0137] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

[0138] Solvates of a compound provided herein or a salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.

[0139] Compound of formula (1-5) can be prepared according to Scheme 1, wherein R², R³, R⁴, Y, and m are as defined for formula (I), or any applicable variations detailed herein and Z is R¹ or a leaving group (e.g., halogen) that can be readily converted to R¹. Scheme 1

1-5

[0140] Condensation of 1 ,4-dicarbonyl compound (1-1) with amine H₂N-R² through a Paal- Knorr synthesis gives the pyrrole compound (1-2). Formylation of pyrrole (1-2) under Vilsmeier-Haack conditions provides intennediate compound (1-3). Nucleophilic addition of compound (1-4) to the aldehyde of compound (1-3), followed by dehydration gives the compound of (1-5).

[0141] An exemplary embodiment of the preparative method in Scheme 1 is shown in Scheme la

Scheme la

[0142] When Z is a leaving group (e.g., halogen) that can be readily converted to R¹, the conversion can occur via a coupling reaction. In particular, when R¹ is -NR⁶R⁷, the coupling can occur under Buckwald-Hartwig animation conditions. Compound of formula (II-2) can be prepared according to Scheme 2, wherein R², R³, R⁴, R⁵, R⁶, Y, and m are as defined for formula (I), or any applicable variations detailed herein and Z¹ is a leaving group (e.g., halogen) that can be readily converted to R¹.

Scheme 2 R⁴ ^ ^

H ΠNΙ RΓ ⁶R r\⁷

-_R2 Buchwald-Hartwig (^R?R6N)m -jr _^J_^ 2

(Z¹)_m +

amination

11-1 II-2

An exemplary embodiment of the preparative method in Scheme 2 is shown 2a.

Scheme 2a

EXAMPLES

[0144] The chemical reactions in the Examples described can be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art wall be recognized as having applicability for preparing other compounds of the invention.

Example 1

Synthesis of(E)-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)

8b Compound 1

[0145] To a stirred solution of Comp-8b (0.5 g, 2.51 mmol), 2-methylquinoxaline (0.4 g, 2.77 mmol) in a sealed tube, piperidine (0.021mg, 0.251mmol) was added and heated to 140 °C for 4 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water, extracted with EtOAc (50 X 3 mL). The organic layer was washed with water, brine, separated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude compound obtained was purified by column chromatography (silica, 100- 200 mesh, 7% Ethyl acetate in Hexane) to afford (E)-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol- 3-yl)vinyl)quinoxaline (1; 0.1 g, 12%) as yellow solid.

[0146] HPLC Purity: 94.91%

[0147] MS (ESI) m/e |M+H]^+/ Rt/%: 326.05/2.22/96.2%

[0148] ¹H NMR (400 MHz, DMSO-£¾) δ 2.00 (s, 3H), 2.17 (s, 3H), 6.42 (s, IH), 6.98 (d, J = 15.89 Hz, 1H), 7.34 (d, J=7.34 Hz, 2H) 7.50 - 7.52 (m, 1 H), 7.55 - 7.59 (m, 2 H), 7.68 - 7.71 (m, 1 H), 7.76 - 7.79 (m, 1 H), 7.94 - 8.00 (m, 3 H), 9.24 (s, 1 H).

Example 2

Synthesis of (E)-2-(benzo[d]oxazol-2-yl)-3-(2, 5-dimethyl-l -phenyl- lH-pyrrol-3- yljacrylonitrile

Compound 2

[0149] Compound 2a: 2-Aminophenol (1 g, 9.17 mmol), acetic acid (2 mL) and malononitrile (0.61 g, 9.24 mmol) was heated to reflux in ethanol (10 mL) for 16 h. Progress of the reaction was monitored by TLC. After completion, all volatiles were removed under reduced pressure to get crude mass which was dissolved in ethyl acetate and washed with water. The organic layer was washed with brine, separated, dried over anhydrous Na₂SC>4 and concentrated in vacuo to afford 2-(benzo[d]oxazo]-2-yl)acetonitrile (2a; 1.0 g, 69%) as a yellow oil.

[0150] MS (ESI) m/e [M+H]⁺ Rt/%: 158.95/1.65/96.4%

[0151] Compound 2: To a stirred solution of K₂C0₃ (0.524 g, 3.80 mmol) in water (5 mL) was added Comp-2a (0.299 g, 1.90 mmol), Comp-8b (0.378 g 1.90 mmol) and stirred for 2h at RT. After completion, the reaction mixture was diluted with water and extracted with EtOAc (3x 50 mL). The organic layer was washed with water, brine, separated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 25% ethyl acetate in Hexane) to afford (E)-2- (¾enzo[d]oxazol-2-yl)-3-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)aciylonitrile (2; 0.15 g, 23%) as pale yellow solid.

[0152] HPLC Purity: 97.45%

[0153] MS (ESI) m/e [M+H]⁺ Rt/%: 340.05/2.37/99.8%

[0154] ¹H NMR (400 MHz, DMSO-d₆) δ 2.03 (s, 3H), 2.24 (s, 3H), 6.96 (s, 1H), 7.38-7.42 (m, 4H), 7.56 - 7.61 (m, 3 H), 7.73-7.75 (m, 2H), 8.27 (s, 1 H).

Example 3

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3- yljvinyljquinoxaline

Compound 3

[0155] Compound 3a: To a stirred solution of hexane-2,5-dione (1.00 g, 8.76 mmol) and 1- methylpiperidin-4-amine (1.00 g, 8.76 mmol) was added crystals of iodine (0.022 g, 0.087 mmol) and the reaction mixture was stirred at room temperature for 4h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured on crushed ice and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude compound was purified by column chromatography (silica, 100-200 mesh, 10% MeOH:DCM) to afford 4-(2,5- dimethyl-lH-pyrrol-l-yl)-l-methylpiperidine (3a; 0.80 g, 48%) as a colorless oil.

[0156] MS (ESI) m/e [M+H]^+/ Rt/%: 193.10/0.65/81.63%.

[0157] Compound 3b: A solution of POCl₃ (0.63 g, 4.15 mmol) in DMF (5 mL) was cooled to 0 °C and stirred for 20 min. Comp-3a (0.80 g, 4.15 mmol) in DMF (2 mL) was added to it and heated to 100°C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and poured on crushed ice and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude compound was purified by column chromatography (silica, 100-200 mesh, 10% MeOH:DCM) to afford 2,5-dimethyl-l-(l- methylpiperidin-4-yl)-lH-pyrrole-3-carbaldehyde (3b; 0.50 g, 55%) as an off-white solid.

[0158] MS (ESI) m/e [M+H]^+/ Rt %: 221.10/0.31/82.49%.

[0159] Compound 3: To a stirred mixture of Comp-3b (0.200 g, 0.907 mmol) and 2- methylquinoxaline (0.130 g, 0.907 mmol) was added catalytic piperidine (7.0 mg, 0.0907 mmol) and heated to 140°C for 6 h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to room tempearature, H₂0 (10 mL) was added and extracted with EtOAc. The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 10% MeOH:DCM) to afford 2-(2- (2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)quinoxaline (3; 0.13 g, 42%) as pale yellow solid.

[0160] HPLC Purity: 98.03%.

[0161] MS (ESI) m/e [M+H]^+/ Rt/%: 347.15/1.21/99.31%.

[0162] ¹H NMR (400 MHz, CDCl₃) δ 1.95-1.99 (m, 2H) 2.38 (s, 3H) 2.49 (s, 3H) 2.57 - 2.64 (m, 2H) 2.66 (s, 3H) 2.72 - 2.83 (m, 2H) 3.46-3.50 (m, 2H) 4.08 - 4.16 (m, 1H) 6.27 (s, 1H) 6.92 (d, J=16.14 Hz, 1H) 7.59 - 7.66 (m, 1H) 7.68 - 7.75 (m, 1H) 7.82 (d, J=16.14 Hz, 1H) 7.99-8.03 (m, 2H) 8.94 (s, 1H).

Example 4

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-(pyridin-3-yl)-lH-pyrrol-3-yl)vinyl)q

[0163] To a mixture of Comp-79b (0.21 g, 1.04 mmol) and 2-methylquinoxaline (0.15 g, 1.04 mmol) was added piperidine (0.1 mL) and the reaction mixture was heated at 180 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completi on the crude reaction mixture obtained was purified by column chromatography (silica, 230-400 mesh, 0- 2% MeOH in DCM) followed by preparative HPLC purification to afford (E)-2-(2-(2,5- dimethyl-l-(pyridin-3-yl)-lH-pyrrol-3-yl)vinyl)quinoxaline (4: 0.08 g, 25%) as an orange solid.

[0164] HPLC Purity: 95.2%

[0165] MS (ESI) m/e [M+H]^+/ Rt/%: 327.15/1.85/89.5%

[0166] ¹H NMR (400 MHz, DMSO-d₆) δ 2.02 (s, 3H), 2.19 (s, 3H), 6.47 (s, 1H), 7.01 (d, J = 16.14 Hz, 1H), 7.58 - 7.65 (m, 1H), 7.67 - 7.74 (m, 1H), 7.78 (t, J= 7.58 Hz, 1H), 7.88 - 7.91 (m, IH), 7.94 - 8.02 (m, 3H), 8.61 (d, J= 1.96 Hz, 1H), 8.70 (d, J= 4.40 Hz, 1H), 9.25 (s, 1H).

Example 5

Synthesis of (E)-3-(2,5-dimethyl-3-(2-(quinomlin-2-yl)viny

chloride

[0167] To a stirred solution of Comp-4 (0.06 g, 0.18 mmol) in dioxane (2 mL), was added 4M HC1 in dioxane (1 mL), and the reaction mixture was stirred at 0 °C for 30 min. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to get crude residue, was triturated with EtOAc and pentane to afford (E),-3-(2,5-dimethyl-3-(2-(quinoxalin-2-yl),vinyl),-lH-pyrrol-l-yl),pyridin- 1-ium chloride (5; 0.045 g, 55%), as a dark brown solid.

[0168] HPLC Purity: 95.1%

[0169] MS (ESI) m/e [M]^+/ Rt/%: 327.10/1.97/98.2%

[0170] ¹H NMR (400 MHz, DMSO-d₆) δ 2.03 (s, 3H), 2.21 (s, 3H), 5.67 (brs, 1H), 6.48 (s, 1H), 7.04 (d, J= 16.14 Hz, 1H), 7.70 - 7.83 (m, 3H), 8.00 - 8.05 (m, 2H), 8.07 - 8.12 (m, 2H), 8.75 - 8.80 (m, 2H), 9.33 (s, 1H).

Example 6

Synthesis of (E)-4-(2-(2-(2,5-dimethyl-1-phenyl-lH-pyrrol-3-yl)viny

yljmorpholme and (E)-4-(3-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)quinoxalin-6- yl)morpholine

[0171] Compounds 6a and 7a: To a stirred solution of 4-bromobenzene-l,2-diamine (1 g, 5.37 mmol) in acetonitrile (10 mL) was added 2-oxopropanal (1 mL) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford 6-bromo-2-methylquinoxaline and 7-bromo-2- methylquinoxaline (6a and 7a, respectively; 1 g, 83%) as a yellow solid.

[0172] ¹H NMR (400 MHz, CDCl₃ mixture of isomers) δ 2.77 (s, 2 H), 2.79 (s, 3 H), 7.79 (dd, J= 8.80, 1.96 Hz, 1.05 H), 7.83 (dd, J= 8.80, 1.96 Hz, 0.73 H), 7.89 (d, J= 8.80 Hz, 0.71 H), 7.94 (d, J= 8.80 Hz, 1 H), 8.21 (d, J= 1.96 Hz, 1.02 H), 8.26 (d, J= 1.96 Hz, 0.65 H), 8.75 (s, 2 H).

[0173] Compounds 6b and 7b: To a stirred solution of Comp-6a and Comp-7a mixture (0.25 g, 1.13 mmol) in toluene (5 mL) was added t-BuONa (0.32 g, 3.40 mmol) followed by morpholine (0.10 g, 1.13 mmol) were added and the reaction mixture was degassed with argon for 15 min. BI AP (0.21 g, 0.34 mmol) and Pd₂(dba)₃ (0.1 g, 0.13 mmol) were added and the reaction mixture was heated at 110 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford 4-(2-methylquinoxalin-6-yl)morpholine and 4-(3-methylquinoxalin-6-yl)morpholine (6b and 7b, respectively; 0.15 g, 58%) as a yellow solid.

[0174] ¹H NMR (400 MHz, CDCl₃ mixture of isomers) δ 2.73 (s, 3 H), 3.33 - 3.39 (m, 4 H), 3.91 - 3.96 (m, 4 H), 7.24 (d, J= 2.93 Hz, 0.62 H), 7.30 (d, J= 2.93 Hz, 0.39 H), 7.45 (dd, J = 9.29, 2.93 Hz, 0.7 H), 7.50 (dd, J = 9.29, 2.45 Hz, 0.47 H), 7.89 (d, J = 9.29 Hz, 0.41 H), 7.93 (d, J= 9.29 Hz, 0.59 H), 8.54 (s, 0.58 H), 8.64 (s, 0.34 H).

[0175] Compounds 6 and 7: To a mixture of Comp-6b and Comp-7b mixture (0.35 g, 1.53 mmol) and Comp-8b (0.22 g, 1.53 mmol), was added piperidine (0.05 g), and the reaction mixture was heated at 150 °C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-10% MeOH in DCM), followed by prep HPLC purification to afford (E)-4-(2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)quinoxalin-6- yl)morpholine (6; 0.05 g, 8%), and (E)-4-(3-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3- yl)vinyl)quinoxalin-6-yl)morpholine (7; 0.05 g, 8%), as a black solids.

[0176] Compound 6:

[0177] HPLC Purity: 99.7%

[0178] MS (ESI), m/e [M+H]+/ Rt/%: 41 1.25/2.04/99.0%

[0179] ¹H NMR (400 MHz, DMSO-d₆), δ 2.00 (s, 3 H), 2.15 (s, 3 H), 3.30 - 3.37 (m, 4 H), 3.77 - 3.82 (m, 4 H), 6.37 (s, 1 H), 6.91 (d, J = 16.14 Hz, 1 H), 7.22 (d, J= 2.45 Hz, 1 H), 7.33 (d, J= 7.34 Hz, 2 H), 7.47 - 7.52 (m, 1 H), 7.54 - 7.59 (m, 2 H), 7.66 (dd, J = 9.29, 2.45 Hz, 1 H), 7.80 (d, J= 3.42 Hz, 1 H), 7.83 (d, J= 3.42 Hz, 1 H), 9.08 (s, 1 H).

[0180] Compound 7:

[0181] HPLC Purity: 99.4%

[0182] MS (ESI), m/e [M+H]+/ R/%: 41 1.25/2.13/98.6%

[0183] ¹H NMR (400 MHz, DMSO-d₆), δ 2.00 (s, 3 H), 2.15 (s, 3 H), 3.31 - 3.36 (m, 4 H), 3.77 - 3.82 (m, 4 H), 6.37 (s, 1 H), 6.91 (d, J = 16.14 Hz, 1 H), 7.22 (d, J= 2.45 Hz, 1 H), 7.33 (d, J= 7.34 Hz, 2 H), 7.47 - 7.53 (m, 1 H), 7.53 - 7.59 (m, 2 H), 7.66 (dd, J = 9.29, 2.45 Hz, 1 H), 7.80 (d, J= 3.42 Hz, 1 H), 7.83 (d, J= 3.42 Hz, 1 H), 9.08 (s, 1 H).

Example 7

of(E)-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-5- morpholinobenzo[ d]oxazole Br

^f^ Toluene, 90 °C, 16 h ^l!^^fi-d

³⁶ 39.5% Compound 8

[0184] To a solution of Comp-36 (3 g, 7.63 mmol) in toluene (30 mL) t-BuONa (2.19 g,

22.9 mmol) followed by morpholine (0.99 g, 11.45 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (1.41 g, 2.29 mmol) and Pd2(dba)3

(0.69 g, 0.76 mmol) were added and the reaction mixture was heated at 90°C for 16h.

Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The crude obtained was purified by column

chromatography (silica, 100-200 mesh, 40% ethyl acetate in Hexane) to afford (E)-2-(2-(2,5- dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-5-morpholinobenzo[ii]oxazole (8; 1.2 g, 39.5%) as a yellow solid.

[0185] HPLC Purity: 99.3%.

[0186] MS (ESI) m/e [M+H]⁺ Rt/%: 400.20/2.29/98.01 %.

[0187] ¹H NMR (400 MHz, CD(¾) δ 2.05 (s, 3 H) 2.17 (s, 3 H) 3.13 - 3.22 (m, 4 H) 3.85 - 3.97 (m, 4 H) 6.30 (s, 1 H) 6.64 (d, J=15.75 Hz, 1 H) 6.93 (dd, J=8.86, 1.97 Hz, 1 H) 7.18 - 7.25 (m, 3 H) 7.38 (d, J=8.86 Hz, 1 H) 7.44 - 7.55 (m, 3 H) 7.76 (d, J=15.75 Hz, 1 H).

Example 8

Synthesis of (E)-2-(2-(l-cyclopentyl-2, 5-dimethyl-lH-pyrrol-3-yl)vinyl)quinoxaline

82b

[0188] To a mixture of 2-methylquinoxaline (0.2 g, 1.38 mmol) and Comp-82b (0.26 g, 1.38 mmol) was added piperdine (0.1 mL) and the reaction mixture was heated at 150 °C for 8 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100- 200 mesh, 0-20% EtOAc in hexane) to afford (E)-2-(2-(l-cyclopentyl-2,5-dimethyl-lH- pyrrol-3-yl)vinyl)quinoxaline (9; 0.1 g, 23%), as a yellow solid.

[0189] HPLC Purity: 96.4%

[0190] MS (ESI) m/e [M+H]+/ Rt %: 318.20/2.21/95.3% [0191] ¹H NMR (400 MHz, CDCl₃) δ 1.68 - 1.76 (m, 2 H), 1.89 - 2.05 (m, 4 H), 2.05 - 2.15 (m, 2 H), 2.34 (s, 3 H), 2.47 (s, 3 H), 4.52 - 4.66 (m, 1 H), 6.24 - 6.30 (m, 1 H), 6.91 (d, J =15.65 Hz, 1 H), 7.58 - 7.65 (m, 1 H), 7.68-7.72 ( m, 1 H), 7.85 (d, J=15.65 Hz, 1 H), 8.01 - 8.02 (m, 2 H) 8.95 (s, 1 H).

Example 9

Synthesis of (E)-2-(2-(l-(2-fluorophenyl)-2,5-dimethyl-lH-pyrrol-3-yl)viny

[0192] To a stirred solution of 2-methylbenzo[d]oxazole (0.1 g, 0.75 mmol) in THF (2 mL) KO'Bu (1 mL, IM in THF) was added at -40 °C and reaction was stirred at -40 °C for 30 inin, then Comp-10a (0.16 g, 0.75 mmol) in THF (2 mL) was added and the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was evaporated to get crude mass which was purified by reverse phase Grace (Reveleris, C-18- WP reverse phase column, 80% ACN/water as eluent) to afford (E)-2-(2-(l-(2-fluorophenyl)-2,5-dimethyl-lH-pyrrol-3-yl)vinyl)benzo[d]oxazole (10; 0.04 g, 16%), as a yellow solid.

[0193] HPLC purity: 98.83%

[0194] MS (ESI) m/e [M+H]⁺/Rt/%: 333.10/2.45/99.8%

[0195] ¹H NMR (400 MHz, CDCl₃) δ 2.05 (s, 3 H), 2.15 - 2.22 (m, 3 H), 6.30 - 6.40 (m, 1 H), 6.62 - 6.71 (m, 1 H), 7.27 - 7.35 (m, 5 H), 7.45 - 7.53 (m, 2 H), 7.67 (dd, J=6.11, 2.69 Hz, 1 H), 7.80 (d, J=15.65 Hz, 1 H).

[0196] Comp-10a may be prepared according to the procedure to prepare Comp-8b using 2-fluoroaniIine.

Example 10

Synthesis of (E)-2-(2-(l-phenyl-lH-pyrrol-3-yl)vinyl)quinoxaline I

[0197] Compound 11 a: To a stirred solution of lH-pyrrole-3-carbaldehyde (0.2 g, 2.10 mmol) and iodobenzene (0.42 g, 2.10 mmol) in DMF (5 mL) was added K₂C0₃ (0.58 g, 4.20 mmol) followed by copper iodide (0.04 g, 0.21 mmol) and the reaction mixture was heated at 100 °C for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-10% EtOAc in hexane) to afford l-phenyl-lH-pyrrole-3-carbaldehyde (11a, 0.2 g, 55%) as an off-white solid.

[0198] MS (ESI) m/e [M+H]+/ Rt'%: 172.0/1.72/99.8%

[0199] ¹H NMR (400 MHz, CD(¾) δ 6.82 - 6.84 (m, 1 H), 7.10 - 7.13 (m, 1 H), 7.36 - 7.42 (m, 1 H), 7.43 - 7.47 (m, 2 H), 7.48 - 7.54 (m, 2 H), 7.67 - 7.71 (m, 1 H), 9,89 (bs, 1 H).

[0200] Compound 1 1 : To a mixture of 2-methylquinoxaline (0.2 g, 1.38 mmol) and Comp- 11a (0.23 g, 1.38 mmol) was added piperidine (0.11 g, 0.13 mmol) and the reaction mixture was heated at 140 °C for 5 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford (E)-2-(2-(l- phenyl-lH-pyrrol-3-yl)vinyl)quinoxaline (11; 0.04 g, 10%), as ayellow solid.

[0201] HPLC Purity: 95.9%

[0202] MS (ESI) m/e [M+H]+/ Rt/%: 298.15/2.24/97.7%

[0203] ¹H NMR (400 MHz, CDCl₃) δ 6.71 - 6.77 (m, 1 H), 7.13 - 7.17 (m, 1 H), 7.29 - 7.35 (m, 1 H), 7.37 - 7.40 (m, 1 H), 7.40 - 7.52 (m, 3 H), 7.64 - 7.79 (m, 2 H), 7.83 - 7.91 (m, 1 H), 7.94 - 8.22 (m, 2 H), 8.01 - 8.09 (m, 2 H), 8.86 - 9.23 (m, I H).

Example 11

Synthesis of (E)-2-(2-(l-(4-fluorophenyl)-2,5-dimethyl-lH-pyrrol-3-yl)vin^ CHO

POCI3, DMF

0-100 °C, 16 h

O l₂, rt,2h Piperidine

140°C, 5 h

F

F

12a 12b

Compound 12

[0204] Compound 12a: To a mixture of hexane-2,5-dione (0.8 g, 7.01 mmol) and 4- fluoroaniline (0.78 g, 7.01 mmol) was added iodine (0.18 g, 0.7 mmol). The reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column

chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford l -(4- fluorophenyl)-2,5-dimethyl-lH-pyrrole (12a; 1 g, 75%) as a yellow oil.

