NZ714797B2 - Primary carboxamides as btk inhibitors - Google Patents

Abstract

The invention provides carboxamide compounds of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions, including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, psoriatic arthritis, psoriasis, ankylosing spondylitis, interstitial cystitis, asthma, systemic lupus erythematosus, lupus nephritis, B cell chronic lymphocytic lymphoma, multiple sclerosis, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin's lymphoma, activated B-celllike diffuse large B-cell, lymphoma, multiple myeloma, diffuse large B-celllymphoma, follicular lymphoma, hairy cell leukemia or Lymphoblastic lymphoma. onditions, including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, psoriatic arthritis, psoriasis, ankylosing spondylitis, interstitial cystitis, asthma, systemic lupus erythematosus, lupus nephritis, B cell chronic lymphocytic lymphoma, multiple sclerosis, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin's lymphoma, activated B-celllike diffuse large B-cell, lymphoma, multiple myeloma, diffuse large B-celllymphoma, follicular lymphoma, hairy cell leukemia or Lymphoblastic lymphoma.

Description

PRIMARY CARBOXAMIDES AS BTK INHIBITORS RELATED APPLICATIONS This application claims priority to and the benefit of the filing date of US. Provisional Application No. 61/839,729, filed on June 26, 2013 and US. Provisional Application No. 61/897,577, filed on October 30, 2013, the entire content of each of which is orated herein by reference.

BACKGROUND OF THE INVENTION The protein s represent a large family of proteins that play a central role in the regulation of a wide variety of cellular processes and maintenance of cellular function. A partial, non- limiting, list of these kinases include: non-receptor tyrosine kinases such as the Tec family (BTK, ITK, Tec, ETK/BMX & RLK/TXK), Janus kinase family (Jak1, Jak2, Jak3 and Tyk2); the fusion kinases, such as BCR-Abl, focal adhesion kinase (FAK), Fes, Lck and Syk; receptor ne kinases such as epidermal growth factor or (EGFR), the platelet-derived growth factor receptor kinase (PDGF-R), the receptor kinase for stem cell factor, c-kit, the hepatocyte growth factor receptor, c- Met, and the fibroblast growth factor or, FGFR3; and serine/threonine kinases such as b-RAF, mitogen-activated n s (e.g., MKK6) and SAPK2B. Aberrant kinase actiVity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate tion of the immune and s systems. The novel compounds of this invention inhibit the actiVity of one or more protein kinases and are, therefore, expected to be useful in the treatment of kinase-mediated es.

Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase with a key role in immunoreceptor signaling (BCR, FcaR, FcyR, DAP12, Dectin-1, GPVI etc) in a host of hematopoietic cells including B cells, ets, mast cells, basophils, eosinophils, macrophages and neutrophils as well as osteoclasts involved in bone destruction (for reViews, see Brunner et al., 2005 Histol.

Histopathol., 20:945, Mohamed et al., 2009 Immunol. Rev., 228:58). Mutations in BTK are known to lead to X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice, which are characterized by limited B-cell production & d antibody titers (Lindvall et al., 2005 Immunol. Rev., 203200). The combined action of BTK in multiple cell types makes it an attractive target for autoimmune disease. BTK is related with sequence homology to other Tec family s (ITK, Tec, ETK/BMX & RLK/TXK).

In B-lymphocytes, BTK is required for B-cell development and for Ca2+ zation following of B-cell receptor (BCR) ment (Khan et al., 1995 Immunity 3:283; Genevier et al., 1997 Clin. Exp. Immun., 110:286) where it is believed to downstream of Src family kinases (such as Lyn), Syk & PI3K. BTK has been shown to be important for both thymus-dependent and thymusindependent type 2 responses to ns (Khan et al., Immunity 1995; 3; 283). In mast cells, studies using BTK mouse outs (Hata et al., 1998 J. Exp. Med., 187:1235; Schmidt et al., 2009 Eur. J.

Immtm, 39:3228) indicate a role for BTK in FcSRI induced signaling, histamine e & production of cytokines such as TNF, IL-2, & IL-4. In platelets, BTK is important for ing through the glycoprotein VI (GPVI) receptor that responds to collagen and has been shown to promote et aggregation and contribute to cytokine production from fibroblast-like synoviocytes (Hsu et al., 2013 Immtm Letters, 15097). In monocytes and macrophages, the action of BTK in invoked in FcyRI induced signaling and may also have role in Toll-Like Receptor-induced cytokine ses including TLR2, TLR4, TLR8 & TLR9 (Horwood et al., 2003 J. Exp. Med., 197:1603; Horwood et al., 2006 J.

Immunol, 176:3635; Perez de Diego et al., 2006 Allerg. Clin. Imm, 117:1462; Doyle et al., 2007 J.

Biol. Chem, 282:36959, Hasan et al., 2007 Immunology, 123:239; Sochorava et al., 2007 Blood, 53; Lee et al., 2008, J. Biol. Chem, 283:11189).

Therefore, inhibition of BTK is expected to intervene at several critical ons of the inflammatory reactions resulting in an effective suppression of autoimmune response. As such es involving B-cell receptor tion, antibody-Fc receptor interactions & GPVI or signaling may be modulated by treatment with BTK inhibitors. BTK inhibition is likely to act on both the tion of autoimmune disease by blocking BCR ing and the effector phase by abrogation of FcR signaling on macrophages, neutrophils, basophils, and mast cells. Furthermore, ng BTK would provide additional benefit Via inhibition of osteoclast maturation and therefore attenuate the bone erosions & overall joint destruction associated with rheumatoid arthritis. Inhibiting BTK may be useful in treating a host of inflammatory and allergic diseases — for example (but not limited to), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and type I ensitivity reactions such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, allergic asthma and systemic anaphylaxis. For a reView on targeting BTK as a treatment for inflammatory disorders and munity as well as leukemias and lymphomas, see Uckun & Qazi, 2010 Expert Opin. Ther. Pat, 20:1457. Because BTK is highly expressed in cancers of the hematopoietic system & BTK-dependent signaling in believed to be disregulated there, BTK inhibitors are expected to be useful treatments for B-cell lymphomas/leukemias & other oncologic disease — for example (but not limited to) acute lymphoblastic leukemia (ALL), chronic lymphocytic ia (CLL), non- Hodgkin’s ma (NHL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia (for reView, see Buggy & Elias 2012 Int Rev Immunol. 31:119). Taken together, BTK inhibitors provide a strong method to treat a host of inflammatory diseases and immunological disorders as well as hematologic cancers.

SUMMARY OF THE INVENTION In a first embodiment the invention provides a compound of Formula (1): /,Z \A x /E a (I) or a pharmaceutically acceptable salt, pro-drug, biologically active metabolite, , or stereoisomer thereof, n: X is NR2 or S; Y is N or CR1, and Z is N or CR1; or, Y is CRIR2 and Z is CRIRZ; A is N or CR4; E is N or CR5; R1 is independently H, deuterium, CN, halogen, CF3, -NR°R°, -N(Ra)C(O)Rb, ally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted aryl, optionally substituted (C3-C6)cycloalkyl, optionally substituted (C3- C6)cycloalkenyl, optionally substituted heteroaryl, or optionally substituted saturated or partially saturated heterocyclyl; R2 is independently H, deuterium, or optionally substituted (C1-C3)alkyl; R3 is halogen, -N(Ra)2, optionally substituted aryl, optionally substituted (C3- C7)cycloalkyl, optionally substituted saturated or partially saturated cyclyl, or optionally substituted aryl; or R3 is -R301-L-R302 wherein R301 is a bond, -O-, -OCH2-, -NRd-, or ally substituted (C1-C3)alkylene, L is ally tuted phenyl, optionally substituted (C3-C6)cycloalkyl, optionally substituted heteroaryl or a saturated or partially saturated heterocyclyl ning one or more heteroatoms, at least one of which is nitrogen; or L is —L1-L2 wherein L1 is attached to R301 and L1 is optionally substituted phenyl, optionally tuted heteroaryl or optionally substituted saturated or partially saturated carbocycle or a saturated or partially saturated heterocyclyl; and L2 is a bond, CH2, NRd, CH2N(H), S(O)2N(H), or —0-; R302 is CN, , optionally tuted -C(=O)R302a, -(CH2)n-optionally substituted saturated or partly saturated heterocyclyl or optionally substituted — S(O)2(C2)alkenyl; wherein R302a is optionally substituted (C1-C4)alkyl, optionally substituted (C2-C4)alkenyl, (C2-C4)alkynyl, -C(O)-(C1-C4)alkyl, optionally substituted saturated or partially unsaturated (C3-C6)cycloalkyl, ally substituted aryl, ally substituted aryl, -N(H)- optionally substituted heteroaryl or —(CH2)n-optionally substituted unsaturated or partly saturated heterocyclyl; R4 is H, deuterium, CN, optionally substituted (C1-C3)alkyl, optionally tuted (C3-C6) cycloalkyl or optionally substituted saturated or partially saturated heterocyclyl or optionally substituted heteroaryl; wherein the optionally substituted saturated or partially ted heterocyclyl; and optionally substituted aryl contain at least one nitrogen atom; R3 and R4 the carbon atoms to which they are attached, form an , together with optionally substituted, saturated, unsaturated or partially unsaturated 5 or 6 ed carbocyclic ring or an optionally substituted, saturated, or partially unsaturated 5 or 6 membered heterocyclic ring ning one or more heteroatoms selected from N, S and O; R5 is H, deuterium, halogen, or optionally substituted (C1-C3)alkyl; Ra is independently selected from H, -C(O)-optionally substituted )alkenyl, optionally substituted (C1-C6)alkyl, -(CH2)n-optionally substituted (C3-C6)cycloalkyl, -(CH2)n- ally substituted heterocyclyl, or -(CH2)n-optionally substituted aryl; Rb is H, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, -CH2-O-optionally substituted aryl, or -CH2-O- optionally substituted heteroaryl; RC is independently H, optionally substituted (C1-C6)alkyl, optionally substituted (C3- C6)cycloalkyl, optionally substituted saturated or partially ted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; Rd is H, ally substituted heterocyclyl, -(CH2)-optionally substituted (C3- C6)cycloalkyl, -(CH2)-optionally tuted heteroaryl or optionally substituted (C1-C3)alkyl; Rf is optionally substituted (C1-C3)alkyl, optionally substituted (C2-C4)alkenyl or optionally substituted (C2-C4)alkynyl; and n is independently 0 or 1.

In a second embodiment the invention provides a compound according to the first embodiment, wherein Y is CR1 and R1 of Y is H, optionally substituted ethenyl, optionally tuted ethyl, optionally substituted , optionally substituted 2,3-dihydrobenzofuranyl, optionally substituted 1,4-dioxanyl, optionally substituted 3,4-dihydro-2H—benzo[b][1,4]oxazinyl, optionally substituted 6,7—dihydro-4H—pyrazolo[5,l-c][l,4]oxazinyl, optionally substituted chromanyl, optionally substituted cyclohexenyl, optionally substituted ropyl, optionally substituted ydrofuranyl, optionally substituted isochromanyl, optionally substituted l,2,3,4-tetrahydroisoquinolinyl , optionally substituted isoxazolyl, optionally substituted morpholinyl, optionally substituted oxetanyl, optionally substituted phenyl, optionally substituted piperidinyl, optionally substituted zinyl, optionally substituted 3,6-dihydro-2H—pyranyl, optionally substituted pyrano[4,3-b]pyridinyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted 3H—pyridin-l-one, optionally substituted l,2,3,6-tetrahydropyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted 2,5-dihydropyrrolyl, optionally substituted tetrahydropyranyl or optionally substituted ydro-2H—thiopyranyl.

In a third embodiment the invention provides a compound according to any of the foregoing embodiments wherein R1 is H or R1 is optionally tuted by one or more substituents independently selected from the group ting of CN, OH, :0, halogen, )alkyl, (C 1- C4)all In a fourth embodiment the ion provides a compound according to any of the foregoing ments wherein R3 is -N(H)C(O)CH=CH2, optionally substituted isoxazolyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted l.

In a fifth embodiment the invention es a compound according to any of the foregoing embodiments according to claim 4, wherein R3 is ally tuted by one or more substituents ndently selected from -NH2, -NHCH3, )alkyl and -C(O)(C2-C4)alkenyl.

In a sixth embodiment the ion provides a compound according to any of the foregoing ments wherein X is NR2 and R2 is H.

In a seventh embodiment the invention provides a compound according to any of the foregoing embodiments wherein Y is CR1 and R1 of Y is H, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted pyrazolyl, or optionally substituted l,2,3,6- tetrahydropyridinyl.

In an eighth embodiment the invention provides a compound according to any of the foregoing embodiments wherein Y is CR1 and R1 of Y is optionally substituted by one or more substituents ndently selected from halogen, (C1-C4)alkyl, -C(O)(C1-C4)alkyl, and -S(O)2(C1- C4)all In a ninth embodiment the invention provides a compound according to any of the foregoing embodiments wherein Z is N or Z is CR1 and R1 on is H; and A is CR4 and R4 is H or inyl substituted with —C(O)CH=CH2.

In a tenth embodiment the invention provides a compound according to any of the foregoing embodiments wherein the compound is 4-(3-aminomethy1pheny1)(1-(methy1su1fony1)-1,2,3,6-tetrahydropyridinyl)-1H- indolecarboxamide; 2-(4-fluorophenyl)(pyridiny1)-1H-indolecarboxamide; 4-(pyridiny1)p-toly1—1H-indole-7—carboxamide; 2-(4-fluoropheny1)(pyridiny1)- 1H-indolecarboxamide; 2-(4-fluorophenyl)( 1H-pyrazoly1)-1H-indolecarboxamide; 4-(3,5-dimethy1isoxazolyl)p-toly1—1H-indole-7—carboxamide; 2-(1-acetylpiperidinyl)(3 -aminomethy1pheny1)-1H-indolecarboxamide; 4-(pyridinyl)p-toly1— 1H-indole-7—carboxamide; 4-(thiopheny1)p-toly1—1H-indole-7—carboxamide; 4-(2-aminopheny1)-1H-indolecarboxamide; 4-(3-aminomethy1phenyl)-1H-indole-7—carboxamide; 4-(5-aminopyridiny1)-1H-indolecarboxamide; minopyridiny1)-1H-indolecarboxamide; 4-(2-aminoethylamino)(4-fluorophenyl)-1H-indole-7—carboxamide; minoethy1amino)p-toly1—1H-indole-7—carboxamide; 4-(pyrimidin-5 -y1)p-toly1— 1H-indolecarboxamide; 4-(1H-pyrazoly1)p-toly1— olecarboxamide; 4-(1H-pyrazol-5 -y1)p-toly1—1H-indolecarboxamide; 2-(4-fluorophenyl)(pyrimidiny1)-1H-indolecarboxamide; 4-(thiazolyl)p-toly1—1H-indolecarboxamide; 4-(pyridinyl)p-toly1— 1H-indole-7—carboxamid; opheny1)p-toly1—1H-indole-7—carboxamide; 4-(1-methy1—1H-pyrazolyl)p-toly1—1H-indole-7—carboxamide; 4-(1H-pyrazol-3 -y1)p-toly1—1H-indolecarboxamide; 4-(2-aminopheny1)(1-(methy1su1fonyl)-1,2,3,6-tetrahydropyridiny1)-1H-indole-7— carboxamide; 2-(1-(methy1su1fony1)-1 ,2,3,6-tetrahydropyridinyl)pheny1—1H-indolecarboxamide; 4-(3-aminomethy1pheny1)(4,4-difluorocyclohexeny1)1H-indolecarboxamide; 4-(3-aminomethy1phenyl)- 1H-pyrrolo[2,3-c]pyridinecarboxamide; 4-(1-acryloy1piperidin-3 -y1)-1H-indolecarboxamide; 4-(1 -acryloylpiperidin 3-yl)(l -methyl- 1H-pyrazolyl)- 1H-indolecarboxamide; 4-(2-aminoethylamino)p-tolyl-1H-indolecarboxamide; 4-((lR,2R)aminocyclohexylamino)(4-fluorophenyl)-lH-indolecarboxamide*; 4-( 1 -methyl- 1H-pyrazolylamino)p-tolyl- 1H-indolecarboxamide; 4-iodo(pyridinyl)-1H-indolecarboxamide; 4-(3-aminomethylphenyl)(l-(methylsulfonyl)-l ,2,3,6-tetrahydropyridinyl)-1H- indolecarboxamide; 4-(3,5-dimethylisoxazolyl)(4-fluorophenyl)-lH-indolecarboxamide; 4-(2-aminophenyl)( l -(methylsulfonyl)- l ,2,3,6-tetrahydropyridinyl)- ole carboxamide; or 2-(1-Acetylpiperidinyl)(3-aminomethylphenyl)-lH-indolecarboxamide.

In an eleventh embodiment the invention provides a compound according to any of the first through third embodiments wherein R3 is L-R302, and R301 is a bond, N(H), N(CH3), CH2 , C(H)(optionally substituted (C1-C3)alkyl), O, or OCHZ.

In an twelfth ment the invention provides a compound according to the any of the first through third or eleventh embodiments wherein L is optionally substituted azetidinyl, optionally substituted entyl, optionally substituted 3,6-diazabicyclo[3.2.0]heptanyl, optioinally substituted 1,4-dioxanyl, optionally substituted linyl, optionally substituted xepanyl, optionally substituted phenyl, optionally substituted piperidinyl, or ally substituted pyrrolidinyl; or L is Ll-L2 wherein L1 is optionally substituted exyl, optionally substituted cyclopentyl optionally substituted phenyl, optionally substituted piperidinyl, ally substituted pyridinyl; L2 is N(H), N(CH3), N(CH2CH20H), N(CH2CH(CH3)2), N(oxetanyl), N(CH2- cyclopentyl), N(CH2-thiazolyl), O, S(O)2N(H), or ).

In an thirteenth embodiment the invention provides a compound according to any of the first through third and eleventh and twelfth embodiments wherein L or L1 is optionally substituted with one or more tuents independently selected from halogen, CN, OH, (C1-C4)alkoxy, (C1-C4)alkyl, -CH20H, -N(H)CH2-heteroaryl, oxy, and -OCH2-heteroaryl.

In an fourteenth embodiment the invention provides a compound ing to any of the first through third and eleventh through thirteenth embodiments wherein R302 is —C(O)CH3, - C(O)C(O)CH3, -C(O)CF2(Cl), -CH(CH3)2, -CH2Cl, -CH2CN, -C(O)CH2CN, -C(O)CH2CH3, - C(O)CH2F, -C(O)CH(CH3)2, -C(O)-CH2CH(CH3)2, H(CH3)(Cl), -C(O)CH2CH(CH3)CH3, - C(O)CH(Cl)CH2CH3, -CH2CHZOH, -C(O)CH2CH2N(CH3)2, -C(O)CH=CH2, -C(O)CECH, - C(O)CH=CHCl, -C(O)CH=CHCH3, -C(O)C CH3, -C(O)C(CH2CH3)=CH2, - C(O)CH=CHCH(CH3)2, -C(O)CH=CHC(O)OH, -C(O)CH=CHC(O)N(H)CH2CH3, - C(O)CH=CHCH2N(CH3)2, -C(O)CH=CHC(O)OCH3, -C(O)CH=CHC(O)OCH2CH3, - C(O)CH=CHC(O)N(H)CH3, -C(O)CH=CHC(O)CH2CHZOCH3, -C(O)CH=CHC(O)N(CH3)2, - C(O)CH=CHC(O)N(H)CH2CH3, -C(O)CH=CHC(O)N(H)CH2CHZOCH3, - =CHCH2N(H)CH2CHZOCH3, -C(O)C(CN)=C(OH)(CH3), -C(O)CH=CH-optionally substituted pyrazolyl—C(O)CH=CHCH2N(H)-optionally substituted cyclopropyl, — C(O)CH=CHCH2N(H)CH2-optionally substituted tetrahydrofuranyl, H=CHC(O)NH2,— C(O)CH=CHC(O)N(H)- ally substituted cyclopropyl, -C(O)C(CH3)=CHCH3, - C(O)C(CH3)=CHCH2CH3, -C(O)C(=CH2)CH2N(CH3)2, -C(O)C(=CH2)CH2NH2, - C(O)C(=CH2)CH2N(H)(CH3), -C(O)C(=CH2)CH3, —C(O)C(=CH2)CH2- optionally substituted morpholinyl, —C(O)C(=CH2)-optionally substituted phenyl, -CH2- optionally substituted benzo[d]isothiazolyl, -C(O)-CH2-O-optionally substituted , -CH2-optionally substituted thiazolyl, -CH2CH2-optionally substituted morpholinyl, -C(O)CHzO-optionally substituted phenyl, — C(O)CH2CH2-optionally substituted piperazinyl, -C(O)CH2CH2- optionally substituted dinyl, - C(O)CHZO-optionally substituted pyridinyl, —C(O)CH2CH2 optionally substituted idinyl,— C(O)CH=CH ally substituted cyclopropyl,—C(O)CH=CHCH2- optionally substituted morpholinyl, —C(O)CH=CHCH2- optionally substituted pi peridinyl,—C(O)CH=CH- optionally substituted pyrazolyl,—C(O)CH=CH-optionally substituted pyridinyl, —C(O)CH=CH-optionally substituted thiazolyl, -C(O)-optionally substituted cyclohexenyl, -C(=O)-optionally substituted cyclohexyl, -C(O)-optionally substituted cyclopentenyl, -C(O)-cyclopentyl, optionally substituted imidazo[l,2-a]pyrazinyl, ally substituted tetrahydroimidazo[l,2-a]pyrazinyl, optionally substituted dihydr- isoindolyl, ally substituted l,2,3,4-tetrahydro-isoquinolinyl, optionally tuted isoquinolinyl, -C(O)-optionally substituted isoxazolyl, -C(O)-optionally tuted oxazolyl, optionally substituted oxetanyl,—C(=O)- optionally substituted phenyl, optionally substituted piperidinyl, -C(O)-optionally tuted piperidinyl, optionally substituted pyrazolyl, -C(O)CHZO- ally substituted pyridazinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinazolinyl, optionally tuted dihydroquinolinyl, ally substituted —C(O)-tetrahydrobenzo[b]thiophenyl, -C(O)-optionally substituted tetrahydropyranyl, - C(O)-optionally substituted tetrahydropyridinyl, —C(O)-thiazolyl, -C(O)N(H)-thiazolyl, — C(O)NHCH2CN, or —S(O)2CH=CH2.

In a fifteenth embodiment the invention provides a compound according to any of the first through third or thirteenth through enth embodiments n X is NR2 and R2 is H.

In a sixteenth embodiment the invention provides a compound according to any of the first through third or thirteenth through fifteenth embodiments wherein Y is CR1 and R1 of Y is optionally substituted With one or more substituents independently selected from halogen, CN, =0, (C 1- C4)alkyl, (C2-C4)alkenyl, -CH2NH2, -CH2CHZOH, -CH2CH(OH)CH2CH3, -CH2CH(OH)CHZOH, - CHZCHZOCHZCH3, -CH2C(OH)(CH3)2, -CH2NHC(O)(C1-C4)alkyl, C(O)CH2C1, - CHZNHC(O)CH2CN, -CH2NHC(O)CH2CH2N(CH3)2, -CH2NHC(O)C(=CH2)CH3, -CH2NHC(O)(C2- C4)alkynyl, -CH2NHC(O)CH2CH2-piperidinyl, -(C1-C4)alkyl-morpholinyl, -CH2NHC(O)CH20- phenyl wherein the phenyl is ally substituted with halogen, (C1-C4)alkoxy, -C(O)(C1-C4)alkyl, - C(O)(C1-C4)alkoxy, -C(O)N(H)2, -C(O)N(CH3)2, -C(O)-morpholinyl, -C(O)-pyrrolidinyl, -N(CH3)2, - NHC(O)(C1-C4)alkyl, -NHC(O)(C2-C4)alkenyl, )CH2CN, -S(O)2(C1-C4)alkyl, -S(O)2- pyrrolidinyl, morpholinyl, tetrahydropyranyl, or 4-methylpiperazinecarbonyl.

In a seventeenth embodiment the invention es a compound according to any of the first through third or thirteenth through sixteenth embodiments wherein Z is CR1 and R1 of Z is H, (C 1- yl, -NHC(O)CH2Cl, -NHC(O)CH2CN, -NHC(O)(C2-C4)alkenyl, -NHC(O)(C2-C4)alkynyl, -NHC(O)C(=CH2)CH3, )CH2-phenyl wherein the phenyl is optionally substituted with halogen, or pyrazolyl substituted with CH3.

In a enth embodiment the invention provides a compound according to any of the first through third or thirteenth through eenth embodiments wherein R302 is optionally tuted with one or more substituents ndently selected from halogen, CF3, OCF3, =O, CHFZ, CN, C(O)OH, OH, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkyl, 4)alkleN, -(C1- C4)alkle(O)NH2, -C(O)NH2, -C(O)N(H)(C1-C4)alkyl, -C(O)N(C1-C4)alkyl)2, -C(O)N(H)cyclopropyl, -C(O)(C1-C4)alkoxy, NH2, N(H)CH3, N(CH3)2, or optionally substituted benzyl.

In a nineteenth embodiment the ion provides a compound according to any of the first through third or thirteenth through eighteenth embodiments wherein X is NR2 wherein R2 is H; Y is CR1 wherein R1 is H, CH3, substituted pyrazolyl, 6,7—dihydro-4H-pyrazolo[5,l- c] [l ,4]oxazinyl or tetrahydrofuranyl; Z is CR1 wherein R1 is H; E is CR5 wherein R5 is H; R3 is —R301-L-R302 wherein R301 is a bond, —o—, -N(H)-, -N(CH3)- or -C(H)(CH3)-; L is azetidinyl, 3,6-diazabicyclo[3.2.0]heptanyl, morpholinyl, xepanyl, piperidinyl, or pyrrolidinyl; wherein the azetidinyl is optionally substituted with CH3; and n the piperidinyl is optionally substituted with —CH20H; and R302 is —C(O)CH=CH2 or -C(O)CECH.

