NZ621092B2 - COMPOUNDS AND COMPOSITIONS AS c-KIT KINASE INHIBITORS - Google Patents

COMPOUNDS AND COMPOSITIONS AS c-KIT KINASE INHIBITORS Download PDF

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NZ621092B2
NZ621092B2 NZ621092A NZ62109212A NZ621092B2 NZ 621092 B2 NZ621092 B2 NZ 621092B2 NZ 621092 A NZ621092 A NZ 621092A NZ 62109212 A NZ62109212 A NZ 62109212A NZ 621092 B2 NZ621092 B2 NZ 621092B2
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imidazo
methylphenyl
oxadiazolyl
pyridinecarboxamide
formula
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NZ621092A
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NZ621092A (en
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Xiaolin Li
Xiaodong Liu
Jon Loren
Valentina Molteni
Juliet Nabakka
Bao Nguyen
Hank Michael James Petrassi
Vince Yeh
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Novartis Ag
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Priority claimed from PCT/US2012/052621 external-priority patent/WO2013033070A1/en
Publication of NZ621092A publication Critical patent/NZ621092A/en
Publication of NZ621092B2 publication Critical patent/NZ621092B2/en

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Abstract

The disclosure provides compounds of formulae (I) and (II) and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, as well as methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of c-kit or c-kit and PDGFR (PDGFR?, PDGFR?) kinases. In one embodiment the compound is N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl]-2-methylphenyl}imidazo[1,2-a]pyridine-3-carboxamide. embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of c-kit or c-kit and PDGFR (PDGFR?, PDGFR?) kinases. In one embodiment the compound is N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl]-2-methylphenyl}imidazo[1,2-a]pyridine-3-carboxamide.

Description

COMPOUNDS AND COMPOSITIONS AS c-Kit KINASE INHIBITORS FIELD OF THE INVENTION The invention relates to tors of PDGFR and/or c-kit kinases, and methods of using such compounds.
BACKGROUND OF THE INVENTION Protein kinases (PK) are a large set of structurally related oryl transferases having highly conserved structures and catalytic functions. Protein kinases are enzymatic components of the signal transduction pathways which catalyze the transfer of the terminal phosphate from ATP to the hydroxy group of tyrosine, serine and/or threonine residues of proteins, and are therefore categorized into families by the substrates they phosphorylate: Protein ne Kinases (PTK), and Protein /Threonine Kinases.
Protein kinases play a critical role in the control of cell growth and differentiation and are responsible for the control of a wide variety of cellular signal transduction processes, n protein kinases are key mediators of cellular signals leading to the production of growth factors and cytokines. The overexpression or inappropriate expression of normal or mutant protein kinases plays a significant role in the development of many diseases and disorders including, central nervous system disorders such as Alzheimer's, inflammatory ers such as arthritis, bone diseases such as osteoporosis, lic disorders such as diabetes, blood vessel proliferative disorders such as angiogenesis, autoimmune es such as rheumatoid arthritis, ocular diseases, cardiovascular disease, atherosclerosis, cancer, thrombosis, psoriasis, restenosis, schizophrenia, pain sensation, transplant rejection and infectious diseases such as viral, and fungal infections.
SUMMARY OF THE INVENTION Provided herein are compounds, and pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the e tives, protected derivatives, individual s and mixture of isomers f, which are inhibitors of c- kit kinase, or inhibitors of c-kit and PDGFR (PDGFRoc and PDGFRB) kinases.
In one aspect provided herein such compounds, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. es), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers f, have a structure according to Formula (I) or Formula (II): R11 11 HN NI HN _ R11 R11 1’ _ O R2 \ N N O R2 (R2°>m/ \ \ f (R20) /_<\ f N m N Formula (I) Formula (II) wherein: m is 1 and R20 is selected from H, halo, C1-Cealkyl, C1-Cehaloalkyl, C1- Cehaloalkoxy, deuterium, deuterated C1-Cealkyl, -CN, -(CR92)nOR4, -C(O)R4, )nC(=O)OR4, R10, -(CR92)nR‘O, -((CR92),,O),R4, )nO(CR92)nR7, -(CR92)nC(=O)R4, -C(=O)N(R4)2, -OFl4 and -(CR92)nCN; or m is 4 and R20 is deuterium; Fl1 is selected from C1-Cealkyl and halo; each Fl11 is independently selected from H, halo, and C1-Cealkyl; L1 is a bond, —NH- or -C(=O)NH-; L2 is )n-, -CHR6-, -(CR92)nO-, -NH-, -(CR92)nC(=O)-, -C(=O)O(CR92)n-, -(CR92)nOC(=O)NR4-, -(CF192)nNFl“C(=O)(CF192)n -, -(CR92)nNR4C(=O)- or -(CR92)nNR4C(=O)O- ; R2 is R3 or L2R3; Fl3 is selected from an unsubstituted Cs-Cscycloalkyl, a cyclobutanone, a cyclopentanone and a substituted Cs-Cscycloalkyl, wherein the substituted Cs- Cscycloalkyl of R2 is substituted with 1-4 substituents independently selected from C1-Cealkyl, halo, C1-Cehaloalkyl, -OR4, -CN, -C(=O)OR4, -C(=O)R4, -C(=O)R7, - C(=O)OR5, -(CR92)nOR4, -O(CR92)nOR4, -C(=O)O(CR92)nOR4, -N(R4)2, =N-OR4, CR92)nR5, NR42, -NR4C(=O)OR4, -NR4C(=O)(CR92)nOR4, - NR4(CR92)nOR4, -NR4S(=O)2R4, -N(C(=O)OR4)2, =CH2, =CH(CR92)nOR4, R8, - (CR92)nR8, deuterated lkoxy, -S(=O)2R4, 2R7, -S(=O)2R8, - N(R4)2, -S(=O)2NHC(=O)OR4, -S(=O)2(CR92)nC(=O)OR4, - S(=O)2(CR92)nOR4, a spiro attached ane, a spiro ed dioxolane which is substituted with C1-Cealkyl, a spiro ed dioxane, a spiro attached tetrahyrofuranly, a spiro attached oxetane, a spiro attached cyclobutanone, a spiro attached cyclobutanol, a 0, alkyl bridge, an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S substituted with 1-3 substituents independently selected from C1-Cealkyl, halo, C1-Cehaloalkyl, C1-Cehaloalkoxy, -OFl4 and R8; each R4 is independently selected from H and C1-Cealkyl; 2012/052621 R5 is an unsubstituted Cs-Cscycloalkyl an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently ed from N or O or a Cs-Cscycloalkyl substituted with 1-3 substituents independently selected from C1-Cealkyl; each Fl6 is independently ed from -NHC(O)OR4, -OFi4 and -(CR92)nOR4; each R7 is independently selected from C1-Cehaloalkyl; R8 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an tituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently ed from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently ed from N, O or S, a substituted Cs-Cscycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted , the substituted 5-6 membered aryl with 1-3 atoms independently selected from N, O or S, the substituted 5 ed heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51 -(C(R9)2)nC(O)OR4, -C(O)OR4 and -S(O)2R4; each R9 is independently selected from H and C1-Cealkyl; R10 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered aryl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an tituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted , the substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently ed from N, O or S, the substituted 5 ed heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents ndently selected from C1-Cealkyl, -(C(R9)2)nOR4, -(C(R9)2)nR5, -(C(Flg)2)nC(O)OFl4 and R4; tis 1,2or3, and each n is independently selected from 1, 2, 3 and 4.
In certain embodiments of compounds of Formula (I) or Formula (II), m is 1 and R20 is ed from H, F, C1-Cealkyl, aloalkyl, C1-Cehaloalkoxy, deuterium, deuterated C1-Cealkyl, -CN, -(CR92)nOR4, -C(O)R4, - (CR92)nC(=O)OR4, R10, -(CR92),R‘0, -((CR92)nO)tR4, -(CR92)nO(CR92)nR7, — (CR92)nC(=O)R4, -C(=O)N(R4)2, -OR4 and -(CR92)nCN; or m is 4 and R20 is deuterium; Fl1 is selected from C1-Cealkyl and halo; each Fl11 is independently selected from H, halo, and C1-Cealkyl; L1 is a bond, —NH- or -C(=O)NH-; L2 is -(CR92)n-, -CHR6-, -(CR92)nO-, -NH-, -(CR92)nC(=O)-, -C(=O)O(CR92)n-, -(CR92)nOC(=O)NR4-, -(CF192)nNFl“C(=O)(CF192)n -, -(CR92)nNR4C(=O)- or -(CR92)nNR4C(=O)O- ; R2 is R3 or L2R3; Fl3 is selected from an tituted ycloalkyl, a cyclobutanone, a cyclopentanone and a substituted Cs-Cscycloalkyl, wherein the substituted Cs-Cscycloalkyl of R2 is substituted with 1-4 substituents independently selected from C1-Cealkyl, halo, C1-Cehaloalkyl, -OR4, -CN, -C(=O)OR4, -C(=O)R4, -C(=O)R7, -C(=O)OR5, -(CR92)nOR4, -O(CR92)nOR4, -C(=O)O(CR92)nOR4, -N(R4)2, =N-OR4, =N-O-(CR92)nR5, -C(=O)NR42, =O)OR4, -NR4C(=O)(CR92)nOR4, -NR4(CR92)nOR4, -NR4S(=O)2R4, -N(C(=O)OR4)2, =CH2, =CH(CR92)nOR4, R8, -(CR92)nR8, deuterated lkoxy, -S(=O)2R4, -S(=O)2R7, 2R8, -S(=O)2N(R4)2, -S(=O)2NHC(=O)OR4, -S(=O)2(CR92)nC(=O)OR4, -S(=O)2(CR92)nOR4, a spiro attached dioxolane, a spiro attached dioxolane which is substituted with C1-Cealkyl, a spiro attached e, a spiro attached tetrahyrofuranly, a spiro attached oxetane, a spiro attached cyclobutanone, a spiro attached cyclobutanol, a 0, alkyl bridge, an unsubstituted 5-6 membered cycloalkyl with 1-2 heteroatoms independently selected from N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S substituted with 1-3 substituents independently selected from C1-Cealkyl, halo, aloalkyl, C1-Cehaloalkoxy, -OFl4 and R8; each R4 is ndently selected from H and C1-Cealkyl; R5 is an unsubstituted Cs-Cscycloalkyl an tituted 5-6 membered heterocycloalkyl with 1-2 atoms ndently selected from N or O or a Cs-Cscycloalkyl substituted with 1-3 substituents independently selected from C1-Cealkyl; each Fl6 is independently selected from -NHC(O)OR4, -OFi4 and -(CR92)nOR4; each R7 is independently selected from C1-Cehaloalkyl; R8 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-3 heteroatoms independently ed from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 atoms ndently selected from N, O or 8, an tituted ycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms ndently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cscycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered aryl with 1-3 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered cycloalkyl of R8 are substituted with 1-3 substituents independently selected from lkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51 -(C(R9)2)nC(O)OR4, -C(O)OR4 and -S(O)2R4; each R9 is independently selected from H and C1-Cealkyl; R10 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 atoms independently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the tuted phenyl, the substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 tuents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51'(C(R9)2)nC(O)OR4 and -S(O)2Fi4 tis 1,2or3, and each n is independently ed from 1, 2, 3 and 4.
In certain embodiments of nds of Formula (I) or Formula (II), and the ceutically acceptable salts, pharmaceutically acceptable es (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, the compound of Formula (I) or Formula (II) is a compound having a structure of Formula (la), Formula (Ila), Formula (lb), Formula (llb), Formula (lc), Formula (Ho), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (It) or Formula (llf): R11 N‘é N _ R11 0 R2 \ N O R2 N (R20) \ ‘ (Rm)m L4 \ m N N Formula (la) Formula (lla) R11 R11 N Formula((lc) Formula (llc) R” R 1 R1 / O \ HN N4 HN\QYCKN _ N4/ R20 <\ R2 N{*0 R2 0 \ RZOQN\ \ N N Formula (Id) Formula (Ild) N N Formula (le) Formula (lle) R1] R11 R1Q N RIG 0 N / ‘0 N \N N,\ HN RIIH HN _ R11H R20 N 0 R2 R20 0 R2 l \ \ \ \ N N Formula (If) Formula (llf) wherein: m is 1 and R20 is selected from H, halo, C1-Cealkyl, C1-Cehaloalkyl, C1-Cehaloalkoxy, ium, deuterated C1-Cealkyl, -CN, -(CR92)nOR4, -C(O)R4, -(CR92)nC(=O)OR4, R10, )nR‘O, -((CR92),,O),R4, -(CR92)nO(CR92)nR7, -(CR92)nC(=O)R4, - C(=O)N(R4)2, -OFl4 and )nCN; or m is 4 and R20 is deuterium; Ft1 is selected from lkyl and halo; each Fl11 is independently selected from H, halo, and C1-Cealkyl; L2 is -(CR92)n-, -CHR6-, -(CR92)nO-, -NH-, -(CR92)nC(=O)-, -C(=O)O(CR92)n-, -(CR92)nOC(=O)NR4-, -(CF192)nNFl“C(=O)(CF192)n -, -(CR92)nNR4C(=O)- or - (CR92)nNR4C(=O)O- ; R2 is R3 or L2R3; Fl3 is selected from an unsubstituted Cs-Cscycloalkyl, a utanone, a cyclopentanone and a substituted Cs-Cscycloalkyl, wherein the substituted Cs-Cscycloalkyl of R2 is substituted with 1-4 substituents independently selected from C1-Cealkyl, halo, C1-Cshaloalkyl, 2012/052621 -OR4, -CN, -C(=O)OR4, -C(=O)R4, -C(=O)R7, -C(=O)OR5, -(CR92)nOR4, -O(CR92)nOR4, -C(=O)O(CR92)nOR4, -N(R4)2, =N-OR4, =N-O-(CR92)nR5, -C(=O)NR42, -NR4C(=O)OR4, =O)(CR92)nOR4, -NR4(CR92)nOR4, -NR4S(=O)2R4, -N(C(=O)OR4)2, =CH2, =CH(CR92)nOR4, R8, -(CR92)nR8, deuterated C1-Cealkoxy, -S(=O)2R4, -S(=O)2R7, -S(=O)2R8, -S(=O)2N(R4)2, -S(=O)2NHC(=O)OR4, -S(=O)2(CR92)nC(=O)OR4, -S(=O)2(CR92)nOR4, a spiro attached dioxolane, a spiro attached ane which is substituted with C1-Cealkyl, a spiro ed dioxane, a spiro attached tetrahyrofuranly, a spiro attached oxetane, a spiro attached cyclobutanone, a spiro attached utanol, a 0, alkyl bridge, an unsubstituted 5-6 membered cycloalkyl with 1-2 heteroatoms independently selected from N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently ed from N, O and S substituted with 1-3 substituents independently selected from C1-Cealkyl, halo, C1-Cehaloalkyl, C1-Cshaloalkoxy, -OFl4 and R8; each R4 is independently selected from H and C1-Cealkyl; R5 is an unsubstituted Cs-Cscycloalkyl an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently ed from N or O or a Cs-Cscycloalkyl tuted with 1-3 substituents independently selected from C1-Cealkyl; each Fl6 is ndently selected from -NHC(O)OR4, -OFi4 and -(CR92)nOR4; each R7 is independently selected from C1-Cshaloalkyl; R8 is selected from an unsubstituted phenyl, tituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the tuted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, the substituted 5 ed heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and tuted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51 -(C(R9)2)nC(O)OR4, -C(O)OR4 and -S(O)2R4; each R9 is independently selected from H and C1-Cealkyl; R10 is ed from an unsubstituted phenyl, unsubstituted 5-6 ed heteroaryl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently ed from N, O or S, a tuted phenyl, a substituted 5 ed heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms ndently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 ed heterocycloalkyl of R8 are substituted with 1-3 substituents ndently selected from C1-Cealkyl, )2)nOR4, '(C(R9)2)nR51'(C(R9)2)nC(O)OR4 and -S(O)2R4; tis 1,2or3, and each n is independently selected from 1, 2, 3 and 4.
In certain embodiments of compounds of Formula (la), Formula (lla), Formula (lb), a (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (It) or Formula (llf), m is 1 and R20 is selected from H, -F, C1-Cealkyl, C1-Cehaloalkyl, C1-Cshaloalkoxy, deuterium, deuterated C1-Cealkyl, -CN, -(CR92)nOR4, -C(O)R4, -(CR92)nC(=O)OR4, R10, -(CR92)nR‘O, -((CR92)nO),R4, -(CR92)nO(CR92)nR7, -(CR92),,C(=O)R4, - C(=O)N(R4)2, -OFl4 and -(CR92)nCN; or m is 4 and R20 is deuterium; Fl1 is selected from C1-Cealkyl and halo; each Fl11 is independently selected from H, halo, and C1-Cealkyl; L2 is )n-, -CHR6-, -(CR92)nO-, -NH-, )nC(=O)-, -C(=O)O(CR92)n-, -(CR92)nOC(=O)NR4-, -(CF192)nNFl“C(=O)(CF192)n -, -(CR92)nNR4C(=O)- or - nNR4C(=O)O- ; R2 is R3 or L2R3; Fl3 is selected from an unsubstituted Cs-Cscycloalkyl, a cyclobutanone, a cyclopentanone and a substituted Cs-Cscycloalkyl, wherein the tuted Cs-Cscycloalkyl of R2 is substituted with 1-4 substituents independently selected from C1-Cealkyl, halo, C1-Cehaloalkyl, -OR4, -CN, -C(=O)OR4, -C(=O)R4, R7, -C(=O)OR5, -(CR92)nOR4, - O(CR92)nOR4, O(CR92)nOR4, -N(R4)2, =N-OR4, =N-O-(CR92)nR5, - C(=O)NR42, -NR4C(=O)OR4, =O)(CR92)nOR4, -NR4(CR92)nOR4, - O)2R4, -N(C(=O)OR4)2, =CH2, =CH(CR92)nOR4, R8, -(CR92)nR8, deuterated C1-Cealkoxy, -S(=O)2R4, -S(=O)2R7, -S(=O)2R8, -S(=O)2N(R4)2, -S(=O)2NHC(=O)OR4, -S(=O)2(CR92)nC(=O)OR4, -S(=O)2(CR92)nOR4, a spiro attached dioxolane, a spiro attached dioxolane which is substituted with C1-Cealkyl, a spiro attached dioxane, a spiro attached tetrahyrofuranly, a spiro attached oxetane, a spiro attached utanone, a spiro ed cyclobutanol, a 0, alkyl bridge, an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S substituted with 1-3 substituents independently selected from C1- Cealkyl, halo, C1-Cehaloalkyl, C1-Cehaloalkoxy, -OFl4 and R8; each R4 is independently selected from H and C1-Cealkyl; R5 is an unsubstituted Cs-Cscycloalkyl an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N or O or a Cs-Cscycloalkyl substituted with 1-3 tuents independently selected from C1- each Fl6 is independently selected from -NHC(O)OR4, -OFi4 and )nOR4; each R7 is independently selected from C1-Cehaloalkyl; R8 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or 8, an tituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 ed heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms ndently selected from N, O or S, a substituted Cs-Cscycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, n the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, the substituted 5 ed heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51 -(C(R9)2)nC(O)OR4, -C(O)OR4 and -S(O)2R4; each R9 is independently selected from H and C1-Cealkyl; R10 is selected from an unsubstituted , unsubstituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or 8, an tituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 ed heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, a substituted phenyl, a tuted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the tuted phenyl, the substituted 5-6 membered heteroaryl with 1-2 atoms ndently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51'(C(R9)2)nC(O)OR4 and -S(O)2R4; tis 1,2or3, and each n is ndently selected from 1, 2, 3 and 4.
In certain embodiments of compounds of Formula (I) or Formula (II), and the pharmaceutically acceptable salts, ceutically acceptable es (e.g. hydrates), the N-oxide derivatives, protected derivatives, dual isomers and mixture of isomers thereof, the compound of Formula (I) or Formula (II) is a compound having a structure of Formula (la), Formula (Ila), Formula (lb) or Formula (llb): R11 R] R]QY N O\ \O \ HN IN R11 N54 R11 N 0 R2 \ N o R2 /(\ N (R20) /\—<\ \ (R20)m \‘_<\ \ m N N Formula (la) Formula (lla) R11 R11 R1QN—(/ R1 N Qg o ‘0 N54 \ HN \IN RllH HN R11 N , N o R2 N o R2 (R20) /\—<\ fIn (R20)m/\_<\ f\ N N Formula (lb) Formula (Ilb) wherein: m is 1 and R20 is selected from H, halo, C1-Cealkyl, C1-Cehaloalkyl, C1-Cehaloalkoxy, deuterium, deuterated C1-Cealkyl, -CN, -(CR92)nOR4, 4, -(CR92)nC(=O)OR4, R10, -(CR92)nR‘O, -((CR92),,O),R4, )nO(CR92)nR7, -(CR92)nC(=O)R4, - C(=O)N(R4)2, -OFl4 and -(CR92)nCN; or m is 4 and R20 is deuterium; Fl1 is selected from C1-Cealkyl and halo; each Fl11 is independently selected from H, halo, and C1-Cealkyl; L2 is )n-, -CHR6-, -(CR92)nO-, -NH-, -(CR92)nC(=O)-, -C(=O)O(CR92)n-, -(CR92)nOC(=O)NR4-, -(CF192)nNFl“C(=O)(CF192)n -, -(CR92)nNR4C(=O)- or - (CR92)nNR4C(=O)O- ; R2 is R3 or L2R3; Ft3 is selected from an unsubstituted Cs-Cscycloalkyl, a cyclobutanone, a cyclopentanone and a substituted Cs-Cscycloalkyl, wherein the substituted Cs-Cscycloalkyl of R2 is substituted with 1-4 tuents ndently selected from C1-Cealkyl, halo, C1-Cehaloalkyl, -OR4, -CN, -C(=O)OR4, R4, -C(=O)R7, -C(=O)OR5, -(CR92)nOR4, -O(CR92)nOR4, -C(=O)O(CR92)nOR4, -N(R4)2, =N-OR4, CR92)nR5, -C(=O)NR42, -NR4C(=O)OR4, -NR4C(=O)(CR92)nOR4, -NR4(CR92)nOR4, =O)2R4, -N(C(=O)OR4)2, =CH2, =CH(CR92)nOR4, R8, -(CR92)nR8, deuterated C1-Cealkoxy, -S(=O)2R4, -S(=O)2R7, 2R8, -S(=O)2N(R4)2, -S(=O)2NHC(=O)OR4, -S(=O)2(CR92)nC(=O)OR4, -S(=O)2(CR92)nOR4, a spiro attached dioxolane, a spiro attached dioxolane which is substituted with C1-Cealkyl, a spiro attached dioxane, a spiro attached tetrahyrofuranly, a spiro attached oxetane, a spiro attached cyclobutanone, a spiro attached cyclobutanol, a 0, alkyl bridge, an tituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms ndently selected from N, O and S substituted with 1-3 substituents independently selected from C1-Cealkyl, halo, C1-Cshaloalkyl, C1-Cehaloalkoxy, -OFl4 and R8; each R4 is independently selected from H and C1-Cealkyl; R5 is an unsubstituted Cs-Cscycloalkyl an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N or O or a ycloalkyl substituted with 1-3 substituents independently selected from C1-Cealkyl; each Fl6 is independently selected from -NHC(O)OR4, -OFi4 and -(CR92)nOR4; each R7 is independently selected from C1-Cshaloalkyl; R8 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-3 heteroatoms ndently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 atoms selected from N, an unsubstituted 4-6 ed heterocycloalkyl with 1-2 heteroatoms independently ed from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a tuted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms ed from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51 -(C(R9)2)nC(O)OR4, -C(O)OR4 and -S(O)2R4; each R9 is independently selected from H and C1-Cealkyl; R10 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-2 heteroatoms ndently ed from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 atoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an tituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 atoms selected from N, a substituted 4-6 ed cycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cscycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms ed from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51'(C(R9)2)nC(O)OR4 and -S(O)2R4; tis 1,2or3, and each n is independently selected from 1, 2, 3 and 4.
In certain embodiments of compounds of Formula (la), Formula (Ila), Formula (lb) or a (llb), m is 1 and R20 is selected from H, -F, C1-Cealkyl, C1-Cehaloalkyl, C1-Cshaloalkoxy, ium, ated C1-Cealkyl, -CN, -(CR92)nOR4, -C(O)R4, -(CR92)nC(=O)OR4, R10, -(CR92)nR‘O, -((CR92)nO),R4, -(CR92)nO(CR92)nR7, -(CR92)nC(=O)R4, - C(=O)N(R4)2, -OFt4 and -(CR92)nCN; or m is 4 and R20 is deuterium; Fl1 is selected from C1-Cealkyl and halo; each Fl11 is independently selected from H, halo, and C1-Cealkyl; L2 is -(CR92)n-, -CHR6-, -(CR92)nO-, -NH-, -(CR92)nC(=O)-, -C(=O)O(CR92)n-, -(CR92)nOC(=O)NR4-, 2)nNFl“C(=O)(CF192)n -, -(CR92)nNR4C(=O)- or - (CR92)nNR4C(=O)O- ; R2 is R3 or L2R3; Fl3 is selected from an unsubstituted Cs-Cscycloalkyl, a utanone, a entanone and a substituted Cs-Cscycloalkyl, wherein the substituted ycloalkyl of R2 is substituted with 1-4 substituents independently selected from lkyl, halo, C1-Cehaloalkyl, -OR4, -CN, OR4, -C(=O)R4, -C(=O)R7, -C(=O)OR5, -(CR92)nOR4, - O(CR92)nOR4, -C(=O)O(CR92)nOR4, 2, =N-OR4, =N-O-(CR92)nR5, - C(=O)NR42, -NR4C(=O)OR4, -NR4C(=O)(CR92)nOR4, -NR4(CR92)nOR4, - NR4S(=O)2R4, -N(C(=O)OR4)2, =CH2, =CH(CR92)nOR4, R8, -(CR92)nR8, deuterated C1-Cealkoxy, -S(=O)2R4, -S(=O)2R7, -S(=O)2R8, -S(=O)2N(R4)2, -S(=O)2NHC(=O)OR4, 2(CR92)nC(=O)OR4, -S(=O)2(CR92)nOR4, a spiro ed dioxolane, a spiro attached dioxolane which is substituted with C1-Cealkyl, a spiro attached dioxane, a spiro attached tetrahyrofuranly, a spiro attached oxetane, a spiro attached cyclobutanone, a spiro attached cyclobutanol, a 0, alkyl bridge, an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S substituted with 1-3 substituents independently selected from C1- Cealkyl, halo, C1-Cehaloalkyl, C1-Cehaloalkoxy, -OFl4 and R8; WO 33070 each R4 is independently selected from H and C1-Cealkyl; R5 is an tituted Cs-Cscycloalkyl an unsubstituted 5-6 membered heterocycloalkyl with 1-2 atoms independently selected from N or O or a Cs-Cscycloalkyl substituted with 1-3 tuents independently selected from C1- Cealkyl; each Fl6 is independently selected from -NHC(O)OR4, -OFi4 and -(CR92)nOR4; each R7 is independently selected from C1-Cshaloalkyl; R8 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 atoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 atoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the tuted phenyl, the substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are tuted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51 -(C(R9)2)nC(O)OR4, -C(O)OR4 and -S(O)2R4; each R9 is independently selected from H and C1-Cealkyl; R10 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-2 atoms independently selected from N, O or 8, an tituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered cycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, a tuted phenyl, a tuted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cscycloalkyl, a idinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms ed from N, substituted Cs-Cscycloalkyl and substituted 4-6 ed heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from lkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51'(C(R9)2)nC(O)OR4 and -S(O)2R4; tis 1,2or3, and each n is independently selected from 1, 2, 3 and 4.
In certain embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), a (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), Fl1 is selected from -CH3 and F.
In certain embodiments of any of the aforementioned compounds of a (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), a (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), Fl1 is -CH3.
In n embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), a (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), each Ft11 is independently selected from H, F and -CH3.
In certain embodiments of any of the aforementioned compounds of a (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), each Fl11 is H.
In certain embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), a (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or a (llf), Fl3 is selected from an unsubstituted Cs-Cscycloalkyl, a cyclobutanone, a cyclopentanone and a substituted Cs-Cscycloalkyl, n the substituted Cs- Cscycloalkyl of Ft3 is substituted with 1-4 substituents independently selected from C1- Cealkyl, halo, C1-Cehaloalkyl, -OR4, -(CR92)nOR4, -O(CR92)nOR4, 2, =N-OR4, =N-O- (CR92),,R5, -NR4C(=O)OR4, -NR4C(=O)(CR92),,OR4, -NR4(CR92)nOR4, -NR4S(=O)2R4, - N(C(=O)OR4)2, =CH2, 92)nOR4, R8, deuterated C1-Cealkoxy, a spiro attached dioxolane, a spiro attached dioxolane which is substituted with C1-Cealkyl, a spiro attached dioxane, a spiro attached tetrahyrofuranly, a spiro attached cyclobutanone, a spiro ed cyclobutanol, an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N and O and a 5-6 membered heterocycloalkyl with 1-2 atoms ndently selected from N and O tuted with 1-3 substituents independently selected from C1-Cealkyl.
In certain embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), a (lld), Formula (le), Formula (lle), a (lf) or Formula (llf), each Fl6 is independently selected from, -OFi4 and -(CR92)nOR4.
In certain ments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), each R4 is independently selected from H, methyl, ethyl, propyl, butyl, ipropyl and t-butyl.
In certain embodiments of any of the aforementioned nds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), each R5 is independently ed from cyclopropyl or morpholinyl.
In certain embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), each Fl6 is independently selected from OH and -CH20H.
In n embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), a (lld), Formula (le), a (lle), Formula (lf) or Formula (llf), each R7 is independently selected from CH2F, -CHF2, F2, -CH20F3 and -CF3.
In certain embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), a (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), each R9 is independently selected from H, methyl and ethyl.
In certain embodiments of any of the aforementioned nds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), a (llc), Formula (ld), Formula (lld), a (le), Formula (lle), a (lf) or Formula (llf), R8 is selected from an an unsubstituted ycloalkyl and an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N.
In certain embodiments of any of the entioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), a (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), R2 is R3.
In certain ments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or 2012/052621 Formula (llf), Fl3 is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, , each of which is unsubstituted or each of which is substituted with 1-4 substituents independently selected from -F, -CH3, 'CHchg, -CF3, -OH, -OCH3, -CH200H3, -NH2, - 2, 'OCchHgoCHg, =N-OCH3, =N-OCH20H3, =N-OCH(CH3)2, =N-OH, =N-O- CH2R5, =N-O-CH20H2R5, -NHC(=O)OC(CH3)3, -NHC(=O)OCH3, -NHC(=O)CHzOCH3, - NHCHZCHZOCHs, -NHCHZCHZOH, -NHS(=O)ZCH3, -N(C(=O)OCH3)2, =CH2, =CHCHZCH20H, -OCD3, cyclopropyl, triazolyl, pyrazolyl, a spiro attached dioxolane, a spiro attached dioxolane which is tuted with a -CH3, a spiro attached dioxane, a spiro attached tetrahyrofuranly, a spiro attached cyclobutanone, a spiro attached cyclobutanol, dinyl and piperazinyl substituted with a -CH3, or Ft3 is a cyclobutanone or a cyclopentanone.
In n embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), R3 is cyclopropyl substituted with 1 or 2 F, or R3 is cyclobutyl substituted with 2 ..
In certain ments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), m is 1 and R20 is selected from H, halo, lkyl, C1-Cehaloalkyl, C1- Cehaloalkoxy, deuterated C1-Cealkyl, -CN, -(CR92)nOR4, )nC(=O)OR4, R10, - (CR92)nR‘O, -((CR92)nO)tR4, -(CR92)nO(CR92)nR7, -(CR92),,C(=O)R4, and -C(=O)N(R4)2.
In certain embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), a (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), m is 1 and R20 is selected from H, -F, -CH3, -CF3, -CD3, -CN, -OCHF2, - C(CH3)OH, -CHZCH20(=O)OC(CH3)3, -CHZOCH20HZOH, 'CHgoCchFs, -C(=O)NH2, - CH20H20(CH3)2OH, 'CHgoCchHzoCHs, chHgF, 20(=O)CH3, -CH20H and -CH200H3.
In certain ments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), a (le), a (lle), Formula (lf) or a (llf), m is 1 and R20 is -CH3.
In certain ments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), m is 1 and R20 is H.
In certain embodiments of any of the aforementioned compounds of Formula (I), Formula (II), Formula (la), Formula (Ila), Formula (lb), Formula (Ilb), Formula (Ic), Formula (Ilc), Formula (Id), a (Ild), Formula (Ie), Formula (Ile), Formula (If) or Formula (Ilf), R10 is selected from morpholinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperazinyl, piperazinyl, pyrazolyl, pyrazolyl, pyrazol yl, pyrazolyl, lyl, 1H-1,2,3-triazolyl, 4H-1,2,4-triazolyl, ,4-triazolyl, thiazolyl, thiazolyl, lyl, imidazolyl, imidazolyl, imidazolyl, each of which is unsubstituted or each of which is substituted with 1-3 substituents independently selected from C1-Csalkyl, -(CR92)nOR4, -(C(R9)2)nC(O)OR4, -(C(Fi9)2)nFi5 and -S(=O)2R4, or R10 is selected from a oxazolidinone and a pyrrolidinone.
In certain embodiments of any of the aforementioned compounds of Formula (I), Formula (II), a (la), Formula (Ila), Formula (lb), Formula (Ilb), Formula (Ic), Formula (Ilc), Formula (Id), Formula (Ild), Formula (Ie), Formula (Ile), Formula (If) or Formula (Ilf), R10 is selected from morpholinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperazinyl, piperazinyl, pyrazolyl, pyrazolyl, pyrazol yl, lyl, triazolyl, 1H-1,2,3-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, thiazolyl, thiazolyl, thiazolyl, imidazolyl, imidazolyl, imidazolyl, each of which is unsubstituted or each of which is substituted with 1-3 substituents independently selected from -CH3, 'CHchon, -CHzC(O)OH, 'CHchon, -CHZC(CH3)2OH, - S(O)ZCH3 and -CHzCH2-R5.
In certain embodiments of any of the aforementioned compounds of Formula (I), Formula (II), a (la), a (Ila), Formula (lb) or Formula (Ilb), m is 4 and R20 is ium.
Certain embodiments of the compounds of Formula (I) or a (II) are selected from: 3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-{2—methyl[5-(3-oxocyclopentyl)-1,2,4-oxadiazol yl]phenyl}imidazo[1,2—a]pyridinecarboxamide; 5-(3-hydroxymethylcyclobutyl)- 1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2-a]pyridinecarboxamide; 5-[3- (hydroxyimino)cyclobutyl]-1,2,4-oxadiazolyl}methylphenyl)imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazolyl] methylphenyl}imidazo[1,2—a]pyridinecarboxamide; N-{5-[5-(3-hydroxy methylcyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2—a]pyridine carboxamide; N-(5-{5-[3-(methoxyimino)cyclobutyl]-1,2,4-oxadiazolyl}-2— methylphenyl)imidazo[1,2—a]pyridinecarboxamide; N-[5-(5-{5,8—dioxaspiro[3.4]octan-2— yl}-1,2,4-oxadiazolyl)methylphenyl]imidazo[1,2—a]pyridinecarboxamide; N-(2— methyl{5-[(6R)methyl-5,8—dioxaspiro[3.4]octanyl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2-a]pyridinecarboxamide; N-[5-(5-{5,9-dioxaspiro[3.5]nonan-2—yl}- 1,2,4-oxadiazolyl)methylphenyl]imidazo[1,2-a]pyridinecarboxamide; N-{2—methyl- -[5-(3-oxocyclobutyl)-1,2,4-oxadiazolyl]phenyl}imidazo[1,2—a]pyridinecarboxamide; N-(2-methyl{5-[(68)methyl-5,8—dioxaspiro[3.4]octan-2—yl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4- oxadiazolyl]methylphenyl}imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[3- (ethoxyimino)cyclobutyl]-1,2,4-oxadiazolyl}methylphenyl)imidazo[1,2—a]pyridine carboxamide; N-[5-(5-{3-[(cyclopropylmethoxy)imino]cyclobutyl}-1,2,4-oxadiazolyl)-2— methylphenyl]imidazo[1,2—a]pyridinecarboxamide; N-[2-methyl(5-{3-[(propan-2— yloxy)imino]cyclobutyl}-1,2,4-oxadiazolyl)phenyl]imidazo[1,2-a]pyridine carboxamide; N-{5-[5-(3-aminocyclobutyl)-1,2,4-oxadiazolyl]-2— phenyl}imidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[3-(2— methoxyethoxy)cyclobutyl]-1,2,4-oxadiazolyl}methylphenyl)imidazo[1,2—a]pyridine- oxamide; N-{5-[5-(3-methoxycyclobutyl)-1,2,4-oxadiazolyl]-2— methylphenyl}imidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[1- xymethyl)cyclopropyl]-1,2,4-oxadiazolyl}methylphenyl)imidazo[1,2- a]pyridinecarboxamide; tert-butyl N-{1-[3-(3-{imidazo[1,2-a]pyridineamido} methylphenyl)-1,2,4-oxadiazolyl]cyclopropyl}carbamate; 5-(1- methanesulfonamidocyclopropyl)-1,2,4-oxadiazolyl]-2—methylphenyl}imidazo[1,2- a]pyridinecarboxamide; methyl 3-(3-{imidazo[1,2-a]pyridineamido} methylphenyl)-1,2,4-oxadiazolyl]cyclopropyl}-N-(methoxycarbonyl)carbamate; methyl N-{1-[3-(3-{imidazo[1,2—a]pyridineamido}methylphenyl)-1,2,4-oxadiazol y|]cyc|opropy|}carbamate; N-(5-{5-[3-hydroxy(trifluoromethyl)cyclobutyl]-1,2,4- oxadiazolyl}methylphenyl)imidazo[1,2—a]pyridinecarboxamide; 1- methylcyclopropyl N-{[3-(3-{imidazo[1,2—a]pyridineamido}methylphenyl)-1,2,4- oxadiazol-S-yl]methyl}carbamate; methyl N-{1-[3-(3-{imidazo[1,2-a]pyridineamido} methylphenyl)-1,2,4-oxadiazolyl]cyclobutyl}carbamate; N-{5-[5-(1- methanesulfonamidocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1 ,2- a]pyridinecarboxamide; N-(5-{5-[1-(dimethylamino)cyclopropyl]-1,2,4-oxadiazolyl}- 2—methylphenyl)imidazo[1,2—a]pyridinecarboxamide; N-{2—methyl[5-(3- methylidenecyclobutyl)-1,2,4-oxadiazolyl]phenyl}imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(3-cyclopropylhydroxycyclobutyl)-1,2,4-oxadiazolyl]-2— methylphenyl}imidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[3-(3- hydroxypropylidene)cyclobutyl]-1 ,2,4-oxadiazolyl}methylphenyl)imidazo[1 ,2- a]pyridinecarboxamide; N-[2-methyl(5-{5-oxaspiro[3.4]octanyl}-1,2,4-oxadiazol- henyl]imidazo[1,2—a]pyridinecarboxamide; N-[5-(5-{[(3,3- difluorocyclobutyl)amino]methyl}-1,2,4-oxadiazolyl)methylphenyl]imidazo[1 ,2- 2012/052621 a]pyridine—3-carboxamide; N-(2—methyl{5-[(2,2,3,3-tetrafluorocyclobutoxy)methyl]- 1,2,4-oxadiazoIyl}phenyl)imidazo[1 ,2-a]pyridine—3-carboxamide; N-{5-[5-(3- fluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}imidazo[1,2—a]pyridine carboxamide; 5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylpheny|} (hydroxymethyl)imidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyI]methylpheny|}[(2—hydroxyethoxy)methyl]imidazo[1,2—a]pyridine— oxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazoIyI]methylpheny|} (methoxymethyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyI]methylpheny|}(1H-pyrazoIyl)imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylpheny|}[1- (2-hydroxyethyI)-1H-pyrazoIyl]imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3- difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}(1-methy|—1H-pyrazoI y|)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|— 3-y|]methylpheny|}(1-methy|—1H-pyrazoIyl)imidazo[1,2—a]pyridine—3-carboxamide; 5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylpheny|}[1-(2—hydroxy-2— methylpropyI)-1H-pyrazoIyl]imidazo[1,2—a]pyridine—3-carboxamide; N-(2—methyI{5- [3-(1H-pyrazoIy|)cyc|obuty|]-1,2,4-oxadiazolyl}phenyl)imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylpheny|} (1 ,3-thiazoIyl)imidazo[1 ,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1 ,2,4-oxadiazo|y|]f|uoropheny|}(1-methy|—1 H-pyrazoIyl)imidazo[1,2-a]pyridine— 3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]f|uoropheny|} [1 -(2—hydroxy-2—methylpropy|)-1 H-pyrazoIyl]imidazo[1 ,2—a]pyridinecarboxamide; N- {5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylpheny|}(1- methanesuIfonylpiperidinyl)imidazo[1,2-a]pyridine—3-carboxamide; 5-(3,3- difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}{1-[2—(morpho|inyl)ethyl]- 1H-pyrazoIy|}imidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazoIyl]f|uoropheny|}{1-[2-(morpholinyl)ethyl]-1H-pyrazoI y|}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|— 3-y|]methylpheny|}[(2,2,2-trifluoroethoxy)methyl]imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylphenyI}(3- oxobutyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4- zo|y|]methy|phenyI}(3-hydroxy-B-methylbutyl)imidazo[1,2—a]pyridine—3- carboxamide; N-(5-{5-[2—(1-hydroxycyclopropyl)ethyl]-1,2,4-oxadiazo|—3-yI} methylphenyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyI]methylphenyl}[2—(morpholinyl)ethyl]imidazo[1,2—a]pyridine carboxamide; N-[5-(5-cyclobutyI-1 ,2,4-oxadiazoIyI)methylphenyl]imidazo[1 ,2- a]pyridine—3-carboxamide; N-{5-[5-(3,3-dimethylcyclobutyl)-1,2,4-oxadiazo|—3-yI] phenyl}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyI]methylpheny|}(morpho|iny|)imidazo[1,2—a]pyridine—3- carboxamide; 6-cyano-N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazo|—3-yI] methylphenyl}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazo|y|]f|uoropheny|}(5-methy|—4H-1,2,4-triazo|—3-yl)imidazo[1,2- a]pyridine—3-carboxamide; 3-N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazo|—3-yI] phenyl}imidazo[1,2—a]pyridine—3,6-dicarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- oxadiazolyI]methylphenyl}[2—(4-methylpiperaziny|)ethy|]imidazo[1,2- a]pyridine—3-carboxamide; 5-(2,2—difluorocyclopropyl)-1,2,4-oxadiazo|—3-yI] methylphenyl}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyI]methylpheny|}(1H-1,2,3-triazo|—4-y|)imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylpheny|}[1- (2-hydroxyethyI)-1H-1,2,3-triazo|—4-yl]imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3- difluorocyclobutyI)-1,2,4-oxadiazolyI]-2,4-dimethylphenyl}imidazo[1,2-a]pyridine—3- carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylphenyl}(2— oxo-1,3-oxazolidinyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3- difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}methy|imidazo[1,2—a]pyridine— 3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazoIyI]methylpheny|} methylimidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4- oxadiazoIyl]methylphenyI}fluoroimidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5- (3,3-difluorocyclobutyl)-1,2,4-oxadiazo|y|]methylpheny|}fluoroimidazo[1,2- a]pyridine—3-carboxamide; 7-cyano-N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazo|—3-yl]- ylpheny|}imidazo[1,2—a]pyridinecarboxamide; N-[5-(5-cyclopentyI-1,2,4- oxadiazoI-B-yl)methy|pheny|]imidazo[1,2—a]pyridine—3-carboxamide; N-[2-methyI(5- {6-oxospiro[3.3]heptan-2—y|}-1,2,4-oxadiazoIyl)phenyl]imidazo[1,2—a]pyridine—3- carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylphenyl}(2— oxopyrrolidiny|)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyI]methylpheny|}[(2,2-difluoroethoxy)methyl]imidazo[1,2- a]pyridine—3-carboxamide; N-{5-[5-(3-ethylcyclobutyl)-1,2,4-oxadiazo|—3-yI] methylphenyl}imidazo[1,2—a]pyridine—3-carboxamide; 5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyI]methylpheny|}(5-methyl-4H-1,2,4-triazo|—3-yl)imidazo[1,2- a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|—3-yI] methylphenyI}methylimidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3- difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}(morpholinyl)imidazo[1,2- a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|—3-yI] methylpheny|}(1H-imidazoIy|)imidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3- difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}[(2— fluoroethoxy)methyl]imidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3- difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}[3-(methoxymethyl)-1H-1,2,4- Iyl]imidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(2,2—difluorocyclopropyI)-1,2,4- oxadiazo|y|]methy|phenyI}[(2,2,2—trifluoroethoxy)methyl]imidazo[1,2—a]pyridine carboxamide; N-[5-(5-cyclobutyI-1,2,4-oxadiazolyI)methylphenyI][(2,2,2- trifluoroethoxy)methyl]imidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[(1R)-2,2— difluorocyclopropyI]-1,2,4-oxadiazolyl}methy|pheny|)imidazo[1,2—a]pyridine—3- carboxamide; N-(5-{5-[(1S)-2,2—difluorocyclopropyl]-1,2,4-oxadiazo|—3-y|}-2— methylphenyl)imidazo[1,2—a]pyridine—3-carboxamide; N-(5-{5-[3-hydroxy (trifluoromethyl)cyclobutyl]-1,2,4-oxadiazolyI}methylphenyI)methylimidazo[1,2- a]pyridine—3-carboxamide; 6-fluoro-N-(5-{5-[3-hydroxy(trifluoromethyl)cyclobutyl]- 1,2,4-oxadiazolyl}methy|pheny|)imidazo[1,2—a]pyridine—3-carboxamide; N-(5-{5- [(1R,2S)-2—f|uorocyclopropyl]-1,2,4-oxadiazolyl}methy|pheny|)imidazo[1,2- a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|—3-yI] methylpheny|}-5,6,7,8—tetradeuteroimidazo[1,2—a]pyridine—3-carboxamide; N-{5-[(3,3- difluorocyclobutyl)carbamoyI]methylphenyl}imidazo[1,2—a]pyridine—3-carboxamide; 7- fluoro-N-(5-{5-[3-hydroxy-B-(trifluoromethyl)cyclobutyI]-1,2,4-oxadiazo|—3-yI} methylphenyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyI]methylpheny|}(4-methyl-1H-imidazoIy|)imidazo[1,2- dine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|—3-yI] methylpheny|}[(2R,68)-2,6-dimethylmorpholinyl]imidazo[1,2-a]pyridine—3- carboxamide; N-(5-{5-[3-methoxy(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazo|—3-yI} phenyl)imidazo[1,2—a]pyridine—3-carboxamide; 6-fluoro-N-(5-{5-[1- (methoxymethyl)cyclobutyl]-1,2,4-oxadiazolyl}methy|pheny|)imidazo[1,2—a]pyridine— 3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazoIyI]methylpheny|} [1-(2—methoxyethyI)methyl-1H-1,2,4-triazo|—3-yl]imidazo[1,2—a]pyridine—3-carboxamide; -{6-hydroxyspiro[3.3]heptan-2—yI}-1,2,4-oxadiazo|—3-yI) methylphenyl]imidazo[1,2—a]pyridine—3-carboxamide; N-(5-{5-[(1S,2S)-2— fluorocyclopropyI]-1,2,4-oxadiazoly|}methylphenyl)imidazo[1,2—a]pyridine—3- carboxamide; 7-methyl-N-(2-methyl{5-[(2,2,3,3-tetrafluorocyclobutoxy)methyI]-1,2,4- oxadiazoIy|}phenyl)imidazo[1,2—a]pyridine—3-carboxamide; 6-methyl-N-(2—methyI{5- [(2,2,3,3-tetrafluorocyclobutoxy)methyl]-1,2,4-oxadiazoIy|}phenyl)imidazo[1,2- a]pyridine—3-carboxamide; N-[5-(5-cyclopropyI-1,2,4-oxadiazo|—3-yI) methylphenyl]imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(cyclopropylmethyI)-1,2,4- zo|y|]methy|pheny|}imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(1R,2S)- 2-fluorocyclopropyI]-1,2,4-oxadiazolyI}methylphenyI)methylimidazo[1,2- a]pyridine—3-carboxamide; N-(5-{5-[(1S,2R)f|uorocyc|opropyl]-1,2,4-oxadiazo|—3-y|}-2— methylphenyl)methylimidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[(1R)-2,2— difluorocyclopropyl]-1,2,4-oxadiazolyl}-2,4-dimethylphenyl)imidazo[1,2—a]pyridine carboxamide; N-(5-{5-[(1S)-2,2—diiluorocyclopropyl]-1,2,4-oxadiazolyl}-2,4- dimethylphenyl)imidazo[1,2—a]pyridinecarboxamide; 5-[(1R,2S)-2— fluorocyclopropyl]-1,2,4-oxadiazolyl}-2—methylphenyl)imidazo[1,2—a]pyridine carboxamide; 5-(3-fluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl} methylimidazo[1,2—a]pyridinecarboxamide; N-{5-[5-(3-fluorocyclobutyl)-1,2,4- oxadiazolyl]methylphenyl}methylimidazo[1,2—a]pyridinecarboxamide; N-(5-{5- [(1S,2R)fluorocyclopropyl]-1,2,4-oxadiazolyl}methylphenyl)imidazo[1,2- dinecarboxamide; methyl N-{3,3-difluoro[3-(3-{imidazo[1,2—a]pyridine amido}methylphenyl)-1,2,4-oxadiazolyl]cyclobutyl}carbamate; methyl N-{3,3- difluoro[3-(4-methyl{7-methylimidazo[1,2—a]pyridineamido}phenyl)-1,2,4- oxadiazolyl]cyclobutyl}carbamate, and 5-(3,3-diiluorocyclobutyl)-1,2,4-oxadiazol- 3-yl]methylphenyl}[(2—fluoroethoxy)methyl]imidazo[1,2—a]pyridinecarboxamide.
Other preffered embodiments of the compounds of Formula (I) or Formula (II) are selected from: N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]-2—methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-(5-{5-[(1R)-2,2—difluorocyclopropyl]-1,2,4-oxadiazolyl}-2— methylphenyl)imidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[(1S)-2,2— difluorocyclopropyl]-1,2,4-oxadiazolyl}methylphenyl)imidazo[1,2—a]pyridine carboxamide; N-(5-{5-[(1S,2R)-2—fluorocyclopropyl]-1,2,4-oxadiazolyl}-2— methylphenyl)imidazo[1,2—a]pyridinecarboxamide, and 5-[(1R,2S)-2— fluorocyclopropyl]-1,2,4-oxadiazolyl}-2—methylphenyl)imidazo[1,2—a]pyridine carboxamide.