[0205] MS (ESI) m/e [M+H]⁺ /Rt/%: 189.95/2.18/88.95%

[0206] Compound 12b: A solution of POCl₃ (0.5 mL, 5.29 mmol) in DMF (5 mL) was cooled to 0 °C and stirred for 20 min. Comp-12a (1 g, 5.29 mmol) in DMF (5 mL) was added to it and heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to RT and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford l-(4-fluorophenyl)-2,5-dimethyl-lH-pyrrole-3-carbaldehyde (12b, 1 g, 88%) as an off- white solid.

[0207] MS (ESI) m/e [M+H]⁺ /Rt %: 218.05/ 1.87/ 99.48%

[0208] Compound 12: To a mixture of Comp-12b (0.2 g, 0.92 mmol) and 2- methylquinoxaline (0.13 g, 0.92 mmol) was added piperidine (0.008 g, 0.09 mmol) and the reaction mixture was heated at 140 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford (E)-2- (2-(l-(4-fluorophenyl)-2,5-dimethyl-lH-pyrrol-3-yl)vinyl)quinoxaline (12; 0.06 g, 19%), as a light brown solid.

[0209] HPLC purity: 97.59%

[0210] MS (ESI) m/e [M+H]⁺ /Rt %: 344.05/2.34/99.0%

[0211] ¹H NMR (400 MHz, DMSO-d₆) δ 1.95 - 2.10 (m, 3 H), 2.11 - 2.25 (m, 3 H), 6.39 - 6.49 (m, 1 H), 6.94 - 7.05 (m, 1 H), 7.33 - 7.53 (m, 4 H), 7.67 - 7.85 (m, 2 H), 7.89 - 8.11 (m, 3 H), 9.22 - 9.31 (m, 1 H).

Example 12

Synthesis of(E)-2-(2-(J-(4 :hlorophenyl)-2,5-dimeihyl-IH-pyrrol-3-yl)vmy

Compound 13

[0212] Compound 13a: To a mixture of 4-chloroaniline (0.5 g, 3.93 mmol) and hexane-2,5- dione (0.45 g, 3.93 mmol) was added iodine (0.1 g, 0.39 mmol). The reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column

chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford l-(4- chlorophenyl)-2,5-dimethyl-lH-pyrrole (13a; 0.5 g, 62%) as a yellow oil.

[0213] MS (ESI) m/e [M+H]⁺/Rt %: 206.05/2.31/88.58%

[0214] Compound 13b: A solution of POCl₃ (0.28 mL, 2.92 mmol) in DMF (5 mL) was cooled to 0 °C and stirred for 20 min. Comp-13a (0.5 g, 2.43 mmol) in DMF (5 mL) was added to it and heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to RT and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford l-(4-chlorophenyl)-2,5-dimethyl-lH-pyrrole-3-carbaldehyde (13b, 0.3 g, 53%) as an off-white solid.

[0215] MS (ESI) m/e [M+H]⁺/Rt %: 234.05/1.98/96.58%

[0216] Compound 13: To a mixture of Comp-13b (0.32 g, 1.38 mmol) and 2- methylquinoxaline (0.2 g, 1.38 mmol) was added piperdine (0.012 mL, 0.13 mmol) and the reaction mixture was heated at 140 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford (E)-2- (2-(l-(4-chlorophenyl)-2,5-dimethyl-lH-pyrrol-3-yl)vinyl)quinoxaline (13; 0.03 g, 6%), as an off white solid.

[0217] MS (ESI) m/e |M+H|⁺/Rt/%: 360.10/2.46/97.7%

[0218] ¹H NMR (400 MHz, CDCl₃) δ 2.06 (s, 3H), 2.21 (s, 3H), 6.38 (s, 1H), 7.00 (d, J=15.65 Hz, 1H), 7.16 - 7.22 (m, 2H), 7.48 - 7.52 (m, 2H), 7.61 - 7.67 (m, 1H), 7.70-7.74 (m, 1H), 7.87 (d, J=16.14 Hz, 1H), 8.03 (t, J=7.34 Hz, 2H), 8.98 (s, 1H).

Example 13

Synthesis of (E)-2-(2-(2,5-dimethyl-l-(4-(trifluoromethylJpheftylj-lH-pyrrol-3- yl)vinyl)quinoxaline

Compound 14

[0219] Compound 14a: To a mixture of hexane-2,5-dione (1 g, 8.77 mmol) and 4- (trifluoromethyl)aniline (1.5 g, 8.77 mmol) was added iodine (0.001 g). The reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column

chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford 2,5-dimethyl-l-(4- (trifluoromethyl)phenyl)- lH-pyrrole (14a; 0.4 g, 21%) as a yellow oil.

[0220] MS (ESI) m/e [M+H]⁺/Rt %: 240.25/2.19/65.99%

[0221] Compound 14b: A solution of POCl₃ (0.16 mL, 1.67 mmol) in DMF (5 mL) was cooled to 0 °C and stirred for 20 min. Comp-14a (0.4 g, 1.67 mmol) in DMF (2 mL) was added to it and heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to RT and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford 2,5-dimethyl-l-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carbaldehyde (14b, 0.3 g, 78%) as a pale yellow solid.

[0222] MS (ESI) m/e [M+H]⁺/Rt/%: 268.05/1.89/92.9%

[0223] Compound 14: To a mixture of Comp-14b (0.2 g, 0.75 mmol) and 2- methylquinoxaline (0.1 g, 0.75 mmol) was added piperidine (0.006 g, 0.075 mmol) and the reaction mixture was heated at 140 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford (E)-2- (2-(2,5-dimethyl-l-(4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)vinyl)quinoxaline (14; 0.11 g, 37%), as an off white solid.

[0224] HPLC purity: 95.63%

[0225] MS (ESI) m/e [M+H]7Rt %: 394.25/2.31/96.0%

[0226] ¹H NMR (400 MHz, CDCh) δ 2.09 (s, 3H), 2.23 (s, 3H), 6.41 (s, 1H), 7.02 (d, J=15.65 Hz, 1H), 7.39 (d, J=8.31 Hz, 2H), 7.62 - 7.68 (m, 1H), 7.71-7.75 (m, 1H), 7.80 (d, J=8.31 Hz, 2H), 7.88 (d, J=16.14 Hz, 1H), 8.03 (t, J=7.58 Hz, 2H), 8.98 (s, 1H).

Example 14

Synthesis of (E)-4-(2,5-dimethyl-S-(2-(quinoxalin-2-yl)vin^ CHO

o

N I H₂ *^■ POCI_3l D F

0-100 °C, 2 h

o

l₂, rt,2h Piperidine,140°C, 4h

CN

CN CN

15a

N

CN

Compound 15

[0227] Compound 15a: To a mixture of 4-aminobenzonitrile (0.5 g, 4.23 mmol) and hexane-2,5-dione (0.5 g, 4.66 mmol) was added iodine (0.05 g, 0.21 mmol). The reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-10% EtOAc in hexane) to afford 4-(2,5-dimethyl- lH-pyrrol-l-yl)benzonitrile (15a; 0.6 g, 75%) as a yellow oil.

[0228] MS (ESI) m/e [M+H]+/ Rt'%: 197.20/1.92/96.6%

[0229] Compound 15b: A solution of POCl₃ (1.7 mL, 18.36 mmol) in DMF (20 mL) was cooled to 0 °C and stirred for 20 min. Comp-15a (0.6 g, 3.06 mmol) in DMF (2 mL) was added to it and heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to RT and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford 4-(3-formyl-2,5-dimethyl-lH-pyrrol-l-yl)benzonitrile (15b, 0.5 g, 73%) as an off white solid.

[0230] MS (ESI) m/e [M+H]+/ Rf'%: 225.15/1.59/61.24%

[0231] Compound 15: To a mixture of Comp-15b (0.2 g, 0.89 mmol) and 2- methylquinoxaline (0.1 g, 0.89 mmol) was added piperidine (0.02 g, 0.22 mmol) and the reaction mixture was heated at 140 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford (E)-4- (2,5-dimethyl-3-(2-(quinoxalin-2-yl)vinyl)-lH-pyrrol-l-yl)benzonitrile (15; 0.09 g, 29%), as an off white solid.

[0232] HPLC Purity: 96.78%

[0233] MS (ESI) m/e [M+H]+/ Rt/%: 351.20/2.29/97.3%

[0234] ¹H NMR (400 MHz, CDCl₃) δ 2.08 (s, 3H), 2.22 (s, 3H), 6.41 (s, 1H), 7.00 (d, J=16.14 Hz, 1H), 7.38 (d, J=8.31 Hz, 2H), 7.61 - 7.68 (m, 1H), 7.70-7.74 (m, 1H), 7.81 - 7.88 (m, 3H), 7.99 - 8.06 (m, 2H), 8.96 (s, 1H).

Example 15

Synthesis of(E)-4-(2,5-dimethyl-3-(2-(quino lin-2-yl)vinyl)-JH-pyrrol-J- yljbenzenesulfonamide

Compound 16

[0235] Compound 16a: To a mixture of 4-aminobenzenesulfonamide (0.5 g, 2.90 mmol) and hexane-2,5-dione (0.5 g, 4.36 mmol) was added iodine (0.07 g, 0.29 mmol). The reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-10% EtOAc in hexane) to afford 4-(2,5-dimethyl- lH-pyrrol-l-yl)benzenesulfonamide (16a; 0.7 g, 99%) as a yellow oil.

[0236] MS (ESI) m/e |M+H]⁺/Rt/%: 251.25/1.58/31.8%

[0237] Compound 16b: A solution of POCl₃ (0.3 mL, 3.36 mmol) in DMF (10 mL) was cooled to 0 °C and stirred for 20 min. Comp-16a (0.7 g, 2.80 mmol) in DMF (2 mL) was added to it and heated to 100 °C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to RT and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford 4-(3-forn¾-'l-2,5-dimethyl-lH-pyrrol-l-yl)benzenesulfonamide (16b, 0.5 g, 65%) as an off white solid.

[0238] Compoud 16: To a mixture of Comp-16b (0.4 g, 1.38 mmol) and 2- methylquinoxaline (0.2 g, 1.38 mmol) was added piperidine (0.012 g, 0.14 mmol) and the reaction mixture was heated at 140 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford (E)-4- (2,5-dimethyl-3-(2-(quinoxalin-2-yl)vinyl)-lH-pyi ol-l-yl)benzenesulfonamide (16; 0.025 g, 5%), as an off white solid.

[0239] HPLC purity : 99.14%

[0240] MS (ESI) m/e [M+H]⁺ Rt %: 405.15/1.96/99.8%

[0241] ¹H NMR (400 MHz, DMSO-d₆) δ 2.04 (s, 3 H), 2.21 (s, 3 H), 6.47 (s, 1 H), 6.96 - 7.06 (m, 1 H), 7.54 (brs, 2 H), 7.59 (d, J=7.34 Hz, 2 H), 7.69 - 7.83 (m, 2 H), 7.93 - 8.05 (m, 5 H), 9.26 (s, I H).

Example 16

Synthesis of (E)-2-(2-(2,5-dimethyl-l-(3-(Mfluoromethyl)pheny

yljvinyljquinoxalme

17a 17b

Compound 17

[0242] Compound 17a: To a mixture of hexane-2,5-dione (0.5 g, 4.38 mmol) and 3- (trifluoromethyl)aniline (0.7 g, 4.38 mmol) was added iodine (0.01 g, 0.04 mmol). The reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford 2,5- dimethyl-l-(3-(trifluoromethyl)phenyl)-lH-pyrrole (17a; 0.45 g, 43%) as a yellow oil.

[0243] MS (ESI) m/e [M+H]⁺ /Rt %: 240.25/2.18/79.25%

[0244] Compound 17b: A solution of POCl₃ (0.2 mL, 1.88 mmol) in DMF (5 mL) was cooled to 0 °C and stirred for 20 min. Comp-17a (0.4 g, 1.88 mmol) in DMF (2 mL) was added to it and heated at 100 °C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford 2,5-dimethyl-l-(3-(trifluoromethyl)phenyl)-lH-pyrrole-3-carbaldehyde (17b, 0.4 g, 80%) as an off white solid.

[0245] MS (ESI) m/e [M+H]⁺/Rt %: 268.30/1.86/99.9%

[0246] Compound 17: To a mixture of Comp-17b (0.2 g, 0.75 mmol) and 2- methylquinoxaline (0.1 g, 0.75 mmol) was added piperidine (0.006 g, 0.075 mmol) and the reaction mixture was heated at 140 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford (E)-2- (2-(2,5-dimethyl-l-(3-(trifluoromethyl)phenyl)-lH-pyiTol-3-yl)vinyl)quinoxaline (17; 0.08 g, 29%), as an off white solid.

[0247] HPLC purity : 96.82%

[0248] MS (ESI) m/e [M+H]⁺/Rt %: 394.15/2.45/95.4%

[0249] ¹H NMR (400 MHz, CDCl₃) δ 2.07 (s, 3H), 2.21 (s, 3H), 6.40 (s, 1 H), 7.00 (d, J=15.65 Hz, 1 H), 7.45 (d, J=7.83 Hz, 1 H), 7.53 (s, 1 H), 7.62 - 7.68 (m, 2 H), 7.70 - 7.75 (m, 2 H), 7.86 (d, J=15.65 Hz, 1 H), 8.02 (t, J=7.09 Hz, 2 H), 8.97 (s, 1 H).

Example 17

Synthesis of (E)-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yty

Compound 8

[0250] Compound 18a: A solution of ethyl 3-oxobutanoate (25 g, 192.30 mmol) and DMF.DMA (25 g, 211.51 mmol) was heated at 110 °C for 1 h. The reaction mixture was cooled to room temperature and to it was added phenylhydrazine (25 g, 230.55 mmol) in methanol (100 mL) and the reaction mixture was heated at 80 °C for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure to afford methyl 5-methyl-l-phenyl-lH-pyrazole-4-carboxylate (18a, 25 g, 56%) as yellow oil used for the next step without purification.

[0251] MS (ESI) m/e [M+H]^+/ Rt/%: 217/1.66/91.3%

[0252] ¹H NMR (400 MHz, CDCI₃), δ 2.54 (s, 3H), 3.86 (s, 3H), 7.40 - 7.48 (m, 3 H), 7.48 - 7.55 (m, 2 H), 8.03 (s, 1 H).

[0253] Compound 18b: To a stirred solution of Comp-18a (10 g, 43.47 mmol) in THF (100 mL) was added 1M LAH (65 mL, 65.20 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and quenched with sat Na₂SO₄ solution and filtered through celite. The residue was washed with EtOAc (100 mL) and the filtrate was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford (5-methyl-l- phenyl-lH-pyrazol-4-yl)methanol (18b; 7 g, 86%) as a yellow solid. The compound was used for the next step without purification.

[0254] MS (ESI) m/e [Μ+Η] ⁺ Rt %: 189/1.54/80.3%

[0255] ¹H NMR (400 MHz, DMSO-d₆) δ 2.28 (s, 3 H), 4.37 (d, J= 5.38 Hz, 2 H), 4.80 (t, J = 5.14 Hz, 1 H), 7.37 - 7.45 (m, 1 H), 7.48 - 7.53 (m, 4 H), 7.55 (s, 1 H).

[0256] Compound 18c: To a stirred solution of Comp-18b (6.5 g, 34.57 mmol) in DCM (100 mL) was added Dess-Martin periodinane (DMP; 16 g, 38.01 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC. After completion the reaction mixture was quenched with sat NaHC0₃ solution and extracted with DCM (100 mL X 2). The combined organic layer was washed with water (50 mL), dried over anhydrous Na₂SC»4 and concentrated under reduced to afford 5-methyl-l -phenyl- lH-pyrazole-4-carbaldehyde (18c; 5 g, 79%) as a buff color solid used for the next step without purification.

[0257] MS (ESI) m/e [M+H]⁺ Rt %: 187/1.49/46.0%

[0258] ¹H NMR (400 MHz, DMSO-d₆) δ 2.56 (s, 3 H) 7.51-7.56 (m, 1H) 7.56 - 7.60 (m, 4 H) 8.16 (s, 1 H) 9.94 (s, 1 H).

[0259] Compound 18: To a stirred solution of Comp-18c (0.1 g, 0.53 mmol) and 2- methylquinoxaline (1 g, 10.08 mmol) was added piperidine (0.1 mL) and the reaction mixture was heated in sealed tube at 180 °C for 4 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL X 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 230-400 mesh, 10-30% EtOAc in hexane) to afford (E)-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yl)vinyl)quinoxaline (18; 0.06 g, 29%) as a yellow solid.

[0260] HPLC Purity : 95.6%

[0261] MS (ESI) m/e [M+H]⁺ Rt %: 313.15/1.93/96.1%

[0262] ¹H NMR (400 MHz, CDCh) δ 2.52 (s, 3 H), 7.16 (d, J= 16.14 Hz, 1 H), 7.40 - 7.55 (m, 5 H), 7.66 - 7.71 (m, 1 H), 7.74 (d, J = 8.31 Hz, 1 H), 7.79 (d, J = 16.63 Hz, 1 H), 8.02 - 8.10 (m, 3 H), 8.98 (s, 1 H).

Example 18

Synthesis of (E)-2-(2-(5-methyl-l-phenyl H-pyrazol-4-yl)viny

ay N _ _/r-

3

1 M KtBuO in THF

THF, - ^"40^! <D

°C-rt, 3 h "-~N

Compound 19

[0263] To a stirred solution of 2-methylbenzo[d]oxazole (0.5 g, 3.75 mmol) in THF (10 mL) was added 1M i-BuOK in THF (5 mL) at -40 °C and the reaction mixture was stirred for 30 min at the same temperature. Comp-18c (0.7 g, 3.75 mmol) in THF (2 mL) was added portion wise at -40 °C and the reaction mixture was stirred at room temperature for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by prep HPLC purification to afford (E)-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4- yI)vinyl)benzo[<i]oxazole (19, 0.15 g, 13%) as an off white solid.

[0264] HPLC purity : 99.7%

[0265] MS (ESI) m/e [M+H]^+/ Rt %: 302.10/2.09/99.9%

[0266] ^XH NMR (400 MHz, CDCl₃) δ 2.41 - 2.55 (m, 3 H), 6.83 - 6.89 (m, 1 H), 7.31 - 7.36 (m, 2 H), 7.43 - 7.56 (m, 6 H), 7.68 - 7.74 (m, 2 H), 7.98 - 8.00 (m, 1 H).

Example 19

Synthesis of (E)-2-(2-(l -cyclopenlyl-2,5-dimethyl-l H-pyrrol-3-yl)vinyl)ben∑o[d]oxazole

[0267] To a stirred solution of 2-methylbenzo[d]oxazole (0.14 g, 1.047 inmol) in THF (10 rnL) was added 1M f-BuOK in THF (2 mL, 2.08 mmol) at -78 °C and the reaction mixture was stirred for 30 min at the same temperature. Comp-82b (0.2 g, 1.047 mmol) in THF (2 mL) was added portion wise at -78 °C and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SC>4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford (E)-2-(2-(l- cyclopentyl-2,5-dimethyl-lH-pyrrol-3-yl)vinyl)benzo[if]oxazole (20, 0.07 g, 22%) as an off- white solid.

[0268] HPLC purity : 99.66%

[0269] MS (ESI) m/e [M+H]⁺ Rt %: 307.10/2.31/98.56%

[0270] ¹H NMR (400 MHz, CDCl₃) δ 1.65 - 1.74 (m, 2 H), 1.88 - 2.00 (m, 4 H), 2.03 - 2.12 (m, 2 H), 2.29 - 2.33 (m, 3 H), 2.39 - 2.44 (m, 3 H), 4.50 - 4.61 (m, 1 H), 6.15 - 6.21 (m, 1 H), 6.52 - 6.61 (m, 1 H), 7.22 - 7.29 (m, 2 H), 7.43 - 7.49 (m, 1 H), 7.62 - 7.66 (m, 1 H), 7.71 - 7.78 (m, 1 H).

Example 20 Synthesis of (E)-4-(2-(2-(5-methyl-l-pheftyl-lH-pyrazol-4-yl)vinyl)quino lin-6- yljmorpholine and (E)-4-(3-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yl)viny

yljmorpholine

(compounds 21 and 22)

mixture of Isomer A and Isomer B

[0271] To a stirred solution of Comp-35 and Comp-102 mixture (0.15 g, 0.38 mmol) in toluene (3 mL) was added t-BuONa (0.1 g, 1.14 mmol) followed by morpholine (0.1 g, 1.15 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.071g, 0.12 mmol) and Pd₂(dba)₃ (0.035 g, 0.038 mmol) were added and the reaction mixture was heated at 130 °C for 5 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford a mixture of Isomer A (0.025 g, 16%) and Isomer B (0.025 g, 16%) as a yellow solid.

[0272] Isomer A:

[0273] HPLC Purity: 96.8%

[0274] MS (ESI) m/e [M+H]+/ Rt/%: 398.30/2.15/98.0%

[0275] ¹H NMR (400 MHz, CDCh) δ 2.52 (s, 3H), 3.35 - 3.45 (m, 4H), 3.90 - 3.99 (m, 4H), 7.11 (d, J=16.14 Hz, 1H), 7.40 - 7.46 (m, 2H), 7.47 - 7.55 (m, 4H), 7.75 (d, J=16.14 Hz, 1H), 7.92 (d, J=9.29 Hz, 1H), 8.02 (s, 1H), 8.76 (s, 1H) (1H merged in the solvent peak).

[0276] Isomer B:

[0277] HPLC Purity: 95.2%

[0278] MS (ESI) m/e [M+H]+/ Rt/%: 398.60/2.15/97.8% ¹H NMR (400 MHz, CDCl₃) δ 2.52 (s, 3 H), 3.36 - 3.42 (m, 4 H), 3.91 - 3.98 (m, 4 H), 7.12 (d, J=16.14 Hz, 1 H), 7.29 (d, J=2.45 Hz, 1 H), 7.43 - 7.55 (m, 6 H), 7.68 (d, J=16.14 Hz, 1 H), 7.93 (d, J=9.29 Hz, 1 H), 8.01 (s, 1 H), 8.86 - 8.89 (m, 1 H).

Example 21

Synthesis of (E)-2-(2-(5-melhyl-l-phenyl-lH-pyra∑ol-4-yl)vinyl)-6-(piperidin-l- yl)quinoxaline and (E)-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yl)vinyl)-7-(piperidin-1- yl)quinoxaline

(compounds 23 and 24)

[0279] To a stirred solution of Comp-35 and Comp-102 mixture (0.15 g, 0.38 mmol) in toluene (3 mL) was added t-BuONa (0.1 g, 1.14 mmol) followed by piperidine (2; 0.1 g, 1.15 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.07g, 0.11 mmol) and Pd₂(dba)₃ (0.035 g, 0.038 mmol) were added and the reaction mixture was heated at 130 °C for 5 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford a mixture of Isomer A (0.03 g, 20%) and Isomer B (0.035 g, 23%) as a yellow solid.