In a twentieth embodiment the invention provides a nd according to any of the first through third or thirteenth through nineteenth embodiments wherein the compound is: acry10ylazetidin-3 -y1)(methyl)amin0)- 1H-indolecarboxamide; cetylthiophen-Z-y1)p-t01y1- 1H-indolecarboxamide; 4-(1 -(4-meth0xybenzyl)- 1H-pyrazol-S-y1amin0)p-t01y1- lH-indolecarboxamide; 4-(3-(6-flu0r0—4-0X0quinazolin-3(4H)-y1)methylphenyl)(pyridinyl)-1H-indole carboxamide; 4-(3-(6-flu0r0—4-0X0quinazolin-3(4H)-y1)methylphenyl)(pyridinyl)-1H-indole carboxamide; 4-(2-methyl-3 0quinazolin-3(4H)-yl)phenyl)(pyridiny1)-1H-indole carboxamide; 4-(2-methyl-3 -(4,5 ,6,7-tetrahydr0benz0[b]thiophene-Z-carboxamido)phenyl)(pyridin-3 - yl)- 1H-indole-7—carb0xamide; 4-(2-methyl(1-0X0is0ind01inyl)phenyl)(pyridiny1) - 1H-indolecarb0xamide; 4-(2-methyl(6-methy1—1-0X0is0ind01inyl)phenyl)(pyridinyl)-1H-indole-7 - carboxamide; 4-(3-(6-flu0r0—1-oxoisoindolin-Z-yl)methylphenyl)(pyridinyl)-1H-indole-7 - carboxamide; 4-(3-(6-flu0r0—1-oxoisoindolin-Z-yl)methylphenyl)(4-flu0r0phenyl)-lH-indole carboxamide; 2-(4-flu0r0phenyl)(2-methyl(4,5 ,6,7-tetrahydr0benz0[b ]thiophene-Z- carboxamido)phenyl) - 1H-indolecarb0xamide; N-(3-(7-carbamoyl-Z-(pyridin-S -y1)-1H-ind01y1)methylphenyl)thiazolecarboxamide 2,2,2-triflu0r0acetate; N-(3-(7-carbamoyl-Z-(pyridin-S -y1)-1H-ind01yl)methylphenyl)thiazole-Z-carboxamide; (R)(3-(4-0X0quinazolin-3(4H)-yl)piperidiny1)-lH-indolecarboxamide*; (4-flu0r0phenyl)(3-(4-0X0quinazolin-3(4H)-yl)piperidiny1)-1H-indole-7 - carboxamide*; (R)(3-(4-0X0quinazolin-3(4H)-yl)piperidiny1)(pyridinyl)-lH-indole carboxamide*; (R)(1-methyl-1H-pyraz01—4-yl)(3-(4-0X0quinazolin-3(4H)-yl)piperidiny1)-1H-indole- oxamide*; (R)(3 -(6-flu0r0—4-0X0quinaz01in-3(4H)-yl)piperidiny1)(4-flu0r0phenyl)- 1H-indole-7— carboxamide*; 2-(1-methyl-1H-pyraz01yl)(2-methy1(4-0X0quinazolin-3(4H)-y1)phenyl)- 1H-indole- 7-carboxamide; 4-(2-methyl-3 -(4-0X0quinazolin-3(4H)-yl)phenyl)- 1H-indole-7—carb0xamide; 2-(1-acetyl-1,2,3,6-tetrahydr0pyridinyl)(2-methyl(4-0X0quinazolin-3(4H)- yl)phenyl)- 1H-indole-7—carb0xamide; (R)(3-(4-tert-butylbenzamido)piperidiny1)(pyridiny1)-lH-indolecarboxamide*; (R)(3-(4-tert-butylbenzamido)piperidinyl)-lH-indolecarboxamide*; (R)-N-( 1 -(7-carbamoyl- 1H-ind01yl)piperidiny1)methy10Xazolecarb0xamide* ; (R)(3-(3-thiaz01—2-ylureid0)piperidiny1)-lH-indolecarboxamide*; 4-(3-(4-tert-butylbenzamido)methylphenyl)- 1H-indolecarboxamide; 4-(3-(7—cyclopr0pylflu0r0—4-0X0quinazolin-3(4H)-yl)piperidinyl)-1H-indole-7 - carboxamide; (R)(3-(4-tert-butylbenzamido)piperidinyl)(1-methyl-1H-pyraz01—4-yl)-lH-indole carboxamide*; (R)(3-(4-methoxybenzamido)piperidiny1)(1-methy1—1H-pyraz01—4-yl)-lH-indole carboxamide*; (R)tert-butyl-N—(1-(7-carbam0y1-1H-ind01yl)piperidiny1)isoxazolecarb0xamide*; (1-methyl-1H-pyraz01—4-yl)(3-(4-(trifluoromethyl)benzamido)piperidiny1)-1H- indole-7—carb0xamide*; (R)(3 -(4-meth0xybenzamido)piperidiny1) - 1H-indole-7—carb0xamide* ; (R)(3-(4-(trifluoromethyl)benzamido)piperidinyl)-1H-indolecarboxamide*; (3-(4-(difluoromethyl)benzamido)piperidiny1)(1-methy1—1H-pyraz01—4-yl)-1H- indole-7—carb0xamide*; 4-(3-(6-flu0r0—4-0X0quinazolin-3(4H)-y1)methylphenyl)(1-methyl-1H-pyraz01—4-yl)- 1H-indolecarboxamide; 2-(3 , 6-dihydr0—2H-pyrany1)(2-methyl-3 -(4-0X0quinazolin-3(4H)-yl)phenyl)-1H-indole- 7-carboxamide; 2-(4-flu0r0phenyl)(2-methyl(4-0X0quinazolin-3(4H)-y1)phenyl)- ole-7— carboxamide; (R)(3-(4-(1-amin0—2-methyl0X0pr0panyl)benzamid0)piperidiny1)(1-methyl- 1H-pyraz01—4-yl)- 1H-indolecarboxamide*; (R)(1-methyl-1H-pyraz01—4-yl)(3-(4-(trifluoromethoxy)benzamid0)piperidinyl)-1H- indole-7—carb0xamide*; 2-(1-(2-hydr0xyethyl)-1H-pyraz01yl)(2-methyl-3 -(4-0X0quinazolin-3(4H)-yl)phenyl) - 1H-indolecarboxamide; (R)(3-(6-flu0r0—1-oxoisoindolin-Z-yl)piperidiny1)(1-methy1—1H-pyraz01—4-yl)-1H- indole-7—carb0xamide*; 2-(3 , dr0—2H-pyrany1)(3 0r0—4-oxoquinazolin-3(4H)-y1)methy1phenyl)- 1H-indolecarboxamide; 2-(1-acetyl-1 ,2,3,6-tetrahydr0pyridiny1)(3-(6-flu0r0—4-0X0quinazolin-3(4H)-y1) methylphenyl) - 1H-indolecarb0xamide; N-(3-(7—carbam0yl(1-methy1—1H-pyraz01—4-yl)-1H-ind01yl)methylphenyl)thiazole carboxamide; 4-(3-(6-flu0r0—4-0X0quinazolin-3(4H)-y1)(hydr0xymethyl)phenyl)(1-methyl-1H- 1yl)- 1H-indolecarboxamide; 2-(1-methy1—1H-pyraz01yl)(2-methy1(4,5 ,6,7-tetrahydr0benz0[b]thiophene carboxamido)phenyl) - 1H-indolecarb0xamide; (R)(3-(4-Cyclopr0pylbenzamido)piperidiny1)(1 -methy1—1H-pyraz01yl)-lH-indole- 7-carboxamide*; 2-(2,5-dihydr0— 1H-pyrr01—3-y1)(2-methy1—3-(4-0X0quinazolin-3(4H)-yl)phenyl) - 1H-indole- 7-carboxamide; 4-(2-methy1—3 -(4-0X0quinazolin-3(4H)-yl)phenyl)(1 ,2,3 ,6-tetrahydr0pyridiny1)- 1H- indolecarb0xamide; 2-(1 -((R)-2,3-dihydr0xypr0pyl)- 1H-pyraz01y1)(2-methy1(4-0X0quinazolin-3(4H)- yl)phenyl)- 1H-indole-7—carb0xamide* ; N—(3-(7-carbam0yl(1-methy1—1H-pyraz01—4-yl)-1H-ind01yl) (hydroxymethyl)phenyl)thiazolecarb0xamide; 2-(1-acetyl-1,2,3,6-tetrahydr0pyridiny1)(3 -(4-tert-butylbenzamido)methy1phenyl)- 1H-indolecarboxamide; 2-(1-acetyl-1,2,3,6-tetrahydr0pyridinyl)carbam0y1-1H-ind01—4-y1) phenyl)thiazolecarb0xamide; cetyl-1 ,2,3,6-tetrahydr0pyridinyl)(2-methy1(4,5,6,7— tetrahydrobenz0[b]thiophenecarboxamido)phenyl)- 1H-indolecarboxamide; 2-(1-acetyl-1,2,3,6-tetrahydr0pyridiny1)(3 -(4-cyclopr0pylbenzamido)methy1phenyl)- 1H-indolecarboxamide; 4-(2-methy1—3-(1-0X0—3,4-dihydr0is0quin01in-2(1H)-y1)phenyl)(1-(methy1sulf0nyl)- 1,2, 3 , 6-tetrahydr0pyridinyl) - lH-indolecarb0xamide; 2-(1 -methy1—2,5-dihydr0— 1H-pyrr01—3-y1)(2-methy1(4-0X0quinazolin-3(4H)-y1)phenyl)- 1H-indolecarboxamide; 2-(1-acetyl-2,5-dihydr0— r01—3-y1)(2-methy1-3 -(4-0X0quinazolin-3(4H)-yl)phenyl) - 1H-indolecarboxamide; ethyl 3-(7-carbam0y1(2-methyl-3 -(4-0X0quinazolin-3(4H)-y1)phenyl)- 1H-ind01y1)-2,5 - dihydro— 1H-pyrrolecarboxylate; 2-(1-methy1—1,2,3,6-tetrahydr0pyridinyl)(2-methyl(4-0X0quinazolin-3(4H) - yl)phenyl)- 1H-indole-7—carb0xamide; 4-(2-methy1—3 -(4-0X0quinazolin-3(4H)-yl)phenyl)(1 -(methy1sulf0nyl) - 1 ,2,3 ,6- ydropyridinyl)- 1H-indolecarboxamide; N—(3-(7—Carbam0yl(1-(methy1su1f0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H-ind01y1) methylphenyl)thiazolecarb0xamide; N—(3-(7—Carbam0yl(1-(methy1su1f0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H-ind01y1) methylphenyl)thiazolecarb0xamide; 2-(1 -((S)-2,3-dihydr0xypr0pyl)- 1H-pyraz01y1)(2-methy1(4-0X0quinazolin-3(4H)- nyl)- 1H-indole-7—carb0xamide; N-(3-(7-carbam0yl(1-methy1—1H-pyraz01—4-yl)-1H-ind01yl)methy1phenyl)-N— methylthiazolecarb0xamide; N-(3-(7-carbam0yl(1-methy1—1H-pyraz01—4-yl)-1H-ind01yl)methy1phenyl)-N— (oxetany1)thiazolecarboxamide; cetyl-1,2,3,6-tetrahydr0pyridiny1)(3-(4-(2-cyanopropanyl)benzamid0) methylphenyl) - olecarb0xamide; 4-(2-methy1—3 -(4-0X0quinazolin-3(4H)-yl)phenyl)(pyrimidin-S-yl)-1H-indole carboxamide; 4-(3-(6-flu0r0—4-0X0quinazolin-3(4H)-y1)methylphenyl)(pyrimidin-S-y1)-1H-indole carboxamide; 4-(3-(4-(diflu0r0methyl)benzamidO)methylphenyl)(pyrimidin-5 -y1)-1H-indole carboxamide; 4-(3-(4-cyclopr0pylbenzamido)methy1phenyl)(pyrimidin-S-y1) - 1H-indole-7— carboxamide; 4-(3-(6-flu0r0—4-0X0quinazolin-3(4H)-y1)methy1phenyl)(1-(2-hydr0xy methylpropyl)- 1H-pyraz01—4-yl) - 1H-indolecarb0xamide; (1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)(3-(8-0X0—5,6- dihydroimidazofl yrazin-7(8H)-yl)piperidinyl)-1H-indolecarboxamide*; (R)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)(3-(8-0X0imidazo[1,2-a]pyrazin- 7(8H)-yl)piperidiny1)-lH-indolecarboxamide*; 4-(2-methy1—3 -(oxetany1amin0)phenyl)(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridin yl)- 1H-indole-7—carb0xamide; 4-(2-methy1—3-(1-0X0—3,4-dihydr0is0quin01in-2(1H)-y1)phenyl)(1-(methy1sulf0nyl)- 1,2, 3 , 6-tetrahydr0pyridinyl) - lH-indolecarb0xamide; 4-(3-(4-(difluoromethyl)benzamid0)methy1phenyl)(1-(methy1su1f0nyl)-1 ,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; 4-(3-(4-hydr0xy(trifluoromethyl)cyclohexanecarboxamido)methy1phenyl)(1 - (methylsulfonyl)- 1 ,2,3 ,6-tetrahydr0pyridiny1)- 1H-indole-7—carb0xamide; (R)(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)(3-(1-0X0—3,4- dihydrois0quin01in-2( 1H)-y1)piperidiny1) - 1H-indole-7—carb0xamide* ; 2-(1-acetylpiperidinyl)(3 -(4-cyclopr0pylbenzamido)methy1phenyl)- 1H-indole-7— amide; (R)-N-( 1 -(7-carbam0y1 ( 1 -(methy1sulf0nyl)- 1 ,2,3 ,6-tetrahydr0pyridinyl) - 1H-ind01 yl)piperidiny1)methy10xazolecarb0xamide* ; (R)(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)(2-0X0—1,3'-bipiperidin-1'—yl)- 1H-indolecarboxamide*; 2-(1-methy1—1H-pyraz01yl)(2-methy1(4-0X0quinazolin-3(4H)-y1)phenyl)-1H- benzo[d] imidazolecarb0xamide; 4-(3-(4-(diflu0r0methyl)-N—(0xetanyl)benzamidO)methy1phenyl)(1-(methylsulf0nyl)- 1,2, 3 , 6-tetrahydr0pyridinyl) - lH-indolecarb0xamide; 4-(2-methy1—3 -(oxetany1amin0)phenyl)- 1H-indolecarb0xamide; 4-(3-(4-(diflu0r0methyl)benzamidO)methylphenyl) - 1H-indolecarboxamide; 4-(3-(2-hydr0xyethylamin0)methy1phenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; (R)-N-( 1 -(7-carbam0y1 ( 1 -(methy1sulf0nyl)- 1 ,2,3 ,6-tetrahydr0pyridinyl) - 1H-ind01 yl)piperidiny1)thiazolecarboxamide *; 4-(3-(cyclohexanecarboxamid0)methylphenyl)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; 4-(3-(4-(diflu0r0methyl)-N—(2-hydr0xyethyl)benzamido)methy1phenyl) ( 1 - lsulfonyl)- 1 ,2,3 ,6-tetrahydr0pyridiny1)- 1H-indole-7—carb0xamide; 7—Carbam0yl(1-(methy1su1f0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H-ind01y1) methylphenyl)is0thiazolecarboxamide; 4-(2-methy1—3-(tetrahydr0-2H-pyrancarboxamido)phenyl)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; ethy1—3-(1-methy1piperidineCarboxamid0)phenyl)(1-(methy1sulf0nyl)-1 ,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; 4-(2-methy1—3-(1-methy1piperidinecarboxamido)phenyl)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; 4-(3-(cyclopentanecarboxamido)methy1phenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; N—(3-(7—Carbam0yl(1-(methy1su1f0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H-ind01y1) methylphenyl)methylthiazolecarboxamide; 4-(3-(3-methoxycyclohexanecarboxamid0)methylphenyl)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; ethy1—3 -(3-methylbutanamido)phenyl)(1-(methy1sulf0nyl)-1 ,2,3,6- ydropyridinyl)- 1H-indolecarboxamide; 4-(3-is0butyramid0—2-methylphenyl)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)- 1H-indolecarboxamide; 4-(2-methy1—3 tinamido)phenyl)(1 -(methy1sulf0nyl)- 1 ,2,3 ,6-tetrahydr0pyridinyl) - 1H-indolecarboxamide; 4-(3-acrylamido—2-methylphenyl)(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H- indolecarb0xamide; N—(3-(7—Carbam0yl(1-(methy1su1f0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H-ind01y1) phenyl)methylthiazolecarboxamide; 7—carbam0yl(1-methy1—6-0X0-1,6-dihydr0pyridinyl)-1H-ind01—4-yl) methylphenyl)thiazolecarb0xamide; N—((3R,4R)(7—carbam0yl(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridiny1)-lH-indol- 4-yl)hydr0xypiperidinyl)thiazolecarboxamide; (R)(3-acrylamid0piperidiny1)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)-1H- indole-7—carb0xamide*; 4-(2-methy1—3-(thiaz01ylmethylamino)phenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; 4-(2-methy1—3-(N-(thiaz01ylmethyl)acrylamido)phenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; (Z)(2-methyl-3 -(2-methylbutenamid0)phenyl)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; (E)(3-(4-(dimethylamino)butenamid0)methylphenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; 4-(2-methy1—3 -(3-(piperidinyl)pr0panamid0)phenyl)(1-(methy1su1f0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; 4-(3-(2-cyan0acetamid0)methy1phenyl)( 1 -(methy1sulf0nyl)- 1 ,2,3 ,6-tetrahydr0pyridin yl)- 1H-indole-7—carb0xamide; 4-(2-methy1—3-pr0pi0namid0phenyl)(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)- 1H-indolecarboxamide; 4-(3-methacrylamid0—2-methylphenyl)(1-(methy1su1f0nyl)-1,2,3,6-tetrahydr0pyridiny1)- olecarboxamidel; 4-(3-(2-ch10r0-2,2-difluoroacetamido)methy1phenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; 4-(3-(2-ch10r0pr0panamid0)methy1phenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; (E)(3-butenamid0—2-methylphenyl)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridin yl)- 1H-indole-7—carb0xamide; N1-(3-(7—carbam0yl(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)-1H-ind01y1) methylphenyl); 4-(3-(2-(4-flu0r0phen0xy)acetamid0)methy1phenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- lH-indolecarboxamide; 4-(2-methy1—3 -(3-(pyrr01idiny1)pr0panamid0)phenyl)(1-(methylsulf0nyl)-1 ,2,3,6- tetrahydropyridinyl)- lH-indolecarboxamide; 4-(3-(2-(4-cyan0phen0xy)acetamid0)methy1phenyl)(1-(methy1su1f0nyl)-1,2,3,6- tetrahydropyridinyl)- lH-indolecarboxamide; 4-(2-methy1—3 -(2-(pyridiny10xy)acetamido)phenyl)( 1 -(methy1sulf0nyl)- 1 ,2,3 ,6- tetrahydropyridinyl)- olecarboxamide; 4-(3-(cyclopentenecarb0xamid0)methy1phenyl)(1-(methy1sulf0nyl)-1 ,2,3,6- tetrahydropyridinyl)- lH-indolecarboxamide; (E)(2-methyl(2-methy1pentenamid0)phenyl)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)- lH-indolecarboxamide; (Z)(3-(3-ch10r0acrylamid0)methylphenyl)(1-(methy1su1f0nyl)-1,2,3,6- tetrahydropyridinyl)- lH-indolecarboxamide; thyl 4-(3-(7-carbam0yl(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H- ind01yl)methylphenylamino)0X0buten0ate; 4-(3-(cyclohexenecarb0xamid0)methy1phenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- lH-indolecarboxamide; (ID-ethyl 4-(3-(7—Carbam0y1(1-(methy1sulf0nyl)-1 -tetrahydr0pyridiny1)-lH-indol- 2-methy1phenylamin0)0X0buten0ate; 4-(2-methy1—3-(2-phen0xyacetamido)phenyl)(1-(methy1sulf0nyl)-1,2,3,6- tetrahydropyridinyl)- lH-indolecarboxamide; 2-flu0r0acetamid0)methy1phenyl)(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridin- 4-yl)- 1H-indolecarboxamide; 4-(3-acrylamid0—2-methylphenyl)(4,4-diflu0rocyclohexeny1)-lH-indolecarboxamide; 4-(2-(acrylamidomethyl)phenyl)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H- carb0xamide; 4-(3-(3-(dimethylamino)pr0panamido)methy1phenyl)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)- lH-indolecarboxamide; 4-(2-acrylamid0phenyl)(1 -(methy1sulf0nyl)- 1 ,2,3 ,6-tetrahydr0pyridinyl) - lH-indole-7— carboxamide; 4-(3-(acrylamidomethyl)phenyl)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H- indolecarb0xamide; 4-(3-(acrylamidomethyl)phenyl)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridiny1)-1H- indolecarb0xamide; 4-(3-(2-cyan0pyrimidiny1amin0)phenyl)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridin- 4-yl)- 1H-indolecarboxamide; 4-(3-(6-cyclopr0pylflu0r0— 1 -0X0is0quin01in-2( 1H)-y1)(hydroxymethyl)phenyl)(1- methyl- 1H-pyraz01—4-yl)- 1H-indolecarboxamide; 4-(3-acrylamid0phenyl)- 1H-indole-7—carb0xamide; 4-(3-acry1amid0—2-methylphenyl)- lH-indolecarboxamide; 4-(3-acry1amid0—2-methylphenyl)(2-meth0xypyridiny1) - 1H-indolecarb0xamide; 4-(2-methy1—3 -(2-(pyridiny10xy)acetamido)phenyl)( 1 -(methy1sulf0nyl)- 1 ,2,3 ,6- tetrahydropyridinyl)- olecarboxamide; N1-(3-(7—carbam0yl(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)-1H-ind01y1) methylphenyl)fumaramide; 4-(3-(2-ch10r0butanamid0)methy1phenyl)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridin- 4-yl)- 1H-indolecarboxamide; 4-(2-methy1—3 -(3-(4-methy1piperazinyl)pr0panamid0)phenyl)(1-(methy1sulf0nyl)- 1,2, 3 , 6-tetrahydr0pyridinyl) - lH-indolecarb0xamide; 4-(2-methy1—3 -(2-(pyridazin-3 -y10xy)acetamid0)phenyl)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; 2-(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)(3-(thiaz01—2-y1meth0xy)phenyl) - 1H- indolecarb0xamide; methyl 3-(4-(3-acrylamid0—2-methylphenyl)carbam0yl-1H-ind01y1)benz0ate; 4-(3-acrylamidOmethylphenyl)(3-meth0xyphenyl)- 1H-indolecarb0xamide; 4-(3-acrylamidOmethylphenyl)(4-meth0xyphenyl)- 1H-indolecarb0xamide; crylamido—2-methylphenyl)(6-methy1pyridin-3 -yl)-1H-indolecarboxamide; 4-(3-acrylamidOmethylphenyl)(3-carbam0ylphenyl)- 1H-indole-7—carb0xamide; N-(3-(7-carbam0y1-3 -methy1—1H-ind01yl)methylphenyl)thiazolecarb0xamide; 4-(3-acrylamidOmethylphenyl)(3 ,5-dimethy1is0xaz01—4-yl) - lH-indolecarboxamide; crylamidOmethylphenyl)( 1 -(tetrahydr0-2H-pyrany1)- 1H-pyraz01—5-y1)-1H- indolecarb0xamide; 4-(3-acrylamidOmethylphenyl)(3 ,5-dimethy1— 1H-pyraz01yl)- 1H-indole-7— carboxamide; 4-(3-acrylamidOmethylphenyl)(1-is0pr0py1-1H-pyraz01yl)-lH-indole carboxamide; 4-(3-acrylamidOmethylphenyl)(1,3-dimethy1— az01yl)- ole-7— carboxamide; crylamidOmethylphenyl)(1-ethy1—1H-pyraz01—4-yl)-lH-indolecarboxamide; 4-(3-acrylamid0—2-methylphenyl)(1-is0buty1—1H-pyraz01yl)-lH-indolecarboxamide; WO 10255 (E)-N—(3-(3-butenamido—7—carbam0yl-1H-ind01yl)methylphenyl)thiazole carboxamide; N-(3-(7-carbam0y1-3 -methacrylamid0-1H-ind01—4-yl)methylphenyl)thiazole carboxamide; N-(3-(3-butynamido—7—carbam0yl-1H-ind01yl)methylphenyl)thiazole carboxamide; 7—carbam0yl-3 -(2-(4-fluorophenoxy)acetamid0)-1H-ind01y1) methylphenyl)thiazole-Z-carboxamide; 4-(3-acrylamidO-Z-methylphenyl)(2-flu0r0pyridiny1)-lH-indolecarboxamide; 4-(3-acrylamidO-Z-methylphenyl)(1-ethy1—1H-pyraz01—4-yl)-lH-indolecarboxamide; 2-(3-acetamid0phenyl)(3-acry1amid0—2-methylphenyl)- ole-7—carb0xamide; 4-(3-acry1amid0—2-methylphenyl)(2-meth0xypyridinyl)- lH-indolecarboxamide; 4-(3-acrylamidO-Z-methylphenyl)(3-cyan0phenyl)- 1H-indolecarboxamide; methyl 4-(4-(3-acrylamid0—2-methylphenyl)carbam0yl-1H-ind01y1)benz0ate; 4-(3-acrylamidO-Z-methylphenyl)(2,3-dihydr0benzofuran-S-yl)-1H-indolecarboxamide; 4-(3-acrylamidO-Z-methylphenyl)(3-flu0r0phenyl) - 1H-indolecarboxamide; 4-(3-acrylamidO-Z-methylphenyl)(3 -(dimethylamino)phenyl) - 1H-indolecarb0xamide; 4-(2-(2-ch10r0acetamid0)phenyl)(1 -(methy1sulf0nyl)-1 ,2,3,6-tetrahydr0pyridiny1)-1H- indolecarb0xamide; 4-(2-acetamid0phenyl)(1-(methy1sulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)-lH-indole amide; 4-(3-acrylamidO-Z-methylphenyl)(2-methyl(pyrr01idiny1su1f0ny1)phenyl)-lH-indole- 7-carboxamide; 4-(3-acry1amid0—2-methylphenyl)(2-flu0r0phenyl)- lH-indolecarboxamide; N-(3-(3-acry1amid0—7—carbam0yl-1H-ind01yl)methylphenyl)thiazolecarboxamide; N-(3-(7-carbam0y1-3 -(2-Ch10r0acetamid0)-1H-ind01yl)methylphenyl)thiazole carboxamide; 4-(3-acry1amid0—2-methylphenyl)(1-methy1—1H-pyraz01—5-y1) - 1H-indolecarb0xamide; 4-(3-acrylamidO-Z-methylphenyl)(pyridinyl)- 1H-indole-7—carb0xamide; 4-(3-acrylamid0—2-methylphenyl)(1-(2-m0rph01inoethyl)-1H-pyraz01yl)-lH-indole carboxamide; 4-(3-acrylamidO-Z-methylphenyl)(6-m0rph01in0pyridiny1)-lH-indolecarboxamide; 4-(3-acrylamidO-Z-methylphenyl)(3-(4-methylpiperazinecarb0nyl)phenyl)-lH-indole carboxamide; N-(3-(2-(2-(acrylamidomethyl)phenyl)Carbam0yl-1H-ind01yl)methylphenyl)thiazole- 2-carboxamide; N-(3-(2-(2-(acetamidomethyl)phenyl)carbam0yl-1H-ind01yl)methylphenyl)thiazole- 2-carboxamide; N-(3-(7-carbamoyl-Z-(Z-(propionamidomethyl)phenyl)- 1H-ind01y1) methylphenyl)thiazole-Z-carboxamide; N-(3-(2-(2-(butyramidomethyl)phenyl)carbam0yl- 1H-ind01—4-y1) methylphenyl)thiazole-Z-carboxamide; (E)-N—(3-(2-(2-(butenamidomethyl)phenyl)carbam0yl- 1H-ind01—4-y1) methylphenyl)thiazole-Z-carboxamide; N-(3-(7-carbamoyl-Z-(Z-(methacrylamidomethyl)pheny1)- 1H-ind01—4-y1) methylphenyl)thiazole-Z-carboxamide; N-(3-(7-carbam0y1(2-(propi01amid0methy1)phenyl)- 1H-ind01y1) methylphenyl)thiazole-Z-carboxamide; N-(3-(2-(2-(butynamidomethyl)phenyl)Carbamoyl- 1H-ind01—4-y1) methylphenyl)thiazole-Z-carboxamide; 7-carbam0yl(2-((2-cyan0acetamid0)methyl)phenyl)-1H-ind01—4-y1) methylphenyl)thiazole-Z-carboxamide; 7-carbamoyl-Z-(Z-((3 -(dimethylamino)pr0panamido)methyl)phenyl)-1H-ind01—4-y1) methylphenyl)thiazole-Z-carboxamide; N-(3-(7-carbamoyl-Z-(Z-((3 -(piperidinyl)pr0panamid0)methyl)phenyl)-1H-ind01y1) methylphenyl)thiazole-Z-carboxamide; N-(3-(7-carbam0yl(2-((2-phen0xyacetamid0)methyl)phenyl)- 1H-ind01—4-y1) methylphenyl)thiazole-Z-carboxamide; N-(3-(7-carbam0y1(2-((2-(4-flu0r0phen0xy)acetamido)methyl)phenyl)- 1H-ind01y1) methylphenyl)thiazole-Z-carboxamide; N-(3-(7-carbam0y1(2-((2-Ch10r0acetamid0)methyl)phenyl)- 01—4-y1) methylphenyl)thiazole-Z-carboxamide; N-(3-(2-(2-(amin0methyl)phenyl)carbam0y1-1H-ind01yl)methylphenyl)thiazole carboxamide; 4-(3-acry1amid0—2-methylphenyl)(4-flu0r0phenyl)- lH-indolecarboxamide; crylamidO-Z-methylphenyl)pheny1— 1H-indolecarb0xamide; 4-(3-acrylamidO-Z-methylphenyl)(2-(methylsulfonyl)phenyl) - 1H-indolecarb0xamide; 4-(3-acrylamidO-Z-methylphenyl)(4-(dimethylcarbam0y1)phenyl) - 1H-indole-7— carboxamide; 4-(3-acry1amid0—2-methylphenyl)(pyrimidiny1)-lH-indolecarboxamide; 4-(3-acrylamidO-Z-methylphenyl)(pyridiny1)-lH-indolecarboxamide; 4-(3-acrylamidO-Z-methylphenyl)(4-(morpholinecarbony1)phenyl)- 1H-indole-7— carboxamide; 4-(3-acrylamidO-Z-methylphenyl)(4-(pyrr01idine-1 -carb0nyl)phenyl)- 1H-indole carboxanfide; 4-(3-acrylamido—Z-methylphenyl)(4-(4-methylpiperazinecarb0nyl)phenyl)-lH-indole carboxanfide; 4-(3-acrylamidO-Z-methylphenyl)(4-(methylsulfonyl)phenyl) - 1H-indolecarb0xamide; 4-(3-acry1amid0—2-methylphenyl)(6-meth0xypyridiny1) - 1H-indolecarb0xamide; 4-(3-acrylamidO-Z-methylphenyl)(4-cyan0phenyl)- 1H-indolecarboxamide; 4-(3-acrylamidO-Z-methylphenyl)(2-meth0xyphenyl)- 1H-indolecarb0xamide; N-(3-(7-carbam0y1-3 -(2-cyan0acetamid0)-1H-ind01yl)methylphenyl)thiazole carboxanfide; 4-(2-acrylamid0phenyl)- ole-7—carb0xamide; 4-(3-acrylamidO-Z-methylphenyl)(4-(m0rph01in0methyl)phenyl)- ole carboxanfide; 4-(3-acrylamidO-Z-methylphenyl)(4-carbam0ylphenyl)- 1H-indole-7—carb0xamide; 4-(3-acry1amid0—5-(thiaz01ylmethylamin0)phenyl)(1-(methy1sulf0nyl)-1 - tetrahydropyridinyl)- 1H-indolecarboxamide; 4-(2-methyl-3 -(N-methylacrylamido)phenyl)- 1H-indolecarboxamide; 4-(3-(methylamin0)phenyl)- 1H-indole-7—carb0xamide; 4-(3-(N-methylacrylamido)phenyl) - 1H-indole-7—carb0xamide; 4-(2-methyl-3 -(2-methylenebutanamid0)phenyl)- 1H-indolecarboxamide; ethyl-3 -(3-(pyrr01idiny1)pr0panamid0)phenyl)-lH-indolecarboxamide; 4-(3-methacrylamido—Z-methylphenyl)- 1H-indolecarboxamide; (E)(3 - (3-cyclopr0pylacrylamid0)methy1phenyl)- 1H-indolecarboxamide; (E)(2-methyl(3 diny1)acrylamid0)phenyl)- lH-indolecarboxamide; (E)(2-methyl(3 -(1-methy1—1H-pyraz01y1)acrylamid0)phenyl)-lH-indole carboxanfide; (ID-ethyl 4-(3-(7-carbam0y1-1H-ind01yl)methylphenylamin0)0X0buten0ate; (E)(3-(4-(dimethylamino)butenamido)methy1phenyl)- lH-indolecarboxamide; (2-methyl(3 -(pyridin-3 -y1)acrylamido)phenyl) - 1H-indolecarboxamide; (E)(2-methyl(4-methylpent-Z-enamid0)phenyl)- 1H-indolecarboxamide; N1-(3-(7-carbamoyl- 1H-ind01—4-y1)methylphenyl)-N4-ethylmaleamide; 4-(3-acetamid0—2-methylphenyl)- 1H-indolecarb0xamide; (E)(3-butenamidO-Z-methylphenyl)- 1H-indolecarb0xamide; 4-(2-methyl-3 -(3-morpholinopropanamido)phenyl)- 1H-indolecarb0xamide; (E)(2-methyl(3 z01yl)acrylamido)phenyl)- 1H-indolecarboxamide; 4-(2-methyl-3 -(2-pheny1acrylamid0)phenyl)- 1H-indolecarb0xamide; (E)(2-methyl(4-(piperidinyl)butenamid0)phenyl)-lH-indolecarboxamide; (E)(2-methyl(4-((tetrahydrofuran-Z-yl)methylamino)butenamid0)phenyl)- 1H-indole- 7-carboxamide; (E)(3 -(4-(2-methoxyethylamino)butenamid0)methy1phenyl) - ole-7— carboxamide; (E)(3 -(4-(cyclopropylamino)butenamido)methy1phenyl)- 1H-indole-7—carb0xamide; (E)(2-methyl(4-morpholinobut-Z-enamid0)phenyl)- 1H-indolecarb0xamide; (E)(2-methyl(4-(4-methy1piperazinyl)butenamid0)phenyl)-lH-indole carboxamide; 4-(3-acry1amid0—4-(benzyloxy)phenyl)- 1H-indolecarb0xamide; 4-(3-acry1amid0—5-(benzyloxy)phenyl)- 1H-indolecarb0xamide; 4-(3-acry1amid0—4-(thiaz01y1meth0xy)phenyl)- 1H-indole-7—carb0xamide; 4-(3-acry1amid0—5-(thiaz01y1meth0xy)phenyl)- ole-7—carb0xamide; 4-(2-acrylamid0(thiaz01y1meth0xy)phenyl)- 1H-indole-7—carb0xamide; 4-(3-acry1amid0—2-methylphenyl)- 1H-pyrr010[2,3-c]pyridinecarb0xamide; 4-(2-acry1amid0—4-(benzyloxy)phenyl)- 1H-indolecarb0xamide; 4-(5-acry1amid0pyridin-3 -y1) - 1H-indolecarb0xamide; 4-(2-acrylamidopyridinyl) - 1H-indolecarb0xamide; N1-(3-(7-carbam0yl-1H-ind01yl)pheny1)-N4-(2-meth0xyethyl)maleamide; N1-(3-(7-carbam0yl-1H-ind01yl)phenyl)-N4-ethylmaleamide; 4-(3-(1-methy1-1,2,5,6-tetrahydr0pyridinecarb0xamid0)phenyl)- 1H-indolecarboxamide; 4-(3-(Vinylsulfonamido)phenyl) - 1H-indole-7—carb0xamide; 4-(3-(2-0X0pr0panamid0)phenyl)- 1H-indolecarb0xamide; (ID-methyl 4-(3-(7-carbam0yl-1H-ind01yl)phenylamin0)0X0buten0ate; cyan0methylcarbam0y1)phenyl)- 1H-indolecarboxamide; N-(3-(7—carbam0yl-1H-ind01—4-yl)phenyl)-5 -methylis0xazolecarb0xamide; N1-(3-(7-carbamoyl- 01—4-yl)phenyl)-N4-methy1fumaramide; N1-(3-(7-carbamoyl- 1H-ind01—4-yl)phenyl)-N4,N4-dimethylfumaramide; N1-(3-(7-carbam0yl-1H-ind01yl)phenyl)-N4-ethylfumaramide; N1-(3-(7-carbam0yl-1H-ind01yl)phenyl)-N4-cyclopr0pylfumaramide; (E)(3 -(7-Carbamoyl- 1H-ind01—4-y1)phenylamin0)0X0buten0ic acid; 4-(3-(N-is0buty1acrylamid0)phenyl)- 1H-indole-7—carb0xamide; 1 -Acry10yl- 1 ,2, 3 acid amide; , 6-tetrahydr0—pyrr010[2,3 -e]indole-S-carb0xy1ic 4-acry1amid0— 1H-indolecarb0xamide; 4-(3-(N—(cyanomethyl)sulfam0y1)phenyl) - olecarboxamide; 4-(3-acry1amid0phenyl)-1H-pyrr010[3,2-c]pyridine-7—carboxamide; cry1amid0—2-methylphenyl)- 1H-pyrr010[3 ,2-c]pyridinecarb0xamide; 4-(3-((2-0X0pr0panamid0)methyl)phenyl)- 1H-indolecarb0xamide; 4-(3-acrylamid0phenyl)-1H-indazolecarb0xamide; 4-(3-acrylamido—Z-methoxyphenyl)- 1H-indole-7—carb0xamide; 4-(3-acrylamidO-Z-fluorophenyl)- 1H-indolecarboxamide; 4-(5-acrylamidO-Z-fluorophenyl)- 1H-indolecarboxamide; 4-(3-acrylamidOflu0r0phenyl)- 1H-indolecarboxamide; 4-(5-acrylamidO-Z-chlorophenyl)- 1H-indolecarboxamide; 4-(5-acrylamid0-2,4-diflu0r0phenyl)- 1H-indolecarboxamide; 4-(3-acry1amid0—4-cyanophenyl)- olecarb0xamide; 4-(3-acry1amid0—2,6-diflu0r0phenyl)-lH-indolecarboxamide; 4-(3-acry1amid0—5-methy1phenyl) - 1H-indolecarb0xamide; cry1amid0—4-methylphenyl)- lH-indolecarboxamide; 4-(3-acrylamido—4-methoxyphenyl)- 1H-indole-7—carb0xamide; 4-(3-acry1amid0—5-meth0xyphenyl)- 1H-indole-7—carb0xamide; 4-(3-acrylamidOchlorophenyl)- olecarboxamide; 4-(5-acrylamid0-2,3-diflu0r0phenyl)- 1H-indolecarboxamide; 4-(3-acry1amid0—5-cyan0phenyl)- 1H-indolecarb0xamide; cry1amid0—2-cyanophenyl)- 1H-indolecarb0xamide; 4-(3-acrylamidophenyl)Viny1- 1H-indole-7—carb0xamide; 4-(3-acrylamidophenyl)ethy1— ole-7—carb0xamide; 4-(3-(2-(m0rph01in0methyl)acrylamido)phenyl)- 1H-indolecarboxamide; 4-(3-(2-((dimethylamin0)methyl)acrylamido)phenyl)- 1H-indolecarboxamide; (E)(3-(4-(dimethylamino)butenamido)methy1phenyl)- 1H-pyrr010[2,3-c]pyridine carboxanfide; 4-(( 1R,3S)acry1amidocyclohexyl)- 1H-indolecarboxamide; 4-(cisacry1amidocyclohexyl)-lH-indolecarboxamide; 4-(( 1 S,3S)acry1amidocyclohexyl)- 1H-indolecarboxamide; 4-(transacry1amidocyclohexyl)-lH-indolecarboxamide; 4-(cisacry1amidocyclohexyl)-lH-indolecarboxamide; 4-(3-(2-(amin0methyl)acrylamido)phenyl)- 1H-indolecarboxamide; 4-((1R,3S)acry1amidocyclopentyl)-lH-indolecarboxamide; 2-((methylamin0)methyl)acrylamido)phenyl)- 1H-indolecarb0xamide; 4-(3-acry1amid0phenyl)methy1-lH-indolecarboxamide; 4-((1S,3S)acry1amidocyclopentyl)- lH-indolecarboxamide; 4-(3-acry1amid0phenyl)(2-ethoxyethyl)-lH-indole0arboxamide; 4-(3-acry1amid0phenyl)(2-hydr0xyethyl)-lH-indolecarboxamide; 4-(1-acry10ylpiperidin 3-y1)(1-methy1—1H-pyraz01—4-yl)-lH-indolecarboxamide; 2014/044247 4-(3-acrylamidOmethylphenyl)(1-is0pr0py1-1H-pyraz01yl)-lH-indole carboxamide; 4-(3-(4-cyclopr0pylbenzamid0)methy1phenyl)(1-(methy1su1f0nyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indolecarboxamide; ethy1—3-(1-methy1piperidinecarboxamido)phenyl)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)- olecarboxamide; 4-(3-(N-(cyclopentylmethyl)acrylamido)phenyl)- 1H-indole-7—carb0xamide; ethyl 4-(7—Carbam0y1(2-methyl-3 -(4-0X0quinazolin-3(4H)-y1)phenyl)- 1H-ind01y1)5 ,6- dihydropyridine-1(2H)-carb0xylate; (R)(3-(4-0X0quinazolin-3(4H)-yl)piperidiny1)-1H-indolecarb0nitrile; 4-(2,6-dich10r0benzyl)(p—t01yl) - 1H-indolecarb0xamide; (E)(3 -(2-cyan0-3 -hydr0xybutenamid0)phenyl) - 1H-indolecarboxamide; 4-(cisacry1amidocyclopentyl)-lH-indolecarboxamide; 4-(transacry1amidocyclopentyl) - 1H-indolecarb0xamide; 4-(transacry1amidocyclopentyl) - 1H-indolecarb0xamide; 4-((1-acry10ylazetidin-3 -y1)oxy) - 1H-indolecarb0xamide; (S)(1-(1-acry10ylazetidin-3 -y1)ethyl)- 1H-indolecarboxamide; (R)(1-(1-acry10ylazetidin-3 -y1)ethyl)- 1H-indolecarboxamide* ; 4-((1-acry10ylazetidin-3 -y1)(methyl)amin0)- 1H-pyrr010 [2,3-c]pyridinecarboxamide; (R)(1 -acry10ylpiperidin-3 -y1) - 1H-indole-7—carb0xamide* ; (S)( 1 -acry10y1piperidiny1)-lH-indolecarboxamide*; (S)(1-acry10ylpiperidiny1)methyl- 1H-indolecarb0xamide; (R)(1-acry10ylpiperidiny1)methyl- 1H-indolecarb0xamide; (R)(4-acry10ylm0rph01inyl)(1-methy1—1H-pyraz01—4-yl)-lH-indolecarboxamide; (S)(4-acry10ylm0rph01inyl)(1-methy1-1H-pyraz01—4-yl)-lH-indolecarboxamide; (R)(1-acry10y1pyrr01idiny1)(6,7—dihydr0—4H-pyraz010[5, l-c] [1 ,4]oxazinyl)-1H- indolecarb0xamide; 2-methy1(methy1(1-pr0pi010ylazetidinyl)amin0)- 1H-indolecarboxamide; (1-acry10y1pyrr01idiny1)(6,7-dihydr0—4H-pyraz010[5, l-c] [1 ,4]oxazinyl)-1H- indolecarb0xamide; (R)(4-acry10yl-1,4-0xazepanyl)-1H-pyrr010[3,2-c]pyridinecarb0xamide; (S)(4-acry10yl-1,4-oxazepanyl)-1H-pyrr010[3,2-c]pyridine-7—carb0xamide; (R)(1-acry10ylpiperidiny1)-1H-pyrr010[3,2-c]pyridine-7—carboxamide; (1-acry10ylpiperidiny1)-1H-pyrr010[3,2-c]pyridinecarboxamide; (1-acry10ylpiperidiny1)(1 -methyl- 1H-pyraz01yl)thiaz010[5,4-c]pyridine carboxamide; (S)-7—(1-acry10ylpiperidiny1)(1 -methyl- az01yl)thiaz010[5,4-c]pyridine carboxamide; (S)(4-acry10yl-1,4-oxazepanyl)-lH-indolecarboxamide; 4-((3S,5R)acry10yl-5 -(hydroxymethyl)piperidiny1)- 1H-indolecarb0xamide; 4-((3S ,5S)acry10yl(hydroxymethyl)piperidin-3 -y1)- 1H-indolecarb0xamide; 4-((3R,5S)acry10yl-5 -(hydroxymethyl)piperidiny1)- 1H-indolecarb0xamide; 4-((3R,5R)acry10yl-5 -(hydroxymethyl)piperidiny1)-lH-indolecarboxamide; (R)(1-acry10y1pyrr01idiny1)(1-methy1—1H-pyraz01—4-yl)-lH-indolecarboxamide; (S)(1-acry10y1pyrr01idiny1)(1-methy1—1H-pyraz01—4-yl)-lH-indolecarboxamide; 4-(( 1 R,3R)acry1amidocyclopentyl)-lH-indolecarboxamide; (S)(1-acry10ylpiperidin-3 -yl)- 1H-pyrr010 [2,3-c]pyridinecarb0xamide; (R)(1-acry10ylpiperidinyl)- 1H-pyrr010 [2,3-c]pyridinecarb0xamide; (R)methyl(1-pr0pi0ny1pyrr01idin-3 -y1) - 1H-indolecarb0xamide; (S)methyl(1 -pr0pi0ny1pyrr01idin-3 -y1) - 1H-indolecarb0xamide; 4-((1-acry10ylazetidin-3 -y1)(methyl)amin0) (isochromanyl)- 1H-indolecarboxamide; 4-((1-acry10ylazetidin-3 -y1)(methyl)amin0)(6,7-dihydr0—4H-pyraz010[5, 1 -c] [1 ,4]ovain yl)- 1H-indole-7—carb0xamide; acry10ylazetidinyl)(methyl)amin0)(4,4-diflu0rocyclohexen-1 -y1)-1H-indole carboxamide; 4-((1-acry10ylazetidinyl)(methyl)amin0)(4-(methylsulfonyl)cyclohexen-1 H- indolecarb0xamide; 4-((1-acry10ylazetidin-3 -y1)(methyl)amin0)(6-m0rph01in0pyridiny1)-1H-indole carboxamide; 4-((1-acry10ylazetidin-3 -y1)(methyl)amin0)(7 , dr0—5H-pyran0[4,3-b]pyridin-3 -y1)- olecarboxamide; 4-((1-acry10ylazetidin-3 -y1)(methyl)amin0)(chr0manyl) - 1H-indolecarb0xamide; 4-((1-acry10ylazetidin-3 -y1)(methyl)amin0)(5-(morph01in0methyl)pyridinyl)-1H- carb0xamide; acry10ylazetidin-3 -y1)(methyl)amin0) ( 1 -methyl- 1H-pyraz01—4-yl)- 1H-indole-7 - carboxamide; 4-((1-acry10ylazetidin-3 -y1)(methyl)amin0)(3 ,4-dihydr0—2H-benz0[b] [1 ,4]oxazinyl)- 1H-indolecarboxamide; 4-((1-acry10ylazetidinyl)(methyl)amin0)(1-methy1—1H-pyraz01—5-yl)-1H-indole-7 - carboxamide; 4-((1-acry10ylazetidin-3 -y1)(methyl)amin0)(2-ethy1- 1 ,2,3,4-tetrahydr0is0quin01inyl)- lH-indolecarboxamide; 4-(( l -acryloylazetidin-3 -yl)(methyl)amino) (l ,3-dimethyl- 1H-pyrazolyl)- ole carboxamide; 4-(( l -acryloylazetidinyl)(methyl)amino)(l , l-dioxidotetrahydro-2H-thiopyranyl)-1H- indolecarboxamide; 4-(( l -acryloylazetidin-3 -yl)(methyl)amino) ( l -propylpiperidinyl)- l H-indole carboxamide; 4-(( l -acryloylazetidin-3 -yl)(methyl)amino)(tetrahydrofuran-3 -yl)- 1H-indole carboxamide; 4-(( l -acryloylazetidin-3 -yl)(methyl)amino)(3-hydroxyoxetan-3 -yl) - 1H-indole carboxamide; 4-(( l -acryloylazetidin-3 -yl)(methyl)amino)methyl- lH-indolecarboxamide; (R)(4-acryloyl- l ,4-oxazepanyl)- 1H-indolecarboxamide; ( l -acryloylpyrrolidinyl)methyl- 1H-indolecarboxamide*; (R)( l -acryloylpyrrolidinyl)methyl- 1H-indolecarboxamide *; 4-(( l R,SS)acryloyl-3,6-diazabicyclo[3.2.0]heptanyl)- 1H-indolecarboxamide; 4-(( l S ,5R)acryloyl-3,6-diazabicyclo[3.2.0]heptanyl)- 1H-indolecarboxamide; (R)( l -( l -acryloylazetidin-3 -yl)ethyl)- 1H-pyrrolo[3 ,2-c]pyridinecarboxamide; (S)( l -( l -acryloylazetidinyl)ethyl)- 1H-pyrrolo[3 ,2-c]pyridinecarboxamide; 4-(( l -acryloylazetidinyl)amino)- 1H-pyrrolo[2,3-c]pyridinecarboxamide; 4-(( l -acryloylmethylazetidinyl)(methyl)amino)- lH-indolecarboxamide; 4-(( l azetidinyl)(methyl)amino)methyl- 1H-indolecarboxamide; 4-(2-chlorofluorobenzyl)p-tolyl- 1H-indolecarboxamide; (S)(( l oylazetidinyl)(methyl)amino)(tetrahydrofuran-3 -yl)- 1H-indole amide; (R)(( l oylazetidinyl)(methyl)amino)(tetrahydrofuran-3 -yl)- 1H-indole carboxamide; (S)(4-acryloyl- l ,4-oxazepanyl)- 1H-pyrrolo[2,3-c]pyridinecarboxamide; (R)(4-acryloyl- l ,4-oxazepanyl) - 1H-pyrrolo[2,3-c]pyridinecarboxamide; (S)( l oylpiperidinyl)(l -methyl- 1H-pyrazolyl)- olecarboxamide; or (R)( l -acryloylpiperidin-3 -yl) ( 1 -methyl- 1H-pyrazolyl)- 1H-indolecarboxamide.