Certain embodiments of the compounds of Formula (I) or Formula (II) are selected from: N-[5-(3-cyclopropyl-1,2,4-oxadiazolyl)methylphenyl]imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(3,3-diiluorocyclobutyl)-1,3,4-oxadiazolyl]-2— methylphenyl}imidazo[1,2—a]pyridinecarboxamide; N-{5-[5-(3-hydroxy methylcyclobutyl)-1,2,4-oxadiazolyl]-2—methylphenyl}imidazo[1,2—a]pyridine carboxamide; N-(5-{5-[(32)(methoxyimino)cyclopentyl]-1,2,4-oxadiazolyl}-2— phenyl)imidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[(32) (hydroxyimino)cyclopentyl]-1,2,4-oxadiazolyl}methylphenyl)imidazo[1,2—a]pyridine- 3-carboxamide; N-(2—methyl{5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3-hydroxymethylcyclobutyl)- 1,2,4-oxadiazolyl]-2—methylphenyl}imidazo[1,2-a]pyridinecarboxamide; N-{2—methyl- -[5-(3-oxocyclobutyl)-1,2,4-oxadiazolyl]phenyl}imidazo[1,2—a]pyridinecarboxamide; WO 33070 N-{5-[5-(3-hydroxycyclobutyl)-1,2,4-oxadiazolyI]methylpheny|}imidazo[1,2- a]pyridine—3-carboxamide; N-(2-methyl{5-[3-(piperidiny|)cyc|obutyI]-1,2,4-oxadiazo|— 3-y|}phenyl)imidazo[1,2—a]pyridinecarboxamide; N-(2—methyl{5-[3-(morpholin y|)cyc|obuty|]-1,2,4-oxadiazoIy|}phenyl)imidazo[1,2—a]pyridine—3-carboxamide; N-(2— {5-[3-(4-methylpiperaziny|)cyc|obuty|]-1,2,4-oxadiazo|—3- y|}phenyl)imidazo[1,2-a]pyridine—3-carboxamide; N-{2—methyl[5-(3-{[2-(morpho|in y|)ethoxy]imino}cyclobutyI)-1,2,4-oxadiazolyl]phenyl}imidazo[1,2-a]pyridine—3- carboxamide; tert-butyl N-{3-[3-(3-{imidazo[1,2—a]pyridine—3-amido}methy|phenyl)- 1,2,4-oxadiazo|y|]cyc|obuty|}carbamate; N-{5-[5-(3-aminocyclobutyI)-1,2,4-oxadiazo|— 3-y|]methylpheny|}imidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(3- methanesulfonamidocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}imidazo[1 ,2- a]pyridine—3-carboxamide; 1-methylcyclopropyl N-{2—[3-(3-{imidazo[1,2—a]pyridine—3- amido}methylphenyI)-1,2,4-oxadiazo|y|]ethy|}carbamate; N-{5-[5-(1- aminocyclopropyI)-1,2,4-oxadiazolyI]methylpheny|}imidazo[1,2—a]pyridine—3- carboxamide; 5-[1-(2-methoxyacetamido)cyclopropyI]-1,2,4-oxadiazo|—3-yI} methylphenyl)imidazo[1,2—a]pyridine—3-carboxamide; N-[5-(5-{3-[(2— methoxyethyl)amino]cyclobuty|}-1,2,4-oxadiazo|y|)methylphenyl]imidazo[1,2- a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|—3-yI] fluorophenyl}imidazo[1,2—a]pyridine—3-carboxamide; N-(5-{5-[3-methoxy (trifluoromethyl)cyclobutyl]-1,2,4-oxadiazolyI}methylphenyI)-N-methylimidazo[1,2- a]pyridine—3-carboxamide; tert-butyl 3-(3-{imidazo[1,2-a]pyridine—3-amido} phenyI)-1,2,4-oxadiazo|y|]cyc|obuty|}carbamate; 5-(1-aminocyclobutyl)- 1,2,4-oxadiazolyI]methylpheny|}imidazo[1,2-a]pyridine-B-carboxamide; N-{2—fluoro- -[5-(3-methylidenecyclobutyl)-1,2,4-oxadiazoly|]pheny|}imidazo[1,2—a]pyridine—3- carboxamide; N-(5-{5-[1-(hydroxymethyl)cyclopropyl]-1,2,4-oxadiazo|—3-y|}-2— methylphenyl)imidazo[1,2—a]pyridine—3-carboxamide; N-[5-(5-{[(2,2— difluorocyclopropyl)formamido]methy|}-1,2,4-oxadiazolyl)methy|pheny|]imidazo[1,2- a]pyridine—3-carboxamide; 1-methylcyclopropyl N-[(3-{4-methyI[7- (trifluoromethyl)imidazo[1,2-a]pyridine—3-amido]pheny|}-1,2,4-oxadiazo|—5- y|)methy|]carbamate; methyl N-{3-[3-(3-{imidazo[1,2-a]pyridine—3-amido} methylphenyI)-1,2,4-oxadiazo|y|]cyc|obuty|}carbamate; tert-butyl 3-[3-({5-[5-(3,3- difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}carbamoyl)imidazo[1,2—a]pyridin- 6-yl]propanoate; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyI]methylpheny|} [(4-methylpiperaziny|)methy|]imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3- difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}{[4-(2-hydroxyethyl)piperazin- 1-yl]methy|}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4- oxadiazo|y|]methy|phenyI}[(2-methoxyethoxy)methyl]imidazo[1,2—a]pyridine carboxamide; 2-{4-[3-({5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]-2— methylphenyl}carbamoyl)imidazo[1,2—a]pyridinyl]-1H-pyrazolyl}acetic acid; N-{5-[5- (1-hydroxycyclopropyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl} (difluoromethoxy)imidazo[1,2—a]pyridinecarboxamide; N-(2—methyl{5-[3-(1H-1,2,4- triazolyl)cyclobutyl]-1,2,4-oxadiazolyl}phenyl)imidazo[1,2-a]pyridinecarboxamide; 6-fluoro-N-{5-[5-(3-hydroxycyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-[5-(5-cyclobutyl-1,2,4-oxadiazolyl) fluorophenyl]imidazo[1,2—a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)- oxadiazolyl]-2—methylphenyl}(2—hydroxymethylpropyl)imidazo[1 ,2- a]pyridinecarboxamide; N-{5-[5-(3,3-diiluorocyclobutyl)-1,2,4-oxadiazolyl]-2— methylphenyl}[(2-oxo-1,3-oxazolidinyl)methyl]imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}(2— ymethylpropyl)imidazo[1,2—a]pyridinecarboxamide; N-{5-[5-(3,3- dimethylcyclobutyl)-1,2,4-oxadiazolyl]fluorophenyl}imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]fluorophenyl}(5- methyl-4H-1,2,4-triazolyl)imidazo[1,2-a]pyridinecarboxamide; 6-fluoro-N-{5-[5-(3- hydroxymethylcyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2-a]pyridine- oxamide; N-{5-[5-(2-hydroxycyclopropyl)-1,2,4-oxadiazolyl]-2— methylphenyl}imidazo[1,2—a]pyridinecarboxamide; N-{3-[5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyl]-2,6-dimethylphenyl}imidazo[1,2—a]pyridinecarboxamide; 7-cyano- N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]-2—methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-{5-[5-(3,3-diiluorocyclobutyl)-1,2,4-oxadiazolyl]-2— methylphenyl}(1-hydroxyethyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3- difluorocyclobutyl)-1,2,4-oxadiazolyl]-2—methylphenyl}(5-methyl-1H-imidazol dazo[1,2—a]pyridinecarboxamide; 5-(3,3-diiluorocyclobutyl)-1,2,4-oxadiazol- 3-yl]methylphenyl}[(2—methoxyethoxy)methyl]imidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[(1S)-2,2-difluorocyclopropyl]-1,2,4-oxadiazolyl}methylphenyl) methylimidazo[1,2—a]pyridinecarboxamide; N-{5-[5-(1-fluorocyclobutyl)-1,2,4- oxadiazolyl]methylphenyl}imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(1- hydroxycyclobutyl)-1,2,4-oxadiazolyl]-2—methylphenyl}imidazo[1,2—a]pyridine carboxamide; N-{5-[5-(1-carbamoylcyclopropyl)-1,2,4-oxadiazolyl]methylphenyl} imidazo[1,2—a]pyridinecarboxamide and N-{5-[5-(3,3-diiluorocyclobutyl)-1,2,4- oxadiazolyl]methylphenyl}(piperidinyl)imidazo[1,2—a]pyridinecarboxamide.
Another aspect provided herein are pharmaceutical compositions that include a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), a (lc), Formula (llc), Formula (ld), WO 33070 Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), and a pharmaceutically acceptable carrier. In certain embodiments of such pharmaceutical compositions, the pharmaceutical composition is formulated for intravenous administration, intravitrial administration, intramuscular administration, oral administration, rectal administration, transdermal administration, pulmonary administration, inhalation administration, nasal administration, topical administration, ophthalmic stration or otic administration. In other embodiments, such pharmaceutical compositions are in the form of a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray on, a suppository, a solution, an emulsion, an ointment, eye drop or ear drop. In other embodiments, such pharmaceutical compositions are ated for oral administration and are in the form of a tablet, a pill, a capsule, a , a solution, or an emulsion. In other embodiments, such pharmaceutical compositions are formulated for oral stration and are in the form of a , a pill, or a capsule. In other embodiments, such pharmaceutical compositions further include one or more additional therapeutic agents. In other embodiments, such aforementioned pharmaceutical compositions further include one or more additional therapeutic agents.
Another aspect provided herein are medicaments for treating a patient with a disease or disorder associated with c-kit or PDGFR kinase activity, or c-kit and PDGFR kinase activity, and such medicaments include a eutically effective amount of a compound of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf). In certain embodiments of this aspect the disease is a mast- cell associated disease, a respiratory e, an inflammatory disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), an mune disorder, a lic disease, a fibrosis disease, a dermatological disease, pulmonary arterial hypertension (PAH) or primary pulmonary hypertension (PPH). In other embodiments of this , the disease is asthma, ic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel me (IBS), inflammatory bowel disease (IBD), uticaria, dermatosis, type I es or type II diabetes. r aspect provided herein are medicaments for treating a disease mediated by c-kit or PDGFR kinase activity, or c-kit and PDGFR kinase ty, in a patient in need f, and such medicaments include a therapeutically ive amount of a compound of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (Hi), and the disease is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), an autoimmune disorder, a lic disease, a fibrosis disease, a dermatological disease, pulmonary arterial hypertension (PAH) or primary pulmonary hypertension (PPH).
In n embodiments of this aspect, the disease is asthma, ic rhinitis, pulmonary arterial hypertension (PAH), pulmonary is, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), uticaria, dermatosis, type I diabetes or type II es.
Another aspect provided herein is the use of a compound of Formula (I), Formula (II), Formula (la), a (lla), a (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), a (lle), a (lf) or Formula (llf) in the manufacture of a medicament for treating a disease or disorder in a patient where c-kit or PDGFR kinase activity, or c-kit and PDGFR kinase activity is implicated.
Another aspect provided herein includes methods for treating a disease or disorder where c-kit or PDGFR kinase activity, or c-kit and PDGFR kinase activity is implicated, wherein the method includes administering to a system or subject in need of such treatment an effective amount of a compound of a (I), Formula (II), Formula (la), a (lla), Formula (lb), Formula (llb), a (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (lf) or Formula (llf), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby treating the disease or disorder. In certain embodiments of such methods, the methods include administering the nd to a cell or tissue system or to a human or animal subject. In certain embodiments of such methods, the disease or ion is a metabolic disease, a fibrotic disease, a respiratory disease, an inflammatory e or disorder, a ological disease or an autoimmune disease. In certain embodiments of such methods, the disease or condition is asthma, allergic is, ble bowel syndrome (IBS), inflammatory bowel disease (IBD), pulmonary arterial hypertension (PAH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, urticaria, dermatoses, atopic dermatitis, type I diabetes or type II diabetes.
Another aspect provided herein is a compound of Formula (I), Formula (II), Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), a (le), Formula (lle), Formula (lf) or Formula (llf) for use in treating a disease mediated by c-kit, PDGFRoc, PDGFRB or combination thereof, wherein the disease is selected from a mast-cell associated disease, a respiratory disease, an matory disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), an autoimmune disorder, a metabolic disease, a fibrosis disease, a dermatological disease, pulmonary arterial hypertension (PAH) and primary pulmonary hypertension (PPH). In n embodiments of this aspect, the disease is selected from a mast-cell 2012/052621 associated disease, a respiratory disease, an inflammatory disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), an autoimmune disorder, a metabolic disease, a fibrosis disease, a ological disease, pulmonary arterial hypertension (PAH) and primary pulmonary hypertension (PPH). In other embodiments the disease is , allergic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac is, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel e (IBD), uticaria, osis, type I diabetes or type II diabetes.
DETAILED DESCRIPTION OF THE INVENTION Definitions The term “alkyl,” as used herein, refers to a saturated branched or straight chain hydrocarbon. In certain embodiments such alkyl groups are optionally tuted. As used herein, the terms alkyl", "C1-C4alkyl", "C1-Csalkyl", "C1-Cealkyl", "C1-C7alkyl" and "C1-Csalkyl" refer to an alkyl group containing at least 1, and at most 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. If not otherwise specified, an alkyl group generally is a C,- 06 alkyl. Non-limiting examples of alkyl groups as used herein e methyl, ethyl, npropyl , isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
The term “alkoxy,” as used herein, refers to the group —ORa, where Fla is an alkyl group as defined herein. As used herein, the terms "C1-Csalkoxy", "C1-C4alkoxy", "C1- Csalkoxy", "C1-Cealkoxy", "C1-C7alkoxy" and "C1-Cgalkoxy" refer to an alkoxy group wherein the alkyl moiety contains at least 1, and at most 3, 4, 5, 6, 7 or 8, carbon atoms.
Non-limiting examples of alkoxy groups, as used herein, include methoxy, ethoxy, n- propoxy, isopropoxy, n-butyloxy, loxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and the like.
The term “cycloalkyl,” as used herein, refers to a ted, monocyclic, fused ic, fused tricyclic, spirocyclic or d polycyclic ring ly. As used herein, the terms "Cs-Cscycloalkyl", "Cs-Cecycloalkyl", "Cs-C7cycloalkyl", "Cs-Cscycloalkyl, "Cs- Cgcycloalkyl and "Cs-Cmcycloalkyl refer to a cycloalkyl group wherein the saturated monocyclic, fused bicyclic or bridged clic ring assembly contain at least 3, and at most 5, 6, 7, 8, 9 or 10, carbon atoms. Non-limiting examples of cycloalkyl groups, as used herein, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like.
The term "halo,” as used herein, refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (l) substituents.
The terms “haloalkyl” or “halo-substituted alkyl,” as used herein, refers to an alkyl group as defined herein, tuted with one or more halo groups as defined herein. The halo groups are the same or different. The haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl, including perhaloalkyl. A perhalo-alkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms. A monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
Such haloalkyl groups are also refered to herein as "C1-Cshaloalkyl", haloalkyl", "C1-Cshaloalkyl", haloalkyl", "C1-C7haloalkyl" and "C1-Cghaloalkyl" wherein the alkyl group contains at least 1, and at most 3, 4, 5, 6, 7 or 8 carbon atoms, respectively.
Non-limiting examples of such branched or straight chained haloalkyl groups, as used herein, include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, romethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and ropropyl. In certain embodiments, a haloalkyl group is trifluoromethyl.
The term “heteroaryl,” as used herein, refers to a 5-6 membered heteroaromatic monocyclic ring having 1 to 4 heteroatoms ndently selected from nitrogen, oxygen and sulfur, an 8-10 membered fused bicyclic ring having 1 to 4 heteroatoms independently ed from nitrogen, oxygen and sulfur and where at least one of the rings is aromatic, or a 12-14 membered fused tricyclic ring having 1 to 4 heteroatoms ndently selected from nitrogen, oxygen and sulfur and where at least one of the rings is aromatic. Such fused bicyclic and tricyclic ring systems may be fused to one or more aryl, cycloalkyl, or heterocycloalkyl rings. Non-limiting examples of heteroaryl groups, as used herein, include 2- or 3-furyl; 1-, 2-, 4-, or 5—imidazolyl; 3-, 4-, or 5- isothiazolyl; 3-, 4-, or 5-isoxazolyl; 2-, 4-, or 5-oxazolyl; 4- or 5-1,2,3-oxadiazolyl; 2- or 3- pyrazinyl; 1-, 3-, 4-, or 5- pyrazolyl; 3-, 4-, 5- or 6-pyridazinyl; 2-, 3-, or 4-pyridyl; 2-, 4-, 5- or 6-pyrimidinyl; 1-, 2- or olyl; 1- or 5-tetrazolyl; 2- or 5-1,3,4-thiadiazolyl; 2-, 4-, or -thiazolyl; 2- or 3-thienyl; 2-, 4- or 6-1,3,5-triazinyl; 1-, 3- or 5-1,2,4-triazolyl; 1-, 4- or 5- 1,2,3-triazolyl; 1- or 9-acridinyl; 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10- , 2-, 3-, 4-, 5-, 6-, 7-, 8-, g]isoquinoline; 2-, 4-, 5- or 7-benzoxazolyl; 1-, 2-, 4-, 5-, 6-, or 7- , 6-, benzimidazolyl; 2-, 4-, 5-, 6-, or othiazolyl; 2-, 3-, 4-, 5-, 6-, 7-benzo[b]thienyl; 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-benzo[b]oxepine; 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl; 1-, 2-, 3-, 4-, -, 6-, 7-, 8, or azolyl; 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl; 2-, 4-, or 5-4H-imidazo[4,5-d] thiazolyl; 2-, 3-, 5-, or 6- imidazo[2,1-b] thiazolyl; 2-, 3-, 6-, or 7-imidazo[1,2— b][1,2,4]triazinyl; 1-, 3-, 4-, 5-, 6-, or 7-indazolyl; 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl; 1-, 2- ,3-, 4-, 5-, 6-, or lyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-isoindolyl; 1-, 3-, 4-, 5-, 6-, 7-, or 8- isoquinoliyl; 2-, 3-, 4-, 5-, 6-, or 7-naphthyridinyl; 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl; 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10- phenathrolinyl; 1-, 2- ,3-, 4-, 6-, 7-, 8-, or 9-phenazinyl; 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10- phenothiazinyl; 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl; 1-, 4-, 5-, 6-, 7-, or 8- phthalazinyl; 2-, 4-, 6-, or 7-pteridinyl; 2-, 6-, 7-, or 8- purinyl; 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10 -, or 11-7H-pyrazino[2,3-c]carbazolyl; 2-, 3-, 5-, 6-, or 7-furo[3,2—b]-pyranyl; 1-, 3-, or 5-1H- pyrazolo[4,3-d]-oxazolyl; 2-, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl; 1-, 2-, 3-, 4-, 5-, or 8- 5H-pyrido[2,3-d]-o-oxazinyl; 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl; 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl; 2-, 3- ,4-, 5-, 6-, 7-, or 8-quinazolinyl; 2-, 3-, 4-, or 5-thieno[2,3-b]furanyl, and 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl.
The term “hetero atoms,” as used herein, refers to nitrogen (N), oxygen (0) or sulfur (S) atoms.
The term “heterocycloalkyl,” as used herein refers to a to saturated 3-6 membered monocyclic hydrocarbon ring structure, a saturated 6-9 membered fused bicyclic hydrocarbon ring structure, or a saturated 10-14 membered fused tricyc|ic hydrocarbon ring structure, wherein one to four of the ring carbons of the hydrocarbon ring structure are replaced by one to four groups independently selected from -O-, -NR-, or -S-, n R is hydrogen, C1-C4alkyl or an amino protecting group.
Non-limiting examples of heterocycloalkyl groups, as used , include aziridinyl, inyl, aziridinyl, aziridinyl, yl, oxiranyl, oxiranyl, thiiranyl, thiiran yl, thiiranyl, azetadinyl, azetadinyl, azetadinyl, azetadinyl, oxetanyl, oxetan yl, yl, oxetanyl, thietanyl, thietanyl, thietanyl, thietanyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, idinyl, pyrrolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrofuranyl, ydrothienyl, ydrothienyl, tetrahydrothienyl, tetrahydrothienyl, tetrahydrothienyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, tetrahydropyranyl, ydropyranyl, tetrahydropyranyl, ydropyranyl, tetrahydropyranyl, ydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl, ydrothiopyranyl, tetrahydrothiopyran-5—yl, tetrahydrothiopyranyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, piperazinyl, zinyl, piperazinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, oxathianyl, oxathianyl, oxathianyl, oxathianyl, oxathianyl, dithianyl, dithianyl, dithian yl, dithianyl, dithianyl, azepanyl, azepanyl, azepanyl, azepanyl, azepan yl, azepanyl, azepanyl, azepanyl, yl, oxepanyl, oxepanyl, oxepan yl, oxepanyl, oxepanyl, oxepanyl, nyl, thiepanyl, thiepanyl, n yl, thiepanyl, thiepanyl, thiepanyl, dioxolanyl, dioxolanyl, dioxolanyl, dioxolanyl, thioxanyl, thioxanyl, thioxanyl, thioxanyl, thioxanyl, dithiolanyl, dithiolanyl, dithiolanyl, dithiolanyl, pyrrolinyl, pyrrolinyl, pyrrolinyl, in yl, pyrrolinyl, pyrrolinyl, imidazolinyl, imidazolinyl, imidazolinyl, imidazolinyl, imidazolinyl, olidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl, pyrazolin yl, pyrazolinyl, pyrazolidinyl, pyrazolidinyl, pyrazolidinyl, pyrazolidinyl, pyrazolidinyl, pyrazolidinyl, hexahydro-1,4-diazepinyl, dihydrofuranyldihydropyranyl, 1,2,3,6-tetrahydropyridinyl, 2H-pyranyl, anyl, dihydropyranyl, dihydrothienyl, ofuranyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, pyrrolidinyl one, piperidinylone piperidinylone, dinylone, and 2H-pyrrolyl.
The term “acceptable” with respect to a compound, formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
The term “administration” or istering” of the subject compound means ing a compound of Formula (I) or Formula (II), a pharmaceutically able salt, a pharmaceutically acceptable e, or solvate f to a subject in need of treatment.
The term “autoimmune disease,” or “autoimmune er,” as used herein, refers diseases wherein cells uncontrollably attack the body's own tissues and organs (autoimmunity), producing inflammatory ons and other serious ms and diseases. Non-limiting examples of autoimmune es include idiopathic thrombocytopenic purpura, hemolytic anemia, systemic lupus erythematosus, rheumatoid arthritis (RA), multiple sclerosis (MS), immune-mediated or type 1 diabetes mellitus, immune ed glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammatory bowel diseases, Crohn's e, psoriasis, mune thyroid diseases, and Hashimoto's e, Hashimoto's thyroiditis, dermatomyositis, goodpasture syndrome, enia gravis pseudoparalytica, ophtalmia sympatica, phakogene uveitis, chronical aggressive hepatitis, primary billiary cirrhosis, autoimmune hemolytic anemy, Werlof disease, vitiligo vulgaris, Behcet's disease, collagen disease, uveitis, Sjogren's syndrome, autoimmune myocarditis, autoimmune hepatic diseases, autoimmune gastritis, pemphigus, Guillain- Barre syndrome, and HTLVassociated myelopathy.
The term “carrier,” as used herein, refers to al compounds or agents that facilitate the incorporation of a compound described herein into cells or tissues.
The terms “co-administration” or “combined administration” or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily stered by the same route of administration or at the same time.
The term “dermatological disease” or “dermatological disorder,” as used herein refers to a skin disorder. Such dermatological ers e, but are not limited to, proliferative or inflammatory disorders of the skin such as, atopic dermatitis, bullous disorders, collagenoses, t dermatitis , Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, actinic sis, basal cell carcinoma and urticaria.
The term “diluent,” as used herein, refers to chemical compounds that are used to dilute a compound described herein prior to delivery. Diluents can also be used to stabilize compounds described herein.
The terms “effective amount” or peutically effective amount,” as used herein, refer to a sufficient amount of a compound described herein being stered which will relieve to some extent one or more of the ms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective ” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in y or duration, the effect of other therapeutic agents on a system. An cing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
The terms “fibrosis” or “fibrosis disease,” as used herein, refers to conditions that follow acute or chronic inflammation and are ated with the abnormal accumulation of cells and/or collagen and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, , lung, or skin, and includes such disorders as idiopathic pulmonary fibrosis and cryptogenic fibrosing itis.
The term “inflammatory disease or disorders,” as used , refers to those diseases or conditions that are characterized by one or more of the signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and loss of function (functio laesa, which may be l or complete, temporary or permanent). Inflammation takes many forms and includes, but is not limited to, inflammation that is one or more of the following: acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, WO 33070 2012/052621 disseminated, exudative, fibrinous, ing, focal, omatous, lastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative. Inflammatory disorders further include, without being limited to those affecting the blood vessels (polyarteritis, temporal arthritis); joints itis: crystalline, osteo-, psoriatic, ve, rheumatoid, Reiter's); gastrointestinal tract (Disease,); skin (dermatitis); or le organs and tissues (systemic lupus erythematosus).
As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline ty of a biological activity or process.
The term “pharmaceutically acceptable,” as used herein, refers to a material, such as a r or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
The term "pharmaceutically acceptable carrier", as used herein, es any and all ts, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, ning agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329).
Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical itions is contemplated.
The term “pharmaceutically acceptable salt,” as used herein, refers to a ation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compounds described herein.
The terms “combination” or “pharmaceutical combination,” as used herein mean a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, by way of example, a compound of Formula (I) or a (II) and an additional therapeutic agent, are both administered to a patient aneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, by way of example, a compound of Formula (I) or Formula (II) and an additional therapeutic agent, are both administered to 2012/052621 a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to il therapy, e.g. the administration of 3 or more active ients.
The terms sition” or “pharmaceutical composition,” as used herein, refers to a mixture of at least one compound, such as the compounds of Formula (I) or Formula (II) provided herein, with at least one and optionally more than one other pharmaceutically acceptable chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
The term “respiratory disease,” as used herein, refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, trachea, bronchi, and lungs. Respiratory diseases e, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) , acute severe asthma, chronic asthma, al asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary e, including chronic itis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or ainNay mation and cystic fibrosis, and hypoxia.
The term ct” or “patient,” as used , encompasses mammals and non- mammals. es of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. Frequently the subject is a human, and may be a human who has been diagnosed as in need of treatment for a e or disorder disclosed herein.
As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
The term “c-kit inhibitor,” as used herein, refers to a nd which inhibits c-kit kinase.
The term “disease or disorder associated with c-kit activity,” as used herein, refers to any disease state associated with a c-kit kinase. Such diseases or ers include, but are not limited to, a mast-cell ated disease, inflammatory diseases, respiratory diseases, is diseases, a dermatological disease, metabolic diseases and autoimmune diseases, such as, by way of e only, asthma, dermatitis, allergic rhinitis, pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, ble bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, rheumatoid arthritis, le sclerosis, uticaria, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), dermatosis, diabetes, type I diabetes and type II diabetes.
The term “PDGFR inhibitor,” as used herein, refers to a compound which inhibits PDGFR kinase.
The term “disease or disorder associated with PDGFR ty,” as used herein, refers to any disease state associated with a PDGFR kinase. Such diseases or disorders include, but are not limited to, inflammatory diseases, respiratory diseases, is diseases, metabolic diseases and autoimmune diseases, such as, by way of example only, asthma, dermatitis, allergic rhinitis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, rheumatoid arthritis, multiple sclerosis, pulmonary al hypertension and diabetes.
The term “an optical isomer” or “a stereoisomer”, as used herein, refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. The term "chiral" refers to molecules which have the property of non-superimposability on their mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. Therefore, the invention es enantiomers, diastereomers or tes of the compound. “Enantiomers” are a pair of isomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic” mixture. The term is used to designate a racemic mixture where appropriate.
"Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute chemistry is specified according to the Cahn- lngold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or 8.
Resolved compounds whose te configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or tatory) which they rotate plane zed light at the wavelength of the sodium D line. Certain compounds bed herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, reomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
The term "a therapeutically effective amount" of a compound of the present invention, as used , refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a n activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a e, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the WO 33070 present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by c-kit kinase or c-kit and PDGFR kinases, or (ii) associated with c- kit kinase or c-kit and PDGFR kinase activity, or (iii) characterized by activity (normal or abnormal) of c-kit kinase or c-kit and PDGFR kinases; or (2) reducing or inhibiting the ty of c-kit kinase or c-kit and PDGFR kinases; or (3) reducing or inhibiting the expression of c-kit kinase or c-kit and PDGFR kinases. In another non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially ng or inhibiting the activity of c-kit kinase or c-kit and PDGFR kinases; or at least partially reducing or inhibiting the expression of c-kit kinase or c-kit and PDGFR s.
The terms “treat, treating” or “treatment,” as used herein, refers to methods of alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, ting the disease or condition, arresting the pment of the disease or ion, relieving the disease or condition, causing sion of the e or condition, relieving a condition caused by the disease or ion, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
In addition, as used , the term “treat , treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the e or at least one of the clinical symptoms thereof). In r embodiment “treat”, ing" or "treatment" refers to ating or ameliorating at least one physical ter including those which may not be discernible by the patient. In yet another embodiment, “treat”, "treating" or "treatment" refers to modulating the disease or er, either physically, (e.g., stabilization of a discernible symptom), logically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treat”, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
The nd names provided herein were obtained using ChemDraw Ultra 10.0 (CambridgeSoft®) or JChem version 5.3.1 (ChemAxon).
Unless specified otherwise, the term “compounds of the present invention” or “compounds provided herein” refers to compounds of Fomula (l) and Formula (II), and subformulae thereof (such as Formula (la), Formula (lla), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), Formula (If) and Formula (llf)), and pharmaceutically acceptable salts, hydrates or solvates, stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled nds (including deuterium substitutions) thereof. Compounds of the present invention further comprise polymorphs of nds of Fomula (l) and Formula (II) (or subformulae thereof) and salts thereof.
As used herein, the term "a,” "an,” "the” and similar terms used in the context of the present ion (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or ise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
Various enumerated embodiments of the invention are described herein. It will be ized that features specified in each ment may be combined with other specified features to provide further embodiments of the present invention.
Description of the Preferred Embodiments Provided herein are compounds, pharmaceutically acceptable salts, solvates, N- oxides and isomers thereof, that are inhibitors of c-kit kinase or c-kit and PDGFR kinases. Certain embodiments of compounds provided herein have an IC50 for PDGFR inhibition to leo for c-kit inhibition ratio (IC50 PDGFR/ICsQ C.kit) in the range of 750 to 1000.
Certain embodiments of compounds provided herein have an IC50 for PDGFR inhibition to IC50 for c-kit inhibition ratio (IC50 PDGFR/IC50 C.kit) in the range of 500 to 750. n embodiments of nds provided herein have an lC50 for PDGFR inhibition to lC50 for c-kit inhibition ratio (IC50 IC50 C.kit) in the range of 250 to 500. Certain embodiments of nds provided herein have an IC50 for PDGFR inhibition to IC50 for c-kit inhibition ratio (IC50 PDGFR/IC50 C.kit) in the range of 100 to 250. Certain embodiments of nds provided herein have an lC50 for PDGFR tion to lC50 for c-kit inhibition ratio (le0 PDGFR/IC50 C.kit) in the range of 75 to 100. Certain embodiments of compounds provided herein have an leo for PDGFR inhibition to leo for c-kit inhibition ratio (IC50 PDGFR/IC50 C. kit) in the range of 50 to 75. Certain embodiments of compounds provided herein have an leo for PDGFR inhibition to leo for c-kit inhibition ratio (IC50 PDGFR/IC50 CM) in the range of to 50. Certain embodiments of compounds provided herein have an lC50 for PDGFR inhibition to leo for c-kit inhibition ratio (IC50 IC50 C.kit) in the range of 10 to 25. n ments of compounds provided herein have an IC50 for PDGFR inhibition to IC50 for c-kit inhibition ratio (IC50 PDGFR/IC50 c-kit) in the range of 7.5 to 10. Certain embodiments of compounds provided herein have an lC50 for PDGFR inhibition to lC50 for c-kit inhibition ratio (IC50 PDGFR/IC50 c—kit) in the range of 5 to 7.5. Certain embodiments of compounds ed herein have an IC50 for PDGFR inhibition to IC50 for c-kit tion ratio (IC50 IC50 C.kit) in the range of 2.5 to 5. Certain embodiments of compounds provided herein have an leo for PDGFR inhibition to leo for c-kit inhibition ratio (IC50 PDGFR/IC50 Hit) in the range of 1 to 2.5. Certain embodiments of compounds provided herein have an lC50 for lC50 for PDGFR inhibition to c-kit inhibition ratio (le0 pDGFR/ICso C. kit) in the range of 0.95 to 2.5.
Also provided herein are pharmaceutical compositions that include such compounds.
Further provided herein are methods for the ent of diseases and/or disorders associated with c-kit kinase or c-kit and PDGFR kinases using such compounds and pharmaceutical compositions.
The c-kit kinase, or c-kit and PDGFR kinase, tors of the present invention are compounds having the structure of Formula (I) or Formula (II), and pharmaceutically able salts, pharmaceutically able solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof: L 0‘N 1 RIQL /N‘o \ HN / 1% R” N HN _ R11 N" O R2 2 \ N \ N O R (R20)m/\\_<\ fl (R20)m/\_<\ r Formula (|) Formula (II) wherein: m is 1 and R20 is selected from H, halo, lkyl, C1-C6haloalkyl, C1-C6haloalkoxy, deuterium, deuterated C1-C6alkyl, -CN, -(CR92)nOR4, -C(O)R4, - (CR92)nC(=O)OR4, R10, -(CR92)nR‘O, -((CR92)nO),R4, -(CR92)nO(CR92)nR7, - (CR92)nC(=O)R4, -C(=O)N(R4)2, -OFi4 and -(CR92)nCN; or m is 4 and R20 is deuterium; Fl1 is selected from C1-C6alkyl and halo; each Fl11 is independently selected from H, halo, and C1-C6alkyl; L1 is a bond, —NH- or -C(=O)NH-; L2 is -(CR92)n-, -CHR6-, -(CR92)nO-, -NH-, )nC(=O)-, O(CR92)n-, -(CR92)nOC(=O)NR4-, -(CFi92)nNFi“C(=O)(CFi92)n -, -(CR92)nNR4C(=O)- or -(CR92)nNR4C(=O)O- ; R2 is R3 or L2R3; R3 is selected from an unsubstituted C3-C8cycloalkyl, a cyclobutanone, a cyclopentanone and a substituted C3-C8cycloalkyl, wherein the substituted Cs-Cscycloalkyl of R2 is substituted with 1-4 substituents independently selected from lkyl, halo, C1-Cehaloalkyl, -OR4, -CN, OR4, -C(=O)R4, R7, -C(=O)OR5, -(CR92)nOR4, -O(CR92)nOR4, O(CR92)nOR4, -N(R4)2, =N-OR4, =N-O-(CR92)nR5, -C(=O)NR42, -NR4C(=O)OR4, -NR4C(=O)(CR92)nOR4, -NR4(CR92)nOR4, =O)2R4, -N(C(=O)OR4)2, =CH2, =CH(CR92)nOR4, R8, -(CR92)nR8, ated C1-Cealkoxy, -S(=O)2R4, -S(=O)2R7, -S(=O)2R8, -S(=O)2N(R4)2, 2NHC(=O)OR4, -S(=O)2(CR92)nC(=O)OR4, -S(=O)2(CR92)nOR4, a spiro attached dioxolane, a spiro attached dioxolane which is substituted with C1-Cealkyl, a spiro attached dioxane, a spiro attached tetrahyrofuranly, a spiro attached oxetane, a spiro attached utanone, a spiro attached cyclobutanol, a 0, alkyl bridge, an unsubstituted 5-6 ed heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S, a 5-6 membered cycloalkyl with 1-2 heteroatoms independently selected from N, O and S substituted with 1-3 tuents independently selected from C1-Cealkyl, halo, C1-Cshaloalkyl, C1-Cehaloalkoxy, -OFl4 and R8; each R4 is independently selected from H and C1-Cealkyl; R5 is an unsubstituted Cs-Cscycloalkyl an tituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N or O or a Cs-Cscycloalkyl substituted with 1-3 substituents independently selected from C1-Cealkyl; each Fl6 is independently selected from -NHC(O)OR4, -OFi4 and -(CR92)nOR4; each R7 is independently selected from C1-Cehaloalkyl; R8 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 ed cycloalkyl with 1-2 heteroatoms independently ed from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cscycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted ycloalkyl and substituted 4-6 ed heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, )2)nOR4, '(C(R9)2)nR51 -(C(R9)2)nC(O)OR4, -C(O)OR4 and -S(O)2R4; each R9 is independently selected from H and lkyl; R10 is ed from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, a substituted , a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered cycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, the substituted 5 membered aryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and tuted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 tuents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51'(C(R9)2)nC(O)OR4 and -S(O)2R4; tis 1,2or3, and each n is independently selected from 1, 2, 3 and 4.
In certain embodiments of compounds of Formula (I) or a (II), and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected tives, individual isomers and mixture of isomers thereof, the compound of Formula (I) or Formula (II) is a compound having a structure of Formula (la), Formula (Ila), Formula (lb) or Formula (llb) N N Formula (la) Formula (lla) R11 R11 R1QN R1 N 0 / \O fifi HN “N \IN N N" _ RHH _ R“ N o R2 R2 , (Wm/F4f, N o (Rm/LG f N N Formula (lb) Formula (llb) wherein: m is 1 and R20 is selected from H, halo, C1-Cealkyl, C1-Cehaloalkyl, C1-Cehaloalkoxy, deuterium, deuterated lkyl, -CN, -(CR92)nOR4, 4, -(CR92)nC(=O)OR4, R10, )nR‘O, '((CR92)nO)tR4I "(CR92)nO(CR92)nR7I -(CR92)nC(=O)R4, -C(=O)N(R4)2, -OFl4 and -(CR92)nCN; or m is 4 and R20 is deuterium; Fl1 is ed from C1-Cealkyl and halo; each Fl11 is independently selected from H, halo, and lkyl; L2 is -(CR92)n-, -CHR6-, -(CR92)nO-, -NH-, -(CR92)nC(=O)-, -C(=O)O(CR92)n-, -(CR92)nOC(=O)NR4-, -(CF192)nNFl“C(=O)(CF192)n -, -(CR92)nNR4C(=O)- or - (CR92)nNR4C(=O)O- ; R2 is R3 or L2R3; R3 is selected from an unsubstituted Cs-Cscycloalkyl, a utanone, a cyclopentanone and a substituted Cs-Cscycloalkyl, wherein the tuted Cs-Cscycloalkyl of R2 is substituted with 1-4 substituents independently selected from C1-Cealkyl, halo, C1-Cehaloalkyl, -OR4, -CN, -C(=O)OR4, -C(=O)R4, -C(=O)R7, -C(=O)OR5, -(CR92)nOR4, -O(CR92)nOR4, -C(=O)O(CR92)nOR4, -N(R4)2, =N-OR4, =N-O-(CR92)nR5, -C(=O)NR42, -NR4C(=O)OR4, -NR4C(=O)(CR92)nOR4, -NR4(CR92)nOR4, =O)2R4, -N(C(=O)OR4)2, =CH2, =CH(CR92)nOR4, R8, -(CR92)nR8, deuterated C1-Cealkoxy, -S(=O)2R4, -S(=O)2R7, -S(=O)2R8, -S(=O)2N(R4)2, -S(=O)2NHC(=O)OR4, 2(CR92)nC(=O)OR4, -S(=O)2(CR92)nOR4, a spiro attached dioxolane, a spiro attached dioxolane which is substituted with C1-Cealkyl, a spiro ed dioxane, a spiro attached tetrahyroiuranly, a spiro attached oxetane, a spiro attached cyclobutanone, a spiro attached cyclobutanol, a 0, alkyl bridge, an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S substituted with 1-3 substituents independently selected from C1-Cealkyl, halo, C1-Cshaloalkyl, C1-Cehaloalkoxy, -OFi4 and R8; each R4 is ndently selected from H and C1-Cealkyl; R5 is an unsubstituted Cs-Cscycloalkyl an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N or O or a Cs-Cscycloalkyl substituted with 1-3 substituents independently selected from C1-Cealkyl; each Fl6 is ndently selected from -NHC(O)OR4, -OFi4 and -(CR92)nOR4; each R7 is independently selected from C1-Cehaloalkyl; R8 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an tituted 4-6 membered cycloalkyl with 1-2 atoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a tuted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cscycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the tuted phenyl, the substituted 5-6 ed heteroaryl with 1-3 heteroatoms independently selected from N, O or S, the tuted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted ycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51 -(C(R9)2)nC(O)OR4, -C(O)OR4 and R4; each R9 is independently selected from H and C1-Cealkyl; R10 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 ed heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a tuted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, a tuted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a tuted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a idinone, wherein the tuted phenyl, the substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 ed heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51'(C(R9)2)nC(O)OR4 and -S(O)2R4; tis 1,2or3, and each n is independently selected from 1, 2, 3 and 4.
In certain embodiments of compounds of Formula (I) or Formula (II), and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide tives, protected derivatives, individual isomers and mixture of isomers thereof, the compound of Formula (I) or Formula (II), is a compound having a structure of a (la), Formula (Ila), Formula (lb), Formula (llb), Formula (lc), Formula (llc), Formula (ld), Formula (lld), Formula (le), Formula (lle), a (If) or Formula (Ill): R11 N (180)1an_ N O R2 Formula(|b) Formula (llb) R11 R” / O R20 R20 \ HN R1Q\<O\NHN Q? R“ N, _ R11 N—“lk o R2 \ N O R2 \ l N N a (lo) Formula (llc) R] I R11 R 1 R1 N\ o / O \N HN HN R” N_. _ R11 N4 R20<\ 2‘ fN O R2 R20-<\ Nfo R2 N N Formula (Id) Formula (lld) R1 N N / ‘0 HN H R1 1 N4 _N O R2 N Formula (le) Formula (lle) R11 R11 R1 R N O\ N / ‘O HNQNK H / R11 N’ N _ R11 \ N O R2 R20 N 0 R2 \ l \ \ N N Formula (If) Formula (llf) wherein: m is 1 and R20 is selected from H, halo, C1-Cealkyl, C1-Cehaloalkyl, C1-Cehaloalkoxy, deuterium, ated C1-Cealkyl, -CN, -(CR92)nOR4, -C(O)R4, -(CR92)nC(=O)OR4, R10, -(CR92)nR‘O, -((CR92)nO),R4, -(CR92)nO(CR92)nR7, -(CR92)nC(=O)R4, - C(=O)N(R4)2, -OFt4 and -(CR92)nCN; or m is 4 and R20 is deuterium; Fl1 is selected from C1-Cealkyl and halo; each Fl11 is independently selected from H, halo, and C1-Cealkyl; L2 is -(CR92)n-, , -(CR92)nO-, -NH-, -(CR92)nC(=O)-, -C(=O)O(CR92)n-, )nOC(=O)NR4-, -(CF192)nNFl“C(=O)(CF192)n -, -(CR92)nNR4C(=O)- or - (CR92)nNR4C(=O)O- ; R2 is R3 or L2R3; Ft3 is selected from an unsubstituted Cs-Cscycloalkyl, a cyclobutanone, a cyclopentanone and a substituted Cs-Cscycloalkyl, wherein the substituted Cs-Cscycloalkyl of R2 is substituted with 1-4 tuents independently selected from C1-Cealkyl, halo, aloalkyl, -OR4, -CN, -C(=O)OR4, -C(=O)R4, -C(=O)R7, -C(=O)OR5, -(CR92)nOR4, -O(CR92)nOR4, -C(=O)O(CR92)nOR4, 2, =N-OR4, =N-O-(CR92)nR5, -C(=O)NR42, -NR4C(=O)OR4, =O)(CR92)nOR4, -NR4(CR92)nOR4, -NR4S(=O)2R4, -N(C(=O)OR4)2, =CH2, =CH(CR92)nOR4, R8, -(CR92)nR8, deuterated C1-Cealkoxy, -S(=O)2R4, -S(=O)2R7, -S(=O)2R8, -S(=O)2N(R4)2, -S(=O)2NHC(=O)OR4, 2(CR92)nC(=O)OR4, -S(=O)2(CR92)nOR4, a spiro attached dioxolane, a spiro ed dioxolane which is substituted with C1-Cealkyl, a spiro attached dioxane, a spiro attached tetrahyrofuranly, a spiro ed oxetane, a spiro attached cyclobutanone, a spiro attached cyclobutanol, a 0, alkyl bridge, an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O 2012/052621 and S substituted with 1-3 substituents independently selected from C1-Cealkyl, halo, C1-Cshaloalkyl, C1-Cehaloalkoxy, -OFl4 and R8; each R4 is independently selected from H and C1-Cealkyl; R5 is an unsubstituted Cs-Cscycloalkyl an unsubstituted 5-6 membered cycloalkyl with 1-2 atoms independently selected from N or O or a CS-Cscycloalkyl substituted with 1-3 substituents independently selected from C1-Cealkyl; each Fl6 is independently selected from -NHC(O)OR4, -OFi4 and -(CR92)nOR4; each R7 is independently ed from C1-Cshaloalkyl; R8 is ed from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or 8, an tituted 5 membered aryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted Cs-Cscycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently ed from N, O or S, a substituted Cs-Cgcycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, the substituted 5 ed heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-Cealkyl, -(C(R9)2)nOR4, '(C(R9)2)nR51 -(C(R9)2)nC(O)OR4, -C(O)OR4 and -S(O)2R4; each R9 is ndently selected from H and C1-Cealkyl; R10 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or 8, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or 8, an tituted Cs-Cscycloalkyl, a tuted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 atoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 atoms independently selected from N, O or S, a substituted Cs-Cgcycloalkyl, a idinone, pyrrolidinone and a pyrrolidinone, n the substituted phenyl, the substituted 5-6 membered aryl with 1-2 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted Cs-Cscycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from lkyl, -(C(R9)2)nOR4, )2)nR51'(C(R9)2)nC(O)OR4 and -S(O)2R4; tis 1,2or3, and each n is independently selected from 1, 2, 3 and 4.
The compounds of Formula (I) or Formula (II), ceutically acceptable salts, es, N-oxides and isomers thereof, and pharmaceutical compositions provided herein also includes all le isotopic variations of such nds, and pharmaceutically acceptable salts, solvates, N-oxides and isomers thereof, and pharmaceutical compositions. Therefore, any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. lsotopically labeled nds have structures depicted by the formulas given herein except that one or more atoms are ed by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, , en, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 130, 14C, 15N, 18F 31P, 32P, 358, 36Cl, 125l respectively.
The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H and 14C, or those into which non-radioactive isotopes, such as 2H and 13C are present. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed aphy (SPECT) including drug or substrate tissue distribution , or in radioactive treatment of patients. In particular, an 18F or labeled nd may be particularly desirable for PET or SPECT studies. lsotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those d in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
Further, substitution with r isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for e increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a tuent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The WO 33070 term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the l nce of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium oration), or at least 6633.3 (99.5% deuterium incorporation).
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of llization may be isotopically substituted, e.g. D20, d6- acetone, de-DMSO.
Compounds of the invention, i.e. compounds of Formula (I) and Formula (II) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable stal formers. These stals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include ng, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in . Hence the invention further provides co-crystals comprising a compound of Formula (I) and Formula (II).
Processes for Making Compounds of Formula (I) or Formula (II) General procedures for preparing compounds of Formula (I) or Formula (II) are described in the Examples, infra. In the reactions bed, reactive functional groups, for example hydroxy, amino, imino, thio or carboxy , where these are desired in the final product, may be ted to avoid their unwanted participation in the reactions.
Conventional protecting groups may be used in accordance with standard practice (see e.g., T.W. Greene and P. G. M. Wuts in “Protective Groups in c Chemistry,” John Wiley and Sons, 1991 ).
In certain embodiments, the compounds of Formula (|) or a (II) provided herein are ed as a pharmaceutically acceptable acid addition salt by reacting the free base form of the nd of Formula (|) or Formula (II) with a stoichiometric amount of an appropriate pharmaceutically acceptable organic acid or inorganic acid or a suitable anion exchange reagent. In other embodiments, a pharmaceutically acceptable base addition salt of compounds of Formula (I) or Formula (II) is prepared by reacting the free acid form of the compound of a (I) or Formula (II) with a stoichiometric amount of an appropriate ceutically acceptable organic base or inorganic base or a suitable ion exchange reagent. Such reactions are typically carried out in water or in an organic solvent, or in a e of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. atively, the salt forms of the compounds of Formula (I) or Formula (II) are prepared using salts of the starting materials or intermediates. In certain embodiments, the compounds of Formula (I) or Formula (II) are in the form of other salts including, but not d to, oxalates and oroacetates. In certain embodiments, hemisalts of acids and bases are formed, for example, hemisulphate and hemicalcium salts.
Such pharmaceutically acceptable acid addition salts of compounds of Formula (I) or Formula (II) include, but are not limited to, a hydrobromide, hloride, sulfate, nitrate, succinate, maleate, formate, acetate, adipate, tye, bicarbonate/carbonate, propionate, te, citrate, te, e, benzoate, salicylate, glutamate, ate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, ethanedisulfonate, camphorsulfonate, chlortheophyllonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate), hexanoate salt, bisulphate/sulphate, borate, camsylate, cyclamate, ate, esylate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hippurate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, ionate, laurylsulphate, malate, malonate, mandelate, mesylate, methylsulphate, naphthoate, ate, naphthylate, 2—napsylate, nicotinate, octadecanoate, oleate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen ate, polygalacturonate, pyroglutamate, saccharate, stearate, sulfosalicylate, tannate, tosylate, trifluoroacetate and xinofoate salts.
The organic acid or inorganic acids used to form certain pharmaceutically acceptable acid addition salts of compounds of Formula (I) or Formula (II) include, but are not limited to, romic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, malonic acid, mandelic acid, formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, fumaric acid, citric acid, tartaric acid, lactic acid, benzoic acid, salicylic acid, glutamic acid, aspartic acid, toluenesulfonic acid, sulfosalicylic acid, benzenesulfonic acid, methanesulfonic acid, sulfonic acid, naphthalenesulfonic acid, such as 2—naphthalenesulfonic acid, or hexanoic acid.
Such pharmaceutically acceptable base on salt of compounds of Formula (I) or Formula (II) include, but are not limited to, ammonium, aluminium, arginine, benzathine, calcium, choline, , diethylamine, diolamine, glycine, isopropylamine, cholinate, diethanolamine, piperazine, iron, lysine, magnesium, meglumine, olamine, potassium, silver, sodium, tromethamine and zinc salts.
The organic or inorganic bases used to form certain pharmaceutically acceptable base addition salt of compounds of Formula (|) or Formula (II) include, but are not d to, salts derived from ammonium salts and metals from columns | to XII of the periodic table, or salts derived from primary, secondary, and tertiary amines, substituted amines including lly occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
In certain embodiments, the free acid or free base forms of the nds of Formula (I) or Formula (II) provided herein are prepared from the corresponding base addition salt or acid addition salt from, respectively. For example a compound Formula (|) in an acid addition salt form is ted to the corresponding free base by treating with a le base (by way of example only, an ammonium hydroxide solution, a sodium hydroxide, and the like). For example, a nd of a (|) in a base addition salt form is converted to the corresponding free acid by treating with a le acid (by way of example only, hydrochloric acid).
Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing y, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002.
In n embodiments, compounds of Formula (I) or Formula (II) in unoxidized form are prepared from N-oxides of compounds Formula (I) or Formula (II) by treating with a reducing agent (by way of example only, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (by way of example only, acetonitrile, ethanol, s dioxane, or the like) at 0 to 80°C.
In certain embodiments, compounds of Formula (|) or Formula (II) are prepared as protected derivatives using methods known to those of ordinary skill in the art. A detailed description of the techniques able to the creation of protecting groups and their removal can be found in T. W. Greene, cting Groups in Organic try,” 3rd edition, John Wiley and Sons, Inc, 1999.
In certain embodiments, compounds of Formula (|) or Formula (II) are prepared or formed, as solvates (e.g., hydrates). In n embodiments, hydrates of compounds of Formula (I) or Formula (II) are prepared by tallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
Furthermore, the compounds of the present ion, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular x of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water.
The nds of the t invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be t in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric , at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if le, be t in cis- (Z)- or trans- (E)- form.
Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the tuents, into the pure or ntially pure ric or optical isomers, reomers, racemates, for example, by chromatography and/or fractional llization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and ting the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl ic acid, di-0,0’-p-toluoyl tartaric acid, mandelic acid, malic acid or camphorsulfonic acid. Racemic products can also be resolved by chiral tography, e.g., high pressure liquid tography (HPLC) using a chiral ent.
In certain embodiments, compounds of Formula (I) or Formula (II) are prepared as their individual stereoisomers. In other embodiments, the compounds of Formula (I) or a (II) provided herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active ing agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In certain embodiments, tion of enantiomers is carried out using covalent diastereomeric derivatives of the compounds of Formula (I) or Formula (II), or by using dissociable complexes (e.g., crystalline diastereomeric .
Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, vity, etc.) and are readily separated by taking advantage of these dissimilarities. In certain embodiments, the diastereomers are separated by chromatography, or by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in zation. A more detailed description of the ques applicable to the resolution of stereoisomers of nds from their racemic e can be found in Jean Jacques, Andre Collet, Samuel H.
Wilen, “Enantiomers, Racemates and Resolutions,” John Wiley And Sons, Inc, 1981.
Mixtures of isomers obtainable according to the ion can be ted in a manner known to those skilled in the art into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic t mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and tes can be separated, for example, by the ion of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of onal crystallisation, or by chromatography over optically active column materials.
Depending on the choice of the starting materials and procedures, certain ments of the compounds of the present invention are present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant to include all such possible isomers, including racemic mixtures, riomeric mixtures and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or configuration.
All tautomeric forms are also intended to be included.
Compounds of Formula (I) or Formula (II) are made by processes described herein and as illustrated in the Examples.lntermediates and final products can be worked up WO 33070 and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like. The invention relates also to those forms of the s in which a compound obtainable as an ediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the t invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art.
Non-limiting examples of synthetic schemes used to make compounds of the invention are rated in reaction schemes (l)-(|V). The R1, R20, R11 and R2 groups as defined herein.
Scheme (|) illustrates the synthesis of compounds of Formula (I) by coupling the amine with the carboxylic acid in the presence of a base and a coupling reagent. By way of example only, the coupling reagent is HATU and the base is ropylethylamine.
Scheme (I) (\lio) 2 R11 N O), \ \i (R20)...
Scheme (ll) rates the synthesis of compounds of Formula (II) by coupling the amine with the carboxylic acid in the presence of a base and a ng reagent. By way of example only, the ng reagent is HATU and the base is diisopropylethylamine.
Scheme (II) R' R 1 1 N/VLOH R1 R11 ]: I WmN it] />’R2 .N t ,yR2 R11O‘N M20 \[7 (M20) Scheme (Ill) illustrates the synthesis of compounds of Formula (I) by formation of the zole from the corresponding N'-hydroxyformimidamide and carboxylic acid.