[0280] Isomer A:

[0281] HPLC Purity: 97.9%

[0282] MS (ESI) m/e [M+H]+/ Rt/%: 396.25/2.33/99.0%

[0283] ¹H NMR (400 MHz, CDCl₃) δ 1.64 - 1.73 (m, 2 H), 1.73 - 1.81 (m, 4 H), 2.50 - 2.53 (m, 3 H), 3.36 - 3.45 (m, 4 H), 7.05 - 7.14 (m, 1 H), 7.21 - 7.26 (m, 1 H), 7.40 - 7.57 (m, 6H), 7.68 - 7.76 (m, 1 H), 7.83 - 7.88 (m, 1 H), 8.00 - 8.04 (m, 1 H), 8.68 - 8.74 (m, 1 H). [0284] Isomer B:

[0285] HPLC Purity: 99.2%

[0286] MS (ESI) m/e [M+H]+/ Rt/%: 396.15/2.16/98.4%

[0287] ¹H NMR (400 MHz, CDCh) δ 1.65 - 1.72 (m, 2 H), 1.73 - 1.81 (m, 4 H), 2.47 - 2.53 (m, 3 H), 3.39 - 3.43 (m, 4 H), 7.07 - 7.14 (m, 1 H), 7.40 - 7.45 (m, 1 H), 7.46 - 7.56 (m, 5 H), 7.62 - 7.67 (m, 1 H), 7.85 - 7.89 (m, 1 H), 8.00 - 8.01 (m, 1 H), 8.82 - 8.85 (m, 1 H), (1 proton merged in solvent peak).

Example 22

Synthesis of ^'(E)-f>-cyclopropyl-2-(2-(5-methyl-l -phenyl-^

and (E)-7 yclopropyl-2-(2-(5-methyl-l-phenyl-lH-pyrazo^

(compounds 25 and 26)

[>— B(OH)₂

Pd₂(dba)_3, BINAP, NaOtBu, Toluene, 130 °C, 5 h

mixture of Isomer A and Isomer B

[0288] To a stirred solution of Comp-35 and Comp-102 mixture (0.15 g, 0.38 mmol) in toluene (3 mL) was added t-BuONa (0.1 g, 1.14 mmol) followed by cyclopropylboronic acid (0.03 g, 0.38 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.071 g, 0.11 mmol) and Pd₂(dba)₃ (0.035 g, 0.038 mmol) were added and the reacti on mixture was heated at 130 °C for 5 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford a mixture of Isomer A (0.025 g, 18%) and Isomer B (0.025 g, 18%) as a yellow solid.

[0289] Isomer A:

[0290] HPLC Purity: 92.6%

[0291] MS (ESI) m/e [M+H]+ Rt/%: 353.15/2.13/83.4% [0292] ¹H NMR (400 MHz, CDCl₃) δ 0.87 - 0.94 (m, 2 H), 1.09 - 1.16 (m, 2 H), 2.08 - 2.17

(m, 1 H), 2.50 - 2.54 (m, 3 H), 7.10 - 7.17 (m, 1 H), 7.41 - 7.55 (m, 6 H), 7.66 - 7.79 (m, 2

H), 7.90 - 7.96 (m, 1 H), 8.01 - 8.03 (m, 1 H), 8.86 - 8.94 (m, 1 H).

[0293] Isomer B:

[0294] HPLC Purity: 97.3%

[0295] MS (ESI) m/e [M+HJ+/ Rt/%: 353.15/2.12/89.1%

[0296] ¹H NMR (400 MHz, CDCl₃) δ 0.88 - 0.93 (m, 2 H), 1.10 - 1.17 (m, 2 H), 2.08 - 2.17 (m, 1 H), 2.49 - 2.53 (m, 3 H), 7.11 - 7.16 (m, 1 H), 7.40 - 7.55 (m, 6 H), 7.65 - 7.80 (m, 2 H), 7.91 - 7.95 (m, 1 H), 8.01 - 8.03 (m, 1 H), 8.86 - 8.94 (m, 1 H).

Example 23

Synthesis of (E)-7-chloro-2-(2-(5-methyl-l-phenyl-lH-p and (E)-6n:hloro-2-(2-(5-methyl-l-phenyl-lH-pyra∑ol-4-yl)vinyl)quinoxaline

[0297] Compound 28a: To a suspension of Pd C (0.1 g, 10%) in methanol (20 mL) was added 5-chloro-2-nitroaniline (1 g, 5.81 mmol) followed by hydrazine hydrate (3.6 g, 72.52 mmol) and the reaction mixture was heated at 80 °C for 15 min. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to afford 4-chlorobenzene- 1,2-diamine (28a, 1.2 g, crude) as an orange colored semi solid.

[0298] Compounds 28b and 30b: To a stirred solution of Comp-28a (1 g, 7.04 mmol) in water (30 mL) was added 2-oxopropanal (0.7 g, 10.56 mmol)) and the reaction mixture was stirred at RT for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was extracted with DCM (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230- 400 mesh, 20-30% EtOAc:hexane) to afford 7-chloro-2-methylquinoxaline and 6-chloro-2- methylquinoxaline (28b and 30b, respectively; 0.8 g, 64%) as a pale yellow solid.

[0299] MS (ESI) m/e [M+H]⁺ /Rt/%: 179.10/1.61/96.3%

[0300] ¹H NMR (400 MHz, CDCh 2: 1 mixture of isomers) δ 2.77 (s, 3H) 7.61 - 7.70 (m, 1H) 7.92 - 8.08 (m, 2H) 8.72 & 8.74 (s, 0.57 H & s, 0.29 H)

[0301] Compounds 28 and 30: To a mixture of Comp-28b and Comp-30b mixture (0.5 g, 2.80 mmol) and Comp-18c (0.5 g, 2.80 mmol) was added piperidine (0.1 g, 1.40 mmol) and the reaction mixture was heated at 180 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to RT quenched with water and extracted with DCM (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude obtained was purified by prep HPLC purification to afford a mixture of regioisomers (E)-7- chloro-2-(2-(5-methyl- 1 -phenyl- lH-py razol-4-yl)vinyl)quinoxaline and (E)-6-chloro-2-(2-(5- methyl-1 -phenyl- lH-pyrazol-4-yl)vinyl)quinoxaline (28 and 30, respectively: 0.06 g, 6%) as a brown solid.

[0302] HPLC purity: 91.37%

[0303] MS (ESI) m/e [M+H]⁺ /Rt/%: 347.15/2.34/99.4%

[0304] ¹H NMR (400 MHz, CDCl_3, 2: 1 mixture of isomers) δ 2.53 (s, 3 H), 7.14 (d,

J=16.14 Hz, 1 H), 7.45 - 7.55 (m, 5 H), 7.62-7.72 (m, 1 H), 7.79 - 7.86 (m, 1 H), 7.97 - 8.02 (m, 1 H), 8.03 - 8.08 (m, 2 H), 8.93 & 8.96 (s, 0.62 H & 0.27 H).

Example 24

Synthesis of (E)-6-methoxy-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yl)viny and (E)-7-methoxy-2-(2-(5-methyl-l-phenyl-lH-py azol-4-yl)v^

(compounds 31 and 32)

^^κΓ ^ M_pn-^^N"^ Piperidine (cat),

wⁱeu IN 110 °C, 3 h "^N

40a 99a mixture of Isomer A and Isomer B

[0305] To a mixture of Comp-40a and Comp-99a mixture (0.1 g, 0.57 mmol) and Comp- 18c (0.1 g, 0.57 mmol) was added piperidine (0.2 mL) and the reaction mixture was heated at 110 °C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 230-400 mesh, 0-2% MeOH in DCM) followed by prep HPLC purification to afford a mixture of Isomer A (0.03 g, 15.3 %) and Isomer B (0.02 g, 10.2 %) as pale yellow solid.

[0306] Isomer A:

[0307] HPLC purity: 95.95%

[0308] MS (ESI) m/e [M+H]⁺/Rt %: 343.15/2.08/88.1%

[0309] ^XH NMR (400 MHz, CD₃OD) δ 2.50 (s, 3H), 4.00 (s, 3H), 7.24 (d, J=l 6 Hz, 1H), 7.38 - 7.40 (m, 2H), 7.51 - 7.60 (m, 5H), 7.88-7.92 (m, 2H), 8.12 (s, IH), 8.91 (s, 1H).

[0310] Isomer B:

[0311] HPLC purity: 91.44%

[0312] MS (ESI) m/e [M+H]7Rt %: 343.15/2.08/75.8%

[0313] ¹H NMR (400 MHz, CD₃OD) δ 2.50 (s, 3H), 4.00 (s, 3H), 7.25 (d, J=16.8 Hz, 1H), 7.40 - 7.53 (m, 5H), 7.57 - 7.61 (m, 2H), 7.84 (d, J = 16.4 Hz, 1H), 7.94 (d, J= 9.2 Hz, 1H), 8.11 (s, 1H), 9.03 (s, 1H).

Example 25

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-( l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)-5- morpho nobenzofdJoxazole

Compoud 33

[0314] Compound 33a: To a stirred solution of Comp-8e (0.1 g, 0.47 mmol) in THF (10 mL) 1M LDA in THF was added at -78 °C (0.9 mL, 0.94 mmol) and the reaction mixture was stirred for 30 min at the same temperature. Comp-3b (0.1 g, 0.47 mmol) in THF (2 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After reaction was complete, saturated aqueous ammonium chloride solution was added to the ice cold reaction mixture and extracted with EtOAc (10 mL X 2). The organic layer was washed with brine, separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 2-3% MeOH in DCM) to afford (E)-5-bromo-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3- yl)vinyl)benzo[d]oxazole (33a; 0.1 g, 51%) as pale yellow solid.

[0315] MS (ESI) m/e [M+H]⁺/Rt/%: 414.10/1.65/85.9%

[0316] Compound 33: To a stirred solution of Comp-33a (0.1 g, 0.24 mmol) in toluene (10 mL) t-BuONa (0.04 g, 0.48 mmol) followed by morpholine (0.04 g, 0.48 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.04 g, 0.07 mmol) and Pd₂(dba)3 (0.02 g, 0.024 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 0-5% MeOH in DCM) to afford (-¾)-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)-5- morpholinobenzo[d]oxazole (33; 0.06 g, 65%) as a yellow solid.

[0317] HPLC purity: 97.47%

[0318] MS (ESI) m/e [M+H]⁺/Rt/%:421.05/1.21/98.27%

[0319] ¹H NMR (400 MHz, CDCl_?) δ 1.87 (d, J=12.23 Hz, 2H), 2.20 - 2.30 (m, 4H), 2.34 (s, 3H), 2.44 (s, 6H), 3.15-3.17 (m, 6H), 3.90-3.92 (m, 4H), 3.96 - 4.05 (m, IH), 6.18 (s, 1H), 6.55 (d, J=15.65 Hz, IH), 6.90 - 6.95 (m, 1H), 7.18 (s, 1H), 7.37 (d, J=8.80 Hz, IH), 7.70 (d, J=15.65 Hz, IH).

Example 26

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-( l-methylpiperidin-4-yi)-lH-pyrrol-3-yl)vinyi)-6- fluoroquinoxaline and (E)-2-(2-(2, 5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3- yl)vinyl)-7-fluoroquinoxaline

ο

3b

o

^{N H}2 ACN,rt,16 h Piperidine, 140 °C

34a 101a

Compound 34 Compound 101

[0320] Compounds 34a and 101a: To a stirred solution of 4-fluorobenzene-l,2-diamine (1 g, 7.94 lnmol) in acetonitrile (10 mL) was added 2-oxopropanal (1 mL) at 0 °C and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford 6-fluoro-2-methylquinoxaline and 7-fluoro-2-methylquinoxaline (34a and 101a, respectively; 0.8 g, 62%) as an off white solid.

[0321] MS (ESI) m/e |M+H]^+/ Rt/%: 162.95/1.44/88.74%

[0322] Compounds 34 and 35: To a mixture of Comp-34a and Comp-lOla mixture (0.07 g, 0.45 mmol) and Comp-3b (0.1 g, 0.45 mmol) was added piperidine (0.02 g, 0.23 mmol)) and the reaction mixture was heated at 130 °C for 5 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 2% MeOH in DCM) to afford a mixture of (E)-2-(2- (2,5 -dimethyl- 1 -( 1 -methy lpiperidin-4-y 1)- lH-py rrol-3-y l)viny l)-6-fluoroquinoxaline and (E)- 2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyn-ol-3-yl)vinyl)-7-fluoroquin (34 and 101, respectively: 0.04 g, 27%) as a yellow solid.

[0323] HPLC Purity: 97.3%

[0324] MS (ESI) m/e [M+H]^+/ Rt/%: 365.20/1.27/96.9%

[0325] ¹H NMR (400 MHz, DMSO-i¾) δ 1.72-1.75 (m, 2H), 2.06 - 2.12 (m, 2 H), 2.15 - 2.21 (m, 2 H), 2.24 (s, 3 H), 2.29 (s, 3 H), 2.43 (s, 3H), 2.90-2.93 (m, 2 H), 3.93 - 4.02 (m, 1 H), 6.23 (s, 1 H), 6.84 (d, J= 15.65 Hz, 1 H), 7.55-7.61 (m, 1 H), 7.67 - 7.72 (m, 1 H), 7.92 (d, J= 15.65 Hz, 1 H), 8.02-8.06 (m, 1 H), 9.17 (s, 1 H). Example 27

Synthesis of(E)-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-p^

fluoroquinoxaline and (E)-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol.-3- yl)vinyl)-7-fluoroquinoxaline

Br-

Compound 102

[0326] To a mixture of Comp-6a and Comp-7a mixture (0.2 g, 0.90 mmol) and Comp-18c (0.2 g, 1.08 mmol) was added piperidine (0.2 mL) and the reaction mixture was heated at 130 °C for 5 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100- 200 mesh, 0-10% MeOH in DCM) to afford a mixture of (E)-6-bromo-2-(2-(5-methyl-l- phenyl-lH-pyrazol-4-yl)vinyl)quinoxaline and (E)-7-bromo-2-(2-(5 -methy 1-1 -phenyl- I H- pyrazol-4-yl)vinyl)quinoxaline (35 and 102, respectively: 0.04 g, 13%) as a yellow solid.

[0327] HPLC Purity: 90.75%

[0328] MS (ESI) m/e [M+H]+/ Rt/%: 391.0/2.20/97.29%

[0329] ¹H NMR (400 MHz, CDCl₃) δ 2.50 - 2.54 (m, 3 H), 7.09 - 7.16 (m, 1 H), 7.40 - 7.57 (m, 5 H), 7.73 - 7.86 (m, 2 H), 7.89 - 7.95 (m, 1 H), 8.03 - 8.05 (m, 1 H), 8.22 - 8.26 (m, 1 H), 8.92 - 8.97 (m, 1 H).

Example 28

Synthesis of(E)-5-bromo-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)v^

[0330] Compound 8a: Hexane-2,5-dione (25 g, 219.2 mmol) was added dropwise to aniline (20.39 g, 219.2 mmol) at 0 °C followed by addition of iodine (2.78 g, 21.92 mmol) and the reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with DCM and concentrated in vacuo and the crude obtained was purified by column chromatography (silica, 100-200 mesh, 7-8% Ethyl acetate in Hexane) to afford 2,5-dimethyl-l-phenyl-lH- pyrrole (8a; 20 g, 53%) as a colorless liquid.

[0331] MS (ESI) m/e [M+H]⁺ Rt %: 172/2.25/99.2%.

[0332] ^XH NMR (400 MHz, DMSO-d₆) δ 1.94 (s, 6H) 5.78 (s, 2H) 7.23 (d, J=7.34 Hz, 2H) 7.40 - 7.45 (m, 1H) 7.48 - 7.54 (m, 2H).

[0333] Compound 8b: To a solution of Comp-8a (15 g, 87.71 mmol) in DMF (150 mL) was added POCI3 (8.18 mL, 87.71 mmol) at 0°C and the reaction mixture was heated at 100°C for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, quenched with saturated solution of sodium bicarbonate and extracted with EtOAc. The organic layer was washed with water, brine, separated, dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 2, 5 -dimethyl- 1 -phenyl- lH-pyrrole-3- carbaldehyde (8b; 10 g, 57%) as a brown liquid. The compound was used as such for the next step without purification.

[0334] MS (ESI) m/e [M+H]^+/ Rt/%: 200.15/1.77/97.9%. [0335] ¹H NMR (400 MHz, DMSO-d₆) δ 1.94 (s, 3 H) 2.23 (s, 3 H) 6.29 (s, 1 H) 7.35 (d, J=6.85 Hz, 2 H) 7.52 - 7.62 (m, 3 H) 9.81 (s, 1 H).

[0336] Compound 8d: To a solution of 4-bromo-2-nitrophenol (30 g, 137.6 mmol) in MeOH: H₂0 (300 mL 4:1) at 0°C, SnCl₂ (130 g, 688 mmol) was added slowly and the reaction mixture was heated at 70°C for 6h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo and the residue was neutralized with aqueous sodium bicarbonate solution, diluted with ethyl acetate and filtered through celite. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to afford 2-amino-4- bromophenol (8d; 15 g, 60%) as a white solid.

[0337] MS (ESI) m/e [M+H]⁺ Rt/%: 189.85/1.33/99.3%.

[0338] ¹H NMR (400 MHz, CD(¾) 1.64 (brs, 2 H) 6.58 - 6.63 (m, 1 H) 6.74 - 6.80 (m, 1 H) 6.87 - 6.90 (m, 1 H) 7.29 (brs, 1 H).

[0339] Compound 8e: A solution of Comp-8d (15 g, 79.78 mmol) in 1,1,1-triethoxy ethane (75 mL) was heated at 100°C for 6h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo and the crude obtained was purified by column chromatography (silica, 100-200 mesh, 10% Ethyl acetate in Hexane) to afford 5-bromo-2-methylbenzo[d]oxazole (8e; 10 g, 59%) as a yellow solid.

[0340] MS (ESI) m/e [M+H]⁺ Rt %: 211.95/1.93/93.3%.

[0341] ^XH NMR (400 MHz, CDCl₃) δ 2.65 (s, 3H) 7.33 - 7.37 (m, 1H) 7.39 - 7.44 (m, 1H) 7.79 (s, l H).

[0342] Compound 36: To a solution of Comp-8e (10 g, 47.16 mmol) and Comp-8b (7.51 g, 37.73 mmol) in THF:tBuOH (50 mL 4:1) was added t-BuOK (15.84 g, 141.5 mmol) at room temperature and the reaction mixture was stirred for 30 min. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and the compound was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 10-12% ethyl acetate in Hexane) to afford (E)-5- bromo-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)benzo[ii]oxazole (36; 8 g, 43%) as a yellow solid.

[0343] HPLC purity: 96.39%

[0344] MS (ESI) m/e [M+H]⁺/Rt/%: 395.10/2.28/94.2% [0345] ¹H NMR (400 MHz, CDCl₃) δ 2.02 (s, 3 H), 2.18 (s, 3 H), 6.31 (s, 1 H), 6.60 - 6.67 (m, 1 H), 7.20 - 7.25 (m, 2 H), 7.35 - 7.39 (m, 2 H), 7.46 - 7.54 (m, 3 H), 7.78 (d, J=2.45 Hz, 1 H), 7.83 (s, 1H).

Example 29

Synthesis of ^'(E)- 7-chloro-2-(2-( 2, 5-dimethyl-l-(l-melhylpiperidin-4-yl)- lH-pyrrol-3- yl)vinyl)-6-fluoroquinoxaline and (E)-6-chloro-2-(2-(2,5-dimethyl-l-(l-methyJpiperidin-4- yl)-lH-pyrrol-3-yl)vmyl)-7-fluoroquiftoxaline

[0346] Compound 37a: To a stirred solution of KNO3 (2 g, 20.61 mmol) in trifluroacetic anhydride (20 mL), 4-chloro-3-fluoroaniline (2 g, 13.74 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 16 h Progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured in sat NaHC0₃ solution and extracted with EtOAc (50 mL X 2). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get crude as an oil. The crude w^?as dissolved in methanol (25 mL), and K₂C0₃ (9.4 g, 68.70 mmol) was added and the reaction mixture was stirred at RT for 1 h. After completion, the reaction mixture was concentrated under reduced pressure, the crude obtained was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 5% EtOAc in hexane) to afford 4-chloro-5-fluoro-2-nitroaniline (37a, 2.1 g, 76%) as a yellow solid. [0347] ¹H NMR (400 MHz, CDCl₃) δ 6.20 (br. s, 2 H), 6.61 (d, J=12 Hz, 1 H), 8.25 (d, J=8 Hz, 1 H).

[0348] Compound 37b: To a solution of Comp-37a (2 g, 10.49 mmol) in acetic acid (10 mL) was added iron powder (3 g, 52.47 mmol) and the reaction mixture was heated at 70 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, quenched with 2NNaOH and extracted EtOAc (50 mL X 2). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 30% EtOAc in hexane) to afford 4-chloro-5-fluorobenzene-l,2-diamine (37b; 0.9 g, 53%) as a light brown solid.

[0349] MS (ESI) m/e [M+H]⁺/Rt/%: 161.10/1.19/72.3%

[0350] ¹H NMR (400 MHz, DMSO-d₆) δ 4.55 (s, 2 H), 4.88 (s, 2 H), 6.43 (d, J=l 1.25 Hz, 1 H), 6.52 (d, J=7.34 Hz, 1 H).

[0351] Compounds 37c and 107c: To a stirred solution of Comp-37b (0.9 g, 5.60 mmol) in acetonitrile (20 mL) was added 2-oxopropanal (0.9 mL) at 0 °C and the reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with H₂0 (50 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford a mixture of 7-chloro- 6-fluoro-2-methylquinoxaline and 6-chloro-7-fluoro-2-methylquinoxaline (37c and 107c, respectively; 0.8 g, 72%) as light yellow solid.

[0352] MS (ESI) m e [M+H]⁺/Rt/%: 196.95/1.73/97.6%

[0353] ¹H NMR (400 MHz, CDCl₃ 2: 1 mixture of isomers) δ 2.75 (s, 3 H), 7.71 & 7.77 (d, J=9.29 Hz, 0.6H & 0.3 H), 8.08 & 8.14 (d, J=7.82 Hz, 0.6H & 0.3H), 8.70 & 8.71 (s, 0.6 H & 0.3H).

[0354] Compounds 37 and 107: To a mixture of Comp-3b (0.2 g, 1.01 mmol) and Comp- 37c and Comp-107c mixture (0.22 g, 1.01 mmol) was added piperdine (1 mL) and the reaction mixture was heated at 130 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-10% MeOH in DCM) followed by prep HPLC purification to afford mixture of regioisomer (in ratio 2: 1) (E)-7-chloro-2-(2-(2,5- dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)-6-fluoroquinoxaline and (E)-6- chloro-2-(2-(2,5-dimethyl- 1 -(1 -methylpiperidin-4-yl)- lH-pyrrol-3-yl)vinyl)-7- fluoroquinoxaline (37 and 107, respectively; 0.05 g, 14%) as a yellow solid.