In a twenty-first embodiment the invention provides a method of treating a disease comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

In a twenty-second embodiment the invention provides a compound according to any of foregoing embodiments, wherein the disease is toid tis, juvenile rheumatoid arthritis, osteoarthritis, Crohn’ s e, inflammatory bowel disease, ulcerative colitis, psoriatic arthritis, psoriasis, ankylosing litis, interstitial cystitis, asthma, systemic lupus erythematosus, lupus nephritis, B cell chronic lymphocytic lymphoma, multiple sclerosis, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin’s lymphoma, activated B- cell like e large B-cell lymphoma, le myeloma, diffuse large B-cell lymphoma, ular lymphoma, hairy cell leukemia or Lymphoblastic lymphoma.

In a twenty-third embodiment the invention provides kit comprising a packaged t comprising components with which to administer a compound a compound according to any of foregoing embodiments for treatment of an autoimmune disorder.

In a twenty-fourth ment the invention provides a kit according to the twenty-third embodiment, wherein the packaged product comprises a compound of claim 1 and instructions for use.

In a twenty-fifth embodiment the ion provides a pharmaceutical composition comprising a compound according to any of ht efirst thorugh twentieth embodiments and one or more ceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION Protein kinases are a broad and diverse class, of over 500 enzymes, that include nes, growth factors receptors, signal transduction ediates, apoptosis related kinases and cyclin dependent kinases. They are responsible for the transfer of a phosphate group to specific tyrosine, serine or threonine amino acid residues, and are y classified as tyrosine and serine/threonine kinases as a result of their substrate specificity.

The n kinases represent a large family of proteins that play a central role in the regulation of a wide variety of cellular processes and maintenance of cellular function. A partial, non- limiting, list of these kinases include: non-receptor tyrosine kinases such as the Tec family (BTK, ITK, Tec, ETK/BMX & RLK/TXK), Janus kinase family (Jakl, Jak2, Jak3 and Tyk2); the fusion kinases, such as BCR-Abl, focal adhesion kinase (FAK), Fes, Lck and Syk; receptor tyrosine s such as epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor kinase (PDGF-R), the receptor kinase for stem cell factor, c-kit, the hepatocyte growth factor receptor, c- Met, and the fibroblast growth factor receptor, FGFR3; and serine/threonine kinases such as b-RAF, mitogen-activated protein s (e.g., MKK6) and SAPKZB. Aberrant kinase actiVity has been observed in many disease states including benign and malignant proliferative ers as well as diseases resulting from opriate activation of the immune and nervous s. The novel compounds of this invention inhibit the actiVity of one or more protein kinases and are, therefore, expected to be useful in the treatment of -mediated diseases.

Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase with a key role in immunoreceptor signaling (BCR, FcaR, FcyR, DAP12, Dectin-l, GPVI, etc.) in a host of hematopoietic cells ing B cells, platelets, mast cells, basophils, eosinophils, macrophages and neutrophils as well as osteoclasts involved in bone destruction (for reViews, see Brunner et al., 2005 Histol. Histopathol., 20:945, Mohamed et al., 2009 Immunol. Rev., 228:58). Mutations in BTK are known to lead to X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice, which are characterized by limited B-cell production & reduced antibody titers (Lindvall et al., 2005 Immunol. Rev., 203200). The combined action of BTK in multiple cell types makes it an attractive target for autoimmune e. BTK is d with sequence homology to other Tec family s (ITK, Tec, ETK/BMX & RLK/TXK).

In B-lymphocytes, BTK is ed for B-cell development and for Ca2+ mobilization following B-cell receptor (BCR) engagement (Khan et al., 1995 Immunity 3:283; Genevier et al., 1997 Clin. Exp. Immun., 110:286) where it is believed to be downstream of Src family kinases (such as Lyn), Syk & PI3K. BTK has been shown to be important for both thymus-dependent and thymus- independent type 2 responses to antigens (Khan et al., Immunity I995; 3; 283). In mast cells, studies using BTK mouse knock-outs (Hata et al., 1998 J. Exp. Med., 187:1235; Schmidt et al., 2009 Eur. J.

Immun., 39:3228) indicate a role for BTK in FcSRI induced signaling, histamine release & production of cytokines such as TNF, IL-2, & IL-4. In platelets, BTK is important for signaling through the glycoprotein VI (GPVI) or that ds to en and has been shown to promote platelet ation and contribute to cytokine production from fibroblast-like synoviocytes (Hsu et al., 2013 Immun. s 15097). In tes and macrophages, the action of BTK is invoked in FcyRI d signaling and may also have role in Toll-Like Receptor-induced cytokine responses including TLR2, TLR4, TLR8 & TLR9 (Horwood et al., 2003 J. Exp. Med., 197:1603; Horwood et al., 2006 J.

Immunol., 35; Perez de Diego et al., 2006 Allerg. Clin. Imm., 117:1462; Doyle et al., 2007 J.

Biol. Chem, 282:36959, Hasan et al., 2007 Immunology, 123:239; Sochorava et al., 2007 Blood, 109:2553; Lee et al., 2008, J. Biol. Chem, 283:11189).

Therefore, inhibition of BTK is expected to intervene at several critical junctions of the inflammatory reactions ing in an effective suppression of autoimmune response. As such es involving B-cell receptor activation, antibody-Fc receptor interactions & GPVI receptor signaling may be modulated by treatment with BTK inhibitors. BTK inhibition is likely to act on both the initiation of autoimmune disease by blocking BCR signaling and the effector phase by abrogation of FcR signaling on macrophages, neutrophils, basophils, and mast cells. Furthermore, blocking BTK would provide additional benefit Via inhibition of osteoclast maturation and therefore attenuate the bone ns & overall joint destruction associated with rheumatoid arthritis. Inhibiting BTK may be useful in treating a host of inflammatory and allergic diseases — for example (but not limited to), rheumatoid tis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and type I hypersensitivity reactions such as allergic rhinitis, ic conjunctivitis, atopic itis, allergic asthma and systemic anaphylaxis. For a reView on targeting BTK as a treatment for inflammatory disorders and munity as well as ias and lymphomas, see Uckun & Qazi 2010 Expert Opin Ther Pat 20:1457. Because BTK is highly expressed in cancers of the hematopoietic system & BTK-dependent signaling in believed to be disregulated there, BTK inhibitors are expected to be useful treatments for B-cell lymphomas/leukemias & other oncologic disease — for example (but not limited to) acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), non- Hodgkin’s lymphoma (NHL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia (for review, see Buggy & Elias 2012 Int Rev Immunol. 31:119). Taken together, BTK inhibitors provide a strong method to treat a host of inflammatory diseases and immunological disorders as well as hematologic cancers.

All kinases bind a common molecule, ATP, and therefore have structurally similar binding s. ore, one of the challenges for any kinase inhibitor is that they are prone to t more than one kinase due to the homology of the g pocket. For example, staurosporine, a well characterized promiscuous kinase inhibitor, has been shown to inhibit at least 253 with a kd of <3 uM s from the human kinome (see Nature Biotechnology, 208, 26, p. 127). Additionally, several marketed kinase inhibitors are known to inhibit more than one intended kinase, for example Imatinib (Gleevec®) targets ABL, ARG, PDGFR-0MB and c-KIT kinases, sorafenib (Nexavar®) targets B- RAF, VEGFRs, 0MB, FLT3 and c-KIT and sunitinib (Sutent®) targets VEGFR, PDGFR, CSFlR, FLT3 and c-KIT e Reviews Drug Discovery 2011, 10, 111). tion of certain kinases in the human kinome are known to have undesired effects when used as ceutical treatment. For instance, a number of kinase targets have been implicated in playing a role in the cardiotoxicity profiles for kinase inhibitors that are currently on the market.

These kinases can include, but not limited to, VEGFR2, PI3K, AKT, PDGFR-0MB, AMPK, GSK3, ERKs, CDK2, Aurora, PLK, JNK, CAMKII< PDK1, mTOR, LKB1, CAMKKB, MEK1/2, PKA, PKCOC, RAF1, B-RAF, EGFR, ERBB2, c-Kit, ABL, ARG, JAK2, FAK, DMPK, LTK, ROCK, LKB1, LDB3, PIM, GRK2, GRKS, ASK1, and PTEN (see Nature Reviews Drug ery 2011, 10:111).

One example from a marketed kinase inhibitor is that in clinical trials with nib, patients were found to be at increased risk for hypertension (see The Lancet 2006, 368:1329; and J. Clin. Oncol. 2009, 27:3584). Subsequent research on the mechanism for the increased hypertension suggest that while PDGFR and VEGFR may be playing a role, off-target kinase inhibition, such as AMPK, may also be contributing to sunitinib’s increased risk for hypertension (Curr. Hypertens. Rep. 2011, 13:436). Additionally, there is a patent ation, US 2011/0212461, that has been filed that is a method for the prediction of toxicity based on the activity versus a list of kinases including CSFlR, KIT, FYN, PDGFR beta, FGR, LCK, Ephrin or B2, FRK, ABL1, PDGFRl alpha, HCK, ABL2, LYN, ZAK, YESl, MAP4K4, PKN1, BRAF, DDR2, MAP4K5 and STK24. Therefore, identification of kinase inhibitors with a selective profile Btk kinase are desirable. The compounds of this invention are selective for the inhibition of Btk over other kinases.