Scheme (III) WO 33070 R1 R11 R1 R11 o o o NCNjN NH2 | HOJLRZ “\NVR2 “N\OH CDI, NMP NCNyN N-o (R20)m (“11120) Scheme (IV) illustrates the synthesis of compounds of Formula (II) by ion of the oxadiazole from the corresponding N'-hydroxyformimidamide and carboxylic acid.
Scheme (IV) O R11 0M9ON‘<(\]NR10 R1 R“ NVLOH—>N 0 _. N5*N 0 RH 0M6 {\JH R“ OH R20)m (R2O)m R YNH22 HATU, DIEA Q)” R“ 0NW2 (R20)m The es provided herein are offered to illustrate, but not to limit, the compounds of Formula (I) or Formula (II) provided herein, and the preparation of such compounds.
Pharmacology and Utility n tyrosine kinases (PTK) play a central role in the tion of a wide variety of cellular processes and maintaining control over cellular on. Protein kinases catalyze and regulate the process of phosphorylation, whereby the kinases covalently attach phosphate groups to proteins or lipid targets in response to a variety of extracellular signals. Examples of such stimuli include hormones, neurotransmitters, growth and differentiation factors, cell cycle events, environmental stresses and nutritional stresses. An extracellular stimulus may affect one or more cellular responses related to cell , migration, differentiation, secretion of es, activation of transcription s, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, ogical and neurodegenerative es, cancer, cardiovascular diseases, respiratory diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases.
Examples of protein-tyrosine s e, but are not limited to, (a) tyrosine kinases such as lrk, lGFR-1,Zap-70, Bmx, Btk, CHK (Csk homologous kinase), CSK (C-terminal Src Kinase), ltk-1, Src (c-Src, Lyn, Fyn, Lck, Syk, Hck, Yes, Blk, Fgr and Frk), Tec, , Abl, EGFR (EGFR-f/ErbB-f, ErbB-2/NEU/HER-2, ErbB-3 and ErbB-4), FAK, FGF1 R (also FGFRf or FGR-f), FGF2R (also FGR-2), MET (also Met-l or , PDGFR (or and [3), Tie-1, Tie-2 (also Tek-1 or Tek), VEGFRf (also FLT-1), VEGFR2 (also KDR), FLT-3, FLT-4, c-KIT, JAKf, JAK2, JAK3, TYK2, LOK, RET, TRKA, PYK2, ALK (Anaplastic Lymphoma ), EPHA (1-8), EPHB (1-6), RON, Fes, Fer or EPHB4 (also EPHB4-1), and (b) and serine/threonine kinases such as Aurora, c-RAF, SGK, MAP kinases (e.g., MKK4, MKK6, etc.), SAPK2d, SAPK2B, Ark, ATM (1-3), CamK (1-lV), CamKK, Chk1 and 2 (Checkpoint kinases), CKI, CK2, Erk, lKK-l (also lKK-oc or CHUK), lKK-2 (also lKK-B), llk, Jnk (1-3), LimK (1 and 2), MLK3Raf (A, B, and C), CDK (1-10), PKC (including all PKC subtypes), Plk (1-3), NIK, Pak (1-3), PDKf, PKR, RhoK, RIP, RIP- 2, GSK3 (or and [3), PKA, P38, Erk (1-3), PKB (including all PKB subtypes) (also AKT-f, AKT-2, AKT-3 or AKT3-1), lRAKf, FRK, SGK, TAK1 and Tp1-2 (also COT).
Phosphorylation modulates or regulates a variety of cellular processes such as proliferation, growth, differentiation, metabolism, apoptosis, motility, transcription, translation and other signaling processes. Aberrant or excessive PTK activity has been observed in many e states including, but not limited to, benign and malignant proliferative disorders, diseases resulting from inappropriate activation of the immune system and diseases resulting from opriate activation of the s systems.
Specific diseases and e conditions include, but are not limited to, autoimmune disorders, allograft rejection, graft vs. host disease, diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, synovial pannus invasion in arthritis, multiple sis, myasthenia gravis, diabetes mellitus, diabetic angiopathy, retinopathy of prematurity, infantile hemangiomas, non-small cell lung, bladder and head and neck cancers, prostate cancer, breast cancer, ovarian cancer, gastric and pancreatic cancer, sis, fibrosis, rheumatoid tis, atherosclerosis, restenosis, mmune disease, allergy, respiratory diseases, asthma, lantation rejection, inflammation, thrombosis, retinal vessel eration, inflammatory bowel disease, Crohn's disease, ulcerative s, bone diseases, transplant or bone marrow transplant rejection, lupus, chronic pancreatitis, ia, septic shock, fibroproliferative and differentiative skin diseases or disorders, central nervous system diseases, neurodegenerative diseases, disorders or conditions related to nerve damage and axon degeneration subsequent to a brain or spinal cord injury, acute or chronic cancer, ocular diseases, viral infections, heart disease, lung or pulmonary diseases or kidney or renal es and bronchitis.
Tyrosine kinases can be broadly classified as receptor-type (having ellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular) protein tyrosine kinases. Tyrosine kinases er the terminal phosphate of ATP to tyrosine residues of proteins thereby activating or vating signal transduction ys. Inappropriate or uncontrolled activation of many of these kinase (aberrant protein tyrosine kinase activity), for example by over-expression or mutation, results in rolled cell growth. Many of the protein tyrosine kinases, whether a receptor or non-receptor tyrosine kinase have been found to be involved in ar signaling pathways involved in numerous pathogenic conditions, including, but not limited to, immunomodulation, mation, or proliferative disorders such as cancer. c—Kit Mast cells are tissue elements derived from a particular subset of hematopoietic stem cells that express CD34, c-kit and CD13 antigens. Mast cells are characterized by their heterogeneity, not only regarding tissue location and structure but also at the functional and histochemical levels. lmmature mast cell progenitors circulate in the bloodstream and differentiate into various s. These entiation and proliferation processes are under the influence of cytokines, one of ance being Stem Cell Factor (SCF), also termed c-Kit ligand, Steel factor or Mast Cell Growth Factor. The Stem Cell Factor receptor is encoded by the protooncogene, c-kit, which is expressed in hematopoietic progenitor cells, mast cells, germ cells, interstitial cells of Cajal (ICC), and some human tumors, and is also expressed by non hematopoietic cells.
Stem cell factor (SCF), also known as c-kit ligand, is the primary regulating factor for human mast cell growth and function. The SCF receptor, c-kit receptor, is a Type III transmembrane receptor n tyrosine kinase which initiates cell growth and proliferation signal transduction cascades in response to SCF binding. Ligation of c-kit receptor by SCF induces its dimerization ed by its transphorylation, leading to the recruitment and tion of various intracytoplasmic ates. These activated substrates induce multiple intracellular signaling pathways responsible for cell proliferation and activation. These proteins are known to be involved in many cellular mechanisms, which in case of disruption, lead to disorders such as abnormal cell proliferation and migration, as well as inflammation.
The relationship between mast cells, SCF and c-kit receptor is sed in the following references: Huang, E. et at, “The l’rernatopoletic growth factor KL is encoded by the Si icons and is the iigand oi the c—lrit receptor, the gene product of the W locus”, Cali, 63, 225~233, 1999; Zsebo, KM. et at, “Stem celi factor is encoded at the Si iocus of the mouse and is the ligand for the c-kit tyrosine kinase receptor", Cell, 99, 219—2241, 1990; Zheng, S. et at,“ Cytokine production by ceil cuitures irom bronchial subepitheiiai myoiibrohlasts”, J. Pathol., 189, 95—19, 1998; Zhang, S. et ai., “Human mast ceiis express stent ceii ", J. Pathol., 185, sense, 1998; Kassei, (It. et at, “Up and down— reguiatich by giucocorticoids of the constitutive expression of the mast cell growth factor stem ceii factor by human iung fibroblasts in culture”, Moi. Pharmacol., 54, 10734 079, 1998; Kasset, O. et ai., “Human bronchiai smccth muscie ceiis in culture produce Stem Ceii Factor", Eur. . 9., 18, , 1999; , O. et at, “The Stem Ceii Factor, Stem ceii factor, its Properties and Potentiai Roie in the Airways", ary Pharmacology a Therapeutics“, 14, 227---288, 2991; cie Paulie, A. et ai, “Stem celi factor is iocaiized in, reieased from, and cieaved by human mast ceiis”, J. immunot, 1153, 279942808, 1999; ivloi, CD. et ai., “Structure c1 a c—lrit product compiex reveais the basis for kinase transactiyatioh”, J. Biol. Chem, 2278, 3146141464, 2993; lemura, A. et at, “The chit iigand, stem celi factor, promotes mast cell survival by suppressing apoptosis”, Am, J. Patriot, 144, 3214328, 1994; Nilssoh, G. et at, “Stem celi factor is a chen'rotaotio factor for human mast celis”, J. lmnrunol., 153, 87’17—8728, 1992-1; Meininger, Cat. et al., “The c—kit receptor iigand functions as a mast ceit chemoattractant”, Blood, 79, 958w953, 1992, and i, 't'. et at, “Steet iaotor and o—kit reguiate natrix adhesion“, Blood, 83, 1933—1938, 1994.
The feliowing references discuss the it slgnaiing pathway and its relationship with various downstream ys and the chship with diseases associated with mast ceiis: Thomr’nes, 14. et ai., “identification of Tyr~793 and Tyr—936 as the primary association sites for 8th and Gris? in the chit/stem ceii factor receptor”, 81001119an J. 341, 211—219, 1999; lshlzuka, T. et ai., “Stern ceit ‘iactor augments Fc epsiion Ri— 2012/052621 mediated TN F-aipha tion and ates MAP kinases via a different pathway in MiG/'9 mast ceiis”, J. immunol, ‘iS‘i, 3624-8630, t998; Timokhina, E. et at, “Kit ing through Pi B—kirtase and Sn: kinase pathways: an essentiai roie for Raci and JNK activation in mast ceii proiiieration”, Eli/1530 J., 17, 6250~6262, 1998; Tang, B. et at, “Tet: kinase ates with c-kit and is tyrosine phosphcryiated and activated iciidwing stern ceii iactor binding”, Mol. Cell. Bibi, 14, 8432—8437, 1994, and Ueda, S. et at, ”Criticai roies oi c-Kit tyrosine residues 55? and 719 in stem ceii factor—induced chemotaxis: contribution of src iamiiy kirtase and PiS—kinase on caicium rnobiiization and ceii migration", Biooo', £39 3342~3349, 2002.
Mast cells are the primary effector cells in allergic mation. Mast cells are also ed in other pathogenic processes such as acute inflammation and is.Mast cells present in tissues of patients are implicated in or bute to the genesis of diseases such as autoimmune diseases ple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (|BD)), allergic es (allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and insect bite skin inflammation and bronchial asthma), tumor angiogenesis, germ cell tumors, mast cell tumors, gastrointestinal stromal tumors, small-cell lung cancer, melanoma, breast cancer, acute enous leukemia, astoma, neuroblastoma and mastocytosis, inflammatory diseases, es, type I diabetes, type II diabetes, irritable bowel syndrome (IBS), CNS disorders and interstitial cystitis. In these diseases, mast cells participate in the destruction of tissues by releasing a cocktail of different proteases and mediators rized into three groups: med granule-associated mediators (histamine, proteoglycans, and l proteases), lipid-derived mediators (prostaglandins, thromboxanes and leucotrienes), and various cytokines (IL-1, |L-2, |L-3, |L-4, |L-5, |L-6, |L-8, TNF-oc, GM-CSF, MIP-Loc, MIP-IB, MIP-2 and IFN- y). The liberation by activated mast cells of mediators (TN F-oc, histamine, rienes, prostaglandins etc.) as well as proteases may i) induce inflammation and vasodilatation and ii) participate in the tissue destruction process.
In addition, mast cell activation induces diverse effector responses, such as secretion of allergic mediators, proteases, chemokines such as MCP-f and RANTES, leukotrienes, prostaglandins and neurotrophins; and induction of ne gene transcription (IL-4, |L-5, |L-6, |L-13, TNF—oc and GM-CSF). These mediators contribute to creating the asthmatic phenotype by their effects on endothelial cells, smooth muscle cells and fibroblasts and on extracellular matrix, and by recruiting other inflammatory cells.
Asthma is characterized by airflow obstruction, bronchial hyper responsiveness and airway inflammation. Airway inflammation is the major factor in the development and perpetuation of asthma. ln allergic asthma, allergens are thought to initiate the inflammatory process by ng a T-lymphocyte mediated response (TH2) that results in the production of allergen-specific lgE. lgE binds to its high-affinity receptor FcaRl on pulmonary mast cells, triggering a type | (lgE-mediated) immediate allergic response.
Thus, mast cells play a role in asthma.
The activation of mast cells by different stimuli such as , trauma, ion and neurotransmitters, also participate in the exacerbation of the chemical imbalance causing CNS disorders. More specifically, mast cell ulation is stimulated by common neurotransmitters such as neurotensin, somatostatin, substance P and choline, by growth or survival factors, notably such as NGF. Mast cells involved in the response to such stimulus can be brain mast cells but also other mast cells releasing the content of their granules in the blood stream that ultimately reach sensory, motor or brain neurons.
Following mast cells activation, released granules liberate various factors capable of modulating and altering neurotransmission and neurons survival. Among such factors, serotonin is important since an increase of the level of free serotonin has been ed in depressed patients. Alternatively, the sudden burst of nin may be followed by a period of nin shortage, leading to pain and migraine. As a uence, it is believed that mast cells exacerbate in ine or paracrine manner the deregulation of neurotransmission. For example, anxiety or stress-induced release of ransmitters such as serotonin tes mast cells, which in turn release the content of their es, further contributing to the chemical imbalance in the brain leading to CNS disorders.
Other mediators released by mast cells can be categorized into vasoactive, ptive, proinflammatory and other neurotransmitters. Taken together, these factors are able to induce disturbance in the activity of neurons, whether they are sensory, motor, or CNS neurons. In addition, patients afflicted with ytosis are more inclined to develop CNS disorders than the normal population. This can be explained by the presence of activating mutations in the c-kit receptor, which induce degranulation of mast cells and a burst of factors contributing to chemical imbalance and neurotransmission alteration.
The activation of mast cells by different drugs, including, but not limited to, salicylic derivatives, morphine derivatives, opioids, heroin, amphetamines, alcohol, nicotine, analgesics, anesthetics, and anxyolitics results in the degranulation of mast cells, which participate in the bation of the chemical imbalance responsible for drug habituation and withdrawal syndrome. ing mast cells activation, released granules liberate various factors capable of modulating and altering neurotransmission. Among such factors is morphine which is bound or stored in mast cells granules. Tobacco smoke also induces the release of mediators from canine mast cells and modulates prostaglandin production g to asthma. In addition, patients afflicted with mastocytosis are more incline to develop substance use disorders than the normal population. This can be explained by the presence of ting mutations in the c-kit receptor, which induce degranulation of mast cells and a burst of factors contributing to chemical imbalance and neurotransmission alteration.
Mast cells have also been identified to be involved in or to contribute to drug dependence and withdrawal symptoms.
The relationship between mast cells, SCF and o-kit kinase in various diseases is discussed in the ing ierelernoes: Oliveira et al., “Stem Cell Factor: A Hemopoietic ne with Important Targets in Asthma”, Current Drug s, 2: 313-318, 2003; Puxeddu et al., “Mast cells in allergy and beyond”, The International Journal of Biochemistry & Cell y, 35: 1601 -1 607, 2003; Rottem et al., “Mast cells and munity”, Autoimmunity Reviews, 4: 21 -27, 2005; Woolley, D.E. et al., “The mast cell in inflammatory arthritis”, N. Engl. J. Med, 348:1709—1711, 2003; Benoist, C. et ai., “Mast cells in mune disease”, Nature, 420:875—878, 2002; Nigrovic, P.A. et at, “Mast cells in inflammatory arthritis”, Arthritis Res. Ther., 7:1—1 1, 2005; Wang, HW. et at, “lv'lasl oell accumulation and cytokine expression in the tight skin mouse model oi scleroderma”, Exp. Dorm-amt, 14, 295-002, 2005; , N. et al., “Demonstration oi mast cell shernotactio activity in oaiveolar lavage lluid collected from asthmatic patients before and during pollen season”, J. Allergy Clin. immortal, 105, 455451, 2000; Ma, Y. et at, inone derivatives inhibit tutively activated hill” s and kill neoplastic mast oells”, J. invest; Qerrnatol., 114-, 302—304, 2000; Kobayashi, Y. et al., “Mst Cells as a Target ol Rheumatoid Arthritis Treatment“, Jpn. J. Pharmacol., 7- ‘it, 2002, and AtMuhsen, 8.2. at at, “The expression at stem cell factor and o—klt receptor in human asthmatic airways”, Clin. Exp. Allergy, 34, 0114316, 2004. in addition, the treatment at asthma and arthritis with stration at a e-kit inhibitor is presented in the lollowing references: uohi et at, “S'l'l57t inhibits growth and adhesion at human mast cells in culture”, Journal oi Leukocyte Biology, 74: t020-‘i 034, 2003; Berlin at al., “Treatment of Cookroach Allergen Asthma Model with imatinib Attenuates Airway ses”, American Journal oi Respiratory and Critical oare Medicine, l7‘l: 35-39, 2005; Ekland et al., “Treatment of rheumatoid arthritis with imatinib mesylate: clinical ement in three refractory cases”, Annals of Medicine, 35: 362- 367, 2003; Miyachi et al., “Efficacy of imatinib mesylate (STI571) treatment for a patient with rheumatoid arthritis developing chronic myelogenous leukemia”, Clinical Rheumatology, 22: 329-332, 2003; Juurikivi et al., “Inhibition of c-kit tyrosine kinase by imatinib mesylate induces apoptosis in mast cells in rheumatoid synovial: a potential approach to the treatment of arthritis”, Ann. Rheum. Dis., 64: 1126-1131, 2005; Wolf, AWL, et al., “The kinase inhibitor imatinib mesyiate inhibits 'i'NF—aipha tion in vitro and prevents TNF—dependent acute hepatic inflammation”, Proc. Natl. Acad. Sci. Li. S. A. 1021362243627, 2005; Leath et al., “Novel and emerging therapies for ”, Drug Discovery Today, 10(23/24): 1647-1655, 2005; Berlin et al., ition of SCF attenuates peribronchial remodeling in chronic cockroach allergen-induced asthma”, Laboratory Investigations, 86: 557-565, 2006; Paniagua et al., “Selective tyrosine kinase tion by ib mesylate for the treatment of autoimmune arthritis”, The Journal of al Investigation, 116(10): 2633-2642, 2006; Wenzel et al., “Update in Asthma”, American Journal of Respiratory and Critical care Medicine, 173: 6, 2006; Chaudhary et al., “Pharmacological Differentiation of Inflammation and Fibrosis in the Bleomycin Model”, American Journal of Respiratory and Critical care Medicine, 173: 769-776, 2006, and Reber et al., “Review: Stem cell factor and its or c-Kit as targets for inflammatory diseases”, European Journal of cology, 533: 327-340, 2006.
The activity of the c-kit receptor is regulated in normal cells, and the normal functional ty of this c-kit gene product is important for the maintenance of normal hematopoeisis, melanogenesis, genetogensis, and growth and differentiation of mast cells. Inhibition of c-kit kinase activity reduces the growth and differentiation of mast cells and thereby mediates the diseases and/or conditions associated with mast cells, such as autoimmune diseases, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (IBD), respiratory diseases, allergic diseases, allergic rhinitis, allergic sinusitis, lactic syndrome, urticaria, angioedema, atopic dermatitis, ic contact itis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and insect bite skin inflammation, ial asthma, tumor angiogenesis, germ cell tumors, mast cell tumors, gastrointestinal stromal tumors, small-cell lung cancer, melanoma, breast cancer, acute myelogenous leukemia, glioblastoma, lastoma and mastocytosis, inflammatory diseases, diabetes, type I diabetes, type II diabetes, irritable bowel syndrome (IBS), CNS disorders and interstitial cystitis In addition to its ance in normal cellular physiologic activities, c-kit kinase plays a role in the biological aspects of certain human cancers, and unregulated c-kit kinase activity is implicated in the pathogenesis of human cancers, and in certain tumors types.
Proliferation of tumor cell growth mediated by c-kit can occur by a specific mutation of the c-kit polypeptide that results in ligand independent activation or by autocrine stimulation of the or. In the former case, ons that cause constitutive activation of c-kit kinase activity in the e of SCF binding are implicated in malignant human cancers, including germ cell tumors, mast cell tumors, gastrointestinal stromal , small-cell lung cancer, melanoma, breast cancer, acute myelogenous leukemia, glioblastoma, lastoma and mastocytosis.
A proliferation assay for the evaluation of the eftioacy oi o~i<it inhibitors and PDGFR inhibitors is given in Kuriu et at, “Proiiteration oi human myeioid ieukemia ceii tine associated with the tyrosinephosphoryiation and activation ot the photo-oncogene o-vkit product”, Biood, 78(11): 2834—2840 , 1991; Heinrich et al., “inhibition oi o—kit receptor ne kinase activity by STiST‘i, a seiective tyrosine kinase inhibitor”, Biood, 90(3): 925—932, 2000; Buohdunger et at, “Abi Pr‘otein~'t'yrosine Kinase inhibitor S'i'i57i inhibits in Vitro Signet Transduction Mediated by c~i<it and PtateietDerived Growth Factor Receptors", The Jourhai oi Pharmaooiogy and Experimentai Therapeutics, 2850 ): t39~ MS, 2000; and Srhotich et at, “The antiahgiogenic protein kinase inhibitors SU5410 and 81.30008 inhibit the SCF receptor (CD-kit) in a human myeioid ia ceii tine and in aoute myeioid ieukemia biasts”, Biood, 97(5): 1413-443 200i. This assay use MO7e cells, which are a human akaryocytic leukemia cell line that depend on SCF for eration. These reterenoes in combination with Berlin et al., Ekland et al., and Miyachi et al., (cited above) show that that a c-kit kinase inhibitor screened via this proliferation assay was later found to treat toid arthritis and asthma. in addition, a compound that was initiatiy ted for its eiticaoy as a chit inhibitor using a broiiteration assay based on Ba/‘FS. oeits and Ba/FB—derived ceiis (see WC) 2004.1’01903) was tater tound to be ive in the treatment ot mast ceit tumours and asthma (see Beiiamy F, et at, “ Pi’iarrnacokinetics oi masitinib in cats", Vet. Res, , June to (ebub) 2009; Hahn KA. et at, ”it/iastinib is sate and eiteotive tor treatment oi canine maot ceii tumours”, J. Vet. intern. Med, 22, t30t-1309, 2008 and Humbert M. et at, iviastinih, a o-kit/PDGF receptor tyrosine kinase inhibitor, improves disease controi in severe corticosteroid-dependent asthmatics”, 04, 11944201, 2009. c-kit receptor has a substantial homology to the PDGF receptor and to the CSF-f receptor (c-Fms).
Platelet-derived Growth Factor (PDGF) receptor family PDGF (Platelet-derived Growth Factor) is commonly occurring growth factor which plays an important role both in normal growth and in pathological cell proliferation. By way of e, such as that observed in carcinogenesis and in diseases of the smooth- muscle cells of blood vessels, for example in atherosclerosis and thrombosis. The PDGF growth factor family consists of PDGF-A, PDGF-B, PDGF-C and PDGF-D, which form either homo- or heterodimers (AA, AB, BB, CC, DD) that bind to the protein ne kinase receptors PDGFB-or and PDGFR-B. Dimerization of the growth s is a prerequisite for activation of the kinase, as the monomeric forms are inactive. The two receptor isoforms dimerize upon binding resulting in three le receptor combinations, ococ, PDGFB-BB and PDGFB—ocB. Growth factor AA binds only to - doc, growth factor BB can bind with -ococ, -[3[3 and -oc[3, growth factors CC and AB specifically interact with -ococ and -oc[3, and growth factor DD binds to -[3[3. The PDGF- receptor plays an important role in the maintenance, growth and development of hematopoietic and non-hematopoietic cells.
Key downstream mediators of PDGFB signaling are Bas/mitogen-activated protein kinase (MAPK), Pl-3 kinase and phospholipase-y (PLCy) pathways. MAPK family members regulate various biological functions by orylation of target les (transcription factors and other kinases) and thus contribute to regulation of cellular processes such as proliferation, differentiation, apoptosis and immunoresponses. Pl-3 kinase activation generated P|P3 which ons as a second messenger to activate downstream tyrosine kinases Btk and ltk, the Ser/Thr kinases PDKf and Akt (PKB). Akt activation is ed in survival, eration and cell growth. After activation PLC hydolyses its ate, Ptdlns(4,5)P2, and forms two secondary messengers, diacylglycerol and 4,5)P3 which stimulates intracellular processes such as proliferation, angiogenesis and cell motility.
PDGFB is expressed on early stem cells, mast cells, myeloid cells, mesenchymal cells and smooth muscle cells. Only PDGFB-B is implicated in myeloid leukemias- usually as a translocation partner with Tel, Huntingtin interacting n (HIP1) or Rabaptin5. Activation mutations in PDGFB-oc kinase domain are associated with gastrointestinal stromal tumors (GIST).
Certain embodiments of compounds of Formula (I) and Formula (II) provided herein inhibit PDGF receptor (PDGFBoc and PDGFRB) activity and c-kit kinase ty, and are useful for the ent of diseases, which respond to an inhibition of the PDGF receptor kinase. Therefore, certain compounds of Formula (I) and Formula (II) provided herein are useful for the treatment of tumor diseases, such as gliomas, sarcomas, prostate tumors, small cell lung cancer and tumors of the colon, breast, and ovary. In on certain embodiments of compounds of Formula (I) and Formula (II) provided herein are useful to treat disorders, such as thrombosis, psoriasis, scleroderma, fibrosis, asthma, lic diseases and hypereosinophilia. nds of Formula (I) and Formula (II) provided herein are also effective against diseases associated with vascular smooth-muscle cell migration and proliferation, such as restenosis and atherosclerosis.
Patients with obliterative bronchiolitis (OB), a chronic rejection of nic lung transplants, often show an elevated PDGF tration in bronchoalveolar lavage fluids. In certain embodiments, compounds of Formula (I) and Formula (II) provided herein exhibit useful effects in the treatment of disorders arising as a result of transplantation, for example, allogenic transplantation, ally tissue ion, such as obliterative bronchiolitis (OB).
In certain ments, compounds of a (I) and Formula (II) provided herein are useful for the protection of stem cells, for example to combat the hemotoxic effect of chemotherapeutic agents, such as rouracil.
The compounds of Formula (|) and Formula (II) provided herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, are inhibitors of c-kit kinase activity or are inhibitors of c-kit kinase activity and PDGFR (or and [3) kinase activity. In certain embodiments, the compounds of Formula (|) and Formula (II) provided herein, and the ceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and e of isomers thereof, are inhibitors of c-kit kinase activity and PDGFR (or and [3) kinase activity. In other embodiments, the nds of Formula (|) and Formula (II) provided herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide tives, protected tives, individual isomers and mixture of isomers thereof, are inhibitors of either c-kit kinase activity. Such compounds of Formula (I) and Formula (II) provided herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of s thereof, are useful for treating diseases or disorders in which c-kit kinase, or c-kit and PDGFR (or and/or [3) , contributes to the pathology and/or mology of a disease or disorder. Such diseases or disorders include, but are not limited to, a mast cell associated disease, inflammatory diseases, respiratory diseases, an allergy disorder, fibrosis diseases, metabolic diseases, autoimmune diseases, a CNS related er, a neurodegenerative disorder, neurological diseases, dermatoligical diseases, a versus-host disease, a pain condition, a neoplastic disorder, a cardiovascular disease and cancer.
Non-limiting examples of such diseases include asthma, allergic rhinitis, allergic sinusitis, bronchial , irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pulmonary arterial hypertension (PAH), thic arterial hypertension (IPAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, liver fibrosis, cardiac fibrosis, scleroderma, ria, dermatoses, atopic dermatitis, allergic contact dermatitis, diabetes, type I es, type II diabetes, rheumatoid arthritis, multiple scherosis, cytopenias (by way of example only, anemia, leucopenia, neutropenia, thrombocytopenia, granuloctopenia, pancytoia and idiopathic thrombocytopenic purpura), systemic lupus erythematosus, c obstructive pulmonary disease (COPD), adult respiratory distress me (ARDS), ulcerative colitis, Crohns disease, psoriasis, mas (by way of example only, B and T cell lymphomas), myelodysplasic syndrome, breast cancer, pancreatic cancer, papillary thyroid carcinoma, ovarian oma, human adenoid cystic carcinoma, non small cell lung cancer, ory breast carcinoma, congenital fibrosarcoma, ital mesoblastic ma, acute myelogenous leukemia, chronic myeloid leukemia metastasis, cancer-related pain, neuroblastoma, osteosarcoma, melanoma, bone metastases, a tumor of breast, renal, lung, prostate, pancreas, colon, ovary, thyroid, colorectal tumors, neuronal tumors, uterine tumors, gastrointestinal stromal tumors (GIST), gliomas, sarcomas, tumor enesis, germ cell tumors, mast cell tumors, glioblastoma, neuroblastoma, ytosis, osteoporosis, hypereosinophilia, restenosis, atherosclerosis, anaphylactic syndrome, angioedema, ma nodosum, erythema multiforme, cutaneous necrotizing venulitis, insect bite skin inflammation, CNS disorders and interstitial cystitis.
In certain embodiments, the compounds of a (|) and Formula (II) provided herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, are useful for treating diseases or disorders in which c-kit kinase contributes to the pathology and/or mology of a e or disorder. Non- limiting examples of such diseases include asthma, allergic rhinitis, allergic sinusitis, bronchial asthma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pulmonary arterial hypertension (PAH), pulmonary fibrosis, liver fibrosis, c fibrosis, scleroderma, urticaria, oses, atopic dermatitis, ic contact dermatitis, diabetes, type I diabetes, type II diabetes, toid arthritis, multiple scherosis, cytopenias (by way of example only, anemia, leucopenia, neutropenia, thrombocytopenia, granuloctopenia, pancytoia and idiopathic ocytopenic purpura), systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), ulcerative colitis, Crohns disease, psoriasis, lymphomas (by way of example only, B and T cell lymphomas), myelodysplasic syndrome, breast cancer, pancreatic cancer, papillary thyroid carcinoma, ovarian carcinoma, human adenoid cystic carcinoma, non small cell lung cancer, secretory breast carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, acute myelogenous leukemia, chronic myeloid leukemia metastasis, -related pain, neuroblastoma, osteosarcoma, melanoma, bone metastases, a tumor of breast, renal, lung, prostate, as, colon, ovary, thyroid, colorectal tumors, neuronal tumors, uterine tumors, gastrointestinal stromal tumors (GIST), gliomas, sarcomas, tumor angiogenesis, germ cell tumors, mast cell tumors, glioblastoma, neuroblastoma, ytosis, osteoporosis, hypereosinophilia, restenosis, sclerosis, lactic syndrome, angioedema, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis, insect bite skin inflammation, CNS disorders and interstitial cystitis.
In certain embodiments, the compounds of Formula (|) and Formula (II) provided herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide tives, protected derivatives, individual isomers and mixture of isomers thereof, are useful for treating es or disorders in which c-kit kinase and PDGFR (or and/or [3) kinase bute to the pathology and/or symptomology of a disease or er. Non-limiting es of such diseases e asthma, allergic rhinitis, allergic sinusitis, bronchial asthma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pulmonary arterial hypertension (PAH), pulmonary fibrosis, liver fibrosis, c fibrosis, scleroderma, urticaria, oses, atopic dermatitis, allergic contact dermatitis, es, type I diabetes, type II diabetes, rheumatoid arthritis, multiple scherosis, cytopenias (by way of example only, anemia, leucopenia, neutropenia, thrombocytopenia, granuloctopenia, pancytoia and idiopathic thrombocytopenic purpura), systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome , ulcerative colitis, Crohns e, psoriasis, lymphomas (by way of example only, B and T cell lymphomas), myelodysplasic syndrome, breast cancer, pancreatic cancer, papillary thyroid carcinoma, ovarian carcinoma, human adenoid cystic carcinoma, non small cell lung cancer, secretory breast carcinoma, congenital fibrosarcoma, congenital mesoblastic nephroma, acute myelogenous leukemia, chronic myeloid leukemia metastasis, -related pain, neuroblastoma, osteosarcoma, melanoma, bone metastases, a tumor of breast, renal, lung, prostate, pancreas, colon, ovary, thyroid, colorectal tumors, neuronal tumors, uterine tumors, gastrointestinal stromal tumors (GIST), gliomas, sarcomas, tumor angiogenesis, germ cell tumors, mast cell tumors, glioblastoma, neuroblastoma, ytosis, osteoporosis, hypereosinophilia, restenosis, atherosclerosis, anaphylactic syndrome, angioedema, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis, insect bite skin inflammation, CNS disorders and titial cystitis.
Another aspect provided herein includes methods for treating a cell-proliferative disease, sing administering to a system or subject in need of such treatment an effective amount of a compound of Formula (|) and a (II), or pharmaceutically acceptable salts or pharmaceutical compositions thereof; wherein the cell-proliferative disease is lymphoma, osteosarcoma, ma, or a tumor of breast, renal, prostate, colorectal, d, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.
In certain embodiments, the compounds of a (I) and Formula (II), pharmaceutically acceptable salts, solvates, N-oxides and isomers thereof, pharmaceutical compositions, and/or combinations provided herein are used in the treatment diseases and/or disorders including, but not limited to, asthma, bronchial asthma, allergic asthma, intrinsic , extrinsic asthma, exercise-induced asthma, drug-induced asthma ding aspirin and NSAlD-induced) and dust-induced asthma, chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic itis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, ing cryptogenic fibrosing alveolitis, idiopathic interstitial nias, fibrosis complicating anti-neoplastic therapy and chronic infection, ing tuberculosis and aspergillosis and other fungal ions; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; ssive activity including treatment of c cough ated with inflammatory and secretory conditions of the ainNays, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory ial virus, influenza, coronavirus (including SARS) and adenovirus.
In certain embodiments, the compounds of Formula (I) and Formula (II), ceutically acceptable salts, solvates, N-oxides and isomers thereof, pharmaceutical compositions, and/or combinations provided herein are used in the treatment of dermatological disorders including, but not limited to, psoriasis, atopic dermatitis, t dermatitis or other eczematous dermatoses, and delayed-type ensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, basal cell carcinoma, actinic keratosis, d lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, ria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian me, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous mas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions.
In certain embodiments, the nds of Formula (I) and Formula (II), pharmaceutically acceptable salts, solvates, N-oxides and isomers thereof, pharmaceutical compositions, and/or combinations provided herein are used in the ent of rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's ditis, Crohns disease, inflammatory bowel disease (IBD), Graves' disease, n's disease, diabetes mellitus, idiopathic WO 33070 thrombocytopaenic purpura, eosinophilic fasciitis, hyper-lgE syndrome, antiphospholipid syndrome and Sazary syndrome.
In certain embodiments, the compounds of Formula (I) and Formula (II), pharmaceutically acceptable salts, solvates, N-oxides and s f, and pharmaceutical compositions provided herein are used in the treatment of cancer including, but not limited to, prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative s, such as n's and non-Hodgkin's ma; including the prevention and treatment of atic disease and tumor recurrences, and paraneoplastic syndromes.
Provided herein are compounds of Formula (I) and Formula (II), pharmaceutically acceptable salts, pharmaceutically acceptable es (e.g. es), the N-oxide derivatives, protected tives, individual s and mixture of isomers thereof, and pharmaceutical compositions containing at least one compound of Formula (I) or Formula (II), or pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, dual isomers or mixture of isomers f, for use in activating c-kit kinase activity, or c-kit kinase and PDGFR (or and/or [3) kinase ty, and thereby are used to in the prevention or treatment of diseases and/or disorders associated with c-kit kinase activity, or c-kit kinase and PDGFR (or and/or [3) kinase activity.
Also provided herein are methods for the treatment of a subject suffering from a disease and/or disorder associated with c-kit kinase activity, wherein the method includes stering to the subject in need thereof, an effective amount of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers or mixture of s thereof, either alone or as part of a pharmaceutical composition as described herein.
Also provided herein are methods for the treatment of a subject suffering from a disease and/or disorder associated with c-kit kinase activity and PDGFR (or and/or [3) kinase activity, wherein the method includes administering to the subject in need thereof, an effective amount of a compound of Formula (I) or Formula (II), or ceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide tives, protected derivatives, individual isomers or mixture of isomers thereof, either alone or as part of a pharmaceutical composition as described herein.
Provided herein is the use of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, ted derivatives, individual isomers or mixture of isomers 2012/052621 thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with c-kit kinase activity. Also provided herein is the use of a nd of Formula (I) or Formula (II), or pharmaceutically able salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers or mixture of isomers thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with c-kit kinase activity and PDGFR (or and/or [3) kinase ty.
Furthermore, provided herein is the use of a compound having Formula (I) or Formula (II), or pharmaceutically acceptable salts or ceutical compositions thereof, and optionally in combination with a therapeutically effective amount of a second agent, in the manufacture of a medicament for treating a disease or condition modulated by kinase activity, particularly c-kit, or c-kit and PDGFR (or and [3).
In accordance with the foregoing, the present invention further provides a method for preventing or ng any of the diseases or disorders described above in a subject in need of such treatment, which method comprises stering to said subject a therapeutically effective amount of a nd of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. (See, “Administration and ceutical Compositions,” infra).
Administration and Pharmaceutical Compositions For the therapeutic uses of compounds of Formula (I) and Formula (II), or pharmaceutically able salts, solvates, N-oxides or isomers thereof, described herein, such compounds are administered in therapeutically effective amounts either alone or as part of a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions, which comprise at least one compound of Formula (I) or a (II), or ceutically able salts solvates, N-oxides or isomers thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In addition, such compounds and compositions are administered singly or in combination with one or more additional eutic agents. The method of administration of such compounds and itions include, but are not d to, oral administration, rectal administration, transdermal administration, parenteral, intravenous administration, intravitreal administration, intramuscular administration, pulmonary administration, inhalation administration, intranasal stration, topical administration, ophthalmic administration or otic administration. In certain embodiments the method of administration of such compounds and compositions is oral administration. In other 2012/052621 embodiments the method of stration of such compounds and compositions is pulmonary stration, inhalation administration or intranasal administration.
The therapeutically ive amount will vary depending on, among others, the disease indicated, the severity of the disease, the age and relative health of the subject, the potency of the compound administered, the mode of administration and the treatment desired. In certain embodiments, the daily dosage of a compound of Formula (I) and Formula (II), satisfactory results are indicated to be obtained ically at daily dosages of from about 0.03 to 2.5mg/kg per body weight. In certain embodiments, the daily dosage of a compound of Formula (I) and a (II), administered by inhalation, is in the range from 0.05 rams per kilogram body weight ) to 100 rams per kilogram body weight (pg/kg). In other embodiments, the daily dosage of a compound of Formula (I) and Formula (II), administered orally, is in the range from 0.01 rams per kilogram body weight (pg/kg) to 100 milligrams per kilogram body weight (mg/kg). An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about 100mg of a compound of Formula (I) and Formula (II), conveniently administered, e.g. in divided doses up to four times a day or in controlled release form. In certain ment, unit dosage forms for oral administration comprise from about 1 to 50 mg of a compound of Formula (I) and Formula (II).
Other aspects provided herein are processes for the preparation of pharmaceutical composition which comprise at least one nd of Formula (I) or Formula (II), or pharmaceutically acceptable salts, solvates, N-oxides or isomers thereof. In certain embodiments, such processes include admixing a compound of the Formula (I) or Formula (II), or pharmaceutically acceptable salts, es, N-oxides or isomers thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical compositions comprising a compound of Formula (I) or Formula (II) in free form, or in a pharmaceutically acceptable salt, solvate, N-oxide or isomeric form, in association with at least one pharmaceutically acceptable carrier, diluent or excipient are manufactured by , granulating and/or coating methods. In other embodiments, such compositionsoptionally contain excipients, such as preserving, stabilizing, g or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In other embodiments, such compositions are sterilized.
In certain embodiments, the pharmaceutical itions comprising at least one compound of Formula (I) or Formula (II) are adapted for oral administration for the treatment of diseases and/or disorders ated with c-kit kinase activity. In other embodiments, the pharmaceutical compositions comprising at least one compound of Formula (I) or Formula (II) are adapted for oral administration for the treatment of diseases and/or disorders associated with c-kit kinase and PDGFR (or and/or [3) kinase 2012/052621 activity.
In certain embodiments, the pharmaceutical compositions comprising at least one compound of Formula (I) or Formula (II) are adapted for inhalation adminitsation, including ary administration, inhalation administration or intranasal administration, for the treatment of diseases and/or disorders associated with c-kit kinase activity. In other embodiments, the pharmaceutical compositions comprising at least one compound of Formula (I) or Formula (II) are adapted for inhalation adminitsation, including pulmonary administration, inhalation administration or intranasal administration,for the treatment of diseases and/or disorders associated with c-kit kinase and PDGFR (or and/or [3) kinase activity.
In certain ments, the pharmaceutical compositions comprising at least one compound of Formula (I) or a (II) are adapted for tion adminitsation, including pulmonary administration, inhalation administration or intranasal administration, for the treatment of respiratory diseases with c-kit kinase activity. In certain embodiments, the respiratory disease is allergic rhinitis or asthma. In other embodiments, the pharmaceutical compositions comprising at least one compound of a (I) or Formula (II) are d for inhalation adminitsation, including pulmonary administration, tion administration or intranasal administration,ior the treatment of respiratory diseases associated with c-kit kinase and PDGFR (or and/or [3) kinase activity.
In certain embodiments, the respiratory disease is allergic rhinitis or asthma.
In n embodiments, the ceutical compositions comprising at least one compound of Formula (I) or Formula (II) are adapted for parenteral or intravenous administration, for the ent of diseases and/or disorders associated with c-kit kinase activity. In other embodiments, the pharmaceutical compositions comprising at least one compound of Formula (I) or Formula (II) are adapted for parenteral or intravenous administration,ior the treatment of diseases and/or disorders associated with c-kit kinase and PDGFR (or and/or [3) kinase activity.
Oral Dosage Forms In certain embodiments, the pharmaceutical compositions containing at least one compound of Formula (I) or Formula (II) are administered orally as te dosage forms, wherein such dosage forms include, but are not limited to, capsules, gelatin capsules, s, tablets, chewable tablets, powders, granules, syrups, flavored syrups, solutions or suspensions in s or non-aqueous liquids, edible foams or whips, and -water liquid emulsions or water-in-oil liquid emulsions.
The es, gelatin capsules, caplets, tablets, chewable tablets, powders or granules, used for the oral administration of at least one compound of Formula (I) and Formula (II) are prepared by admixing at least one compound of Formula (I) and Formula (II) e ingredient) together with at least one excipient using conventional pharmaceutical compounding techniques. miting examples of excipients used in oral dosage forms described herein include, but are not limited to, binders, fillers, disintegrants, lubricants, ents, nts, flavors, preservatives and sweeteners.
Non-limiting examples of such binders include, but are not d to, corn starch, potato starch, starch paste, pre-gelatinized starch, or other starches, sugars, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (by way of example only, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose and microcrystalline cellulose), magnesium aluminum silicate, polyvinyl pyrrolidone and combinations thereof.
Non-limiting examples of such fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), rystalline cellulose, powdered cellulose, dextrates, kaolin, ol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. In certain ments, the binder or filler in pharmaceutical compositions provided herein are present in from about 50 to about 99 weight t of the pharmaceutical composition or dosage form.
Non-limiting examples of such disintegrants include, but are not limited to, gar, alginic acid, sodium alginate, calcium carbonate, sodium carbonate, microcrystalline cellulose, croscarmellose sodium, vidone, polacrilin potassium, sodium starch glycolate, potato or tapioca , pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and combinations thereof. In certain embodiments, the amount of disintegrant used in the pharmaceutical compositions provided herein is from about 0.5 to about 15 weight percent of disintegrant, while in other embodiments the amount is from about 1 to about 5 weight percent of disintegrant.
Non-limiting examples of such lubricants include, but are not limited to, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other s, sodium lauryl sulfate, talc, hydrogenated vegetable oil (by way of e only, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, agar, silica, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated l of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.) and combinations f. In certain embodiments, the amount of ants used in the pharmaceutical compositions provided herein is in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms.
Non-limiting examples of such diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine or combinations thereof.
In certain embodiments, tablets and capsules are prepared by uniformly admixing at least one compound of Formula (I) or Formula (II) (active ingredients) with liquid carriers, finely divided solid rs, or both, and then shaping the product into the desired tation if necessary. In certain ments, tablets are ed by compression. In other embodiments, tablets are prepared by molding.
In certain embodiments, at least one compound of Formula (I) or Formula (II) is orally administered as a controlled release dosage form. Such dosage forms are used to provide slow or controlled-release of one or more compounds of Formula (I) or a (II). Controlled release is obtained using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer gs, microparticles, liposomes, microspheres, or a combination thereof. In certain embodiments, controlled-release dosage forms are used to extend activity of the nd of Formula (I) or Formula (II), reduce dosage frequency, and increase patient compliance.
Administration of compounds of Formula (I) or Formula (II) as oral fluids such as solution, syrups and s are prepared in unit dosage forms such that a given quantity of solution, syrups or elixirs ns a predetermined amount of a nd of a (I) or Formula (II). Syrups are prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions are ated by dispersing the compound in a non-toxic vehicle.
Non-limiting examples of excipients used in as oral fluids for oral administration include, but are not d to, solubilizers, emulsifiers, flavoring agents, preservatives, and coloring agents. Non-limiting examples of lizers and emulsifiers include, but are not d to, water, glycols, oils, alcohols, ethoxylated isostearyl alcohols and polyoxy ne sorbitol ethers. Non-limiting examples of preservatives include, but are not limited to, sodium benzoate. miting examples of flavoring agents include, but are not limited to, peppermint oil or natural ners or saccharin or other artificial sweeteners.
Parenteral Dosage Forms In certain embodiments pharmaceutical compositions containing at least one nd of Formula (I) or Formula (II) are administered parenterally by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial.
WO 33070 Such parenteral dosage forms are administered in the form of sterile or sterilizable injectable solutions, suspensions, dry and/or lized products ready to be ved or suspended in a ceutically able vehicle for injection (reconstitutable powders) and emulsions. Vehicles used in such dosage forms include, but are not limited to, Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and ed Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl l, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Transdermal Dosage Forms In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I) or Formula (II) are stered transdemally. Such transdermal dosage forms include "reservoir type" or "matrix type" patches, which are applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of a compound of a (I) or Formula (II). By way of example only, such transdermal devices are in the form of a bandage comprising a backing member, a oir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and ermined rate over a prolonged period of time, and means to secure the device to the skin. In other embodiments, matrix transdermal formulations are used.
Formulations for transdermal delivery of a compound of Formula (I) orFormula (ll) e an effective amount of a nd of Formula (I) or Formula (II), a carrier and an optional diluent. A carrier includes, but is not limited to, absorbable pharmacologically acceptable solvents to assist passage through the skin of the host, such as water, e, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.
In certain embodiments, such transdermal delivery systems include penetration enhancers to assist in delivering one or more compounds of Formula (I) or a (II) to the tissue. Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl ide; polyethylene glycol; pyrrolidones such as nylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or ble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
In other embodiments, the pH of such a transdermal pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, is adjusted to improve delivery of one or more nds of a (I) or Formula (II). In other embodiments, the polarity of a solvent carrier, its ionic strength, or tonicity are adjusted to improve delivery. In other embodiments, compounds such as stearates are added to advantageously alter the hydrophilicity or lipophilicity of one or more compounds of Formula (I) or a (II) so as to improve delivery. In n embodiments, such stearates serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a ry-enhancing or penetration-enhancing agent. In other embodiments, different salts, hydrates or solvates of the nds of Formula (I) or a (II) are used to further adjust the properties of the resulting composition.
In certain embodiments compounds of Formula (I) or Formula (II) are transderrmally delivered from a patch by iontophoresis.
Topical Dosage Forms In certain embodiments at least one compound of Formula (I) or Formula (II) is administered by topical application of pharmaceutical composition containing at least one compound of Formula (I) or Formula (II) in the form of lotions, gels, ointments solutions, emulsions, suspensions or creams. Suitable formulations for topical ation to the skin are aqueous solutions, ointments, creams or gels, while formulations for ophthalmic administration are aqueous solutions. Such formulations optionally contain solubilizers, stabilizers, tonicity enhancing , buffers and preservatives.
Such topical formulations include at least one carrier, and optionally at least one diluent. Such carriers and diluents include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.
In certain embodiments, such topical formulations include penetration enhancers to assist in delivering one or more compounds of Formula (I) or Formula (II) to the tissue.
Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and ydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as nylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and s water- soluble or insoluble sugar esters such as Tween 80 orbate 80) and Span 60 (sorbitan monostearate).
Inhalation Administration In certain embodiments pharmaceutical itions containing at least one compound of Formula (I) or Formula (II) are administered by inhalation. tion refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Dosage forms for inhaled stration are formulated as aerosols, dry powders, suspensions, or solution compositions. Dry powder compositions contain at least one compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt f as a finely d powder together with one or more pharmaceutically- acceptable excipients as finely d powders. Such pharmaceutically-acceptable excipients used in dry powders include, but are not limited to, lactose, starch, mannitol, and mono-, di-, and polysaccharides. In certain embodiments, the finely divided powder is prepared by micronisation and milling, wherein the size-reduced (micronised) nd is defined by a D50 value of about 1 to about 10 microns.
Aerosol formulations for inhalation administration comprise a solution or fine suspension of at least one compound of Formula (I) or Formula (II) in a pharmaceutically acceptable aqueous or non-aqueous solvent/propellant. Suitable propellants include halocarbons, hydrocarbons, and other ied gases. entative propellants include: trichlorofluoromethane (propellant 1 1 ), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane llant 1 14), tetrafluoroethane (H FA-134a), 1 ,1 - difluoroethane (H FA-1 52a), romethane (H FA-32), pentafluoroethane (H FA-12), luoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. In addition, such pharmaceutical compositions ally comprise a powder base such as lactose, glucose, trehalose, mannitol or , and optionally a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate. Aerosol also optionally contain additional pharmaceutically-acceptable excipients such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve solubility, or to improve taste.
The particle size of a micronized compound of Formula (I) or Formula (II) contained in an aerosol formulation is less than 100 s, while in other embodiments less than microns. In certain embodiments the particle size is in the range of from 1 to 10 microns, in other embodiments from 1 to 5 microns, while in still other ments from 2 to 3 microns.
Thus provided herein is a pharmaceutical aerosol formulation comprising at least one compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt f and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, ally in combination with a surfactant and/or a cosolvent. In certain embodiments, in such pharmaceutical aerosol formulation the propellant is ed from 1,1,1,2- tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.
In certain embodiments, suspensions and solutions sing at least one compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, formulated for inhalation administration are administered via a zer. The solvent or suspension agent utilized for nebulization is any pharmaceutically-acceptable liquid such as water, aqueous saline, ls or s, (by way of example only, ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene glycol or es thereof).
Saline solutions utilize salts which display little or no pharmacological activity after administration. Such salt include, but are not limited to, alkali metal or ammonium halogen salts or organic acids (by way of example only, ascorbic acid, citric acid, acetic acid and tartaric acid). Such suspensions optionally contain other pharmaceutically- able excipients provided herein.
In certain embodiments, compounds of Formula (I) or Formula (II) are administered ly to the lung by inhalation using a Metered Dose lnhaler ("MDI"), which utilizes canisters that contain a suitable low boiling propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other le gas, or a Dry Powder lnhaler (DPI) device which uses a burst of gas to create a cloud of dry powder inside a container, which is then be inhaled by the patient. In certain embodiments, capsules and cartridges of gelatin for use in an inhaler or insufflator are ated containing a powder mixture of a compound of Formula (I) or Formula (II) and a powder base such as lactose or starch. In certain embodiments, compounds of Formula (I) or Formula (II) are delivered to the lung using a liquid spray device, n such s use extremely small nozzle holes to aerosolize liquid drug formulations that can then be ly inhaled into the lung. In other embodiments, compounds of Formula (I) or Formula (II) are delivered to the lung using a nebulizer device, wherein a nebulizers creates an aerosols of liquid drug formulations by using ultrasonic energy to form fine particles that can be y inhaled. In other embodiments, compounds of Formula (I) or Formula (II) are delivered to the lung using an electrohydrodynamic ("EHD") aerosol device wherein such EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions.
In certain embodiments, the proportion of a (I) or Formula (II) or pharmaceutically acceptable salt thereof used in powders for inhalation or insufflation is within the range of from 0.1 to 10%. In other embodiments, the proportion of Formula (I) or Formula (II) or pharmaceutically able salt thereof used in powders for inhalation or insufflation is within the range of from 0.1 to 5%. In certain embodiments, l formulations contain from 20pg to 10mg of a compound of a (I) or Formula (II), while in other ments, aerosol formulations contain from 20pg to 2000pg of a compound of Formula (I) or Formula (II). In certain embodiments, aerosol formulations contain from 20pg to 500pg of a compound of Formula (I) or Formula (II). In certain embodiments, a compound of Formula (I) or Formula (II) is administered once daily by inhalation administration, while in other embodiments a compound of Formula (I) or Formula (II) is administered several times daily by inhalation stration, By way of example only, such le daily dosages occur 2, 3, 4 or 8 times daily, giving for example 1 2 or 3 doses each time.