[0355] HPLC purity : 98.25%

[0356] MS (ESI) m/e [M+H]⁺/Rt/%: 399.05/1.43/98.4%

[0357] ¹H NMR (400 MHz, DMSO-d₆) δ 1.69 - 1.77 (m, 2 H), 1.98 - 2.10 (m, 2 H), 2.12 - 2.20 (m, 2 H), 2.21 - 2.24 (m, 3 H), 2.28 (s, 3 H), 2.41 - 2.46 (m, 3 H), 2.84 - 2.97 (m, 2 H), 3.91 - 4.02 (m, 1 H), 6.19 - 6.26 (m, 1 H), 6.78 - 6.88 (m, 1 H), 7.89 - 8.04 (m, 2 H), 8.16 - 8.30 (m, 1 H), 9.18 - 9.27 (m, 1 H).

Example 30

Synthesis of (E)-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)-6, 7- difluoroquinoxaline

[0358] To a mixture of Comp-46a (0.1 g, 0.55 mmol) and Comp-3b (0.12 g, 0.55 mmol) was added t-BuONa (1.5 mL in THF) and the reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 100- 200 mesh, 2% MeOH in DCM) followed by prep HPLC purification to afford (E)-2-(2-(2,5- dimethyl- 1 -(1 -methylpiperidin-4-yl)- lH-pyrrol-3-yl)vinyl)-6,7-difluoroquinoxaline (38; 0.02 g, 10%) as a yellow solid.

[0359] HPLC Purity: 99.6%

[0360] MS (ESI) m/e [M+H]^+/ Rt/%: 383.25/1.34/96.7%

[0361] ¹H NMR (400 MHz, DMSO-d₆) δ 1.70 - 1.76 (m, 2 H), 2.02 - 2.10 (m, 2 H), 2.14- 2.9 (m, 2 H), 2.22 (s, 3H), 2.28 (s, 3 H), 2.43 (s, 3H), 2.90 (d, J= 11.25 Hz, 2 H), 3.94 - 3.99 (m, 1 H), 6.22 (s, 1 H), 6.83 (d, J= 15.65 Hz, 1 H), 7.90 (d, J= 15.65 Hz, 1 H), 7.97 (dd, J = 11.74, 8.31 Hz, 1 H), 8.01 - 8.07 (m, 1 H), 9.20 (s, 1 H).

Example 31 Synthesis of (E)-6-cyclopropyl-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl) yl)vinyl)quinoxaline and (E)-7-cyclopropyl-2-(2-(2, 5-dimethyl-l-(l-methylpiperidin-4-yl)- lH-pyrrol-3-yl)vinyl)quinoxaline

[0362] To a stirred solution of Comp-68a and Comp-69a mixture (0.15 g, 0.35 mmol) in toluene: water (2:1, 3 mL), K3PO4 (0.2 g, 1.06 mmol), triphenyl phosphine (0.09 g, 0.35 mmol) followed by cyclopropylboronic acid (0.09 g, 1.06 mmol) were added and the reaction mixture was degassed with argon for 15 min. Pd(OAc)₂ (0.02 g, 0.10 mmol) was added and the reaction mixture was heated at 80 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure. The crude obtained was purified by prep HPLC purification to afford a mixture of regioisomers (E)-6-cyclopropyl-2-(2-(2,5-dimethyl- l-(l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)quinoxaline and (E)-7-cyclopropyl-2-(2- (2,5-dimethyl-l-(l-methylpipericun-4-y])-lH-pyrrol-3-yl)vinyl)quinoxaline (39 and 98, respectively; 0.04 g, 28%) as an off-white solid.

[0363] HPLC purity: 95.20%

[0364] MS (ESI) m/e [M+H]⁺ /Rt/%: 387.25/1.55/98.95%

[0365] ¹H NMR (400 MHz, CDCl₃, 2: 1 mixture of isomers) δ 0.87-0.89 (m, 4H), 1.11 (d, J=7.34 Hz, 2H), 1.27 (s, 3H), 1.86 (d, J=12.23 Hz, 2H), 2.06 - 2.26 (m, 3H), 2.36 (s, 3H), 2.40 (s, 3H), 3.09 (d, J=9.78 Hz, 2H), 3.97 (t, J=12.23 Hz, 1H), 6.24 (s, 1H), 6.88 (d, J=15.65 Hz, 1H), 7.35 - 7.47 (m, 1H), 7.60 - 7.68 (m, 1H), 7.76 - 7.84 (m, 1H), 7.87-7.90 (m, 1H), 8.84 & 8.89 (s, 0.58H & s, 0.31H).

Example 32 Synthesis of (E)-2-(2-(2, 5-dimethyl-l-( l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyi)-6- methoxyquinoxaline and (E)-2-(2-(2, 5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3- yl)vinyl)-7-methoxyquinoxaline

40a 99a

Compound 40 Compound 99

[0366] Compounds 40a and 99a: To a stirred solution of 4-methoxybenzene-l,2-diainine (0.5 g, 3.62 mmol) in acetonitrile (5 mL) was added 2-oxopropanal (0.26 g, 3.62 mmol) at 0 °C and the reacti on mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford a mixture of 6-methoxy-2- methylquinoxaline and 7-methoxy-2-methylquinoxaline (40a and 99a, respectively; 0.5 g, 79%) as a yellow solid.

[0367] Compounds 40 and 99: To a mixture of Comp-40a and Comp-99a mixture (0.1 g, 0.57 mmol) and Comp-3b (0.1 g, 0.57 mmol) was added piperidine (0.024 g, 0.28 mmol) and the reaction mixture was heated at 110 °C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 230-400 mesh, 0-2% MeOH in DCM) to afford a mixture of regioisomers (E)-2-(2-(2,5-dimethyl-l -(1 -methylpiperidin-4-yl)- l H-pyrrol-3-yl)vinyl)-6- methoxy quinoxaline and (7±)-2-(2-(2,5-dimethyl- 1 -(1 -methylpiperidin-4-y 1)- lH-pyrrol-3- yl)vinyl)-7-methoxyquinoxaline (40 and 99, respectively; 0.05 g, 24%) as a pale yellow solid.

[0368] HPLC Purity: 99.38%

[0369] MS (ESI) m/e [M+H]+/ Rt/%: 377.20/1.24/99.7%

[0370] ¹H NMR (400 MHz, CDCl_3, 4: 1 mixture of isomers) δ 1.89 (d, J=12.23 Hz, 2H), 2.33 (s, 3H), 2.37 - 2.42 (m, 2H), 2.45 (s, 3H), 2.52 (s, 3H), 2.54 - 2.63 (m, 2H), 3.33 (d, .7=11.25 Hz, 2H), 3.95 (s, 3H), 3.99 - 4.08 (m, IH), 6.22 (s, 1H), 6.85 (d, .7=15.65 Hz, 1H), 7.28 - 7.35 (m, 1H), 7.77 (d, J=16.14 Hz, 1 H), 7.86 (d, J=8.80 Hz, 1H), 8.40 (s, 1H), 8.75 & 8.84 (s, 0.78H & 0.19H).

Example 33

Synthesis of (E)-2-(2-(2,5-dimethyl-]-(l-methylpiperidm-4-yl)^

(trifluoromelhoxy)quinoxaline and (E)-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH- pyrrol-3-yl)vinyl)-6-(ti'ifluoromethoxy)quinoxaUne

41a 100a

Compound 41 Compound 100

[0371] Compounds 41a and 100a: To a stirred solution of 4-(trifluoromethoxy)benzene- 1,2-diamine (0.5 g, 2.60 mmol) in acetonitrile (10 mL) was added 2-oxopropanal (0.5 mL) and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 30-40% EtOAc in hexane) to afford a mixture of 2-methyl-7-

(trifluoromethoxy)quinoxaline and 2-methyl-6-(trifluoromethoxy)quinoxaline (41a and 100a, respectively; 0.5 g, 84%) as a pale yellow solid.

[0372] MS (ESI) m/e |M+H]⁺/Rt/%: 228.95/1.79/89.5%

[0373] Compounds 41 and 100: To a mixture of Comp-41a and Comp-lOOa mixture (0.3 g, 1.31 mmol) and Comp-3b (0.29 g, 1.31 mmol) was added i-BuOk (1 mL, 1M in THF) and the reaction mixture was heated at 50 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with w^?ater and extracted with EtOAc (50 mL X 2). The organic layer was washed with water, brine, separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude obtained was purified by prep HPLC purification to afford a mixture of regioisomers (E)-2-(2-(2,5- dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)-7-(trifluoromethoxy)quinoxaline and (E)-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-1H-pyrrol-3-yl)vinyl)-6-

(trifluoromethoxy)quinoxaline (41 and 100, respectively; 0.09 g, 17%) as a yellow solid.

[0374] HPLC purity : 98.19%

[0375] MS (ESI) m/e [M+H]⁺/Rt/%: 431.20/1.69/97.8%

[0376] ¹H NMR (400 MHz, DMSO-d_6, 2: l mixture of isomers) δ 1.73 (d, J=l 1.25 Hz, 2H), 2.01 - 2.11 (m, 2H), 2.14-2.17 (m, 2H), 2.23 (s, 3H), 2.29 (s, 3H), 2.44 (s, 3H), 2.91 (d, J=10.27 Hz, 2H), 3.92 - 4.02 (m, 1H), 6.24 (s, 1H), 6.85 (d, J=15.65 Hz, 1H), 7.62 - 7.78 (m, 1H), 7.85 (s, 1H), 7.91 - 7.98 (m, 1H), 8.04 - 8.13 (m, 1H), 9.24 & 9.28 (s, 0.56H & 0.34H).

Example 34

Synthesis of (E)-5-cyclopropyl-2-(2-(2, 5-dimethyl-l-phenyl-lH-pyrrol-3- yl)vinyl)benzo[ d ]oxazole

[0377] To a stirred solution of Comp-36 (0.07 g, 0.17 mmol) in dioxane:water (4: 1, 5 mL) K₃PO₄ (0.1 1 g, 0.53 mmol), triphenyl phosphine (0.046 g, 0.175 mmol) followed by cyclopropyl boronic acid (0.046 g, 0.53 mmol) were added and the reaction mixture was degassed with argon for 15 min. Pd(OAc)₂ (0.01 g, 0.053 mmol) was added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by prep HPLC to afford (E)-5-cyclopropyl-2-(2-(2,5-dimethyl-l- phenyl-lH-pyrrol-3-yl)vinyl)benzo[d]oxazole (43; 0.03 g, 47%) as an off-white solid.

[0378] HPLC purity : 97.98%

[0379] MS (ESI) m/e [M+H]⁺/ Rt/%: 355.20/ 2.42/ 96.9%

[0380] ¹H NMR (400 MHz, DMSO-d₆) δ 0.68 - 0.73 (m, 2 H), 0.93 - 0.99 (m, 2 H), 1.95 - 1.99 (m, 3 H), 2.00 - 2.08 (m, 1 H), 2.09 - 2.14 (m, 3 H), 6.43 - 6.45 (m, 1 H), 6.61 - 6.67 (m, 1 H), 7.03 - 7.07 (m, 1 H), 7.30 - 7.36 (m, 3 H), 7.47 - 7.53 (m, 2 H), 7.54 - 7.60 (m, 2 H), 7.65 - 7.72 (m, 1 H).

Example 35 Synthesis of (E)-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yl)vinyl)-5- morpholinobenzo[d]oxazole

Br-

Pd₂(dba)₃, BINAP,

KOfBu, THF, NaOfBu, Toluene, rt, 12 h 100 °C, 12 h

8e

Compuond 44

[0381] Compound 44a: To a stirred solution of Comp-8e (0.3 g, 1.42 mmol) in THF (10 mL) was added i-BuOK (0.47 g, 4.26 mmol) at 0 °C and the reaction mixture was stirred for 30 min at the same temperature. Comp-18c (0.31 g, 1.70 mmol) in THF (5 mL) was added at 0 °C and the reaction mixture was stirred at the same temperature for 1 h, followed by RT for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and

concentrated under reduced pressure. The crude obtained was purified by column

chromatography (silica, 230-400 mesh, 0-20% EtOAc in hexane) to afford (E)-5-bromo-2-(2- (5-methyl-l-phenyl-lH-pyrazol-4-yl)vinyl)benzo|d]oxazole (44a, 0.09 g, 17%) as an off- white solid.

[0382] MS (ESI) m/e [M+H]⁺ /Rt %: 379.95/2.33/95.6%

[0383] Compound 44: To a stirred solution of Comp-44a (0.09 g, 0.23 mmol) in toluene (5 mL) t-BuONa (0.068 g, 0.70 mmol) followed by morpholine (0.025 g, 0.28 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.04 g, 0.07 mmol) and Pd₂(dba) (0.02 g, 0.023 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 40% ethyl acetate in Hexane) to afford (E)-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yl)vinyl)-5- morpholinobenzo[<ai]oxazole (44; 0.029 g, 32%) as an off-white solid. [0384] HPLC puril : 98.19%

[0385] MS (ESI) m/e [M+H]⁺ t %: 387.20/1.91/98.7%

[0386] ¹H NMR (400 MHz, CDCl₃) δ 2.47 - 2.51 (m, 3 H), 3.15 - 3.21 (m, 4 H), 3.89 - 3.95 (m, 4 H), 6.80 - 6.86 (m, 1 H), 6.97 - 7.01 (m, 1 H), 7.21 - 7.23 (m, 1 H), 7.40 - 7.49 (m, 4 H), 7.50 - 7.55 (m, 2 H), 7.63 - 7.69 (m, 1 H), 7.96 - 7.98 (m, 1 H).

Example 36

Synthesis of (E)-5-(4 -difl oropiperidin-l-yl)-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3- yljvinyljbenzo[d]oxazole

Compound 45

[0387] To a solution of Comp-36 (0.5 g, 1.27 mmol) in toluene (10 mL) t-BuONa (0.37 g, 3.82 mmol) followed by 4,4-difluoropiperidine as hydrochloride salt (0.22 g, 1.40 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.24 g, 0.38 mmol) and Pd2(dba)3 (0.1 16 g, 0.12 mmol) were added and the reaction mixture was heated at 100°C for 12h. Progress of the reacti on was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The crude obtained was purified by column chromatography (silica, 100-200 mesh,) to afford (E)-5-(4,4-difluoropiperidin-l- yl)-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)benzo[i |oxazole (45; 0.15 g, 27%) as a yellow solid.

[0388] HPLC Purity: 97.09%.

[0389] MS (ESI) m/e [M+H]^+/ Rt/%: 434.20/2.36/99.41 %.

[0390] ¹H NMR (400 MHz, DMSO-d₆) δ 1.98 (s, 3 H) 2.06 - 2.16 (m, 7H) 3.29-3.31 (m, 4H) 6.43 (s, 1 H) 6.63 (d, J=15.65 Hz, 1 H) 7.04 (dd, J=8.80, 2.45 Hz, 1 H) 7.22 (d, J=2.45 Hz, 1 H) 7.33 (d, J=7.34 Hz, 2 H) 7.47 - 7.53 (m, 2 H) 7.54 - 7.60 (m, 2 H) 7.66 (d, J=16.14 Hz, 1 H).

Example 37

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-6.7-difluoroquinoxaline

[0391] Compound 46a: 2-Oxopropanal (1.6 g, 22.22 mmol) was added to 4,5- difluorobenzene-l,2-diamine (3.2 g, 22.22 mmol) at room temperature and the reaction mixture was heated at 80°C for 1.5h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled and the precipitated solid was filtered and dried to afford 6,7-difluoro-2-methylquinoxaline (46a; 3.3 g, 83%) as a brown stick\' solid.

[0392] MS (ESI) m/e [M+H]^+/ Rt/%: 181.05/1.61/96.6%.

[0393] ¹H NMR (400 MHz, CDCl₃) δ 2.78 (s, 3H) 7.74 - 7.86 (m, 2H) 8.73 (s, 1H).

[0394] Compound 46: To a solution of Comp-46a (1.65 g, 9.16 mmol) in THF:tBuOH (17.5 mL 16: 1.5) was added t-BuOK (3.08 g, 27.49 mmol) and the reaction mixture was stirred for 10 min. Comp-8b (1.82 g, 9.16 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 10-12% ethyl acetate in Hexane) followed by prep HPLC purification to afford (E)-2-(2-(2,5-dimethyl-l - phenyl- lH-pyrrol-3-yl)vinyl)-6,7-difluoroquinoxaline (46; 0.77 g, 23%) as a yellow solid.

[0395] HPLC Purity: 99.3%.

[0396] MS (ESI) m/e [M+H]^+/ Rt/%: 362.15/2.49/99.80%.

[0397] ¹H NMR (400 MHz, DMSO-< ) δ 2.00 (s, 3 H) 2.16 (s, 3 H) 6.41 (s, 1 H) 6.96 (d, J=16.14 Hz, 1 H) 7.34 (d, J=7.34 Hz, 2 H) 7.48 - 7.53 (m, 1 H) 7.54 - 7.59 (m, 2 H) 7.94 - 8.01 (m, 2 H) 8.02 - 8.10 (m, 1 H) 9.25 (s, 1 H).

Example 38

Synthesis of (E)-2-(2-(2, 5-dimeihyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-5-fluorob^

[0398] To a stirred mixture of Comp-50c (0.2 g, 1.32 mmol) in THF (20 mL) was added solution of i-BuOK (2 mL, 1 M in THF) at 0 °C. Comp-8b(0.26 g, 1.32 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H₂0 (5 mL) and extracted with EtOAc (50 mL X 2). The organic layer was washed with brine, separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 10-20% EtOAc in hexane) to afford (E)-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)- 5-fluorobenzo|d]oxazole (47, 0.04 g, 10%) as a yellow solid.

[0399] HPLC purity : 99.79%

[0400] MS(ESI) m/e [M+H]⁺ Rt %: 333.0/2.32/95.5%

[0401] ¹H NMR (400 MHz, CD(¾) δ 1.99 - 2.04 (m, 3 H), 2.12 - 2.17 (m, 3 H), 6.21 - 6.30 (m, 1 H), 6.57 - 6.64 (m, 1 H), 6.92 - 7.00 (m, 1 H), 7.16 - 7.22 (m, 2 H), 7.33 - 7.40 (m, 1 H), 7.41 - 7.53 (m, 3 H) 7.61 - 7.90 (m, 2 H).

Example 39

Synthesis of (E)-6-fluoro-2-(2-(5-methyl-l-( l-methylpiperidin-4-yl)-lH-pyrazol-4- yl)vinyl)quinoxaline and (E)-7-fluoro-2-(2-(5-methyl-l-(l-methylpiperidin-4-yl)-lH^

4-yl)vinyl)quinoxaline

48d 48e

[0402] Compound 48a: To a stirred solution of l-methylpiperidin-4-one (10 g, 88.37 mmol) in methanol (200 mL) was added tot-butyl hydrazinecarboxylate (17.5 g, 132.55 mmol) and the reaction mixture was heated at 80 °C for 6 h. The reaction mixture was cooled to 0 °C and to it was added NaCNBH₃ (16.6 g, 265.11 mmol) and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was dissolved in EtOAc (500 mL) and washed with satNaHCCh solution. The organic layer was washed with water, brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford fcrt-butyl 2-(l-methylpiperidin-4-yl)hydrazine-l-carboxylate (48a, 4.5 g, 38%) as a pale yellow solid. The compound was used for the next step without purification

[0403] MS (ESI) m/e [M+H]⁺/Rt/%: 230.15/0.61/29.02% [0404] Compound 48b: To a solution of Comp-48a (4 g, 17.44 mmol) in dioxane (20 mL) was added 4M HC1 in dioxane (20 mL) at 0 °C and the reaction mixture was stirred at RT for 5 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was dissolved in methanol, neutralized with carbonate on polymer, which was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to afford 4-hydrazineyl-l- methylpiperidine (48b, 2.1 g, 93%) as pale yellow oil. The compound was used for the next step without purification.

[0405] ¹H NMR (400 MHz, DMSO- d₆ + D₂0) δ 1.57 - 1.65 (m, 1 H), 1.92 (br s, 1 H), 2.11 (br s, 1 H), 2.71 (s, 3 H), 2.90 - 3.01 (m, 2 H), 3.07 - 3.14 (m, 1 H), 3.18 - 3.28 (m, 1 H), 3.39 - 3.49 (m, 2 H).

[0406] Compound 48c: A solution of ethyl 3-oxobutanoate (3 g, 23.21 mmol) and

DMF.DMA (1.4 g, 23.21 mmol) was heated at 110 °C for 1 h. The reaction mixture was cooled to RT and to it was added Comp-48b (2 g, 15.47 mmol) in ethanol (20 mL) and the reaction mixture was heated at 80 °C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in EtOAc (50 mL) and washed with WHO. The organic layer was washed with water, brine dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford ethyl 5-methyl-l-(l-methylpiperidin-4-yl)-lH-pyrazole-4-carboxylate (48c, 3 g, crude) as pale yellow oil. The compound was used for the next step without purification.

[0407] MS (ESI) m/e [M+H]⁺/Rt/%: 252.10/1.01/96.2%

[0408] Compound 48d: To a stirred solution of Comp-48c (3 g, 11.89 mmol) in THF (10 mL) was added LAH (5 g, 23.92 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h. Progress of the reacti on was monitored by TLC. After completion, the reacti on mixture was cooled to 0 °C and quenched with EtOAc followed by water and filtered through celite. The residue was washed with 10% MeOH in DCM (50 mL) and the filtrate was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford (5-methyl-l-phenyl- 1 H-pyrazol-4-yl)methanol (48d, 1 g, crude) as a yellow solid. The compound was used for the next step without purification.

[0409] MS (ESI) m/e [M+H]⁺/Rt/%: 210.10/0.31/68.81%

[0410] Compound 48e: To a stirred solution of Comp-48d (1 g, 4.77 mmol) in DCM (20 mL) was added Dess-Martin periodinane (3 g, 7.16 mmol) at 0 °C and the reaction mixture was stirred at RT for 6 h. Progress of the reaction was monitored by TLC. After completion the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 5% MeOH in DCM) to afford 5- me1hyl-] -(l-me1hylpiperidin-4-yl)-lH-pyrazole-4-carbaldehyde (48e, 0.9 g, 91%) as an off white solid.

[0411] MS (ESI) m/e [M+H]⁺/Rt %: 208.10/0.33/55.6%

[0412] Compound 48 and 105: To a mixture of Comp-34a and Comp-lOla mixture (0.05 g, 0.30 mmol) and Comp-48e (0.06 g, 0.30 mmol) was added piperidine (0.05 mL) and the reaction mixture was heated at 130 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 230-400 mesh, 0-2% MeOH in DCM) followed by prep HPLC purification to afford a mixture of regioisomers (E)-6-fluoro-2-(2-(5-methyl-l-(l- methylpiperidin-4-yl)-lH-pyrazol-4-yl)vinyl)quinoxaline and (E)-7-fluoro-2-(2-(5-methyl-l - (l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)vinyl)quinoxaline (48 and 105, respectively; 0.02 g, 20%) as a yellow solid.