Many of the kinases, whether a receptor or non-receptor tyrosine kinase or a S/T kinase have been found to be ed in cellular signaling pathways involved in numerous enic conditions, including immunomodulation, inflammation, or proliferative disorders such as cancer.

Many autoimmune diseases and disease associated with chronic inflammation, as well as acute responses, have been linked to excessive or unregulated production or activity of one or more cytokines.

The compounds of the invention are also useful in the treatment of rheumatoid arthritis, asthma, allergic asthma, osteoarthritis, juvenile arthritis, lupus, lupus nephritis, systemic lupus erythematosus (SLE), ankylosing litis, an ocular condition, interstitial cystitis, a cancer, a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, lastoma, teratocarcinoma, hypersensitivity reactions, hyperkinetic movement disorders, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, aordic and peripheral aneuryisms, hypothalamic-pituitary-adrenal axis evaluation, aortic dissection, arterial ension, arteriosclerosis, arteriovenous fistula, ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, e, syphilis of the cardiovascular system, systemic anaphalaxis, systemic atory response syndrome, systemic onset le rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, Viral and fungal infections, Vital encephalitis/aseptic meningitis, Vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft ion of any organ or tissue, heart transplant rejection, hemachromatosis, alysis, hemolytic uremic syndrome/thrombolytic ocytopenic purpura, hemorrhage, idiopathic pulmonary is, antibody ed cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, za A, ionizing radiation re, iridocyclitis/uveitis/optic neuritis, juvenile spinal muscular atrophy, lymphoma, a, leukaemia, ant ascites, hematopoietic cancers, a diabetic condition such as insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy or microangiopathy, sickle cell anaemia, chronic inflammation, glomerulonephritis, graft rejection, Lyme disease, von Hippel Lindau disease, pemphigoid, Paget’s e, fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperViscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma or edema following burns, , radiation, , hypoxia, ischemia, ovarian hyperstimulation syndrome, post ion syndrome, post pump syndrome, I cardiotomy syndrome, preeclampsia, menometrorrhagia, endometriosis, pulmonary hypertension, infantile hemangioma, or infection by Herpes simplex, Herpes , human immunodeficiency Virus, parapoxvirus, protozoa or toxoplasmosis, progressive ucleo palsy, primary ary ension, radiation therapy, Raynaud's phenomenon, Raynaud's disease, Refsum's e, regular narrow QRS tachycardia, renovascular hypertension, restrictive cardiomyopathy, sarcoma, senile chorea, senile dementia of Lewy body type, shock, skin allograft, skin changes syndrome, ocular or macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, Vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardt’s disease, Eales e, retinopathy, macular degeneration, restenosis, ischemia/reperfusion injury, ischemic stroke, vascular ion, carotid ctive disease, ulcerative colitis, inflammatory bowel disease, diabetes, es mellitus, insulin dependent diabetes mellitus, allergic diseases, dermatitis scleroderma, graft versus host disease, organ transplant rejection (including but not limited to bone marrow and solid organ rejection), acute or chronic immune disease associated with organ transplantation, sarcoidosis, inated intravascular coagulation, Kawasaki's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, septic shock, toxic shock syndrome, sepsis syndrome, cacheXia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, n's disease, idiopathic Addison's disease, sporadic, polyglandular ency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory ss syndrome, ia, alopecia areata, seronegative arthopathy, arthropathy, Reiter's disease, psoriatic pathy, ulcerative c pathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, gus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, mune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious a, peripheral vascular disorders, peritonitis, pernicious anemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic mune hepatitis, Acquired Immunodeficiency Disease me, Acquired Immunodeficiency Related Diseases, Hepatitis A, tis B, Hepatitis C, His bundle arrythmias, HIV infection/HIV neuropathy, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, ure ovarian failure, fibrotic lung disease, chronic wound g, cryptogenic fibrosing alveolitis, nflammatory interstitial lung disease, interstitial pneumonitis, pneumocystis carinii pneumonia, pneumonia, connective tissue disease associated interstitial lung disease, mixed connective tissue disease, associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus ated lung disease, dermatomyositis/polymyositis ated lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis ated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis rans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, fectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-l autoimmune hepatitis (classical autoimmune or lupoid tis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthritis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic aenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasculitis of the s, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, acute and chronic pain (different forms of pain), Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, ic sclerosis, Sjogren’s syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, ty, transplants, and diseases involving inappropriate vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile iomas in human beings. In addition, such compounds may be useful in the treatment of disorders such as s, effusions, and exudates, ing for example macular edema, cerebral edema, acute lung injury, adult respiratory distress me (ARDS), proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as diabetic nephropathy, malignant nephrosclerosis, otic microangiopathy syndromes, and glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb enesis, ischemia/reperfusion injury, peptic ulcer Helicobacter related diseases, Virally-induced angiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and pathies such as those associated With diabetic pathy, retinopathy of prematurity, or age- related r degeneration. In addition, these compounds can be used as active agents against hyperproliferative disorders such as thyroid hyperplasia (especially Grave’s disease), and cysts (such as hypervascularity of n stroma characteristic of polycystic ovarian me (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.

In yet other embodiments, the compounds described herein can be used to treat a cancer, e.g., B-cell proliferative disorders, Which include, but are not limited to diffuse large B cell lymphoma, follicular lymphoma, c cytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplamacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, odal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell ma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt’s lymphoma/leukemia, lymphomatoid granulomatosis, pancreatic cancer, solid or hematological tumors, a benign or malignant tumor, carcinoma of the brain, kidney (e.g., renal cell carcinoma (RCC)), us cell carcinoma, salivary gland carcinoma, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, as, lung, vagina, endometrium, cerVix, testis, urinary tract, esophagus, larynx, skin, bone or thyroid, a, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a sia, a sia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, mas, (including, for example, dgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termed Hodgkin's or Hodgkin's disease)), a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or a leukemia.

In yet other embodiments, the compounds bed herein can be used to treat Behcet's disease, osteoporosis, bone cancer, and bone metastasis, systemic sclerosis, contact dermatitis and other eczematous itis, seborrhoetic dermatitis, lichen planus, epidermolysis a, angiodermas, vasculitides, cutaneous eosinophilias, or vernal conjunctivitis.

In yet other embodiments, the compounds described herein can be used to treat those conditions characterized by inflammation of the nasal mucus membrane, including acute rhinitis, allergic, atrophic is and c rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous is and scrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis, sarcoidosis, farmer's lung and related diseases, d lung, and idiopathic interstitial pneumonia.

Compounds of Formula (I) of the invention can be used alone or in ation with an additional agent, e.g., a therapeutic agent, said additional agent being selected by the skilled artisan for its ed purpose. For example, the onal agent can be a therapeutic agent cognized as being useful to treat the disease or condition being treated by the compound of the present invention. The additional agent also can be an agent that imparts a cial attribute to the therapeutic composition e.g., an agent that affects the Viscosity of the composition.

It should further be understood that the combinations which are to be included within this ion are those combinations useful for their intended purpose. The agents set forth below are illustrative for purposes and not intended to be limited. The combinations, which are part of this invention, can be the compounds of the present invention and at least one additional agent selected from the lists below. The ation can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.

Preferred combinations are eroidal anti-inflammatory drug(s) also referred to as NSAIDS which include drugs like ibuprofen. Other preferred ations are corticosteroids including prednisolone; the well known side-effects of steroid use can be reduced or even eliminated by tapering the steroid dose required when treating patients in combination with the compounds of this invention. Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of Formula (I) of the invention can be combined include the ing: cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL- l2, IL-l5, IL-l6, IL-21, IL-23, interferons, I, , FGF, MMP-13 and PDGF.

Compounds of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.l), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).

Preferred combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists like chimeric, humanized or human TNF antibodies, D2E7 (US. Patent 6,090,382, HUMIRATM), CA2 (REMICADETM), ITM (golimumab), CIMZIATM, ACTEMRATM, CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFngG (ENBRELTM) or ngG (Lenercept), and also TNFOL converting enzyme (TACE) inhibitors; similarly IL-l tors (Interleukin-l-converting enzyme inhibitors, IL-lRA etc.) may be effective for the same reason.

Other preferred combinations include Interleukin 11. Yet other preferred combinations are the other key players of the autoimmune response which may act parallel to, dependent on or in concert with IL-18 function; especially preferred are IL-l2 antagonists including IL-l2 antibodies or soluble IL-l2 receptors, or IL-12 binding ns. It has been shown that IL-12 and IL-18 have overlapping but ct functions and a ation of antagonists to both may be most effective. Yet another preferred combination is pleting anti-CD4 inhibitors. Yet other preferred combinations include antagonists of the co-stimulatory pathway CD80 (B7.l) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands.

A compound of Formula (I) of the invention may also be combined with agents, such as methotrexate, 6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquine, lamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, aline, salmeteral), nes (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, fen, osteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which ere with signalling by proinflammatory cytokines such as TNFOL or IL-1 (e.g., NIK, IKK, JAKl, JAK2, JAK3, p38 or MAP kinase inhibitors), IL-lB converting enzyme tors, T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and tives thereof (6. g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (EnbrelTM) and p55TNFRIgG (Lenercept), sIL-lRI, sIL-lRII, sIL-6R), antiinflammatory cytokines (e. g. IL-4, IL-10, IL-11, IL-13 and TGFB), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen, oxib, sulfasalazine, WO 10255 methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, inolone ide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone rate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, obalamin/fa/pyridoxine, acetaminophen, alendronate sodium, prednisolone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine hondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium, zole, cyclophosphamide, rituximab, IL-l TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-l2, Anti-ILl5, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, SlPl agonists (such as FTY720), PKC family inhibitors (such as staurin or AEB-07l) and Mesopram.

Preferred combinations include methotrexate or leflunomide and in moderate or severe rheumatoid arthritis cases, cyclosporine and anti-TNF antibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of Formula (I) of the invention can be combined include the following: budenoside; epidermal growth factor; corticosteroids; porin, sulfasalazine; aminosalicylates; 6- mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-lB monoclonal dies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-l2, IL-15, IL-l6, IL-23, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolate l; leflunomide; NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; complement inhibitors; rgic agents; agents which interfere with signalling by proinflammatory nes such as TNFOL or IL-1 (6. g. NIK, IKK, p38 or MAP kinase tors); IL-lB converting enzyme inhibitors; TNFOL converting enzyme inhibitors; T-cell signalling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; aptopurines; angiotensin ting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (6. g. soluble p55 or p75 TNF ors, sIL-lRI, sIL-lRII, sIL-6R) and antiinflammatory cytokines (e. g. IL-4, IL-10, IL-11, IL-13 and TGFB). Preferred examples of therapeutic agents for s disease with which a nd of Formula (I) can be combined include the ing: TNF antagonists, for example, anti-TNF dies, D2E7 (US. Patent 6,090,382, HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM) inhibitors and PDE4 inhibitors. A compound of Formula (I) can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, osalicylic acid; olsalazine; and agents which interfere With synthesis or action of proinflammatory cytokines such as IL-1, for example, IL-lB converting enzyme inhibitors and ; T cell signaling inhibitors, for example, tyrosine kinase inhibitors; 6-mercaptopurine; IL-ll; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; prednisolone sodium succinate; diphenoxylate/atrop sulfate; mide hydrochloride; methotrexate; omeprazole; folate; oxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; onide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium phosphate; ethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide disodium; codeine ate/apap; colesevelam HCl; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis With Which a compound of Formula (I) can be combined include the following: corticosteroids; prednisolone; methylprednisolone; oprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-Bla (AVONEX®; Biogen); eron-Blb (BETASERON®; Chiron/Berlex); interferon oc-n3) (Interferon Sciences/Fujimoto), interferon-Qt (Alfa Wassermann/J&J), interferon BIA-IF (Serono/Inhale Therapeutics), Peginterferon 06 2b (Enzon/Schering-Plough), Copolymer l (Cop-l; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; antibodies to or antagonists of other human cytokines or growth s and their receptors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-l2, IL-23, IL-l5, IL-l6, EMAP-II, GM-CSF, FGF, and PDGF. A compound of Formula (I) can be ed With antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A nd of Formula (I) may also be combined With agents such as rexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, an SlPl agonist, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents Which interfere With signalling by proinflammatory cytokines such as TNFOL or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-lB ting enzyme inhibitors, TACE inhibitors, T-cell ing tors such as kinase tors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, e cytokine receptors and derivatives thereof (6. g. soluble p55 or p75 TNF receptors, sIL-lRI, sIL-lRII, sIL-6R) and antiinflammatory cytokines (e. g. IL-4, IL-10, IL-13 and TGFB).

Preferred examples of therapeutic agents for multiple sclerosis in Which a compound of Formula (I) can be combined to include interferon-B, for example, IFNBla and IFNBlb; copaxone, corticosteroids, caspase tors, for example inhibitors of caspase-1, IL-l inhibitors, TNF inhibitors, and antibodies to CD40 ligand and CD80.

A compound of Formula (I) may also be combined With agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer e, natalizumab, sinnabidol, 06-immunokine NNSOS, AER-215062, AnergiX.MS, chemokine receptor nists, BER-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone ap 1258 (RDP-1258), sTNF-Rl, talampanel, teriflunomide, TGF-beta2, otide, VLA-4 antagonists (for example, TR-l4035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitis With Which a compound of a (I) can be combined include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, sone, and anti-TNF antibodies, D2E7 (US. Patent 6,090,382; HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM).

Non-limiting examples of therapeutic agents for asthma With Which a compound of a (I) can be ed include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, inolone acetonide, beclomethasone dipropionate, opium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, prednisolone sodium succinate, clarithromycin, ukast, formoterol fumarate, influenza Virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofenadine hloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, inhaler assist , guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate, nesin/d-methorphan, p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, exin, pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil , terbutaline sulfate, epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenol sulfate.

Non-limiting examples of therapeutic agents for COPD With Which a compound of Formula (I) can be combined include the following: albuterol e/ipratropium, ipratropium bromide, salmeterol/fluticasone, rol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, nide, formoterol fumarate, triamcinolone ide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, p- ine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for HCV With which a compound of Formula (I) (can be combined e the following: Interferon-alpha-ZOL, Interferon-alpha-ZB, Interferon-alpha conl, Interferon-alpha-nl, ted eron-alpha-ZOL, pegylated interferon-alpha-ZB, ribaVirin, peginterferon alfa-2b + ribaVirin, oxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497 and any compounds that are used to treat HCV through intervention With the following targets: HCV polymerase, HCV protease, HCV helicase, and HCV IRES (internal ribosome entry site).

Non-limiting examples of eutic agents for thic ary Fibrosis With Which a compound of Formula (I) (can be combined include the following: prednisone, azathioprine, albuterol, cine, albuterol sulfate, digoxin, gamma interferon, methylprednisolone sodium succinate, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone nate, levofloxacin, metaproterenol e, morphine sulfate, oxycodone HCl, potassium chloride, triamcinolone acetonide, tacrolimus anhydrous, calcium, interferon-alpha, methotrexate, mycophenolate mofetil and interferon-gamma-lB.

Non-limiting examples of therapeutic agents for myocardial infarction With Which a compound of Formula (I) can be ed e the following: aspirin, nitroglycerin, metoprolol tartrate, enoxaparin , heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide mononitrate, n, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, quinapril hloride/magnesium carbonate, bumetanide, alteplase, rilat, amiodarone hydrochloride, tirofiban HCl m-hydrate, diltiazem hydrochloride, captopril, irbesartan, valsartan, propranolol hydrochloride, fosinopril sodium, lidocaine hydrochloride, eptifibatide, cefazolin sodium, atropine sulfate, aminocaproic acid, spironolactone, interferon, sotalol hydrochloride, potassium chloride, docusate sodium, dobutamine HCl, alprazolam, pravastatin sodium, atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride, isosorbide dinitrate, epinephrine, dopamine hydrochloride, bivalirudin, rosuvastatin, ibe/simvastatin, avasimibe, and cariporide. miting examples of therapeutic agents for psoriasis With Which a compound of Formula (I) can be ed include the following: calcipotriene, clobetasol propionate, inolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, nazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol nate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, lic acid, lin, clocortolone pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/na lact, mineral anut oil, petroleum/isopropyl myristate, en, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, ept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab. miting examples of eutic agents for psoriatic tis With Which a compound of Formula (I) can be combined include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, porine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone rate/apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (US. Patent 6,090,382, HUMIRATM), and efalizumab.

Non-limiting examples of eutic agents for osis With Which a compound of Formula (I) can be combined include the following: sirolimus, paclitaxel, everolimus, imus, ABT-578, and acetaminophen.

Non-limiting es of therapeutic agents for sciatica With Which a compound of Formula (I) can be combined include the following: hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HCl, methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, sone, codeine phosphate/apap, tramadol HCl/acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin, acetaminophen, diazepam, nabumetone, oxycodone HCl, dine HCl, diclofenac sodium/misoprostol, propoxyphene n-pap, asa/oxycod/oxycodone ter, ibuprofen/hydrocodone bit, ol HCl, etodolac, propoxyphene HCl, amitriptyline HCl, carisoprodol/codeine phos/asa, morphine sulfate, multivitamins, naproxen sodium, orphenadrine citrate, and temazepam. red examples of therapeutic agents for SLE (Lupus) With Which a compound of Formula (I) can be combined include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids, for example, prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, for example, oprine, cyclophosphamide, mycophenolate mofetil, rexate; inhibitors of PDE4 or purine synthesis inhibitor, for example Cellcept®. A compound of Formula (I) may also be combined With agents such as sulfasalazine, 5- aminosalicylic acid, olsalazine, Imuran® and agents Which ere With synthesis, production or action of proinflammatory cytokines such as IL-1, for e, caspase inhibitors like IL-lB converting enzyme inhibitors and IL-lra. A compound of Formula (I) may also be used with T cell signaling inhibitors, for e, tyrosine kinase inhibitors; or les that target T cell activation molecules, for example, CTLAIgG or 7 family antibodies, anti-PD-l family antibodies. A compound of a (I) (can be combined with IL-11 or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg antibody), or anti-receptor receptor dies, for example, anti-IL-6 receptor antibody and antibodies to B-cell e molecules. A compound of Formula (I) may also be used with LJP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti- CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF nists, for example, anti-TNF antibodies, D2E7 (US. Patent 6,090,382; HUMIRATM), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG CEPTTM).

In this ion, the following tions are applicable: A "therapeutically effective amount" is an amount of a compound of Formula (I) or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleViates, at least lly, one or more symptoms of the condition. A therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically ive will depend upon the patient’s size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.

"Pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are ed by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, c acid, salicylic acid, lactic acid, ic acid (6. g. (+) or (-)-tartaric acid or mixtures thereof), amino acids (6. g. (+) or (-)-amino acids or mixtures thereof), and the like. These salts can be prepared by methods known to those skilled in the art.

Certain compounds of Formula (I) which have acidic substituents may exist as salts with pharmaceutically acceptable bases. The present invention includes such salts. Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art.

Certain nds of Formula (I) and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.

Certain compounds of Formula (I) and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and es thereof.

Certain compounds of Formula (I) may contain one or more chiral centers, and exist in different optically active forms. When compounds of Formula (1) contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. The enantiomers may be resolved by methods known to those skilled in the art, for example by formation of reoisomeric salts which may be separated, for example, by crystallization; ion of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific t, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into r chemical entity by one of the separation procedures described above, a further step is ed to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

When a compound of Formula (1) contains more than one chiral center, it may exist in reoisomeric forms. The reoisomeric compounds may be separated by methods known to those skilled in the art, for example tography or crystallization and the dual enantiomers may be separated as described above. The present invention includes each diastereoisomer of compounds of Formula (I) (and mixtures thereof.

Certain compounds of Formula (I) may exist in different tautomeric forms or as different geometric isomers, and the t invention includes each tautomer and/or geometric isomer of compounds of Formula (I) and es thereof.

Certain compounds of Formula (I) may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.

The t invention includes each conformational isomer of compounds of Formula (I) and es thereof.

Certain compounds of Formula (I) may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of Formula (I) (and mixtures f.

As used herein the term rug" refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). ugs are often useful because, in some situations, they may be easier to ster than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The pro-drug may also have improved solubility in pharmacological compositions over the parent drug. An example, without limitation, of a ug would be a compound of the present invention n it is administered as an ester (the "pro-drug") WO 10255 to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is lically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial.

Pro-drugs have many useful properties. For example, a ug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After stration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.

Exemplary pro-drugs upon cleavage release the ponding free acid, and such yzable ester-forming residues of the compounds of this ion include but are not limited to carboxylic acid substituents wherein the free hydrogen is replaced by )alkyl, (C1- C12)alkanoyloxymethyl, (C4-C9)l-(alkanoyloxy)ethyl, yl-l-(alkanoyloxy)-ethyl haVing from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl haVing from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl haVing from 4 to 7 carbon atoms, l-methyl-l-(alkoxycarbonyloxy)ethyl haVing from 5 to 8 carbon atoms, oxycarbonyl)aminomethyl haVing from 3 to 9 carbon atoms, l-(N—(alkoxycarbonyl)amino)ethyl haVing from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactonyl, di-N,N—(C1-C2)alkylamino(C2-C3)alkyl (such as B-dimethylaminoethyl), carbamoyl-(Cl-C2)alkyl, N,N—di(C1-C2)-alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.

Other ary pro-drugs release an alcohol of Formula (I) wherein the free hydrogen of the hydroxyl substituent (e.g., R1 contains yl) is replaced by (C1-C6)all As used herein, the term "bridged (Cs-Cm) cycloalkyl group" means a saturated or unsaturated, bicyclic or polycyclic bridged hydrocarbon group haVing two or three C3-C10 cycloalkyl rings. Non bridged cycloalkyls are excluded. Bridged cyclic hydrocarbon may include, such as bicyclo[2. l . l]hexyl, bicyclo[2.2. yl, bicyclo[2.2.2]octyl, bicyclo[3.2. l]octyl, bicyclo[4.3.l]decyl, bicyclo[3.3.l]nonyl, bornyl, bornenyl, norbornyl, norbornenyl, 6,6- dimethylbicyclo [3.1.1]heptyl, tricyclobutyl, and adamantyl.

As used herein the term "bridged (CZ-Clo) heterocyclyl" means bicyclic or polycyclic aza- bridged hydrocarbon groups and may include azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl, azabicyclo[3.2. l]octanyl, azabicyclo[2.2. l]heptanyl, 2-azabicyclo[3.2. l]octanyl, azabicyclo[3.2.l]octanyl, azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, and azabicyclo [3.3.1]nonanyl.

The term "heterocyclic," "heterocyclyl" or "heterocyclylene," as used herein, include non- ic, ring systems, including, but not limited to, monocyclic, bicyclic, tricyclic and spirocyclic rings, Which can be completely saturated or Which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system) and have 5 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, Which should not be construed as limiting the scope of this invention, the following are es of heterocyclic rings: azepinyl, azetidinyl, indolinyl, isoindolinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, ludinyl, thiomorpholinyl, ydropyranyl, tetrahydrofuranyl, tetrahydroindolyl, rpholinyl and tropanyl.

The term "heteroaryl" or "heteroarylene" as used herein, e aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, and have 5 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, Which should not be construed as limiting the scope of this invention: azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, azolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furanyl, olyl, imidazopyridinyl, l, indazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrazolyl, thiadiazolyl, thienyl, 6H-pyrrolo[2,3-e][l,2,4]triazolo[4,3-a]pyrazinyl, 6H- imidazo[l ,5-a]pyrrolo[2,3-e]pyrazinyl, l,6-dihydropyrazolo[3 ,4-d]pyrrolo[2,3-b]pyridine, 3H- 3,4,6,8a-tetraaza-asindacenyl, 3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazinyl, pyrazolo[3,4-d]pyrrolo[2,3- b]pyridinyl, l,6-dihydro-l,2,5,6-tetraza-as-indacenyl, 3H-3,4,8a-triaza-as-indacenyl, 6Hoxa-2,5,6- -as-indacenyl, 3,6-dihydro-2,3,6-tetraaza-as-indacenyl, l,6-dihydro-dipyrrolo[2,3-b;2’ 3 ’ - d]pyridinyl, 6Hthia-2,5,6-triaza-as-indacenyl or l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine.

As used herein, "alkyl," "alkylene" or notations such as "(C1-C8)" include straight chained or branched hydrocarbons Which are completely saturated. Examples of alkyls are methyl, ethyl, propyl, pyl, butyl, pentyl, hexyl and isomers thereof. As used herein, "alkenyl," ylene," "alkynylene" and "alkynyl" means C2-C8 and es straight chained or branched hydrocarbons Which contain one or more units of ration, one or more double bonds for alkenyl and one or more triple bonds for alkynyl.

As used herein, "aromatic" groups (or "aryl" or "arylene" groups) include aromatic carbocyclic ring systems (6. g. phenyl) and fused polycyclic aromatic ring systems (6. g. yl, biphenyl and l,2,3,4-tetrahydronaphthyl).

As used herein, "cycloalkyl" or "cycloalkylene" means C3-C12 monocyclic or multicyclic (e.g., bicyclic, tricyclic, spirocyclic, etc.) hydrocarbons that is completely ted. Examples of a cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, "cycloalkenyl" means C3-C12 monocyclic or multicyclic (e.g., bicyclic, tricyclic, spirocyclic, etc.) hydrocarbons that has one or more unsaturated bonds but does not amount to an aromatic group. Examples of a cycloalklenyl group are cyclopentenyl and cyclohexenyl.

As used herein, many es or substituents are termed as being either "substituted" or "optionally substituted". When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents, where if more than one substituent then each substituent is independently selected. Such means for substitution are well- known in the art and/or taught by the t disclosure. For es of exemplification, which should not be construed as limiting the scope of this invention, some examples of groups that are substituents are: (C1-C8)alkyl groups, (C2-C8)alkenyl , (C2-C8)alkynyl groups, (C3- C10)cycloalkyl groups, halogen (F, Cl, Br or I), halogenated (C1-C8)alkyl groups (for example but not limited to —CF3), -O-(C1-Cg)alkyl groups, =0, =CH2, -OH, -CH20H, -CH2NH2, )alkyl-OH, - CHZCHZOCHZCH3, -S-(C1-Cg)alkyl groups, -SH, -NH(C1-Cg)alkyl groups, -N((C1-Cg)alkyl)2 groups, - NHZ, -C(O)NH2, -CH2NHC(O)(C1-C4)alkyl, C(O)CH2C1, -CH2NHC(O)CH2CN, - CHZNHC(O)CH2CH2N(CH3)2, -CH2NHC(O)C(=CH2)CH3, -CH2NHC(O)(C2-C4)alkynyl, - CHZNHC(O)CH2CH2-piperidinyl, -(C1-C4)alkyl-morpholinyl, C(O)CHZO-phenyl wherein the phenyl is optionally substituted with n, (C1-C4)alkoxy, C1-C4)alkyl, -C(O)(C1-C4)alkoxy, -C(O)N(H)2, (CH3)2, -C(O)(C1-C6)heteroaryl, -N(CH3)2, -NHC(O)(C1-C4)alkyl, )(C2- C4)alkenyl, -NHC(O)CH2CN, -S(O)2(C1-C4)alkyl, -S(O)2(C1-C6)heteroaryl, -S(O)2(C1-C6) (C1- C6)heterocyclyl, 4-methylpiperazinecarbonyl, -(C1-C4)all The term "kit" as used herein refers to a packaged product comprising components with which to administer a compound of Formula (I) of the invention for treatment of an autoimmune er. The kit preferably comprises a box or container that holds the components of the kit. The box or container is d with a label or a Food and Drug Administration approved protocol. The box or container holds components of the ion which are preferably contained within plastic, polyethylene, polypropylene, ethylene, or propylene vessels. The vessels can be capped-tubes or bottles. The kit can also include instructions for administering a compound of Formula (1).

One or more compounds of this invention can be administered to a human patient by themselves or in ceutical compositions where they are mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein.

Mixtures of these nds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. A therapeutically effective dose refers to that amount of the compound or compounds ient to result in the prevention or attenuation of a disease or condition as described herein. Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition. le routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary ions, as well as intrathecal, direct entricular, intravenous, intraperitoneal, intranasal, or cular injections.

Alternatively, one may administer the compound in a local rather than a systemic manner, for example, Via injection of the compound directly into an edematous site, often in a depot or ned release formulation.

Furthermore, one may administer the drug in a targeted drug delivery , for example, in a liposome coated with elial cell-specific antibody.