In certain embodiments, the pharmaceutical composition containing at least one compound of a (I) or Formula (II), or pharmaceutically acceptable salts and solvates thereof, described herein, also contain one or more absorption enhancers. In certain embodiments, such absorption enhancers include, but are not limited to, sodium glycocholate, sodium caprate, N-IauryI-B-D-maltopyranoside, EDTA, and mixed micelles.
In certain embodiments pharmaceutical itions containing at least one compound of Formula (I) or a (II) are stered intranasally. The dosage forms for nasal administration are formulated as aerosols, solutions, drops, gels or dry powders. Aqueous formulations for administration to the lung or nose optionally include conventional exciplanfs as provided , such as buffering agents, tonicity modifying agents and the iike.
Rectal stration In certain embodiments ceutical compositions containing at least one compound of Formula (I) or Formula (II) are administered rectally in the form of suppositories, enemas, ointment, creams rectal foams or rectal gels. In certain embodiments such suppositories are prepared from fatty emulsions or suspensions, cocoa butter or other glycerides.
In certain embodiments ceutical compositions containing at least one compound of Formula (I) or Formula (II) are administered opthamically as eye drops.
Such formulations are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing , buffers and preservatives.
Otic Administration In n embodiments pharmaceutical compositions containing at least one compound of Formula (I) or Formula (II) are administered otically as ear drops. Such formulations are aqueous solutions that optionally contain solubilizers, izers, tonicity enhancing agents, buffers and preservatives.
Depot Administration In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I) or Formula (II) are formulated as a depot preparation. Such formulations are administered by implantation (for example subcutaneously or intram rly) or by intramuscular injection. In certain embodiments, such formulations include polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion ge resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
Combination Treatment In certain embodiments, a compound of Formula (I) or Formula (II) of the present invention, or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, or a pharmaceutical composition containing at least one nd of Formula (I) or Formula (II) provided herein, is administered alone (without an additional eutic agent) for the treatment of a disease or disorder associated with c-kit kinase activity.
In certain embodiments, a compound of Formula (I) or a (II) of the present invention, or a ceutically acceptable salts, pharmaceutically acceptable es (e.g. hydrates), the N-oxide tives, protected derivatives, individual isomers and mixture of isomers thereof, or a pharmaceutical composition containing at least one nd of Formula (I) or Formula (II) provided herein, is administered alone (without an onal therapeutic agent) for the treatment of a disease or disorder associated with c-kit kinase activity and PDGFR (or and/or [3) kinase activity.
In other ments, a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, or a pharmaceutical composition containing at least one compound of Formula (I) or Formula (II), is administered in ation with one or more additional therapeutic , for the treatment of a disease or disorder associated with c-kit kinase activity.
In other embodiments, a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, or a pharmaceutical composition containing at least one compound of Formula (I) or Formula (II), is administered in combination with one or more additional therapeutic agents, for the treatment of a disease or disorder associated with c-kit kinase ty and PDGFR (or and/or [3) kinase activity.
In other ments, a compound of Formula (I) or Formula (II), or a ceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of s thereof, or a ceutical composition containing at least one compound of Formula (I) or Formula (II), is formulated in combination with one or more additional eutic agents and administered for the treatment of a disease or disorder associated with c-kit kinase activity.
In other embodiments, a compound of Formula (I) or a (II), or a pharmaceutically acceptable salts, pharmaceutically able solvates (e.g. hydrates), the e derivatives, ted derivatives, individual isomers and mixture of isomers thereof, or a pharmaceutical composition containing at least one compound of Formula (I) or Formula (II), is formulated in combination with one or more additional therapeutic agents and administered for the treatment of a disease or disorder associated with c-kit kinase activity and PDGFR (or and/or [3) kinase activity.
In other embodiments, a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of s thereof, or a pharmaceutical composition containing at least one compound of Formula (I) or Formula (II), is administered sequentially with one or more additional therapeutic agents, for the treatment of a e or er associated with c-kit kinase activity.
In other embodiments, a compound of Formula (I) or Formula (II), or a ceutically able salts, pharmaceutically acceptable es (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, or a pharmaceutical composition containing at least one compound of Formula (I) or Formula (II), is administered tially with one or more additional therapeutic agents, for the treatment of a disease or disorder associated with c-kit kinase activity and PDGFR (or and/or [3) kinase ty.
In other embodiments, the combination treatments provided herein include administration of a compound of Formula (I) or a (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable es (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, or a ceutical composition containing at least one compound of Formula (I) or Formula (II), prior to administration of one or more onal therapeutic agents, for the treatment of a disease or disorder associated with c-kit kinase activity.
In other embodiments, the combination treatments provided herein include administration of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. es), the N-oxide derivatives, ted derivatives, individual isomers and mixture of isomers thereof, or a pharmaceutical composition containing at least one compound of Formula (I) or Formula (II), prior to administration of one or more additional therapeutic agents, for the treatment of a disease or disorder associated with c-kit kinase activity and PDGFR (or and/or [3) kinase activity.
In other embodiments, the combination treatments provided herein include administration of a compound of Formula (I) or Formula (II), or a pharmaceutically able salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, ted derivatives, dual isomers and mixture of isomers thereof, or a pharmaceutical ition containing at least one nd of Formula (I) or Formula (II) to administration of one or more additional therapeutic , for the , subsequent treatment of a disease or disorder associated with c-kit kinase activity.
In other embodiments, the combination treatments provided herein include administration of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. es), the N-oxide derivatives, ted derivatives, individual s and mixture of isomers thereof, or a ceutical composition containing at least one compound of Formula (I) or Formula (II), subsequent to administration of one or more additional therapeutic agents, for the treatment of a disease or disorder associated with c-kit kinase activity and PDGFR (or and/or [3) kinase activity.
In n embodiments, the combination treatments provided herein include administration of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, dual isomers and e of isomers thereof, or a pharmaceutical composition containing at least one compound of Formula (I) or Formula (II), concurrently with one or more additional therapeutic agents, for the treatment of a disease or disorder associated with c-kit kinase activity.
In certain embodiments, the combination treatments provided herein include administration of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, or a pharmaceutical composition containing at least one nd of Formula (I) or Formula (II), concurrently with one or more additional therapeutic agents, for the ent of a disease or er associated with c-kit kinase activity and PDGFR (or and/or [3) kinase activity.
In certain embodiments of the combination therapies described herein, the compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the e derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the additional therapeutics agent(s) act additively. In n embodiments of the combination therapies described , the compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. es), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the additional therapeutics s) act synergistically.
The additional therapeutic agents used in ation with at least one compound of Formula (I) or Formula (II) of the present invention, or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and e of isomers thereof, include, but are not limited to antiemetic agents, anti-inflammatory agents, immunomodulatory , cytokines, antidepressants, hormones, alkylating agents, antimetabolites, antitumour antibiotics, antimitotic agents, topoisomerase inhibitors, cytostatic agents, anti-invasion agents, antiangiogenic agents, inhibitors of growth factor function, anticancer agents and toll-like receptor modulators.
In some embodiments, the compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected tives, individual isomers and mixture of isomers f, are used in combination with a second therapeutic agent for treating asthma. In certain combinations, the second therapeutic agent is a bronchodilator, an anti- inflammatory agent, a leukotriene antagonist, or an lgE blocker.
The antiemetic agents used in combination with compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, ine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine, thioproperazine, tropisetron, and combinations thereof.
The anti-inflammatory agents used in combination with compounds of a (I) or Formula (II), or a ceutically able salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, dual isomers and mixture of isomers thereof, e, but are not limited to, non-steroidal anti- inflammatory drugs such as salicylic acid, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, alazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, cam, meloxicam, ampiroxicam, am, pivoxicam, tenoxicam, nabumetome, butazone, nbutazone, antipyrine, aminopyrine, apazone and nimesulide, leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin, steroids including, but not limited to, etasone diproprionate, amcinonide, ethasone dipropionate, betametasone, thasone benzoate, betamethasone diproprionate, betamethasone sodium WO 33070 phosphate, betamethasone valerate, clobetasol proprionate, clocortolone pivalate, hydrocortisone, hydrocortisone derivatives, desonide, desoximatasone, dexamethasone, flunisolide, flucoxinolide, flurandrenolide, halcinocide, medrysone, methylprednisolone, ednisolone acetate, methylprednisolone sodium succinate, mometasone furoate, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebuatate, prednisone, inolone, triamcinolone acetonide, triamcinolone diacetate, and triamcinolone hexacetonide and other anti-inflammatory agents including, but not limited to, methotrexate, cine, allopurinol, probenecid, thalidomide or a tive thereof, 5-aminosalicylic acid, retinoid, dithranol or calcipotriol, sulfinpyrazone and benzbromarone.
The immunomodulatory agents used in combination with compounds of a (|) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the e tives, protected derivatives, individual isomers and mixture of isomers thereof, include, but are not limited to, azathioprine, tacrolimus, cyclosporin methothrexate, leflunomide, corticosteroids, cyclophosphamide, cyclosporine A, porin G, mycophenolate mofetil, ascomycin, rapamycin (sirolim us), FK-506, bine, deoxyspergualin, brequinar, enolic acid, nitriloamindes (such as, by way of example only, leflunamide), T cell receptor modulators, and cytokine receptor modulators, peptide mimetics, and antibodies (such as, by way of example only, human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)2 fragments or epitope binding fragments), nucleic acid molecules (such as, by way of example only, nse nucleic acid molecules and triple helices), small molecules, organic compounds, and nic compounds. Examples of T cell or tors include, but are not limited to, anti-T cell receptor antibodies (such as, by way of example only, anti-CD4 dies (such as, by way of example only, cM- T412 (Boehringer), lDEC-CE9.1TM (IDEC and SKB), mAB 4162W94, Orthoclone and OKTcdr4a (Janssen-Cilag)), anti-CD3 antibodies (such as, by way of example only, Nuvion (Product Design Labs), OKT3 on & Johnson), or Rituxan (IDEC)), anti- CD5 antibodies (such as, by way of example only, an anti-CD5 ricin-linked immunoconjugate), anti-CD7 antibodies (such as, by way of example only, CH H-380 (Novartis)), anti-CD8 antibodies, anti-CD40 ligand monoclonal antibodies (such as, by way of example only, lDEC-131 (IDEC)), anti-CD52 antibodies (such as, by way of example only, CAMPATH 1H (llex)), anti-CD2 antibodies, anti-CD11a antibodies (such as, by way of example only, Xanelim (Genentech)), 7 antibodies (such as, by way of example only, lDEC-114 (IDEC)), CTLA4-immunoglobulin, and toll or-like (TLR) modulators. Examples of cytokine receptor modulators include, but are not limited to, soluble cytokine receptors (such as, by way of example only, the extracellular domain of WO 33070 a TNF-oc or or a fragment thereof, the extracellular domain of an lL-1[3 receptor or a fragment thereof, and the extracellular domain of an lL-6 receptor or a fragment thereof), cytokines or fragments thereof (such as, by way of example only, interleukin , lL-3, lL-4, lL-5, lL-6, lL-7, lL-8, lL-9, lL-10, lL-11, lL-12, lL-15, TNF-oc, interferon oc, lFN-[3, lFN-y, and GM-CSF), anti-cytokine receptor antibodies (such as, by way of example only, anti-lFN receptor antibodies, anti-lL-2 receptor antibodies (such as, by way of example only, Zenapax (Protein Design Labs)), anti-lL-4 receptor antibodies, anti- lL-6 receptor dies, anti-lL-10 receptor antibodies, and anti-lL-12 receptor antibodies), ytokine antibodies (such as, by way of example only, anti-lFN antibodies, anti-TN F-oc antibodies, anti-lL-1[3 antibodies, L-6 antibodies, anti-lL-8 antibodies (such as, by way of example only, ABX-lL-8 (Abgenix)), and anti-lL-12 antibodies).
The alkylating agents used in combination with nds of a (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, include, but are not limited to, nitrogen mustards, ethylenimines, melamines, alkyl sulfonates, nitrosoureas, carmustine, lomustine, triazenes, melphalan, mechlorethamine, cis-platin, oxaliplatin, latin, cyclophosphamide, ifosfamide, melphalan, chlorambucil, hexamethylmelaine, thiotepa, busulfan, tine, streptozocin, dacarbazine and temozolomide.
The antimetabolites used in combination with compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable es (e.g. es), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, include, but are not limited to, cytarabile, abine and antifolates such as, by way of example only, fluoropyrimidines (by way of example only, 5- fluorouracil and tegafur), raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea.
The antitumour otics used in ation with compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, ceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual s and mixture of isomers thereof, include, but are not limited to, anthracyclines, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mycin.
The antimitotic agents used in combination with compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, include, but are not limited to, vinca alkaloids (by 2012/052621 way of e only, vincristine, vinblastine, vindesine and vinorelbine), taxoids (by way of example only, taxol, paclitaxel and re) and polokinase inhibitors.
The topoisomerase inhibitors used in combination with compounds of Formula (I) or Formula (II), or a ceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, include, but are not d to, epipodophyllotoxins by way of example only, etoposide and teniposide, ine, topotecan, irinotecan and camptothecin.
In other ments, the ations described herein include combination of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically able solvates (e.g. es), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, with a leukotriene biosynthesis inhibitor, 5—lipoxygenase (5-LO) inhibitor or 5—lipoxygenase activating n (FLAP) antagonist such as; zileuton; ABT-761;fenleuton; tepoxalin; - 79175; Abbott-85761; a N-(5—substituted)-thiophenealkylsulfonamide; 2,6-di-tert- butylphenolhydrazones; a ytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2—cyanonaphthalene nd such as L- 739,010; a 2— cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAYx1005.
In other embodiments, the combinations described herein include combination of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, with a receptor antagonist for leukotrienes (LTB4, LTC4, LTD4, and LTE4) selected from the group consisting of the phenothiazinls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BllL 284/260; and compounds such as zafirlukast, ablukast, montelukast, SINGULAIRT'V', pranlukast, verlukast (MK-679), RG-12525, Flo-245913, iralukast (CGP 45715A), and BAYx7195.
In other embodiments, the combinations described herein include combination of a compound of Formula (I) or a (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the e derivatives, protected derivatives, individual isomers and mixture of isomers thereof, with a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including ylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor, including, but not limited to, cilomilast or ilast, an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
In other embodiments, the combinations described herein include combination of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. es), the N-oxide derivatives, protected tives, individual s and mixture of isomers thereof, with a histamine type 1 receptor antagonist such as cetirizine, |oratadine, des|oratadine, fexofenadine, acrivastine, terfenadine, astemizole, tine, |evocabastine, ch|orpheniramine, promethazine, cyclizine, or mizolastine.
In other embodiments, the combinations described herein include combination of a nd of Formula (I) or a (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, with a gastroprotective histamine type 2 receptor antagonist. In other embodiments, the combinations described herein include combination of a compound of Formula (I) and Formula (II), or a pharmaceutically acceptable salt or solvate thereof, described herein, with an antagonist of the histamine type 4 receptor.
In other embodiments, the combinations bed herein e combination of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, ted derivatives, individual isomers and mixture of isomers thereof, with an alpha-l/alpha-2 adrenoceptor agonist vasoconstrictor homimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, oline hydrochloride or ethylnorepinephrine hydrochloride.
In other ments, the combinations described herein include combination of a compound of Formula (I) or Formula (II), or a pharmaceutically able salts, pharmaceutically acceptable solvates (e.g. hydrates), the e derivatives, protected derivatives, individual isomers and mixture of isomers thereof, with a glucocorticoid, such as flunisolide, triamcinolone ide, beclomethasone dipropionate, budesonide, fluticasone propionate, onide or mometasone e.
In other embodiments, the combinations bed herein include combination of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof, with an immunoglobulin (lg), gamma globulin, lg preparation or an antagonist or antibody modulating lg function such as anti-lgE (omalizumab).
In other embodiments, the combinations described herein include combination of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, protected derivatives, individual isomers and e of isomers thereof, with a chemotherapeutic agent to treat a cell proliferative disorder, including but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or intestinal tumor. miting examples of chemotherapeutic agents used in such combinations are cyclines, alkylating agents (e.g., mitomycin C), alkyl sulfonates, aziridines, nimines, methylmelamines, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, folic acid analogs (e.g., dihydrofolate reductase inhibitors such as methotrexate), purine s, pyrimidine analogs, s, podophyllotoxins, platinum-containing agents, interferons, and interleukins. Other non-limiting examples of chemotherapeutic agents used in such combinations are busulfan, improsulfan, piposulfan, epa, carboquone, meturedepa, uredepa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlornaphazine, hosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, aclacinomycins, actinomycin F(1), anthramycin, azaserine, bleomycin, cactinomycin, carubicin, carzinophilin, chromomycin, omycin, ubicin, ycin, 6- diazooxonorleucine, bicin, epirubicin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, ur, cytarabine, dideoxyuridine, doxifluridine, abine, floxuridine, fluorouracil, tegafur, L-asparaginase, pulmozyme, aceglatone, aldophosphamide glycoside, aminolevulinic acid, amsacrine, bestrabucil, bisantrene, carboplatin, cisplatin, defofamide, demecolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, etoposide, flutamide, gallium nitrate, hydroxyurea, eron-alpha, interferon-beta, interferon-gamma, interleukin-2, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, bicin, podophyllinic acid, 2—ethylhydrazide, procarbazine, razoxane, sizofiran, spirogermanium, paclitaxel, tamoxifen, teniposide, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, urethane, vinblastine, vincristine, and vindesine.
In certain embodiments, the combination ents provided herein include administration of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salts, ceutically acceptable solvates (e.g. es), the N-oxide tives, protected derivatives, individual isomers and mixture of isomers thereof, or a pharmaceutical composition containing a compound of Formula (I) and Formula (II) in combination with one or more additional therapeutic agents, for the treatment of Pulmonary Arterial Hypertension (PAH). Such additional therapeutic agents include phosphodiesterase-5 inhibitors, prostanoids, elin receptor antagonists, calcium channel blockers, oxygen therapy, iloprost, sildenafil, tadalifil, digoxin, furosemide, spironolactone, warfarin, epoprostenol, treprostinil, bosentan and ambrisentan.
Examples The following examples are offered to illustrate, but not to limit, the nds of Formula (I) or Formula (II) of the present invention, and the preparation of such compounds. 8 nthesis of intermediates S nthesis of 3- imidazo 1 2-a ridinecarboxamido meth lbenzoic acid 4 O 0 1. oxalyl chloride NVLOH + H2N /0 fl. Nyfi /O \ N N ome 0M6 2. 2, TEA \ / 1 2 CHZCI2 O\ 3 LiOH THF:MeOH:H20 Ngim To a sion of o[1,2-a]pyridinecarboxylic acid (1) (4.09 g, 25.3 mmol) in dichloromethane (100 mL) and DMF (0.25 mL) at 0 °C was added oxalyl chloride (4.15 mL, 48.0 mmol) dropwise over 10 minutes. The reaction was slowly warmed to room temperature and stirred until complete conversion was detected by LCMS. The reaction was subsequently reduced to dryness and suspended in dichloromethane (100 mL) and was added a solution of methyl 3-aminomethylbenzoate (2) (4.6 g, 27.9 mmol) in romethane (100 mL) and triethylamine (7.1 mL). Contents were stirred at room temperature for 4 hours and diluted with dichloromethane (100 mL). The reaction was washed with water, saturated , brine, dried over magnesium sulfate, ed and d to dryness. The crude solid was triturated with diethyl ether to remove excess aniline and dried to afford methyl 3-(imidazo[1,2-a]pyridinecarboxamido) methylbenzoate (3) as a white solid. MS m/z 310.1 (M+1)+.
To a sion of dazo[1,2-a]pyridinecarboxamido)methylbenzoate (3) (5.43 g, 17.6 mmol) in THF (225 ml) and MeOH (150 mL) was added LiOH 3 M (17.5 mL) and water (50 mL). The reaction was d at room temperature for 12 hours then reduced in volume on roto-vap to remove THF and MeOH. The mixture was diluted with 2012/052621 water (75 mL) and neutralized with HCI (17.5 mL of a 3M solution). The resulting itate was filtered, washed with water and dried under vacuum to afford 3- zo[1,2-a]pyridinecarboxamido)methylbenzoic acid (4) as a white solid. 1H NMR (400MHz, de-DMSO) 6 10.0 (s, 1H), 9.45 (dt, J: 6812 Hz, 1H), 8.58 (s, 1H), 7.98 (d, J: 2.0 Hz, 1H), 7.79 (dt, J= 9.2,1.2 Hz, 1H), 7.76 (dd, J: 8.0,1.6 Hz,1H), 7.52 (ddd, J: 9.2,9.2,1.2 Hz, 1H), 7.43 (d, J: 8.0 Hz, 1H), 7.17 (td, J: 6.8,1.2 Hz, 1H), 2.35 (s, 3H). MS m/z296.1 (M+1)+.
S nthesis of N- 5- N'-h drox imido l meth l hen l imidazo1 2-a ridine carboxamide (9) O 0m 1. oxalyl chloride + DCM \ N\/§/U\OH H N \ a 2 “WAN \\ \N H N 2. 7, Pr2NEt \ / 1 7 \ / DCE E) 0 °C to 60 0C NH20H, EfOH, 0 00 to 5o 00 To a suspension of imidazo[1,2-a]pyridinecarboxylic acidC>(1) (16.6 g, 102 mmol) in dichloromethane (300 mL) and DMF (0.5 mL) at 0 °C was added oxalyl chloride (45 mL, 510 mmol) dropwise over 10 minutes. The reaction was slowly warmed to room temperature and stirred until complete conversion was detected by LCMS in MeOH. The reaction was subsequently reduced to dryness and suspended in roethane (100 mL) and was added to a on of 3-aminomethylbenzonitrile (7) (15 g, 113 mmol) in roethane (200 mL) and Pr2NEt (55 mL) at 0 0C. After the addition, the cold bath was removed and contents were stirred at room temperature for 1 hour and then heated to 50 °C for another 2 hours. After the completion of the reaction, the mixture was cooled and a white precipitate . The mixture was filtered and the solid was washed with cold dichloromethane. About 10 g of the desired N-(5-cyano methylphenyl)imidazo[1,2-a]pyridinecarboxamide (8) was obtained. The filtrate was washed with saturated NH4CI, saturated NaHCOs, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude solid was triturated with diethyl ether to remove excess aniline and filtered to afford another crop of N-(5-cyano methylphenyl)imidazo[1,2-a]pyridinecarboxamide (8) as a white solid. MS m/z 277.1 (M+1).
To a stirred and cooled (0 oC) suspension of N-(5-cyanomethylphenyl)imidazo[1,2- a]pyridinecarboxamide (8) (10 g, 36.2 mmol) in EtOH (225 ml) was added NHZOH (6 mL, 50% in water solution). After the addition, the reaction was d at room temperature for 2 hours then heated at 50 °C for another 2 hours. After cooling to room temperature, the mixture was stored in the fridge overnight. The resulting precipitate was filtered, washed with cold EtOH and dried under vacuum to afford N-(5-(N'- hydroxycarbamimidoyl)methylphenyl)imidazo[1,2-a]pyridinecarboxamide (9) as a white solid. 1H NMR (400MHz, O) 6 9.40 (dt, J: 6.8,1.2 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J: 2.0 Hz, 1H), 7.79 (dt, J= 9.2,1.2 Hz, 1H), 7.76 (dd, J: 8.0,1.6 Hz,1H), 7.52 (ddd, J: 9.2,9.2,1.2 Hz, 1H), 7.43 (d, J: 8.0 Hz, 1H), 7.17 (td, J: 6.8,1.2 Hz, 1H), 2.49 (s, 3H). MS m/z310.1 (M+1)+.
S nthesis of N- 2-meth I5 5- 3-oxoc clobut l -1 2 4-oxadiazol l hen l imidazof 2- carboxamide 10 HATU Pr2NEf % \ 0m N \ 0mN DMF 110°C N / .
Q N\ \ / 9 10 HATU (1.41 g, 3.72 mmol) was added in one portion to a stirred solution of 3- oxocyclobutanecarboxylic acid (0.405 g, 3.55 mmol) and Pr2NEt (0.62 mL, 3.7 mmol) in dry DMF (5 mL). After 10 minutes, N-(5-(N'-hydroxycarbamimidoyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (9) (1.0 g, 3.23 mmol) was added in one n and continued to stir for another 30 minutes. The resulting on was heated (110 0C) for 30 minutes and then cooled to room temperature. The solvent was evaporated and the residue was partitioned with ted NH4C| and EtOAc. The organic layer was dried with MgSO4 and filtered. The residue was purified on silica gel using 10% MeOH in dichloromethane to obtain N-(2-methyl(5-(3-oxocyclobutyl)-1,2,4- oxadiazolyl)phenyl)imidazo[1,2-a]pyridinecarboxamide (10). 1H NMR (400MHz, d6- DMSO) 610.20 (s, 1 H), 9.53—9.51 (m, 1 H), 8.71 (s,1 H), 8.08 (d, J=1.6 Hz,1 H), 7.91 — 7.88 (m, 1 H), 7.85 (dd, J: 2.0, 8.0 Hz,1 H), 7.72 — 7.68 (m, 1 H), 7.51 (d, J: 8.4 Hz,1 H), 7.34 — 7.30 (m, 1 H), 4.12 — 4.04 (m, 1 H), 3.70 — 3.53 (m, 4 H), 2.37 (s, 3 H).
MS m/z388.1 (M+1)+.
S nthesis of N- 5- 5- 1s 3s h drox c clobut l -1 2 4-oxadiazol l methylphenyl)imidazo|1,2-a|pyridinecarboxamide (19) 2012/052621 Nij@110 L-selectride éN‘o N/\ N/\ THF -78 °C 19 0 OH L-selectride (1.7 mL, 1 M in THF, 1.7 mmol) was added dropwise to a stirred solution of N-(2-methyl(5-(3-oxocyclobutyl)-1,2,4-oxadiazolyl)phenyl)imidazo[1,2-a]pyridine- 3-carboxamide (10) (0.5 g, 1.29 mmol) in THF at -78 0C. After 30 minutes, the reaction was warmed to 0 °C and quenched with 1N NaOH. The mixture was partitioned with EtOAc and brine. The organic phase was dried over MgSO4 and purified over silica gel using 10% MeOH in dichloromethane to give N-(5-(5-((1s,3s)hydroxycyclobutyl)-1,2,4- oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridinecarboxamide (19) as a white solid. 1H NMR (400MHz, d4-MeOH) 610.03 (s, 1H), 9.47 — 9.45 (m, 1H), 8.59 (s, 1H), 8.08 (s, 1 H), 7.83 — 7.78 (m, 2H), 7.52 — 7.48 (m, 2H), 7.20 — 7.16 (m, 1 H), 5.41 (d, J = 8 Hz, 1 H), 4.18 — 4.10 (m, 1 H), 2.73 — 2.68 (m, 2H), 2.37 (s, 3H), 2.27 — 2.20 (m, 2H). MS m/z 390.1 .
S nthesis of 7- trifluorometh l imidazo 1 2-a carbox lic acid 24 $03\ F3C F30 / /N / LiOH O\CF3 Cl \ N’/ 22 \ Nfl Ethyl 2-chloroacetate (20 mL, 187 mmol) and ethyl formate (15.1 mL, 187 mmol) were added simultaneously to a stirred and cooled suspension of potassium tert- butoxide (21.4 g, 188 mmol) in dry diisopropylether (300 mL). After the addition, the reaction was warmed to room temperature and stirred overnight. The yellow suspension was filtered and the solid potassium 2-chloroethoxyoxopropenolate (22) was vacuum dried and used directly in the following step.
To a stirring sion of 4-(trifluoromethyl)pyridinamine (128 mg, 0.791 mmol) and potassium 2-chloroethoxyoxoprop—1-enolate (22) (500 mg, 2.64 mmol) in EtOH (5 mL) at room temperature was added sulfuric acid (70 uL, 1.32 mmol) dropwise.
The reaction mixture was stirred at room temperature overnight then heated at 78 °C for 3 hours. The reaction was cooled to room temperature and the solvent was concentrated. The residue was taken in water and the pH was adjusted between 6-8 with WO 33070 saturated sodium bicarbonate. The crude product was extracted with ethyl acetate. The organic was washed with brine and dried over anhydrous sodium sulfate. The crude product 7-(trifluoromethyl)imidazo[1,2-a]pyridinecarboxylate (23) was purified by silica chromatography. MS m/z 259.3 (M+1)+.
To a stirring on of ethyl 7-(trifluoromethyl)imidazo[1,2-a]pyridinecarboxylate (23) (100 mg, 0.387 mmol) in THF:MeOH(4:1, 1.5 mL) was added 2N LiOH (0.25 mL).
The reaction was heated at 60 °C for 1 hour. Then, cooled to room ature and the pH was adjusted between 4-5 with 1N HCI. The solvent was partially concentrated and the resulting aqueous layer was lyophilized to give fluoromethyl)imidazo[1,2- a]pyridinecarboxylic acid (24). 1H NMR (400MHz, de-DMSO) 6 9.44 (d, J = 7.2 Hz, 1 H), 8.40 (s,1 H), 8.31 — 8.30 (m, 1 H), 7.48 (dd, J=2.0, 7.6 Hz,1 H). MS m/z231.2 (M+1) f.
The following compounds were prepared according to the protocol described for 7- (trifluoromethyl)imidazo[1,2-a]pyridinecarboxylic acid (24).
Intermediate Stwe uret Physucal Data' number OH 1H NMR (400MHz, ds-DMSO)69.64—9.62 24a F30 / 11% (m,1 H), 8.39 (s,1 H), 8.01 (d, J=9.2 Hz,1 \\ H), 7.81 (dd, J=2.0, 9.2 Hz,1 H). MS m/z N 231.2 (M+1)+. 24b F / 11% MS .2(M+1)+.
\ \N / /N \ N / 240 fi MS m/z181.2 (M+1)+. 240' \ Ni MS m/z188.1 (M+1)+.
Ms m/z188.1 (M+1)+.
MS m/z241.0 (M+1)+.
/ /N \ Nfi/ MS m/z270.0 (M+1)+.
/O OH 400MHz, de-DMSO)68.94(d, J: / 2.0 Hz, 1H), 8.13 (s,1 N H), 7.70 (d, J:9.6 Hz, \ \\ 1 H),7.31 (dd, J:2.8, 9.8 Hz,1 H),3.85 (s, N 3H). MS m/z193.1 (M+1)+.
/ :N \ N / MS m/z177.6 (M+1)+.
/ /N \ N / MS m/z177.6 (M+1)+.
/ /N \ N\§\ MS m/z209.06 (M+1)+. 1H NMR (400MHz, de-DMSO) 5 9.21 (s, 1 H), 8.22 (s,1 H), 7.76 (d, J: 9.2 Hz, 1 H), 7.50 (dd, J: 1.6, 9.2 Hz, 1 H), 3.72 — 3.69 (m, 4 H), 3.40 — 3.28 (m, 2 H), 2.99 — 2.92 (m, 4 H), 2.88—2.82 m, 2 H . MS m/z 276.13 M+1 +.
NAFN 1H NMR (400MHz, ds-DMSO) 5 9.29 (d, J: 24m gwfi 1.6 Hz, 1 H), 9.15 (dd, J: 1.6, 4.4 Hz, 1 H), OH 8.4 (3,1 H), 8.20 (d, J: 4.4 Hz, 1 H). MS m/z 164.1 (M+1)+. 24" DQD MS .0 (M+1)+.
D D / N 1H NMR (400MHz, ds-DMSO) 5 8.79 (s, 1 H), 24o 8.49 (3,1 H), 7.84 (m, 2 H), 3.80 (m, 4 H), 3.16 (m, 4 H). MS m/z248.1 (M+1)+.
H NMR (400MHz, de-DMSO) 5 9.69 (dd, J: 0.8,2.0 Hz,1 H), 9.54 (s,1 2 (3,1 H), 8.23 (s,1 H), 8.09 (dd, J: 0.8, 9.6 Hz, 1 H), 7.95 (dd, J: 2.0, 9.6 Hz,1 H), 7.87 (s, 1 H) MS m/Z248.1 M+1 +.
MS m/z 216.0 (M+1)+.
MS m/z 205.0 (M+1)+.
MS m/z 270.0 (M+1)+.
MS .1 (M+1)+.
MS m/z243.1 (M+1)+. 24V Br MS m/z241.0 (M+1)+.
S nthesis of 6- 3-c ano r0 | imidazo1 2—a ridinecarbox lic acid 25 Br + BUN A/CN \ / NH2 K0/\AOEt H2804 RT to 78 °C 245N\:OE+ Pd2(dba)3 [(t—Bu)3PH]BF4 N,N-dicyclohexylmethylamine 31303 / N Pd/C NC \ N / 1-4,dioxane, 95 °C EfOH: EfOAc(1: 1) LiOH THF: MeOH (4: 1) 50°C Now/iiw To a stirring suspension of 5-bromopyridinamine (1.2 g, 7.05 mmol) and ethyl 2- chlorohydroxyacrylate potassium salt (6.6 g, 28.19 mmol) (prepared in a similar manner as 22) in EtOH (100 mL) at room temperature was added sulfuric acid (751 uL, 14.10 mmol) dropwise. The reaction e was heated at 78 °C overnight. The reaction was cooled to room temperature and the solvent was concentrated. The e was taken in water and the pH was adjusted between 6-8 with saturated sodium bicarbonate.
The crude product was ted with ethyl acetate. The organic was washed with brine and dried over anhydrous sodium e. The crude product was purified by silica chromatography to yield ethyl 6-bromoimidazo[1,2-a]pyridinecarboxylate (245). MS m/z 270.2 (M+1) +.
A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridinecarboxylate (245) (500 mg, 1.86 mmol), allyl cyanide (224 uL, 2.79 mmol), tris(dibenzylideneacetone)dipalladium(0) (26 mg, 0.028 mmol), )3PH]BF4 (16 mg, 0.056 mmol), and N,N-dicyclohexylmethylamine (433 uL, 2.04 mmol) in anhydrous 1,4- dioxane (6 mL) was heated at 95 °C overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated. The crude product was purified by silica tography to give ethyl 6-(3-cyanopropenyl)imidazo[1,2-a]pyridine carboxylate (24v). MS m/z 256.4 (M+1) +.
To a stirring solution of ethyl 6-(3-cyanopropenyl)imidazo[1,2-a]pyridine carboxylate (24v) (400 mg, 1.57 mmol) in EtOH : EtOAc (1:1, 10 mL) was added catalytic Pd/C (10 wt%, wet basis). The reaction was hydrogenated by balloon ght then filtered through celite. The crude product ethyl 6-(3-cyanopropyl)imidazo[1,2- a]pyridinecarboxylate (24w) was used in the next step without r purification. MS m/z 258.4 (M+1) +.
To a stirring solution of ethyl 6-(3-cyanopropyl)imidazo[1,2-a]pyridinecarboxylate (24w) (375 mg, 1.46 mmol) in THF : MeOH (4:1, 5 mL) was added 2N LiOH (500 uL).
The reaction was heated at 50 °C for 45 minutes then cooled to room temperature and the pH was ed between 3-4 with 1N HCI. The solvent was partially concentrated and the remaining aqueous was lyophilized to yield 6-(3-cyanopropyl)imidazo[1,2- a]pyridinecarboxylic acid (25). 1H NMR (400MHz, de-DMSO) 6 9.21 — 9.19 (m, 1 H), 8.45 (s,1 H), 7.85 (dd, J: 0.8, 9.2 Hz,1 H), 7.70 (dd, J: 1.6, 9.2 Hz,1 H), 2.82 (t, J: 7.2 Hz, 2 H), 2.55 (t, J: 7.2 Hz, 2 H), 1.97 — 1.90 (m, 2 H). MS m/z 230.3 (M+1)+.
S s of 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth laniline 37 30020 _’ NH2 CN D NH20H B°C\ Boc\ H2N DMAP, THF N CN EtOH, 60 °C N H H | 60 °C N\ 7 34 35 OH HOZC ELF F F TFA —> BOC\N N\ —> F HZNDY!“\ WI: CDI, NMP H N~o 37 (Boc)20 (50 g, 227 mmol) was added portion-wise to a stirred on of 3-amino methylbenzonitrile (7) (10 g, 75.7 mmol) and DMAP (0.5 g) in THF (250 mL). After 30 minutes, the reaction was heated at 60 °C overnight. The crude reaction mixture was purified over silica gel to obtain a white solid tert-butyl 5-cyanomethylphenylcarbamate (34) (17.5 g, quantitative yield). MS m/z 233.1 (M+1)+.
NHZOH (20 mL, 50% in water) was added to a stirred solution of tert-butyl 5-cyano methylphenylcarbamate (34) (17.5 g, 75.3 mmol) in EtOH (200 mL) and the resulting solution was heated at 50 °C for 10 hours. The solvent was then evaporated and the product was titurated with EtOAc and hexane to obtain a white solid (Z)-tert-butyl 5-(N'- hydroxycarbamimidoyl)methylphenylcarbamate (35) in a quantitative yield which was used without further purification. MS m/z 266.1 (M+1)+.
CDI (1.2 g, 7.34 mmol) was added portion-wise to a stirred solution 3,3- difluorocyclobutanecarboxylic acid (1 g, 7.34 mmol) in NMP (10 mL). After 30 minutes, (Z)-tert-butyl hydroxycarbamimidoyl)methylphenylcarbamate (35) (1.8 g, 7.34 mmol) was added in one portion and stirred for r hour at room temperature. The solution was then heated via microwave at 120 °C for 20 minutes. The on was partitioned with EtOAc and water. The organic phase was ted, dried over MgSO4 and purified over silica gel to afford tert-butyl (5-(5-(3,3-difluorocyclobutyl)-1,2,4- oxadiazolyl)methylphenyl)carbamate (36) (1.2 g, 45% yield). MS m/z 366.1 (M+1)+.
Tert-butyl (5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)carbamate (36) (1.2 g, 3.3 mmol) was ved in TFA (10 mL) and stirred at room temperature for 15 minutes. Then TFA was removed under vaccum to give the residue which was lized by addition of 2M Na2003 solution (20 mL). The solution was ted with EtOAc and the organic phase was dried over Na2804. Evaporation of solvent gave 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylaniline (37) as a white solid (0.9 g, 100% yield), which was used without further purification. 1H NMR (400MHz, de-DMSO) 6 7.33 (d, J: 1.2 Hz, 1H), 7.14 (dd, J: 1.2, 7.6 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 5.37 (br, 2H), 3.84 (m, 1H), 2.98-3.24 (m, 4H), 2.12 (s, 3H). MS m/z 266.1 (M+1) f.
S nthesis of Z fluoro-N- 5- N'-h drox carbamimido lmeth l hen l imidazof 2- a ridinecarboxamide 40 N/\HkOH O 1 .oxay cll hlon'd e DMF, DCM N/fi/Um CN NHZOH, ”HZ \ \ N \ H N N \ H l EtOH, N N\ \ / D OH \ / 50°C F H2N CN 24b 39 F 40 2. DIEA, DCE o to 70 OC Oxalyl chloride (10 mL, 110 mmol) was added dropwise to a stirred suspension of 6- imidazo[1,2-a]pyridinecarboxylic acid (24b) (2 g, 11 mmol) and catalytic amounts of DMF in dichloromethane (20 mL). After 5 hours, the solvent was evaporated and the solid was suspended in dry DCE (20 mL) and added to a stirred on of 3- aminomethylbenzonitrile (1.45 g, 11 mmol) and DIEA (6 mmol) in DOE (10 mL) at 0 0C. After the addition, the reaction was heated at 60 °C for 5 hours. The mixture was subjected to standard aqueous work and silica purification to give N-(5-cyano methylphenyl)fluoroimidazo[1,2-a]pyridinecarboxamide (39) as a solid. 1H NMR (400MHz, O)610.14(s, 1 H), 9.45 (dd, J: 5.2, 2.0 Hz, 1H), 8.62 (s,1 H), 7.90 — 7.87 (m, 2 H), 7.68—7.63 (m, 1 H), 7.53 (d, J: 8.0 Hz,1 H), 2.37 (s, 3H). MS m/z 295.1 (M+1) f.
NHZOH (5 mL, 16.1 mmol) was added in one portion to a stirred sion of N-(5- cyanomethylphenyl)fluoroimidazo[1,2-a]pyridinecarboxamide (39) (0.95 g, 3.23 mmol). The resulting suspension was heated at 60 °C overnight and then cooled to 0 oC.
The product, (Z)fluoro-N-(5-(N'-hydroxycarbamimidoyl)methylphenyl)imidazo[1,2- a]pyridinecarboxamide (40) was collected by filtration. MS m/z 328.1 (M+1) +.
S nthesis of 6-bromo-N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen zo1 2-a ridinecarboxamide 42 N 1. w 35205oxalyl chloride2. Pyridine \ \0 24V 42 To a ng suspension of 6--bromoimidazo[1,2-a]pyridinecarboxylic acid (24v) (300 mg, 1.25 mmol), in anhydrous dichloromethane (10 mL) at 0 °C under Argon was added se oxalyl chloride (116 uL, 1.37 mmol). Then, three drops of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 45 min. The solvent was concentrated and the crude solid was added portion-wise to a stirring solution of methyl 3-(3-(3-aminomethylphenyl)-1,2,4-oxadiazolyl)azetidinecarboxylate (31) (330 mg, 1.25 mmol) in anhydrous pyridine (5 mL) at 0 °C. The reaction was stirred to room temperature under Argon for 2 h. Then, the reaction was ed with water.
The solvent was concentrated and the crude t was purified by silica chromatography to yield 6-bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (205 mg, 67% yield).
The following compounds were prepared according to the protocol described for 6- bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2- a]pyridinecarboxamide (42).
Intermediate Structure Physical Data number MS m/z 492.0, 494.0 (M+1)+. 1H NMR (400MHz CDCI3)69.44(dd, J=0.8,7.6 Hz, 1H), 8.56(d =J1.6 Hz, 1H), 8.18(s,1H),7 96 (dd,J= 0.8,2.0 Hz, 1H), 7.89(dd, J=1. 6, 8.0Hz,1H),7.6,2(s1H),7.42(dJ = 8.0Hz,1H),7.1,7(dd J: 2.0 7.2Hz, 1H), 3.68 (m, 1H), 3.18 (m, 4H), 2.45 s,3H .MS m/z488.0, 490.0 M+1 +.
F MS m/z 439.0 .
NWF\ A e of 4-fluoronitrobenzonitrile (5.0 g, 30.1 mmol) and Fe powder (5.05 g, 90.3 mmol) in AcOH (100 mL) was heated at 80 °C for 1 hour under N2. Then the t was removed under vacuum and water (200 mL) was added to the residue. The solution was adjusted to pH 6 by addition of Na2003 and extracted with DCM (2 x 200 mL). The organic layers were combined, dried over Na2804, filtered and concentrated to yield 3- aminofluorobenzonitrile (48), which was used without further purification. MS m/z 137.0 (M+1)+.
To a stirring suspension of imidazo[1,2-a]pyridinecarboxylic acid (1) (3.0 g, 18.5 mmol) in ous dichloromethane (50 mL) at 0 °C was added dropwise oxalyl chloride (4.84 mL, 55.5 mmol). Then, three drops of anhydrous DMF was added and the reaction e was stirred at room temperature for 15 minutes. The solvent was concentrated and the crude solid was added to a stirring solution of 3-amino fluorobenzonitrile (48) (2.5 g, 18.5 mmol) in anhydrous pyridine (50 mL) at room temperature. The reaction was stirred for 20 minutes and quenched with water (200 mL) with stirring for another 10 minutes. Then the precipitate was filtered and dried in air to yield N-(5-cyanofluorophenyl)imidazo[1,2-a]pyridinecarboxamide (49). 1H NMR (400MHz, de-DMSO) 6 10.40 (s, 1H), 9.43 (td, J: 1.2, 6.8 Hz, 1H), 8.63 (s, 1H), 8.21 (dd, J : 2.0, 7.2 Hz, 1 H), 7.78-7.84 (m, 2H), 7.54-7.63 (m, 2H), 7.22 (dt, J : 1 .2, 6.8, 1 H).
MS m/z281.1 (M+1)+.
NHZOH (10 mL, 32.1 mmol) was added in one portion to a stirred sion of N-(5- cyanofluorophenyl)imidazo[1,2-a]pyridinecarboxamide (49) (3.6 g, 12.85 mmol) in EtOH (100 mL). The resulting suspension was heated at 70 °C for 3 hours and then the solvent was removed to yield N-(2-iluoro(N'- hydroxycarbamimidoyl)phenyl)imidazo[1,2-a]pyridinecarboxamide (50). 1H NMR (400MHz, ds-DMSO)610.21 (s, 1H), 9.70 (s, 1H), 9.45 (td, J: 1.2, 7.2 Hz, 1H), 8.61 (s, 1H), 7.95 (dd, J: 2.4, 7.6 Hz, 1H), 7.79 (td, J: 1.2, 8.8 Hz, 1H), 7.51-7.60 (m, 2H), 7.31-7.37 (m, 1 H), 7.19 (dt, J : 1 .2, 6.8, 1 H), 5.88 (s, 2H). MS m/z 314.1 (M+1) +.
The following compounds were prepared according to the protocol described for N- (2-iluoro(N'-hydroxycarbamimidoyl)phenyl)imidazo[1,2-a]pyridinecarboxamide (50). ediate Structure number Physical Data / :N 1H NMR (400MHz, de-DMSO) 5 9.96 \ N& (s, 1H), 9.65 (s, 1H), 9.44 (td, J: NH 0.8, 6.8 Hz, 1H), 8.55 (s, 1H), 7.78 50a 0QWMOH H (td, J: 1.2, 9.2 Hz, 1H), 7.52 (m, 2H), 7.21 (d, J: 11.6 Hz, 1H), 7.17 NH (dt, J: 1.2, 6.8, 1H), 5.81 (s,2H), F 2.28 (s, 3H). MS m/z 328.1 (M+1)+. 50b 0 MS m/z 422.1 (M+1)+. 1H NMR (400MHz, ds-DMSO) 5 9.89 (s, 1H), 9.44 (dt, J: 8.8, 1.2 Hz, 1H), 9.33 (s, 1H), 8.55 (s, 1H), 7.78 (dt, J : 9212 Hz, 1H), 7.49-7.52 (m, 1H), 7.28 (s, 1H), 7.14-7.18 (m, 2H), 5.72 (s, 2H), 2.34 (s, 3H), 2.24 (s, 3H).
Ms m/z324.1 (M+1)+. 1H NMR z, ds-DMSO) 5 9.84 (s, 1H), 9.43 (d, J: 8.8 Hz, 1H), 8.59 50d (s, 1H), 7.78 (d, J: 8.8 Hz, 1H), 7.50 (d, J: 8.0 Hz, 1H), 7.17 (m, 3H), .78 (s, 2H), 2.25 (s, 3H), 2.24 (s, 3H). MS m/z324.1 (M+1)+. 1H NMR (400MHz, ds-DMSO) 5 9.90 (s, 1H), 9.80 (s, 1H), 9.32 (d, J: 7.2 Hz, 1H), 8.50 (s, 1H), 7.89 (d, J: 2.0 50e Hz, 1H), 7.58 (m, 1H), 7.50 (dd, J: 1.8, 8.0 Hz, 1H), 7.29 (d, J: 8.0 Hz, 1H), 7.02 (dd, J: 1.8, 7.2 Hz, 1H), .80 (s, 2H), 2.42 (s, 3H), 2.27 (s, 3H). MS m/z324.1 (M+1)+.
H NMR (400MHz, O) 5 .09 (s, 1H), 9.83 (m, 1H), 9.80 (s, 1H), 8.58 (s, 1H), 7.78 (dd, J: 0.8, 50f 9.8 Hz, 1H), 7.89 (d, J: 1.8 Hz, 1H), 7.88 (dd, J: 2.0, 9.2 Hz, 1H), 7.52 (dd, J: 1.8, 8.0 Hz, 1H), 7.31 (d, J: 8.0 Hz, 1H), 5.81 (s,2H),2.27 (s, 3H .MS m/z 388.0, 390.0 M+1 +.
S nthesis of5-aminofluorometh Ibenzonitrile 51 CuCN U. —> UP H2N Br NMP H2N CN A mixture of ofluoromethylaniline (2.04 g, 10.0 mmol), CuCN (889 mg, 10.0 mmol) and Cul (1.9 g, 10.0 mmol) in NMP was purged with N2 for 5 minutes and then sealed and heated at 195 °C for 30 minutes under microwave condition. The mixture was subjected to standard aqueous workup to give a residue which was purified by silica chromatography to yield 5-aminofluoromethylbenzonitrile (51) (540 mg, 36% yield). MS m/z151.0 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l h l hen l ethynylimidazo|1,2-a|pyridinecarboxamide (53) 2012/052621 Cul O O \ N /N\ N O PdCl2(PPh3)2 NR,»N N N H ’ x \ / x \ N N\ E13N o ch03 NVLm 0 \ \ \ N N N N \ / TMS——_ —> \ —» MeOH \ / \ / 42f DMF, MW 53 Br 52 F F // F 7-Bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) phenyl)imidazo[1,2-a]pyridinecarboxamide (42f) (50.0 mg, 0.10 mmol), Cul (3.82 mg, 0.02 mmol), PdC|2(PPh3)2 (14.0 mg, 0.02 mmol), triethylamine (20.0 mg, 0.20 mmol) and ethynyltrimethylsilane (20 mg, 0.20 mmol) were mixed in DMF (1 mL) in a 1 mL mircowave vial. The vial was capped and heated at 110 °C for 5 s under microwave condition. Once complete, the on e was diluted and extracted with EtOAc. The organic layers were combined, dried over NaZSO4, ed, concentrated and purified by silica chromatography to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol- 3-yl)methylphenyl)((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridinecarboxamide (52). MS m/z 506.1 (M+1)+.
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl) ((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridinecarboxamide (52) (50 mg, 0.1 mmol) was dissolved in MeOH (1 mL) and K2C03 (42 mg, 0.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL). The resulting precipitate was filtered and dried to give N-(5-(5-(3,3- difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)ethynylimidazo[1,2-a]pyridine- 3-carboxamide (53). MS m/z 434.1 (M+1)+.
S nthesis of 6- triiso ro lsil lox meth limidazo1 2-a ridinecarbox lic acid 61 “Axe“ H28049 pyridine LiOH NI / EtOH (Q03 ImifigeTIPSCI| —>OT|PS OTIPS RT to 78 0C \:1N\§\OH To a stirring suspension of (6-aminopyridinyl)methanol (1.24 mg, 10.0 mmol) and ethyl 2-chlorohydroxyacrylate, potassium salt (29) (3.76 g, 20.0mmol) in EtOH (10 mL) at room temperature was added conc sulfuric acid (10.0 mmol) dropwise. The reaction mixture was stirred at room temperature for 15 minutes and pyridine (0.92 g, 12.0 mmol) was added. The resulting e was heated at 85 °C overnight. The reaction was 2012/052621 cooled to room temperature and the solvent was concentrated. The residue was taken in water and the on was adjusted to pH 8 with saturated sodium bicarbonate. The crude product was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The crude product ethyl 6- (hydroxymethyl)imidazo[1,2-a]pyridinecarboxylate (59) was purified by silica chromatography. 1H NMR (400MHz, d6-DMSO) 6 9.16 (d, J= 6.8 Hz, 1H), 8.26 (s, 1H), 7.67 (s, 1H), 7.19 (dd, J: 1.6, 6.8 Hz, 1H), 5.57 (t, J: 6.4 Hz, 1H), 4.63 (d, J: 6.0, 2H), 4.36 (q, J: 7.2 Hz, 2H), 1.35 (t, J: 6.8 Hz, 3H). MS m/z221.1 (M+1)+.
To a suspension of ethyl 6-(hydroxymethyl)imidazo[1,2-a]pyridinecarboxylate (59) (497.0 mg, 2.26 mmol), DMAP (12.2 mg, 0.1 mmol) and 1H-imidazole (154.0 mg, 2.26 mmol) in dichloromethane (10 mL), was added TIPSCI (523.0 mg, 2.71 mmol). The resulting mixture was stirred overnight at room temperature. The solvent was removed under vacuum to yield crude ethyl riisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine- 3-carboxylate (60). MS m/z 377.2 (M+1)+.
The crude ethyl 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridinecarboxylate (60) obtained above was dissolved in THF/MeOH/H2O (32:1, 5 mL). 6N LiOH (2.27 mL, 13.6 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. All ts were removed and 6N HCI was added until pH 5-6. EtOAc (5 mL) was added and the mixture was stirred for 1 hour. The precipitate was filtered and dried to give 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridinecarboxylic acid (61 ). 1H NMR (400MHz, de-DMSO) 6 9.37 (s, 1H), 8.21 (s, 1H), 7.76 (dd, J: 1.2, 9.2 Hz,1H), 7.46 (dd, J: 2.0, 9.2 Hz, 1H), 4.94 (s, 2H), 1.20 (m, 3H), 1.08 (d, J: 6.8 Hz, 18H). MS m/z 349.2 (M+1)+.