[0413] HPLC purity: 89.57%

[0414] MS (ESI) m/e [M+H]⁺/Rt/%: 352.20/1.98/96.1%

[0415] ¹H NMR (400 MHz, CD₃OD, 4: 1 mixture of isomers) δ 2.05 (d, J=\ 1.74 Hz, 2 H), 2.30 - 2.38 (m, 2 H), 2.59 (s, 3 H), 2.68 (t, J=11.74 Hz, 2 H), 3.26-3.28 (m, 2H), 4.36 - 4.45 (m, 1 H), 7.15 (d, J=16.14 Hz, 1 H), 7.53 - 7.59 (m, 1 H), 7.64 (dd, J=9.78, 2.93 Hz, 1 H), 7.85 - 7.94 (m, 2 H), 8.03 - 8.08 (m, 1 H), 9.01 & 9.07 (s, 0.8 H & 0.2 H) (3H's merged in solvent peak).

Example 40

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-(pyridin-3-yl)-lH-pyrrol-3-yl)vinyl)-6- fluoroquinoxaline and (E)-2-(2-(2, 5-dimethyl-l-(pyridin-3-yl)-lH-pyrro!.-3-yl)vinyl)- 7- fluoroquinoxaline

Compound 49

79b

+

Piperidine (cat),

130 °C, 16 h

34a 101a F

Compound 106

[0416] To a mixture of Comp-34a and Comp-lOla mixture (0.05 g, 0.30 mmol) and Comp- 79b (0.06 g, 0.30 mmol) was added piperidine (0.05 mL) and the reaction mixture was heated at 130 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column

chromatography (silica, 230-400 mesh, 0-2% MeOH in DCM) followed by prep HPLC purification to afford a mixture of regioisomers (E)-2-(2-(2,5-dimethyl-l-(pyridin-3-yl)-lH- pyrrol-3-yl)vinyl)-6-fluoroquinoxaline and (E)-2-(2-(2,5-dimethyl-l-(pyridin-3-yl)-lH- pyrro]-3-yl)vinyl)-7-fluoroquinoxaline (49 and 106, respectively; 0.02 g, 20%) as a yellow solid.

[0417] HPLC purity: 86.16%

[0418] MS (ESI) m/e [M+H]7Rt/%: 345.45/1.96/95.47%

[0419] ¹H NMR (400 MHz, CD₃OD) δ 2.07 (s, 3 H), 2.23 (s, 3 H), 6.46 (s, 1 H), 7.01 (d, J=15.65 Hz, 1 H), 7.49 - 7.58 (m, 1 H), 7.62 - 7.75 (m, 2 H), 7.85 - 7.91 (m, 1 H), 8.01 - 8.11 (m, 2 H), 8.55 (d, J=1.96 Hz, 1 H), 8.69 (d, J=3.91 Hz, 1 H), 9.04 & 9.10 (s, 0.7H & 0.14H).

Example 41

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-( l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)-5- fluorobenzo[d]oxazole

[0420] Compound 50a: To a solution of 4-fluorophenol (23 g, 205 mmol) in acetic acid (120 mL) was added nitric acid (17.5 mL, 0.31 mmol) dropwise at 0°C over a period of 15 min. The reaction mixture was allowed to stir from 0°C to room temperature for 2h. Progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice cold water. The precipitated solid was filtered, washed with cold water and dried to afford 4-fluoro-2-nitrophenol (50a; 21 g, 65%) as a yellow solid.

[0421] ¹H NMR (400 MHz, DMSO-d₆) δ 7.13-7.17 (m, 1 H) 7.44-7.49 (m, 1 H) 7.79 (dd, J=8.56, 3.18 Hz, 1 H) 10.96 (s, 1 H).

[0422] Compound 50b: To a solution of Comp-50a (20 g, 127 mmol) in methanol (200 mL) was added 20% Pd/C (2 g) and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and washed with methanol. The filtrate was concentrated in vacuo and the crude obtained was purified by column chromatography (silica, 100-200 mesh) to afford 2-amino-4-fluorophenol (50b; 12 g, 74%) as a brown solid.

[0423] MS (ESI) m/e [M+H]^+/ Rt %: 128/0.63/83.2%.

[0424] ^XH NMR (400 MHz, DMSO-d₆) δ 4.79 (brs, 2 H) 6.09-6.14 (m, 1 H) 6.35 (dd, J=10.76, 2.93 Hz, 1 H) 6.53-6.57 (m, 1 H) 8.90 (s, 1 H). [0425] Compound 50c: A solution of Comp-50b (1.00 g, 7.87 mmol) in 1,1,1- triethoxy ethane (5 mL) was heated at 100°C for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo below 30°C and the crude obtained was purified by column chromatography (silica, 100-200 mesh,

0- 20% Ethyl acetate in Hexane) to afford 5-fluoro-2-methylbenzo[d]oxazole (50c; 0.9 g, 76%) as a brown oil.

[0426] MS (ESI) m/e [M+H]⁺ Rt %: 151.95/1.72/92.3%.

[0427] ¹H NMR (400 MHz, DMSO-d₆) δ 2.61 (s, 3 H) 7.16 - 7.23 (m, 1 H) 7.53 (dd, J=8.80, 2.45 Hz, 1 H) 7.67-7.70 (m, 1 H).

[0428] Compound 50d: Hexane-2,5-dione (16 mL, 137.5 mmol) was added dropwise to tert-butyl 4-aminopiperidine-l-carboxylate (25 g, 125 mmol) at 0°C followed by addition of catalytic amount of iodine and the reaction mixture was stirred at room temperature for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to afford tert-butyl 4-(2,5-dimethyl- lH-pyrrol-l-yl)piperidine-l-carboxylate (50d; 28 g, 81%) as a brown solid.

[0429] MS (ESI) m/e [M+H]⁺ Rt/%: 279.36/2.17/95.1 1 %.

[0430] ¹H NMR (400 MHz, DMSO-d₆) δ 1.40 (s, 9 H) 1.68-1.72 (m, 2 H) 1.85-1.95 (m, 2 H) 2.18 (s, 6 H) 2.81-2.84 (m, 2 H) 3.99 - 4.12 (m, 3 H) 5.56 (s, 2 H).

[0431] Compound 3a: To a solution of Comp-50d (17 g, 61.15 mmol) in THF (170 mL) was added 1M solution of LAH in THF (92 mL, 91.72 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with saturated solution of sodium sulphate at 0°C. The reaction mixture was filtered through Celite bed and the filtrate was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 4-(2,5-dimethyl-lH-pyrrol-l-yl)-

1- methylpiperidine (3a; 10.5 g, 89%) as colorless oil. Crude compound was used as such for the next step without purification.

[0432] MS (ESI) m/e [M+H]⁺ Rt/%: 193.15/0.72/92.4%.

[0433] Compound 3b: To a solution of Comp-3a (18 g, 93.75 mmol) in DMF (180 mL) was added POC13 (8.75 mL, 93.75 mmol) at 0°C and the reaction mixture was heated at 80°C for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, quenched with saturated solution of sodium bicarbonate and extracted with methyl THF. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 10% MeOH in DCM) to afford 2,5-dimethyl-l-(l -methylpiperidin-4- yl)-lH-pyrrole-3-carbaldehyde (3b; 7.8 g, 38%) as brown oil.

[0434] MS (ESI) m/e [M+H]^+/ Rt %: 221.15/0.36/72.8%.

[0435] ¹H NMR (400 MHz, DMSO-d₆) δ 1.70-1.74 (m, 2 H) 1.98 - 2.07 (m, 2 H) 2.12 - 2.17 (m, 1 H) 2.20 (s, 3 H) 2.26 (s, 3 H) 2.53 (s, 3 H) 2.84-2.86 (m, 2H) 2.87-2.89 (m, 1 H) 3.95-4.03 (m, 1 H) 6.11 (s, 1 H) 9.70 (s, 1 H).

[0436] Compound 50: To a solution of Comp-50c (3.95 g, 26.15 mmol) in THF:iBuOH (50 mL 4: 1 ) was added t-BuOK (8.78 g, 78.47 mmol) and the reaction mixture was stirred for 10 min. Comp-3b (5.18 g, 23.54 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H₂0 and extracted with EtOAc. The organic layer was washed with brine, separated, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 2-3% MeOH in ethyl acetate) to afford (E)-2-(2-(2,5-dimethyl-l-(l- me1hylpiperidin-4-yl)-lH-pyrrol-3-y])viny])-5-fluorobenzo[d]oxazole (50; 1.8 g, 20%) as yellow solid.

[0437] HPLC Purity: 98.7%.

[0438] MS (ESI) m/e |M+H|^+/ Rt/%: 354.20/1.42/98.2%.

[0439] ¹H NMR (400 MHz, DMSO-c¾ δ 1.69-1.72 (m, 2 H) 1.98 - 2.07 (m, 2 H) 2.11 - 2.17 (m, 2H) 2.20 (s, 3 H) 2.27 (s, 3H) 2.38 (s, 3 H) 2.88 (d, J=11.25 Hz, 2 H) 3.92-3.98 (m, 1 H) 6.26 (s, 1 H) 6.51 (d, J=15.65 Hz, 1 H) 7.11-7.16 (m, 1 H) 7.46 (dd, J=9.05, 2.69 Hz, 1 H) 7.62 - 7.71 (m, 2 H).

Example 42

Synthesis of (E)-6, 7-difluoro-2-(2-(5-methyl-I-(l-methylpiperidin-4-yl)-IH-pyraz

yljvinyljquinoxaline

Compound 51

[0440] To a mixture of Comp-46a (0.15 g, 0.83 mmol) and Comp-48e (0.17 g, 0.83 mmol) was added i-BuOK (2 inL) and the reaction mixture was stirred at RT for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was adsorbed on silica and purified by column chromatography (silica, 230-400 mesh, 0-2% MeOH in DCM) followed by prep HPLC purification to afford (E)-6,7-difluoro-2-(2-(5- methyl-l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)vinyl)quinoxaline (51, 0.028 g, 10%) as a yellow solid.

[0441] HPLC purity: 97.25%

[0442] MS (ESI) m/e |M+H]⁺/Rt/%: 370.25/1.25/98.3%

[0443] ¹H NMR (400 MHz, CDCI3) δ 1.99 - 2.08 (m, 2 H), 2.31 - 2.40 (m, 2H), 2.43-2.45 (m, 2 H), 2.47 (s, 3H), 3.11 - 3.24 (m, 2 H), 4.08 - 4.16 (m, 1 H), 7.04 (d, J=16.14 Hz, 1 H), 7.72 - 7.83 (m, 3 H), 7.86 (s, 1 H), 8.89 (s, 1 H) (3H's merged in solvent peak).

Example 43

Synthesis of (E)-l-(2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-S-yl)vin^

yl)pyrrolidin-2-one

[0444] To a stirred solution of Comp-36 (0.1 g, 0.25 mmol) in toluene (5 mL) t-BuONa (0.05 g, 0.50 mmol) followed by pyrrolidin-2-one (0.04 g, 0.51 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.05 g, 0.08 mmol) and Pd₂(dba)₃ (0.02 g, 0.02 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 40% ethyl acetate in Hexane) to afford (E)- 1 -(2-(2-(2,5 -dimethyl- 1 -phenyl- lH-pyrrol-3 -yl)vinyl)benzo| d] oxazol-5 -yl)pyrrolidin-2- one (52; 0.06 g, 65%) as a yellow solid.

[0445] HPLC purity: 95.69%

[0446] MS (ESI) m/e [M+H]⁺ /Rt/%: 398.15/2.09/98.6%

[0447] ^XH NMR (400 MHz, CDCl₃) δ 2.02 - 2.07 (m, 3 H), 2.15 - 2.26 (m, 5 H), 2.61 - 2.69 (m, 2 H), 3.90 - 3.98 (m, 2 H), 6.30 - 6.33 (m, 1 H), 6.62 - 6.68 (m, 1 H), 7.20 - 7.25 (m, 2 H), 7.44 - 7.55 (m, 4 H), 7.67 - 7.70 (m, 1 H), 7.70 - 7.75 (m, 1 H), 7.77 - 7.83 (m, 1 H).

Example 44

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-phenyl-lH-pyirol-3-yl)vinyl)-N-(2- methoxyethyl)benzo[d]oxazol-5-amine eO

Pd₂(dba)₃, BINAP MeO^'

NaOfBu, toluene

100 °C, 12 h Compound 53

[0448] To a stirred solution of Comp-36 (0.1 g, 0.25 mmol) in toluene (5 mL) t-BuONa (0.05 g, 0.51 mmol) followed by 2-methoxyethan-l -amine (0.04 g, 0.51 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.002 g, 0.004 mmol) and Pd₂(dba)3 (0.01 g, 0.013 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 10-30% EtOAc in Hexane) to afford (i¾-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-N-(2- methoxyethyl)benzo[d]oxazol-5-amine (53; 0.03 g, 31%) as a yellow solid.

[0449] HPLC purity: 96.56%

[0450] MS (ESI) m/e [M+H]⁺ /Rt/%: 388.20/2.00/95.9%

[0451] ¹H NMR (400 MHz, CDCl₃) δ 1.99 - 2.09 (m, 3 H), 2.14 - 2.22 (m, 3 H), 3.30 - 3.38 (m, 2 H), 3.39 - 3.47 (m, 3 H), 3.63 - 3.70 (m, 2 H), 3.98 - 4.11 (m, 1 H), 6.28 - 6.33 (m, 1 H). 6.57 - 6.69 (m, 2 H), 6.87 - 6.93 (m, 1 H), 7.20 - 7.25 (m, 2 H), 7.43 - 7.55 (m, 3 H), 7.70 - 7.77 (m, 1 H) (1H merged in solvent peak).

Example 45 Synthesis of (E)-N-(2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)benzo[d]oxazol-5- yljmethanesulfonamide

3 ^J6⁰ ' L // NaOfBu, PhMe C„ompoud . 5.4.

^⁴-^ 90 °C, 16 h ^¾

[0452] To a stirred solution of Comp-36 (0.2 g, 0.51 mmol) in toluene (5 mL) f-BuONa (0.1 g, 1.02 mmol) followed by methanesulfonamide (0.1 g, 1.02 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.05 g, 0.076 mmol) and Pd₂(dba)3 (0.02 g, 0.025 mmol) were added and the reaction mixture was heated at 90 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 0-5% MeOH in DCM) to afford (E)-N-(2- (2-(2,5-dime&yl-l -phenyl-1 H-pyrrol-3^

(54; 0.04 g, 20%) as a yellow solid.

[0453] HPLC purity: 99.7%

[0454] MS (ESI) m/e [M+H]⁺ Rt/%: 408.25/2.20/94.1 1 %

[0455] ¹H NMR (400 MHz, DMSO-d₆) δ 1.96 - 1.99 (m, 3 H), 2.11 - 2.13 (m, 3 H), 2.95 - 2.97 (m, 3 H), 6.43 - 6.47 (m, 1 H), 6.63 - 6.69 (m, 1 H), 7.14 - 7.19 (m, 1 H), 7.32 - 7.36 (m, 2 H), 7.44 - 7.48 (m, 1 H), 7.49 - 7.53 (m, 1 H), 7.53 - 7.63 (m, 4 H), 7.68 - 7.75 (m, 1 H).

Example 46

Synthesis of (E)-2-(2-(2, 5-dimethyl-l -phenyl- lH-pyrr Ol-3-yl)vinyl)-N,N- dimethylbenzo[d]oxa∑ol-5-amine

IT H

/f Pd₂(dba)₃, BINAP

^, ^~~0 NaOfBu, toluene

³⁶ 90 °C, 16 h Compound 55

[0456] To a stirred solution of Comp-36 (0.1 g, 0.25 mmol) in toluene (5 mL), t-BuONa (0.05 g, 0.51 mmol) followed by dimethylamine solution in THF (2 mL) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.05 g, 0.08 mmol) and Pd₂(dba)3 (0.02 g, 0.03 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 40% ethyl acetate in Hexane) to afford (E)-2-(2-(2,5 -dimethyl- 1 -phenyl- 1 H-py rrol -3-y l)viny l)-N,N-dimethy lbenzo[d] oxazol -5 -amine (55; 0.05 g, 55%) as a yellow solid.

[0457] HPLC purity : 97.11 %

[0458] MS (ESI) m/e |M+H]^+/ Rt/%: 358.25/2.13/99.4%

[0459] ¹H NMR (400 MHz, CDCl₃) δ 2.03 - 2.08 (m, 3 H), 2.15 - 2.21 (m, 3 H), 2.96 - 3.02 (m, 6 H), 6.28 - 6.33 (m, 1 H), 6.60 - 6.68 (m, 1 H), 6.75 - 6.81 (m, 1 H), 7.01 - 7.06 (m, 1 H), 7.20 - 7.26 (m, 2 H), 7.32 - 7.37 (m, 1 H), 7.43 - 7.55 (m, 3 H), 7.71 - 7.79 (m, 1 H).

Example 47

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-5-(pyrrolidin-1- yl)benzo[d]oxazole

[0460] To a stirred solution of Comp-36 (0.1 g, 0.25 mmol) in toluene (5 mL) t-BuONa (0.05 g, 0.50 mmol) followed by pyrrolidine (0.04 g, 0.51 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.05 g, 0.08 mmol) and Pd₂(dba)3 (0.02 g, 0.02 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 40%) ethyl acetate in Hexane) to afford (E)-2- (2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-5-(pyrrolidin-l-yl)benzo[d]oxazole (56; 0.06 g, 65%) as a yellow solid.

[0461] HPLC purity: 95.3%

[0462] MS (ESI) m/e |M+H]^+/ Rt/%: 384.20/2.55/98.4%

[0463] ¹H NMR (400 MHz, CDCI3) δ 1.99 - 2.10 (m, 7 H), 2.14 - 2.19 (m, 3 H), 3.29 - 3.37 (m, 4 H), 6.28 - 6.32 (m, 1 H), 6.53 - 6.57 (m, 1 H), 6.61 - 6.67 (m, 1 H), 6.79 - 6.84 (m, 1 H), 7.20 - 7.25 (m, 2 H), 7.31 - 7.35 (m, 1 H), 7.43 - 7.55 (m, 3 H), 7.70 - 7.78 (m, 1 H).

Example 48 Synthesis of (E)-l-(2-(2-(2, 5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3- yl)vinyl)quinoxalin-6-yl)pyrrolidin-2-one and (E)-l-(3-(2-(2, 5-dimethyl-l-(l- melhylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)quim^

NH

Br-

Pd₂(dba)₃/BINAP

N— + Br' N—

tBuONa, toluene

90°C,12h

[0464] To a stirred solution of Comp-68a and Comp-69a mixture (0.2 g, 0.47 mmol) in toluene (3 mL), i-BuONa (0.13 g, 1.40 mmol) followed by pyrrolidin-2-one (0.12 g, 1.41 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.14 g, 0.23 mmol) and Pd₂(dba)3 (0.04 g, 0.047 mmol) were added and the reaction mixture was heated at 90 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS.

After completion, the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure. The crude obtained was purified by column

chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford a mixture of regioisomers (E)- 1 -(2-(2-(2,5-dimethyl- 1 -(1 -methylpiperidin-4-yl)- lH-pyrrol-3- yl)vinyl)quinoxalin-6-yl)pyrrolidin-2-one and (E)- 1 -(3-(2-(2,5-dimethyl- 1 -( 1 - me1hylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)quinoxalin-6-yl)pyrrolidin-2-on (57 and 103, respectively; 0.03 g, 15%), as a yellow solid.

[0465] HPLC purity: 93.25%

[0466] MS (ESI) m/e |M+H]⁺ /Rt %: 430.25/1.15/95.1%

[0467] ¹H NMR (400 MHz, CDCI3 1:1 mixture of isomers) δ 0.88-0.91 (m, 1H), 1.85 (d, J=12.23 Hz, 2H), 2.10 (t, J=11.74 Hz, 2H), 2.22 - 2.29 (m, 3H), 2.35 (s, 6H), 2.49 (s, 3H), 2.71 (t, J=8.07 Hz, 2H), 3.04 (d, J=11.74 Hz, 2H), 3.92 - 3.98 (m, 1H), 4.01-4.05 (m, 2H), 6.25 (s, IH), 6.88-6.91 (m, lH), 7.74 - 7.87 (m, 2H), 7.97-7.80 (m, 1H), 8.44 - 8.57 (m, 1H), 8.86 & 8.89 (s, 0.36H & 0.34H).

Example 49 Synthesis of (E)-2-(2-(2, 5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrro^ methoxyethyl)quinoxalin-6-amine and (E)-3-(2-(2,5-dimethyl-l-(l-methylpiperidm-4-yl)-lH- pyrrol-3-yl)vinyl)-N-(2-methoxyethyl)quinoxalin-6-amine

(compounds 58 and 59)

mixture of Isomer A and Isomer B

[0468] To a stirred solution of Comp-68a and Comp-69a mixture (0.2 g, 0.47 mmol) in toluene (3 mL), i-BuONa (0.13 g, 1.35 mmol) followed by 2-methoxyethan-l -amine (0.1 g, 1.33 mmol) were added and the reaction mixture was degassed with argon for 15 min.

BINAP (0.14 g, 0.23 mmol) and Pd₂(dba)₃ (0.04 g, 0.044 mmol) were added and the reaction mixture was heated at 90 °C for 12 h. Progress of the reaction was moni tored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure. The crude obtained was purified by Prep HPLC to afford a mixture of Isomer A (0.03 g, 17%) and Isomer B (0.03 g, 17%) as yellow solids.

[0469] Isomer A:

[0470] HPLC purity: 88.27%

[0471] MS (ESI) m/e [M''2+H]⁺/Rt/%: 211/1.08/99.02%

[0472] ¹H NMR (400 MHz, CDCl₃): δ 1.72-1.74 (m, 2H), 1.84 (d, J=l 1.74 Hz, 2H), 2.10 (t, J=11.25 Hz, 2H), 2.35 (s, 6H), 2.47 (s, 3H), 3.04 (d, J=11.25 Hz, 2H), 3.43 (s, 3H), 3.44 - 3.48 (m, 2H), 3.70 (t, J=4.89 Hz, 2H), 3.87 - 4.02 (m, 1H), 4.52 (br s, 1H), 6.23 (s, 1H), 6.84 (d, J=15.65 Hz, 1H), 6.93 (s, 1H), 7.00 (dd, J=9.05, 2.20 Hz, 1H), 7.70 - 7.78 (m, 2H), 8.63 (s, 1H).

[0473] Isomer B:

[0474] HPLC purity: 87.4%

[0475] MS (ESI) m/e [M/2+H]⁺/Rl/%: 210.80/1.14/91.03%

[0476] ¹H NMR (400 MHz, DMSO-t ) δ 1.72 (d, J=11.25 Hz, 2H), 2.02 - 2.10 (m, 2H), 2.13 - 2.19 (m, 2H), 2.22 (s, 3H), 2.27 (s, 3H), 2.38 (s, 3H), 2.90 (d, J=10.76 Hz, 2H), 3.31 (s, 3H), 3.33-3.35 (m, 2H), 3.57 (t, J=5.38 Hz, 2H), 3.89 - 3.99 (m, 1H), 6.14 (s, 1H), 6.49- 6.51 (m, 1H), 6.73 (d, J=16.14 Hz, 1H), 6.77 (d, J=2.45 Hz, 1H), 7.22 - 7.29 (m, 1H), 7.61 (d, J=8.31 Hz, 1H), 7.64 (s, 1H), 8.86 (s, lH).