The pharmaceutical compositions of the present invention may be ctured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, leVigating, emulsifying, encapsulating, entrapping or lyophilizing ses.

Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more logically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' on, Ringer's solution, or physiological saline . For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. ceutical ations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in ular, fillers such as sugars, including lactose, e, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or nylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyVinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyVinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium e, r solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for fication or to characterize ent combinations of active compound doses.

Pharmaceutical ations that can be used orally e push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft es, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use ing to the present invention are conveniently delivered in the form of an aerosol spray presentation from rized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to r a metered amount. es and cartridges of e. g. n for use in an r or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e. g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or ons in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. onally, suspensions of the active compounds may be prepared as appropriate oily ion suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the Viscosity of the suspension, such as sodium ymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable izers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The compounds may also be formulated in rectal compositions such as itories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described preViously, the compounds may also be ated as a depot ation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection). Thus, for e, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion ge resins, or as gly soluble derivatives, for e, as a sparingly e salt.

An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be the VPD co-solvent system. VPD is a solution of 3% w/V benzyl alcohol, 8% w/V of the nonpolar surfactant polysorbate 80, and 65% w/V polyethylene glycol 300, made up to volume in te ethanol. The VPD co-solvent system W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied erably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the on size of polyethylene glycol may be ; other biocompatible polymers may replace polyethylene glycol, e. g. polyVinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic ceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also may be employed, gh usually at the cost of greater ty. Additionally, the compounds may be red using a sustained-release system, such as semipermeable matrices of solid hobic polymers containing the therapeutic agent. Various ned-release materials have been established and are well known by those d in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid or gel phase rs or excipients. es of such carriers or excipients include but are not limited to calcium carbonate, m phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Many of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, , ic, malic, ic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.

Pharmaceutical compositions suitable for use in the t invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose.

More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleViate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art.

For any compound used in a method of the present invention, the therapeutically effective dose can be estimated initially from cellular assays. For example, a dose can be formulated in ar and animal models to achieve a circulating concentration range that includes the IC50 as determined in cellular assays (e.g., the concentration of the test compound which achieves a half-maximal inhibition of a given protein kinase activity). In some cases it is appropriate to determine the IC50 in the presence of 3 to 5% serum albumin since such a determination approximates the binding effects of plasma protein on the compound. Such information can be used to more tely determine useful doses in humans. Further, the most preferred compounds for systemic administration ively inhibit protein kinase signaling in intact cells at levels that are safely achievable in plasma.

A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical ures in cell cultures or experimental s, e.g., for determining the maximum tolerated dose (MTD) and the ED50 (effective dose for 50% maximal response). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED50. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating trations that include the ED50 with little or no toxicity. The dosage may vary within this range ing upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the indiVidual physician in View of the patient’s condition (see, e.g., Fingl et al., 1975, in The cological Basis of Therapeutics, Ch. 1, p. 1). In the treatment of , the stration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.

Dosage amount and interval may be adjusted indiVidually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data; e. g. the concentration necessary to achieve 50-90% inhibition of protein kinase using the assays described . Dosages necessary to e the MEC will depend on indiVidual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

Dosage als can also be determined using the MEC value. nds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

The amount of composition administered will, of course, be dependent on the subject being treated, on the subject’s weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

The compositions may, if d, be presented in a pack or dispenser deVice which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser deVice may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible ceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition.

In some formulations it may be beneficial to use the compounds of the present ion in the form of les of very small size, for example as obtained by fluid energy milling.

The use of compounds of the present invention in the manufacture of pharmaceutical compositions is rated by the following description. In this description the term "active compound" denotes any compound of the invention but particularly any compound which is the final product of one of the ing Examples.

WO 10255 a) Capsules In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose can be de-aggregated and blended. The mixture can be filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound. b) Tablets Tablets can be prepared, for example, from the ing ingredients.

Parts by weight Active compound 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch can be de-aggregated, blended and the resulting mixture can be granulated with a solution of the polyvinylpyrrolidone in l. The dry granulate can be d with the magnesium stearate and the rest of the starch. The mixture is then ssed in a tabletting machine to give tablets each ning a unit dose or a part of a unit dose of active compound. c) Enteric coated tablets Tablets can be prepared by the method described in (b) above. The tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in l:dichloromethane (1:1). d) Suppositories In the preparation of itories, for example, 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.

In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients. For e, the compounds of this invention can be administered in combination with another therapeutic agent that is known to treat a disease or condition described herein. For example, with one or more additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block ellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization. The compounds of the invention can be administered prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of stration is appropriate. The additional pharmaceutical agents include, but are not limited to, demic steroids, , ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines, PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF-lR inhibitors, PKC inhibitors, PI3 kinase inhibitors, calcineurin inhibitors and immunosuppressants. The compounds of the invention and the onal pharmaceutical agents act either additively or synergistically. Thus, the administration of such a combination of substances that inhibit angiogenesis, vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deletrious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone. In the treatment of malignant ers combinations With antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present ion.

The present invention also comprises the use of a compound of Formula (I) as a medicament.

A further aspect of the present invention provides the use of a compound of Formula (I) or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenesis- dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, particularly human beings.

The present invention also provides a method of treating ar hyperpermeability, inappropriate neovascularization, proliferative diseases and/or disorders of the immune system Which comprises the administration of a therapeutically effective amount of a compound of Formula (I) to a mammal, particularly a human being, in need thereof.

ABBREVIATIONS Ac Acetyl AcOH l acetic acid Bn Benzyl BnBr Benzyl bromide Boc t-Butoxycarbonyl BocZO t-butyl dicarbonate BPO Benzoyl peroxide br broad t-BuOH tert-Butanol n rmaldehyde d Doublet dba ylideneacetone DCAD (E)-Bis(4-chlorobenzyl) diazene- l ,2-dicarboxylate DCE 1,2-Dichloroethane DCM romethane (methylene chloride) dd Doublet of doublets DIEA isopropylethylamine DMA Dimethylacetamide DMAP 4-Dimethylaminopyridine DME l ,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dppf l l '-Bis(diphenylphosphino)ferrocene EDC l-(3-dimethylaminopropyl)ethylcarbodiimide EDC-HCl Nl -((ethylimino)methylene)-N3 ,N3-dimethylpropane-l mine hydrochloride equiv Equivalent(s) EtOAc Ethyl acetate EtzO Diethyl ether EtOH Ethanol Fmoc Fluorenylmethyloxycarbonyl g ) h Hour(s) HATU 4-(3-Acrylamidophenyl)ethyl- 1H-indole-7—carboxamide HOBt lH-Benzo[d][1,2,3]triazol-l-ol hydrate HPLC High-pressure liquid chromatography IPA Isopropyl alcohol KHMDS Potassium bis(trimethylsilyl)amide KOAC Potassium e KOt-Bu Potassium tert-butoxide LC/MS Liquid chromatography/mass spectrometry LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide m Multiplet M Molar MeCN Acetonitrile MeOH Methyl l min Minute(s) mmol Millimole MS Mass spectrometry MsCl Methanesulfonyl chloride MTBE tert-Butyl methyl ether n- Normal (nonbranched) N Normal NaBH(OAc)3 Sodium triacetoxyhydroborate NaHMDS Sodium imethylsilyl)amide n-BuLi n-Butyl lithium NaOt-Bu Sodium tert-butoxide NBS N-bromosuccinimide NCS rosuccinimide NH4OAc Ammonium acetate NMP ylpyrolidinone NMR Nuclear magnetic resonance szdba3 Tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)2 Palladium(II) acetate Pet ether petroleum ether pH -10g[H+] Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)2C12 Bis(triphenylphosphine)palladium(II) chloride PMB para-Methoxybenzyl PPh3 Triphenylphosphine ppm Parts per million PrOH Propanol psi Pounds per square inch PyBOP (( lH-benzo[d] [ l ,2, 3 ] triazol- l -yl)oxy)tri(pyrrolidin- l - yl)phosphonium orophosphate(V) Rt Retention time rt Room temperature s Singlet SEM 2-(Trimethylsilyl)ethoxymethyl SEMCl methylsilyl)ethoxymethyl chloride SFC Supercritical fluid chromatography SPE Solid phase extraction Triplet Tertiary TBAF tetrabutylammonium fluoride TBME tert-Butyl methyl ether TBDMS tert-Butyldimethylsilane TBSCl tert-Butyldimethylsilyl chloride TBTU 2-(lH-Benzo[d] [l ,2,3]triazol- l -yl)- l , l ,3,3-tetramethylisouronium tetrafluoroborate TEA Triethylamine tert- Tertiary tert-Butyl X-Phos 2-Di-tert-butylphosphino-Z',4',6'—triisopropylbiphenyl TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer tography TMS Trimethylsilyl TMSCl Trimethylsilyl chloride TMSI Trimethylsilyl iodide TsCl p-Toluenesulfonyl chloride UV Ultraviolet wt% Weight percent X-Phos 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl GENERAL SYNTHETIC SCHEMES Compounds of the invention may be prepared using the synthetic transformations illustrated in Schemes I-XVIII. Starting als are commercially available, may be prepared by the procedures described herein, by literature procedures, or by procedures that would be well known to one d in the art of organic chemistry.

Methods for ing IH-indole-7—carboxamide compounds 9 of the invention are illustrated in Scheme 1. In Scheme 1, step a, commercially available 4-bromonitrobenzoic acid 1 is reacted with Vinylmagnesium bromide Via a i indole synthesis using methods known to one skilled in the art (for e Preparation #1, step A) to give indole 2. Indole 2 can be alkylated with methyl iodide e 1, step b) to provide methyl IH-indole-7—carboxylate 3 using methods known to one skilled in the art (for example Preparation #1, step B). The resulting indole 3 may be tosyl (Ts) protected (Scheme 1, step c) using conditions such as those described in Preparation #1, step C or those bed in Greene, T.W. and Wuts, P.G.M. "Protective Groups in Organic Synthesis, 3rd Edition", 1999, Wiley-Interscience; Larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition", 1999, Wiley-VCH. In step d, directed lithiation of methyl 4-bromotosyl-IH-indolecarboxylate 4 followed by trapping of the anion with iodine yields methyl 4-bromoiodo-IH-indolecarboxylates 5 using conditions such as those described in Preparation #1 step D. Tosyl protected methyl 4-bromoiodo-IH-indolecarboxylates 5 may be hydrolyzed and deprotected under aqueous base conditions in one step e to give 4-bromoiodo-1H- indolecarboxylic acid 6 using ions such as those described in Preparation #1, step E or known to one skilled in the art (for example, the books from Larock, R.C. or Greene, T.W. and Wuts, P.G.M. nced above). In step f, 4-bromoiodo-IH-indolecarboxylic acid 6 may be ted to a primary amide 7 as shown using conditions such as those described in General ure D. The 4-bromoiodo-IH-indolecarboxamide 7 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Suzuki or Stille coupling reactions such as those described in General Procedure A and Example #22, step A. atively, in step i, the tosyl protected indoles 5 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Suzuki or Stille coupling reactions described by General Procedure A (for example Preparation #15 step A). ysis of esters 10 gives acids 11 (Scheme I, step j) using well known conditions such as those bed in Preparation #15, step B or General Procedure C. In step k, carboxylic acid 11 may be coverted to primary amides 12 as shown using conditions such as those described in General Procedure D. Removal of the sulfonamide protecting group of indoles 12 may be accomplished using ions such as those described in General Procedure N, or by methods known to one skilled in the art (for example, Larock, R.C. or Greene, T.W. and Wuts, P.G.M. referenced above) to give indoles 8 (Scheme I, step 1). Indoles 8 are reacted with a boronate ester or boronic acid, either commercially available or prepared by methods known to one skilled in the art (see, for example, Larock, R.C. "Comprehensive Organic Transformations: A Guide to onal Group Preparations, 2nd edition", 1999, Wiley-VCH or General Procedure P), using Suzuki coupling conditions, such as those described by General Procedure A, to give ole-7—carboxamide compounds 9. Alternatively, in step h, indoles 8 may o a y of reactions known to one skilled in the art (for e, , R.C. referenced above) including, but not d to, Buchwald or Negishi coupling ions as described by General Procedures T and U. Further functionalization of the R" group in indoles 9 can be performed, if desired, using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, s 9 containing a double bond may be reduced to saturated systems using enation conditions such as those described in General Procedure L. Ethers can be prepared from indoles 9 containing an alcohol using condition such as those described in General Procedure Q. In addition amides, ureas, sulfonamides, aryl amines, heteroaryl amines, or sulfonyl ureas can be prepared from indoles 9 containing a primary or secondary amine (for example General Procedures D, E, I, H, and J). Also, deprotection of s 9 containing a protecting group in either R' or R" can be performed using conditions such as those described in Greene, T.W. and Wuts, P.G.M. referenced above or in General Procedures G, M, or N. For example, for R" containing a TBDMS-protected alcohol, the protecting group can be removed to yield an ected alcohol (for example General Procedure M) and the deprotected compounds 9 may then be reacted further as described above. Alternatively, compound 4 may first undergo a coupling reaction in step m, ing but not d to, such as , Buchwald, or i using conditions as described b General Procedures A,T and U to give compounds 107 followed by an tion reaction as illustrated in General Procedure Y to give compounds 108 (step n). Indoles 108 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Suzuki or Stille coupling reactions such as those described in General Procedure A to give compounds 109. One can WO 10255 then envisage that compounds 109 can undergo hydrolysis, amidation and de-tosylation reactions similar to steps j, k and I to arrive at nds 9.

SchemeI Br R" Br Br Br a \ b \ C__ \ _m. \ N N N N NO \ \ 2 H H Ts Ts O OH O O/ O O O O O OH 1 2 | 107 | d n Br Br Br Ru \ - 9 R <— \ f e | \ \ \ ‘— | ' | | H N N N N H ‘ H \ T5 T5 O NH2 O NH O OH O O 2 O O 8 5 7 | | 108 i o h | R.. Br Br \ \ R. \ k J R' R. \ R'<— \ R'<— N N\ N N\ N\ \ T5 T5 T5 O O 0 O O NH2 O NH2 O OH l I 12 109 9 11 10 An alternative method preparing IH-indole-7—carboxamide nds 9 of the invention are illustrated in Scheme 11. In step a, indole 3 from Scheme I may be protected with a SEM group using conditions known in the literature such as those found in , T.W. and Wuts, P.G.M. referenced above or as those described in Preparation #10, step A. The resulting SEM protected indole 13 can undergo directed lithiation followed by trapping of the anion with an electrophile (for example iodomethane) yielding indole 14 as shown in step b using conditions described in Example #19, step A or trapping the anion with iodine as shown in step g yielding methyl 4-bromoiodo((2- (trimethylsilyl)ethoxy)methyl)-1H-indolecarboxylate 17 using conditions such as those described in Preparation #10, step B). In step h, indole 14 may o a variety of reactions known to one skilled in the art including, but not limited to, Suzuki or Stille coupling ons such as those described in Larock, R.C. referenced above, General Procedure A, and Preparation #10, step C.

Hydrolysis of esters 14 gives acids 15 (step c) using well known conditions such as those described in Preparation #10, step D, or General Procedure C. Indole carboxylic acids 15 may be converted to primary amides 16 as shown using conditions such as those described in General Procedure D. The SEM ting group of IH-indole-7—carboxamide compounds 16 may be d by methods such as those described in Preparation #10, step E or using conditions such as described in Greene, T.W. and Wuts, P.G.M. referenced above to give IH-indolecarboxamides 8. Indoles 8 may then be reacted further as described above (Scheme 1) to give the targeted lH-indolecarboxamide nds 9.

Scheme 11 \ _.a b \ \ R H N\SEM N‘ / SEM O O o O O 3 13 l R Br V 14 | \ 1 SEM c O O 17 I Br Br f \ R-‘_e \ \ ' . R \ R.<_ R <— N N \ H H \ SEM 0 OH o NH2 0 NH2 O NH2 16 15 An additional method preparing indolecarboxamide compounds 9 of the invention is illustrated in Scheme III. Hydrolysis of ester 17 gives acid 18 (step a) using well known conditions such as those described in Preparation #10, step D or General Procedure C. Acid 18 may be coverted to a primary amide 19 as shown using conditions such as those described in l Procedure D.

The SEM protecting group of indole 19 may be removed by methods such as those described in Example #19, step D or using conditions such as described in Greene, T.W. and Wuts, P.G.M. referenced above to give olecarboxamides 7. Indoles 7 may then be reacted further as described above above to give the ed lH-indolecarboxamide compounds 9.

Scheme III :2»9H?» \ IZ Rn Br \ \ R' <— R' H N o NH2 0 NH2 An alternative method preparing IH-indole-7—carboxamide compounds 9 of the invention is illustrated in Scheme IV. Indole 19 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Stille coupling reactions such as those described in e #22, step A or Suzuki ng reaction as those described in General Procedure A. In step b, indolecarboxamides 16 are reacted With a boronate ester or boronic acid either commercially available or can be prepared by methods known to one skilled in the art (see, for example, Example #22, step B; Larock, R.C. "Comprehensive Organic Transformations: A Guide to onal Group Preparations, 2nd edition", 1999, Wiley-VCH; or General Procedure A) using Suzuki coupling conditions (for example, Example #19 or General Procedure A). The SEM protecting group of indoles 20 may be d by methods such as those described in Example #22, step D or using conditions such as described in Greene, T.W. and Wuts, P.G.M. referenced above to give IH-indolecarboxamides 9. Indoles 9 may then be reacted r as described above.

Scheme IV 9*9%?as» carboxamide compounds 9 of the invention can also be ed using the route illustrated in Scheme V. In step a, methyl ester 21 is prepared using standard condition such as those described in General Procedure F, or Larock, R.C. referenced above. Enolizable ketones 23 react with m- nitroaniline 22 to give 4- ndoles 24 (step b) using standard conditions such as those described in General ure F, or Tetrahedron, 2004, 60(2), 347. In step c, acids 24 may be converted to primary amides 25 as shown using conditions such as those described in General Procedure D or F.

Amino s 26 are prepared by reduction of the nitro group of primary amides 25 using methods known to one skilled in the art (for example, l Procedure F, or Larock, R.C. nced above).

Diazotization of 26 followed by iodination gives 27 using standard condition such as those described in General Procedure F, or Larock, R.C. referenced above. In step f, indoles 27 may undergo a y of reactions known to one skilled in the art (for example, Larock, R.C. nced above) ing, but not limited to, Suzuki, Buchwald, or Negishi coupling conditions as described by General Procedures A, T and U. Indoles 9 may then be reacted further as described above.

SchemeV N02 N02 N02 N02 a O b —> ALF," —» \ R- —> CD», NH2 NH2 23 H H O OH o o/ o OH o¢‘\NH2 21 24 25 R" NH2 N N N H H H o NH2 0 NH2 o¢\NH2 9 27 26 Methods for preparing IH-indole-7—carboxamide compounds 30 of the ion are illustrated in Scheme VI. In Scheme VI, step a, commercially available 4-bromo-IH-indole-7— carbonitrile [Sinova] 28 is hydrolyzed to give primary amide 29 using conditions such as those described in ation #2 or known to one skilled in the art (for example, the books from Larock, R.C. or Greene, T.W. and Wuts, P.G.M. referenced above). In step b, indole 29 may undergo a variety of reactions known to one d in the art (for example, Larock, R.C. nced above) including, but not limited to, Suzuki, Buchwald, or Negishi coupling conditions as described by General Procedures A, T and U. Alternatively, indole 29 can be converted to the boronate ester 31 using reactions such as those described in General Procedure P. Indole 31 may undergo a Suzuki coupling using conditions such as those described in General Procedure A or known to one skilled in the art (for example, Larock, R.C. referenced above). Further functionalization of the R’ group in indoles 30 can be performed, if desired, using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, indoles 30 containing a double bond may be reduced to saturated systems using hydrogenation ions such as those described in General Procedure L.

Ethers can be prepared from indoles 30 containing an alcohol using condition such as those described in General Procedure Q. In addition amides, ureas, sulfonamides, aryl amines, heteroaryl amines, or yl ureas can be prepared from indoles 30 with an R' containing a primary or secondary amine (for example General Procedures D, E, I, H, and J). Also, deprotection of the R' group in IH-indole- 7—carboxamide compounds 30 to yield an unprotected compound can be med using ions such as those described in Greene, T.W. and Wuts, P.G.M. referenced above or in General Procedures G, M, or N. For example, a protecting group such as a Boc group can be removed from a protected amine to yield the unprotected amine (for example l Procedure G) and the deprotected compounds 30 may then be reacted further as described above.

Scheme VI Br Br R' a b \ —> \ —> \ N N N H H H H o NH2 0 NH2 28 29 W 30 N /: o NH2 Methods for preparing IH-indole-7—carboxamide compounds 35 of the invention are illustrated in Scheme VII. Nitration of indole 29 (Scheme VII step a) can be performed using conditions such as those bed in Preparation #7, step C or known to one skilled in the art (for example, Larock, R.C. referenced above). In step b, indole 32 may undergo a variety of reactions known to one skilled in the art (for example, , R.C. referenced above) including, but not d to, Suzuki, Buchwald, or Negishi coupling conditions as described by General Procedures A, T and U. Amino indoles 34 are prepared from the reduction of nitroindoles 33 using s known to one skilled in the art (for e, Preparation #7, step E, or Larock, R.C. referenced above). The amino s 34 may be coverted to give amides 35 as shown in step d using conditions such as those described in General Procedure D or E.

Scheme VII Br Br No2 R' No2 R' a b c \ —> \ —> \ —> \ N N N N H H H H O NH2 0 NH2 0 NH2 0 NH2 29 32 34 R. \N’R' o NH2 Methods for ing IH-pyrrolo[3,2-c]pyridinecarboxamides 39 of the invention are illustrated in Scheme VIII. In Scheme VIII, step a, 6-bromonitronicotinic acid [European Journal of Medicinal Chemistry 1977, 12(6), 541] 36 is reacted with Vinylmagnesium bromide Via a Bartoli indole synthesis using methods known to one skilled in the art (for e Preparation #9, step A) to give pyrrolo[3,2-c]pyridine 37. In step b, the acid of compounds 37 may be converted to primary amides 38 as shown using conditions such as those described in General Procedure D. o[3,2- c]pyridine 38 may undergo a y of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Suzuki, Buchwald, or Negishi coupling ions as bed by General Procedures A, T and U. r functionalization of the R' group in pyrrolo[3,2-c]pyridines 39 can be performed, if desired, using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, indoles 39 containing a double bond may be reduced to saturated s using hydrogenation conditions such as those described in l Procedure L. Ethers can be prepared from indoles 39 containing an alcohol using condition such as those described in General Procedure Q. In addition amides, ureas, sulfonamides, aryl amines, heteroaryl amines, or sulfonyl ureas can be prepared from s 39 containing a primary or secondary amine (for example General Procedures D, E, I, H, and J). Also, deprotection of indoles 39 containing a protecting group in R' can be performed using conditions such as those described in Greene, T.W. and Wuts, P.G.M. referenced above or in General Procedures G, M, or N. For example, for R" containing a TBDMS-protected alcohol, the ting group can be removed to yield an unprotected alcohol (for example General Procedure M) and the deprotected compounds 39 may then be d further as described above.

Scheme VIII Br Br Br R' a b N \ N \ N \ C § 3 N \ | ————>-| -————>-| ————’-| \ /’ // // // N02 H H H o OH O OH o NH2 0 NH2 36 37 39 Methods for ing IH-pyrrolo[2,3-c]pyridinecarboxamides 44 of the invention are illustrated in Scheme IX. In Scheme IX, step a, 5-bromochloronitropyridine 40 is reacted with Vinylmagnesium bromide Via a Bartoli indole synthesis using methods known to one d in the art (for example, e #2, step A) to give pyrrolo[2,3-c]pyridine 41. In step b, pyrrolo[2,3-c]pyridine 41 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not d to, Suzuki, Buchwald, or Negishi coupling conditions as described by General Procedures A, T and U to give pyrrolo[2,3-c]pyridines 42. In step C, Pd- ed carbonylation of pyrrolo[2,3-c]pyridines 42 gives esters 43 using methods known to one skilled in the art such as those described in Example #2, step C. Esters 43 may o ammonolosis such as those described in Example #2, step D or known to one skilled in the art (for example, Larock, R.C. referenced above) give compounds 44. r functionalization of the R’ group in pyrrolo[2,3- c]pyridines 44 can be performed, if desired, using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, indoles 44 containing a double bond may be reduced to saturated systems using hydrogenation conditions such as those described in General Procedure L. Ethers can be prepared from indoles 44 containing an alcohol using ion such as those described in General Procedure Q. Also, deprotection of indoles 44 containing a protected alcohol can be performed using conditions such as those described in Greene, T.W. and Wuts, P.G.M. referenced above or in General Procedures M. In addition amides, ureas, sulfonamides, aryl , heteroaryl amines, or sulfonyl ureas can be prepared from indoles 44 with an R' ning a primary or secondary amine (for example General Procedures D, E, I, H, and J). Also, deprotection of the R' group in IH-indolecarboxamide compounds 44 to yield an unprotected compound can be performed using conditions such as those described in Greene, T.W. and Wuts, P.G.M. nced above or in l Procedures G, M, or N. For example, a protecting group such as a Boc group can be removed from a protected amine to yield the unprotected amine (for example General Procedure G) and the deprotected compounds 44 may then be reacted further as described above.

SchmneIX Br Br R \ \. b \\ ————" | \—>| \—>|\\C | N02 H H H CI CI 0 o o/ 40 42 43 N // N 0 NW Methods for preparing IH-indolecarboxamides 51 of the ion are illustrated in Scheme X. In Scheme X, step a, indole 45 under goes a Vilsmeier—Haack reaction using methods known to one skilled in the art (for example, e #3, step A) to give aldehyde 46. The reductive amination of aldehyde 46 with 4-methoxybenzylamine (PMB) using conditions such as those bed in General Procedure H gives amine 47 (Scheme X, step b). Hydrolysis of ester 47 gives acid 48 (step c) using well known conditions such as those described in Example #3, step C or General Procedure C. Acid 48 may be converted to a primary amide 49 as shown using conditions such as those described in General Procedure D. Indole 49 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not d to, Suzuki, Buchwald, or Negishi coupling conditions as described by General Procedures A, T and U. s 50 may be ted to give methyl indoles 51 using conditions such as those described in Example #3, step F.

Scheme X ,P'V'B PMB Br Br ,0 Br NH Br NIH a b c N N N H H H H O O o o/ o o/ 0 OH 45 46 47 48 ,P'V'B PMB R. R' NH Br NIH \ <_f_ \ <_e_ \ N N H H H o NH2 0 NH2 0 NH2 51 50 49 Methods for preparing l,2,3,6-tetrahydropyrrolo[2,3-e]indolecarboxamides 58 of the invention are illustrated in Scheme XI. Nitration of 5-bromoindoline 52 (Scheme XI, step a) can be performed using conditions such as those described in Example #4, step A or known to one skilled in the art (for example, Larock, R.C. referenced above). The ing indoline 53 may be protected (Scheme XI, step b) using conditions described in Greene, T.W. and Wuts, P.G.M. referenced above (for example, a Boc ting group using ions such as those described in Example #4, step B or those described in Greene, T.W. and Wuts, P.G.M. referenced above). In Scheme XI, step C, indoline 54 is reacted with Vinylmagnesium bromide via a Bartoli indole sis using methods known to one skilled in the art to give indole 55 using conditions described in Example #4, step C. In step d, Pd—mediated cyanation of bromide 55 gives the corresponding nitrile 56 (for example Example #4, step D or Tetrahedron Letters 1999, 40(47), 8193-8195). Subsequent hydrolysis of nitrile 56 gives a primary amide 57 (Scheme XI, step 6) using s known to one d in the art (for example, General Procedure 0). The primary amide 57 may be converted to give amides 58 as shown in step f using conditions such as those described in General Procedure D or E.

Scheme XI ,BOC [Boo NH N N a b c _> —> —> \ N02 N02 H Br Br Br 52 53 54 55 N NH NH \ ._f_ \ .__e \ N N N H H H H2N O H2N 0 58 57 56 Methods for preparing benzimidazoles 64 of the invention are illustrated in Scheme XII. In step a, 4,7—dibromobenzo[c][l,2,5]thiadiazole 59 may undergo a variety of reactions known to one skilled in the art (for e, Larock, R.C. referenced above) including, but not limited to, Suzuki, Buchwald, or Negishi coupling conditions as described by General Procedures A, T and U. In step b, Pd—mediated cyanation of bromide 60 gives the corresponding nitriles 61 (for example Tetrahedron s 1999, 40(47), 8193-8195). Nitriles 61 can undergo ring opening to give diamine 62 using conditions such as those described in e #14, step C. As shown in Scheme XII, step d, the cyclization of the diamine 62 can be accomplished by reacting with aldehydes (for example, e #14, step D). Hydrolysis of nitrile 63 gives idazoles 64 (Scheme XII, step 6) using methods known to one skilled in the art such as those described in General Procedure 0.