S s of 7- 1H- razol limidazo 1 2-a ridinecarbox lic acid 63 Q\ N \ / Pd(PPh3)4 K2C03 \ I N \ 62 | DMF 80 00 H To a solution of 5-ethyl 7-bromoimidazo[1,2-a]pyridinecarboxylate 24g (202 mg, 0.75 mmol) in DMF (2 mL) was added (1 zolyl)boronic acid (101 mg, 0.903 mmol), 1.8 M K2003 (1.3 mL, 2.26 mmol) and Pd(PPh3)4 (87 mg, 0.075 mmol). The reaction was evacuated and backfilled with nitrogen twice then heated at 160 9C for 10 minutes in a microwave oven. After the reaction mixture was filtered h a pad of Celite, the mixture was diluted with a saturated solution of NH4C| and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2804 and concentrated to give ethyl 7-(1H-pyrazolyl)imidazo[1,2-a]pyridinecarboxylate (62). MS (m/z) 257.1 (M+1)+.
To a stirring solution of ethyl 7-(1H-pyrazolyl)imidazo[1,2-a]pyridinecarboxylate (62) (103 mg, 0.4 mmol) in THF:MeOH:H20 (32:1, 1.6 mL) was added 6N LiOH (0.035 mL). The reaction was stirred at room temperature for 20 minutes. The pH was adjusted between 4-5 with 3N HCI. The resulting mixture was concentrated to yield 7-(1H-pyrazol- 3-yl)imidazo[1,2-a]pyridinecarboxylic acid (63). MS (m/z) 229.2 .
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l triiso ro lsil lox meth limidazof 2-a ridinecarboxamide 64 / /N 1oxa|y| chloride /CNr/ OTIPS OH123%W 2 Pyridine o FF ,4 \( 61 \ 37 :) NW No To a stirring sion of 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine carboxylic acid (61) (260 mg, 0.74 mmol) in anhydrous dichloromethane (5 mL) at room temperature oxalyl chloride was added dropwise (0.19 mL, 2.22 mmol). Then, one drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 15 minutes. The t was trated and the crude solid was added to a stirring solution of 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylaniline (37) (180 mg, 0.74 mmol) in ous pyridine (5 mL) at room temperature. The on was stirred for 20 minutes and the solvent was removed to afford residue. To the above residue was added water (20 mL) and sonicated to give precipitate. Then the itate was filtered, dried in air and purified by silica chromatography to afford N-(5-(5-(3,3- difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl) (((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridinecarboxamide (64). MS m/z 596.3 (M+1) f.
S nthesis of N- 5-aminometh l hen limidazo 1 2-a ridinecarboxamide 67 o 1. oxalyl chloride TFA, Megs, DMF, DCM NHBOC DCM NH2 NVLOH —> N/§HLNH —> N\\ \ \ N N N 2. DIEA 66 / 67 \ / 1 DCM \ / \ H2N NHBoc Oxalyl chloride (10 mL) was added dropwise to a stirred solution of imidazo[1,2- a]pyridinecarboxylic acid (1) (3 g, 18.5 mmol) in dry dichloromethane (100 mL) and a few drops of DMF. The resulting solution was stirred at room temperature for 5 hours before it was evaporated to dryness and fresh dichloromethane was added to the ing acid chloride to make a suspension. In a te flask, tert-butyl 3-amino methylphenylcarbamate (65) (4.5 g, 20.3 mmol) and DIEA (10 mL) was dissolved in romethane (100 mL) and the above acid chloride solution was added . The resulting solution was stirred overnight at room temperature. Saturated NH4C| was added to the reaction solution and the phases were ted. The organic layer was dried over Na2804 and filtered. After evaporation, the residue was purified over silica gel column using hexane and EtOAc to give tert-butyl 3-(imidazo[1,2-a]pyridine carboxamido)methylphenylcarbamate (66) as a slightly yellow solid.
TFA (50 mL) was added to a stirred suspension of tert-butyl 3-(imidazo[1,2- a]pyridinecarboxamido)methylphenylcarbamate (66) in Megs (5 mL) and dichloromethane (10 mL). After 2 hours the solution was evaporated and partitioned with dichloromethane and saturated NaHCOs. The aqueous layer was extracted several times with dichloromethane and the combined organic layers were dried over NaZSO4.
N-(5-aminomethylphenyl)imidazo[1,2-a]pyridinecarboxamide (67) was isolated and used t further cation. 1H NMR (400MHz, CDCls) 6 9.44 (d, J: 6.8 Hz, 1 H), 8.05 (3,1 H), 7.67 (d, J: 8.8 Hz,1 H), 7.38 — 7.33 (m, 2 H), 6.98 — 6.94 (m, 2 H), 2.19 (s, 3 H). MS m/z 267.1 (M+1)+.
S nthesis of E -N- 5- 2-h drox no meth l hen limidazo 1 2-a ridine carboxamide (69) O 0 n N’OH BrCN, NH20H o U Q 67 Q 63 Q 69 To N-(5-aminomethylphenyl)imidazo[1,2-a]pyridinecarboxamide (67) (4.53 g, 15 mmol) in MeOH (100 mL) was added KOAc (4.41 g, 45 mmol) and the mixture was stirred at room temperature for 5 minutes then cooled to 0 00 before a solution of BrCN (1.62 g, 15 mmol) in MeOH (30 mL) was added dropwise. The resulting mixture was slowly warmed to room temperature and stirred overnight. The solvent was evaporated and to the residue was added water (150 mL). The mixture was stirred at room temperature for 1 hour, filtered and washed with water (2 x 20 mL), then air dried to give N-(5-cyanamidomethylphenyl)imidazo[1,2-a]pyridinecarboxamide (68) as a white solid.
To a suspension of N-(5-cyanamidomethylphenyl)imidazo[1,2-a]pyridine amide (68) 3.52 g (12.1 mmol) in 200 mL of EtOH was added 0.75 mL NHZOH (50 wt% in water, 12.1 mmol). The resulting mixture was stirred at room temperature overnight. The precipitate was filtered, washed with EtOH (10 mL) and air dried to give N-(5-(2-hydroxyguanidino)methylphenyl)imidazo[1,2-a]pyridinecarboxamide (69) as a white solid, which was used directly in the next step without further purification. 1H NMR (400MHz, d6-DMSO) 6 9.44 (s, 1H), 9.46 (dd, J: 6.8, 0.8 Hz,1 H), 8.54 (s,1 H), 8.34 (s,1 H), 7.76 (dd, J: 7.2, 2.2 Hz,1 H), 7.59 (s,1 H), 7.52 — 7.43 (m, 2 H), 7.18 — 7.06 (m, 2 H), 2.13 (s, 3 H). MS m/z325.1 (M+1)+.
S nthesis of 6- 3- tert—butox oxo ro limidazo1 2-a ridinecarbox lic acid 72 Pd2(dba)3 / /N [(f-Bu)3PH]BF4 o / /N cyclohexylmethylamine \ N / + VH3J< O \ N / Br \ OEf 1,4-dioxane O 0E1 o 0 24s 70 / /N / /N H ,Pd/C 2N LiOH 2 +0 / \ N\§\ —, THFiMeOH +0 EtOH:EfOAc OH o OEt 0 o O A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridinecarboxylate (245) (500 mg, 1.86 mmol), tert-butyl te (408 uL, 2.79 mmol), tris(dibenzylideneacetone)diplalladium(0) (51 mg, 0.056 mmol), [(t-Bu)3PH]BF4 (27 mg, 0.093 mmol) and cyclohexylmethylamine (738 uL, 3.48 mmol) in anhydrous 1,4- dioxane (5 mL) was heated at 95 °C overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated and the crude product was purified by silica chromatography to yield ethyl 6-(3-(tert-butoxy)oxopropen y|)imidazo[1,2-a]pyridinecarboxylate (70). MS m/z 317.14 (M+1)+.
A stirring mixture of ethyl 6-(3-(tert-butoxy)oxopropenyl)imidazo[1,2- a]pyridinecarboxylate (70) (460 mg, 1.80 mmol) and 10 wt% Pd/C (wet) in ethanol:ethylacetate (1:1, 10 mL) was hydrogenated overnight. The reaction was filtered over celite and the solvent was trated. Crude ethyl 6-(3-tert-butoxy oxopropyl)imidazo[1,2-a]pyridinecarboxylate (71) was used in the next step without further purification. MS m/z 319.16 (M+1)+.
A stirring mixture of ethyl 6-(3-tert-butoxyoxopropyl)imidazo[1,2-a]pyridine ylate (71) (400 mg, 1.26 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1 4 mL) was heated at 60 °C for 30 minutes. The reaction was cooled to room ature and the pH was ed between 3-5 with 10% citric acid. The solvent was partially reduced.
The resulting solid was collected by vacuum filtration and washed with excess water.
Crude 6-(3-(tert—butoxy)oxopropyl)imidazo[1,2-a]pyridinecarboxylic acid (72) was dried and used in the next step without further purification. 1H NMR (400MHz, de-DMSO) WO 33070 9.11 (s,1 H), 8.20 (s,1 H), 7.72 (dd, J: 0.8, 9.2 Hz,1 H), 7.50 (dd, J: 1.6, 9.2 Hz,1 H), 2.91 (t, J: 6.8 Hz, 2 H), 2.60 (t, J: 7.2, 2 H), 1.33 (s, 9 H). MS m/z291.13 (M+1)+.
S nthesis of 6- 2-c anoeth l o 1 2-a ridinecarbox lic acid 75 / N / [(t—Bu)3PH]BF4 / /N \ N / + Br ”ON N,N-dicyclohexylmethylamine —’NC \Mg/ 0 1,4-dioxane 0E1 245 73 / /N H2, Pd/C NCA/é/N/OE 2N LiOH \ N / EtOH. EtOAC THF.MeOH OH 75 A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridinecarboxylate (245) (250 mg, 0.929 mmol), acrylonitrile (92 uL, 1.39 mmol), tris(dibenzylideneacetone)diplalladium(0) (26 mg, 0.0279 mmol), [(t-Bu)3PH]BF4 (13 mg, 0.0465 mmol) and N,N-dicyclohexylmethylamine (217 uL, 1.02 mmol) in anhydrous 1,4- e (4 mL) was heated at 95 °C overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated and crude 6-(2- cyanovinyl)imidazo[1,2-a]pyridinecarboxylate (73) was purified by silica chromatography. MS m/z 242.09 (M+1)+.
A ng mixture of ethyl 6-(2-cyanovinyl)imidazo[1,2-a]pyridinecarboxylate (73) (115 mg, 0.451 mmol) and 10 wt% Pd/C (wet) in ethanol:ethylacetate (1:1, 5 mL) was hydrogenated overnight. The reaction was filtered over celite and the solvent was removed. Crude ethyl 6-(2-cyanoethyl)imidazo[1,2-a]pyridinecarboxylate (74) was used in the next step without further purification. MS m/z 244.10 (M+1)+.
A ng mixture of ethyl 6-(2-cyanoethyl)imidazo[1,2-a]pyridinecarboxylate (74) (100 mg, 0.411 mmol) and 2N LiOH (0.2 mL) in THF:MeOH (4:1, 3 mL) was heated at 50 °C for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted n 3-5 with 10% citric acid. The solvent was partially reduced. The resulting solid was collected by vacuum filtration and washed with excess water. Crude 6-(2-cyanoethyl)imidazo[1,2-a]pyridinecarboxylic acid (75) was dried and used in the next step without further purification. MS m/z416.07 (M+1)+.
S nthesis of 6- 3-oxobut l imidazo1 2-a ridinecarbox lic acid 78 Pd2(dba)3 Br/</\:NOE +\)OJ\ [(t- Bu))3PH]BF4 N N-_dicyclohexy|methy|amine 1 4-dioxane :N/ghioa H2 Pd/C t&%t 2N LiOH EtOH: EtOAc THFMeOH Wfiigflm 77 78 A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridinecarboxylate (245) (250 mg, 0.929 mmol), methyl vinyl ketone (151 uL, 1.86 mmol), tris(dibenzylideneacetone)diplalladium(0) (26 mg, 0.0279 mmol), [(t-Bu)3PH]BF4 (13 mg, 0.0465 mmol) and N,N-dicyclohexylmethylamine (217 uL, 1.02 mmol) in anhydrous 1,4- dioxane (4 mL) was heated at 95°C overnight. The reaction was cooled to room temperature and filtered. The t was concentrated and crude 6-(3-oxobut enyl)imidazo[1,2-a]pyridinecarboxylate (76) was purified by silica chromatography. MS m/z 259.10 (M+1)+.
A stirring mixture of ethyl 6-(3-oxobutenyl)imidazo[1,2-a]pyridinecarboxylate (76) (200 mg, 0.774 mmol) and 10 wt% Pd/C (wet) in ethanol:ethylacetate (1:1, 8 mL) was hydrogenated overnight. The on was filtered over celite and the solvent was concentrated. Crude 6-(3-oxobutyl)imidazo[1,2-a]pyridinecarboxylate (77) was used in the next step without further purification. MS m/z261.12 (M+1)+.
A stirring mixture of ethyl 6-(3-oxobutyl)imidazo[1,2-a]pyridinecarboxylate (77) (190 mg, 0.730 mmol) and 2N LiOH (0.2 mL) in THF:MeOH (4:1, 3 mL) was heated at 50°C for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially reduced. The ing solid was collected by vacuum tion and washed with excess water. Crude 6-(3-oxobutyl)imidazo[1,2-a]pyridinecarboxylic acid (78) was dried and used in the next step without further purification. MS m/z 233.08 (M+1)+.
S nthesis of 6- 3-oxobut l o1 2-a ridinecarbox lic acid 80 o o OEt OEt OH N OM8 0‘ CI 2N L'OH' F / N F i/CND A 3 \ N HO \N \ ACN THF:MeOH F o F o \N A e of ethyl 7-hydroxyimidazo[1,2-a]pyridinecarboxylate (24t) (500 mg, 2.43 mmol) and sodium chlorodifluoroacetate (444 mg, 2.91 mmol) in anhydrous acetonitrile (8 mL) was heated in the microwave at 125 °C for 12 minutes. The solvent was concentrated and the crude product ethyl 7-(difluoromethoxy)imidazo[1,2-a]pyridine carboxylate (79) was purified by silica tography. MS m/z 257.07 (M+1)+.
A stirring mixture of ethyl 7-(difluoromethoxy)imidazo[1,2-a]pyridinecarboxylate (79) (150 mg, 0.585 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1, 5 mL) was heated at 60 °C for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 4-5 with 1N HCI. The solvent was partially reduced and the crude product was ed by reverse phase preparative HPLC to yield 6-(3- oxobutyl)imidazo[1,2-a]pyridinecarboxylic acid (80). MS m/z 229.03 (M+1)+.
S nthesis of 3- 3- 3- imidazo 1 2-a ridinecarboxamido meth l hen l -1 2 4- zol lc clobut lmethanesulfonate 81 19 81 Q_§’:Q To a ng suspension of N-(5-(5-(3-hydroxycyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (220 mg, 0.565 mmol) (19) in anhydrous DCM (10 mL) at 0 °C was added DIEA (197 uL, 1.13 mmol) and methanesulfonyl chloride (542 uL, 0.678 mmol). The reaction was stirred to room for 30 s. The crude t was purified by silica chromatography to give 3-(3-(3- (imidazo[1,2-a]pyridinecarboxamido)methylphenyl)-1,2,4-oxadiazolyl)cyclobuty| methanesulfonate (81). MS m/z 468.13 (M+1)+.
S nthesis of 7- 3-oxobut l imidazof 2-a ridinecarbox lic acid 86 Pd2(dba)3 JK [(t— Bu)3PH]BF4 NN-d—icyclohexylmethylamine 1 4-dioxanei1N\§\OEt H2, Pd/C 2N LiOH EtOH: EtOAc THFMeOH A stirring mixture of ethyl 7-bromoimidazo[1,2-a]pyridinecarboxylate (24g) (500 mg, 1.86 mmol), methyl vinyl ketone (301 uL, 3.72 mmol), tris(dibenzylideneacetone)diplalladium(0) (51 mg, 0.056 mmol), [(t-Bu)3PH]BF4 (27 mg, 0.093 mmol) and N,N-dicyclohexylmethylamine (433 uL, 2.04 mmol) in anhydrous 1,4- dioxane (10 mL) was heated at 95 °C overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated and crude ethyl 7-(3-oxobut enyl)imidazo[1,2-a]pyridinecarboxylate (84) was purified by silica chromatography. MS m/z 259.10 .
A stirring mixture of ethyl 7-(3-oxobutenyl)imidazo[1,2-a]pyridinecarboxylate (84) (92 mg, 0.356 mmol) and 10 wt% Pd/C (wet) in ethanol:ethylacetate (1 :1, 8 mL) was hydrogenated overnight. The reaction was ed over celite and the solvent was concentrated. Crude ethyl 7-(3-oxobutyl)imidazo[1,2-a]pyridinecarboxylate (85) was used in the next step without further purification. MS m/z261.12 (M+1)+.
A stirring mixture of ethyl 7-(3-oxobutyl)imidazo[1,2-a]pyridinecarboxylate (85) (90 mg, 0.346 mmol) and 2N LiOH (0.5 mL) in THF:MeOH (4:1 3 mL) was heated at 60 °C for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially concentrated and the crude t was purified by reverse phase preparative HPLC to yield 7-(3- oxobutyl)imidazo[1,2-a]pyridinecarboxylic acid (86). MS m/z 233.08 (M+1)+.
S nthesis of 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l fluoroaniline 88 F F CDI NH20H NMP ' F N N H2N 0” ‘OH 2 EfOH H2“ \ WF 2) MW125°C N4 NH O 43 37 88 NHZOH (50% wt in water, 3.5 mL, 60.0 mmol) was added in one n to a stirred suspension of 3-aminofluorobenzonitrile (48) (1.36 g, 10.0 mmol) in EtOH (25 mL).
The resulting sion was heated at 70 °C for overnight and then the solvent was d to yield 3-aminofluoro-N-hydroxybenzimidamide (87), MS m/z 170.1 (M+1)+.
To a solution of 3,3-difluorocyclobutanecarboxylic acid (0.90 g, 6.6 mmol) in NMP (5 mL) was slowly added CDI (1.07 g, 6.6 mmol). The resulting mixture was d at room temperature for 30 minutes. Then 3-aminofluoro-N-hydroxybenzimidamide (87) (0.56 g, 3.3 mmol) was added and stirred for another 30 minutes until LCMS indicated complete on. The mixture was then heated at 125 °C for 15 minutes in a microwave reactor and poured into water (100 mL). The e was extracted with EtOAc (2 x 50 mL), dried over NaZSO4, filtered and concentrated to give a crude product which was purified by silica-gel chromatography (0-60 % EtOAc in hexanes) to afford 5- (5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)fluoroaniline (88). 1H NMR (400MHz, CDCI3) 6 7.53 (dd, J: 2.0, 8.4 Hz, 1H), 7.43-7.48 (m, 1H), 7.10 (dd, J: 10.8, 8.4 Hz, 1H), 3.90 (br, 2H), 3.67 (m, 1H), 3.09-3.18 (m, 4H). MS m/z 270.1 (M+1)+.
S nthesis N- 5- 5- 3 uoroc clobut l -1 2 4-oxadiazol l meth l hen l i eridin zof 2-a ridinecarboxamide 92 O OH 1. Propylphosphonic 91 anhydride 2. TFA N To a on of 5-ethyl 7-bromoimidazo[1,2-a]pyridinecarboxylate (24g) (300 mg, 1.11 mmol) in DMF (9 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-5,6-dihydropyridine-1(2H)-carboxylate (414 mg, 1.34 mmol), K2003 (1.8M, 1.85 mL, 3.33 mmol) and Pd(PPh3)4 (87 mg, 0.11 mmol). The reaction was evacuated and backfilled with nitrogen twice then heated at 160 9C for 10 minutes via microwave. After the reaction mixture was filtered through a pad of Celite, the mixture was d with a saturated solution of NH4C| and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2804 and concentrated to give crude ethyl 7-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridinyl)imidazo[1,2-a]pyridine carboxylate (89) (MS (m/z) 372.1 (M+1)+.
H2 (balloon) was introduced to a stirred mixture of Pd(OH)2/C (0.055 g) and ethyl 7- (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridinyl)imidazo[1,2-a]pyridine carboxylate (89) (0.55 g, 1.48 mmol) in MeOH (5 mL). After 6 hours, the mixture was filtered through a pad of Celite and the t was evaporated to give the crude t.
The residue was purified over silica using EtOAc and hexanes to give ethyl 7-(1-(tert- butoxycarbonyl)piperidinyl)imidazo[1,2-a]pyridinecarboxylate (90). 1H NMR (400MHz, CD202) 6 9.27 (d, J: 7.2 Hz, 1H), 8.27 (s, 1H), 7.64 (s, 1H), 7.04 (dd, J=1.6, 7.2 Hz, 1H), 4.43 (q, J: 7.2 Hz, 2H), 4.31 (m, 2H), 2.87 (m, 1H), 2.83 (m, 2H), 1.95 (m, 2H), 1.67 (m, 2H), 1.49 (s, 9H), 1.43 (t, J: 7.2 Hz, 3H). MS m/z 374.2 (M+1)+.
To a stirring suspension of ethyl tert-butoxycarbonyl)piperidinyl)imidazo[1,2- a]pyridinecarboxylate (90) (84 mg, 0.23 mmol) in THF:MeOH:HZO (32:1, 1 mL) was added 6N LiOH (0.13 mL). The reaction was stirred at room temperature for 2.5 hours then neutralized with NH4C| and concentrated to afford 7-(1-(tert- carbonyl)piperidinyl)imidazo[1,2-a]pyridinecarboxylic acid (91) which was immediately used without purification. MS (m/z) 346.1 (M+1)+.
To a stirring solution of 7-(1-(tert-butoxycarbonyl)piperidinyl)imidazo[1,2- a]pyridinecarboxylic acid (91) (124 mg, 0.36 mmol), and 5-(5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyl)methylaniline (60) (96 mg, 0.36 mmol) in ethyl acetate (0.3 mL) was added propylphosphonic anhydride (50 wt % in ethyl acetate 1.07 mL). The reaction was heated at 90 °C for 12 hours. The resulting mixture was diluted in ethyl acetate and washed with 1N Na2C03. The product stayed in aqueous layer and was concentrated to afford tert-butyl 4-(3-((5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)- 2-methylphenyl)carbamoyl)imidazo[1,2-a]pyridinyl)piperidinecarboxylate. The solid was taken up in trifluoroacetic acid and stirred for 25 minutes. The solvent was concentrated and placed under high vacuum to yield N-(5-(5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyl)methy|phenyl)(piperidinyl)imidazo[1,2-a]pyridine carboxamide (92). MS (m/z) 493.1 (M+1)+.
S nthesis of 7-meth l-ds-imidazof 2-a ridinecarbox lic acid 95 NMOEt O O CD3MQ| M \ N\ LIOH 0E1 NMOH N PEPPSI \ \ / IPrl \ / \ / 249 Dgc 94 D30 95 To a stirring solution of ethyl 7-bromoimidazo[1,2-a]pyridinecarboxylate (24g) (500 mg, 1.86 mmol), PEPPSI (63.2mg, 0.093 mmol) and 2-iodopropane (928 uL, 9.3 mmol) in anhydrous THF (3 mL) at 000 under a stream of en was added methyl-d3- magnesium iodide (5.6 mL, 5.57 mmol). The on was stirred to room temperature for 5 hours. Then, the reaction was quenched with NH4CI. The crude product was extracted with ether, washed with water and brine and dried over sodium e. The product was ed on silica gel using 10% MeOH in dichloromthane to yield ethyl 7-methyl-d3- imidazo[1,2-a]pyridinecarboxylate (94). 1H NMR (400MHz, de-DMSO) 6 8.85 (dd, J: 0.4, 7.0 Hz, 1H), 7.98 (s, 1H), 7.36 (s, 1H), 6.86 (dd, J=1.6, 7.2 Hz, 1H), 4.10 (q, J: 7.2 Hz,2H), 1.09 (t, J: 7.2 Hz, 3H). MS m/z 208.1 (M+1)+.
To a ng suspension of ethyl 7-methyl-d3-imidazo[1,2-a]pyridinecarboxylate (94) (142 mg, 0.69 mmol) in THF: MeOH: H20 (32:1, 3 mL) was added 6N LiOH (0.34 mL). The reaction was d at room temperature for 2 hours then neutralized with sodium bisulfate monohydrate and concentrated to afford 7-methyl-d3-imidazo[1,2- a]pyridinecarboxylic acid (95), which was immediately used without purification. MS (m/z) 180.1 (M+1)+.
S nthesis of 6- 222-trifluoroethox meth limidazof 2-a ridinecarbox lic acid 98 1)MsCl DIEA / :N HOQOB DCM L0H| F3CVO \ N / 2) K2CO3 CVOVC'iNOE OH CF3CH20H 970 0 To a soultion of ethyl 6-(hydroxymethyl)imidazo[1,2-a]pyridinecarboxylate (59) (460 mg, 2.2 mmol) and DIEA (0.78 mL, 4.4 mmol) in DCM (5 mL) was added MsCl (303 mg, 2.64 mmol). The mixture was stirred at room temperature for 10 minutes then subjected to standard aqueous work up to give a residue. The crude product was dissolved in 2,2,2-trifluoroethanol (2 mL) and and was added K2C03 (608 mg, 4.4 mmol).
The reaction mixture was heated at 80 °C for 2 hours. Once complete, the reaction e was d and extracted with EtOAc. The organic layers were combined, dried over NaZSO4, filtered and concentrated to afford a residue which was purified by silica chromatography to yield ethyl 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridine ylate (97). 1H NMR (400MHz, CDCI3) 6 9.33 (m, 1H), 8.32 (s, 1H), 7.76 (dd, J: 0.8, 9.2 Hz, 1H), 7.47 (dd, J: 2.0, 9.2 Hz, 1H), 4.76 (s, 2H), 4.44 (q, J: 7.2 Hz, 2H), 3.92 (q, J: 8.4 Hz, 2H), 1.45 (t, J: 7.2 Hz, 3H). MS m/z 303.1 (M+1)+.
A solution of ethyl 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridine carboxylate (97) (280 mg, 0.92 mmol) in THF/MeOH/HZO (32:1, 5 mL) was treated with 6N LiOH (0.92 mL, 5.52 mmol) and stirred at room temperature for 1 hour. All solvents were removed and 6N HCI was added to adjust pH 56 Then the mixture was purified by HPLC to give 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridinecarboxylic acid (98). 1H NMR (400MHz, de-DMSO) 6 9.34 (m, 1H), 8.40 (s, 1H), 7.88 (dd, J= 0.8, 9.2 Hz, 1H), 7.65 (dd, J: 1.6, 9.2 Hz, 1H), 4.83 (s, 2H), 4.18 (q, J: 9.6 Hz, 2H). MS m/z 275.1 (M+1)+.
S s of 6- 3- methox meth l -1H-1 2 zol l imidazo 1 2-a ridine ylic acid (99) 110°C 99 To a solution of ethyl 6-cyanoimidazo[1,2-a]pyridinecarboxylate (24q) (265 mg, 1.23 mmol) and 2-methoxyacetohydrazide (193 mg, 1.85 mmol) in 2-ethoxyethanol (5 mL) was added NaOMe (0.5 M in MeOH, 3.7 mL). The mixture was heated at 110 °C in a sealed vial overnight. The reaction mixture was purified by HPLC to give 6-(3- (methoxymethyl)-1H-1,2,4-triazolyl)imidazo[1,2-a]pyridinecarboxylic acid (99). MS m/z 274.1 (M+1)+.
S nthesis of 6-carbamo limidazof 2-a ridinecarbox lic acid 110 / /N / /N \ N / LiOH H2N \ N / NC _.
OEt THFIMeOH O OH O O 24q 11o To a stirring on of ethyl 6-cyanoimidazo[1,2-a]pyridinecarboxylate (24q) (500 mg, 2.32 mmol) in OH (4:1, 5 mL) was added 2N LiOH (4 mL). The reaction was heated at 60 °C for 2 h then acidified with 10% citric acid. The solvent was partially concentrated and the resulting solid was collected by vacuum filtration and was washed with excess water. The product was ed from the crude solid to afford 6- carbamoylimidazo[1,2-a]pyridinecarboxylic acid (110). 1H NMR (400MHz, d6-DMSO) 6 9.80 (s, 1H), 8.33 — 8.31 (m, 1H), 8.29 (s, 1H), 7.95 (dd, J: 2.0, 9.6 Hz, 1H), 7.83 (dd, J: 0.8, 9.2 Hz, 1H), 7.69 (s, 1H). MS m/z 205.05 (M+1)+.
S nthesis of 6- 2- 4-meth l i erazin l eth l imidazo 1 2-a carbox lic acid 1114! BU38n\/\0/\ + / ’N Pd(PPh)4 /N _3_4 /\o \ \ N / THF:H20 \ N / / Toluene \ N OH Br 90°C 0 243 111 / \ I | ”:1“ [“3 E] / N N / /N —> N / NaBH(OAc)3 THF:MeOH \ Na \ N\§\ OEt 0H 0 o 113 114 To a stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridinecarboxylate (24s) (1 g, 3.72 mmol) and tetrakis(triphenylphosphine)palladium(0) (215 mg, 0.19 mmol) in anhydrous toluene (10 mL) under argon was added tributyl[2-ethoxyethenyl]stannane (1.7 g, 4.65 mmol). The reaction mixture was heated in a microwave sealed tube overnight at 90 °C. The reaction was cooled to room temperature and was filtered through celite. The solvent was concentrated and the crude product was purified by silica tography to afford (E)-ethyl 6-(2-ethoxyvinyl)imidazo[1,2-a]pyridine carboxylate (111). MS m/z 261.3 .
A stirring solution of ethyl 6-(2-ethoxyvinyl)imidazo[1,2-a]pyridinecarboxylate (111) (240 mg, 1.15 mmol) in THF:H20 (1:1, 4 mL) was heated at 50 °C overnight. The reaction was cooled to room temperature and neutralized with saturated solution of sodium bicarbonate. The ccrude product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and crude ethyl 6-(2-oxoethyl)imidazo[1,2-a]pyridine carboxylate (112) was used in the next step without further purification. MS m/z 233.3 (M+1) f.
To a stirring solution of crude ethyl 6-(2-oxoethyl)imidazo[1,2-a]pyridine carboxylate (112) (214 mg ,0.92 mmol) in DCM (5 mL) and 1-methylpiperazine (231 uL, 2.30 mmol) at room temperature was added portion-wise sodium triacetoxyborohydride (586 mg, 2.77 mmol). The reaction was stirred at room temperature overnight. The solvent was concentrated. The crude was taken in 10% sodium bicarbonate and ethyl e. The organic was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by silica chromatography to afford methyl 6-(2-(4-methylpiperazinyl)ethyl)imidazo[1,2- a]pyridinecarboxylate (113). MS m/z 304.4 (M+1) +.
To a stirring solution of methyl 6-(2-(4-methylpiperazinyl)ethyl)imidazo[1,2- dinecarboxylate (113) (215 mg, 0.68 mmol) in THFzMeOH (4:1, 4 mL) was added 2N LiOH (3 mL). The on was heated at 60 °C for 45 minutes. The pH was adjusted between 4-5 with 1N HCI and concentrated. The crude product was purified by preparative HPLC to affod 6-(2-(4-methylpiperazinyl)ethyl)imidazo[1,2-a]pyridine ylic acid (114). 1H NMR (400MHz, de-DMSO) 6 9.25 (s, 1H), 8.35 (s, 1 H), 7.83 (d, J: 9.2 Hz, 1H), 7.61 (dd, J: 1.6, 9.2 Hz, 1H), 4.65 — 4.19 (m, 8H), 3.49 — 3.30 (m, 2H), 3.04 — 2.99 (m, 2H), 2.81 (s, 3H). MS m/z 316.1 (M+1)+.
S nthesis of 6-acet l-N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen limidazof 2-a ridinecarboxamide 115 / /N mN 1. oxalylchloride \ N / + H2” NZ‘O DCM 0 OH F 2. Pyridine 24r 37 F 0°C to RT 115 F To a stirring suspension of 6-acetylimidazo[1,2-a]pyridinecarboxylic acid (24r) (71 mg, 0.39 mmol) in dichloromethane (2 mL) was added dropwise oxalyl chloride (173 uL, 1.98 mmol) and a drop of anhydrous N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 30 minutes and concentrated. The residue was d with 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylaniline (37) (85 mg, 0.29 mmol) in anhydrous pyridine (2 mL) with stirring at room temperature for 30 s. The crude product was purified on silica gel using 10% MeOH in dichloromethane to give 6- acetyl-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2- a]pyridinecarboxamide (115). 1H NMR (400MHz, d6-DMSO) 610.24 (s, 1H), 10.13 (s, 1 H), 8.70 (s, 1 H), 8.08 (d, J = 1.6 Hz, 1 H), 7.95 (dd, J = 2.0, 9.6 Hz, 1 H), 7.88 — 7.84 (m 2H), 7.52 (d, J: 8.4 Hz, 1 H), 3.92 — 3.84 (m, 1 H), 3.24 — 3.02 (m, 4H), 2.64 (s, 3H), 2.38 (s, 3H). MS m/z 433.16 (M+1)+.
S nthesis of 5- 5- 3-methox trifluorometh l c clobut l -1 2 4-oxadiazol l methlaniline 125 ONI HEN” Hofimoc_, 02p\E\ ON/ \ E TMSCF3, TBAF O 27 122 /N‘ “5,, / /N\ N o N 0 \o’ ‘o o SnCl \ 2 02” / N‘hcszcog. DMF —> N‘ —.2 H2N CF3 h CF3 OH 0 NE 123 124 / 125 /O To a stirring solution of 3-oxocyclobutanecarboxylic acid (595 mg, 5.12 mmol) in 1- methylpyrrolidinone (6 mL) was added 1,1'-carbonyldiimidazole (831 mg, 5.12 mmol).
The reaction was stirred for 5 minutes. Then, N'-hydroxymethylnitrobenzimidamide (27) (500 mg, 2.56 mmol) was added and the reaction was d for 15 minutes. Next, the reaction was heated in the microwave at 130 °C for 10 minutes. The crude product was taken in ethyl acetate and water. The organic was washed with 2x water/brine mixture and dried over anhydrous sodium e. The solvent was concentrated and the crude product was purified by silica chromatography to afford 3-(3-(4-methyl nitrophenyl)-1,2,4-oxadiazolyl)cyclobutanone (122). MS m/z 274.07 .
To a stirring solution of 3-(3-(4-methylnitrophenyl)-1,2,4-oxadiazol yl)cyclobutanone (122) (250 mg, 0.915 mmol) in anydrous THF (2 mL) at 0 °C was added 3 (429 uL, 2.75 mmol) and TBAF in THF and 5% water (50 uL). The reaction turned a light red color and further deepened with continuous stirring. The reaction was stirred to room temperature for 10 minutes. Then, the reaction was cooled back to 0 °C and TBAF in THF and 5% water (0.4 mL) was slowly added and the reaction was stirred for 25 minutes at room temperature. The reaction turned into a deep purple color. The solvent was concentrated and the crude product 4-methyl nitrophenyl)-1,2,4-oxadiazolyl)(trifluoromethyl)cyclobutanol (123) was purified by silica chromatography (tlc hexanes:ethylacetate (3:2)). 344.08 (M+1)+.
To a stirring suspension of 3-(3-(4-methylnitrophenyl)-1,2,4-oxadiazolyl) (trifluoromethyl)cyclobutanol (123) (65 mg, 0.189 mmol) and cesium carbonate (93 mg, 0.284 mmol) in anhydrous DMF (1 mL) was added dimethyl sulfate (18 L, 0.189 mmol).
The reaction was stirred at room temperature overnight. The reaction was poured into a separatory funnel containing water and ethyl e. The organic was washed with 2x brine mixture and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography. (124). MS m/z 358.09 .
Step 4. A stirring mixture of 5-(3-methoxy(trifluoromethyl)cyclobutyl)(4-methyl nitrophenyl)-1,2,4-oxadiazole (124) (40 mg, 0.112 mmol) and tin (ll) chloride dihydrate (101 mg, 0.448 mmol) in ethanol (2 mL) was heated at 65 °C for 2 hours. The reaction was cooled to room ature and the pH was adjusted between 8-10 with saturated sodium bicarbonate. The slurry was filtered and washed with aqueous ethanol. The solvent was partially reduced and the crude product was extracted with ethyl acetate.
The organic was washed with 1x water and dried over anhydrous sodium sulfate. The crude product was purified by silica tography to yield 5-(5-(3-methoxy uoromethyl)cyclobutyl)-1,2,4-oxadiazolyl)methylaniline (125). 1H NMR z, de-DMSO) 6 10.24 (s, 1H), 10.13 (s, 1H), 8.70 (s, 1H), 8.08 (d, J: 1.8 Hz, 1H), 7.95 (dd, J = 2.0, 9.8 Hz, 1 H), 7.88 — 7.84 (m, 2H), 7.52 (d, J = 8.4 Hz, 1 H), 3.92 — 3.84 (m, 1 H), 3.24 — 3.02 (m, 4H), 2.84 (s, 3H), 2.38 (s, 3H). MS m/z433.18 (M+1)+.
S nthesis of 5- 5- 1R 2S fluoroc clo r0 | -1 2 4-oxadiazol l meth laniline and - 5- 1S 2R fluoroc clo r0 | -1 2 4-oxadiazol l meth laniline 131 and 132 WO 33070 2012/052621 OzhmN\OH Zn ”“2 N CDI, NMP 02N /N‘o NH4C| H2N / ‘o 27 —’ Nt/ _' Nté MW115°C EtOH/H20(4-1) ..
+ F F ‘>’ j . c trans D’ racemic trans ,,,,, HO V” 129 130 racemic trans Chiral chromatography 131 132 Peak 1 Peak 2 Arbitrarily assigned (1R, 2S} Arbitrarily assigned (1 8, 2R} To a stirring solution of transFluoro-cyclopropanecarboxylic acid (0.38 g, 3.68 mmol) in anhydrous NMP (12 mL) was added 1,1 '-carbony|diimidazo|e (CDI) (0.59 g, 3.68 mmol). The reaction was stirred for 3 minutes. N'-hydroxymethyl nitrobenzimidamide (27) (0.72 g, 3.68 mmol) was added and the reaction was stirred for minutes then heated in the microwave at 120 °C for 15 minutes. The crude product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified on silica gel using ethyl acetate and hexane to yield 5-(2- fluorocyclopropyl)(4-methylnitrophenyl)-1,2,4-oxadiazole (129). MS m/z 264.1 (M+1)+.
To a suspenion of 5-(2-fluorocyclopropyl)(4-methylnitrophenyl)-1,2,4- oxadiazole (129) (162 mg, 0.62 mmol) in EtOHzH20 (4:1) (3.3 mL) was added zinc dust (161 mg, 2.46 mmol) and ammonium chloride (132 mg, 2.46 mmol). The reaction mixture was heated at 85 °C for 24 hours, then filtered hot over celite and rinsed with ethyl acetate. The solvent was concentrated to give 2-fluorocyclopropyl)-1,2,4- oxadiazolyl)methylaniline (130).
The tion of enantiomers was performed using a 21.2 x 250 mm Lux-Cellulose- 2 column at a flow rate of 80g/min, using COz/Methanol (85: 15) at 30 oC. Analytical methods using the same column and solvent e showed peak 1 eluting at 2.80 min, and peak 2 at 3.28 min. Peak 1 was arbitrarily assigned to be the isomer (1R,28)- 2-f|uorocyc|opropy|)-1,2,4-oxadiazoIyl)methylaniline (131) and Peak 2 was assigned to be the isomer 5-(5-((1S,2R)f|uorocyclopropyl)-1,2,4-oxadiazolyl) methylaniline (132). MS m/z234.1 (M+1)+.
S nthesis of 2-meth l 5- 2 2 3 3-tetrafluoroc clobutox meth l -1 2 4-oxadiazol-3 line (138) 1. MSCI DIEA )4 DCM 1- O 3‘ J'\/OAC OK 2. K2COF3 0 : fill 03% \ 2. MW125 °C 3. TFA 0454:: NOH 3. LiOH O\©\(NN7/OH Mjfijmg—J 1380 CDI (1.76 g, 10.78 mmol) was added portion-wise to a stirred solution of 2- acetoxyacetic acid (1.27 g, 10.78 mmol) in NMP (5 mL). After 10 minutes, (Z)-tert-butyl -(N'-hydroxycarbamimidoyl)methylphenylcarbamate (35) (1.43 g, 5.39 mmol) was added in one portion and stirred for another hour at room temperature. The solution was then heated via microwave at 125 °C for 15 s. The solution was partitioned with EtOAc and water. The organic phase was separated, dried over Na2804 and concentrated to give a residue which was dissolved in TH F/MeOH/H20 (32:1, 5 mL) and followed by addition of 6N LiOH (5.4 mL). The resulting mixture was stirred for 10 minutes. Then aqueous 2M NaHCOs (30 mL) was added and the solution was extracted with EtOAc. The organic layers were dried over Na2804 and concentrated to give a residue which was ed over silica gel to afford tert-butyl (5-(5-(hydroxymethyl)-1,2,4- oxadiazolyl)methylphenyl)carbamate (137). MS m/z 306.0 (M+1)+.
Tert-butyl (5-(5-(hydroxymethyl)-1,2,4-oxadiazolyl)methylphenyl)carbamate (137) (0.35 g, 1.15 mmol) was dissovled in dichloromethane (5 mL) and ed by addtion of DIEA (0.6 mL, 3.45 mmol) and MsCl (197 mg, 1.72 mmol). The reaction was stirred for 10 minutes. The mixture was diluted with dichloromethane (10 mL) and washed with water. The organic layers were combined, dried over , filtered and concentrated to give a e which was ved in 2,2,3,3-tetrafluorocyclobutanol (2 mL) and followed by addition of K2003 (476 mg, 3.45 mmol). The reaction mixture was heated at 90 °C for 2-3 hours. The mixture was diluted with water (10 mL) and ted with EtOAc. The organic layers were combined, dried over NaZSO4, filtered and concentrated. To this residue was added TFA (1 mL) and stirred for 15 minutes. Then aqueous Na2003 (2M, 20 mL) was added and extracted with EtOAc. The organic layers were dried over NaZSO4, filtered and concentrated. Purification by column chromatography on silica gel gave 2-methyl(5-((2,2,3,3- luorocyclobutoxy)methyl)-1,2,4-oxadiazolyl)aniline (138). 1H NMR (400MHz, CDCIs) 6 9.36 (bs, 2H), 8.12 (d, J: 1.2 Hz, 1H), 7.91 (dd, J: 1.2, 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.95 (dd, J: 14.4, 68.4 Hz, 2H), 4.51 (m, 1H), 2.95 (m, 1H), 2.51-2.68 (m 4H). MS m/z332.0 (M+1)+.
S nthesis of 6- 2 4-dimeth lthiazol | imidazo 1 2-a ridinecarbox lic acid 146 / N 1,4-Dioxane ’/ ium e Br [(c H)3P] PdCl6 5)?) 2 2 /95°c O/\ fig!“ O/\ 0 BFH 1,4-Dioxane ’ 2M N82C03 S /N T (C17H14P)2Fe - PdCl2 135 °c / /N THF:MeOH (4:1) / /N 2N LiOH \ N / \ N\i N):s /\ OH s o o N): o 146 145 A mixture of ethyl 6-bromoimidazo[1,2-a]pyridinecarboxylate (24s) (500 mg, 1.86 mmol), bis(pinacolato)diboron (472 mg, 1.86 mmol), dichlorobis (triphenylphosphine)palladium (65 mg, 0.093 mmol) and potassium acetate (456 mg, 4.65 mmol) in ous dioxane (8 mL) was heated at 95 °C for 4 hours. The reaction turned black. The reaction was cooled and filtered through . The solvent was concentrated. The oil was taken in EtOAc. The organic was washed with water/brine mixture, brine and dried over anhydrous sodium sulfate. The crude t was purified by silica chromatography. MS m/z 317 (M+1)+.
A mixture of 5-bromo-2,4-dimethylthiazole (171 mg, 0.89 mmol), ethyl 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)imidazo[1,2-a]pyridinecarboxylate (144) (250 mg, 1.07 mmol), [1 ,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(|l) (39 mg, 0.05 mmol) and a solution of 2M sodium carbonate (300 uL) in ous dioxane (4 mL) was heated in the microwave at 135 °C for 25 s. The reaction was filtered through celite. The crude product was taken in water and ethylacetate. The organic was washed with water/brine mixture and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography. MS m/z 302.09 (M+1)+.
A mixture of ethyl 6-(2,4-dimethylthiazolyl)imidazo[1,2-a]pyridinecarboxylate (145) (190 mg, 0.630 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1 4 mL) was heated at 60 °C for 30 minutes. The reaction was cooled to room temperature and the pH was adjusted between 4-5 with 10% citric acid. The solvent was lly reduced and the resulting solid was collected by vacuum filtration to give 6-(2,4-dimethylthiazol y|)imidazo[1,2-a]pyridinecarboxylic acid (146). 1H NMR (400MHz, d6-DMSO) 6 9.34 (s, 1H), 8.29 (s, 1H), 7.87 (dd, J: 0.8, 9.2 Hz, 1H), 7.62 (dd, J: 2.0, 9.2 Hz, 1H), 2.66 (s, 3H), 2.41 (s, 3H). MS m/z 274.06 (M+1)+.
S nthesis of 5- 5- 2 uoroc clo ro l -1 2 4-oxadiazol l -2 4-dimeth Ianiline 150 EtOH/ DIEA/ sulfuric acid Hydroxylamine HCI U nitric acid 78 °c ’ H ' CN OZN CN 02N / ‘OH 147 148 O NMP/ CDI/ 130 °C ”OWF F H2N O EtOH/ SnCI2 02N N\ N\ F 78 °c F ‘49 &F 150 &F To a ng on of 2,4-dimethylbenzonitrile (1 g, 7.62 mmol) in sulfuric acid (12 mL) at -10 °C was added dropwise nitric acid (325 uL, 7.62 mmol) over a period of 10 minutes. The reaction was stirred between -10 to 0 °C for 10-15 minutes. The reaction was monitored by tlc for completion. The reaction was poured into a flask containing ice.
The resulting solid was ted by vacuum filtration and washed with excess water. MS m/z 177.06 (M+1)+.
A stirrng mixture of 2,4-dimethylnitrobenzonitrile (147) (3.5 g, 19.58 mmol), hydroxylamine hydrogen de (2 g, 29.38 mmol) and N,N-diisopropylethylamine (6.8 mL, 39.17 mmol) in ethanol (40 mL) was heated at 78 °C for 2.5 hours. The reaction was cooled to room temperature and the solvent was concentrated. The crude product was purified by silica chromatography. MS m/z210.08 (M+1)+.
To a stirring solution of 2,2-difluorocyclopropanecarboxylic acid (100 mg, 0.819 mmol) in ous 1-methylpyrrolidinone (2 mL) was added 1,1'-carbony|diimidazo|e (133 mg, 0.819 mmol). The reaction was stirred for 5 minutes. Then, the reaction was added to a flask containing N'-hydroxy-2,4-dimethylnitrobenzimidamide (148) (171 mg, 0.819 mmol) and the reaction was stirred for 25 minutes. Next, the reaction was heated in the ave at 130 °C for 12 minutes. The reaction was taken in ethyl acetate and water. The organic was washed with water/brine e and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography. MS m/z 296.08 (M+1)+.
A stirring mixture of 5-(2,2-difluorocyclopropyl)(2,4-dimethylnitrophenyl)-1,2,4- oxadiazole (149) (190 mg, 0.644 mmol) and tin (ll) chloride dihydrate (581 mg, 2.57 mmol) in ethanol (10 mL) was heated at 78 °C for 2 hours. The reaction was cooled to room temperature and the pH was adjusted to basic with a saturated solution of sodium onate. The resulting solid was filtered through a plug of celite and washed with excess ethanol. The solvent was partially reduced and the crude product was extracted with ethyl acetate. The organic was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by silica chromatography. 1H NMR (400MHz, O) 6 7.21 (s, 1H), 6.93 (s, 1H), 4.96 (s, 2H), 3.70 — 3.62 (m, 1 H), 2.47 — 2.41 (m, 1 H), 2.37 — 2.28 (m, 1 H), 2.35 (s, 3H), 2.08 (s, 3H). MS m/z 266.10 (M+1)+.
S nthesis of N- 5- 5- 1-aminoc clo ro l -1 2 4-oxadiazol l -2 meth l hen limidazo1 2-a ridinecarboxamide 156 “(YIN /N\ 4N HCI \ H O N N/VLNm%v/\ dioxane HN \N/ O/xo F67 fl 156 To a vial was added tert-butyl (1 -(3-(3-(imidazo[1 ,2-a]pyridinecarboxamido) methylphenyl)-1,2,4-oxadiazolyl)cyclopropyl)carbamate (F67) (275 mg, 0.6 mmol) and 4N HCI in 1,4-dioxane (3 mL). The reaction was stirred for 30 minutes. The solvent was concentrated and placed under high vacuum. The solid was taken in water/acetonitrile and the pH was ed to l with an aqueous solution of ammonium carbonate and lyophilized to afford N-(5-(5-(1-aminocyclopropyl)-1,2,4-oxadiazolyl)-2 methylphenyl)imidazo[1,2-a]pyridinecarboxamide (156). MS m/z 375.1 (M+1)+.
S nthesis of 1- tert-butox carbon l amino -3 uoroc clobutanecarbox lic acid 164 O 0 E102C COzEt EC C2 CO2Et Br M HQCIZ EtO OEt H2, Pd/C PCC Cl\/Q+ —> —> —> O NaH, 1,4—dioxane O EtOH OH DCM Ph Ph 157 158 159 EtO C2 CO Et2 EtO C2 CO Et2 302C COZH EtO C2 H ‘BOC LiOH H02C NHBoc DAST DPPA —> —> F F EtOl-l: H20 (5:1) o F F TEA,It—BuOH F F 1,4—dloxane F F 160 161 162 163 164 To a stirred mixture of benzyl bromide (10g, 59 mmol) and (88 mg) of y chloride was added epichlorohydrin (5.4g, 59 mmol). The reaction e was heated for 12 hours at 100 oC. Product formation was confirmed by TLC. The crude product was purified by column chromatography using 20% ethyl acetate/hexanes to give (((1- bromochloropropanyl)oxy)methyl)benzene (157). 1H NMR (400MHz, CDZClz) 6 7.4 — 7.36 (m, 5H), 4.69 (d, J = 2.4 Hz, 2H), 4, 3.90 — 3.85 (m, 1 H), 3.77 (d, J = 5.2 Hz, 2H), 3.63 (q, J: 2.4 Hz, 2H). MS m/z 263.10 (M+1)+.
To a stirred sion of sodium hydride (920 mg, 23 mmol, 60% in l oil) in dry dioxane (33 mL), was added diethyl ma|onate (3.5 mL, 23 mmol) dropwise over min. After the addition was complete, (((1-bromochloropropan y|)oxy)methy|)benzene (157) (6.1g, 23 mmol) was added over 20 minutes. The mixture was then heated at reflux for 24 hours. After cooling to room temperature, sodium e (920 mg, 23 mmol) in dioxane (2 mL) was added to the mixture and heating at reflux for r 48 hours. The solvent was partially d under reduced pressure and the e was treated with water (50mL). The mixture was extracted with ethyl acetate (3 x 30 mL), dried with magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography using hexanes/ ethyl acetate as eluent (25%) to yield diethyl 3-(benzyloxy)cyclobutane-1,1-dicarboxylate (158). 1H NMR (400MHz, CDZCIZ) 6 7.39 — 7.30 (m, 5H), 4.4 (s, 2H), 4.23 — 4.13 (m, 5H), 2.83 — 2.78 (m, 2H), 2.55 — 2.49 (m, 2H), 1.32 — 1.25 (m, 6H). MS m/z 307.2 (M+1 )+.
To a solution of diethyl 3-(benzyloxy)cyclobutane-1,1-dicarboxylate (158) (1 .43g, 4.7 mmol) in EtOH (18 mL) was added 10% palladium on carbon (143 mg) and the e was enated with a H2 balloon for 12 hours at room ature. The catalyst was removed by filtration using celite, washed with ethyl acetate and EtOH and the solvent was removed under reduced pressure. The crude product was purified via column chromatography using hexanes/ethyl acetate as eluent to yield diethyl 3- hydroxycyclobutane-1,1-dicarboxylate (159). 1H NMR (400MHz, CDZCIZ) 6 4.4 — 4.32 (m, 1 H), 4.21 (qd, J = 7.2, 2.0 Hz, 4H), 2.89 — 2.84 (m, 2H), 2.46 — 2.41 (m, 2H), 2.20 (d, J: 6.4 Hz,1H),1.27(t,J= 7.2 Hz, 6H). MS m/z217.1 (M+1)+.