Example 50

Synthesis of (F.)-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)-N,N- dimethylquinoxalin-6-amine and (E)-3-(2-(2, 5 -dimethyl- l-( I-methylpiperidin-4-yl)-lH- pyrrol-3-yl)vinyl)-N,N-dimethylquinoxalin-6-amine

(compounds 60 and 61)

[0477] To a stirred solution of Comp-68a and Comp-69a mixture (0.12 g, 0.28 mmol) in toluene (5 mL), t-BuONa (0.05 g, 0.56 mmol) followed by dimethylamine (0.025 g, 0.56 mmol) were added and the reaction mixture was degassed with argon for 30 min. BINAP (0.003 g, 0.004 mmol) and Pd₂(dba)₃ (0.013 g, 0.014 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by Prep HPLC to afford a mixture of Isomer A (0.05 g, 45%) and Isomer B (0.04 g, 37%) as a yellow solid.

[0478] Isomer A:

[0479] HPLC purity: 96.56%

[0480] MS (ESI) m/e [M+H]⁺/Rt/%: 390.20/1.14/97.89%

[0481] ¹H NMR (400 MHz, DMSO-<4) δ 1.74-1.76 (m, 2H), 2.17 - 2.25 (m, 4H), 2.28 (s, 3H), 2.30 (s, 3H), 2.41 (s, 3H), 2.98 (d, J=6.02 Hz, 2H), 3.08 (s, 6H), 3.98-4.02 (m, 1H), 6.18 (s, 1H), 6.75 (d, J=15.81 Hz, 1H), 6.87 (d, J=2.76 Hz, 1H), 7.33 (dd, J=9.29, 2.76 Hz, 1H), 7.72 - 7.82 (m, 2H), 8.72 (s, 1H).

[0482] Isomer B: [0483] HPLC purily: 95.5%

[0484] MS (ESI) m/e [M+H]⁺/Rt/%: 390.20/1.22/99.17%

[0485] ¹H NMR (400 MHz, DMSO-d₆) δ 1.72 (d, .7=10.29 Hz, 2H), 2.01 - 2.09 (m, 2H), 2.12 - 2.20 (m, 2H), 2.22 (s, 3H), 2.27 (s, 3H), 2.39 (s, 3H), 2.90 (d, J=10.79 Hz, 2H), 3.07 (s, 6H), 3.91-3.97 (m, 1H), 6.15 (s, 1H), 6.75 (d, J=15.81 Hz, 1H), 6.94 (d, J=2.76 Hz, 1H), 7.44 (dd, J=9.29, 2.76 Hz, 1H), 7.66 (d, J=15.81 Hz, 1H), 7.75 (d, J=9.29 Hz, 1H), 8.94 (s, 1H)

Example 51

Synthesis of(S,EJ-2-(2-(2,5-dimethyl-1-phenyl-lH-pyrrol-3-yl)vinyl)-5-(3- methylmorpholinojbenzo[d]oxazole

[0486] To a stirred solution of Comp-36 (0.1 g, 0.28 mmol) in toluene (5 mL) t-BuONa (0.05 g, 0.57 mmol) followed by (S)-3-methylmorpholine (0.057 g, 0.57 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.052 g, 0.08 mmol) and Pd₂(dba)₃ (0.025 g, 0.028 mmol) were added and the reaction mixture was heated at 90 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 0-5% MeOH in DCM) to afford (S,E)-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-5-(3- methylmorpholino)benzo[d]oxazole (62; 0.02 g, 17%) as a yellow solid.

[0487] HPLC purity : 98.71 %

[0488] MS (ESI) m/e [M+H]⁺/Rt/%: 414.20/2.14/98.0%

1H NMR (400 MHz, DMSO-d₆) δ 0.90 - 0.94 (m, 3 H), 1.96 - 2.03 (m, 4 H), 2.08 - 2.13 (m, 4 H), 3.58 - 3.66 (m, 2 H), 3.85 - 3.96 (m, 3 H), 6.44 (s, 1 H), 6.64 (d, J=15.65 Hz, 1 H), 6.61 - 6.67 (m, 1 H), 6.62 - 6.68 (m, 1 H), 7.30 - 7.37 (m, 2 H), 7.47 - 7.61 (m, 4 H), 7.64 - 7.72 (m, 1 H).

Example 52 Synthesis of (E)-2-(2-(2, 5-dimethyl-l-( l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyi)-6- fluorobenzo[d]oxazole

Compound 67

[0489] Compound 67a: To a stirred solution of 4'-fluoro-2'-hydroxyacetophenone (2 g, 12.98 mmol) in methanol (10 mL) was added 7N ammonia in methanol (10 mL) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to afford 5-fluoro-2-(l-iminoethyl)phenol (67a; 0.5 g, 25%) as off white solid.

[0490] ¹H NMR (400 MHz, DMSO-d₆) δ 2.47 (s, 3 H), 6.18 - 6.24 (m, 2 H), 7.48 - 7.55 (m, 1 H), 10.33 (br s, 1 H), 15.14 (brs, 1 H).

[0491] Compound 67b: To a stirred solution of Comp-67a (0.5 g, 3.26 mmol) in THF (10 mL) was added 2CO3 (0.9 g, 6.52 mmol) followed by N-chlorosuccinimide (0.65 g, 4.89 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and the crude obtained was purified by column chromatography (silica, 100-200 mesh, 0-20% Ethyl acetate in Hexane) to afford 6-fluoro-2- methylbenzo[d]oxazole (67b; 0.2 g, 40%) as a colorless liquid.

[0492] MS (ESI) m/e [M+H]^+/ Rt %: 152/1.83/50.9%

[0493] ^XH NMR (400 MHz, CDCl₃) δ 2.55 (s, 3 H), 7.05 (t, J=9.05 Hz, 1 H), 7.21 (d, J=8.80 Hz, 1 H), 7.53-7.57 (m, 1 H).

[0494] Compound 67: To a stirred solution of Comp-67b (0.1 g, 0.45 mmol) in mixture of THF (5 mL) and iBuOH (0.5 mL) was added f-BuO (0.15 g, 1.35 mmol) and the reaction mixture was stirred for 10 min. Comp-3b (0.07 g, 0.45 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H₂O (5 mL) and extracted with EtOAc (10 mL X 2). The organic layer was washed with brine, separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get crude. The crude obtained was purified by preparative HPLC to afford (E)-2-(2-(2,5- dimethyl-l-(l-methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)-6-fluorobenzo[d]oxazole (67; 0.01 g, 6%) as white solid.

[0495] HPLC Purity: 98.6%

[0496] MS (ESI) m/e [M+H]^+/ Rt/%: 354.20/1.32/99.4%

[0497] ¹H NMR (400 MHz, DMSO-d₆) δ 1.70-1.73 (m, 2 H), 1.99 - 2.07 (m, 2 H), 2.11 - 2.17 (m, 1 H), 2.20 (s, 3H), 2.27 (s, 3H), 2.38 (s, 3H), 2.88 (d, J=10.79 Hz, 2 H), 3.91 - 4.00 (m, 1 H), 6.25 (s, 1 H), 6.51 (d, J=15.81 Hz, I H), 7.14 - 7.22 (m, 1 H), 7.59 - 7.66 (m, 3H) (1H merged in solvent peak).

Example 53

Synthesis of (E)-2-((2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-1H-pyrrol-3- yl)vinyl)quinoxalin-6-yl)amino)ethan-l-ol and (E)-2-((3-(2-(2,5-dimethyl-l-(l- methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)quinoxalin-6-yl)amino)ethan-1-ol

(compounds 68 and 69)

Separation by prepative

HPLC method

Isomer A

mixture of Isomer A and Isomer B u_u^OH TBDMS-CI.DMAP _M^OTBDMS H^2N D F,12 h.rt ^H2N

68c

[0498] Compounds 68a and 69a: To a stirred mixture of Comp-3b (2 g, 9.00 mmol) and Comp-6a and Comp-7a mixture (2 g, 10.81 mmol) was added piperidine (0.3 mL) and heated at 140 °C for 5 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to room temperature and adsorbed on silica and purified by column chromatography (silica, 100-200 mesh, 0-10% MeOH:DCM) to afford a mixture of (E)-6-bromo-2-(2-(2,5 -dimethyl- 1 -(1 -methy lpiperidin-4-y 1)- lH-py rrol-3 - yl)vinyl)quinoxaline and (E)-7-bromo-2-(2-(2,5-dimethyl- 1 -(1 -methy lpiperidin-4-yl)- 1H- py rrol-3 -yl)vinyl)quinoxaline (68a and 69a; 2 g, 52%) as a yellow solid.

[0499] Compounds 68b and 69b: To a stirred solution of Comp-68a and Comp-69a mixture (0.25 g, 0.59 mmol) in toluene (3 mL) was added t-BuONa (0.17 g, 1.76 mmol) followed by Comp-68c (0.11 g, 0.65 mmol) and the reaction mixture was degassed with argon for 15 min. B1NAP (0.11 g, 0.18 mmol) and Pd₂(dba)₃ (0.05 g, 0.06 mmol) were added and the reaction mixture was heated at 90 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure. The crude obtained was purified by column

chromatography (silica, 100-200 mesh, 0-10% MeOH:DCM) to afford a mixture of (E)-N- (2-((tert-butyldimethylsilyl)oxy)e l)-2-(2-(2,5-dimethyl-l-(l-methylpiperidin-4-yl)-lH- py rrol-3 -y l)viny l)quinoxalin-6-amine and (E)-N-(2-((tert-bur ldimethy lsily l)oxy)ethy l)-3 -(2- (2,5 -dimethyl- 1 -(1 -methylpiperidin-4-yl)-lH-pyrrol-3-yl)vinyl)quinoxalin-6-amine (68b and 69b, respectively; 0.2 g, 65%) as a yellow solid.

[0500] Compound 68c: To a stirred solution of 2-aminoethan-l-ol (2 g, 32.78 mmol) in DMF (15 mL) was added DMAP (5.98 g, 49.1 mmol) followed by TBDMS-C1 (4.94 g, 32.78 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-10% EtOAc in hexane) to afford 2-((tert-buty ldimethy lsily l)oxy)ethan-l -amine (68c, 2 g, 35%) as a light brown liquid.

[0501] Isomer A: To a stirred solution of Comp-68b and Comp-69b mixture (0.2 g, 0.39 mmol) in THF (5 mL) was added TBAF (0.1 M in THF, 2 mL) at room temperature.

Reaction was heated at 40 °C for 5 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction was cooled to room temperature to afford the mixture of Isomer A and Isomer B, which was then concentrated under reduced pressure and purified by prep HPLC to afford the major product Isomer A (0.1 g, 50%) as off-white solid.

[0502] Isomer A:

[0503] HPLC Purity: 99.7%

[0504] MS (ESI) m/e |M+H|^+/ Rt/%: 406.20/1.03/97.1%

[0505] ¹H NMR (400 MHz, CD₃OD) 5 0.88 - 0.96 (m, 1H), 1.27 - 1.35 (m, 1H), 1.89-1.92 (m, 2H), 2.35 (s, 3H), 2.39-2.42 (m, 2H), 2.47 (s, 3H), 2.49 (s, 3H), 3.14 - 3.24 (m, 2H), 3.40 (t, J= 5.62 Hz, 2H), 3.83 (t, J = 5.62 Hz, 2H), 4.14 - 4.21 (m, 1H), 6.22 (s, 1H), 6.75 - 6.84 (m, 2H), 7.16 (dd, J= 8.80, 2.45 Hz, 1H), 7.65 (d, J= 8.80 Hz, 1H), 7.81 (d, J= 15.65 Hz, IH), 8.60 (s, 1H) (2 exchangeable H's exchanged with the solvent). Example 54

Synthesis of (E)-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-5-(4-methylpiperazin-1- yl)benzo[d]oxazole

[0506] To a stirred solution of Comp-36 (0.15 g, 0.38 mmol) in toluene (5 mL) t-BuONa (0.07 g, 0.76 mmol followed by 1-methylpiperazine (0.08 g, 0.77 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.07 g, 0.11 mmol) and Pd₂(dba)₃ (0.03 g, 0.038 mmol) were added and the reaction mixture was heated at 90 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 0-5% MeOH in DCM) to afford (E)-2-(2- (2,5-dimethyl-l-phenyl-lH-pyrrol-3-yl)vinyl)-5-(4-methylpiperazin-1-yl)benzo[d]oxazole (70; 0.1 g, 63%) as a yellow solid.

[0507] HPLC purity: 95.12%

[0508] MS (ESI) m/e [M+H]⁺/Rt/%: 413.25/1.51/98.26%

[0509] ¹H NMR (400 MHz, DMSO-d₆) δ 1.98 (s, 3H), 2.11 (s, 3H), 2.29 (s, 3H), 2.56-2.58 (m, 4H), 3.12-3.16 (m, 4 H), 6.44 (s, 1H), 6.63 (d, J=15.65 Hz, 1H), 6.95 - 7.01 (m, 1H), 7.14 (s, 1H), 7.34 (d, J=7.34 Hz, 2H), 7.47 (d, J=9.29 Hz, 1H), 7.52 (d, J=7.34 Hz, IH), 7.55 - 7.61 (m, 2H), 7.66 (d, J=15.65 Hz, 1H).

Example 55

Synthesis of(E)-6-(4,4-difluoropiperidin-1-yl)-2-(2-(2,5-dimethyl-I-phenyl-JH- yl)vmyljbenzo[d]oxazole Br.

O.

Br^

.HCI f-BuOK THF, Pd₂(dba)_3i BINAP, NaOtBu,

rt, 12 h

71a toluene, 110 °C, 12 h

8b

Compound 71

[0510] Compound 71a: To a mixture of Comp-8b (0.47 g, 2.35 mmol) and 6-bromo-2- methylbenzo[d]oxazole (0.5 g, 2.35 mmol) in was added 7-BuOK (2 mL, IM in THF) at 0 °C and the reaction mixture was stirred at RT for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure and the crude obtained was purified by column chromatography (silica, 230-400 mesh, 40-50% EtOAc in hexane) to afford (E)-6-bromo-2-(2-(2,5-dimethyl-l-phenyl-lH- pyrrol-3-yl)vinyl)benzo|i ]oxazole (71a; 0.3 g, 32%) as a yellow solid.

[0511] Compound 71 : To a stirred solution of Comp-71a (0.1 g, 0.25 mmol) in toluene (4 mL) t-BuONa (0.07 g, 0.75 mmol) followed by 4,4-difluoropiperidine hydrochloride (0.047 g, 0.30 mmol) were added and the reaction mixture was degassed with argon for 20 min.

BINAP (0.016 g, 0.025 mmol) and Pd₂(dba)₃ (0.023 g, 0.025 mmol) were added and the reaction mixture was heated at 1 10 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 0-5% MeOH in DCM) followed by prep HPLC purification to afford (E)-6-(4,4- difluoropipericUn- 1 -yl)-2-(2-(2,5-dimethyl- 1 -pheny

(71; 0.03 g, 27%) as a yellow solid.

[0512] HPLC purity: 96.90%

[0513] MS (ESI) m/e [M+H]7Rt/%: 434.25/2.35/93.05%

1H NMR (400 MHz, DMSO-d₆) δ 1.98 (s, 3H), 2.00-2.03 (m, 1 H), 2.07-2.09 (m, 2 H), 2.10 (s, 3 H), 2.11 - 2.13 (m, 1 H), 3.36 - 3.41 (m, 4 H), 6.42 (s, 1 H), 6.61 (d, J=15.65 Hz, 1 H), 7.04 (d, J=8.31 Hz, 1 H), 7.28 (s, 1 H), 7.33 (d, J=7.82 Hz, 2 H), 7.45 - 7.53 (m, 2 H), 7.54 - 7.62 (m, 3 H). Example 56

Synthesis of (E)-5-(3, 3-difluoroazetidin-l-yl)-2-(2-(2, 5-dimethyl-l-phenyl-lH-pyrrol-3- yl)vinyl)benzo[d]oxazole

100 °C, 12 h Compound 72

36

[0514] To a stirred solution of Comp-36 (0.1 g, 0.25 mmol) in toluene (5 mL), t-BuONa (0.05 g, 0.51 mmol) followed by 3,3-difluoroazetidine (0.047 g, 0.51 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.002 g, 0.0038 mmol) and Pd₂(dba)3 (0.01 g, 0.012 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 0-5% MeOH in DCM) to afford (E)-5-(3,3-difluoroazetidin-l-yl)-2-(2-(2,5-dimethyl-l-phenyl-lH-pyrrol-3- yl)vinyl)benzo[d]oxazole (72; 0.04 g, 45%) as a yellow solid.

[0515] HPLC purity: 97.27%

[0516] MS (ESI) m/e [M+H]7Rt/%: 406.20/2.32/94.5%

[0517] 'H NMR (400 MHz, CDCl₃) δ 2.05 (s, 3H), 2.17 (s, 3H), 4.23 - 4.32 (m, 4H), 6.31 (s, 1H), 6.44 (dd, J=8.80, 2.45 Hz, 1H), 6.63 (d, J=15.65 Hz, 1H), 6.75 (d, J=2.45 Hz, 1H), 7.23 (d, J=7.34 Hz, 2H), 7.36 (d, J=8.31 Hz, 1H), 7.46 - 7.55 (m, 3H), 7.77 (d, J=16.14 Hz, 1H).

Example 57

Synthesis of (E)-5-(4, 4-difluoropiperidin-l-yl)-2-(2-(2, 5-dimelhyl-l-(pyridin-3-yl)-lH-pyrrol-

3-yl)vinyl)benzo[d]oxazole

Pd₂(dba)₃, BINAP, NaOfBu, Toluene, 100 °C, 12 h

79b

N

Compound 73

[0518] Compound 73a: To a stirred solution of Comp-79b (0.2 g, 1.00 mmol) and Comp-8e (0.2 g, 1.10 mmol) in THF:f-BuOH (5 mL 4: 1) was added i-BuOK (0.3 g, 3.00 mmol) at 0 °C.and the reaction mixture was stirred at RT for 12 h. Progress of the reaction was

monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure and the crude obtained was purified by column chromatography

(silica, 230-400 mesh, 40-50% EtOAc in hexane) to afford (E)-5-bromo-2-(2-(2,5-dimethyl- l-(pyridin-3-yl)-lH-pyrrol-3-yl)vinyl)benzo[i |oxazole (73a; 0.15 g, 38%) as a yellow solid.

[0519] MS (ESI) m/e [Μ+Η] 7Rt/%: 394.10/2.34/85.37%

[0520] Compound 73: To a stirred solution of Comp-73a (0.15 g, 0.38 mmol) in toluene (5 mL) r-BuONa (0.11 g, 1.14 mmol) followed by 4,4-difluoropiperidine hydrochloride (0.07 g, 0.46 mmol) were added and the reaction mixture was degassed with argon for 30 min.

BINAP (0.07 g, 0.1 1 mmol) and Pd₂(dba)₃ (0.03 g, 0.04 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by prep HPLC purification to afford (E)-5-(4,4- difluoropipericlin-l-yl)-2-(2-(2,5-dimethyl-l-(pyridin-3-yl)-lH-pyrrol-3- yl)vinyi)benzo[d]oxazole (73; 0.03 g, 18%) as a yellow solid.

[0521] HPLC purity: 91.89%

[0522] MS (ESI) m/e [M+H]7Rt %: 435.05/2.07/94.8%

[0523] ¹H NMR (400 MHz, DMSO-d₆) δ 1.96 (s, 3H), 2.01 - 2.08 (m, 4H), 2.10 (s, 3 H), 3.12-3.14 (m, 2 H), 6.46 (s, 1 H), 6.63 (d, J=16.14 Hz, 1 H), 7.02 (dd, J=8.80, 1.96 Hz, 1 H), 7.19 (d, J=1.96 Hz, 1 H), 7.46 (d, J=8.80 Hz, 1 H), 7.55 - 7.59 (m, 1 H), 7.63 (d, J=15.65 Hz, 1 H), 7.84 (d, J=8.31 Hz, 1 H), 8.57 (d, J=1.47 Hz, 1 H), 8.67 (d, J=3.91 Hz, 1 H) (2H's merged in solvent peak).

Example 58

Synthesis of (E)-5-(4,4-difluoropiperidin-l-yl)-2-(2-(2,5-dimethyl-1-(1-methylpiperidin-4-yl)- lH-pyrrol-3-yl)vinyl)benzo[d]oxazole

[0524] To a stirred solution of Comp-33a (0.14 g, 0.33 mmol) in toluene (10 mL) t-BuONa (0.1 g, 0.99 mmol) followed by 4,4-difluoropiperidine hydrochloride salt (0.06 g, 0.40 mmol) were added and the reaction mixture was degassed with argon for 30 min. BINAP (0.06 g, 0.1 mmol) and Pd₂(dba)₃ (0.03 g, 0.03 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 0-5% MeOH in DCM) to afford (E)-5-(4,4-difluoropiperidin-l-yl)-2-(2-(2,5-dimethyl-l-(l-methylpiperidin- 4-yl)-lH-pyrrol-3-yl)vinyl)benzo[d]oxazole (74; 0.065 g, 42%) as a yellow solid.

[0525] HPLC purity: 94.59%

[0526] MS (ESI) m/e [M+H]⁺/Rt %: 455.30/1.43/99.6%

[0527] ¹H NMR (400 MHz, CDCl₃) 51.84 (d, J=l 2.23 Hz, 2H), 2.09 - 2.22 (m, 7H), 2.31- 2.33 (m, 1H), 2.34 (s, 3H), 2.36 (s, 3H), 2.44 (s, 3H), 3.04 (d, J=10.76 Hz, 2H), 3.29 - 3.36 (m, 4H), 3.91-3.98 (m, 1H), 6.18 (s, 1H), 6.55 (d, J=15.65 Hz, 1H), 6.94 (dd, J=8.80, 2.45 Hz, 1H), 7.21 (d, J=1.96 Hz, lH), 7.35 (d, J=8.80 Hz, 1H), 7.71 (d, J=15.65 Hz, 1H).

Example 59

Synthesis of (E)-2-(2-(l-cyclopentyl-2,5-dimethyl-lH-pyrrol-3-yl)vinyl)-5-(4, 4- difluoropiperidin-l-yl)benzo[d]oxa∑ole

[0528] Compound 75a: To a stirred solution of Comp-82b (0.18 g, 0.94 mmol) and Comp- 8e (0.2 g, 0.94 mmol) in THF (20 mL) was added 7-BuOK (0.16 g, 1.41 mmol) at -40 °C and the reaction mixture was stirred at rt for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure and the crude obtained was purified by prep HPLC purification to afford (E)-5-bromo-2-(2- (l-cyclopentyl-2,5-dimethyl-lH-pyrrol-3-yl)vinyl)benzo[d]oxazole (75a; 0.1 g, 27%) as an off white solid.