Scheme XII Br Ru RI R: N a N b N c NH2 : :3 —> / ‘s —> / \s —> \ / \ / N N N NH2 Br Br ON ON 59 60 61 62 N \ .. \>_Ru ‘_e_ N>_R N H H2N O Methods for preparing indazoles 70 of the invention are illustrated in Scheme XIII. In Scheme XIII, step a, 2-aminochloromethylbenzoic acid [Enamine] 65 is esterified using rd conditions such as those described in General Procedure F or Larock, R.C. referenced above.

In step b, the ation of ester 66 gives indazole 67 using s known to one skilled in the art (for example, Example #18, step B or W02007/113596). Hydrolysis of ester 67 gives acid 68 (Scheme XIII, step c) using well known conditions such as those described in General Procedure C.

The acid 68 may be coverted to amide 69 as shown in step d using conditions such as those bed in General Procedure D. Indole 69 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. nced above) including, but not limited to, Suzuki, Buchwald, or Negishi coupling conditions as described by General Procedures A, T and U. Further functionalization of the R’ group in indoles 70 can be med, if desired, using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, indoles 70 containing a double bond may be reduced to saturated systems using hydrogenation conditions such as those described in General ure L. Ethers can be prepared from s 70 containing an alcohol using conditions such as those described in General Procedure Q. In addition amides, ureas, sulfonamides, aryl amines, heteroaryl amines, or sulfonyl ureas can be prepared from indoles 70 with an R' containing a primary or secondary amine (for example l Procedures D, E, I, H, and J).

Also, deprotection of the R' group in IH-indole-7—carboxamide compounds 70 to yield an unprotected compound can be med using conditions such as those described in Greene, T.W. and Wuts, P.G.M. referenced above or in General Procedures G, M, or N. For example, a protecting group such as a Boc group can be removed from a protected amine to yield the unprotected amine (for example WO 10255 General Procedure G) and the ected compounds 70 may then be reacted further as bed above.

Scheme XIII CI CI CI CI a b \ c _> \ —> /N —> N NH2 NH N H H HO 0 \O O \o o HO 0 65 66 R' CI \ e /N 4—— \/N N N H H H2N O H2N o 70 69 Methods for preparing IH-indolecarboxamide compounds 77 of the invention are illustrated in Scheme XIV. In Scheme XIV, step a, indole 71 may be tosyl (Ts) protected (Scheme I, step c) using conditions such as those described in Preparation #1 step C or those described in , T.W. and Wuts, P.G.M. or Larock, R.C. referenced above). In step b, directed lithiation of 4-fluoro-l- tosyl-1H-indolecarbonitrile 72 followed by trapping of the anion with iodine yields indole 73 using conditions such as those bed in ation #1, step D. The 4-fluoroiodo-l-tosyl-IH-indole- 7-carbonitrile 73 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Suzuki coupling ons such as those described in l Procedure A. Further functionalization of the R' group in tosyl protected carbonitriles 74 can be performed, if desired, using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, formation of amides, ethers, ureas, sulfonamides, aryl amines, heteroaryl amines, or sulfonyl ureas can be prepared from compounds 74 with an R' containing a primary or ary amine (for example General Procedures D, E, I, H, and J). Also, deprotection of the R' group in compounds 74 to yield an unprotected compound can be performed using conditions such as those described in Greene, T.W. and Wuts, P.G.M. referenced above or in General Procedures G, M, or N. For example, a protecting group such as a Boc group can be removed from a protected amine to yield the unprotected amine (for e Preparation #27, Step D or General Procedure G) and the deprotected compounds 74 may then be reacted further as described above amine. Indole carbonitriles 74 shown in step d can be reacted with amines Via displacement chemistry using conditions known to one skilled in the art such as those described in General ure B to give compounds 75. Tosyl protected olecarbonitriles 75 may be deprotected under aqueous base conditions in one step to give compound 76 using conditions such as those described in Example #12, step B or known to one skilled in the art (for example, the books from Larock, R.C. or , T.W. and Wuts, P.G.M. nced above). In step f, 1H-indole carbonitriles 76 hydrolyzed to give primary amide 77 using conditions such as those described in Preparation #2 or known to one skilled in the art (for example, the books from Larock, R.C. or Greene, T.W. and Wuts, P.G.M. referenced above). In addition, amides, carbamates, ureas, or substituted amines can be ed from IH-indolecarboxamide compounds 77 containing a y or secondary amine (for example General Procedures). Also, deprotection of 1H-indole carboxamide compounds 77 containing a protected primary or secondary amine can be performed using conditions such as those described in , T.W. and Wuts, P.G.M. referenced above or in General Procedures. For example, for R" or R’" containing a protecting group (for e a Boc group), the protecting group can be removed to yield the ected amine (for example General Procedure G) and the deprotected compounds 3 may then be reacted further as bed above.

Scheme XIV F F F F a b \ —> \ C —> \ | _> \ R' m N N N CN CN TS CN Ts 71 72 73 Rm R'" \N/R Rm \N,R \N ’R N\ R-u— kae— (:E».N 77 76 75 Methods for preparing 7-chlorothiazolo[5,4-c]pyridinecarboxamides 87 of the invention are illustrated in Scheme XV. Wittig reaction of an aldehyde 78 (step a) is performed with a triphenyl phosphonium ylide using standard conditions known to on skilled in the art, such as those described in Preparation #46, step A or Larock, R.C. referenced above, to give (X, B unsaturated methyl ester 79.

This intermediate is d with a boronate or boronic acid Via a Suzuki reaction in step b, using conditions such as those illustrated in Preparation #46, step B. Intermediate 80 is hydrolyzed to give an acid as shown in Preparation #46, step B (step c). In step d, the acid is converted to an acyl azide Via in situ formation of an acyl chloride using standard conditions such as those described Preparation #46, step D or . The acyl aZide intermediate can then undergo a Curtius rearrangement and cyclize to give a pyridone 83 in step e, under high atures (For example, Preparation #46, step E or ). On treatment with POCl3, in step f, pyridinechloride is formed (for example, Preparation #46, step F or ), which can subsequently be treated with NCS in step g, to afford a 4-bromochlorothiazolo[5,4-c]pyridine intermediate 85 as illustrated in Preparation #46, step G. sion of the bromo group in 85 to a cyano functionality is performed Via Pd-catalyzed cyanation reaction and subsequent ysis of the cyano group yields a 7-chlorothiazolo[5,4-c]pyridinecarboxamide as illustrated in Preparation #46, step H. In step j, thiazolo[5,4-c]pyridinecarboxamide 87 may undergo a variety of ons known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Suzuki, Buchwald, or Negishi coupling conditions as described by l Procedures A, T and U to give thiazolo[5,4- c]pyridinecarboxamides 88.

Scheme XV o O O o i. /\ N\ A. A0 / N O / N _C. HO / N I >—Br I \>—Br I \>_R I \>—R S S s S 78 79 80 81 CI CI i N o /|\>.R.9_N /|\>—R<—HN|S>_R_R O S Br o 85 84 83 82 / N i N / N / N\| S>—\ R —> l _.J \ R N\ S\>—R N\| S>— H2N o H2N O 86 87 88 A second alternative for the preparation of IH-pyrrolo[3,2-c]pyridinecarboxamides 39 to the route shown in scheme VIII is shown in scheme XVI, wherein lH-pyrrolo[3,2-c]pyridine carboxamides 39 can also be prepared from commercially available methyl lH-pyrrolo[3,2- c]pyridinecarboxylate 89, which is first tosylated in step a, using standard conditions known to one skilled in the art, as shown in General Procedure AH. The tosylated intermediate 90 is then oxidized (step b) using conditions such as those described in l ure AC to give an N-oxide intermediate 91. In step c the al is halogenated as illustrated in Preparation #45, step C, followed by ysis using a base, to both remove the tosyl group and hydrolyze the ester to an acid using conditions such as those described in General Procedure X. The acid can then undergo a rd amine coupling reaction as illustrated in General Procedure D, to give the amide in step e.

The pyrrolo[3,2-c]pyridine 94 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Suzuki, ld, or Negishi coupling ions as described by General Procedures A, T and U to give compounds 39. Further onalization of the R' group in pyrrolo[3,2-c]pyridines 39 can be performed, if desired, using ons known to one skilled in the art (for example, Larock, R.C. nced above). For example, pyrrolo[3,2-c]pyridines 39 containing a double bond may be reduced to saturated systems using hydrogenation conditions such as those described in General ure L. Ethers can be prepared from indoles 39 containing an alcohol using condition such as those described in General Procedure Q. In addition amides, ureas, sulfonamides, aryl amines, heteroaryl amines, or sulfonyl ureas can be prepared from indoles 39 containing a primary or secondary amine (for example l Procedures D, E, I, H, and J). Also, deprotection of indoles 39 containing a protecting group in R' can be performed using conditions such as those described in , T.W. and Wuts, P.G.M. referenced above or in General Procedures G, M, or N. For example, for R" containing a TBDMS-protected l, the protecting group can be removed to yield an unprotected alcohol (for example General Procedure M) and the ected compounds 39 may then be reacted further as described above.

SchemeXVI N \ \ * +\ N \ \ l Nl \ l/ / \ a N b / N c | M —> \//O —> ‘840 —> / N ‘/ O / O 00" " ° 5’ 0 ° ' $0 0 $611 89 90 91 92 R' CI N|\ \ ‘L "W \ .e_ "l\ \ / N / N N H H 39 94 93 A third alternative to routes shown in schemes VIII and XVI for the preparation of 1H- pyrrolo[3,2-c]pyridinecarboxamides 39 is shown in scheme XVII. In step a, (4- methoxyphenyl)methanamine is treated with dimethyl 3-oxopentanedioate to give intermediate 96, which is not isolated. In step b, it is cyclized in situ Via treatment with chloroacetaldehye using conditions such as those rated in Preparation #37, step A or WO 2005121140. De-protonation of the acidic hydrogen of 97 and reaction with methylformate, in step c, is accomplished using methods known to one skilled in the art (for example Preparation #37, step B, or WO 2005121140) to give intermediate 98. In step d, cyclization of intermediate 98 is performed using conditions such as those illustrated in Preparation #37, step C or WO 2005121140 to give the pyridinone intermediate 99. uent aromatization and halogenation of none intermediate 99 in step e is done using well known conditions (for example ation #37, step D or WO 2005121140) to give pyrrolo[3,2- c]pyridine 100. Hydrolysis of the ester functionality in 100 gives acid 93 (step f) using standard conditions such as those described in General Procedure C. The acid can then o an amine ng reaction as illustrated in General Procedure D, to give the amide in step e. The pyrrolo[3,2- c]pyridine 94 may undergo a variety of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Suzuki, Buchwald, or Negishi coupling conditions as described by General Procedures A, T and U to give compounds 39. Further functionalization of the R' group in pyrrolo[3,2-c]pyridines 39 can be performed, if desired, using reactions known to one skilled in the art (for example, Larock, R.C. nced above). For e, pyrrolo[3,2-c]pyridines 39 containing a double bond may be d to ted systems using enation conditions such as those described in General Procedure L. Ethers can be prepared from indoles 39 containing an alcohol using condition such as those described in General Procedure Q. In addition amides, ureas, sulfonamides, aryl amines, heteroaryl amines, or sulfonyl ureas can be prepared from indoles 39 containing a primary or ary amine (for example l Procedures D, E, I, H, and J). Also, deprotection of indoles 39 containing a protecting group in R' can be performed using conditions such as those described in Greene, T.W. and Wuts, P.G.M. referenced above or in General Procedures G, M, or N. For example, for R" containing a TBDMS-protected alcohol, the protecting group can be removed to yield an unprotected alcohol (for example General ure M) and the deprotected compounds 39 may then be reacted further as described above.

Scheme XVII /O O ‘0 "m" 0 NH 0 a b O O / C / ’ ’ —’ N o N 0 I | / / \ NH NH2 2 / / O\ O o o O 95 96 97 98 R' CI CI CI N’I\._hN’I\._g N/|\._f N/|\._9HN\‘\ \ N \ N \ N \ N H H H H O O H2N o H2N o HO 0 \o o \\©\O\ 39 94 93 100 99 Alternative s for preparing lH-pyrrolo[2,3-c]pyridinecarboxamides 44 of the invention are illustrated in Scheme XVIII. 4-Bromo-lH-pyrrolo[2,3-c]pyridine 101 is oxidized to the N-oxide intermediate using methods known to one skilled in the art (for example General Procedure AC). Cyanation of the N-oxide 102 in step b is accomplished using conditions such as those illustrated in General Procedure AD to give the carbonitrile 103. The carbonitrile 103 may undergo a variety of reactions known to one skilled in the art (for example, , R.C. referenced above) including, but not limited to, Suzuki, Buchwald, or Negishi coupling conditions as described by General Procedures A, T and U to give pyrrolo[2,3-c]pyridines 106. Subsequent hydrolysis of pyrrolo[2,3-c]pyridines 106 in step f, using standard conditions ( for example General Procedure 0) will yield compounds 44. Alternatively the carbonitrile 103 may first be hydrolyzed as shown in in step c to give the amide 104 when ted to known conditions (for example l Procedure 0).

The amide 104 may then undergo a y of reactions known to one skilled in the art (for example, Larock, R.C. referenced above) including, but not limited to, Suzuki, ld, or Negishi coupling conditions as described by l Procedures A, T and U to give compounds 44. Further onalization of the R' group in pyrrolo[2,3-c]pyridines 44 can be performed, if desired, using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For e, pyrrolo[2,3-c]pyridines 44 ning a double bond may be reduced to saturated systems using hydrogenation conditions such as those described in General Procedure L. Ethers can be prepared from o[2,3-c]pyridines 44 containing an alcohol using condition such as those described in General ure Q. In addition amides, ureas, sulfonamides, aryl amines, heteroaryl amines, or sulfonyl ureas can be prepared from pyrrolo[2,3-c]pyridines 44 containing a primary or secondary amine (for example General Procedures D, E, I, H, and J). Also, deprotection of pyrrolo[2,3- c]pyridines 44 containing a protecting group in R' can be performed using conditions such as those described in Greene, T.W. and Wuts, P.G.M. referenced above or in General Procedures G, M, or N.

For example, for R" containing a TBDMS-protected alcohol, the protecting group can be removed to yield an unprotected alcohol (for example General Procedure M) and the deprotected compounds 44 may then be reacted r as described above.

SchemeXVIII Br Br Br Br \ \ \ \ C \ a ® I \ I \ b" / N NI / H H CN H2N o 101 102 103 104 e d R' R' \ f \ I \ _. I \ N / N / N N H H H2N o 106 44 If desired, chiral separation of any of the chiral compounds in Schemes I may be done using methods known to one skilled in the art such as chiral preparative HPLC, chiral SFC or crystallization of diastereomeric salts.

GENERAL PROCEDURES AND ES The l synthetic schemes that were utilized to construct the majority of compounds disclosed in this application are described below in Schemes 1-34. These schemes are provided for rative purposes only and are not to be construed as limiting the scope of the ion.

Scheme 1. Suzuki Reaction of an aryl or heteroaryl halide with an aryl or heteroaryl boronic acid or boronate (General Procedure A) Rll RO\ /R' \ B R' X I —> Ru/ Scheme 2. Nucleophilic displacement of an aryl halide with an amine (General Procedure B) R'\ R" R' u x \ R / If _> Ar [Tl Scheme 3. Hydrolysis of an ester to a carboxylic acid (General Procedure C) O O R'AO’R" —’ R'AOH Scheme 4. ion of an amide from an amine and a carboxylic acid (General Procedure D) R'\ O R'\ A N )L "I R _ [i] II?" Ho R3 Scheme 5. Formation of an amide from an amine and an acid halide or anhydride (General ure E) R' o \ R'\ i T )L NI RI" X R R" R" Scheme 6. Formation of a indolecarboxamide (General Procedure F) No2 N02 A —> \ R' —> \ R' NH2 R' fi fi Ru R" Scheme 7. Acidic cleavage of a otected amine (General Procedure G) R'\'TI,BOC —> H R" R" Scheme 8. Reductive aminati0n of an aldehyde 0r ketone with a primary or secondary amine (General Procedure H) R'\ O R'\ A I H II" N R _, [Tl é" Rm R Scheme 9. Formation of a sulfonamide from an amine and a sulfonyl chloride (General Procedure I) R'\N/H (I? R\N’§‘Rm I CI/aR-u —* Io Ru 0 R" Scheme 10. Substitution of an alkyl halide with an amine nucleophile (General Procedure J) I X H —> R ‘ Eu RI / Ru RI ‘ Scheme 11. Hydrolysis of an acetonide (General Procedure K) RUIN R' 0/%o —> R'MH R". RI" Scheme 12. Hydrogenation of an alkene al Procedure L) Ru R" R/giRl" R/giRl" R' R' Scheme 13. Removal of a silyl group from an 0-silyl ether (General Procedure M) RI Rlllll Rl R\|/o. I..R"" R OH a —» + Ru Rm Ru Scheme 14. Hydrolysis of a sulfonamide (General Procedure N) R\N’R R\N’R' ‘ so 0?? H Scheme 15. Hydrolysis of a nitrile to a y amide (General Procedure 0) R R \\ ’ >=0 N H2N Scheme 16. Formation of a boronate from an aryl halide or heteroaryl halide al Procedure P) /X —> R R/B 0\ Scheme 17: Mitsunobu reaction of an alcohol (General Procedure Q) R'\T,OH Rl\||:{"\O\R"' R" Rn Scheme 18. Reduction of a nitro group to an amine using Fe (General Procedure R) \\N’9 R ,R I H2N Scheme 19. Demethylation of aryl methyl ether (General Procedure S) Ar/ \ —> Ar\OH Scheme 20. Buchwald reaction of an aryl halide or a heteroaryl halide with an amine (General Procedure T) /R' Ar\ /R' Ar’X HIT] —> [T] R R Scheme 21. Negishi cross-coupling reaction of an aryl halide or a heteroaryl halide with an organozinc (General Procedure U) ,R Ar X \ Ar/ %n —> R Scheme 22. Formation of an amide from a Boc-protected amine and a ylic acid (General Procedure V) R' R' \N,Boc \NH " | | | Ru R" R" Scheme 23. sion of a vinyl triflate to a vinyl boronate or boronic acid (General procedure F3C:g R'VQB,OR'V 0’ ‘0 —’ x A RI RII RI RII Scheme 24. Hydrolysis of an ester to a carboxylic acid under basic conditions and removal of a tosyl group from an N-tosyl protected aryl ring (General Procedure X) i F3" 0 \O N‘ _.

L/ Ts HOAL/NH Scheme 25. Iodination of a 1H- indole or a 1H-aza indole ring to give a 2-iodo-1H-indole or a 2- H-azaindole ring (General Procedure Y) )fi \ \ —> R" RIII Scheme 26. Formation of an N-Boc protected amine (General Procedure Z) '7' I N —> N RI / Ru RI / ~R" Scheme 27. Conversion of a ketone to a vinyl triflate (General Procedure AA) i FC\| —> so’éb Scheme 28. Reduction of a double bond and removal of a CBZ group from a CBZ protected amine (General Procedure AB) 9bz R" H Ru R’N\L R, \ R'" Rm R' R' Scheme 29. N-OXidation of an N containing hetero aromatic ring (General Procedure AC) RI" R N(\IR' 9 d/ 9 Ne Ru 0/ R" Scheme 30. Cyanation of an N-oxide containing heteroaryl ring al ure AD) RI" RI" R. RI \ \ | _. | 9 N® / N / 0’ Ru Ru Scheme 31. Reduction of an ester to form an alcohol (General Procedure AE) Scheme 32. Reduction of a pyridine ring to a piperidine ring (General Procedure AF) R' R \ N NH Ru R" Scheme 33. Borylation of a vinyl triflate and Suzuki reaction of the in situ formed boronate with an aryl halide (General Procedure AG) TfO W 0 /O —> A Ig R' R R" R" \ Scheme 34. Formation of an N-tosyl protected heteroaromatic ring (General Procedure AH) LIST OF GENERAL PROCEDURES General Procedure A Suzuki on of an aryl or heteroaryl halide With an aryl or aryl boronic acid or boronate General Procedure B Nucleophilic cement of an aryl halide With an amine General Procedure C Hydrolysis of an ester to a carboxylic acid General Procedure D Formation of an amide from an amine and a carboxylic acid General ure E Formation of an amide from an amine and an acid halide or anhydride General Procedure F Formation of a 4-iodoindolecarboxamide General Procedure G Acidic cleavage of a Boc-protected amine General Procedure H Reductive amination of an aldehyde or ketone With a primary or secondary amine l Procedure I Formation of a sulfonamide from an amine and a yl chloride General Procedure J Substitution of an alkyl halide With an amine nucleophile General Procedure K ysis of an acetonide General Procedure L Hydrogenation of an alkene General Procedure M Removal of a silyl group from an 0-silyl ether General Procedure N Hydrolysis of a sulfonamide General Procedure 0 ysis of a nitrile to a primary amide General Procedure P Formation of a boronate from an aryl halide or heteroaryl halide General Procedure Q Mitsunobu reaction of an alcohol General Procedure R Reduction of a nitro group to an amine using Fe General Procedure S Demethylation of aryl methyl ether General Procedure T Buchwald reaction of an aryl halide or an heteroaryl halide With an amine General Procedure U Negishi cross-coupling on of an aryl halide or a heteroaryl halide With an organozinc General ure V Formation of an amide from a Boc-protected amine and a carboxylic acid General Procedure W Conversion of a Vinyl triflate to a Vinyl boronate or boronic acid General Procedure X Hydrolysis of an ester to a carboxylic acid under basic conditions and removal of a tosyl group from an N—tosyl protected heteroaryl ring l Procedure Y Iodination of a lH— indole or a lH—aza indole ring to give a 2- iodo- lH-indole or a 2-iodo-lH-azaindole ring General Procedure Z Formation of an N-Boc protected amine General Procedure AA Conversion of a ketone to a Vinyl triflate General Procedure AB Reduction of a double bond and removal of a CBZ group from a CBZ ted amine General ure AC N—Oxidation of an N containing hetero aromatic ring General Procedure AD Cyanation of an N—oxide containing heteroaryl ring General Procedure AE Reduction of an ester to form an alcohol General Procedure AF Reduction of a pyridine ring to a piperidine ring General Procedure AG Borylation of a Vinyl triflate and Suzuki reaction of the newly formed boronate with an aryl halide General Procedure AH ion of an l protected heteroaromatic ring The following examples are ordered according to the final general procedure used in their Preparation. The synthetic routes to any novel intermediates are ed by sequentially listing the general procedure (letter codes) in parentheses after their name with additional reactants or reagents as appropriate. A worked example of this protocol is given below using Example #A.3.7 as a non- limiting illustration. Example #A.3.7 is 2-(1-acetyl-l,2,3,6-tetrahydropyridinyl)(3-(4- romethyl)benzamido)methylphenyl)-1H-indolecarboxamide, which was prepared from 2- (l-acetyl-l,2,3,6-tetrahydropyridinyl)bromo-1H-indolecarboxamide using General ure A with 4-(difluoromethyl)-N-(2-methyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolan nyl)benzamide as represented in Scheme A.

Scheme A Br O O H N General Procedure A \ O \ N —» \ N N \ H2N O / \ o o H N2 o Precursor to Example #A.3.7 i—k Example #A.3.7 Preparation #30 The precursor to Example #A.3.7, 2-(l-acetyl-l,2,3,6-tetrahydropyridinyl)bromo-1H- indolecarboxamide, was prepared (as shown in Scheme B) by reacting 4-bromoiodo-IH-indole- 7—carboxamide (Preparation #1) with l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-5,6- dihydropyridin-l(2H)-yl)ethanone, commercially available Combi-Blocks, following the conditions given in General ure A. Hence the Example #A.3.7 would be written as: Example #A.3.7 was prepared from 4-(difluoromethyl)-N—(2-methyl(4,4,5 ,5-tetramethyl- l ,3 ,2-dioxaborolan yl)phenyl)benzamide (Preparation #29) and 2-(l-acetyl-l,2,3,6-tetrahydropyridinyl)bromo-IH- indolecarboxamide (prepared using A with 4-bromoiodo-1H-indole-7—carboxamide [Preparation #1] and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridin-1(2H)-yl)ethanone [Combi-Blocks]) using General Procedure A. In the tables after a General Procedure, this is represented by having one reactant in the title of the table and one in a separate column in the same row as the product.

Scheme B \ 0‘ 0 General Procedure A \ N .. Bow \ N / HZN O 2 O Commerically available ation #1 from Combi-Blocks Precursor to Example #A.3.7 In vitro BTK kinase activity measured by time-resolved fluorescence resonance energy transfer (trFRET) The in-house BTK corresponds to inant human tic domain (aa 393 — 659), which was sed in SF9 cells with an N-terminal his tag and ed by immobilized metal affinity chromatography. BTK was mixed with peptide substrate (biotin-TYRl, Sequence: Biotin-(Ahx)- GAEEEIYAAFFA-COOH, 0.2 uM final) at varying inhibitor concentrations in reaction buffer: 50 mM MOPSO pH 6.5, 10 mM MgC12, 2 mM MnClz, 2.5 mM DTT, 0.01% BSA, 0.1 mM Na3VO4 and 0.001 mM ATP. After about 60 min incubation at room temperature, the on was quenched by addition of EDTA (final concentration: 100 mM) and developed by addition of detection reagents (final approximate concentrations: 30 mM HEPES pH 7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, 80 ng/mL PT66K (europium d anti-phosphotyrosine antibody cat KLB Cisbio, Bedford, MA) and 0.6 ug/mL SAXL (Phycolink streptavidin-allophycocyanin acceptor, cat #PJ25S, Prozyme, San Leandro, CA). The developed reaction was incubated in the dark for about 60 min at room temperature, then read via a time-resolved fluorescence detector (Rubystar, BMG) using a 337 nm laser for excitation and monitoring emission wavelength at 665 nm. Within the linear range of the assay, the observed signal at 665 nm was directly related to phosphorylated product and can be used to ate the IC50 values.

For the purpose of the Tables and Examples below, the Btk IC50 of each compound is expressed as s: A = a compound with IC50 less than 0.1},LM, B = a compound with ICsowithin the range of 0.1 uM to 1 HM, and C = a compound with a Btk IC50 within the range of 1 uM to 10 uM.

Analytical Methods Analytical data was included within the procedures below, in the illustrations of the general procedures, or in the tables of examples. Unless otherwise stated, all 1H NMR data were collected on a Varian 400 MHZ Mercury Plus, Inova, or 400-MR instrument and al shifts are quoted in parts per million (ppm). LC/MS and HPLC data are referenced to the table of LC/MS and HPLC conditions using the lower case method letter provided in Table 1.

Table 1. LCMS and HPLC methods Method Conditions a LC/MS: The gradient was 5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10 mM NH4OAc, mobile phase B was HPLC grade MeCN. The column used for the chromatography is a 4.6 X 50 mm MAC-MOD Halo C18 column (2.7 um particles). Detection methods are diode array (DAD) and evaporative light ring (ELSD) detection as well as positive/negative ospray ionization. b LC/MS: The gradient was 30-60% B in 1.50 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10mM NH4OAc, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 4.6 X 50 mm MAC-MOD Halo C8 column (2.7 um particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization. c LC/MS: The gradient was 5% B for 0.1 min, 5-100% B in 5.1 min with a hold at 100% B for 0.5 min then 100-5% B in 0.3 min (2.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 2.1 X 50 mm PhenomeneX Luna Combi-HTS C8(2) column (5 um particles) at a temperature of 55 OC. Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection under ve APCI ionization conditions. d LC/MS: The nt was 1-90% B in 3.4 min, 90-100% B in 0.45 min, 100-1% B in 0.01 min, and then held at 1% B for 0.65 min (0.8 mL/min flow rate). Mobile phase A was % TFA in water, mobile phase B was 0.018% TFA in MeCN.