To a solution of diethyl 3-hydroxycyclobutane-1,1-dicarboxylate (159) (649 mg, 3 mmol) in DCM (7 mL) was added PCC (1 .37g, 6.3 mmol) and the mixture was stirred for 4 hours at room temperature. The product was filtered through a silica gel plug and the residue was purified using column chromatography with hexanes/ethyl acetate as eluent to yield diethyl 3-oxocyclobutane-1,1-dicarboxylate (160). 1H NMR (400MHz, CD2CI2) 6 4.28 (q, J: 7.2 Hz, 4H), 3.63 (s, 4H), 1.31 (t, J: 7.2 Hz, 6H). MS m/z 215.1 (M+1)+.
To a cooled solution of diethyl 3-oxocyclobutane-1,1-dicarboxylate (160) (4.8g, 22 mmol) in dry DCM (53 mL) was added dropwise a solution of DAST (6.6 mL, 50.2 mmol) and the mixture was stirred at room temperature overnight. The mixture was poured onto ice water and was ted three times with DCM. The solution was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using 25% ethyl acetate/hexanes as eluent to yield diethyl 3,3-difluorocyclobutane-1,1-dicarboxylate (161). 1H NMR (400MHz, CD2Cl2) 64.14 (q, J = 7.2 Hz, 4H), 3.04 (t, J: 12.0 Hz, 4H), 1.18 (t, J: 6.8 Hz, 6H). MS m/z 237.1 (M+1)+.
Diethyl fluorocyclobutane-1,1-dicarboxylate (161) (2.8g, 12 mmol) was dissolved in ice cooled ethanolic potassium hydroxide solution (0.5 M, 11 mL) and water (2.2 mL). The mixture was d at room temperature overnight. An additional 0.5 eq was added to the solution at room temperature and the mixture was stirred at room temperature overnight. Water was added and most of the EtOH was removed under d pressure. The mixture was acidified with 2M HCI and extracted three times with ethyl acetate. The organic layer was dried with magnesium sulfate and concentrated to yield 1-(ethoxycarbonyl)-3,3-difluorocyclobutanecarboxylic acid (162). 1H NMR (400MHz, CDZCIZ) 6 4.33 — 4.24 (m, 2H), 3.26 — 3.13 (m, 4H), 1.34 — 1.27 (m, 3H). MS m/z 209.2 (M+1)+.
To a solution of 1-(ethoxycarbonyl)-3,3-difluorocyclobutanecarboxylic acid (162) (1g, 4.8 mmol) in dry dioxane (18 mL) was added tert-butanol (0.4 mL, 4.3 mmol), DPPA (1.03 mL, 4.8 mmol) and TEA (0.7mL, 4.9 mmol) and the e was refluxed overnight.
Ethyl acetate was added and the c layer was washed twice with 5% citric acid and saturated sodium hydrogen carbonate. The solution was dried and evaporated under reduced pressure. The product was purified using silica gel chromatography using hexanes/ethyl acetate to yield ethyl 1-((tert-butoxycarbonyl)amino)-3,3- difluorocyclobutanecarboxylate (163). 1H NMR z, CD20I2) 6 4.12 (q, J = 6.8 Hz, 2H), 3.18 — 3.08 (m, 2H), 2.73 — 2.55 (m, 2H), 1.34 (s, 9H), 1.19 (t, J = 6.8 Hz, 4H). MS m/z 280.1 (M+1)+.
To a stirring solution of ethyl 1-((tert-butoxycarbonyl)amino)-3,3- difluorocyclobutanecarboxylate( 163) (282 mg, 1.01 mmol) in THF:MeOH:H20 (32:1, 2 mL), was added 3N LiOH (1 mL) and stirred at room temperature. The pH was adjusted to between 4-5 with sodium bisulfate monohydrate and concentrated. The crude product (164) was used in the next step without r purification. MS m/z 252.1 (M+1)+.
S s of N- 5- 5- 1-amino-3 3-difluoroc clobut l -1 2 4-oxadiazol l methylphenyl)imidazo|1,2-a|pyridinecarboxamide (166) WO 33070 NVanr/N‘H0 N \ N / \ NHBOC aN\NHLHN N‘ONHB H 00 Q\ N NHZOH NMP RT MW 120°C 9 164 165 4N HCI LN\ ONH2HCI dioxane N/ To a stirring solution of 1-((tert-butoxycarbonyl)amino)-3,3- difluorocyclobutanecarboxylic acid (164) (45 mg, 0.18 mmol) in anhydrous NMP (1.3 mL) was added 1,1 '-carbonyldiimidazole (CDI) (29 mg, 0.18 mmol). The reaction was stirred for 3 minutes. N-(5-(N'-hydroxycarbamimidoyl)methylphenyl)imidazo[1,2- a]pyridinecarboxamide (9) (69 mg, 0.22 mmol) was added and the reaction was stirred for 25 minutes. Then, the reaction was heated at 120 °C for 15 s. The crude product was taken up in ethyl acetate and water. The organic was washed with 2x water/brine mixture and dried over magnesium sulfate. The solvent was concentrated and the crude product was purified using silica gel chromatography using 60% ethyl acetate/hexanes to afford tert-butyl (3,3-difluoro(3-(3-(imidazo[1,2-a]pyridine amido)methylphenyl)-1,2,4-oxadiazolyl)cyclobutyl)carbamate (165). MS m/z 525.2 (M+1) + To a flask was added tert-butyl (3,3-difluoro(3-(3-(imidazo[1,2-a]pyridine carboxamido)methylphenyl)-1,2,4-oxadiazolyl)cyclobutyl)carbamate (165) (169 mg, 0.3 mmol) and 4N HCI in 1,4-dioxane (1 mL). The reaction was stirred for 30 minutes.
The solvent was concentrated and placed under high vacuum to afford N-(5-(5-(1-amino- 3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridine carboxamide hydrochloride (166). MS m/z 425.2 (M+1)+.
Synthesis of final compounds 8 nthesis of N- 5- 5- 1s 3s h drox meth lc clobut l -1 2 iazol l methylphenyl)imidazo|1,2-a|pyridinecarboxamide (F6) N\VkN M M c1 N H o e g \ N / \ N N\ N —: \ H o N N\ \ / THF,-78°C F6 .
O l’ The ketone ethyl(5-(3-oxocyclobutyl)-1,2,4-oxadiazol y|)pheny|)imidazo[1,2-a]pyridinecarboxamide (10) (0.3 g, 0.77 mmol) in THF (5 mL) was added to a stirred solution of MeMgCl (1.3 mL, 3.9 mmol, 3 M in THF) in THF (20 mL) at -78 °C. After addition, the ing solution was warmed to 0 °C and quenched with saturated NH4CI. The mixture was partitioned with EtOAc and the organic phase was washed with brine and dried over MgSO4. After evaporation the residue was purified over silica gel using 10% MeOH in dichloromethane to obtain N-(5-(5-((1s,3s)hydroxy- 3-methylcyclobutyl)-1,2,4-oxadiazolyl)methy|phenyl)imidazo[1,2-a]pyridine carboxamide (F6). 1H NMR (400MHz, H) 6 9.53 (d, J: 7.2 Hz, 1H), 8.49 (s, 1H), 8.13 — 8.12 (m, 1H), 7.90 (dd, J: 8.2, 2.0 Hz, 1H), 7.75 (d, J: 9.6 Hz, 1H), 7.60 — 7.55 (m, 1H), 7.48 (d, J: 8.0 Hz, 1H), 7.18 (ddd, J: 7.2, 7.2, 1.2 Hz, 1H), 3.48 — 3.40 (m, 1H), 2.58 — 2.54 (m, 4H), 2.42 (s, 3H), 1.48 (s, 3H). MS m/z 404.1 (M+1) +.
S nthesis of N- 5- 5- 3- methox imino c clobut l -1 2 4-oxadiazol l meth l hen limidazo1 2-a ridinecarboxamide F7 0 my O NVLN C|H3N—OMe N N / \ / ~ O Ps-cos MEAN H H O \ N N\ —> \ N N\ MeOH \ / \ / F7 O N‘OMe NHsOMeCI (60 mg, 0.67 mmol) was added in one portion to a stirred suspension of N-(2-methyl(5-(3-oxocyclobutyl)-1,2,4-oxadiazolyl)phenyl)imidazo[1,2-a]pyridine carboxamide (10) (0.13 g, 0.33 mmol) and polymer supported carbonate (0.5 g) in MeOH (10 mL). After 3 hours at room temperature the e was filtered and concentrated.
The residue was dissolved in isopropanol and N-(5-(5-(3-(methoxyimino)cyclobutyl)- 1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridinecarboxamide (F7) was precipitated by adding EtzO. 1H NMR (400MHz, d4-MeOH) 6 9.55 (d, J: 7.2 Hz, 1H), 8.50 (s, 1H), 8.13 — 8.12 (m, 1H), 7.90 (dd, J: 8.2, 2.0 Hz, 1H), 7.75 (d, J: 9.6 Hz, 1H), 7.80 — 7.55 (m, 1 H), 7.48 (d, J : 8.0 Hz, 1 H), 7.18 (ddd, J : 7.2,7.2,1.2 Hz, 1 H), 4.02 — 3.94 (m, 1 H), 3.82 (s, 3H), 3.57 — 3.30 (m, 4H), 2.88 (s, 3H). MS m/z417.1 (M+1) +.
S nthesis of N- 5- 5- 5 8-dioxas iro 3.4 octan l -1 2 4-oxadiazol l methylphenyl)imidazo|1,2-a|pyridinecarboxamide (F8) Om O Ho OH NVLN N N / \ TSOH / ‘ H N/YLN \ H O \ N N\0 —> N N\ \ / Toluene,1000C \ / F8 Ethylene glycol (10 mg), TsOH (5 mg) and N-(2-methyl(5-(3-oxocyclobutyl)-1,2,4- oxadiazolyl)phenyl)imidazo[1,2-a]pyridinecarboxamide (10) (50 mg) were combined in toluene (3 mL) and heated at 100 °C for 5 hours. The reaction was filtered and ed by preparative reverse phase HPLC to afford N-(5-(5-(5,8-dioxaspiro[3.4]octanyl)- 1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridinecarboxamide (F8). 1H NMR (400MHz, d4-MeOH) 6 9.53 (d, J: 7.2 Hz, 1H), 8.50 (s, 1H), 8.13 — 8.12 (m, 1H), 7.90 (dd, J = 8.2, 2.0 Hz, 1 H), 7.75 (d, J = 9.6 Hz, 1 H), 7.60 — 7.55 (m, 1 H), 7.48 (d, J = 8.0 Hz, 1H), 7.18 (ddd, J: 7.2, 7.2, 1.2 Hz, 1H), 4.45 —4.43 (m, 1H), 3.98 — 3.81 (m, 4H), 3.32 — 3.31 (m, 4H), 2.43 (s, 3H). MS m/z 432.1 (M+1)+.
S nthesis of N- 5- 5- 3-fluoroc clobut l -1 2 4-oxadiazol l meth l hen limidazo1 2-a ridinecarboxamide F13 F N + VLN o \ N /N\ \N N\ N F \N H OH W —» NH2 HO NMP,RT U MW120°C To a stirring solution of 3,3-difluorocyclobutanecarboxylic acid (264 mg, 1.94 mmol) in anhydrous NMP (6 mL) was added arbonyldiimidazole (315 mg, 1.94 mmol). The reaction was stirred for 5 s. 5-(N'-hydroxycarbamimidoyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (9) (500 mg, 1.62 mmol) was added and the reaction was stirred for 25 minutes, then heated in the microwave at 120 °C for 12 minutes. The crude product was purified by silica chromatography to give N-(5-(5-(3- f|uorocyc|obuty|)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridine carboxamide (F13). 1H NMR (400MHz, de-DMSO)610.19 (s, 1H),9.53 — 9.50 (m, 1H), 8.70 (s, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.90 — 7.87 (m, 1H), 7.83 (d, J = 1.8, 8.0 Hz, 1H), 7.70 — 7.85 (m, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.33 — 7.29 (m, 1 H), 3.93 —3.84 (m, 1H), 3.25 — 3.02 (m, 4H), 2.37 (s, 3H). MS m/z 410.3 (M+1)+.
S nthesis of N- 5- 5- 1s 3s ox ethox c clobut l -1 2 iazol l methylphenyl)imidazo|1,2-a|pyridinecarboxamide (F18) NON”\\N SEW 1. NaH N H o —> \N N\ HOMr 2 2 e Q F1 8 OfOMe NaH (26 mg, 064 mmol))was added'In one portion to a stirred solution of above alcohol (19) (0.1 g, 0.25 mmol). After1 hour at room temperature, 1-bromo methoxyethane (0.27 mmol) was added dropwise and the resulting solution was heated at 50 °C for 2 hours. The reaction was quenched with MeOH and purified with reverse phase HPLC to give N-(5-(5-((1s,3s)(2-methoxyethoxy)cyclobutyl)-1,2,4-oxadiazol methylphenyl)imidazo[1,2-a]pyridinecarboxamide (F18). 1H NMR (400MHz, d4- MeOH) 5 9.78 (d, J: 7.2 Hz, 1H), 8.79 (s, 1H), 8.15 (d, J: 2.0 Hz, 1H), 8.02 (m, 2H), 7.93 (dd, J: 8.2,1.6 Hz, 1H), 7.60 — 7.56 (m, 1H), 7.50 (d, J: 8.0 Hz, 1H), 4.17 — 4.09 (m, 1 H), 3.59 — 3.52 (m, 4H), 3.45 — 3.38 (m, 1 H), 3.37 (s, 3H), 2.85 — 2.78 (m, 2H), 2.72 —2.54 (m, 2H), 2.44 (s, 3H). MS m/z 448.1 (M+1)+.
S nthesis of N- 5- 5- 3-h drox trifluorometh l c clobut l -1 2 4-oxadiazol l meth l hen limidazo1 2-a ridinecarboxamide F25 N\\ N/N\ /N \O 1. TMSCFgcat. TBAF NVKN \O N/ N/\ To a stirring solution of N-(2-methyl(5-(3-oxocyclobutyl)-1,2,4-oxadiazol yl)phenyl)imidazo[1,2-a]pyridinecarboxamide (10) (150 mg, 0.387 mmol) in anydrous THF (2.5 mL) at 0 °C was added trifluoromethyltrimethylsilane (121 uL, 0.774 mmol) and TBAF (100 uL in THF and 5% water). The reaction was stirred to room temperature for 3 hours. Then TBAF (0.5 mL in THF and 5% water) was added and the on was stirred for 1 hour. The solvent was concentrated and the crude product was ved in ethyl acetate. The c phase was washed with a water, brine and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to yield N-(5-(5-(3-hydroxy(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (F25). 1H NMR (400MHz, d6-DMSO) 10.04 (s, 1 H), 9.47 — 9.45 (m,1 H), 8.60 (s, 1 H), 8.09 (d, J: 1 .6 Hz, 1 H), 7.83 (dd, J : 2.0, 8.0 Hz, 1H), 7.80 — 7.78 (m, 1H), 7.55 — 7.50 (m, 1H), 7.50 (d, J: 8.0 Hz, 1H), 7.20 — 7.16 (m, 1 H), 6.92 (s, 1 H), 3.32 — 3.28 (m, 1 H), 2.99 — 2.93 (m, 2H), 2.68 — 2.60 (m 2H), 2.37 (s, 3H). Ms m/z 458.41 (M+1)+. 2012/052621 S nthesis of N- 5- 5- 1- dimeth lamino c clo ro l -1 2 4-oxadiazol l meth l hen limidazof 2-a ridinecarboxamide F29 / \Z /ZZ To a stirring solution of N-(5-(5-(1-aminocyclopropyl)-1,2,4-oxadiazolyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (156) (0.02 mmol) and CHzO (30 %wt. aqueous solution, 0.2 mL) was added HCOZH (40 %wt. aqueous solution, 0.2 mL).
The on mixture was heated at reflux for 1 hour. The solvent was removed and the crude was purified by preparative HPLC to afford N-(2-methyl(5-((1- (methylsulfonyl)azetidinyl)methyl)-1,2,4-oxadiazolyl)phenyl)imidazo[1 ,2-a]pyridine- 3-carboxamide (F29). MS m/z 403.2 (M+1)+.
S nthesis of N- 5- 5- 3-c clo ro lh drox c clobut l -1 2 4-oxadiazol l meth l hen limidazof 2-a ridinecarboxamide F31 rim/(93%“o\ H O >~__MgBr N N\ NAHOQYNo‘ O THF \ / -78°Cto RT \ F31 HO To a stirring on of N-(2-methyl(5-(3-oxocyclobutyl)-1,2,4-oxadiazol nyl)imidazo[1,2-a]pyridinecarboxamide (10) (250 mg, 0.645 mmol) in anhydrous THF (10 mL) at -78 °C under Argon was added cyclopropylmagnesium e (2.6 mL, 1.3 mmol). The reaction was stirred for 30 minutes at room temperature and quenched with 1N HCI at 0 °C. The crude product was extracted with ethylacetate. The organic layer was washed with saturated ammonium chloride, water and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to give 5— (3-cyclopropylhydroxycyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2- a]pyridinecarboxamide (F31). 1H NMR (400MHz, de-DMSO) 610.04 (s, 1H), 9.47 — 9.45 (m, 1 H), 8.59 (s, 1 H), 8.07 (d, J: 1 .8 Hz, 1 H), 7.83 — 7.78 (m, 2H), 7.55 — 7.52 (m 1H), 7.49 (d, J: 8.0 Hz, 1H), 7.20 — 7.18 (m, 1H), 5.19 (s, 1H), 4.37 — 4.35 (m, 1H), 3.48 — 3.40 (m, 1 H), 2.45 — 2.40 (m, 2H), 2.38 (s, 3H), 1.54 — 1.41 (m, 2H), 1.19 — 1.14 (m 1H), 0.34 — 0.28 (m, 2H), 0.22 — 0.11 (m, 1 H). MS m/z 430.47 (M+1 )+.
S nthesis of N- 5- 5- 3- 3-h drox ro lidene c clobut l -1 2 4-oxadiazol l methylphenyl)imidazo|1,2-a|pyridinecarboxamide (F32) 0 o NVLN / ‘o H /N\O \ N N\ MeOH \NHN N\ \ / TFA \ / F113 HO F32 A stirring solution of N-(5-(5-(3-cyclopropylhydroxycyclobutyl)-1,2,4-oxadiazol yl)methylphenyl)imidazo[1,2-a]pyridinecarboxamide (F113) (130 mg, 0.303 mmol) in triiluoroacetic acid (1 mL) was stirred at room temperature for 1.5 hours. The solvent was concentrated and dried under high vacuum. The crude product was taken in MeOH (1 mL) and a saturated solution of sodium bicarbonate (0.2 mL). The reaction mixture was stirred for 15 minutes. The crude product was extracted with ethyl acetate. The organic phase was washed with water and dried over ous sodium sulfate. The t was trated to obtain the desired product N-(5-(5-(3-(3- ypropylidene)cyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1 ,2- a]pyridinecarboxamide (F32). 1H NMR (400MHz, d6-DMSO) 610.04 (s, 1H), 9.48 — 9.45 (m, 1H), 8.59 (s, 1H), 8.08 (d, J: 1.6 Hz, 1H), 7.82 (dd, J: 1.6 Hz, 7.6 Hz,1H), 7.81 — 7.77 (m, 1 H), 7.55 — 7.52 (m, 1 H), 7.49 (d, J: 8.0 Hz, 1 H), 7.20 — 7.18 (m, 1 H), .28 — 5.23 (m, 1 H), 4.50 (s, 1 H), 3.98 — 3.89 (m, 1 H), 3.40 — 3.37 (m, 2H), 3.23 — 3.14 (m, 2H), 3.09 — 3.03 (m, 2H), 2.38 (s, 3H), 2.08 — 2.02 (m, 2H). MS m/z 430.47 (M+1 )+.
S nthesis of N- 5- 5- 3-fluoroc clobut l -1 2 4-oxadiazol l meth l hen limidazo1 2-a ridinecarboxamide F36 CDI ,N\ F —> N o N + #51H \ N \ N / ~ N N‘ H HO N NHZOH NMP, RT \ / MW120°C To a stirring solution of 3-fluorocyclobutanecarboxylic acid (76 mg, 0.647 mmol) in anhydrous NMP (1.5 mL) was added 1,1'—carbonyldiimidazole (105 mg, 0.647 mmol).
The reaction was stirred for 5 minutes. 5-(N'-hydroxycarbamimidoyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (9) (100 mg, 0.323 mmol) was added and the reaction was stirred for 25 minutes, then heated in the microwave at 120 °C for 10 minutes. The crude product was purified by reverse phase preparative HPLC to give N-(5-(5-(3-iluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2- a]pyridinecarboxamide (F36). 1H NMR (400MHz, d6-DMSO) 610.18 (s, 1H), 9.53 — 9.50 (m, 1 H), 8.89 (s, 1 H), 8.07 (d, J: 1 .8 Hz, 1 H), 7.89 — 7.88 (m, 1 H), 7.84 (dd, J = 1.6, 8.0 Hz, 1H), 7.70 — 7.65 (m, 1H), 7.51 (d, J: 8.0 Hz, 1H), 7.32 — 7.29 (m, 1H), 5.48 — 5.28 (m, 1H), 3.99 —3.91 (m, 1H), 2.81 —2.73 (m, 4H), 2.37 (s, 3H). MS m/z392.14 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l h drox meth limidazo 1 2-a carboxamide F37 TIPSO 64 F H0 F37 F To a solution of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridinecarboxamide (64) (230 mg, 0.39 mmol) in THF (5 mL), was added TBAF (1M in THF, 0.43 mL) and the resulting mixture was stirred for 1 hour. THF was d and the residue was added to a mixture of water (10 mL), MeOH (5 mL) and EtOAc (5 mL). Organic solvents were removed slowly to give a precipitate which was filtered and dried to afford N-(5-(5-(3,3- difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)(hydroxymethyl)imidazo[1,2- a]pyridinecarboxamide (F37). 1H NMR z, CDCls) 6 9.39 (m, 1H), 8.42 (d, J= 1.6 Hz, 1H), 8.04 (s, 1H), 7.70 (dd, J: 1.7, 7.9 Hz, 1H), 7.60 (d, J: 9.2 Hz, 1H), 7.42 (s, 1H), 7.36 (dd, J= 1.7, 9.2 Hz, 1H), 7.23 (d, J= 8.1 Hz, 1H), 4.63 (d, J= 5.7 Hz, 2H), 3.63—3.41 (m, 1H),3.09—2.85 (m,4H), 2.28 (s,3H), 1.82 (t, J: 5.9 Hz, 1H). MS m/z 440.1 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l 2- h drox ethox imidazo12-a carboxamide F38 N / \ N\0 \ N N : H DIEA \ N DCM \ / HO/\/OH F O F HO F K2C03 ( F37 80 c1C OH F38 N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl) (hydroxymethyl)imidazo[1,2-a]pyridinecarboxamide (F37) (0125 mg, 0.285 mmol) was dissolved in DCM (1 mL) and DIEA (0.854 mmol). MsCl (0.57 mmol) was added dropwise. After 15 minutes at roomtemperature the solvent was removed. MeOH (5 mL) and water (10 mL) were added to the residue. After sonication, most of the MeOH was removed from the mixture. Solid t was filtered and dried under vacuum to WO 33070 give the crude mesylate, which was used in the next step without purification. MS m/z 518.0 (M+1)+. A mixture of (3-((5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)carbamoyl)imidazo[1,2-a]pyridinyl)methyl methanesulfonate (10.4 mg, 0.02 mmol) and K2C03 (8.3 mg, 0.06 mmol) in ethane-1,2-diol (0.5 mL) was heated at 80 °C for 20 s. The reaction mixture was purified by ative HPLC to afford N-(5- (5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)(2- hydroxyethoxy)imidazo[1,2-a]pyridinecarboxamide (F38). 1H NMR (400MHz, CDCls) 6 9.56 (m, 1H), 8.60 (d, J: 1.5 Hz, 1H), 8.21 (s, 1H), 7.89 (dd, J: 1.7, 7.9 Hz, 1H), 7.77 (d, J: 9.2 Hz, 1H), 7.60 (s, 1H), 7.50 (dd, J: 1.7, 9.2 Hz, 1H), 7.42 (d, J: 7.9 Hz,1H), 4.65 (s, 2H), 3.82 (s, 2H), 3.73—3.61 (m, 3H), 3.15 (m, 4H), 2.46 (s, 3H), 2.04 (s, 1H). MS m/z 484.2 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l 1H- 4- limidazo1 2-a ridinecarboxamide F40 N\ H \ N‘ H N \ O N N\ .
/ Pd(PPh3)4 1,4-dioxane ’ F Br 130 c’c, MW N! 42a F40 6-Bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (42a) (98.0 mg, 0.2 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (60.0 mg, 0.3 mmol), K3P04 (42.0 mg, 0.2 mmol) and Pd(PPh3)4 (46.2 mg, 0.04 mmol) were added to a flask equipped with a stir bar. The flask was evacuated and backfilled with nitrogen several times. 1,4-Dioxane (1 mL) and the reaction was heated at 130 9C for 20 minutes in a microwave r. The reaction was filtered and purified by preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)(1H-pyrazol yl)imidazo[1,2-a]pyridinecarboxamide (F40). MS m/z 476.1 (M+1)+.
S nthesis N- 5- 5- 3- 1H- razol l c clobut l -1 2 4-oxadiazol l methylphenyl)imidazo|1,2-a|pyridinecarboxamide (F45) O O HN\N NVLN /N\ v N®AN /N‘o Q os2co3 \ / A stirring mixture of 3-(3-(3-(imidazo[1,2-a]pyridinecarboxamido)methylphenyl)- 1,2,4-oxadiazolyl)cyclobutyl esulfonate (81) (25 mg, 0.0535 mmol), 1H- pyrazole (7 mg, 0.0802 mmol) and cesium carbonate (26 mg, 0.107 mmol) in anhydrous DMF (1 mL) was heated at 60 °C for 1 hour. Then, the reaction was cooled to room temperature and filtered. The crude product was ed by reverse phase preparative HPLC to give N-(5-(5-(3-(1H-pyrazolyl)cyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (F45). 1H NMR (400MHz, d6-DMSO) 10.20 (s, 1H), 9.54 — 9.51 (m, 1H), 8.71 (s, 1H), 8.10 (dd, J: 1.8, 7.2 Hz, 1H), 7.89 — 7.85 (m, 3H), 7.70 — 7.88 (m, 1H), 7.54 — 7.50 (m, 2H), 7.33 — 7.29 (m, 1 H), 8.28 — 8.25 (m, 1 H), 5.04 — 4.98 (m, 1 H), 3.82 — 3.73 (m, 1 H), 3.10 — 2.85 (m, 4 ), 2.37 (s, 3H). MS m/z 440.18 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l 1- meth lsulfon l i eridin limidazo1 2-a ridinecarboxamide F49 \ —> N H N‘ Et3N,DCM \ / \ / F 92 F49 F F HN /S\\:O O A solution of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl) (piperidinyl)imidazo[1,2-a]pyridinecarboxamide (92) (15.6 mg, 0.032 mmol) and EtsN (0.013 mL, 0.095 mmol) in dichloromethane (1 mL) was added esulfonyl de (0.0074 mL, 0.095 mmol) and stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4- oxadiazolyl)methylphenyl)(1-(methylsulfonyl)piperidinyl)imidazo[1,2- a]pyridinecarboxamide (F49). MS (m/z) 571.1 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 iazol l meth l hen l 3- oxobutyl)imidazo|1,2-alpyridinecarboxamide (F53) WO 33070 / /N O / 1.
N oxalyl chloride. N\ N\VkN \ Nfi H2N / \O DCM N H N/\0 0 OH N‘ 000 O —> \ / 78 2. Pyridine F 0 F53 F 0°C to RT F To a stirring suspension of 6-(3-oxobutyl)imidazo[1,2-a]pyridinecarboxylic acid (78) ( 150 mg, 0.646 mmol) in anhydrous dichloromethane (5 mL) at 0 °C under Argon was added dropwise oxalyl chloride (60 uL, 0.710 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the on mixture was stirred at room ature for 45 minutes. The solvent was concentrated. A stirring mixture of the acid chloride and 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylaniline (37) (86 mg, 0.323 mmol) in anhydrous pyridine (3 mL) was stirred at room temperature for 3 hours. The crude product was purified by silica chromatography to give N-(5-(5-(3,3- difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)(3-oxobutyl)imidazo[1 ,2- a]pyridinecarboxamide (F53). 1H NMR (400MHz, de-DMSO) 510.19 (s, 1H), 9.37 (s, 1H), 8.70 (s, 1H), 8.08 (d, J: 1.6 Hz, 1H), 7.86 — 7.83 (m, 2H), 7.66 (dd, J: 1.6, 9.2 Hz, 1H), 7.51 (d, J: 8.0 Hz, 1H), 3.92 —3.84 (m, 1H), 3.24 — 3.05 (m, 4H), 2.89 —2.86 (m, 4H), 2.37 (s, 3H), 2.11 (s, 3H). MS m/z 480.18 (M+1)+.
S nthesis of N- 5- 5- 3 uoroc clobut l -1 2 4-oxadiazol l meth l hen l 3- h drox meth lbut l imidazo 1 2-a ridinecarboxamide F54 To a ng solution of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)(3-oxobutyl)imidazo[1,2-a]pyridinecarboxamide (F53) (40 mg, 0.083 mmol) in anhydrous THF (2 mL) at -78 °C under a stream of Argon was added methylmagnesium bromide (83 uL, 0.25 mmol). The reaction was stirred to room temperature for 30 minutes. The reaction was cooled to 0 °C and was quenched with saturated NH4C| (2 mL). The crude product was extracted with ethylacetate. The organic was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by e phase preparative HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)(3-hydroxy- 3-methylbutyl)imidazo[1,2-a]pyridinecarboxamide (F54). 1H NMR (400MHz, d6-DMSO) 6 10.18 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8.08 (d, J: 1.6 Hz,1H),7.86 — 7.82 (m, 2H), 7.65 — 7.62 (m, 1H), 7 51 (d, J: 8.4 Hz, 1H), 3.91 — 3.84 (m, 1H), 3.25 — 3.04 (m, 4H), 2.78 —2.73 (m, 2H), 2.37 (S, 3H), 1.71 — 1.67 (m, 2H), 1.16 (S, 6H). MS m/Z 496.21 (M+1)+.
S nthesis of N- 5- 5- 2- 1-h drox c clo ro l eth l -1 2 4-oxadiazol l meth l hen limidazo1 2-a ridinecarboxamide F55a T1(OiPr)4N/\KU\©\(NO O 330 o N/N\ /\’/U\\ /N\ N\\N N H O O EtMgBr \ —> N/ \ / F55a )‘ To a stirring solution of methyl 3-(imidazo[1,2-a]pyridinecarboxamido) methylphenyl)-1,2,4-oxadiazolyl)propanoate (93) (100 mg, 0.25 mmol) in anhydrous THF at -15 °C under argon was added dropwise a solution of ethylmagnesium bromide (247 L, 0.74 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was quenched with saturated NH4CI. The crude product was extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. The crude product was purified by preparative HPLC to to yield both N--(-5(5-(2-(1- hydroxycyclopropyl)ethyl)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridine amide (F55a) and isopropyl 3-(3-(3-(imidazo[1,2-a]pyridinecarboxamido) methylphenyl)-1,2,4-oxadiazolyl)propanoate (F55b). 1H NMR for (F55a) (400MHz, CD205) 6 9.89 (d, J= 6.8 Hz, 1H), 9.81 (s, 1H), 9.56 (s, 1H), 8.21 (s, 1H), 8.19 (d, J: 8.0 Hz, 1H), 8.0 (t, J: 8.0 Hz, 1H), 7.88 (dd, J: 1.6, 7.6 Hz 1H), 7.53 (t, J: 7.2 Hz, 1H), 7.42 (d, J: 8.0 Hz, 1H), 3.23 (t, J: 7.2 Hz, 2H), 2.47 (s, 3H), 2.12 (t, J: 7.2 Hz, 2H), 0.79 (t, J: 6.8 Hz 0.53 , 2H), (t, J: 6.8 Hz 2H). MS m/z 404.2 (M+1)+. 1H NMR for (F55b) (400MHz, 002012) 5 9.85 (d, J: 6.8 Hz, 1H), 9.47 (s, 1H), 9.21 (s, 1H), 8.28 (d, J: 1.8 Hz, 1H), 8.13 (d, J: 9.2 Hz, 1H), 7.94 — 7.87 (m, 2H), 7.47 (t, J: 6.8 Hz, 1H), 7.42 (d, J: 8.0 Hz, 1H), 5.04 (m, 1H), 3.28 (I, J: 7.2 Hz, 2H), 2.91 (I, J: 7.2 Hz, 2H), 2.44 (s, 3H), 1.25 (d, J: 6.4 Hz, 8H). MS m/z 434.2 .
S nthesis ofN3- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l methylphenyl)imidazo|1,2-a|pyridine-3,6-dicarboxamide (F62) 1. oxalylchloride O OHON\§TOHHN DCM \ ‘0 2. Pyridine—>N<//KFOFBmil/:g': 00 to RT00 37 F To a stirring suspension of 6-carbamoylimidazo[1,2-a]pyridinecarboxylic acid (110) (50 mg, 0.172 mmol) in anhydrous romethane (2 mL) at 0 °C under Argon was added se oxalyl chloride (16 uL, 0.189 mmol). Then, a drop of anhydrous N,N- dimethylformamide was added and the reaction mixture was stirred at 0 °C for 1 hour.
The solvent was concentrated. A stirring mixture of the acid chloride and methyl 5—(5- (3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylaniline (37) (23 mg, 0.0861 mmol) in anhydrous pyridine (2 mL) was stirred at room temperature for 20 minutes. The crude product was purified by reverse phase ative HPLC to give N3-(5-(5—(3,3- difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridine-3,6- dicarboxamide (F62). 1H NMR (400MHz, de-DMSO) 6 10.18 (s, 1H), 9.99 — 9.98 (m, 1H), 8.68 (s, 1H), 8.28 (s, 1H), 8.10 (d, J: 1.6 Hz, 1H), 7.98 (dd, J: 1.6, 9.2 Hz, 1H), 7.88 — 7.83 (m, 2H), 7.66 (s, 1 H), 7.52 (d, J: 8.0 Hz, 1 H), 3.91 — 3.84 (m, 1 H), 3.22 — 3.06 (m 4H), 2.38 (s, 3H). MS m/z 452.14 (M+1 )+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l 2- 4-meth l i erazin leth limidazo 1 2-a ridinecarboxamide F63 | O E I N N / /N '42“ij ‘o HATU DIEA \ Nfi + NEFNW \ N/ 114 37 N\ To a stirring on of ethyl 6-(2-(4-methylpiperazinyl)ethyl)imidazo[1,2- a]pyridinecarboxylate (114) (25 mg, 0.087 mmol) in anhydrous NMP (1 mL) was added HATU (26 mg, 0.104 mmol) and DIEA (23 uL, 0.130 mmol). The on mixture was stirred at room temperature for 10 minutes. Then, 5-(5—(3,3-difluorocyclobutyl)-1,2,4- oxadiazolyl)methylaniline (37) (23 mg, 0.087 mmol) was added and the reaction was stirred for two days. The crude product was purified by reverse phase ative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl) (2-(4-methylpiperazinyl)ethyl)imidazo[1,2-a]pyridinecarboxamide (F63). MS m/z 453.14 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l mor holinoimidazo12-a ridinecarboxamide F59 /N Pd2((dea)3 ‘o rac—BINAP NVKN /N‘o Br t—BuONa H \ N N\ Toluene F59 F A mixture of 7-bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (42f) (50.0 mg, 0.10 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), rac-BINAP (18.7 mg, 0.03mmol), NaOt-Bu (14.4 mg, 0.15 mmol) and morphline (17.4 mg, 0.2 mmol) in toluene (3 mL) was heated at 110 °C overnight. Once complete, the reaction mixture was diluted and ted with EtOAc.
The organic layers were combined, dried over NaZSO4, filtered and concentrated to afford a e which was purified by HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazolyl)methylphenyl)morpholinoimidazo[1,2-a]pyridine carboxamide (F59). MS m/z 495.1 .
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l fluoro hen l 5- meth l-4H-1 2 4-triazol l imidazo 1 2-a ridinecarboxamide F61 A mixture of 6-cyano-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) f|uoropheny|)imidazo[1,2-a]pyridinecarboxamide (42h) (15.0 mg, 0.034 mmol), CuBr (9.2 mg, 0.007 mmol), Cs2003 (39 mg, 0.12 mmol), and acetimidamide hydrochloride (6.6 mg, 0.07 mmol) in DMSO (1 mL) was heated at 120 °C overnight. The reaction mixture was purified by HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol yl)fluorophenyl)(5-methyl-4H-1,2,4-triazolyl)imidazo[1,2-a]pyridine amide (F61). MS m/z 495.1 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 iazol l h l hen l 1H- 1,2,3-triazolyl)imidazo|1,2-a|pyridinecarboxamide (F65) 1 ) \‘AOANS O O NVLNbyN Cuso4 N/yLN /N\ ‘0 sodium ascorbate O \ H /H20 \ N N‘ N N\ \ / 2) / NaOH \ 53 MeOH F // F F [\lll \ A mixture of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl) ethynylimidazo[1,2-a]pyridinecarboxamide (53) (10 mg, 0.023mmol), azidomethyl pivalate (3.64 mg, 0.023 mmol), CuSO4 (2 uL of 0.5M aqueous solution, 0.001 mmol) and sodium ascorbate (1.4 mg, 0.007 mmol) in tBuOH/H20 (1 mL, 2:1) was stirred at room temperature overnight. Then the on mixture was diluted and extracted with EtOAc. The organic layers were ed, dried over NaZSO4, filtered and concentrated to afford a residue which was dissolved in MeOH (1 mL). Aqueous NaOH (0.6 mL, 1N) was added and the on e was stirred for 30 minutes. The above mixture was purified by HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)(1H-1,2,3-triazolyl)imidazo[1,2-a]pyridinecarboxamide (F65). MS m/z 477.1 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l 1- 0 KEY 30st O NyLN /N\ /N\ CUSO4 0 N#N O sodium ate H N N ‘ N N \ t-BuOH/HZO \ / \ / 2) NaBH4 MeOH F F \ 53 F66 A mixture of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl) ethynylimidazo[1,2-a]pyridinecarboxamide (53) (20 mg, 0.046mmol), ethyl 2- azidoacetate (5.9 mg, 0.046 mmol), CuSO4 (4 uL of 0.5M aqueous solution, 0.002 mmol) and sodium ascorbate (2.8 mg, 0.014 mmol) in tBuOH/H20 (1 mL, 2:1) was stirred at room temperature overnight. Then the reaction mixture was diluted and extracted with EtOAc. The organic layers were combined, dried over NaZSO4, filtered and trated to afford a residue which was dissolved in MeOH (2 mL). NaBH4 (17 mg, 0.46 mmol) was added and the reaction mixture was stirred for 30 minutes. The above mixture was purified by HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)(1-(2-hydroxyethyl)-1H-1,2,3-triazolyl)imidazo[1,2-a]pyridine carboxamide (F66). 1H NMR (400MHz, d4-MeOH) 6 9.70 (m, 1H), 8.60-8.80 (m, 2H), 8.33 (s, 1H), 8.16 (d, J: 1.6 Hz, 1H), 7.96 (m, 1H), 7.85 (d, J: 7.2 Hz, 1H), 7.50 (d, J: 8.0 Hz, 1H), 4.62 (t, J: 4.8 Hz, 2H), 4.02 (t, J: 4.8 Hz, 2H), 3.79 (m, 1H), 3.13 (m, 4H), 2.44 (s, 3H). MS m/z521.1 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l 28 SR -2 6-dimeth lmor holino imidazo1 2-a ridinecarboxamide F96 Nt/ZON N/zNgTJ/NaOtBuPd((dba)2 \N Br Dioxane N/QN F F F F 125 °C 0 A mixture of 6-bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (42h) (25 mg, 0.051 mmol), cis-2,6- ylmorpholine (9mg, 0.077 mmol), 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl (4 mg, 0.01 mmol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.003 mmol), and sodium t-butoxide (10 mg, 0.102 mmol) in anhydrous dioxane (1 mL) was heated in the microwave at 125 °C for 25 minutes. The reaction was cooled to room temperature and filtered through a plug of celite. The solvent was trated and the crude product was ed by reverse phase preparative HPLC to afford N-(5-(5-(3,3- difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)((2S,6R)-2,6- dimethylmorpholino)imidazo[1,2-a]pyridinecarboxamide (F96). 1H NMR (400MHz, d6- DMSO) 6 10.17 (s, 1H), 8.95 (d, J=1.6 Hz, 1H), 8.64 (s, 1H), 8.03 (d, J :16 Hz, 1H), 7.84 (dd, J :16, 8.0 Hz, 1 H), 7.79 —7.71 (m, 2H), 7.50 (d, J = 8.0 Hz, 1 H), 3.91 —3.86 (m, 1H), 3.76 —3.71 (m, 2H), 3.54 —3.51 (m, 2H), 3.23 —3.03 (m, 4H), 2.36 (s, 3H), 2.31 — 2.25 (m, 2H), 1.17 (s, 3H), 1.15 (s, 3H). MS m/z 522.22 (M+1)+.
S nthesis of N3- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen zo1 2-a ridine-3 6-dicarboxamide F62 1. oxalyl chloride “10“” DCM 0 /N /\,/U\N ’N‘o \O \ . ~\ 2. Pyridine 0°C to RT \ F O F H2N To a stirring sion of 6-carbamoylimidazo[1,2-a]pyridinecarboxylic acid (110) WO 33070 (50 mg, 0.172 mmol) in anhydrous dichloromethane (2 mL) at 0 °C under Argon was added dropwise oxalyl chloride (16 uL, 0.189 mmol). Then, a drop of anhydrous N,N- dimethylformamide was added and the reaction mixture was stirred at 0 °C for 1 hour.
The solvent was concentrated. A stirring mixture of the acid chloride and methyl 5—(5- (3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylaniline (37) (23 mg, 0.0861 mmol) in anhydrous pyridine (2 mL) was stirred at room temperature for 20 minutes. The crude product was purified by reverse phase preparative HPLC to give N3-(5-(5—(3,3- difluorocyclobutyl)-1,2,4-oxadiazolyl)methy|phenyl)imidazo[1,2-a]pyridine-3,6- dicarboxamide (F62). 1H NMR z, de-DMSO) 6 10.18 (s, 1H), 9.99 — 9.98 (m, 1H), 8.68 (s, 1H), 8.28 (s, 1H), 8.10 (d, J: 1.6 Hz, 1H), 7.98 (dd, J: 1.6, 9.2 Hz, 1H), 7.88 — 7.83 (m, 2H), 7.66 (s, 1 H), 7.52 (d, J: 8.0 Hz, 1 H), 3.91 — 3.84 (m, 1 H), 3.22 — 3.06 (m, 4H), 2.38 (s, 3H). MS m/z 452.14 (M+1 )+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l h l hen l 2- N NVLN [N] /N‘o N HATU,DIEA \ N‘ / N HZN /N‘o / _.
\ Ni NMP \ / 0 F F F63 114 37 0 To a stirring solution of ethyl 6-(2-(4-methylpiperazinyl)ethyl)imidazo[1,2- a]pyridinecarboxylate (114) (25 mg, 0.087 mmol) in anhydrous NMP (1 mL) was added HATU (26 mg, 0.104 mmol) and DIEA (23 uL, 0.130 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then, 5-(5—(3,3-difluorocyclobutyl)-1,2,4- oxadiazolyl)methylaniline (37) (23 mg, 0.087 mmol) was added and the on was stirred for two days. The crude product was purified by reverse phase preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl) (2-(4-methylpiperazinyl)ethyl)imidazo[1,2-a]pyridinecarboxamide (F63). MS m/z 536.3 (M+1)+.
S nthesis of N- 2-meth l 5- 6-oxos iro 3.3 he tan l -1 2 4-oxadiazol l hen limidazo 1 2-a ridinecarboxamide F75 \ H N \ N\ P N N40 \ / \ / 9 F75 To a stirring solution of 6-oxospiro[3.3]heptanecarboxylic acid (50 mg, 0.32 mmol) in anhydrous NMP (1 mL) was added 1,1'-carbony|diimidazo|e (CDI) (52.3 mg, 0.32 mmol). The reaction was stirred for 3 minutes. N-(5-(N'-hydroxycarbamimidoy|) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (9) (100 mg, 0.32 mmol) was added and the reaction was stirred for 25 s. Then, the reaction was heated at 120 °C for minutes. The crude reaction was purified by reverse phase preparative HPLC to give ethy|(5-(6-oxospiro[3.3]heptany|)-1,2,4-oxadiazoIyl)pheny|)imidazo[1,2- a]pyridinecarboxamide (F75). MS m/z 428.2 (M+1)+.
S nthesis of N- 5- 5- 2 2-dif|uoroc c|o r0 | -1 2 4-oxadiazoI | meth | hen limidazof 2-a ridinecarboxamide F87 and F88 O HO F O NH2 F N/§/“\N —> NMN \ H l \ H \ N N I N N \OH CDI, NMP ‘o \ / \ / Chiral Chromatography MMMX or”, ..
U > N \ O C?\ N‘O F87 F88 To a stirring solution of f|uorocyclopropanecarboxylic acid (325 mg, 2.66 mmol) in anhydrous NMP (7 mL) was added 1,1'-carbony|diimidazo|e (CDI) (432 mg, 2.66 mmol). The reaction was stirred for 3 s. N-(5-(N'-hydroxycarbamimidoy|) phenyl)imidazo[1,2-a]pyridinecarboxamide (9) (825 mg, 2.66 mmol) was added and the reaction was stirred for 25 minutes. Then, the reaction was heated at 120 °C for minutes. The crude product was ed on silica gel using 10% MeOH in dichloromethane to give N-(5-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazoIyI) methylphenyl)imidazo[1,2-a]pyridinecarboxamide (F64). 1H NMR (400MHz, d6- DMSO) 6 9.60 (d, J: 7.2 Hz, 1H), 8.56 (d, J: 1.6 Hz, 1H), 8.51 (s, 1H), 8.12 (bs, 1H), 7.87 (dd, J: 2.0, 7.8 Hz, 1H), 7.82 (d, J: 9.2 Hz, 1H), 7.58 — 7.53 (m, 1H), 7.44 (d, J: 8.0 Hz, 1 H), 7.16 (td, J: 0.8, 6.8 Hz, 1 H), 3.19 — 3.12 (m, 1 H), 2.48 (s, 3H), 2.45 — 2.36 (m, 1H), 2.27 —2.18 (m, 1H). MS m/z 396.1 (M+1)+.
The separation of enantiomers was performed using a 20x250mm ChiraIPak IA column at a flow rate of 20mL/min, using Hexanes: EtOH: MeOH (60: 20: 20). Analytical methods using the same column and solvent mixture showed peak 1 eluting at 9.19 min, and peak 2 at 13.34 min. Peak 1 was arbitrarily assigned to be the R isomer (F87) and Peak 2 was assigned to be the S isomer (F88). 1H NMR for F87 (400MHz, CD20I2) 6 9.48 (d, J: 6.8 Hz, 1H), 8.45 (d, J: 1.6 Hz, 1H), 8.35 (bs, 1H), 7.94 (bs, 1H), 7.75 (dd, J :1.8, 11.8 Hz, 1H), 7.89 (d, J: 9.2 Hz, 1H), 7.42 (td, J: 1.2, 8.0 Hz, 1H), 7.32 (d, J: 8.0 Hz, 1H), 7.03 (t, J: 6.8 Hz, 1H), 3.08 — 3.01 (m, 1H), 2.36 (s, 3H), 2.33 — 2.24 (m, 1H), 2.15—2.06 (m, 1H). MS m/z 398.1 . 1H NMR for F88 (400MHz, 002012) 5 9.89 (d, J: 7.2 Hz, 1H), 8.91 (s, 1H), 8.78 (s, 1H), 8.48 (d, J: 1.8 Hz, 1H), 7.92 (d, J: 8.8 Hz, 1H), 7.88 (dd, J: 1.8, 8.0 Hz, 1H), 7.88 (td, J: 1.2, 7.2 Hz, 1H), 7.44 (d, J : 8.0 Hz, 1H), 7.25 (t, J: 7.8 Hz, 1H), 3.19 — 3.12 (m, 1H), 2.44—2.36 (m, 1H), 2.27 —2.18 (m, 1H). MS m/z 398.1 (M+1)+.
S nthesis of N- 5- 5- 6-h drox s iro 3.3 he tan l -1 2 4-oxadiazol l meth l hen limidazof 2-a ridinecarboxamide F100 NMN /% N \/ ‘O F100 To a stirring solution of N-(2-methyl(5-(6-oxospiro[3.3]heptanyl)-1,2,4- oxadiazolyl)phenyl)imidazo[1,2-a]pyridinecarboxamide (F76) (100mg, 0.23 mmol) in anhydrous ol (1 mL) was added sodium borohydride (10.6 mg, 0.28 mmol).
The on mixture was stirred at room temperature for 12 hours. The reaction was quenched with water and the t was concentrated. Purification by silica gel using % MeOH in dichloromethane afforded N-(5-(5-(6-hydroxyspiro[3.3]heptanyl)-1,2,4- oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridinecarboxamide . MS m/z 430.1 (M+1)+.
S nthesis of N- 5- 5- 3-methox trifluorometh l c clobut l -1 2 4-oxadiazol l meth l hen limidazof 2-a ridinecarboxamide F97 / /N / /N F F Propylphosphonlc' F F \ N / H2N NH F anhydride O F 0“ fl” \ 0\ o EfOAc,7O° c 0\ \ fl”\ \ N:o N:o 1 125 A stirring mixture of imidazo[1,2-a]pyridinecarboxylic acid (1) (10 mg, 0.064 mmol) and 5-(5-(3-methoxy(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazolyl)methylaniline (125) (21 mg, 0.064 mmol) in ethylacetate (1 mL) was added propylphosphonic anhydride solution 50 wt. % in ethyl acetate (76 uL, 0.128 mmol). The reaction was heated at 700 C for 3 hours. The reaction was cooled to room temperature and d with a solution of saturated sodium bicarbonate. The organic was separated and washed with 2x water/brine mixture and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography using DCM:EtOAc:MeOH (1 :1 :0.1). N-(5-(5-(3- methoxy(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)imidazo[1,2- dinecarboxamide (F97). 1H NMR (400MHz, d6-DMSO) 6 10.06 (s, 1H), 9.47 — 9.44 (m 1H), 8.59 (s, 1H), 8.08 (d, J: 1.8 Hz, 1H), 7.83 (dd, J: 1.6, 7.8 Hz, 1 H), 7.80 — 7.78 (m, 1 H), 7.55 — 7.50 (m, 1H), 7.50 (d, J: 8.4 Hz, 1 H), 7.20 — 7.18 (m, 1 H), 3.76 — 3.68 (m, 1 H), 3.38 (s, 3H), 2.88 — 2.85 (m, 4H), 2.36 (s, 3H) MS m/z471.15 (M+1)+.
S nthesis of N- 5- 5- 1R 2S fluoroc clo ro l -1 2 4-oxadiazol l meth l hen limidazo1 2-a ridinecarboxamide F110 0 O NyNQH 1. /N‘O H N2 N (883' chloride NVLH + \O —> N Nté \ / NV 2. Pyridine ._ .[>AF 131 D”F F110 To a stirring suspension of imidazo[1,2-a]pyridinecarboxylic acid (1) (52 mg, 0.32 mmol) in anhydrous dichloromethane (2 mL) at 0 °C under Argon was added se oxalyl chloride (56 uL, 0.64 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was concentrated and the crude solid was added n-wise to a stirring solution of 5-(5- ((1R,2S)fluorocyclopropyl)-1,2,4-oxadiazolyl)methylaniline (131) (62 mg, 0.27 mmol) in anhydrous pyridine (1 mL) at 0 °C. The reaction was stirred at room temperature under Argon for 30 minutes and quenched with water. The crude product was ed by preparative HPLC to yield N-(5-(5-((1R,2S)fluorocyclopropyl)-1,2,4- oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridinecarboxamide (F110). MS m/z 378.1 (M+1)+.
S nthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l 1- 2-methox eth l meth l-1H-1 24-triazol l o1 2-a carboxamide §F99) / /N Br’\,OMe ,N\ \ Na K2CO3 / D—>MF >1N NH 0 313W F F N\ N‘ \ \ No N:0 F79 F99 N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)(5-methyl-1H- 1,2,4-triazolyl)imidazo[1,2-a]pyridinecarboxamide (F79) (6.0 mg, 0.012 mmol), 1- bromomethoxyethane (1.7 mg, 0.012 mmol) and K2003 (5.0 mg, 0.036 mmol) in DMF (0.5 mL) was heated at 120 °C for 30 minutes. The reaction mixture was purified by preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl) phenyl)(1-(2-methoxyethyl)methyl-1H-1,2,4-triazolyl)imidazo[1,2- a]pyridinecarboxamide (F99). 1H NMR (400MHz, O) 610.15 (s, 1H), 10.11 (m, 1H), 8.65 (s, 1H), 8.12 (d, J: 1.6 Hz, 1H), 8.06 (dd, J: 2.0, 9.2 Hz, 1H), 7.88 (dd, J= 0.8, 9.2 Hz, 1H), 7.85 (dd, J: 2.0, 8.0 Hz, 1H), 7.52 (d, J: 8.0 Hz, 1H), 4.34 (t, J: 5.2 Hz, 2H), 3.89 (m, 1H), 3.72 (t, J: 5.2 Hz, 2H), 3.24 (s, 3H), .20 (m, 4H), 2.47 (s, 3H), 2.39 (s, 3H). MS m/z 549.1 (M+1)+.