[0529] MS (ESI) m/e [M+H]7Rt/%: 385.15/2.61/74.0%

[0530] Compound 75: To a stirred solution of Comp-75a (0.1 g, 0.26 mmol) in toluene (10 mL) t-BuONa (0.07 g, 0.78 mmol) followed by 4,4-difluoropiperidine hydrochloride (0.04 g, 0.31 mmol) were added and the reaction mixture was degassed with argon for 30 min.

BINAP (0.05 g, 0.08 mmol) and Pd₂(dba)₃ (0.02 g, 0.026 mmol) were added and the reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 0-5% MeOH in DCM) to afford (E)-2-(2-(l-cyclopen1>d-2,5-dimethyl-lH-pyrrol-3-yl)vinyl)-5-(4,4- difluoropiperidin-l-yl)benzo|d]oxazole (75; 0.03 g, 27%) as a yellow solid.

[0531] HPLC purity : 99.19%

[0532] MS (ESI) m/e [M+H]⁺/Rt %: 426.25/2.37/98.8%

[0533] ¹H NMR (400 MHz, CDCl₃) δ 1.68 - 1.75 (m, 2 H), 1.91 - 1.99 (m, 3H), 2.02 - 2.10 (m, 2 H), 2.11 - 2.21 (m, 4 H), 2.31 (s, 3 H), 2.35 (d, J= 11.74 Hz, 1 H), 2.42 (s, 3 H), 3.29 - 3.36 (m, 4 H), 4.53 - 4.60 (m, 1 H), 6.18 (s, 1 H), 6.54 (d, J=15.65 Hz, 1 H), 6.93 (dd, J=8.80, 2.45 Hz, 1 H), 7.20 (d, J=2.45 Hz, 1 H), 7.35 (d, J=8.80 Hz, 1 H), 7.71 (d, J=15.65 Hz, 1 H). Example 60

Synthesis of (E)-4-(2-(6 iifluoroquimxalin-2-yl)vinyl)-^

Compound 76

[0534] Compound 76a: To a stirred solution of ethyl 2-cyanoacetate (5 g, 44.22 mmol) in acetic anhydride (20 mL) was added triethoxy methane (6.5 g, 44.22 mmol) and the reaction mixture was heated at 140 °C for 5 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 230-400 mesh, 0-20% EtOAc in hexane) to afford ethyl (Z)-2-cyano-3-ethoxyacrylate (76a, 4.5 g, 60%) as a pale yellow solid.

[0535] MS (ESI) m/e [M+H]⁺ Rt %: 170.05/1.72/89.7%

[0536] ¹H NMR (400 MHz, CDCl₃) δ 1.32 (t, J=7.15 Hz, 3H), 1.44 (t, J=7.03 Hz, 3 H), 4.23 - 4.30 (m, 2H), 4.34 (q, J=7.03 Hz, 2 H), 8.00 (s, 1 H).

[0537] Compound 76b: To a stirred solution of Comp-76a (4.5 g, 26.61 mmol) in ethanol (50 mL) was added phenylhydrazine (2.87 g, 26.55 mmol) and the reaction mixture was heated at 80 °C for 12 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 230-400 mesh, 20-80% EtOAc in hexane) to afford ethyl 5 -amino- 1 -phenyl- lH-pyrazole-4-carboxylate (76b, 3.4 g, 55%) as a white solid.

[0538] MS (ESI) m/e [M+H]⁺ Rt %: 232.05/1.56/99.6%

[0539] ¹H NMR (400 MHz, CDCh) δ 1.38 (t, J= 7.15 Hz, 3 H), 4.32 (q, J= 7.03 Hz, 2 H), 5.32 (br s, 2 H), 7.39 - 7.46 (m, 1 H), 7.50 - 7.58 (m, 4 H), 7.80 (s, 1 H).

[0540] Compound 76c: To a stirred solution of Comp-76b (3 g, 12.98 mmol) in DCM (20 mL) was added DMAP (2.37 g, 19.4 mmol) followed by Boc anhydride (3.4 g, 15.55 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 4 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 230-400 mesh, 0-10% EtOAc in hexane) to afford ethyl 5-((di-teri- butoxycarbonyl)amino)-l-phenyl-lH-pyrazole-4-carboxylate (76c, 4 g, 71%) as a yellow oil.

[0541] Compound 76d: To a stirred solution of Comp-76c (4 g, 9.27 mmol) in DCM (30 mL) was added 1M DIBAL-H (18 mL, 18.49 mmol) at -78 °C and the reaction mixture was stirred at room temperature for 4 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and quenched with mixture of methanol: water (20 mL) and extracted with DCM (20 mL X 2). The combined organic layer was washed with water (20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford di-tef -butyl (4-(hydrox\'methyl)-l-phenyl-lH-pyrazol-5-yl)carbamate (76d, 2.8 g, 77%) as a brown oil used for the next step without purification.

[0542] MS (ESI) m/e [M+H]⁺ Rt/%: 390.2/1.99/39.3%.

[0543] Compound 76e: To a stirred solution of Comp-76d (2.8 g, 7.19 mmol) in DCM (40 mL) was added Dess-Martin periodinane (DMP; 6.10 g, 14.38 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 4 h. Progress of the reaction was monitored by TLC. After completion the reaction mixture was filtered through celite bed and the residue was washed with DCM (30 mL). The filtrate was washed with sat NaHC0₃ solution, water, dried over anhydrous Na₂SC<4 and concentrated under reduced pressure The crude compound was purified by column chromatography (silica, 230-400 mesh, 0-10% EtOAc in hexane) to afford di-ft?rt-butyl (4-formyl-l -phenyl- lH-pyrazol-5-yl)carbamate (76e, 1.9 g, 68%) as a yellow oil.

[0544] MS (ESI) m/e [M-2Boc+H] ^+/ Rt/%: 188.0/2.00/95.1%

[0545] ¹H NMR (400 MHz, CDCh) δ 1.32 (s, 18H), 7.27 (s, 1H) 7.47 - 7.53 (m, 4H), 8.13 (s, 1H), 9.90 (s, 1H). [0546] Compound 76f: To a stirred solution of Comp-46a (0.23 g, 1.28 mmol) in THF (10 mL) was added piperidine (0.06 g, 0.64 mmol) followed by Comp-76e (0.5 g, 1.29 mmol) and the reaction mixture was heated at 50 °C for 12 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with H₂0 (20 mL) and extracted with EtOAc (2 X 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 10% EtOAc in hexane) to afford di- tert-butyl (E)-(4-(2-(6,7-difluoroquinoxalin-2-yl)vinyl)-l-phenyl-lH-pyrazol-5- yl)carbamate (76f; 0.45 g, 63%) as a yellow oil.

[0547] MS (ESI) m/e [M-Boc+H] ^+/ Rt/%: 450.0/2.09/48.95%

[0548] Compound 76: To a stirred solution of Comp-76f (0.45 g, 0.81 mmol) in dioxane (5 mL) was added 4M HC1 in dioxane (10 mL) and the reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The residue was basified with sat NaHCC solution and extracted with EtOAc (2 X 10 mL). The combined organic layer was washed with water, brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude obtained was purified by prep HPLC purification to afford (E)-4-(2-(6,7-difluoroquinoxalin-2-yl)vinyl)-l -phenyl- lH-pyrazol-5-amine (76; 0.08 g, 28%) as a yellow solid.

[0549] HPLC Purity : 95.6%

[0550] MS (ESI) m/e [M+H]⁺ Rt/%: 350.1/1.84/98.9%

[0551] ¹H NMR (400 MHz, CDCl₃) δ 4.31 (br s, 2 H), 6.91 (d, J= 15.81 Hz, 1 H), 7.43 - 7.49 (m, 1 H), 7.52 - 7.62 (m, 4 H), 7.71 - 7.86 (m, 4 H), 8.86 (s, 1 H).

Example 61

Synthesis of (E)-5 -fluoro-2-(2-(5 -methyl- 1 -( 1 -methy lpiperidin-4-y 1)- lH-py razol-4- y l)viny l)benzo[i | oxazole

48e Compound 78

[0552] To a stirred solution of Comp-48e (0.27 g, 1.32 mmol) and Comp-50c (0.2 g, 1.32 mmol) in THF:t-BuOH (5 mL 4:1) was added f-BuOK (0.15 g, 1.32 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was poured on crushed ice and extracted with EtOAc (30 mL X 2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 30-40% EtOAc in hexane) to afford (E)-5-fluoro-2-(2-(5-methyl-l-(l-methylpiperidin-4-yl)-lH-pyrazol-4- yl)vinyl)benzo[d]oxazole (78, 0.07 g, 15%) as pale yellow solid.

[0553] HPLC purity : 99.89%

[0554] MS (ESI) m/e [M+H]⁺/Rt %: 341.15/1.22/99.6%

[0555] ¹H NMR (400 MHz, DMSO-d₆) δ 1.80 (d, .7=11.25 Hz, 2 H), 2.01 - 2.07 (m, 2 H), 2.08 - 2.17 (m, 2 H), 2.25 (s, 3H), 2.42 (s, 3 H), 2.91 (d, J=8.80 Hz, 2 H), 4.12 - 4.23 (m, 1 H), 6.91 (d, J=16.14 Hz, 1 H), 7.17-7.23 (m, 1 H), 7.54 (dd, J=9.05, 2.69 Hz, 1 H), 7.64 (d, J=16.14 Hz, 1 H), 7.69 (dd, J=8.80, 4.40 Hz, 1 H), 8.05 (s, 1 H).

Example 62

Synthesis of (E)-2-(2-(2, 5-dimethyl-l-(pyridin-3-yl)-lH-pyrrol-3-yl)vin^

fluorobenzo[d]oxazole

79a 79b rt 16h

[0556] Compound 79a: Hexane-2,5-dione (4.3 g, 38.29 mmol) was added dropwise to pyridin-3 -amine (3 g, 31.91 mmol) at 0°C followed by addition of iodine (0.4 g, 3.19 mmol) and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with DCM and concentrated under reduced pressure and the crude obtained was purified by column chromatography (silica, 100-200 mesh, 7-8% Ethyl acetate in Hexane) to afford 3- (2,5-dimethyl-lH-pyrrol-l-yl)pyridine (79a; 3 g, 55%>) as a colorless liquid.

[0557] MS (ESI) m/e [M+H]^+/ Rt/%: 173/1.79/99.5% [0558] ¹H NMR (400 MHz, DMSO-d₆) δ 1.97 (s, 6H), 5.84 (s, 2 H), 7.56 (dd, J=7.82, 4.89 Hz, 1 H), 7.78 (dd, J=8.07, 1.71 Hz, 1 H), 8.51 (d, J=2.45 Hz, 1 H), 8.63 (d, J=4.40 Hz, 1 H).

[0559] Compound 79b: To a stirred solution of Comp-79a (1.5 g, 8.72 mmol) in DMF (10 mL) was added POCI3 (0.8 mL, 8.72 mmol) at 0 °C and the reaction mixture was heated at 100 °C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled, quenched with saturated solution of sodium bicarbonate and extracted with EtOAc (50 mL X 2). The organic layer was washed with water (50 mL), brine (50 mL), separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 2,5-dimethyl-l-(pyridin-3-yl)-lH-pyrrole-3-carbaldehyde (79b; 1 g, 58%) as a brown liquid. The compound was used as such for the next step without purification.

[0560] MS (ESI) m/e [M+H]⁺ Rt/%: 201.05/1.30/98.1%

[0561] ¹H NMR (400 MHz, DMSO-d₆) δ 1.96 (s, 3 H), 2.25 (s, 3 H), 6.33 (s, 1 H), 7.64 (dd, J=8.31, 4.89 Hz, 1 H), 7.90-7.93 (m, 1 H), 8.63 (d, J=2.45 Hz, 1 H), 8.73 (dd, J=4.89, 1.47 Hz, I H), 9.83 (s, 1 H).

[0562] Compound 79: To a stirred solution of Comp-67b (0.2 g, 1.32 mmol) in mixture of THF (10 mL) and fBuOH (0.1 mL) was added t-BuOK (0.4 g, 3.97 mmol) and the reaction mixture was stirred for 10 min. Comp-79b (0.13 g, 0.66 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H₂0 (5 mL) and extracted with EtOAc (10 mL X 2). The organic layer was washed with brine, separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get crude. The crude obtained was purified by preparative HPLC to afford (E)-2-(2-(2,5- dimethyl-l-(pyridin-3-yl)-lH-pyrrol-3-yl)vinyl)-5-fluorobenzo|ii]oxazole (79; 0.06 g, 42%) as yellow solid.

[0563] HPLC Purity: 99.6%.

[0564] MS (ESI) m/e [M+H]^+/ Rt %: 334.10/2.16/99.7%

[0565] ^XH NMR (400 MHz, DMSO-d₆) δ 2.00 (s, 3 H), 2.14 (s, 3 H), 6.52 (s, 1 H), 6.71 (d, J=15.65 Hz, 1 H), 7.14-7.20 (m, 1 H), 7.49-7.52 (m, 1 H), 7.60-7.64 (m, 1 H), 7.66 - 7.70 (m, 1 H), 7.75 (d, J=15.65 Hz, 1 H), 7.88 (d, J=8.31 Hz, 1 H), 8.61 (d, J=1.96 Hz, 1 H), 8.69 - 8.72 (m, 1 H).

Example 63

Synthesis of (E)-2-(2-(l-cyclohexyl-2,5-dimethyl-lH-pyrrol-3-yl)vmyl)

Compound 80

[0566] Compound 80a: To a stirred solution of cyclohexanamine (1 g, 10.08 mmol) and hexane-2,5-dione (1 g, 10.08 mmol) was added crystals of iodine (0.02 g, 0.01 mmol) and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured on crushed ice and extracted with EtOAc (50 mL X 2) The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-10% EtOAc in hexane) to afford l-cyclohexyl-2,5-dimethyl-lH-pyrrole (80a, 1 g, 56%) as a colorless oil.

[0567] MS (ESI) m/e [M+H]^+/ Rt/%: 178.05/2.36/98.4%

[0568] ¹H NMR (400 MHz, CDCl₃) 5 1.18 - 1.29 (m, 1 H), 1.33 - 1.43 (m, 2 H), 1.73-1.76 (m, 1 H), 1.87 - 1.96 (m, 6H), 2.30 (s, 6H), 3.87 - 3.97 (m, 1 H), 5.74 (s, 2 H).

[0569] Compound 80b: A solution of POCl₃ (0.53 mL, 5.64 mmol) in DMF (10 mL) was cooled to 0 °C and stirred for 20 min. Comp-80a (1 g, 5.64 mmol) in DMF (2 mL) was added to it and heated to 100 °C for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 1- cyclohexyl-2,5-dimethyl-lH-pyrrole-3-carbaldehyde (80b, 0.7 g, 60%) as an off-white solid used for the next step without purification.

[0570] ¹H NMR (400 MHz, DMSO-d₆) 6 1.16 - 1.26 (m, 1H), 1.35 - 1.49 (m, 2 H), 1.63- 1.66 (m, 1 H), 1.74 - 1.85 (m, 4 H), 1.87 - 1.98 (m, 2 H), 2.24 (s, 3 H), 3.96 - 4.07 (m, 1 H), 6.09 (s, 1 H), 9.68 (s, 1 H) (3H's merged in solvent peak).

[0571] Compound 80: To a stirred solution of 2-methylquinoxaline (0.1 g, 0.69 mmol) in mixture of THF (5 mL) and ffiuOH (0.1 mL) was added i-BuOK (0.23 g, 2.07 mmol) and the reaction mixture was stirred for 10 min. Comp-80b (0.14 g, 0.69 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H₂O (5 mL) and extracted with EtOAc (10 mL X 2). The organic layer was washed with brine, separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get crude. The crude obtained was purified by preparative HPLC to afford (E)-2- (2-(l-cyclohexyl-2,5-dimethyl-lH-pyrrol-3-yl)vinyl)quinoxaline (80, 0.03 g, 20%) as yellow solid.

[0572] HPLC Purity: 98.4%

[0573] MS (ESI) m/e [M+H]⁺ Rt/%: 332.25/2.49/99.0%

[0574] ¹H NMR (400 MHz, CDCh) δ 1.21 - 1.32 (m, 2H), 1.38 - 1.47 (m, 2 H), 1.76-1.79 (m, 1 H), 1.90 - 2.01 (m, 5 H), 2.35 (s, 3H), 2.47 (s, 3H), 3.93 - 4.01 (m, 1 H), 6.24 (s, 1 H), 6.90 (d, J=15.65 Hz, 1 H), 7.59 - 7.64 (m, 1 H), 7.68-7.72 (m, 1 H), 7.84 (d, J=15.65 Hz, 1 H), 8.00 (t, J=7.34 Hz, 2 H), 8.94 (s, 1 H).

Example 64

Synthesis of (E)-5-(4,4-difluoropiperidin-l-yl)-2-(2-(2,5-dimethyl-l-(3-melhy

lH-pyrrol-3-yl) vinyl)benzo[ d] oxazole

[0575] Compound 81a: To a stirred solution of 3-methylpyridin-2-amine (0.9 g, 8.77 mmol) in toluene (10 mL) was added hexane-2,5-dione (1 g, 8.77 mmol) followed by catalytic addition of pTS A (0.1 g) and the reaction mixture was azeotroped in Dean Stark apparatus at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford 2-(2,5-dimethyl-lH-pyrrol-l-yl)-3-methylpyridine (81a; 1 g, 84 %) as a colorless liquid.

[0576] MS (ESI) m/e |M+H]^+/ Rt/%: 187.1/1.89/48.26%

[0577] Compound 81b: A solution of POCl₃ (0.4 mL, 4.30 mmol) in DMF (5 mL) was cooled to 0 °C and stirred for 30 min. Comp-81a (0.80 g, 4.30 mmol) in DMF (5 mL) was added to it and heated to 100°C for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with 2M NaOH solution, brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 20-25% EtOAc in hexane) to afford 2,5 -dimethyl- 1 -(3 -methylpyridin-2-yl)-lH- pyrrole-3-carbaldehyde 2,5-dimethyl-l-(3-methylpyridin-2-yl)-lH-pyrrole-3-carbaldehyde (81b; 0.7 g, 76%) as a colorless oil.

[0578] MS (ESI) m/e [M+H]⁺ Rt %: 215.3/1.42/96.1 1 %

[0579] Compound 81c: To a solution of Comp-81b (0.4 g, 1.88 mmol) and Comp-8e (0.4 g, 1.88 mmol) in THF (10 mL) was added t-BuOK (0.2 g, 1.88 mmol) and the reaction mixture was stirred at RT for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 30% EtOAc in Hexane) to afford (E)-5-bromo-2-(2-(2,5-dimethyl-l-(3-methylpyridin-2-yl)-lH-pyrrol-3- yl)vinyl)benzo[d]oxazole (81c; 0.45 g, 58%) as a yellow solid.

[0580] MS (ESI) m/e [M+H]⁺ Rt/%: 410.10/2.40/86.44%

[0581] Compound 81 : To a solution of Comp-81c (0.2 g, 0.49 mmol) in toluene (5 mL) t- BuONa (0.14 g, 1.47 mmol) followed by 4,4-difluoropiperidine hydrochloride salt (0.11 g, 0.73 mmol) were added and the reaction mixture was degassed with argon for 15 min.

BINAP (0.06 g, 0.096 mmol) and Pd₂(dba)₃ (0.045 g, 0.05 mmol) were added and the reaction mixture was heated at 110°C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL X 2). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 5-10% MeOH in DCM ) followed by prep HPLC purification to afford (E)-5-(4,4-difluoropiperidin-l-yl)-2-(2-(2,5-dimethyl-l-(3- methylpyridin-2-yl)-lH-pyrrol-3-yl)vinyl)benzo[i¾oxazole (81; 0.05 g, 22%) as a yellow solid.

[0582] HPLC Purity: 98.68%

[0583] MS (ESI) m/e |M+H]^+/ Rt/%: 449.25/2.19/99.27%.

[0584] ¹H NMR (400 MHz, DMSO) δ 1.86 (s, 3 H), 1.98 (s, 3 H), 2.00 (s, 3 H), 2.12 - 2.05 (m, 4 H), in solvent (m, 4 H), 6.43 (s, 1 H), 6.63 (d, J=16 Hz, 1 H), 7.03 ( dd, J=2.0 Hz, 1 H), 7.21 (d, J=1.6 Hz 1 H), 7.47-7.52 (m, 2 H), 7.64 (d, J=16 Hz 1 H), 7.94 (d, J=7.2 Hz, 1 H), 8.48 (d, J=3.2 Hz, 1 H).

Example 65

Synthesis of (E)-2-(2-(l-cyclopentyl-2, 5-dimethyl-lH-pyrrol-3-yl)vinyl)-5- fluorobenzo[d]oxazo!e

Compound 82

[0585] Compound 82a: To a stirred solution of cyclopentanamine (1.00 g, 11.76 mmol) and hexane-2,5-dione (1.3 g, 11.76 mmol) was added crystals of iodine (0.02 g, 0.11 mmol) and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured on crushed ice and extracted with DCM (50 mL X 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 10%) MeOH in DCM) to afford I-cyclopentyl-2,5-dimethyl-lH-pyrrole (82a, 1 g, 52%) as a colorless oil.

[0586] Compound 82b: A solution of POCl₃ (0.63 g, 6.13 mmol) in DMF (5 mL) was cooled to 0 °C and stirred for 20 min. Comp-82a (1 g, 6.13 mmol) in DMF (2 mL) was added to it and heated to 100 °C for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and poured on crushed ice and extracted with EtOAc (50 mL X 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica, 100-200 mesh, 0-20% EtOAc in hexane) to afford l-cyclopentyl-2,5-dimethyl-lH-pyrrole-3-carbaldehyde (82b, 0.7 g, 63%) as an off-white solid.

[0587] MS (ESI) m/e [M+H]⁺ Rt %: 192.05/1.90/96.7%

[0588] ¹H NMR (400 MHz, DMSO-d₆) δ 1.58 - 1.73 (m, 2H), 1.79 - 1.92 (m, 4 H), 1.98 - 2.09 (m, 2 H), 2.24 (s, 3 H), 4.60 - 4.69 (m, 1 H), 6.12 (s, 1 H), 9.69 (s, 1 H) (3H's merged in solvent peak).

[0589] Compound 82: To a stirred solution of Comp-82b (0.1 g, 0.66 mmol) in mixture of THF (5 mL) and ffiuOH (1 mL) was added r-BuOK (0.2 g, 1.98 mmol) and the reaction mixture was stirred for 10 min. Comp-50c(0.1 g, 0.66 mmol) was added portion wise and the reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H₂0 (5 mL) and extracted with EtOAc (10 mL X 2). The organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get crude. The crude obtained was purified by prep HPLC to afford (E)-2-(2-(l-cyclopentyl-2,5- dimethyl-lH-pyrrol-3-yl)vinyl)-5-fluorobenzo[d]oxazole (82; 0.08 g, 40%) as white solid.