The column used for the chromatography was a 2.1 X 50 mm Venusil XBP-C18 column (5 um particles). Detection s are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization. e LC/MS: The gradient was 10% B for 0.1 min, 10-100% B in 1.0 min with a hold at 100% B for 0.2 min then 100-10% B in 0.1 min (1.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water, mobile phase B was HPLC grade MeOH. The column used for the chromatography was a 2.1 X 30 mm Waters BEH C8 column Method Conditions (1.7 um particles) at a temperature of 55 OC. Detection methods are diode array (DAD) and evaporative light scattering (ELSD) ion under positive APCI ionization conditions. f LC/MS: The gradient was 5% B for 0.1 min, 5-100% B in 2.5 min with a hold at 100% B for 0.3 min then 100-5% B in 0.1 min (2.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 2.1 mm X 50 mm PhenomeneX Luna Combi-HTS C8(2) column (5 um les) at a temperature of 55 OC. ion methods are diode array (DAD) and ative light ring (ELSD) detection under positive APCI ionization conditions. g LC/MS: The gradient was 5% B for 0.1 min, 5-100% B in 2.5 min with a hold at 100% B for 0.3 min then 100-5% B in 0.1 min (2.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 2.1 X 50 mm PhenomeneX Luna Combi-HTS C8(2) column (5 um particles) at a temperature of 65 OC. ion methods are diode array (DAD) and evaporative light scattering (ELSD) detection under positive APCI ionization conditions. h LC/MS: The gradient was 10-100% MeCN (A) and 10 mM ammonium acetate in water (B) was used, at a flow rate of 1.0mL/min (0-0.1 min 10% A, 0.1-1.1 min -100% A, 1.1-1.3 min 100% A, 1.3-1.4 min 100-10% A). The column used for the chromatography was a 2.1 X 30 mm Waters BEH C8 column (1.7 um particles) at a temperature of 55 OC. Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection under positive APCI ionization conditions. i HPLC: The gradient was 5-95% B over about 10 min (25 mL/min flow rate).

Mobile phase A was 0.1% TFA in water, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 250 X 21.2 mm PhenomeneX Luna C18(2) 100A AXIA column (10 um particles). Detection method is UV at wavelengths of 220 nM and 254 nM. j LC/MS: The gradient was 5-100% B in 3.4 min with a hold at 100% B for 0.45 min, 100-5% B in 0.01 min, and then held at 5% B for 0.65 min (0.8 mL/min flow rate). Mobile phase A was 10 mM NH4HCO3, mobile phase B was HPLC grade MeCN. The column used for the chromatography is a 2.1 X 50 mm Xbridge Shield RPC18 column (5 um particles). Detection methods are diode array (DAD) and MethOd Conditions evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization. k LC/MS: The gradient was 0-60% B in 2.1 min then 60-100% B to 2.5 min, finally d to 0% B in 0.02min under this condition for 0.5 min (1 mL/min flow rate). Mobile phase A was H20 containing 0.0375% TFA, mobile phase B was MeCN containing 0.018% TFA. The column used for the chromatography is a 2.1 X 30 mm Halo C18 column (2.7 um les). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray tion.) l LC/MS: The gradient was 10-90% B in 1.15 min with a hold at 90% B for 0.4 min, 90-10% B in 0.01 min and then held at 10% B for 0.54 min (1 mL/min flow rate). Mobile phase A 0.0375% TFA in water, mobile phase B was 0.018% TFA in MeCN. The column used for the chromatography is a 2.1 X 30 mm Halo C18 column (2.7 um particles). Detection methods are diode array (DAD) and positive/negative electrospray ionization. m LC/MS: The gradient was 10-80% B in 2.0 min then 80-80% B in 0.48 min, finally changed to 10% B in 0.02 min under this condition for 0.5 min (1.0 mL/min flow rate). Mobile phase A was H20 containing % TFA, mobile phase B was MeCN ning 0.018% TFA. The column used for the chromatography is a 2.1 X 30 mm Halo C18 column (2.7 um particles). Detection methods are diode array (DAD) and positive/negative electrospray ionization. n HPLC: The gradient was 0-30% B over 25 min (80 mL/min flow rate). Mobile phase A was 0.09% TFA in water, mobile phase B was MeCN. The column used for the chromatography was a 50 X 250 mm Luna(2) C18 column (10 um particles). ion method is UV. 0 LC/MS: The gradient was 10-100% B in 3.4 min with a hold at 100% B for 0.45 min, 100-10% B in 0.01 min, and then held at 10% B for 0.65 min (0.8 mL/min flow rate). Mobile phase A was 0.0375% TFA in water, mobile phase B was 0.018% TFA in MeCN. The column used for the chromatography was a 2.1 X 50 mm Venusil XBP-C18 column (5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) ion as well as positive/negative electrospray ionization.

Method Conditions p LC/MS: The gradient was 5-100% B in 3.4 min with a hold at 100% B for 0.45 min, 100-5% B in 0.01 min, and then held at 5% B for 0.65 min (0.8 mL/min flow rate). Mobile phase A was 10 mM NH4HCO3, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 2.1 X 50 mm Xbridge Shield RPC18 column (5 um les). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization. q HPLC: The gradient was a hold at 21% B for 1 min and then 21-51% B over 7 min with a hold at 51% for 4 min (25.0 mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobile phase B was 0.075% TFA in MeCN. The column used for the chromatography was a 30 X 100 mm Luna C18 column (5 um les). Detection method is UV at wavelengths of 220 nm and 254 nm. r HPLC: The gradient was a hold at 25% B for 2 min and then 25-55% B over 12 min (25.0 mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobile phase B was 0.075% TFA in MeCN. The column used for the chromatography was a 30 X 100 mm Luna C18 column (5 um particles). Detection method is UV at wavelengths of 220 nm and 254 nm. s HPLC: The gradient was 10-38% B over 20 min (80 mL/min flow rate). Mobile phase A was 0.09% TFA in water, mobile phase B was MeCN. The column used for the chromatography was a 50 X 250 mm Luna(2) C18 column (10 um particles). ion method is UV. t HPLC: The gradient was a hold at 5% B for 1 min and then 5-35%B over 12 min (25.0 mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobile phase B was MeCN. The column used for the chromatography was a 30 X 100 mm Luna C18 column (5 um particles). Detection method is UV at ngths of 220 nm and 254 nm. u HPLC: The gradient was 7-37% B over 8 min with a hold at 37% B for 2 min (25.0 mL/min flow rate). Mobile phase A was 0.04% NH3'H20 in water, mobile phase B was MeCN. The column used for the chromatography was a 25 X 150 mm Waters Xbridge column (5 um particles). Detection method is UV at wavelengths of 220 nm and 254 nm.

V LC/MS: The gradient was 0-80% B in 3.4 min, 80-100% B in 0.45 min, 100-0% B in 0.01 min, and then held at 0% B for 0.65 min (0.8 mL/min flow rate).

Mobile phase A was 0.0375% TFA in water, mobile phase B was 0.018% TFA in Method Conditions MeCN. The column used for the chromatography was a 2.1 X 50 mm Venusil XBP-C18 column (5 um particles). ion methods are diode array (DAD) and evaporative light ring (ELSD) detection as well as positive/negative electrospray ionization.

W HPLC: The gradient was a hold at 18% B for 1 min and then 18-48% B over 12 min (25.0 mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobile phase B was MeCN. The column used for the chromatography was a 30 X 100 mm Luna C18 column (5 um particles). Detection method is UV at wavelengths of 220 nm and 254 nm.

X HPLC: The gradient was a hold at 23% B for 1 min and then 23-53% B over 12 min (25.0 mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobile phase B was MeCN. The column used for the chromatography was a 30 X 100 mm Luna C18 column (5 um particles). Detection method is UV at ngths of 220 nm and 254 nm. y HPLC: The gradient was a hold at 20% B for 1 min and then 20-35% B over 12 min (25.0 mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobile phase B was MeCN. The column used for the chromatography was a 30 X 100 mm Luna C18 column (5 um particles). ion method is UV at wavelengths of 220 nm and 254 nm. 2 HPLC: The gradient was a hold at 15% B for 1 min and then 15-45% B over 12 min (25.0 mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobile phase B was MeCN. The column used for the chromatography was a 30 X 100 mm Luna C18 column (5 um particles). Detection method is UV at wavelengths of 220 nm and 254 nm. aa HPLC: The gradient was a hold at 5% B for 0.2 min, 5-95% B over 1.7 min with a hold at 95% B for 1.3 min (2.5 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN. The column used for the chromatography was a 4.6 X 50 mm SunFire C18 column (3.5 um particles) at a temperature of 50 OC. Detection method is UV. ab HPLC: The gradient was a hold at 5% B for 0.2 min, 5-95% B over 1.7 min with a hold at 95% B for 1.4 min (2.1 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN. The column used for the chromatography was a 4.6 X 50 mm XBridge C18 column (3.5 um particles) at a temperature of 50 OC. Detection method is UV.

Method Conditions ac HPLC: The gradient was a hold at 5% B for 0.2 min, 5-95% B over 1.7 min with a hold at 95% B for 1.4 min (2.1 mL/min flow rate). Mobile phase A was 10 mM NH4HCO3, mobile phase B was MeCN. The column used for the Chromatography was a 4.6 X 50 mm XBridge C18 column (3.5 um particles) at 50 OC. Detection method is UV. ad HPLC: The gradient was 37-67% B over 23 min (80 mL/min flow rate). Mobile phase A was 0.04% O in water, mobile phase B was MeCN. The column used for the Chromatography was a 50 X 300 mm Gemini column (10 um particles). Detection method is UV at wavelengths of 220 nm and 254 nm. ae LC/MS: The gradient was 10% B for 0.1 min, 10-100% B in 1.0 min with a hold at 100% B for 0.2 min then 100-10% B in 0.1 min (1.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water, mobile phase B was HPLC grade MeCN. The column used for the Chromatography was a 2.1 X 30 mm Waters BEH C8 column (1.7 um particles) at a temperature of 55 OC. Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection under positive APCI tion conditions. af HPLC: The gradient was a hold at 10% B for 0.5 min, 20-100% B over 6.5 min, 95% B for 3 min, and then 95-10% B over 2 min (50.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water and mobile phase B was HPLC grade MeCN.

The column used for the Chromatography was a 30 X 75 mm eneX Luna C8(2) 100A AXIA column (5 um particle). Detection s were Waters 996 array detector and Alltech VareX III evaporative light-scattering detector. ag HPLC: The gradient was a hold at 10% B for 0.5 min, 40-75% B over 6.5 min, 95% B for 3 min, and then 95-10% B over 2 min (50.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water and mobile phase B was HPLC grade MeCN.

The column used for the Chromatography was a 30 X 75 mm PhenomeneX Luna C8(2) 100A AXIA column (5 um particle). Detection methods were Waters 996 diode-array detector and Alltech VareX III evaporative scattering detector. ah Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 15mL TFA in 20L H20; B: MeCN Column: Luna 100 X 30.0 mm, 5n; Flow rate: 25 mL/min; Monitor wavelength: 220&254 nm Gradient: an initial hold at 21% B for 1 min, a gradient of 21% to 51% B in 12 WO 10255 Method Conditions ai Instrument: Shimadzu P preparative HPLC Column: Synergi MaX-RP C18 250 X 80 mm id. 10 u Mobile phase: A for HZO(0.09% TFA) and B for CH3CN Gradient: B from 15% to 43% in 25 min Flow rate: 40 mL/min Injection amount: 50 mg per injection aj Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: TFA/H20=0.075% V/V; B: MECN Column: Luna C18 100 X 30.0 mm, 5n Flow rate: 25 mL/min r wavelength: 220&254nm Gradient: Time B% 0.00 10 12.0 40 14.0 40 14.2 100 16.2 100 16.4 10 18.0 10 ak Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: TFA/H20=0.075% V/V; B: MeCN Column: Luna C18 200 X 21.2 mm, 5n Flow rate: 25 mL/min Monitor wavelength: 220&254 nm Gradient: Time B% 0.00 1 12.0 8 14.0 8 14.2 100 16.2 100 16.4 1 WO 10255 Method Conditions 18.0 1 al Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 15mL TFA in 20L H20; B: MeCN Column: Luna 100 X 30.0 mm,5u Flow rate: 25 mL/min Monitor wavelength: 220&254 nm Gradient: an initial hold at 8% B for 1 min, a gradient of 8% to 38% B in 12 min am Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: TFA/H20=0.075% v/v; B: MeCN Column: Luna C18 100 X 30.0mm, 5n Flow rate: 25 mL/min Monitor wavelength: 220&254 nm Gradient: Time B% 0.00 18 8.00 48 12.0 48 12.1 100 13.6 100 13.7 18 14.7 18 an Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 8 mL NH3.H20 in 20 L H20; B: MeCN Column: waters Xbridge130 X 21.2 mm,5u Flow rate: 25 mL/min Monitor wavelength: 4 nm Gradient: an initial hold at 27% B for 1min, a gradient of 27% to 57% B in 12 min a0 Instrument: zu LC-8A preparative HPLC Column: Luna(2) C18 250 X 50 mm id. 10 u Mobile phase: A for H20 (0.09%TFA) and B for CH3CN Gradient: B from 82% to 82% Flow rate: 100 mL/min Injection amount: 0.7 g per injection Method Conditions ap HPLC: The gradient was a hold at 10% B for 0.5 min, 10-50% B over 6.5 min, 50-80% over 5 min, 80-100% over 0.5 min, with a hold at 100% B for 0.5 min (40 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was MeCN. The column used for the chromatography was a 30 X 75 mm e C8 column (5 um particles) at t temperature. Detection method is UV. aq HPLC: The gradient was a hold at 10% B for 0.5 min, 10-50% B over 3.5 min, 50-80% over 4 min, 80-100% over 1.0 min, with a hold at 100% B for 2.0 min (40 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was MeCN. The column used for the tography was a 30 X 75 mm SunFire C8 column (5 um particles) at ambient temperature. Detection method is UV. ar LC/MS: The gradient was a hold at 5% B for 0.2 min, 5-95% B over 1.7 min with a hold at 95% B for 1.3 min (2.3 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN. The column used for the chromatography was a 4.6 X 50 mm XBridge C18 column (3.5 um particles) at a temperature of 50 OC. Detection methods are diode array (DAD) under positive APCI ionization conditions. as LC/MS: The gradient was 5—60% B in 1.50 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10mM NH4OAc, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 4.6 X 50 mm MAC-MOD Halo C8 column (2.7 um particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection as well as ve/negative electrospray ionization. at LC/MS: The gradient was 5-95% B over 1.2 min, with a hold at 95% for 1.3 min, back to 5% over 0.01 min (2.0 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN. The column used for the chromatography was a 4.6 X 50 mm SunFire C18 column (3.5 um particles) at 50 C. Detection method is UV au LC/MS: The gradient was 5-95% B over 1.3 min, with a hold at 95% for 1.5 min, back to 5% over 0.01 min (1.8 mL/min flow rate). Mobile phase A was 0.01% ammonium acetate in water, mobile phase B was MeCN. The column used for the chromatography was a 4.6 X 50 mm e C18 column (3.5 um particles) at 50 C. Detection method is UV Method Conditions av LC/MS: The gradient was 5-100% B over 1.2 min, with a hold at 100% for 1.3 min (2.0 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN. The column used for the chromatography was a 4.6 X 50 mm Sunfire C18 column (3.5 um les) at 50 C. Detection method is UV and MS aw LC/MS: The gradient was 5-95 % B over 1.3 min, with a hold at 95% for 1.5 min (1.8 mL/min flow rate). Mobile phase A was 0.01% ammonium acetate in water, mobile phase B was MeCN. The column used for the chromatography was a 4.6 X 50 mm Xbridge C18 column (3.5 um particles) at 50 C. Detection method is UV and MS aX LC/MS: The nt was 5-100% B over 1.3 min (2.0 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN.

The column used for the chromatography was a 4.6 X 50 mm Sunfire C18 column (3.5 um particles) at 45 C. Detection method is UV and MS LC/MS: The gradient was 5-100% B over 1.2 min, with a hold at 95% for 1.3 min ay (2.0 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN. The column used for the chromatography was a 4.6 X 50 mm Sunfire C18 column (3.5 um particles) at 50 C. Detection method is UV and MS az LC/MS: The nt was 5-100% B over 1.2 min, with a hold at 100% for 1.3 min (2.0 mL/min flow rate), then down to 95% over 0.01 min. Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN. The column used for the chromatography was a 4.6 X 50 mm Sunfire C18 column (3.5 um particles) at 50 C. Detection method is UV and MS ba LC/MS: The gradient was 5-60% B in 1.50 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 0.1% formic acid in water, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 4.6 X 50 mm MAC-MOD Halo C18 column (2.7 um les). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization. bb LC/MS: The gradient was 5-60% B in 0.60 min then 60-95% B to 1.00 min with a hold at 95% B for 0.30 min (1.3 mL/min flow rate). Mobile phase A was 10 mM ammonium acetate, mobile phase B was HPLC grade MeCN. The column used for the chromatography was a 2.1X50 mm ACE EXcel 2 UHPLC C18 column (2.0 Method Conditions um particles). ion methods were diode array (DAD) and ative light scattering (ELSD) detection as well as positive/negative electrospray ionization. bc ment Gilson 281( PHG008) Column: waters X-bridge ODS C 18 19 X 250mm,10 um Mobile Phase: A: water (10ppM NH4HC03); B: ACN Flow Rate: 30 mL/min Monitor wavelength: 220 & 254 nm Gradient: 10-60% B in 8 min ,stop at 15min bd HPLC: The column used for the chromatography was a 21.2 X 250 mm Hypersil C18 HS column (8 mm particles). The gradient was 40 % B for 4 min, 40-65 % B over 30 min (21 mL/min flow rate). Mobile phase A was 0.05 N aqueous NH4OAc buffer (pH 4.5) and mobile phase B was HPLC grade MeCN. Detection method is UV, 1 = 254 nm be LC/MS: The gradient was 5-100% B over 1.2 min, with a hold at 100% for 1.3 min, then back down to 5% over 0.01 min (2.0 mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN. The column used for the chromatography was a 4.6 X 50 mm Sunfire C18 column (3.5 um les) at 50 C. Detection method is UV and MS Table 2. Chiral HPLC methods Method Conditions 1 The gradient was 20% B in 15.25 min then 20-65% B in 0.05 min and held at 65%B for 6.70min. Then equilibrated back down to 20% and held for 4min. (20 mL/min flow rate). Mobile phase B was 1:1 EtOH/MeOH and mobile phase A was HPLC grade heptane with 0.12% diethylamine added. The column used for the chromatography was a Daicel IA, 20 X 250 mm column (5 um particles).

Detection method was UV Ox, = 264 nm) The method was isocratic 25% B for 25 min (20 mL/min flow rate). Mobile phase B was EtOH and Mobile phase A was HPLC grade heptane with no modifier added. The column used for the chromatography was a Daicel IA, 20 X 250 mm column (5 um particles). Detection methods were evaporative light scattering (ELSD) detection and UV Ox, = 312 nm) Method Conditions .2 min (20 mL/min flow rate). Mobile phase B was EtOH (200 proof), mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The column used for the chromatography was a WhelkOl R,R 21X250 mm column from Regis Technologies (5 um particles).

C). Co-solvent B was 1:1 HPLC grade EtOh:MeCN with 0.1% triethylamine added. t A was SFC grade C02. The column used for the tography was a 30 X 250 mm Daicel Chiralpak AS-H (5 um particles). 6 min (20 mL/min flow rate). Mobile phase B was EtOH (200 proof), mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The column used for the chromatography was a WhelkOl R,R 21X250 mm column from Regis Technologies (5 um particles). stereoisomer (20 mL/min flow rate). Mobile phase B was EtOH (200 proof), mobile phase A was HPLC grade e with 0.2% diethylamine added. The chromatography used a Daicel IA, 21 X 250 mm column (5 um les). mL/min flow rate). Mobile phase B was EtOH (200 proof), mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The chromatography used a Daicel IE, 20 X 250 mm column (5 um les). hold for 4 min (20 mL/min flow rate). Mobile phase B was EtOH (200 proof), mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The chromatography used a Daicel IE, 20 X 250 mm column (5 um particles). mL/min flow rate). Mobile phase B was EtOH (200 proof), mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The chromatography used a Daicel IC, 20 X 250 mm column (5 um particles).

EtOH (200 proof), mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The chromatography used a Daicel IC, 20 X 250 mm column (5 um particles).

Method Conditions mL/min flow rate). Mobile phase B was 200 proof EtOH, mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The column used for the chromatography was a WhelkOl S,S 2lX250 mm column from Regis Technologies (5 um particles). mL/min flow rate). Mobile phase B was HPLC grade IPA, mobile phase A was HPLC grade e with 0.2% lamine added. The column used for the chromatography was a Daciel IC 20X250 mm column (5 um les). mL/min flow rate). Mobile phase B was HPLC grade IPA, mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The column used for the chromatography was a Daciel IF 20X250 mm column (5 um particles).

EtOH (200 proof), mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The chromatography used a Daicel IB, 20 X 250 mm column (5 um particles). for 10 min (20 mL/min flow rate). Mobile phase B was EtOH (200 proof), mobile phase A was HPLC grade heptane with no modifier added. The column used for the chromatography was a l S,S 2lX250 mm column from Regis Technologies (5 um particles).

HPLC grade MeCN, mobile phase A was HPLC grade water with no modifier added. The chromatography used an Astec, Chirobiotic T 21.2 X 250 mm column (5 um particles). mL/min flow rate). Mobile phase B was 200 proof EtOH, mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The column used for the chromatography was a Daicel IF, 20 X 250 mm column (5 um particles). 200 proof EtOH, mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The column used for the chromatography was a Daicel IB, X 250 mm column (5 um particles).

Conditions (LC) Isocratic 20% B for 30 min (20 mL/min flow rate). Mobile phase B was 200 proof EtOH, mobile phase A was HPLC grade heptane with 0.2% diethylamine added. The column used for the chromatography was a Daicel IE, x 250 mm column (5 um particles).

General Purification Methods For the general procedures, the final compounds may be purified by any technique or combination of ques known to one skilled in the art. Some examples that are not limiting include column chromatography with a solid phase (Le. silica gel, alumina, etc.) and a solvent (or ation of solvents) that elutes the desired compounds (Le. hexanes, heptane, EtOAc, DCM, MeOH, EtOH, MeCN, water, etc.); preparatory TLC with a solid phase (Le. silica gel, alumina etc.) and a solvent (or combination of solvents) that elutes the desired compounds (Le. hexanes, heptane, EtOAc, DCM, MeOH, EtOH, MeCN, water, etc.); reverse phase HPLC (see Table 1 for some non-limiting conditions); recrystalization from an appropriate solvent (Le. MeOH, EtOH, IPA, EtOAc, toluene, etc.) or combination of solvents (Le. EtOAc/heptane, EtOAc/MeOH, etc.); chiral LC with a solid phase and an appropriate solvent (Le. EtOH/heptane, MeOH/heptane, IPA/heptane, etc. with or without a modifier such as diethylamine, TFA, etc.) to elute the d compound; chiral SFC with a solid phase and C02 with an appropriate modifier (Le. MeOH, EtOH, IPA with or t additional modifier such as diethylamine, TFA, etc.); precipitation from a combination of ts (Le.

DMF/water, DMSO/DCM, EtOAc/heptane, etc.); trituration with an appropriate solvent (Le. EtOAc, DCM, MeCN, MeOH, EtOH, IPA, n-PrOH, etc.); extractions by dissolving a compound in a liquid and washing with an appropriately immiscible liquid (Le. DCM/water, EtOAc/water, turated NaHCO3, EtOAc/saturated , DCM/10% aqueous HCl, EtOAc/10% aqueous HCl, etc.); distillation (Le. simple, onal, Kugelrohr, etc.); gas chromatography using an appropriate ature, carrier gas and flow rate; sublimation at an riate temperature and pressure; filtration through a media (Le. Florosil®, alumina, Celite®, silica gel, etc.) with a solvent (Le. heptane, hexanes, EtOAc, DCM, MeOH, etc.) or combination of solvents; salt formation with solid support (resin based, Le. ion exchange) or without. Some descriptions of these techniques can be found in the following nces, Gordon, A. J. and Ford, R. A. "The Chemist’s Companion", 1972; os, D.

R. "Experimental Organic Chemistry", 2000; Still, W. C., Kahn, M. and Mitra, A. J. Org. Chem. 1978, 43, 2923; Yan, B. sis and Purification Methods in Combinatorial Chemistry" 2003; Harwood, L. M., Moody, C. J. and Percy, J. M. "Experimental Organic Chemistry: Standard and Microscale, 2nd Edition", 1999; Stichlmair, J. G. and Fair, J. R. "Distillation; Principles and Practices" 1998; Beesley T. E. and Scott, R. P. W. l Chromatography", 1999; Landgrebe, J. A. "Theory and Practice in the Organic Laboratory, 4th Edition", 1993; Skoog, D. A. and Leary, J. J. "Principles WO 10255 of mental Analysis, 4th Edition" 1992; Subramanian, G. "Chiral Separation Techniques 3rd Edition" 2007; KazakeVich, Y. and Lobrutto, R. "HPLC for Pharmaceutical ists" 2007. Final or intermediate compounds prepared Via any of the following General Procedures can be optionally purified using one or more of the purification methods described above.

Preparations and es The general synthetic methods used in each General Procedure follow and e an illustration of a compound that was synthesized using the designated l Procedure. None of the specific conditions and reagents noted herein are to be construed as limiting the scope of the invention and are provided for illustrative purposes only. All starting materials are commercially available from Sigma- Aldrich ding Fluka and Discovery CPR) unless otherwise noted after the chemical name.

Reagent/reactant names given are as named on the commercial bottle or as generated by IUPAC conventions, CambridgeSoft® ChemDraw Ultra 9.0.7, CambridgeSoft® Chemistry E-Notebook V9.0.127 or V11.0.3.68, or AutoNom 2000. Compounds designated as salts (e.g. hydrochloride, acetate) may contain more than one molar equivalent of the salt. nds of the invention where the absolute stereochemistry has been determined by the use of a commercially available enantiomerically pure starting material or a stereochemically defined intermediate, or by X-ray diffraction are d by an asterisk after the example number. ation #1. 4-Br0moi0d0-1H-indolecarb0xamide \ | o NH2 Step A: 4-Br0m0-1H-ind01ecarb0xylic acid Br Br —> \ No2 H O OH O OH To a solution of 4-bromonitrobenzoic acid (30 g, 122 mmol) in anhydrous THF (500 mL) a on of Vinylmagnesium bromide (51.2 mL, 512 mol, 1 N) in THF was added se at about -30 to -50 OC. The reaction mixture was stirred at about -30 to -40 0C for about 2 h. Then the reaction mixture was poured into saturated aqueous NH4Cl solution and the mixture was extracted with EtOAc (200 mL X 2). The combined organic layers were washed with brine, dried over andydrous NaZSO4, filtered and concentrated under reduced pressure to provide 4-br0m0-1H—indolecarb0xylic acid (33 g crude), which was used directly for next step without further purification. 1H NMR (400 MHZ, DMSO-d6) 8 11.42 (m, 1H), 8.11 (bs, 1H), 7.63 (dd, J = 17.4, 8.0 Hz, 1H), 7.45 (dt, J = 14.2, 2.8 Hz, 1H), 7.32 (dd, J = 21.9, 8.0 Hz, 1H), 6.47 (ddd, J = 25.5, 3.1, 2.1 Hz, 1H).

Step B: Methyl 4-br0m0-1H-ind01ecarb0xylate \ —> N H O OH (I) To a solution of 4-bromo-1H—indolecarboxylic acid (33 g, 137 mmol) in DMF (300 mL), Cs2C03 (90 g, 276 mmol) was added and stirred at rt for 1 h. Then thane (29.3 g, 206 mmol) was added se at about 0 OC. The reaction mixture was warmed to rt for about 3 h. The mixture was poured into water and extracted with EtOAc (200 mL X 2). The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and trated under reduced pressure and the residue was purified by silica gel column chromatography to provide methyl 4-br0m0-IH- indole-7—carb0xylate (13.8 g, 20%): 1H NMR (CDCl3) 8 9.98 (s, 1H), 7.76-7.74 (d, J: 8, 1H), 7.39- 7.34 (m, 2H), 6.68-6.66 (m, 1H), 4.00 (s, 3H).

Step C: Methyl 4-br0m0t0syl-1H-ind01ecarb0xylate Br Br \ \ u N O O O O | | To a solution of methyl o-1H—indolecarboxylate (130 g, 512 mmol) in anhydrous THF (1500 mL) was added NaH (18.4 g, 767 mmol) in portions at about 0 OC and d for about 1 h at 0 OC. Then TsCl (117 g, 614 mmol) was added in portions at about 0 OC. The reaction mixture was warmed to rt for about 2 h. The reaction mixture was poured into ice water and extracted with EtOAc (1000 mL X 2). The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography to provide methyl 4-br0m0-I-t0syl-1H-indolecarb0xylate (150 g, 72%): 1H NMR (CDCl3) 8 7.60-7.58 (d, J: 8.4, 2H), 7.54-7.53 (d, J: 3.6, 1H), .44 (d, J: 8, 1H), 7.37-7.35 (d, J: 8.4, 1H), 7.21-7.18 (d, J: 8.4, 2H), 6.77-6.76 (m, 1H), 3.93 (s, 3H), 2.35 (s, 3H).