S nthesis of R -N- 5- 5- 2 2-difluoroc clo r0 | -1 2 4-oxadiazol l -2 4- dimeth l hen limidazof 2-a ridinecarboxamide F108 ON N\ N propyplhosph'onto anhd'dy r1 e \ fl? \N/ / ‘O —>N \ N‘ EtOAc OH F F o 65°C \ / D 1 150 F108 To a stirring suspension of imidazo[1,2-a]pyridinecarboxylic acid (1) (25 mg, 0.154 mmol) and 5-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazolyl)-2,4-dimethylaniline (150) (41 mg, 0.154 mmol) in ethylacetate (1 mL) was added propylphosphonic anhydride solution 50 wt% in ethyl acetate (184 uL, 0.308 mmol). The reaction was heated at 65 °C overnight. The reaction was cooled to room temperature and diluted with a solution of saturated sodium bicarbonate. The organic was ted and washed with water/brine mixture and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography and then by a 20x250mm ChiralPak AD-H column to give (R)-N- (5-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazolyl)-2,4-dimethylphenyl)imidazo[1 ,2- a]pyridinecarboxamide . 1H NMR (400MHz, d4-MeOD) 6 10.04 (s, 1H), 9.46 — 9.44 (m, 1 H), 8.57 (s, 1 H), 7.95 (s, 1 H), 7.79 — 7.76 (m, 1H), 7.53 — 7.49 (m, 1H), 7.36 (s, 1 H), 7.18 — 7.15 (m, 1 H), 3.74 (m, 1 H), 2.55 (s, 3H), 2.47 — 2.35 (m, 2H), 2.31 (s, 3H).
MS m/z 409.14 (M+1)+.
S nthesis of N- 5- 5- 1S 2R fluoroc clo ro l -1 2 4-oxadiazol l meth l hen limidazo1 2-a ridinecarboxamide F113 0 o N/fi/MOH 1. oxalyl chloride /N‘O \ H2N /N DCM NVLNH \ / NE 2. Pyridine \ / ...F "'“F To a stirring sion of imidazo[1,2-a]pyridinecarboxylic acid (1) (52 mg, 0.32 mmol) in ous dichloromethane (2 mL) at 0 °C under Argon was added dropwise oxalyl chloride (56 uL, 0.64 mmol). Then, a drop of ous DMF was added and the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was concentrated and the crude solid was added portion-wise to a stirring solution of 5-(5- ((1S,2R)fluorocyclopropyl)-1,2,4-oxadiazolyl)methylaniline (132) (62 mg, 0.27 mmol) in anhydrous pyridine (1 mL) at 0 °C. The reaction was stirred at room temperature under Argon for 30 minutes and quenched with water. The crude product was purified by preparative HPLC to yield N-(5-(5-((1R,2S)fluorocyclopropyl)-1,2,4- oxadiazolyl)methylphenyl)imidazo[1,2-a]pyridinecarboxamide . MS m/z 378.1 (M+1)+.
S nthesis of meth l 3 3-difluoro 3- 3- imidazo 1 2-a ridinecarboxamido meth l hen l-1 24-oxadiazol lc clobut lcarbamate F175 N\\ N\\ N/ N‘NONHHCI 2 Pyridine N\ N7r \o F F F F174 166 To a stirring solution of N-(5-(5-(1-amino-3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)- 2-methylphenyl)imidazo[1,2-a]pyridinecarboxamide hydrochloride (166) in ous pyridine (1 mL) at 0 °C was added drop-wise methyl chloroformate (19 uL, 0.26 mmol).
The reaction was stirred to room temperature for 20 minutes. The crude was concentrated and ed by preparative HPLC to yield methyl (3,3-difluoro(3-(3- (imidazo[1,2-a]pyridinecarboxamido)methylphenyl)-1,2,4-oxadiazol yl)cyclobutyl)carbamate (F174). MS m/z 483.1 (M+1)+.
Synthesis of N- 5- 5- 3 3-difluoroc clobut l -1 2 4-oxadiazol l meth l hen l 2- fluoroethox meth limidazo12-a carboxamide F176 N<\N))LH N \ N / . 1. MsCl /2N/VAQTN‘O\ N\O N DIEA DCM \ / 2HO/\/OH F HO F K2003 ( F159 80 00 F F176 N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl) (hydroxymethyl)imidazo[1,2-a]pyridinecarboxamide (F159) (95 mg, 0.216 mmol) was dissolved in DCM (1 mL) and DIEA (0.65 mmol). MsCl (0.65 mmol) was added dropwise and the resulting mixture was stirred for 15 minutes at room temperature. The reaction mixture was subjected to aqueous workup, extracted with DCM (2 mL), dried over Na2804 and concentrated to give a crude which was dissolved in 0.8 mL of 2- iluoroethanol followed by addition of K2C03 (90 mg, 0.65 mmol). The resulting mixture was heated at 120 °C for 20 s. The reaction mixture was subjected to standard aqueous workup and purified by silica chromatography to yield N-(5-(5-(3,3- diiluorocyclobutyl)-1,2,4-oxadiazolyl)methylphenyl)((2- fluoroethoxy)methyl)imidazo[1,2-a]pyridinecarboxamide (F176). 1H NMR (400 MHz, CDCI3) 6 9.56 (s, 1H), 8.60 (d, J: 1.6, 1H), 8.21 (s, 1H), 7.89 (dd, J: 1.7, 7.9, 1H), 7.77 (d, J: 9.2, 1H), 7.62 (s, 1H), 7.53 (dd, J: 1.7, 9.2, 1H), 7.42 (d, J: 8.1, 1H), 4.72 — 4.64 (m, 3H), 4.59 — 4.52 (m, 1H), 3.86 — 3.79 (m, 1H), 3.79 — 3.73 (m, 1H), 3.68 (m, 1H), 3.16 (m, 4H), 2.47 (s, 3H). MS m/z 486.1 .
Representative nds of Formula (I) and Formula (II) with c-kit inhibition IC50 values in the range of 1 nM to 100 nM, and prepared ing the procedures described above, are set forth in Table 1.
Table 1 c-kit CITpd Structure Physical Data (Mo7e) 1H NMR (400MHz, dg-DMSO) 5 10.08 (s, 1H), 9.46 (d, J: 7.2 Hz, 1H), 8.61 (s, 1H), 8.21 (d, J: 2.0 Hz, 1H), 7.95 — o \QXQN 7.91 (m, 1H), 7.80 (d, J: 8.0 Hz, 1H), — I 7.57 (d J=8.0 Hz 1H) 7.56—7.52(m F1 Qf”N Nfl 3 3 3 3 0024 1H), 7.19(dt,J=8.0, 1.2 Hz, 1H), 3.71 F — 3.62 (In, 1H), 3.18 — 3.09 (In, 2H), 3.03 — 2.92 (In, 2H), 2.41 (s, 3H).
MS m/z 410.1 .
F2 \N H N? MS m/z 402.1 (M+1)+. 0.058* oflw, F3 Q N MS m/z 404.2 (M+1)+. 0.164* \ \\ Nfi N OH F4 Q1}N NE MS m/z403.1(M+1)+. 0.022 PCT/U82012/052621 c-kit Structure Physical Data (Mo7e) MS m/z 438.1 (M+1)+. 0.024 1H NMR (400MHz, d4-MeOH) 5 9.53 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 8.13 — 8.12 (m, 1H), 7.90 (dd, J = 8.2, 2.0 Hz, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.60 — 7.55 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 0.119 7.18 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 3.48 — 3.40 (m, 1H), 2.58 — 2.54 (m, 4H), 2.42 (s, 3H), 1.46 (s, 3H).
MS m/z 404.1 (M+1)+. 1H NMR (400MHz, d4-MeOH) 5 9.55 (d, J = 7.2 Hz, 1H), 8.50 (s, 1H), 8.13 — 8.12 (m, 1H), 7.90 (dd, J = 8.2, 2.0 Hz, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.60 — 7.55 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 0.015 7.18 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 4.02 — 3.94 (m, 1H), 3.82 (s, 3H), 3.57 — 3.30 (m, 4H), 2.86 (s, 3H).
MS m/z 417.1 (M+1)+. 1H NMR z, d4-MeOH) 5 9.53 (d, J = 7.2 Hz, 1H), 8.50 (s, 1H), 8.13 — 8.12 (m, 1H), 7.90 (dd, J = 8.2, 2.0 Hz, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.60 — 7.55 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 0.055 7.18 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 4.45 — 4.43 (m, 1H), 3.98 — 3.81 (m, 4H), 3.32 — 3.31 (m, 4H), 2.43 (s, 3H).
MS m/z 432.1 (M+1)+.
MS m/z 446.1 (M+1)+. 0.052 F10 MS m/z 446.1 (M+1)+. 0.052 F11 MS m/z 388.1 (M+1)+. 0.041* c-kit Structure Physical Data (Mo7e) MS m/z 446.1 (M+1)+. 0.012 1H NMR (400MHz, O) 5 10.19 (s, 1H), 9.53 — 9.50 (m, 1H), 8.70 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.90 — 7.87 (m, 1H), 7.83 (d, J = 1.6, 8.0 Hz, 1H), 7.70 — 7.65 (m, 1H), 7.51 (d, J = 0.007 8.0 Hz, 1H), 7.33 — 7.29 (m, 1H), 3.93 — 3.84 (m, 1H), 3.25 — 3.02 (m, 4H), 2.37 (s, 3H).
MS m/z 410.3 (M+1)+.
MS m/z 431.2 (M+1)+. 0.012 MS m/z 457.5 (M+1)+. 0.035 MS m/z 445.2 (M+1)+. 0.066 1H NMR (400MHz, dg-DMSO) 5 10.16 (s, 1H), 9.50 — 9.47 (m, 1H), 8.69 (s, 1H), 8.24 (d, J = 4.8 Hz, 2H), 8.08 (d, J = 1.6 Hz, 1H), 7.86 — 8.72 (m, 2H), 7.63 — 7.58 (m, 1H), 7.51 (d, J = 8.0 0.109 Hz, 1H), 7.27 — 7.23 (m, 1H), 4.07 — 3.95 (m, 2H), 2.76 — 2.63 (m, 4H), 2.37 (s, 3H).
MS m/z 389.5 (M+1)+.
MS m/z 448.2 (M+1)+. 0.025 MS m/z 407.2 (M+1)+. 0.009 1H NMR (400MHz, dg-DMSO) 5 10.25 (s, 1H), 9.52 (d, J: 6.1 Hz, 1H), 8.75 (s, 1H), 8 (s, 1H), 7.9 (d, J = 7.7 Hz, 1H), 7.8 (d, J=7 Hz, 1H), 7.71 (m, 1H), 0.049 7.49 (m, 1H), 7.32 (111, 1H), 3.73 (s, 2H), 3.31 (s, 3H), 2.36 (s, 3H), 1.42 (111, 2H), 1.29 (111, 2H). c-kit Structure Physical Data (Mo7e) MS m/z 404.2 . 1H NMR (400MHz, CDC13) 5 9.55 (d, J = 6.9 Hz, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 7.82 (d, J: 7.4 Hz, 1H), 7.76 (d, J = 9 Hz, 1H), 7.72 (s, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.36 (d, J = 7.9 Hz 1H), 0.089 7.06 (t, J: 6.9 Hz 1H), 2.43 (s, 3H), 1.79 (m, 2H), 1.7 (m, 2H), 1.5 (s, 9H).
MS m/z 475.2 (M+1)+.
MS m/z 453.1 (M+1)+. 0.056 1H NMR (400MHz, DMSO) 5 10.15 (s, 1H), 9.48 (d, J: 6.7 Hz, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 8.02 (s, 1H), 7.8 (m, 2H), 7.6 (m, 1H), 7.5 (m, 1H), 7.24 (m, 0.077 1H), 3.06 (s, 3H), 2.36 (s, 3H), 1.67 (m, 4H).
MS m/z 453.1 (M+1)+. 1H NMR (400MHz, CDC13) 5 9.54 (d, J = 7 Hz, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 7.83 (dd, J = 7.9, 1.4 Hz, 1H), 7.77 (d, J = 9 Hz, 1H), 7.73 (s, 1H), 7.45 (dt, J = 8.1, 1.1 Hz, 1H), 7.36 (d, J: 8 Hz, 1H), 0.058 7.06 (t, J: 6.9 Hz, 1H), 3.75 (s, 3H), 2.43 (s, 3H), 1.82 (m, 2H), 1.56 (m, 2H).
MS m/z 433.2 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.04 (s, 1H), 9.47 — 9.45 (m,1H), 8.60 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.83 (dd, J = 2.0, 8.0 Hz, 1H), 7.80 — 7.78 (m, 1H), 7.55 — 7.50 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.20 — 7.16 (m, 1H), 6.92 0.013 (s, 1H), 3.32 — 3.28 (m, 1H), 2.99 — 2.93 (m, 2H), 2.68 — 2.60 (m, 2H), 2.37 (s, 3H).
MS m/z 458.4 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.19 (s, 1H), 9.54 — 9.51 (m, 1H), 8.72 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.95 — 0.058 7.92 (m, 1H), 7.91 — 7.89 (m, 1H), 7.82 (dd, J = 1.6, 7.6 Hz, 1H), 7.73 — 7.69 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.35 2012/052621 c-kit Structure Physical Data (Mo7e) — 7.32 (m, 1H), 4.54 (d, J = 6.0 Hz, 2H), 2.37 (s, 3H), 1.46 (s, 3H), 0.795 — 0.765 (m, 2H), 0.620 —0.587 (m, 2H).
MS m/z 447.5 (M+1)+.
MS m/z 447.46 . 0.069 1H NMR (400MHz, dg-DMSO) 5 10.16 (s, 1H), 9.50 (d, J = 6.9 Hz, 1H), 8.67 (s, 1H), 8.50 (s, 1H), 8.08 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.63 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.27 (s, 1H), 2.98 0.095 (s, 3H), 2.51—2.71 (m, 5H), 2.37 (s, 3H), 1.94—2.05 (m, 2H).
MS m/z 467.51 (M+1)+. 0058 MS m/Z 403.2 (M+1)+. 1H NMR (400MHz, CDC13) 5 9.47 (d, J: 7.2 Hz, 1H), 8.47 (d, J: 1.6 Hz, 1H), 8.14 (s, 1H), 7.80 (sd, J=1.6, 7.6 Hz, 1H), 7.68 (d, J: 8.8 Hz, 1H), 7.58 (s, 1H), 7.37 (m, 1H), 7.31 (d, J: 8.0 Hz, 0.016 1H), 6.97 (dt, J: 0.8, 7.2 Hz, 1H), 4.85 (m, 2H), 3.75 (m, 1H), 3.17 (m, 4H), 2.36 (s, 3H).
MS m/z 386.2 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.03 (s, 1H), 9.46 (d, J = 6.9 Hz, 1H), 8.59 (s, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.84 — 7.76 (m, 2H), 7.55 — 7.46 (m, 2H), 7.11- 7.15 (m, 1H),5.19 (s, 1H), 4.31—4.45 \ N’i NH (m, 1H), 3.31—3.45 (m, 1H), 2.43 (t, J: F31 OflNYQEHq 0'05 9.0 Hz, 2H), 2.37 (s, 3H) 2.11—2.45 (m, 1; 3H),1.56 — 1.38 (m, 2H), 1.17 (t, J: .7 Hz, 1H), 0.36 — 0.25 (m, 2H), 0.24 — 0.09 (m, 1H).
MS m/z 430.47 (M+1)+. c-kit Structure Physical Data (Mo7e) 1H NMR (400MHz, dg-DMSO) 5 10.20 (s, 1H), 9.51 (d, J = 6.9 Hz, 1H), 8.70 (s, 1H), 8.05 (s, 1H), 7.91 — 7.83 (m, 2H), 7.69 (s, 1H), 7.51 (d, J: 8.1 Hz, 1H), 7.31 (s, 1H), .78 (m, 1H), 0.025 4.18 (q, J = 7.9 Hz, 2H), 3.81 (q, J = 7.9 Hz, 2H), 3.23—3.34 (m, 2H), 2.63-2.74 (m, 3H), 2.38 (s, 3H), 1.14—1.24 (m,7H).
MS m/z 430.47 . 1H NMR (400MHz, dg-DMSO) 5 10.11 (d, J = 8.0 Hz, 1H), 9.48 (d, J = 6.9 Hz, 1H), 8.64 (s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.82 (d, J: 9.2 Hz, 2H), 7.62 — 7.55 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 6.5 Hz, 1H), 3.85 —3.77 (111, 0.088 2H), 3.63-3.72 (111, 3H), 3.51 (s, 1H), 2.66 (d, J = 9.8 Hz, 1H), 2.53 (s, 2H), 2.36 (s, 3H), 2.00 (t, J = 7.3 Hz, 1H), 1.93 — 1.77 (m, 2H).
MS m/z 430.47 (M+1)+. 1H NMR (400MHz, CDC13) 5 9.56 (d, J = 7.2 Hz, 1H), 8.62 (d, J = 1.6 Hz, 1H), 8.22 (s, 1H), 7.88 (dd, J: 1.6, 8.0 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.60 (s, 1H), 7.47 (m, 1H), 7.41 (d, J = 8.0 Hz, 0.016 1H), 7.08 (m, 1H), 4.10 (s, 2H), 3.41 (m, 1H), 2.85 (m, 2H), 2.46 (s, 3H), 2.38 (m, 2H), 2.01 (br, 1H).
MS m/z 439.1 (M+1)+. 1H NMR (400MHz, CDC13) 5 = 9.56 (d, J: 6.9 Hz, 1H), 8.64 (d, J: 1.6 Hz, 1H), 8.22 (s, 1H), 7.90 (dd, J: 1.7, 7.9 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.60 (s, 1H),7.51— 7.44 (m, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.08 (t, J = 6.9 Hz, 1H), 0.003 .05 (d, J: 14.2 Hz, 1H), 4.87 (d, J: 14.2 Hz, 1H), 4.53 (m, 1H), 2.94 (m, 1H), 2.74 — 2.50 (m, 1H), 2.47 (s, 3H).
MS m/z 476.1 (M+1)+. 1H NMR (400MHz, d6-DMSO) 5 10.18 (s, 1H), 9.53 — 9.50 (m, 1H), 8.69 (s, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.89 — 7.86 (m, 1H), 7.84 (dd, J = 1.6, 8.0 Hz, 0.028 1H), 7.70 — 7.65 (m, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 — 7.29 (m, 1H), 5.48 — .28 (m, 1H), 3.99 — 3.91 (m, 1H), 2.81 — 2.73 (m, 4H), 2.37 (s, 3H).
Structure Physical Data MS m/z 392.14 . 1H NMR (400MHz, CDC13) 5 9.39 (m, 1H), 8.42 (d, J: 1.6 Hz, 1H), 8.04 (s, 1H), 7.70 (dd, J: 1.7, 7.9 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.42 (s, 1H), 7.36 (dd, J = 1.7, 9.2 Hz, 1H), 7.23 (d, J = 0.06 8.1 Hz, 1H), 4.63 (d, J = 5.7 Hz, 2H), .41 (m, 1H), 3.09—2.85 (m, 4H), 2.28 (s, 3H), 1.82 (t, J = 5.9 Hz, 1H).
MS m/z 440.1 (M+1)+. 1H NMR (400MHz, CDC13) 5 9.56 (m, 1H), 8.60 (d, J: 1.5 Hz, 1H), 8.21 (s, 1H), 7.89 (dd, J: 1.7, 7.9 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.60 (s, 1H), 7.50 (dd, J = 1.7, 9.2 Hz, 1H), 7.42 (d, J = 0.025 7.9 Hz, 1H), 4.65 (s, 2H), 3.82 (s, 2H), 3.73—3.61 (m, 3H), 3.15 (111, 4H), 2.46 (s, 3H), 2.04 (s, 1H).
MS m/z 484.2 (M+1)+. 1H NMR (400MHz, CDC13) 5 9.55 (m, 1H), 8.62 (d, J: 1.6 Hz, 1H), 8.21 (s, 1H), 7.89 (dd, J: 1.7, 7.9 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.59 (s, 1H), 7.50 (dd, J =1.7,9.2 Hz, 1H), 7.41 (d, J = 0.037 8.1 Hz, 1H), 4.54 (s, 2H), 3.78—3.62 (m, 1H), 3.44 (s, 3H), 3.23—3.08 (m, 4H), 2.44 (s, 3H).
MS m/z 454.1 (M+1)+.
MS m/z 476.1 (M+1)+. 0.009 MS m/z 520.2 (M+1)+. 0.011 MS m/z 490.1 (M+1)+. 0.007 MS m/z 490.1 (M+1)+. 0.012 c-kit Structure Physical Data (Mo7e) HgCO/CXNH:N’N/ F MS m/z 548.2 (M+1)+. 0.006 CwNYQLF 1H NMR (400MHz, O) 5 10.20 (s, 1H), 9.54 —9.51 (m, 1H), 8.71 (s, 1H),8.10 (dd, J: 1.6, 7.2 Hz, 1H), 7.89 — 7.85 (m, 3H), 7.70 — 7.66 (m, 1H), 7.54 — 7.50 (m, 2H), 7.33 — 7.29 (m, 0071 1H), 6.28 — 6.25 (m, 1H), 5.04 — 4.96 (m, 1H), 3.82 — 3.73 (m, 1H), 3.10 — 2.85 (m, 4H), 2.37 (s, 3H).
MS m/z 440.18 (M+1)+.
MS m/z 493.1 (M+1)+. 0.013 MS m/z 494.1 (M+1)+. 0.033 1H NMR (400MHz, dg-DMSO) 5 10.35 (s, 1H), 9.63 (s, 1H), 8.61 (s, 1H), 8.38 (dd, J: 2.0, 7.2 Hz, 1H), 8.21 (s, 1H), 7.90-7.96 (m, 2H), 7.56 (dd, J = 8.4, .0 Hz,1H), 4.77 (s, 1H), 4.06 (s, 2H), 0.016 3.91 (m, 1H), 3.08-3.25 (m, 4H), 1.10 (s, 6H).
MS m/z 552.2 (M+1)+.
MS m/z 571.2 (M+1)+. 0.033 MS m/z 588.9 . 0.026 MS m/z 592.8 (M+1)+. 0.085 c-kit Structure Physical Data (Mo7e) 1H NMR (400MHz, CDC13) 5 9.58 (s, 1H), 8.59 (d, J: 1.6 Hz, 1H), 8.23 (s, 1H), 7.90 (dd, J: 1.6, 8.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.63 (s, 1H), 7.51 (dd, J = 2.0, 9.2 Hz, 1H), 7.42 (d, J = 0 079 8.0 Hz, 1H), 4.75 (s, 2H), 3.91 (q, J = 8.4 Hz, 2H), 3.69 (m, 1H), 3.15 (m, 4H), 2.46 (s, 3H).
MS m/z 522.1 (M+1)+. 1H NMR (400MHz, O) 5 10.19 (s, 1H), 9.37 (s, 1H), 8.70 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.86 — 7.83 (m, 2H), 7.66 (dd, J = 1.6, 9.2 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 3.92 — 3.84 (m, 0.045 1H), 3.24 — 3.05 (m, 4H), 2.89 — 2.86 (m, 4H), 2.37 (s, 3H), 2.11 (s, 3H).
MS m/z 480.18 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.18 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.86 — 7.82 (m, 2H), 7.65 — 7.62 (m, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.91 — 3.84 (m, 1H), 3.25 — 0.031 3.04 (m, 4H), 2.78 — 2.73 (m, 2 H), 2.37 (s, 3H), 1.71 — 1.67 (m, 2H), 1.16 (s, 6H).
MS m/z 496.21 (M+1)+. 1H NMR (400MHz, CDZCIZ) 5 9.89 (d, J = 6.8 Hz, 1H), 9.81 (s, 1H), 9.56 (s, 1H), 8.21 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.0 (t, J = 8.0 Hz, 1H), 7.88 (dd, J = 1.6, 7.6 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.42 (d, J: 8.0 Hz, 1H), 3.23 (t, J 0.092 = 7.2 Hz, 2H), 2.47 (s, 3H), 2.12 (t, J = 7.2 Hz, 2H), 0.79 (t, J: 6.8 Hz, 2H), 0.53 (t, J = 6.8 Hz 2H).
MS m/z 404.2 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.10 (s, 1H), 9.46 (s, 1H), 8.63 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.86 — 7.83 (m, F56 °\©\<NYQIF 2H), 7.54 — 7.50 (m, 2H), 4.03 — 4.00 0.054 \ (m, 2H), 3.92 — 3.84 (m, 1H), 3.69 — 3.63 (m, 2H), 3.54 — 3.43 (m, 4H), 3.23 — 3.04 (m, 8H), 2.38 (s, 3H).
Cmpd Structure Physical Data MS m/z 522.22 (M+1)+. 1H NMR (400 MHz, CDZCIZ) 5 9.56 (d, J=6.8, 1H), 8.62 (s, 1H), 8.39 (d, J: 1.6 Hz, 1H), 8.35 (s, 1H), 7.78 (dd, J: 1.7, 7.9 Hz, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 6.9 F57 0.023 Hz, 1H), 3.75 (qd, J: 1.2, 8.8 Hz, 1H), 2.52 — 2.38 (m, 4H), 2.37 (d, J = 4.3 Hz, 3H), 2.18 — 1.89 (m, 2H).
MS m/z 374.3 (M+1)+.
NMR (400 MHz, dg-DMSO) 5 10.20 (s, 1H), 9.53 (d, J: 6.9 Hz, 1H), 8.71 (s, 1H), 8.06 (d, J: 1.6 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.84 (dd, J = 1.7, 7.9 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.51 (d, J F58 = 8.1 Hz, 1H), 7.32 (t, 0.02 J = 6.9 Hz, 1H), 3.95 — 3.84 (m, 1H), 2.36 (s, 3H), 2.29 — 2.17 (m, 4H), 1.25 (s, 3H), 1.12 (d, J: 22.6 Hz, 3H).
MS m/z 402.1 (M+1)+.
F59 MS m/z 495.1 (M+1)+. 0.007 1H NMR (400MHz, dg-DMSO) 5 10.27 (s, 1H), 9.94 —9.93 (m, 1H), 8.71 (s, 1H), 8.08 (d, J: 2.0 Hz, 1H), 7.96 (dd, J = 0.8, 9.2 Hz, 1H), 7.85 (dd, J = 2.0, 8.0 Hz, 1H), 7.80 (dd, J = 1.6, 9.2 Hz, F60 0.092 1H), 7.52 (d, J = 8.0 Hz, 1H), 3.92 — 3.84 (m, 1H), 3.24 — 3.04 (m, 4H), 2.37 (s, 3H).
MS m/z 434.13 (M+1)+.
F61 MS m/z 495.1 (M+1)+. 0.154 1H NMR z, dg-DMSO) 5 10.18 (s, 1H), 9.99 — 9.98 (m, 1H), 8.68 (s, F62 1H), 8.28 (s, 1H), 8.10 (d, J: 1.6 Hz, 0.094 1H), 7.98 (dd, J: 1.6, 9.2 Hz, 1H), 7.88 — 7.83 (m, 2H), 7.66 (s, 1H), 7.52 (d, J Structure Physical Data = 8.0 Hz, 1H), 3.91 — 3.84 (m, 1H), 3.22 — 3.06 (m, 4H), 2.38 (s, 3H).
MS m/z 452.14 (M+1)+.
MS m/z 536.3 (M+1)+. 0.082 1H NMR (400 MHz, CDZCIZ) 5 9.60 (t, J = 11.7 Hz, 1H), 8.57 (t, J = 4.6 Hz, 1H), 8.51 (s, 1H), 8.12 (s, 1H), 7.87 (dd, J = 1.7, 7.9 Hz, 1H), 7.82 (d, J: 9.0 Hz, 1H), 7.62 — 7.48 (m, 1H), 7.48 — 7.37 (m, 1H), 7.16 (td, J = 0.8, 6.9 Hz, 0.052 1H), 3.16 (ddd, J = 7.9, 10.5, 11.3 Hz, 1H), 2.48 (s, 3H), 2.40 (dtd, J = 5.8, 8.1, 12.4 Hz, 1H), 2.22 (tdd, J = 5.6, 8.3, 11.5 Hz, 2H).
MS m/z 396.1 (M+1)+.
MS m/z 477.1 (M+1)+. 0.013 1H NMR (400MHz, d4-MeOH) 5 9.70 (m, 1H), 8.60-8.80 (m, 2H), 8.33 (s, 1H), 8.16 (d, J: 1.6 Hz, 1H), 7.96 (m, 1H), 7.85 (d, J: 7.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 4.62 (t, J = 4.8 Hz, 2H), 0.016 4.02 (t, J = 4.8 Hz, 2H), 3.79 (m, 1H), 3.13 (m, 4H), 2.44 (s, 3H).
MS m/z 521.1 (M+1)+. 1H NMR (400MHz, d4-MeOH) 5 9.75 (d, J = 6.8 Hz, 1H), 8.75 (s, 1H), 8.08 (s, 1H), 8.02 (m, 2H), 7.55 (m, 1H), F67 7.36 (s, 1H), 3.79 (m, 1H), 3.11 (m, 0.049 4H), 2.63 (s, 3H), 2.39 (s, 3H).
MS m/z 424.1 (M+1)+. 1H NMR z, dg-DMSO) 5 10.12 (s, 1H), 9.45 (d, J: 7.6 Hz, 1H), 8.64 (s, 1 H), 8.08 (d, J: 1.6 Hz, 1H), 7.84 F68 (dd, J: 2.0, 8.0 Hz, 1H), 7.76 (m, 1H), 0.039 7.51 (d, J = 8.4 Hz, 1H), 4.54 (t, J = 8.4 Hz, 2H), 4.19 (t, J: 8.4 Hz, 2H), 3.89 (m, 1H), 3.15 (m, 4H), 2.38 (s, 3H).
Structure Physical Data MS m/z 495.1 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 9.97 (s, 1H), 9.33 — 9.31 (m, 1H), 8.52 (s, 1H), 8.07 (d, J: 1.6 Hz, 1H), 7.82 (dd, J = 1.6, 7.6 Hz, 1H), 7.57 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.03 (dd, J = 1.6, 0.020 7.2 Hz, 1H), 3.91 — 3.83 (m, 1H), 3.23 — 3.06 (m, 4H), 2.43 (s, 3H), 2.36 (s, 3H).
MS m/z 423.15 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 9.99 (s, 1H), 9.29 (s, 1H), 8.53 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 1.6, 8.0 Hz, 1H), 7.71 — 7.69 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 1.6, 0.026 9.2 Hz, 1H), 3.91 — 3.84 (m, 1H), 3.23 — 3.05 (m, 4H), 2.36 (s, 6H).
MS m/z 423.15 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.13 (s, 1H), 9.48 — 9.46 (m, 1H), 8.63 (s, 1H), 8.06 (d, J: 2.0 Hz, 1H), 7.90 — 7.86 (m, 1H), 7.84 (dd, J: 1.6, 7.6 Hz, F71 1H), 7.67 — 7.62 (m, 1H), 7.50 (d, J = 0.046 8.0 Hz, 1H), 3.90 — 3.85 (m, 1H), 3.23 — 3.05 (m, 4H), 2.36 (s, 3H).
MS m/z 427.13 . 1H NMR (400MHz, dg-DMSO) 5 10.08 (s, 1H), 9.50 — 9.46 (m, 1H), 8.58 (s, 1H), 8.06 (d, J: 1.6 Hz, 1H), 7.83 (dd, J = 1.6, 7.6 Hz, 1H),7.71— 7.68 (111, F72 1H), 7.50 (d, J: 8.0 Hz, 1H), 7.26 — 0.032 7.22 (m, 1H), 3.90 — 3.85 (m, 1H), 3.23 — 3.04 (111, 4H), 2.36 (s, 3H).
MS m/z 427.13 (M+1)+. 1H NMR z, dg-DMSO) 5 10.29 (s, 1H), 9.55 — 9.52 (m, 1H), 8.77 (s, 1H), 8.59 — 8.57 (m, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.85 (dd, J: 1.6, 7.6 Hz, F73 1H), 7.51 (d, J: 8.4 Hz, 1H), 7.48 (dd, J 0.104 = 2.0, 7.6 Hz, 1H), 3.90 — 3.85 (m, 1H), 3.23 — 3.03 (m, 4H), 2.36 (s, 3H).
MS m/z 434.13 (M+1)+. 2012/052621 c-kit Structure Physical Data (Mo7e) MS m/z 388.0 (M+1)+. 0.033 MS m/z 428.0 (M+1)+. 0.017 MS m/z 493.2 (M+1)+. 0.037 1H NMR (400MHz, CDC13) 5 9.58 (s, 1H), 8.58 (d, J: 1.6 Hz, 1H), 8.25 (s, 1H), 7.89 (dd, J: 1.6, 8.0 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.68 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 5.94 (a, J = 55.2, 0.032 4.0 Hz, 1H), 4.70 (s, 2H), 3.75 (dt, J: 4.0, 13.6 Hz, 2H), 3.68 (m, 1H), 3.17 (m, 4H), 2.46 (s, 3 H).
MS m/z 504.0 (M+1)+.
MS m/z 392.1 (M+1)+. 0.01 1H NMR (400MHz, d4-MeOH) 8 10.21 (m, 1H), 8.52 (s, 1H), 8.19 (d, J: 1.6 Hz, 1H), 8.15 (dd, J: 1.6, 9.2 Hz, 1H), 7.93 (dd, J: 1.6, 8.0 Hz, 1H), 7.82 (dd, J = 0.8, 9.2 Hz, 1H), 7.49 (d, J = 8.0 0.055 Hz, 1H), 3.79 (m, 1H), 3.15 (m, 4H), 2.51 (s, 3H), 2.45 (s, 3H).
MS m/z 490.7 (M+1)+. 1H NMR (400MHz, CDZCIZ) 5 9.56 (d, J = 7.2 Hz, 1H), 8.91 (s, 1H), 8.87 (s, 1H), 8.46 (d, J: 1.2 Hz, 1H), 7.89 (dd, J: 1.6, 8.0 Hz, 1H), 7.69 (s, 1H), 7.44 (d, J: 8.0 Hz, 1H), 7.09 (dd, J: 1.2, 0.019 7.2 Hz, 1H), 3.77 — 3.68 (m, 1H), 3.21 — 3.13 (m, 4H), 2.49 (s, 3H).
MS m/z 427.2 (M+1)+. c-kit Structure Physical Data (Mo7e) MS m/z 495.1 (M+1)+. 0.026 MS m/z 475.7 (M+1)+. 0.078 MS m/z 485.7 (M+1)+. 0.029 MS m/z 520.7 (M+1)+. 0.022 MS m/z 508.1 (M+1)+. 0.069 MS m/z 486.1 (M+1)+. 0.049 1H NMR (400MHz, CD202) 5 9.49 (d, J = 6.8 Hz, 1H), 8.45 (d, J: 1.6 Hz, / /N 1H), 8.35 (s, 1H), 7.94 (s, 1H), 7.75 (dd, \ N\§\ J: 2.0, 7.8 Hz, 1H), 7.69 (d, J: 9.2 NH Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.32 F87 0 0046 (d, J = 8.0 Hz, 1H), 7.03 \NYAVF (t, J = 6.8 Hz, 1H), 3.08—3.01 (m, 1H), 2.36 (s, 3H), N’O 2.33—2.24 (m, 1H), .06 (m, 1H).
MS m/z 396.1 (M+1)+. 1H NMR (400MHz, CDZCIZ) 5 9.70 (d, J = 7.2 Hz, 1H), 8.91 (s, 1H), 8.78 (s, / ,N 1H), 8.46 (d, J: 1.6 Hz, 1H), 7.92 (d, J \ Nfi = 8.8 Hz, 1H), 8.38 (dd, J: 1.6, 8.0 Hz, NH 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.44 (d, J F88 0 0'066 = 8.0 Hz, 1H), 7.25 \N\7\\‘AVF (t, J = 6.8 Hz, 1H), 3.19—3.12 (m, 1H), 2.49 (s, 3H), 2.44— N’O 2.36 (m, 1H), .18 (m, 1H).
MS m/z 396.1 (M+1)+.
Structure Physical Data MS m/z 472.1 (M+1)+. 0.025 1H NMR (400MHz, CDZCIZ) 5 9.69 (s, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 8.11- 8.05 (m, 2H), 7.84 (d, J = 9.6 Hz, 1H), 7.69 (t, J: 4.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 3.61 —3.53 (m, 1H), 3.04 —2.98 0.04 (m, 2H), 2.67 —2.61 (m, 2H), 2.35 (s, 3H).
MS m/z 476.1 (M+1)+. 1H NMR (400MHz, ) 5 9.75 (d, J = 7.2 Hz, 1H), 9.53 (s, 1H), 9.3 (s, 1H), 8.09 (d, J: 1.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.85 (t, J: 8.8 Hz, 1H), 7.75 (dd, 1.6, 7.8, 1H ), 7.39 (t, J: 7.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.07 0.02 — 4.89 (m, 1H), 2.69 —2.60 (111, 1H), 2.34 (s, 3H), 1.82 —1.71 (111, 1H), 1.56- 1.48 (111, 1H).
MS m/z 378.1 (M+1)+.
MS m/z 414.1 (M+1)+. 0.035 MS m/z 385.1 (M+1)+. 0.024 1H NMR (400MHz, CD202) 5 9.51 (t, J = 6.4 Hz, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 7.85 (dd, J: 1.6, 8.0 Hz, 1H), 7.75 (s, 1H), 7.42 (d, J: 8.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.97 (td, J = 2.0, 0.056 7.4, 1H), 3.70 — 3.62 (m, 1H), 3.18 — 3.12 (m, 2H), 2.86-2.81 (m, 2H), 2.26 (s, 3H).
MS m/z 476.1 (M+1)+. c-kit Structure Physical Data (Mo7e) MS m/z 490.1 (M+1)+. 0.077 1H NMR (400MHz, dg-DMSO) 5 10.17 (s, 1H), 8.95 (d, J: 1.6 Hz, 1H), 8.64 (s, 1H), 8.03 (d, J: 1.6 Hz, 1H), 7.84 (dd, J = 1.6, 8.0 Hz, 1H), 7.79 —7.71 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 3.91 — 3.86 (m, 1H), 3.76 —3.71 (m, 2H), 3.54 0.046 —3.51 (m, 2H), 3.23 —3.03 (m, 4H), 2.36 (s, 3H), 2.31 —2.25 (m, 2H), 1.17 (s, 3H), 1.15 (s, 3H).
MS m/z 522.22 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.06 (s, 1H), 9.47 — 9.44 (m 1H), 8.59 (s, 1H), 8.08 (d, J: 1.6 Hz, 1H), 7.83 (dd, J = 1.6, 7.6 Hz, 1H), 7.80 — 7.78 (m, 1H), 7.55 — 7.50 (m, 1H), 7.50 (d, J = 0.046 8.4 Hz, 1H), 7.20 — 7.16 (m, 1H), 3.76 — 3.68 (m, 1H), 3.38 (s, 3H), 2.88 — 2.85 (m, 4H), 2.36 (s, 3H).
MS m/z 471.15 (M+1)+.
F98 NH \0 MS m/z 436.2 (M+1)+. 0.086 1H NMR (400MHz, dg-DMSO) 5 10.15 (s, 1H), 10.11 (m, 1H), 8.65 (s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.06 (dd, J = “NYC“/ ,N 2.0, 9.2 Hz, 1H), 7.88 (dd, J = 0.8, 9.2 Hz, 1H), 7.85 (dd, J = 2.0, 8.0 Hz, 1H), F99 Pf “N NH F 7.52 (d, J = 8.0 Hz, 1H), 4.34 (t, J = 5.2 0.044 CWNYQ‘F Hz, 2H), 3.89 (m, 1H), 3.72 (t, J = 5.2 Hz, 2H), 3.24 (s, 3H), 3.02—3.20 (m, 4H), 2.47 (s, 3H), 2.39 (s, 3H). MS m/z 549.1 . \ [i F100 NH 0” 0flNW/QU MS m/z 430.1 (M+1)+. 0.066 PCT/U82012/052621 c-kit Structure Physical Data (Mo7e) MS m/z 378.1 . 0.067 1H NMR (400MHz, d4-MeOD) 5 9.38 (d, J = 7.2 Hz, 1H), 8.42 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.93 (dd, J = 1.6, 8.0 Hz, 1H), 7.52 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 1.6, 7.2 Hz, 0.009 1H), 5.01 (d, J: 3.6 Hz, 2H), 4.68 (m, 1H), 3.02 (m, 1H), 2.61 (m, 1H), 2.50 (s, 3H), 2.42 (s, 3H).
MS m/z 490.1 (M+1) +. 1H NMR (400MHz, d4-MeOD) 5 9.36 (m, 1H), 8.45 (s, 1H), 8.16 (d, J: 1.6 Hz, 1H), 7.94 (dd, J: 1.6, 8.0 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.47—7.52 (m, 0.016 2H), 5.02 (d, J: 3.2 Hz, 2H), 4.69 (m, 1H), 3.02 (m, 1H), 2.60 (m, 1H), 2.43 (m, 6H).
MS m/z 490.1 (M+1) +.
MS m/z 360.1 (M+1) +. 0.057 1H NMR (400MHz, CD202) 8 9.57 (d, J: 8.0 Hz, 1H), 8.64 (d, J: 1.6 Hz, 1H), 8.24 (s, 1H), 7.87 (dd, J: 1.6, 7.6 Hz,1H), 7.76 (d, J: 8.8 Hz, 1H), 7.65 (bs, 1H), 7.51-7.46 (m, 1H), 7.44 (d, J = 7.6, 1H), 7.10 (td, J: 1.2, 6.8 Hz, 1H), 0.04 2.91 (d, J = 6.8 Hz, 2H), 2.47 (s, 3H), 1.32—1.23 (m, 3H), 0.71-0.66 (m, 2H), 0.41—0.37 (m, 2H).
MS m/z 374.1 (M+1) +.
MS m/z 392.1 (M+1)+. 0.052 PCT/U82012/052621 c-kit Structure Physical Data (Mo7e) MS m/z 392.1 . 0.085 1H NMR (400MHz, dg-DMSO) 5 10.04 (s, 1H), 9.46 — 9.44 (m, 1H), 8.57 (s, 1H), 7.95 (s, 1H), 7.79 — 7.76 (m, 1H), 7.53 — 7.49 (m, 1H), 7.36 (s, 1H), 7.18 — 0.043 7.15 (m, 1H), 3.74 (m, 1H), 2.55 (s, 3H), 2.47 — 2.35 (m, 2H), 2.31 (s, 3H).
MS m/z 409.14 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.04 (s, 1H), 9.46 — 9.44 (m, 1H), 8.57 (s, 1H), 7.95 (s, 1H), 7.79 — 7.76 (m, 1H), 7.53 — 7.49 (m, 1H), 7.36 (s, 1H), 7.18 — 0.089 7.15 (m, 1H), 3.74 (m, 1H), 2.55 (s, 3H), 2.47 — 2.35 (m, 2H), 2.31 (s, 3H).
MS m/z 409.14 (M+1)+.
MS m/z 378.1 (M+1)+. 0.058 1H NMR (400MHz, dg-DMSO) 5 9.98 (s, 1H), 9.33 (d, J: 7.2 Hz, 1H), 8.53 (s, 1H), 8.07 (d, J: 1.6 Hz, 1H), 7.82 (dd, J: 2.0, 8.0 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J : 8.0 Hz, 1H), 7.04 (dd, J : 0.046 1.6, 7.2 Hz, 1H), 5.48 — 5.30 (m, 1H), 3.98 — 3.93 (m, 1H), 2.82 — 2.73 (m, 4H), 2.43 (s, 3H), 2.36 (s, 3H).
MS m/z 406.16 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 9.99 (s, 1H), 9.28 (s, 1H), 8.53 (s, 1H), 8.08 (d, J : 1.6 Hz, 1H), 7.82 (dd, J : 1.6, 8.0 Hz, 1H), 7.70 (d, J : 9.2 Hz, 1H), 7.49 (d, J : 8.0 Hz, 1H), 7.39 (dd, J : 0.056 1.6, 9.2 Hz, 1H), 5.47 — 5.30 (m, 1H), 3.98 — 3.94 (m, 1H), 2.81 — 2.73 (m, 4H), 2.36 (s, 6H).
MS m/z 406.16 (M+1)+.
Canopd Structure Physical Data (Mo7e) . “M / /N \ Na F113 NH 0 MS m/Z 378.1 (M+1)+. 0.056 N ‘.
\ \‘ AF / /N 0 : J0 N >< >:F F175 (be F MS m/z 483.1 (M+1)+. 0.073 / /N o “g :r N F F176 do F MS m/z 497.1 . 0.067 NMR (400 MHz, CDC13) 5 9.56 (s, 1H), 8.60 (d, J: 1.6, 1H), 8.21 (s, 1H), 7.89 (dd, J: 1.7, 7.9, 1H), 7.77 (d, J: 9.2, 1H), 7.62 (s, 1H), 7.53 (dd, J: 1.7, 9.2, 1H), 7.42 (d, J : 8.1, 1H), 4.72 — 4.64 (m, 3H), 4.59 — 4.52 (m, 1H), 3.86 —3.79 (m, 1H), 3.79—3.73 (m, 1H), O :N/N/ F” ){NH 3.68 (m, 1H), 3.16 (m, 4H), 2.47 (s, N F 3H).
F177 @157 3 IF MS m/z 486.1 (M+1)+. 0.029 *20% FBS, otherwise 1% FBS Representative compounds of Formula (I) and Formula (II) with c-kit inhibition leo values greater than 100 nM and prepared following the procedures described above, are set forth in Table 2.
Table 2 Cmpd Structure No. al Data 1H NMR (400MHz, dg-DMSO) 5 10.11 (s, 1H), 9.47 (d, J : 7.2 Hz, 1H), 8.63, (s, 1H), 8.13 (d, J: 1.6 Hz, 1H), 7.87 (dd, J: 8.0, 2.0 Hz, 1H), 7.82 (d, J : 8.8 Hz, 1H), 7.58 (bt, J : 7.2 Hz, 1H), F114 7.55 (d, J : 8.0 Hz, 1H), 7.23 (t, J : 7.2 0322* Hz, 1H), 2.40 (s, 3H), 2.24 — 2.17 (m, 1H),1.14 — 1.01 (m, 2H), 1.01 —0.97 (m, 2H).
MS m/z 360.1 (M+1)+.
Structure al Data (Mo7e) 1H NMR (400MHz, dg-DMSO) 5 10.23 (s, 1H), 9.53 —9.51 (m, 1H), 8.72 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.92 — 7.89 (m, 1H), 7.83 (dd, J: 1.6, 8.0 Hz, 1H), 7.74 —7.69 (m, 1H), 7.54 (d, J = 0.162 8.0 Hz, 1H), 7.36 —7.32 (m, 1H), 3.83 — 3.78 (m, 1H), 3.20 —3.06 (m, 4H), 2.38 (s, 3H). MS m/z 409.14 (M+1)+.
MS m/z 404.2 (M+1)+. 0.182* 1H NMR (400MHz, d4-MeOH) 5 9.77 (d, J = 7.2 Hz, 1 H), 8.78 (s, 1 H), 8.14 — 8.13 (m, 1 H), 8.04 — 8.03 (m, 2 H), 7.95 — 7.93 (m, 1 H), 7.57 (ddd, J = 6.8, 0203 3.83 (s, 3 H), 3.75 — 3.65 (m, 1 H), 3.14 — 2.81 (m, 2 H), 2.75 — 2.51 (m, 2 H), 2.43 (s, 3 H), 2.22 — 2.09 (m, 2 H).
MS m/z 431.1 (M+1)+. 1H NMR (400MHz, d4-MeOH) 5 9.77 (d, J = 7.2 Hz, 1 H), 8.78 (s, 1 H), 8.14 — 8.13 (m, 1 H), 8.04 — 8.03 (m, 2 H), 7.95 — 7.93 (m, 1 H), 7.57 (ddd, J = 6.8, 6.8, 1.2 Hz, 1 H), 7.50 (d, J = 8.0, 1 H), 0.147* 3.75 — 3.65 (m, 1 H), 3.14 — 2.81 (m, 2 H), 2.75 — 2.51 (111,2 H), 2.43 (s, 3 H), 2.22 — 2.09 (m, 2 H).
MS m/z 417.2 (M+1)+.
MS m/z 428.1 (M+1)+. 0.162 1H NMR (400MHz, d4-MeOH) 5 9.53 (d, J = 7.2 Hz, 1 H), 8.49 (s, 1 H), 8.13 — 8.12 (m, 1 H), 7.90 (dd, J = 8.2, 2.0 Hz, 1 H), 7.75 (d, J = 9.6 Hz, 1 H), 7.60 — 7.55 (m, 1 H), 7.48 (d, J = 8.0 Hz, 0.119 1H), 7.18 (ddd, J = 7.2, 7.2, 1.2 Hz, 1 H), 3.48 — 3.40 (m, 1 H), 2.58 — 2.54 (111,4 H), 2.42 (s, 3 H), 1.46 (s, 3 H).
MS m/z 404.1 (M+1)+.
PCT/U82012/052621 c-kit Structure Physical Data (Mo7e) 1.1M MS m/z 388.1 (M+1)+. 0.14 MS m/z 390.1 (M+1)+. 0.135 MS m/z 457.2 (M+1)+. 0.345 1H NMR z, d4-MeOH) 5 9.75 (d, J = 7.2 Hz, 1 H), 8.79 (s, 1 H), 8.18 (d, J = 2.0 Hz, 1 H), 8.02 (m, 2 H), 7.93 (dd, J = 8.2, 2.1 Hz, 1 H), 7.56 — 7.50 (m, 2H), 4.10 — 4.09 (m, 2 H), 3.93 — 3.86 (m, 1 H), 3.80 — 3.73 (m, 2 H), 0.257 3.49 — 3.40 (m, 2 H), 3.14 — 3.05 (m, 2 H), 2.99 — 2.93 (111,2 H), 2.81 — 2.73 (m, 2 H), 2.44 (s, 3 H).
MS m/z 459.1 (M+1)+.
MS m/z 472.2 (M+1)+. 0.393 MS m/Z 516.24 (M+1)+. 0.213 1H NMR (400MHz, dg-DMSO) 5 10.24 (s, 1 H), 9.55 —9.51 (m, 1 H), 8.73 (s, 1 H), 8.07 (d, J = 1.6 Hz, 1 H), 7.92 — 7.88 (m, 1 H), 7.85 (dd, J = 1.2, 7.6 Hz, 1 H), 7.74 — 7.69 (m, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), F127 0.353 7.35 — 7.32 (m, 1 H), 4.37 — 4.30 (m, 1 H), 3.75 — 3.70 (m, 1 H), 2.61 — 2.54 (m, 2 H), 2.50 — 2.47 (111,2 H), 2.37 (s, 3 H), 1.38 (s, 9 H).
MS m/z 489.54 (M+1)+. c-kit Structure Physical Data (Mo7e) 1H NMR (400MHz, dg-DMSO) 5 10.16 (s, 1 H), 9.50—9.47 (m, 1 H), 8.69 (s, 1 H), 8.24 (d, J : 4.8 Hz, 2 H), 8.08 (d, J : 1.6 Hz, 1 H), 7.86 — 8.72 (m, 2 H), 7.63 — 7.58 (m, 1 H), 7.51 (d, J : 8.0 0.109 Hz, 1 H), 7.27 — 7.23 (m, 1 H), 4.07 — 3.95 (m, 2 H), 2.76 — 2.63 (m, 4 H), 2.37 (s, 3 H).
MS m/z 389.54 .
MS m/z 467.51 (M+1)+. 0.143 MS m/z 461.49 (M+1)+. 0.106 1H NMR (400MHz, DMSO) 5 10.37 (s, 1H), 9.52 (d, J: 6.8 Hz, 1H), 8.88 (s, 1H), 8.08 (s, 1H), 7.92 (d, J: 9.1 Hz, 1H), 7.84 (d, J: 7.6 Hz, 1H), 7.74 (m, 0.311 1H), 7.54 (m, 1H), 7.36 (m, 1H), 2.39 (s, 3H), 1.77 (m, 4H).