[0590] HPLC Purity: 99.8%

[0591] MS (ESI) m/e [M+H]⁺ Rt %: 325.2/2.47/99.4%

[0592] ¹H NMR (400 MHz, DMSO- d₆) δ 1.62- 1.64 (m, 2 H), 1.82- 1.84 (m, 4 H), 1.98 - 2.08 (m, 2 H), 2.24 (s, 3 H), 2.36 (s, 3 H), 4.54 - 4.67 (m, 1 H), 6.26 (s, 1 H), 6.50 (d, J=15.65 Hz, 1 H), 7.10 - 7.19 (m, 1 H), 7.46 (dd, J=8.80, 2.45 Hz, 1 H), 7.62 - 7.64 (m, 1 H), 7.67 (d, J=15.65 Hz, 1 H).

Example 66

Synthesis of (E)-3-(3-(2-(5fluorohenzo[d]omzol-2-yl)vinyl)-2,5-dimethyl-lH-pyrrol-l- yljpyridin-l-ium sulfanyl ethane l-ol salt

138 . \^S0₃H

HO^'

MeOH, 0-rt, 1 h

N

Compound 79 HO^'

Compound 83

[0593] To a stirred solution of Comp-79 (0.03 g, 0.09 mmol) in methanol (1 mL) was added 2-hydroxyethane sulphonic acid (0.5 mL) and the reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether and pentane to afford (E)-3-(3-(2-(5-fluorobenzo[d]oxazol-2- yl)vinyl)-2,5-dimethyl-lH-pyrrol-l-yl)pyridin-l-ium sulfanyl ethane l-ol salt (83; 0.025 g, 75%) as yellow solid.

[0594] HPLC Purity: 99.4%.

[0595] MS (ESI) m/e [M+H]⁺ Rt/%: 334.05/2.00/99.8%

[0596] ¹H NMR (400 MHz, DMSO-d₆) δ 2.00 (s, 3 H), 2.14 (s, 3 H), 2.60 (t, J=6.85 Hz, 3 H), 3.61 (t, J=6.85 Hz, 3H), 6.52 (s, 1 H), 6.70 (d, J=16.14 Hz, 1 H), 7.14-7.19 (m, 1 H), 7.50 (dd, J=8.80, 2.45 Hz, 1 H), 7.64 - 7.70 (m, 2 H), 7.74 (d, J=15.65 Hz, 1 H), 7.97 (d, J=8.80 Hz, 1 H), 8.67 (s, 1 H), 8.74 (d, J=4.40 Hz, 1 H).

Example 67

Synthesis of (E)-3-(3-(2-(5-fluorobenzo[d]omzol-2-yl)vinyl)-2,5-dimethyl-lH-pyrrol-l- yljpyridin-l-ium chloride

[0597] To a stirred solution of Comp-79 (0.03 g, 0.09 mmol) in dioxane (1 mL) was added 4M HCI in dioxane (0.5 mL) and the reaction mixture was stirred at room temperature for 1 h.. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure to get crude residue, was triturated with diethyl ether and pentane to afford (E)-3-(3-(2-(5-fluorobenzo[d]oxazol-2-yl)vinyl)-2,5- dimethyl-lH-pyrrol-l-yl)pyridin-l-ium chloride (84; 0.025 g, 75%) as yellow solid.

[0598] HPLC Purity: 99.6%. [0599] MS (ESI) m/e [M]^+/ Rt'%: 334.05/2.00/95.9%

[0600] ¹H NMR (400 MHz, DMSO-<4) δ 2.02 (s, 3 H), 2.16 (s, 3 H), 6.54 (s, 1 H), 6.72 (d, J=16.14 Hz, 1 H), 7.14-7.19 (m, 2 H), 7.50 (dd, J=8.80, 2.45 Hz, 1 H), 7.67 (dd, J=8.80, 4.40 Hz, 1 H), 7.73 (d, J=15.65 Hz, 1 H), 7.89-7.92 (m, 1 H), 8.26 (d, J=7.83 Hz, 1 H), 8.85 (d, J=4.89 Hz, 1 H), 8.89 (s, 1 H).

Example 68

Synthesis of (E)-2-(2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)vinyl)-6-(4-methylpiperazin-1- yl)quinoxaline and (E)-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yl)vinyl)-7-(4-methy

l-yl)quinoxaline

(compounds 94 and 95)

[0601] To a stirred solution of Comp-35 and Comp-102 mixture (0.1 g, 0.25 mmol) in toluene (5 mL) was added t-BuONa (0.05 g, 0.51 mmol) followed by 1-methylpiperazine (0.05 g, 0.51 mmol) were added and the reaction mixture was degassed with argon for 15 min. BINAP (0.002 g, 0.0038 mmol) and Pd₂(dba)₃ (0.011 g, 0.012 mmol) were added and the reaction mixture was heated at 90 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 0-2% MeOH in DCM) to afford a mixture of Isomer A (0.015 g, 15%) and Isomer B (0.015 g, 15%) as a yellow solid.

[0602] Isomer A:

[0603] HPLC Purity: 99.1%

[0604] MS (ESI) m/e [M+H]+/ Rt/%: 411.25/1.27/97.7% [0605] ¹H NMR (400 MHz, CDCl₃) δ 2.34 - 2.39 (m, 3 H), 2.46 - 2.50 (m, 3 H), 2.58 - 2.65

(m, 4 H), 3.38 - 3.45 (m, 4 H), 7.03 - 7.11 (m, 1 H), 7.36 - 7.52 (m, 7 H), 7.68 - 7.75 (m, 1

H), 7.84 - 7.89 (m, I H), 7.97 - 8.00 (m, 1 H), 8.67 - 8.73 (m, 1 H).

[0606] Isomer B:

[0607] HPLC Purity: 99.27%

[0608] MS (ESI) m/e [M+HJ+/ Rt/%: 411.25/1.25/99.2%

[0609] ¹H NMR (400 MHz, CDCl₃) δ 2.35 - 2.40 (m, 3 H), 2.46 - 2.51 (m, 3 H), 2.58 - 2.66 (m, 4 H), 3.38 - 3.45 (m, 4 H), 7.05 - 7.12 (m, 1 H), 7.26 - 7.28 (m, 1 H), 7.38 - 7.53 (m, 6 H), 7.59 - 7.68 (m, 1 H), 7.85 - 7.90 (m, 1 H), 7.96 - 8.00 (m, 1 H), 8.79 - 8.85 (m, 1 H).

Example 69

Synthesis of (E)-6-fluoro-2-(2-(5-nwthyl-l-phenyl-lH-pyrazol-4-yl)vinyl)quimmline and (E)-7-fluoro-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yl)vinyl)qumoxaline

Compound 97

[0610] To a mixture of Comp-18c (0.35 g, 1.88 mmol) and Comp-34a and Comp-lOla mixture (0.3 g, 1.88 mmol) was added piperidine (0.016 g, 0.19 mmol)) and the reaction mixture was heated at 110 °C for 3 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was adsorbed on silica and purified by column

chromatography (silica, 100-200 mesh, 2% MeOH in DCM) to afford a mixture of regioisomers (E)-6-fluoro-2-(2-(5-methyl- 1 -phenyl- lH-py razol-4-yl)vinyl)quinoxaline and (E)-7-fluoro-2-(2-(5-methyl-l-phenyl-lH-pyrazol-4-yl)vinyl)quinoxaline (96 and 97, respectively; 0.1 g, 16%) as a yellow solid.

[0611] HPLC purity: 95.74%

[0612] MS (ESI) m/e [M+H]⁺/Rt/%: 331.15/2.30/97.9% [0613] ¹H NMR (400 MHz, CDCl₃ 4: 1 mixture of isomers) δ 2.53 (s, 3 H), 7.14 (d, J=16.14 Hz, 1 H), 7.43 - 7.57 (m, 6H), 7.67 (dd, J=9.29, 2.93 Hz, 1 H), 7.84 (d, J=16.14 Hz, 1 H), 8.02 - 8.08 (m, 2 H), 8.92 & 8.98 (s, 0.8 H & 0.2 H).

Example 70

Synthesis of (E)-2-(2-(l-cyclohexyl-2,5-dimethyl-lH-pyrrol-3-yl)vinyl)-5- fluorobenzo[d]oxazole

Compound 104

[0614] To a stirred solution of Comp-50c (0.073 g, 0.48 mmol) in mixture of THF (5 mL) and tBuOH (0.5 mL) was added t-BuOK (0.16 g, 1.46 mmol) at 0 °C. Comp-80b (0.1 g, 0.48 mmol) was added portion wise and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with H₂0 (5 mL) and extracted with EtOAc (10 mL X 2). The organic layer was washed with brine, separated, dried over anhydrous Na₂SC>4 and concentrated under reduced pressure. The crude obtained was purified by column chromatography (silica, 100- 200 mesh, 2-5% EtOAc in hexane) to afford (E)-2-(2-(l-cyclohexyl-2,5-dimethyl-lH-pyrrol- 3-yl)vinyl)-5-fluorobenzo[d]oxazole (104, 0.08 g, 51%) as a yellow solid.

[0615] HPLC Purity: 99.4%

[0616] MS (ESI) m/e [M+H]+/ Rt'%: 339.15/2.56/99.8%

[0617] ¹H NMR (400 MHz, DMSO-d₆) δ 1.17 - 1.27 (m, 2 H), 1.35 - 1.45 (m, 2 H), 1.62 - 1.69 (m, 1 H), 1.73 - 1.96 (m, 6 H), 2.22 - 2.27 (m, 3 H), 2.35 - 2.39 (m, 3 H), 6.20 - 6.25 (m, 1 H), 6.46 - 6.53 (m, 1 H), 7.09 - 7.16 (m, 1 H), 7.41 - 7.48 (m, 1 H), 7.60 - 7.66 (m, 1 H), 7.66 - 7.70 (m, 1 H).

Example 71

Inhibition of Gene Expression Using PSA Promoter Assay

[0618] A luciferase reporter gene assay was performed using Dual-Glo® Luciferase Assay System (Promega Corporation). The promoter of target gene PSA (Prostate Specific Antigen) was functionally linked to a firefly luciferase gene (PSA-Fluc), which serves as a proxy marker for gene expression. Androgen receptor binds to androgen response elements (AREs) in the promoter region of the PSA promoter. A pRL-SV40:i?enz7/a luciferase (Rluc) control vectorwas also used to normalize the luciferase activity. Percent inhibition of firefly luciferace expression and IC50 data was determined for test compounds in LNCaP cells and 22Rvl cells. LNCaP cells express AR-FL, and 22Rvl cells express AR-Vs.

[0619] One day prior to transfection, LNCaP cells or 22Rvl cells were plated in 6 well plates and maintained in complete Roswell Park Memorial Institute (RPMI) medium. Cells were transfected using Lipofectamine LTX with Plus reagent (Invitrogen) with the PSA-Fluc vector and a control Rluc vector at a 1 :4 ratio. Post transfection media was changed to 5% (22Rvl cells) or 10% (LNCaP cells) charcoal stripped serum in RPMI medium. The following day, cells were plated in 96 well plates before being treated with 0.1 μΜ 1 μΜ, or 10 μΜ of a test compound. An IC50 was further determined for certain test compounds using a range of compound concentrations. LNCaP cells were further stimulated with DHT (dihydrotestosterone) 1 hour after the test compound was added. 22Rvl cells were not treated with DHT. Approximately 24 hours after the test compound was added, firefly and Renilla luciferase luminescence was measured. The relative luciferase activity (RLA) ratios of luminescence from the experimental reporter (PSA-Fluc) to control reporter (Rluc) were calculated (RLA = Firefly luminescence value / Renilla luminescence value). Relative Response Ratios were determined from the normalized ratios (Renilla luciferase). Percent inhibition of luciferase was calculated based on comparison of treated (with test compound) with the untreated (without test compound) cells. Percent inhibition results are shown in Table 2, and IC50 results are shown in Table 3.

Table 2

= bicalutamide; LBD inhib. = control compound binding the ligand binding domain of AR; *: (n=l) and (n=2) indicate separate experiments; n.i. = no inhibition.

Table 3

*: (n=l) and (n=2) indicate separate experiments.

Example 72

Inhibition of PSA and TMPRSS2 Gene Expression

[0620] Androgen receptor binds to androgen receptor elements (AREs) present in promoter regions of PSA and TMPRSS2 genes. When an AR antagonist binds the AR, expression of PSA and TMPRSS2 is suppressed. Inhibition of PSA and TMPRSS2 expression upon exposure to test compounds can be tested as described in this example.

[0621] LNCaP cells were cultured in RPMI media with 10% charcoal stripped serum for 48 hours prior to treatment with a test compound. The cells were then cultured in the presence of the test compound for 24 before total RNA was isolated from the cells using TRIzol (Invitrogen) and reverse-transcribed using GoScript™ Reverse Transcription System

(Promega). Quantitative PCR was performed with the resulting cDNA using DyNAmo ColorFlash SYBR Green qPCR Kit (Thermo Fisher Scientific) with primers specific for PS A, TMPRSS2, and RPL19. RPL19 is not controlled by AR and was used as a normalizing gene.

[0622] Enzalutamide (a selective AR antagonist) was used as a reference compound, and DMSO and DHT were also used as controls. Fold changes in mRNA expression levels were calculated using a comparative threshold cycle (Q) method, and were compared to untreated cells, cells treated with dihydrotestosterone (DHT) as a control, and cells treated with enzalutamide.

[0623] Enzalutamide (reference control) downregulated PSA and TMPRSS2 gene expression compared to the DHT control in a statistically significant manner. Treatment using 10 μΜ of compound 8 or 3 μΜ of compound 45 downregulated PSA and TMPRSS2 gene expression compared to the DHT control with statistical significance. Treatment using 1 μΜ of compound 50 downregulated both PSA and TMPRSS2 gene expression, with PSA gene expression being downregulated compared to the DHT control with statistical significance. Additionally 1 μΜ of compound 3, 1 μΜ of compound 46, and 1 μΜ of compound 67 downregulated PSA and TMPRSS2 gene expression.

Example 73

Pancreatic Cancer Cell Proliferation Assay

[0624] LNCaP or 22Rvl cells were cultured in RPMI media with 10% fetal bovine serum (FBS) in four 48-well plates (-5000 cells/well) for 24 hours at 37 C in the presence of 5% C0₂. After 24 hours, the RPMI media was replaced with 10% charcoal stripped serum in RPMI medium. The cells were allowed to grow for 48 hours at 37 ^°C in the presence of 5% C0₂. After 48 hours of growth, cells in one of the plates are stained with DAPI and fluorescence was measured to determine the DNA content in each well. For DAPI staining, the media was removed from the wells, the cells were fixed with cold methanol for 3-5 minutes before being washed with phosphate buffered saline (PBS), and DAPI (100 ng/mL) wa added to each well. After 7-8 minutes of incubation at room temperature, the cells were washed twice with PBS, and fluorescence was measured at an excitation wavelength of 358 nm and an emission wavelength of 461 nm. Test compounds were added to the wells in the remaining plates along with dihydrotestosterone (DHT), and the cells were allowed to continue growing at 37 ^°C in the presence of 5% C0₂. Cell media was replaced every 2-3 days. After 0, 2, or 7 days of growth (LNCaP cells), or after 0, 2 or 4 days of growth (22Rvl cells), DNA levels were measured in the wells for one of the plates using DAPI staining. Test compounds were tested in quadruplicate (n=4). Results are shown in FIG. 2A (LNCaP cells) and FIG. 2B (22Rvl cells).

Example 74

Pancreatic Cell Viability Assay

[0625] Cell viability after exposure to test compounds was determined using an

AlamarBlue® (Thermo Fisher Scientific) assay. AlamarBlue® is a cell health indicator that converts resazurin to fluorescent resorufin in the presence of healthy cells. Damaged or unhealthy cells will have less fluorescent signal than undamaged or healthy cells. [0626] LNCaP, 22Rvl, or PC-3 cells were cultured (-5000 cells per well) in RPMI media with 10% fetal bovine serum (FBS) in 96-well clear bottom plates for approximately 18-24 hours at 37 ^°C in the presence of 5% C0₂ before being treated with a test compound (at approximately IX, 3X, or lOX of the determined IC50 amount) or control compound (doxorubicin or pyrvinium chloride). After 72 hours, 10X AlamarBlue® reagent was added to the wells and incubated for 4 hours at 37 ^°C in the presence of 5% C0₂, while being protected from direct light. Fluorescence was measured using an excitation wavelength of 540-570 nm and an emission wavelength of 580-610 nm. Percent cell viability was determined using the raw fluorescence values, and is shown in Table 4.

Table 4

Claims

or a salt thereof, wherein:

X is C(R⁴) or N, wherein when X is N, R³ is other than hydrogen; Y is -O- or -N=CH-;

L is C₂-C6 alkenylene wherein L is optionally substituted by L^a; each R¹ is independently halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃- C₈ cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, - OR⁵, -NR⁶R⁷, cyano, or nitro, wherein each R¹ is independently optionally substituted by halogen, oxo, -OH, or C₁-C₆ alkyl;

R² is C -Cu aryl, C₃-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ce-Cu tayl, Cs-Cg cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R² are each independently optionally substituted by halogen, oxo, -OR⁵, -NR⁶R⁷, -S(=0)R⁵, -S(=O)₂R⁵, -S(=0)₂NR⁶R⁷, cyano, nitro, or C C₆ alkyl optionally substituted by halogen, -OH, or oxo;

R³ and R⁴ are each independently hydrogen, halogen, amino, C₁-C₆ alkyl, C₃-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C^-Cu aryl, or 5- to 10-membered heteroaryl, wherein the amino, C C₆ alkyl, C₃-C_S cycloalkyl, 3- to 12-membered heterocyclyl, C₆-C]4 aryl, and 5- to 10-membered heteroaryl of R³ and R⁴ are each independently optionally substituted by halogen, oxo, cyano, -OR⁵, -NR⁶R⁷, or alkyl optionally substituted by halogen, -oxo, or -OH; m is 0, 1, 2, 3, or 4;

L^a is Cd-Ce alkyl, C₁-C₆ haloalkyl, halogen, -OR⁵, cyano, or oxo; R⁵ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-Ce alkynyl, Cj-Cg cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C8 cycloalkyl, C6-C₁₄ aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R⁵ are each independently optionally substituted by halogen, -OH, oxo, cyano, or C₁-C₆ alkyl optionally substituted by halogen, - OH, or oxo; and

R⁶ and R⁷ are each independently hydrogen, C4-C6 alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃- Cg cycloalkyl, C₆-C₁₄ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, - S(=0)R⁵, or -S(=O)₂R⁵, wherein the Cj-Ce alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃- Cg cycloalkyl, C -Cu aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R⁶ and R⁷ are independently optionally substituted by halogen, -OR⁵, oxo, cyano, or Ci-C6 alkyl, optionally substituted by halogen, -OH, or oxo; and with the proviso that when the compound of formula (I) is a salt, the cation is not a compound of formula (la):

(Ia).

2. The compound of claim 1, or a salt thereof, wherein L is C₂ alkenylene optionally substituted by L^a.

3. The compound of claim 2, or a salt thereof, wherein L is -CH=CH-.

4. The compound of claim 2, or a salt thereof, wherein L is C₂ alkenylene substituted by -CN.

5. The compound of any one of claims 1 to 4, or a salt thereof, wherein R² is optionally substituted Ce-C₁₄ aryl.

6. The compound of claim 5, or a salt thereof, wherein R² is phenyl.

7. The compound of any one of claims 1 to 4, or a salt thereof, wherein R² is optionally substituted C₃-Cg cycloalkyl.

8. The compound of claim 7, or a salt thereof, wherein R² is cyclopentyl.

9. The compound of claim 7, or a salt thereof, wherein R² is cyclohexyl.

10. The compound of any one of claims 1 to 4, or a salt thereof, wherein R² is optionally substituted 3- to 12-membered heterocyclyl.

11. The compound of claim 10, or a salt thereof, wherein R² is optionally substituted 6- membered heterocyclyl.

12. The compound of claim 11, or a salt thereof, wherein R² is optionally substituted piperidinyl.

13. The compound of claim 12, or a salt thereof, wherein R² is l-methylpiperidin-4-yl.

14. The compound of any one of claims 1 to 4, or a salt thereof, wherein R² is optionally substituted 5- to 10-membered heteroaryl.

15. The compound of claim 14, or a salt thereof, wherein R² is optionally substituted 6- memebered heteroaryl.

16. The compound of claim 15, or a salt thereof, wherein R² is optionally substituted pyridinyl.

17. The compound of claim 16, or a salt thereof, wherein R² is pyridin-3-yl.

18. The compound of any one of claims 1 to 17, or a salt thereof, wherein m is 0, 1, or 2.

19. The compound of claim 18, or a salt thereof, wherein m is 0.

20. The compound of claim 18, or a salt thereof, wherein m is 1.

21. The compound of claim 20, or a salt thereof, wherein m is 1 and R¹ is halogen.

22. The compound of claim 20, or a salt thereof, wherein m is 1 and R¹ is optionally substituted 3- to 12-membered heterocyclyl.

23. The compound of claim 22, or a salt thereof, wherein m is 1 and R¹ is optionally substituted piperidinyl or morpholinyl.

24. The compound of claim 20, or a salt thereof, wherein m is 1 and R¹ is optionally substituted C₁-C₆ alkyl.

25. The compound of claim 24, or a salt thereof, wherein m is 1 and R¹ is -CF₃.

26. The compound of claim 20, or a salt thereof, wherein m is 1 and R¹ is -OR⁵.

27. The compound of claim 26, or a salt thereof, wherein m is 1 and R¹ is -OCF₃.

28. The compound of claim 20, or a salt thereof, wherein m is 1 and R¹ is -NR⁶R⁷.

29. The compound of claim 28, or a salt thereof, wherein m is 1, R¹ is -NR⁶R⁷, and R⁶ and R⁷ are independently selected from hydrogen, -CH₂CH₂OH, and -CH2CF3.

30. The compound of claim 18, or a salt thereof, wherein m is 2.

31. The compound of claim 30, or a salt thereof, wherein m is 2 and R¹ is independently selected from halogen, perhaloalkyl, and perhaloalkoxy.

32. The compound of any one of claims 1 to 31, wherein R³ is selected from -CH₃ and -NH₂.

33. The compound of any one of claims 1 to 32, wherein Y is -N=CH- and having the formula (I- A):

(^Rl)m (I-A).

34. The compound of any one of claims 1 to 32, wherein Y is -O- and having the formula (I-

35. The compound of any one of claims 1 to 34, wherein X is N and having the formula (1- C):

36. The compound of any one of claims 1 to 34, wherein X is C(R⁴) and having the formula

(I-D):

R³ (I-D).

37. The compound of claim 36, or a salt thereof, wherein X is C(R⁴) and R⁴ is selected from -CH₃ and -NH₂.

38. A compound selected from the group consisting of Compound Nos. 1-107 in Table 1, or a salt thereof.

39. A compound of any one of claims 1 to 38, wherein the salt is a pharmaceutically acceptable salt.

40. A pharmaceutical composition comprising a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.