MS m/z 375.2 (M+1)+. 1H NMR (400MHz, CDC13) 5 9.79 (d, J:6.9 Hz, 1H), 8.91 (s, 1H), 8.14 (t, J:8.8 Hz,1H), 8.08 (d, J:8.1 Hz, 1H), 8.06 (s, 1H), 7.83 (dd, J:7.6, 1.9 Hz, 1H), 7.63 (t, J:6.9 Hz,1H), 7.45 (t, J:8 0.554 Hz,1H), 4.00 (s, 2H), 3.45 (s, 3H), 2.42 (s, 3H), 1.79 (dd, J:8.6, 5.5 Hz, 2H), 1.55 (dd, J:8, 4.9 Hz,2H).
MS m/z 447.2 (M+1)+.
MS m/z 447.2 (M+1)+. 0.451 F134 MS m/z 414.1 . 0.144 1H NMR (400MHz, dg-DMSO) 5 F135 0.999 MS m/z 486.46 (M+1)+. c-kit Structure Physical Data (Mo7e) 1H NMR (400MHz, dg-DMSO) 8 10.21 (s, 1 H), 9.53 (d, J = 6.8 Hz, 1 H), 8.71 (s, 1 ), 8.20 (s, 1 H), 8.077 (s, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.85 — 7.83 (111,1 2—7.68 (111, 1 H),7.51 (d,J= 0171 8.0 Hz, 1 H), 7.34 — 7.31 (111, 1 H), 2.70 — 2.63 (111,2 H), 2.46 — 2.39 (111, 2 H), 2.37 (s, 3 H), 2.05 — 2.03 (111,2 H), 1.37 (s, 9 H).
MS m/z 489.54 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.11 (s, 1H), 9.47 (d, J=6.9, 1H), 9.19 (s, 3H), 8.66 (s, 1H), 8.14 (d, J=1.7, 1H), 7.91 — 7.82 (In, 2H), 7.63 — 7.58 (In, 1H), 7.55 (d, J=8.2, 1H), 7.25 (t, J=6.9, 0.197 1H), 4.41 (br s, 74-2.85 (111, 3H), 2.66 — 2.70 (In, 2H), 2.39 (s, 3H), 2.12- 2.24 (111, 2H).
MS m/z 389.42 (M+1)+.
MS m/z 390.0 (M+1)+. 0.103 MS m/Z 390.1 (M+1)+. 0.137 1H NMR (400MHz, dg-DMSO) 8 10.17 (s, 1 H), 9.53 — 9.51 (111, 1 H), 9.25 (1, J = 5.6 Hz, 1 H), 8.70 (s, 1 H), 8.07 (d, J = 1.6 Hz, 1 H), 7.90 — 7.87 (111, 1 H), 7.82 (dd, J = 1.6, 8.0 Hz, 1 H), 7.71 — 0.132 7.67 (111, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.33 — 7.29 (111, 1 H), 4.77 — 4.65 (111,2 H), 2.76 — 2.68 (111, 1 H), 2.37 (s, 3 H), 1.96 — 1.89 (111, 2 H).
MS m/Z 453.41 (M+1)+. 1H NMR (400MHz, dg-DMSO) 8 10.23 (s, 1 H), 9.63 —9.61 (111, 1 H), 8.75 (s, 1 H), 8.32 — 8.30 (111, 1 H), 8.09 (d, J = 1.6 Hz, 1 H), 7.93 (1, J: 5.6 Hz, 1 H), 7.,82(dd J=1.,6 8.0,Hz 1H), 7.5,2(d 0.391 Hio>< J= 8.4,Hz 1H), 7.4,6(dd J: 2.0, 7.2 Hz, 1H), 4.5,3(d J= 6.0,Hz 2H), 2.38 (s,3H),1.4,6(s 3H), 0.795— 0.7,64(111 2 H), 0.620 — 0.588 (111, 2 H).
MS m/z 515.46 (M+1)+.
PCT/U82012/052621 c-kit Structure Physical Data (Mo7e) 1.1M MS m/z 447.1 (M+1)+. 0.148 1H NMR (400MHz, d6-DMSO) 5 10.10 (s, 1 H), 9.36 (s, 1 H), 8.62 (s, 1 H), 8.08 (d, J :1.6 Hz, 1 H), 7.83 (dd, J : 1.6, 8.0 Hz, 1 H), 7.78 (d, J : 9.2 Hz, 1 H), 7.59 — 7.56 (m, 1 H), 7.51 (d, J : 0237 8.0 Hz, 1 H), 3.93 — 3.82 (m, 1 H), 3.23 — 3.02 (m, 4 H), 2.91 (t, J : 7.2 Hz, 2 H), 2.60 (t, J : 7.2 Hz, 2 H), 2.36 (s, 3 H), 1.33 (s, 9 H). MS In/z 538.22 MS m/z 522.2 (M+1)+. 0.249 \ Nfi F145 fig MS m/z 552.2 (M+1)+. 0.238 \O/Vofi//N NH F F146 0mj/C/ F MS m/z 498.1 (M+1)+. 0.105 / ,N F147 ”o‘er N °@w# MS m/z 534.1 (M+1)+. 0.351 1H NMR (400MHz, dg-DMSO) 5 10.13 / :N (s, 1 H), 9.50—9.47 (m, 1 H), 8.66 (s,1 \ Ni H), 8.02 (d,J: 1.6 Hz, 1 H),7.86— 1 H), 7.79 (dd, J: 1.6, 7.6 Hz, F148 NH 7.83 (m, 0 0305 1 H), 7.64 — 7.60 (m, 1 H), 7.49 (d, J : NW 8.4 Hz, 1 H), 7.28 — 7.24 (m, 1 H), 2.36 ‘N, (s, 3 H), 1.42 — 1.34 (m, 4 H). MS m/z 376.13 (M+1)+. 1H NMR (400MHz, O) 5 10.18 F O \Fr : N/“/fiNH (s, 1 H), 9.32 (dd, J: 0.8, 6.8 Hz, 1 H), 8.61 (s, 1 H), 8.06 (d, J : 1.6 Hz, 1 H), F149 0% F 7.84 (dd, J : 1.6, 7.6 Hz, 1 H), 7.80 — 0.378 7.43 (m, 1 H), 7.51 (d, J : 8.0 Hz, 1 H), 7.35 (d, J : 7.6 Hz, 1 H), 7.17 (t, J : 7.2 Hz, 1 H), 3.92 — 3.82 (m, 1 H), 3.24 — c-kit Structure Physical Data (Mo7e) 3.02 (m, 4 H), 2.36 (s, 3 H). MS m/z 476.13 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.20 (s, 1 H), 9.54 — 9.50 (m, 1 H), 8.70 — 8.6,6(m 2H), 8.11—8.0,4(m 2H), NF) 7.89— 7.8,4(m 2H), 7.70 m1 0.167 H), 754 751 (m 1H), 7.33— 7.29 (m, 1H), 5.19 5.1,0(m 1H), 3.88— 3.79 (m, 1 H), 3.10 — 2.90 (m, 4 H), 2.38 (s, 3 H). MS m/z 441.17 (M+1)+. 1H NMR (400MHz, d4-MeOH) 8 9.55 (dd, J = 4.4, 2.0 Hz, 1 H), 8.52 (s, 1 H), 8.12 (m, 1 H), 7.92 (dd, J = 8.0, 2.0 Hz, 1 H), 7.79 (dd, J = 9.6, 4.8 Hz, 1 H), 0.181 7.58 (m, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 4.30 (m, 1 H), 3.35 (m, 1 H), 2.81 (m, 2 H), 2.42 (s, 3 H), 2.37 (m, 2 H).
MS m/z 408.1 (M+1)+ NMR (400 MHz, dZ-CHZCIZ) 5 9.82 (d, J=7.0, 1H), 9.35 (s, 1H), 9.13 (s,1H), 8.79 (dd, J=3.7, 7.2, 1H), 8.17 (dd, J=8.8, 1H), 7.98 (ddd, J=2.1, 4.9, 8.6, 1H), 7.95 — 7.89 (m, 1H), 7.48 (td, 0.151 J=1.1, 7.0, 1H), 7.34 (dd, J=1.6, 10.3, 1H), 3.87 (quintet 0f doublets, J=1.2, 8.8, 1H), 2.69 — 2.41 (m, 4H), 2.29 — 2.05 (m, 2H). MS m/z 378.1 (M+1)+.
MS m/z 482.1 (M+1)+. 0.165 MS m/z 509.0 (M+1)+. 0.365 MS m/z 482.1 . 0.39 NMR (400 MHz, dg-DMSO) 5 10.58 (s, 1H), 9.57 (s, 1H), 8.87 (s, 1H), 8.37 (s, 1H), 7.87 (m, 3H), 7.48 (m, 2H), 3.90 0.125 (s, 1H), 2.23 (s, 4H), 1.24 (s, 3H), 1.14 (s, 3H). MS m/z 406.1 (M+1)+.
WO 33070 Structure Physical Data (Mo7e) / ,N fl\ I N—N NH F MS m/z 495.1(M+1) 0.154 FflVWF .
MS m/z 422.1 (M+1)+. 0.175 NMR (400 MHz, dZ-CHZCIZ) 5 9.91 (d, 1:13.1, 1H), 9.84 (t, 1:8.6, 1H), 9.09 (s, 1H), 8.91 (s, 1H), 8.28 (d, 1:1.4, 1H), 8.15 (d, 1:9.0, 1H), 8.06 — 7.97 (m, 1H), 7.90 (dd, 1:1.6, 7.9, 1H), 7.55 0.218 1:6.9, 1H), 7.44 (d, 1:8.0, 1H), 3.30 — 3.21 (m, 2H), 3.19 — 3.09 (m, 2H), 2.51 — 2.34 (m, 3H). MS m/z 376.1 (M+1)+. 1H NMR (400MHz, d4-MeOH) 5 9.77 (d, 1 : 7.2 Hz, 1 H), 8.82 (s, 1 H), 8.06 (m, 2 H), 7.88 (d, 1 : 8.0 Hz, 1 H), 7.58 (dt, 1 : 2.0, 6.8 Hz, 1 H), 7.37 (d, 1 : 0.293 8.0 Hz, 1 H), 3.81 (m, 1 H), 3.14 (m, 4 H), 2.56 (s, 3 H), 2.40 (s, 3 H). MS m/z 424.1 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.29 (s, 1H), 9.55 — 9.52 (m, 1H), 8.77 (s, 1H), 8.59 — 8.57 (m, 1H), 8.08 (d, 1 : 1.6 Hz, 1H), 7.85 (dd, 1: 1.6, 7.6 Hz, 1H), 7.51 (d, 1: 8.4 Hz, 1H), 7.48 (dd, 1 0.104 : 2.0, 7.6 Hz, 1H), 3.90 — 3.85 (m, 1H), 3.23 — 3.03 (m, 4H), 2.36 (s, 3H). MS m/z 434.13 (M+1)+. 1H NMR (400MHz, dg-DMSO) 5 10.15 (s, 1H), 9.49 (s, 1H), 8.67 (s, 1H), 8.08 (d, 1 : 1.6 Hz, 1H), 7.85 — 7.82 (m, 2H), 7.66 (dd, 1 : 1.2, 9.2 Hz, 1H), 7.51 (d, 1 : 8.4 Hz, 1H), 4.90 — 4.86 (m, 0.157 1H), 3.91 — 3.84 (m, 1H), 3.23 —3.04 (m, 4H), 2.37 (s, 3H), 1.40 (d, 1: 6.4 Hz, 3H). MS m/z 453.16 (M+1)+.
MS m/z 490.2 (M+1)+. 0.139 WO 33070 c-kit Structure Physical Data (Mo7e) MS m/z 498.2 (M+1)+. 0.101 MS m/z 410.14 (M+1)+. 0.107 MS m/z 392.15 (M+1)+. 0.111 MS m/z 390.16 (M+1)+. 0.144 MS m/z 421.14(M+1)+. 0.516 MS m/z 493.22 (M+1)+. 0.539 MS m/z 433.19 (M+1)+. 4.28 F171 F 0 O\©\( MS m/z 482.16 (M+1)+. >10 MYQéN F WO 33070 c-kit Structure Physical Data (Mo7e) MS m/Z 480.2 (M+1)+. >10 MS m/z 478.15 (M+1)+. >10 *20% FBS instead of 1% FBS A representative compound of Formula (I) and Formula (II) which was also prepared following the procedures described above, is set forth in Table 3.
Table 3 c-kit Cmpd Structure Physical Data (Mo7e) / /N F174 NH 0 MS m/z 404.2 (M+1)+. 0%WOKN Assays nds of Formula (I) and Formula (II) provided herein were assayed to measure their capacity to inhibit c-kit and PDGFR s using the appropriate assay described below: c-Kit inhibition was ted using the Mo7e cell proliferation assay, and PDGFR inhibition was evaluated using the Rat A10 cell proliferation assay and the Human TG/HA-VSMC cell proliferation assay.
Mo7e cell eration assay The compounds of Table 1 and Table 2 were tested for inhibition of SCF dependent proliferation using human Mo7e cells which endogenously express c-kit in a 384 well format. Three-fold serially diluted test compounds (Cmax=10 mM) were evaluated for their antiproliferative activity of Mo7e cells ated with human recombinant SCF.
After 48 hours of incubation at 37 00, cell viability was measured by adding 25 uL of CellTiter Glo (Promega) to the cells and the luminescence was measured by a CLIPR CCD camera (Molecular Devices).
Rat A10 cell eration assay Rat A10 cells (ATCC) were resuspended in DMEM supplemented with 1% FBS or % FBS and 10 ng/mL recombinant rat B at 20,000 cells/mL. The cells were aliquoted into 384 well plates at 50 uL/well and incubated for 4 hours at 3700. 0.5 uL of test nd 3-fold serially diluted in DMSO was added to each well. The plates were returned to the incubator for a further 68 hours. 25 uL of CellTiter-Glo (Promega) was added to each well and the plates were incubated on the bench for 15 minutes.
Luminescence was then read using a CLIPR CCD camera (Molecular Devices).
Human TG/HA-VSMC cell proliferation assay Human VSMC cells (ATCC) were resuspended in DMEM supplemented with 1% FBS and 30 ng/mL recombinant human PDGF-BB at 60,000 cells/mL. The cells were aliquoted into 384 well plates at 50 uL/well and incubated for 4 hours at 3700. 0.5 uL of test compound 3-fold serially diluted in DMSO was added to each well. The plates were returned to the incubator for a further 68 hours. 25 uL of CellTiter-Glo (Promega) was added to each well and the plates were incubated on the bench for 15 minutes.
Luminescence was then read using a CLIPR CCD camera (Molecular Devices).
Certain Assay Results Various compounds of Formula (I) and Formula (II) in free form or in pharmaceutically acceptable salt form, exhibit pharmacological properties, for e, as indicated by the tests described herein and ted in Table 1 and Table 2. The leo value is given as that concentration of the test compound in question that provoke a response halfway between the baseline and maximum ses. Certain compounds of Formula (I) or Formula (II) having specific leo for c-kit tion values of less than or equal to 100 nM are listed in Table 1, while certain compounds of Formula (I) or Formula (II) having specific IC50 for c-kit inhibition values greater than 100 nM are listed in Table In other embodiments, compounds of Formula (I) or Formula (II) have IC50 values for c-kit inhibition in the range from 1 nM to 1 pM. In other embodiments, compounds of Formula (I) or Formula (II) have leO values for c-kit inhibition in the range from 1 nM to 500 nM. In other embodiments, compounds of a (I) or Formula (II) have IC50 values for c-kit inhibition in the range from 1 nM to 200 nM. In other ments, compounds of a (I) or Formula (II) have IC50 values for c-kit inhibition in the range from 1 nM to 100 nM. In other embodiments, compounds of Formula (I) or Formula (II) have leo values for c-kit inhibition in the range from 1 nM to 50 nM. In other embodiments, compounds of Formula (I) or Formula (II) have IC50 values for c-kit inhibition in the range from 1 nM to 25 nM. In other embodiments, compounds of Formula (I) or Formula (II) have IC50 values for c-kit inhibition in the range from 1 nM to nM. In other ments, compounds of Formula (I) or Formula (II) have IC50 values for c-kit inhibition in the range from 1 nM to 5 nM. In other embodiments, compounds of Formula (I) or Formula (II) have IC50 values for c-kit inhibition in the range from 1 nM to 2.5 nM.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or s in light thereof will be suggested to persons skilled in the art and are to be included within the range and scope of the invention.

Claims (28)

WHAT IS CLAIMED IS:
1. A compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof: Formula (I) Formula (II) wherein: m is 1 and R20 is selected from H, halo, lkyl, C1-C6haloalkyl, C1- 10 C6haloalkoxy, deuterium, deuterated C1-C6alkyl, -CN, -(CR92)nOR4, - C(O)R4, R10, -(CR92)nR10, -((CR92)nO)tR4, -(CR92)nO(CR92)nR7, - (CR92)nC(=O)R4, -C(=O)N(R4)2, -OR4 and )nCN; or m is 4 and R20 is deuterium; R1 is selected from C1-C6alkyl and halo; 15 each R11 is independently selected from H, halo, and C1-C6alkyl; L1 is a bond, –NH- or -C(=O)NH-; L2 is -(CR92)n-, -CHR6-, -(CR92)nO-, -NH-, -(CR92)nC(=O)-, -C(=O)O(CR92)n-, -(CR92)nOC(=O)NR4-, -(CR92)nNR4C(=O)(CR92)n -, -(CR92)nNR4C(=O)- or - (CR92)nNR4C(=O)O- ; 20 R2 is R3 or L2R3; R3 is selected from an unsubstituted C3-C8cycloalkyl, a cyclobutanone, a cyclopentanone and a substituted ycloalkyl, wherein the substituted C3-C8cycloalkyl of R3 is tuted with 1-4 substituents independently selected from C1-C6alkyl, halo, C1- 25 alkyl, -OR4, -CN, -C(=O)OR4, -C(=O)R4, -C(=O)R7, - C(=O)OR5, -(CR92)nOR4, -C(=O)O(CR92)nOR4, -N(R4)2, =N-OR4, =N-O-(CR92)nR5, NR42, -NR4C(=O)OR4, - O)(CR92)nOR4, -NR4(CR92)nOR4, -NR4S(=O)2R4, - )OR4)2, =CH2, =CH(CR92)nOR4, R8, -(CR92)nR8, deuterated 30 C1-C6alkoxy, -S(=O)2R4, -S(=O)2R7, 2R8, -S(=O)2N(R4)2, - S(=O)2NHC(=O)OR4, -S(=O)2(CR92)nC(=O)OR4, - S(=O)2(CR92)nOR4, a spiro attached dioxolane, a spiro attached dioxolane which is substituted with C1-C6alkyl, a spiro attached dioxane, a spiro ed tetrahyrofuranly, a spiro attached oxetane, a spiro attached cyclobutanone, a spiro attached cyclobutanol, a C1 alkyl bridge, an unsubstituted 5-6 ed heterocycloalkyl with 1-2 atoms independently selected from 5 N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S substituted with 1-3 substituents independently selected from C1-C6alkyl, halo, aloalkyl, C1-C6haloalkoxy, -OR4 and R8; each R4 is independently selected from H and C1-C6alkyl; 10 R5 is an unsubstituted C3-C8cycloalkyl , an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N or O or a C3-C8cycloalkyl tuted with 1-3 substituents independently selected from C1-C6alkyl; each R6 is independently ed from -NHC(O)OR4, -OR4 and -(CR92)nOR 4; 15 each R7 is independently selected from C1-C6haloalkyl; R8 is selected from an unsubstituted phenyl, tituted 5-6 membered heteroaryl with 1-3 atoms independently selected from N, O or S, an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 20 heteroatoms independently selected from N, O or S, an unsubstituted C3- C8cycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently ed from N, O or S, a substituted phenyl, a substituted 5 membered heteroaryl with 1-4 atoms ed from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms 25 independently selected from N, O or S, a substituted C3-C8cycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected 30 from N, substituted C3-C8cycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from lkyl, -(C(R9)2)nOR 4, -(C(R9) 5, - 2)nR (C(R 9) 4, -C(O)OR4 and -S(O) 4; 2)nC(O)OR 2R each R9 is independently selected from H and C1-C6alkyl; 35 R10 is ed from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-2 atoms independently selected from N, O or S, an unsubstituted 5 membered heteroaryl with 1-3 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently ed from N, O or S, an unsubstituted C3- C8cycloalkyl, a substituted 5-6 membered heteroaryl with 1-2 atoms independently selected from N, O or S, a substituted phenyl, a substituted 5 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered cycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted C3-C8cycloalkyl, a oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl 10 with 1-2 heteroatoms independently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 atoms selected from N, tuted C3-C8cycloalkyl and substituted 4-6 membered heterocycloalkyl of R10 are substituted with 1-3 substituents ndently selected from C1-C6alkyl, -(C(R9)2)nOR4, -(C(R9)2)nR5, - 15 (C(R9)2)nC(O)OR4 and -S(O)2R4; t is 1, 2 or 3, and each n is independently selected from 1, 2, 3 and 4.
2. The compound of claim 1, wherein the nd is a compound of Formula (Ia), Formula (IIa), Formula (Ib) or Formula (IIb): Formula (Ia) Formula (IIa) Formula (Ib) Formula (IIb) 25 wherein: m is 1 and R20 is selected from H, halo, C1-C6alkyl, C1-C6haloalkyl, C1- C6haloalkoxy, deuterium, deuterated C1-C6alkyl, -CN, -(CR92)nOR4, - C(O)R 4, R10 , -(CR9 10 , -((CR9 4, -(CR9 9 7, - 2)nR 2)nO) tR 2)nO(CR 2)nR (CR 9 4, -C(=O)N(R4) 4 and -(CR9 2)nC(=O)R 2, -OR 2)nCN; or m is 4 and R20 is deuterium; R1 is selected from C1-C6alkyl and halo; 5 each R11 is independently selected from H, halo, and C1-C6alkyl; L2 is -(CR92)n-, , -(CR92)nO-, -NH-, -(CR92)nC(=O)-, -C(=O)O(CR92)n-, -(CR 9 4-, -(CR9 4C(=O)(CR 9 9 4C(=O)- or - 2)nOC(=O)NR 2)nNR 2)n -, -(CR 2)nNR (CR 9 4C(=O)O- ; 2)nNR R2 is R3 or L2R3; 10 R3 is selected from an unsubstituted C3-C8cycloalkyl, a cyclobutanone, a cyclopentanone and a substituted ycloalkyl, wherein the substituted C3-C8cycloalkyl of R3 is substituted with 1-4 substituents ndently selected from C1-C6alkyl, halo, C1- C6haloalkyl, -OR4, -CN, -C(=O)OR4, -C(=O)R4, -C(=O)R7, - 15 C(=O)OR 5, -(CR9 4, -C(=O)O(CR9 4, -N(R4) 4, 2)nOR 2)nOR 2, =N-OR =N-O-(CR 9 5, 2)nR -C(=O)NR42, -NR4C(=O)OR 4, - NR (CR 9 4, R 9 4, -NR4S(=O) 4, - 2)nOR 2)nOR 2R N(C(=O)OR 4) 9 4, R8, -(CR9 8, deuterated 2, =CH2, =CH(CR 2)nOR 2)nR C1-C6alkoxy, -S(=O)2R4, -S(=O)2R7, -S(=O)2R8, -S(=O)2N(R 4) 2, - 20 S(=O) 4, -S(=O) 9 4, - 2NHC(=O)OR 2(CR 2)nC(=O)OR S(=O) 9 4, a spiro attached dioxolane, a spiro attached 2(CR 2)nOR dioxolane which is substituted with C1-C6alkyl, a spiro ed dioxane, a spiro attached tetrahyrofuranly, a spiro ed oxetane, a spiro attached cyclobutanone, a spiro attached 25 cyclobutanol, a C1 alkyl , an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently ed from N, O and S, a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O and S substituted with 1-3 substituents independently selected from C1-C6alkyl, halo, 30 C1-C6haloalkyl, C1-C6haloalkoxy, -OR4 and R8; each R4 is independently selected from H and C1-C6alkyl; R5 is an unsubstituted C3-C8cycloalkyl , an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N or O or a C3-C8cycloalkyl substituted with 1-3 substituents independently 35 ed from lkyl; each R6 is independently selected from -NHC(O)OR4, -OR4 and -(CR92)nOR 4; each R7 is independently selected from C1-C6haloalkyl; R8 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-3 heteroatoms independently ed from N, O or S, an unsubstituted 5 membered heteroaryl with 1-4 atoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 5 heteroatoms independently selected from N, O or S, an unsubstituted C3- C8cycloalkyl, a substituted 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from N, O or S, a substituted , a substituted 5 membered heteroaryl with 1-4 atoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms 10 independently selected from N, O or S, a substituted C3-C8cycloalkyl, a oxazolidinone, pyrrolidinone and a idinone, wherein the tuted phenyl, the substituted 5-6 membered heteroaryl with 1-3 heteroatoms ndently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 atoms selected 15 from N, substituted C3-C8cycloalkyl and substituted 4-6 membered heterocycloalkyl of R8 are substituted with 1-3 substituents independently selected from C1-C6alkyl, -(C(R9)2)nOR 4, -(C(R9) 5, - 2)nR (C(R 9) 4, -C(O)OR4 and -S(O) 4; 2)nC(O)OR 2R each R9 is independently selected from H and C1-C6alkyl; 20 R10 is selected from an unsubstituted phenyl, unsubstituted 5-6 membered heteroaryl with 1-2 heteroatoms independently selected from N, O or S, an unsubstituted 5 membered heteroaryl with 1-3 heteroatoms selected from N, an unsubstituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, an unsubstituted C3- 25 C8cycloalkyl, a substituted 5-6 membered heteroaryl with 1-2 heteroatoms independently ed from N, O or S, a substituted , a substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, a substituted 4-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N, O or S, a substituted C3-C8cycloalkyl, a 30 oxazolidinone, pyrrolidinone and a pyrrolidinone, wherein the substituted phenyl, the substituted 5-6 membered heteroaryl with 1-2 atoms ndently selected from N, O or S, the substituted 5 membered heteroaryl with 1-4 heteroatoms selected from N, substituted C3-C8cycloalkyl and substituted 4-6 membered 35 heterocycloalkyl of R10 are substituted with 1-3 substituents independently selected from C1-C6alkyl, -(C(R9)2)nOR 4, -(C(R9) 5, - 2)nR (C(R 9) 4 and -S(O) 4; 2)nC(O)OR 2R t is 1, 2 or 3, and each n is independently ed from 1, 2, 3 and 4.
3. The compound of claim 1 or claim 2, wherein R1 is ed from -CH3 and F.
4. The compound of any one of claims 1 to 3, wherein R1 is -CH3.
5 5. The compound of any one of claims 1 to 4, n each R11 is independently selected from H, F and -CH3.
6. The compound of any one of claims 1 to 5, wherein each R11 is H.
7. The compound of any one of claims 1 to 6, wherein R3 is selected from an unsubstituted C3-C8cycloalkyl, a cyclobutanone, a cyclopentanone and a 10 substituted C3-C8cycloalkyl, wherein the substituted C3-C8cycloalkyl of R3 is substituted with 1-4 substituents independently selected from lkyl, halo, C1-C6haloalkyl, -OR4, - (CR 9 4, - -N(R4) 4, =N-O-(CR9 5, -NR4C(=O)OR 4, - 2)nOR 2, =N-OR 2)nR NR 4C(=O)(CR 9 4, -NR4(CR 9 4, -NR4S(=O) 4, -N(C(=O)OR4) 2)nOR 2)nOR 2R 2, 15 =CH 9 4, R8, deuterated C 2, =CH(CR 2)nOR koxy, a spiro attached dioxolane, a spiro attached dioxolane which is substituted with C1-C6alkyl, a spiro attached dioxane, a spiro attached tetrahyrofuranly, a spiro attached cyclobutanone, a spiro attached cyclobutanol, an unsubstituted 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected 20 from N and O and a 5-6 membered heterocycloalkyl with 1-2 heteroatoms independently selected from N and O substituted with 1-3 tuents ndently selected from C1-C6alkyl.
8. The compound of any one of claims 1 to 7, wherein each R4 is independently selected from H, methyl, ethyl, propyl, butyl, i-propyl and t-butyl. 25
9. The compound of any one of claims 1 to 8, n R5 is independently selected from cyclopropyl or morpholinyl.
10. The compound of any one of claims 1 to 9, wherein each R7 is ndently selected from CH2F, -CHF2, -CH2CHF 2, -CH2CF 3 and -CF3.
11. The compound of any one of claims 1 to 10, wherein each R9 is independently 30 selected from H, methyl and ethyl.
12. The compound of any one of claims 1 to 11, wherein R8 is selected from an an unsubstituted C3-C8cycloalkyl and an unsubstituted 5 membered heteroaryl with 1-4 heteroatoms selected from N.
13. The compound of any one of claims 1 to 12, wherein R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, , each of which is unsubstituted or each of which is substituted with 1-4 substituents independently selected from -F, -CH3, -CH2CH 3, -CF3, -OH, - OCH 3, -CH2OCH 3, -NH2, -N(CH3)2, =N-OCH3, =N-OCH2CH 3, =N- 5 OCH(CH 5, =N-O-CH 5, - 3)2, =N-OH, =N-O-CH2R 2CH 2R NHC(=O)OC(CH 3)3, O)OCH3, -NHC(=O)CH2OCH 3, - NHCH 2CH 2OCH 3, CH 2OH, -NHS(=O)2CH 3, -N(C(=O)OCH3)2, =CH 2, CH 2OH, -OCD3, cyclopropyl, triazolyl, pyrazolyl, a spiro attached dioxolane, a spiro attached dioxolane which is substituted with 10 a -CH3, a spiro attached dioxane, a spiro attached tetrahyrofuranly, a spiro attached cyclobutanone, a spiro attached cyclobutanol, piperidinyl and piperazinyl substituted with a -CH3, or R3 is a cyclobutanone or a cyclopentanone.
14. The compound of any one of claims 1 to 13, n: 15 R3 is cyclopropyl substituted with 1 or 2 F, R3 is cyclobutyl substituted with 2 F.
15. The compound of any one of claims 1 to 14, wherein m is 1 and R20 is selected from H, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkoxy, deuterated C1-C6alkyl, - 20 CN, -(CR92)nOR 4, R10 , -(CR92)nR10 , -((CR92)nO) 4, -(CR9 9 7, tR 2)nO(CR 2)nR - (CR 9 4, and -C(=O)N(R4) 2)nC(=O)R 2.
16. The compound of any one of claims 1 to 15, wherein m is 1 and R20 is selected from H, -F, -CH3, -CF3, -CD3, -CN, -OCHF2, -CH(CH3)OH, -CH2OCH 2CH 2OH, - CH 2OCH 2CF 3, -C(=O)NH2, -CH2CH 2C(CH 3)2OH, H 2CH 2OCH 3, - 25 CH 2OCH 2CH 2F, -CH2CH 2C(=O)CH 3, -CH2OH and -CH2OCH 3.
17. The compound of any one of claims 1 to 16, wherein m is 1 and R20 is -CH3.
18. The compound of any one of claims 1 to 16, wherein m is 1 and R20 is H.
19. The compound of any one of claims 1 to 18, wherein: R10 is selected from morpholinyl, piperidinyl, piperidinyl, dinyl, 30 piperidinyl, piperidinyl, piperazinyl, piperazinyl, pyrazolyl, pyrazolyl, pyrazolyl, pyrazolyl, triazolyl, ,3-triazolyl, 4H- 1,2,4-triazolyl, 1H-1,2,4-triazolyl, thiazolyl, thiazolyl, thiazolyl, olyl, olyl, olyl, each of which is unsubstituted or each of which is substituted with 1-3 substituents independently selected from C1-Cealkyl, -(CF192)nOFl4,-(C(Fi9)2)nC(O)OFi4,-(C(Fig)2)nFi5 and - S(=O)2R4, or R10 is selected from a oxazolidinone and a pyrrolidinone.
20. The nd of any one of claims 1 to 19, wherein: R10 is selected from morpholinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperazinyl, piperazinyl, pyrazolyl, pyrazolyl, pyrazolyl, lyl, triazolyl, 1 H-1,2,3-triazolyl, 4H- 1,2,4-triazolyl, 1H-1,2,4-triazolyl, thiazolyl, thiazolyl, thiazolyl, imidazolyl, imidazolyl, imidazolyl, each of which is unsubstituted or 10 each of which is substituted with 1-3 tuents independently selected from -CH3, -CHZCH20H, -CHZC(O)OH, -CHZCHZOH, -CHZC(CH3)2OH, - S(O)ZCH3 and 2-R5.
The compound of any one of claims 1 to 14, wherein m is 4 and R20 is deuterium.
22. The compound of claim 1 selected from: 15 N-{5-[3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]-2—methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-{2—methyl[5-(3-oxocyclopentyl)-1,2,4-oxadiazolyl]phenyl}imidazo[1,2- a]pyridinecarboxamide; N-{5-[5-(3-hydroxymethylcyclobutyl)-1,2,4-oxadiazolyl]-2— 20 methylphenyl}imidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[3-(hydroxyimino)cyclobutyl]-1,2,4-oxadiazolyl}-2— phenyl)imidazo[1,2—a]pyridinecarboxamide; N-{5-[5-(4,4-difluorocyclohexyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1 ,2- dinecarboxamide; 25 N-{5-[5-(3-hydroxymethylcyclobutyl)-1,2,4-oxadiazolyl]-2— methylphenyl}imidazo[1,2—a]pyridinecarboxamide; N-(5-{5-[3-(methoxyimino)cyclobutyl]-1,2,4-oxadiazolyl}-2— methylphenyl)imidazo[1,2—a]pyridinecarboxamide; N-[5-(5-{5,8—dioxaspiro[3.4]octanyl}-1,2,4-oxadiazolyl)-2— 30 methylphenyl}imidazo[1,2—a]pyridinecarboxamide; N-(2-methyl{5-[(6R)methyl-5,8—dioxaspiro[3.4]octanyl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2—a]pyridinecarboxamide; N-[5-(5-{5,9-dioxaspiro[3.5]nonanyl}-1,2,4-oxadiazolyl)-2— methylphenyl}imidazo[1,2—a]pyridinecarboxamide; 35 N-{2—methyl[5-(3-oxocyclobutyl)-1,2,4-oxadiazolyl]phenyl}imidazo[1,2- a]pyridinecarboxamide; N-(2-methyl{5-[(6S)methyl-5,8-dioxaspiro[3.4]octanyl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; 5 N-(5-{5-[3-(ethoxyimino)cyclobutyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; 5-{3-[(cyclopropylmethoxy)imino]cyclobutyl}-1,2,4-oxadiazolyl) methylphenyl]imidazo[1,2-a]pyridinecarboxamide; N-[2-methyl(5-{3-[(propanyloxy)imino]cyclobutyl}-1,2,4-oxadiazol 10 yl)phenyl]imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3-aminocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; 5-(3-methoxycyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; 15 N-(5-{5-[1-(methoxymethyl)cyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; tert-butyl N-{1-[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)-1,2,4- oxadiazolyl]cyclopropyl}carbamate; N-{5-[5-(1-methanesulfonamidocyclopropyl)-1,2,4-oxadiazolyl] 20 methylphenyl}imidazo[1,2-a]pyridinecarboxamide; methyl N-{1-[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)-1,2,4- oxadiazolyl]cyclopropyl}-N-(methoxycarbonyl)carbamate; methyl N-{1-[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)-1,2,4- oxadiazolyl]cyclopropyl}carbamate; 25 N-(5-{5-[3-hydroxy(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; 1-methylcyclopropyl N-{[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)- 1,2,4-oxadiazolyl]methyl}carbamate; methyl N-{1-[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)-1,2,4- 30 oxadiazolyl]cyclobutyl}carbamate; N-{5-[5-(1-methanesulfonamidocyclobutyl)-1,2,4-oxadiazolyl] methylphenyl}imidazo[1,2-a]pyridinecarboxamide; 5-[1-(dimethylamino)cyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; ethyl[5-(3-methylidenecyclobutyI)-1,2,4-oxadiazo|—3- y|]pheny|}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3-cyclopropyIhydroxycyclobutyl)-1,2,4-oxadiazo|—3-yI] methylphenyl}imidazo[1,2—a]pyridine—3-carboxamide; N-(5-{5-[3-(3-hydroxypropylidene)cyclobutyI]-1,2,4-oxadiazo|—3-yI} methylphenyl)imidazo[1,2—a]pyridine—3-carboxamide; N-[2-methyI(5-{5-oxaspiro[3.4]octan-2—y|}-1,2,4-oxadiazo|—3- y|)pheny|]imidazo[1,2—a]pyridine—3-carboxamide; N-[5-(5-{[(3,3-difluorocyclobutyl)amino]methy|}-1,2,4-oxadiazo|—3-yI) 10 methylphenyl]imidazo[1,2—a]pyridine—3-carboxamide; N-(2-methyl{5-[(2,2,3,3-tetrafluorocyclobutoxy)methyI]-1,2,4-oxadiazo|—3- y|}phenyl)imidazo[1,2—a]pyridine—3-carboxamide; 5-(3-fluorocyclobutyl)-1,2,4-oxadiazolyI]methylphenyl}imidazo[1,2- dine—3-carboxamide; 15 5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|} (hydroxymethyl)imidazo[1 ,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}[(2— hydroxyethoxy)methyl]imidazo[1 ,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|} 20 (methoxymethyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}(1H- pyrazoIyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}[1-(2— hydroxyethyI)-1H-pyrazoIyl]imidazo[1,2—a]pyridine—3-carboxamide; 25 N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}(1-methy| 1H-pyrazoIyl)imidazo[1 ,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}(1-methy| 1H-pyrazoI-B-yl)imidazo[1 ,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}[1-(2— 30 hydroxy-2—methylpropyI)-1H-pyrazoIyl]imidazo[1,2-a]pyridinecarboxamide; N-(2—methyI{5-[3-(1H-pyrazoIy|)cyc|obuty|]-1 ,2,4-oxadiazo|—3- y|}phenyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}(1,3- thiazoIyl)imidazo[1 ,2-a]pyridine—3-carboxamide; 35 N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|y|]f|uoropheny|}(1-methy|— 1H-pyrazoIyl)imidazo[1 ,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|y|]f|uoropheny|}[1-(2— hydroxy-2—methylpropyI)-1H-pyrazoIyl]imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}(1- methanesuIfonylpiperidinyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}{1-[2- (morpholinyl)ethyI]-1H-pyrazoIyl}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|y|]f|uoropheny|}{1-[2- (morpholinyl)ethyI]-1H-pyrazoIyl}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}[(2,2,2- 10 trifluoroethoxy)methyl]imidazo[1,2—a]pyridinecarboxamide; 5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyI}(3- oxobutyl)imidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyI}(3- hydroxymethylbutyl)imidazo[1,2—a]pyridine—3-carboxamide; 15 5-[2—(1-hydroxycyclopropyl)ethyl]-1,2,4-oxadiazo|—3-y|}-2— methylphenyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}[2- (morpholinyl)ethyl]imidazo[1 ,2—a]pyridine—3-carboxamide; N-[5-(5-cyclobutyI-1,2,4-oxadiazolyI)methylphenyl]imidazo[1,2-a]pyridine—3- 20 carboxamide; N-{5-[5-(3,3-dimethylcyclobutyl)-1 ,2,4-oxadiazo|—3-y|]-2—m ethylpheny|}imidazo[1 ,2- a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|} (morpholinyl)imidazo[1,2—a]pyridine—3-carboxamide; 25 o-N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazo|—3-yI] methylphenyl}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazo|y|]f|uoropheny|}(5-methy|— 4H-1,2,4-triazo|—3-yl)imidazo[1,2—a]pyridine—3-carboxamide; 3-N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazo|—3-yI] 30 methylphenyl}imidazo[1,2—a]pyridine—3,6-dicarboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}[2—(4- methylpiperaziny|)ethy|]imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(2,2—difluorocyclopropyl)-1,2,4-oxadiazo|—3-y|]-2—methylpheny|}imidazo[1,2- a]pyridine—3-carboxamide; 35 N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}(1H-1,2,3- triazoIyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}[1-(2— hydroxyethyI)-1H-1,2,3-triazo|—4-yl]imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-dif|uorocyclobutyI)-1,2,4-oxadiazolyI]-2,4- dimethylpheny|}imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}(2—oxo-1,3- oxazolidinyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|} methylimidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|} 10 methylimidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|} fluoroimidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|} fluoroimidazo[1,2—a]pyridine—3-carboxamide; 15 7-cyano-N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazo|—3-yI] methylphenyl}imidazo[1,2—a]pyridine—3-carboxamide; N-[5-(5-cyclopentyI-1,2,4-oxadiazolyI)methylphenyl]imidazo[1,2—a]pyridine—3- carboxamide; N-[2-methy|(5-{6-oxospiro[3.3]heptan-2—yI}-1,2,4-oxadiazo|—3- 20 ny|]imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}(2— oxopyrrolidiny|)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}[(2,2- difluoroethoxy)methyl]imidazo[1 yridine—3-carboxamide; 25 N-{5-[5-(3-ethylcyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}imidazo[1,2- dine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}(5-methy|— 4H-1,2,4-triazo|—3-yl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|} 30 methylimidazo[1,2-a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|} (morpholinyl)imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylpheny|}(1H- imidazoIyl)imidazo[1,2—a]pyridine—3-carboxamide; 35 N-{5-[5-(3,3-difluorocyclobutyI)-1,2,4-oxadiazolyI]methylphenyl}[(2— fluoroethoxy)methy|]imidazo[1,2—a]pyridine—3-carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}[3- (methoxymethyl)-1H-1,2,4-triazolyl]imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazolyl]methylphenyl}[(2,2,2- trifluoroethoxy)methyl]imidazo[1,2-a]pyridinecarboxamide; 5 N-[5-(5-cyclobutyl-1,2,4-oxadiazolyl)methylphenyl][(2,2,2- trifluoroethoxy)methyl]imidazo[1,2-a]pyridinecarboxamide; 5-[(1R)-2,2-difluorocyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(1S)-2,2-difluorocyclopropyl]-1,2,4-oxadiazolyl} 10 methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[3-hydroxy(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazolyl} methylphenyl)methylimidazo[1,2-a]pyridinecarboxamide; 6-fluoro-N-(5-{5-[3-hydroxy(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; 15 N-(5-{5-[(1R,2S)fluorocyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}-5,6,7,8- tetradeuteroimidazo[1,2-a]pyridinecarboxamide; 7-fluoro-N-(5-{5-[3-hydroxy(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazolyl} 20 methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}(4-methyl- 1H-imidazolyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}[(2R,6S)- 2,6-dimethylmorpholinyl]imidazo[1,2-a]pyridinecarboxamide; 25 N-(5-{5-[3-methoxy(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; 6-fluoro-N-(5-{5-[1-(methoxymethyl)cyclobutyl]-1,2,4-oxadiazolyl} phenyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}[1-(2- 30 yethyl)methyl-1H-1,2,4-triazolyl]imidazo[1,2-a]pyridine carboxamide; N-[5-(5-{6-hydroxyspiro[3.3]heptanyl}-1,2,4-oxadiazolyl) methylphenyl]imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(1S,2S)fluorocyclopropyl]-1,2,4-oxadiazolyl} 35 methylphenyl)imidazo[1,2-a]pyridinecarboxamide; 7-methyl-N-(2-methyl{5-[(2,2,3,3-tetrafluorocyclobutoxy)methyl]-1,2,4- oxadiazolyl}phenyl)imidazo[1,2-a]pyridinecarboxamide; 6-methyl-N-(2-methyl{5-[(2,2,3,3-tetrafluorocyclobutoxy)methyl]-1,2,4- oxadiazolyl}phenyl)imidazo[1,2-a]pyridinecarboxamide; N-[5-(5-cyclopropyl-1,2,4-oxadiazolyl)methylphenyl]imidazo[1,2-a]pyridine carboxamide; 5 N-{5-[5-(cyclopropylmethyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-(5-{5-[(1R,2S)fluorocyclopropyl]-1,2,4-oxadiazolyl}methylphenyl) imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(1S,2R)fluorocyclopropyl]-1,2,4-oxadiazolyl}methylphenyl) 10 methylimidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(1R)-2,2-difluorocyclopropyl]-1,2,4-oxadiazolyl}-2,4- dimethylphenyl)imidazo[1,2-a]pyridinecarboxamide; 5-[(1S)-2,2-difluorocyclopropyl]-1,2,4-oxadiazolyl}-2,4- dimethylphenyl)imidazo[1,2-a]pyridinecarboxamide; 15 N-(5-{5-[(1R,2S)fluorocyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3-fluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl} methylimidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3-fluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl} 20 methylimidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(1S,2R)fluorocyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; methyl -difluoro[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)- 1,2,4-oxadiazolyl]cyclobutyl}carbamate; 25 methyl N-{3,3-difluoro[3-(4-methyl{7-methylimidazo[1,2-a]pyridine amido}phenyl)-1,2,4-oxadiazolyl]cyclobutyl}carbamate, N-[5-(3-cyclopropyl-1,2,4-oxadiazolyl)methylphenyl]imidazo[1,2-a]pyridine carboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,3,4-oxadiazolyl]methylphenyl}imidazo[1,2- 30 a]pyridinecarboxamide; N-{5-[5-(3-hydroxymethylcyclobutyl)-1,2,4-oxadiazolyl] methylphenyl}imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(3Z)(methoxyimino)cyclopentyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(3Z)(hydroxyimino)cyclopentyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-(2-methyl{5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2-a]pyridinecarboxamide; 5 N-{5-[5-(3-hydroxymethylcyclobutyl)-1,2,4-oxadiazolyl] phenyl}imidazo[1,2-a]pyridinecarboxamide; N-{2-methyl[5-(3-oxocyclobutyl)-1,2,4-oxadiazolyl]phenyl}imidazo[1,2- a]pyridinecarboxamide; N-{5-[5-(3-hydroxycyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- 10 a]pyridinecarboxamide; N-(2-methyl{5-[3-(piperidinyl)cyclobutyl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2-a]pyridinecarboxamide; N-(2-methyl{5-[3-(morpholinyl)cyclobutyl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2-a]pyridinecarboxamide; 15 N-(2-methyl{5-[3-(4-methylpiperazinyl)cyclobutyl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2-a]pyridinecarboxamide; N-{2-methyl[5-(3-{[2-(morpholinyl)ethoxy]imino}cyclobutyl)-1,2,4-oxadiazol yl]phenyl}imidazo[1,2-a]pyridinecarboxamide; tert-butyl N-{3-[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)-1,2,4- 20 oxadiazolyl]cyclobutyl}carbamate; N-{5-[5-(3-aminocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; 5-(3-methanesulfonamidocyclobutyl)-1,2,4-oxadiazolyl] methylphenyl}imidazo[1,2-a]pyridinecarboxamide; 25 1-methylcyclopropyl N-{2-[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)- 1,2,4-oxadiazolyl]ethyl}carbamate; N-{5-[5-(1-aminocyclopropyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-(5-{5-[1-(2-methoxyacetamido)cyclopropyl]-1,2,4-oxadiazolyl} 30 methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-[5-(5-{3-[(2-methoxyethyl)amino]cyclobutyl}-1,2,4-oxadiazolyl) methylphenyl]imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]fluorophenyl}imidazo[1,2- a]pyridinecarboxamide; N-(5-{5-[3-methoxy(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazolyl} methylphenyl)-N-methylimidazo[1,2-a]pyridinecarboxamide; 5 tert-butyl N-{1-[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)-1,2,4- oxadiazolyl]cyclobutyl}carbamate; 5-(1-aminocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-{2-fluoro[5-(3-methylidenecyclobutyl)-1,2,4-oxadiazol 10 yl]phenyl}imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[1-(hydroxymethyl)cyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-[5-(5-{[(2,2-difluorocyclopropyl)formamido]methyl}-1,2,4-oxadiazolyl) methylphenyl]imidazo[1,2-a]pyridinecarboxamide; 15 1-methylcyclopropyl N-[(3-{4-methyl[7-(trifluoromethyl)imidazo[1,2-a]pyridine amido]phenyl}-1,2,4-oxadiazolyl)methyl]carbamate; methyl N-{3-[3-(3-{imidazo[1,2-a]pyridineamido}methylphenyl)-1,2,4- oxadiazolyl]cyclobutyl}carbamate; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}[(4- 20 methylpiperazinyl)methyl]imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}{[4-(2- hydroxyethyl)piperazinyl]methyl}imidazo[1,2-a]pyridinecarboxamide; 5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}[(2- methoxyethoxy)methyl]imidazo[1,2-a]pyridinecarboxamide; 25 2-{4-[3-({5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl] methylphenyl}carbamoyl)imidazo[1,2-a]pyridinyl]-1H-pyrazolyl}acetic acid; N-{5-[5-(1-hydroxycyclopropyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; 5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl} 30 (difluoromethoxy)imidazo[1,2-a]pyridinecarboxamide; N-(2-methyl{5-[3-(1H-1,2,4-triazolyl)cyclobutyl]-1,2,4-oxadiazol yl}phenyl)imidazo[1,2-a]pyridinecarboxamide; ro-N-{5-[5-(3-hydroxycyclobutyl)-1,2,4-oxadiazolyl] methylphenyl}imidazo[1,2-a]pyridinecarboxamide; N-[5-(5-cyclobutyl-1,2,4-oxadiazolyl)fluorophenyl]imidazo[1,2-a]pyridine carboxamide; 5 N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}(2- hydroxymethylpropyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}[(2-oxo- azolidinyl)methyl]imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}(2- 10 hydroxymethylpropyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-dimethylcyclobutyl)-1,2,4-oxadiazolyl]fluorophenyl}imidazo[1,2- a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]fluorophenyl}(5-methyl- 4H-1,2,4-triazolyl)imidazo[1,2-a]pyridinecarboxamide; 15 6-fluoro-N-{5-[5-(3-hydroxymethylcyclobutyl)-1,2,4-oxadiazolyl] phenyl}imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(2-hydroxycyclopropyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-{3-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]-2,6- 20 dimethylphenyl}imidazo[1,2-a]pyridinecarboxamide; 7-cyano-N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl] methylphenyl}imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}(1- hydroxyethyl)imidazo[1,2-a]pyridinecarboxamide; 25 N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}(5-methyl- 1H-imidazolyl)imidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}[(2- methoxyethoxy)methyl]imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(1S)-2,2-difluorocyclopropyl]-1,2,4-oxadiazolyl}methylphenyl) 30 methylimidazo[1,2-a]pyridinecarboxamide; N-{5-[5-(1-fluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-{5-[5-(1-hydroxycyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- a]pyridinecarboxamide; N-{5-[5-(1-carbamoylcyclopropyl)-1,2,4-oxadiazolyl]methylphenyl} fluoroimidazo[1,2-a]pyridinecarboxamide and 5 N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}(piperidin- midazo[1,2-a]pyridinecarboxamide.
23. The compound of claim 1 selected from: N-{5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl]methylphenyl}imidazo[1,2- dinecarboxamide; 10 N-(5-{5-[(1R)-2,2-difluorocyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(1S)-2,2-difluorocyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide; N-(5-{5-[(1S,2R)fluorocyclopropyl]-1,2,4-oxadiazolyl} 15 methylphenyl)imidazo[1,2-a]pyridinecarboxamide, and N-(5-{5-[(1R,2S)fluorocyclopropyl]-1,2,4-oxadiazolyl} methylphenyl)imidazo[1,2-a]pyridinecarboxamide.
24. A compound of selected from: N-(5-{5-[3-(2-methoxyethoxy)cyclobutyl]-1,2,4-oxadiazolyl} 20 methylphenyl)imidazo[1,2-a]pyridinecarboxamide, N-{5-[(3,3-difluorocyclobutyl)carbamoyl]methylphenyl}imidazo[1,2-a]pyridine carboxamide; and tert-butyl 3-[3-({5-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazolyl] methylphenyl}carbamoyl)imidazo[1,2-a]pyridinyl]propanoate.
25 25. A pharmaceutical composition comprising a therapeutically effective amount a compound of any one of claims 1 to 24 and a pharmaceutically acceptable carrier.
26. Use of a compound of any one of claims 1 to 24 in the manufacture of a medicament for ng a disease or disorder in a patient where modulation of a kinase is implicated, wherein the kinase is selected from c-kit, PDGFRa and 30 PDGFR b, and wherein the disease is a mast-cell associated disease, a respiratory disease, an matory disorder, ble bowel syndrome (IBS), inflammatory bowel disease (IBD), an mune disorder, a metabolic disease, a fibrosis disease, a dermatological disease, pulmonary arterial ension (PAH) or primary pulmonary hypertension (PPH).
27. The use of claim 26, wherein the disease is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel me (IBS), inflammatory bowel disease (IBD), uticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid 5 arthritis, multiple sis, melanoma, a intestinal l tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, type I diabetes or type II diabetes.
28. The compound of any one of claims 1 to 24, substantially as herein described with reference to any one of the Examples thereof.
NZ621092A 2011-09-01 2012-08-28 COMPOUNDS AND COMPOSITIONS AS c-KIT KINASE INHIBITORS NZ621092B2 (en)

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US201161530028P 2011-09-01 2011-09-01
US61/530,028 2011-09-01
PCT/US2012/052621 WO2013033070A1 (en) 2011-09-01 2012-08-28 COMPOUNDS AND COMPOSITIONS AS c-KIT KINASE INHIBITORS

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