Step D: Methyl 4-br0m0i0d0t0syl-1H-ind01ecarb0xylate Br Br 8 TS To a solution of diisopropylamine (6.2 g, 61.2 mmol) in anhydrous THF (100 mL), d in t-BuLi (3.92 g, 61.2 mmol) in pentane was added at about 0 0C under N2 atmosphere, and the mixture was stirred for about 10 min. The solution of methyl 4-bromotosyl-1H-indolecarboxylate (10 g, 24.49 mmol) in anhydrous THF (100 mL) was added at about -70 0C under N2 atmosphere. After about 30 min, a on of 12 (9.33 g, 36.7 mmol) in anhydrous THF (50 mL) was added. After about min, the cooling bath was removed and the mixture was stirred for about another hour. The mixture was quenched with saturated aqueous Na2S203. Water and EtOAc were added to the mixture.

The layers were separated and the aqueous layer was extracted with EtOAc (300 mL X 2). The combined organic layers were washed with brine, dried with anhydrous Na2S04, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to e methyl 4-br0m0i0d0t0syl-1H-indolecarb0xylate (7.5 g, 38%): 1H NMR (CDCl3): 5 7.64-7.59 (m, 2H), 7.55-7.53 (m, 2H), .27 (m, 2H), 7.17-7.17 (m, 1H), 4.06-4.05 (d, J: 1.2, 3H), 2.49 (s, 3H).

Step E: 4-Br0m0i0d0-1H-ind01ecarb0xylic acid \ I \ —> I \ N Ts H O (I) o OH To a solution of methyl 4-bromoiodotosyl-1H—indolecarboxylate (75 g, 23.4 mmol) in MeOH (750 mL), THF (1500 mL) and water (750 mL), LiOH (67 g, 280 mmol) was added the the reaction mixture was heated at about 45 0C for about 3 h. The resulting solution was concentrated under reduced pressure to remove MeOH and THF, then the solution was adjusted to pH = 6 to 7 with HCl (1 N), the precipitate was filtered and dried by high vacuum to provide 4-br0m0i0d0-1H-indole carboxylic acid (45 g, 88%): 1H NMR d6) 8 11.60 (s, 1H), 7.56 (d, J = 8.0, 1H), 7.31 (m, J = 8.0, 1H) , 6.72 (s, 1H).

Step F: 4-br0m0i0d0-1H-ind01ecarb0xamide Br Br \ \ I . I H N O OH O NH2 To a solution of oiodo-1H-indolecarboxylic acid (45 g, 123 mmol) in DMF (450 mL) was added HOBt (28.2 g, 184 mmol), PyBOP (96 g, 184 mmol), NH4Cl (10 g, 184.5 mmol) and DIEA (63.6 g, 492 mmol). The reaction mixture was stirred at rt for about 2 h. Water was added, the reaction mixture was extracted with EtOAc (1000 mL X 2), the organic phase was dried with anhydrous NaZSO4 and concentrated under reduced re and the residue was purified by column chromatography with Pet ether : EtOAc (20:1 to 1:1) to provide 0i0d0-1H—indole carboxamide (25 g, 56%): 1H NMR (DMSO-d6) 8 11.62 (s, 1H), 8.24 (s, 1H), .60 (d, J = 8, 2H), 7.38-7.36 (d, J: 8, 1H), 6.77 (s, 1H): LC/MS (Table 1, Method d) R, = 3.07 min; MS m/z: 366 (M-H)".

Preparation #2. 4-Br0mo-1H-ind01ecarb0xamide IZ H I I O NH2 To a solution of 4-bromo-1H-indolecarbonitrile (3 g, 13.57 mmol, Sinova) in EtOH (36.2 mL)/DMSO (9.05 mL) was slowly added added hydrogen peroxide (28.0 mL, 274 mmol) and NaOH (28.0 mL, 28.0 mmol). The reaction mixture was stirred at rt for about 1 h. Water was added and the itate was collected by filtration, washed with water, and dried under vacuum to provide 4- bromo-IH—indolecarb0xamide (2.85 g, 88%). LC/MS (Table 1, Method f) R = 1.42 min; MS m/Z: 280 (M+MeCN)+.

Preparation #3. 2-(2-Methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)phenyl)-3,4- dihydroisoquinolin-1(2H)-0ne To a solution of 2,3-dihydro-1H-indenone (30 g, 227 mmol) in DCM (300 mL) was added methanesulfonic acid (300 mL) and the solution was cooled to about 0 OC. Sodium aZide (30 g, 461 mmol) was added to the solution in portions at about 0 OC and the reaction mixture was stirred overnight at rt. The reaction e was neutralized with 20% aqueous NaOH and extracted with DCM (2 X 1 L). The organic phase was dried with anhydrous NaZSO4 and trated to give a residue, which was ed by column chromatography on silica gel to provide 3,4- dihydroisoquinolin-I(2H)-0ne (5 g, 15%): 1H NMR (MeOD) 5 7.93-7.91 (m, 1H), 7.49-7.45 (m, 1H), 7.36-7.45 (m, 1H), 7.28-7.26 (d, 1H), 3.50-3.46 (t, 2H), .94 (t, 2H).

Step B: 2-(3-Br0m0methylphenyl)-3,4-dihydr0is0quin01in-1(2H)-0ne loo N —> or 0 Br A mixture of 3,4-dihydroisoquinolin-1(2H)-one (3.5 g, 13.6 mmol), 1,3-dibromomethylbenzene (17.5 g, 70.5 mmol) and K2C03 (9.85 g, 71.3 mmol) in DMSO (40 mL) was purged with N2, treated with CuI (1.75 g, 9 mmol) and heated to about 160 0C for about 4 h. The reaction mixture was diluted with DCM and filtered through Celite®. The filtrate was washed with 5% ammonia hydroxide, dried and concentrated. The residue was purified by column chromatography on silica gel to provide 2-(3- bromo-Z-methylphenyl)-3,4-dihydr0is0quinolin-I(2H)-0ne (6 g, 80%): 1H NMR (CDCl3) 5 8.16-8.14 (d, 1H), 7.56-7.54 (d, 2H), 7.49-7.41 (t, 1H), 7.26 (d, 1H), 7.25-7.18 (d, 1H), 7.15-7.13 (d, 1H), 3.98- 3.92 (m, 1H), 3.76-3.70 (m, 1H), .22 (m, 1H), 3.13-3.07(m, 1H) 2.36 (s, 3H).

Step C: 2-(2-Methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)phenyl)-3,4- dihydroisoquinolin-1(2H)-0ne To a mixture of romomethylphenyl)-3,4-dihydroisoquinolin-1(2H)-one (4.6 g, 14.6 mmol), bis(pinacolato)diboron (8.8 g, 34.6 mmol) and CH3COOK (9 g, 91.8 mmol) in 1, 4-dioxane (100 mL) and DMSO (20 mL), PdClZ (dppf) (1 g, 1.4 mmol) was added. The reaction mixture was heated at about 120 OC overnight under N2 protection. After cooling to ambient temperature, the reaction mixture was filtered through Celite® the solid was washed with EtOAc, and the filtrate was washed with water and brine, dried over Na2S04, concentrated and the e was purified by column chromatography on silica gel to provide 2-(2-methyl(4,4,5,5-tetramethyl-I,3,2-di0xab0rolan yl)phenyl)-3,4-dihydr0is0quinolin-I(2H)-0ne (1.5 g, 28%): 1H NMR (CDCl3) 5 8.19-8.17 (dd, 1H), 7.80-7.78 (dd, 1H), 7.51-7.47 (t, 1H), .38 (t, 1H), 7.32-7.25 (m, 3H), 3.96-3.89 (m, 1H), 3.77- WO 10255 3.71 (m, 1H), 3.27-3.23 m, 1H), 3.14-3.08 (m, 1H), 2.50 (s, 3H), 1.36 (s, 12H); LC/MS (Table 1, Method 0) R = 3.34 min; MS m/Z: 364 (M+H)+.

Preparation #4. ethyl(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)phenyl)thiazole carboxamide (:1NH2 aNWo _> To a solution of 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (1.9 g, 8.15 mmol, CombiBlocks) in DCM (50 mL), DIEA (2.1 g, 16.3 mmol) and HATU (4.03 g, 10.6 mmol) were added at rt. After about 5 min, thiazolecarboxylic acid (1.9 g, 8.15 mmol) was added and the solution was stirred for about 3 h at rt. The reaction mixture was poured into water, extracted with DCM (100 mL X 2) and the organic phase was washed with brine, dried with anhydrous NaZSO4 and concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc = 10:1 to 3:1) to provide N—(2-methyl(4,4,5,5-tetramethyl- 1,3,2-di0xab0rolanyl)phenyl)thiazole-Z-carboxamide (1 g, 36%): 1H NMR (CDCl3) 5 9.07 (s, 1H), 8.16-8.14 (d, J: 8 Hz, 1H), 7.87-7.86 (t, J: 3.2 Hz, 1H), .55 (m, 2H), 7.20-7.18 (m, 1H), 2.53 (s, 3H), 1.29 (s, 12H).

Preparation #5. 1-Methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)pyridin-2(1H)-0ne ido:{g_\ N \ Step A: 5-Br0m0methylpyridin-2(1H)-0ne Ho —» wooN N To a solution of opyridinol (4 g, 23 mmol) in THF (200 mL) at about 0 0C was added NaH (0.83 g, 34.7 mmol) in portions. The reaction mixture was stirred at rt for about 15 min followed by addition of iodomethane (9.8 g, 69 mmol). The mixture was stirred overnight at rt. After the tion of the reaction (TLC monitoring), the reaction mixture was cooled to about 0 OC, water was added, extracted with EtOAc (100 mL X 2). The organic layer was washed with brine, dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to e 5-br0m0 methylpyridin-Z-(IH)-0ne (3 g, 69%): 1H NMR (MeOD) 5 7.87 (s, 1 H), 7.58-7.55 (m, 1 H), 6.47 (d, J: 9.6 Hz, 1 H), 3.53 (s, 3 H).

Step B: l-Methyl-S-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)pyridin-2(1H)-0ne \ moo To a mixture of 5-bromomethylpyridin-2(1H)-one (1.0 g, 5.32 mmol), KOH (0.78 g, 7.98 mmol) and bis(pinacolato)diboron (0.162 g, 6.38 mmol) in oxane (20 mL), tricyclohexylphosphine (149 mg, 0.532 mmol), Pd2dba3 (487 mg, 0.532 mmol) were added under N2 atmosphere. The mixture was stirred at about 80 0C for about 5 h. Then water was added, the aqueous layer was extracted with EtOAc (50 mL X 2), and the organic layer was dried over ous NaZSO4, concentrated under reduced pressure and the residue was purified by column chromatograph on silica gel to provide I-methyl(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)pyridin-2(1H)-0ne (0.80 g, 64%): 1H NMR (CDCl3) 8 7.70 (s, 1 H), 7.54 (d, J: 8.8 Hz, 1 H), 6.47 (d, J: 8.8 Hz, 1 H), 3.49 (s, 3 H), 1.24 (s, 12 H).

Preparation #6. 4-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-Z-yl)phenylamin0)pyrimidine carbonitrile B709% \N | , CI N/)\\ HN \N \ NH Hm 2 N /N To a microwave Vial was added 4-chloropyrimidinecarbonitrile (100 mg, 0.717 mmol, CombiPhos), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (314 mg, 1.433 mmol), and N- N—isopropylpropanamine (0.250 mL, 1.433 mmol) in MeCN (7mL). The Vial was sealed and heated in a microwave at about 150 0C for about 20 min with stirring. The reaction mixture was cooled to rt and the t removed under a warm stream of en. The residue was dissolved in DCM (10 mL) and washed with water (10 mL). The mixture was separated using a Biotage phase separator and the organics were concentrated in vacuo to afford the crude product. The crude product was added to a silica gel column and was eluted with 10-60% EtAcO/heptane to provide 4-(3- (4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)phenylamin0)pyrimidine-Z-carb0nitrile (0.11 g, 48%): LC/MS (Table 1, Method f) R = 1.89 min; MS m/Z: 323 (M+H)+.

Preparation #7. N-(3-(3-aminocarbamoyl-1H-indolyl)methylphenyl)thiazole carboxamide H2N 0 Step A: o-1H-indolecarboxylic acid Br Br \ \ N N H H \o 0 HO 0 To a on of methyl 4-bromo-1H-indolecarboxylate (6 g, 23 mmol, Preparation #1 step B) in THF (300 mL), water (60 mL) and MeOH (60 mL) was added lithium hydroxide (2.83 g, 118 mmol).

Then the mixture was heated to reflux overnight. After cooling to rt, the solvent was removed under reduced pressure, the aqueous layer was acidified by addition of 4 N HCl to about pH 6. The precipitate was filtered, and the solid was dried to provide 0-1H-indolecarb0xylic acid (5.5 g, 97%): 1H NMR (DMSO-d6) 8 11.39 (br, 1H), .63 (d, J = 8.0 Hz, 1H), 7.46-7.44 (m, 1H), 7.33-7.31 (d, J: 8.0 Hz, 1H), 6.49-6.48 (m, 1H).

Step B: 4-Bromo-1H-indolecarboxamide Br Br \ \ N N HO O H2N O A solution of 4-bromo-1H—indolecarboxylic acid (5.5 g, 22.91 mmol) EDC (6.59 g, 34.4 mmol) and HOBt (5.26 g, 34.4 mmol) in THF (150 mL) and DCM (180 mL) was stirred at rt for 1 h. The mixture was then bubbled with NH3 gas for about 15 min and the resulting mixture was stirred at rt overnight. The mixture was diluted by addition of water and extracted with DCM. The organic phase was washed with brine, dried and concentrated to give a residue, which was suspended in ether and filtered to provide 4-br0m0-1H-indolecarb0xamide (5.3 g, 97%): 1H NMR (DMSO-d6) 8 11.40 (br, 1H), 8.08 (br, 1H), 7.29-7.57 (d, J = 7.6 Hz, 1H), 7.43-7.42 (m, 2H), 7.28-7.26 (d, J = 7.6 Hz, 1H), 6.43-6.42 (m, 1H).

WO 10255 Step C: 4-Br0m0nitr0-1H-indolecarb0xamide Br Br \ \ N N H H H2N o H2N 0 To a solution of 4-bromo-1H-indolecarboxamide (5.3 g, 22.17 mmol) and AgNO3 (11.30 g, 66.5 mmol) in CH3CN (100 mL) was added benzoyl chloride (9.35 g, 66.5 mmol) in CH3CN (20 mL) at about 0 OC and the mixture was stirred at about 0 0C for 1 h in the dark. Water and EtOAc was added.

The organic phase was concentrated to give a residue which was washed with DCM to e 4- bromo-S-nitro-IH—indolecarb0xamide (2.6 g, 41%): 1H NMR (DMSO-d6) 5 12.46 (br, 1H), 8.39- 8.38 (d, J = 3.6 Hz, 1H), 8.33 (br, 1H), 7.77-7.73 (m, 2H), 7.67-7.62 (m, 1H). LC/MS (Table 1, Method l) R = 2.41 min; MS m/Z: 285 (M+H)+.

Step D: N-(3-(7-Carbamoylnitr0-1H-indolyl)methylphenyl)thiazolecarb0xamide [JYONS N02 0 ’ C \ N H2N 0 To a solution of 4-bromonitro-1H-indole-7—carboxamide (4 g, 14 mmol), N—(2-methyl(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)phenyl)thiazolecarboxamide (5.8 g, 16.9 mmol, Preparation #4) in 1,4-dioxane (100 mL) and water (25 mL) was added Pd(PPh3)4 (0.81 g, 0.7 mmol) and CsF (6.4 g, 42 mmol) and the mixture was stirred at about 120 OC overnight under N2. After cooling to rt, the e was diluted by addition of water and extracted with EtOAc. The organic phase was dried and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Table 1, Method ah) to provide crude N-(3-(7-carbamoylnitr0-1H—indolyl)methylphenyl)thiazole-Z- carboxamide (2 g, 33%): LC/MS (Table 1, Method l) R = 1.44 min; MS m/Z: 422 (M+H)+.

Step E: N-(3-(3-Amin0carbam0yl-1H-indolyl)methylphenyl)thiazolecarboxamide Qxfo/ l" Qxfo/ l" HN HN O 0 N02 —> NH2 0 \ O \ N N H H H2N o H2N 0 2014/044247 To a on of N—(3-(7-carbamoylnitro-lH-indolyl)methylphenyl)thiazolecarboxamide (0.20 g, 0.48 mmol) in EtOH (20 mL) was added Raney Ni (0.10 g) and the mixture was stirred at rt under H2 50 psi for about 6 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide crude N—(3-(3-amin0carbamoyl-IH—indolyl) methylphenyl)thiazole-Z-carboxamide (0.11 g, 59%) which was used without further purification: LC/MS (Table 1, Method l) R = 1.54 min; MS m/z: 392 (M+H)+.

Preparation #8. 4-Hydr0xy-N-(2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxab0r01anyl)phenyl)- 4-(trifluoromethyl)cyclohexanecarboxamide mm0 HN Step A: Ethyl 4-hydroxy(trifluoromethyl)cyclohexanecarboxylate F F o o o 0 flow AOWFF OH A round bottom flask was charged with ethyl 4-oxocyclohexanecarboxylate (10.0 g, 58.8 mmol) and CsF (8.92 g, 58.8 mmol) in DME (100 mL) at about 23 OC. The reaction was cooled in an ice bath to about 5 0C, then trimethyl(trifluoromethyl)silane (8.35 g, 58.8 mmol) was added dropwise at such a rate as to maintain reaction temperature below 8 OC. The reaction was stirred about 18 h at about 23 OC. TBAF (19.4 mL, 1M solution in THF, 19.39 mmol) was added drop wise and the mixture was stirred about 20 min. The mixture was diluted with EtOAc (200 mL) and washed with water (3 x 200 mL). The organic layer was dried over , filtered and concentrated under reduced pressure.

The residue was purified on silica gel using a gradient 10 to 50% EtOAc in heptaneto give ethyl 4- hydroxy(trifluoromethyl)cyclohexanecarboxylate (9.27 g, 67%). The product was taken as a mixture of s to the next step without further purification: 1H NMR (DMSO-d6) 8 5.73 (s, 0.5H), 5.72 (s, 0.5H), 4.13 — 4.01 (m, 2H), 2.70 — 2.64 (m, 0.55H), 2.37 — 2.27 (m, 0.45H), 1.90 — l.45(m, 8H), 1.21 -l.l4 (m, 3H). 2014/044247 Step B: )Hydr0xy(trifluoromethyl)cyclohexanecarboxylic acid F F OH 0 OH AOWF0 F OH /\O —> HoWFF F F Dry EtOH (90 mL) was treated with sodium (1.03 g, 45.0 mol) at rt and the mixture was stirred until the sodium dissolved. A solution of ethyl 4-hydroxy(trifluoromethyl)cyclohexanecarboxylate (9.00 g, 37.5 mmol) in EtOH (90 mL) was added and the mixture was heated at about 70 0C under nitrogen for about 18 h. To the mixture was added 2N s NaOH (18.7 mL, 37.5 mmol) and the mixture was stirred with heating at about 70 0C for about 4 h. The on was cooled to rt and concentrated to remove most of the EtOH. The resulting suspension was diluted with water (50 mL) to give a clear solution. The solution was acidified with cone. HCl to pH = 2. The solution was concentrated to a volume of about 50 mL and the precipitated product was ted by filtration. The precipitate was rinsed with water (2 x 8 mL) and dried for about 18 h under reduced pressure to give (1s,4s)hydr0xy(trifluoromethyl)cyclohexanecarboxylic acid as a white solid (5.99 g, 75%): LC/MS (Table 1, Method a) R = 1.35 min; MS m/z 211 (M-H)‘, 1H NMR (DMSO-d6) 8 12.10 (s, 1H), 5.69 (s, 1H), 2.26-2.16 (m, 1H), 1.79-1.69 (m, 4H), 1.69-1.56 (m, 2H), 1.55-1.44 (m, 2H).

Step C: (1s,4s)Hydr0xy-N-(2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)phenyl)- 4-(trifluoromethyl)cyclohexanecarboxamide OH D H o F30 _, o 4+ fiO—fi A solution containing (1s,4s)hydroxy(trifluoromethyl)cyclohexanecarboxylic acid (100 mg, 0.471 mmol) and 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (110 mg, 0.471 mmol, CombiBlocks) in DMF (2.0 mL) was treated with DIEA (0.082 mL, 0.471 mmol) and 2-(3H— [1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (179 mg, 0.471 mmol) and the mixture was stirred at rt for about 1 h. The mixture was diluted with water (5 mL), triturated and the supernatant decanted. The residue was dissolved in EtOAc (10 mL), dried over Na2S04, ed and concentrated. The residue was purified on silica gel using a gradient of 25- 75% EtOAc in heptane. Product fractions were combined, trated and dried to solids under reduced pressure to give (1s,4s)hydr0xy-N—(2-methyl(4,4,5,5-tetramethyl-I,3,2-di0xab0rolan yl)phenyl)(trifluoromethyl)cyclohexanecarboxamide as a solid (135 mg, 67%): LC/MS (Table 1, Method b) R = 1.56 min; MS m/z 428 (M+H)+, 1H NMR (DMSO-d6) 8 9.23 (s, 1H), 7.46 (dd, J = —104— 7.4, 1.4 Hz, 1H), 7.35 (dd, J = 7.9, 1.4 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 5.74 (s, 1H), .34 (m, 1H), 2.32 (s, 3H), 1.90 — 1.67 (m, 6H), 1.60 — 1.42 (m, 2H), 1.30 (s, 12H).

Preparation #9: 0-lH-pyrrolo[3,2-c]pyridinecarb0xamide Step A: 4-Br0m0-lH-pyrrolo[3,2-c]pyridinecarb0xylic acid / N N02 H COOH HO O A solution of 6-bromonitronicotinic acid (3.8 g, 15.4 mmol, Eur. J. Med. Chem. 1977, 12(6), 541) in anhydrous THF (100 mL) was stirred between about -40 and -50 0C for about 5 min. Then vinylmagnesium bromide (1N in THF, 69.2 mL, 69.2 mmol) was added dropwise. The mixture was stirred between about -40 and -50 0C for about 4 h. The mixture was quenched with saturated aqueous NH4Cl (2 mL). The t was removed under reduced pressure to get a e, which was purified by prep-HPLC (Table 1, Method w) to provide 4-br0m0-1H-pyrrolo[3,2-c]pyridine-7— carboxylic acid (1 g, 27%): 1H NMR (DMSO-d6) 8 11.90 (br. s, 1 H), 8.46 (s, 1 H), 7.54 (t, J=2.65 Hz, 1 H), 6.56 (br, 1 H).

Step B: 4-Br0m0-lH-pyrrolo[3,2-c]pyridinecarb0xamide Br Br N\ \ _. N|\ \ l/ / N N H H HO o O NH2 To a solution of 4-bromo-1H—pyrrolo[3,2-c]pyridine-7—carboxylic acid (100 mg, 0.42 mmol) in DMF (2 mL) was added HOBt (95 mg, 0.62 mmol) and EDCI (119 mg, 0.62 mmol). After the reaction mixture was stirred at rt for about 1 h, NH3/THF (10 mL) was added and the resulting mixture was stirred at rt overnight. Then the suspension was filtered and the filtrate was concentrated under reduced pressure. Water was added and extracted with EtOAc. The combined organic phase was washed with brine, dried over NaZSO4, filtered and trated under reduced pressure to provide 4- bromo-IH-pyrrolo[3,2-c]pyridinecarb0xamide (60 mg, 42%). The product was used without further purification: 1H NMR (DMSO-d6) 8 11.89 (br, 1H), 8.51 (s, 1H), 8.27 (br, 1H), 7.68 (br, 1H), 7.52-7.51 (d, J = 2.8 Hz, 1H), 6.52-6.51 (d, J = 3.2 Hz, 1H).

Preparation #10. 0(1-methyl-1H-pyrazolyl)-1H-indolecarb0xamide \ \N\ H "\ WN 0 Step A: Methyl 4-br0m0((2-(trimethylsilyl)eth0xy)methyl)-1H-indolecarb0xylate Br Br \ \ H N o OMe o OMe To a solution of methyl o-1H-indolecarboxylate (35 g, 138 mmol, Preparation #1 step B) in anhydrous THF (1500 mL) was added NaH (10 g, 250 mmol) in portions at about 0 OC and stirred for 1 h at about 0 OC. Then SEMCl (31.9 mL, 180 mmol) was added in portions at about 0 OC. The reaction mixture was allowed to warm up to rt and stirred for about 12 h. Then to the reaction e was added saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and trated under d pressure to give the residue, which was purified by column chromatography on silica gel to give methyl 4-br0m0- I-((2-(trimethylsilyl)ethoxy)methyl)-1H—indolecarb0xylate (32 g, 60%): 1H NMR ) 5 7.62- 7.60 (d, J: 8.4 Hz, 1H), 7.46-7.44 (d, J: 8.0 Hz, 1H), 7.36-7.35 (d, J: 3.2 Hz, 1H), 6.77-6.76 (d, J: 3.6 Hz, 1H), 5.80 (s, 2H), 4.06 (s, 3H), 3.32-3.28 (t, J = 8.0 Hz, 2H), 0.89-0.85 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H).

Step B: Methyl 4-br0m0i0d0((2-(trimethylsilyl)eth0xy)methyl)-1H-indolecarb0xylate Br Br \ \ I N N SEM SEM O OMe O OMe To a solution of methyl 4-bromo((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7—carboxylate (10 g, 26 mmol, Preparation #1 step B) in anhydrous THF (200 mL) was added lithium diisopropylamide (18 mL, 36 mol) at about -70 OC and stirred for about 2 h. Then a solution of 12 (10 g, 39 mmol) in anhydrous THF (50 mL) was added to above solution dropwise at about -70 OC and then stirred for about 2 h. The mixture was poured into aqueous Na2S203 solution and extracted with EtOAc. The combined c phases were washed with brine, dried over NaZSO4, filtered and concentrated under pressure to get a residue, which was purified by column chromatography (eluted with Pet ether:EtOAc = 200:1) to provide methyl 4-br0m0i0d0-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-indole ylate (6.2 g, 47%): 1H NMR (CDCl3) 8 7.50-7.48 (d, J: 8.0 HZ, 1H), 7.42-7.40 (d, J: 8.0 HZ, 1H), 7.10 (s, 1H), 5.90 (s, 2H), 4.06 (s, 3H), .25 (t, J = 8.0 Hz, 2H), 0.87-0.83 (t, J = 8.0 HZ, 2H), 0.00 (s, 9H).

Step C: Methyl 4-br0m0i0d0((2-(trimethylsilyl)eth0xy)methyl)-1H-indolecarb0xylate Br Br \ I \ Cw N N N\ SEM SEM MeO O MeO 0 To a on of methyl 4-bromoiodo((2-(trimethylsilyl)ethoxy)methyl)-1H—indole carboxylate (1.1 g, 2.2 mmol) in DME (20 mL) and water (5 mL) was added 1-methyl(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole (0.49 g, 2.37 mmol), PdC12(dppf) (0.176 g, 0.216 mmol) and Na2C03 (0.894 g, 6.47 mmol). The mixture was heated to reflux for about 3 h. After cooling to rt, water (20 mL) was added to the solution and extracted with EtOAc (50 mL). The organic phase was dried over NaZSO4 and concentrated in vacuo to get a crude product, which was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc = 10:1 ) to provide methyl 0i0d0((2-(trimethylsilyl)ethoxy)methyl)-1H-indolecarb0xylate (0.65 g, 65%): 1H NMR (CDCl3) 8 7.84 (s, 1H), 7.77 (s, 1H), 7.61-7.59 (d, J :72 Hz, 1H), 7.49-7.40 (d, J :80 Hz, 1H), 6.79 (s 1H), 5.84 (s, 2H), 4.14 (s, 3H), 4.11 (s, 3H), 3.20-3.16 (t, J=8.4 Hz, 2H), 0.82-0.78 (t, J :84 Hz, 2H), 0.00 (s, 9H).

Step D: 4-Br0m0(1-methyl-1H-pyrazolyl)((2-(trimethylsilyl)eth0xy)methyl)-lH-indole- 7-carb0xylic acid Br Br \ w \ \N \ —> \ N\ N\ "i N\ SEM SEM MeO O HO 0 To a solution of methyl 4-bromoiodo((2-(trimethylsilyl)ethoxy)methyl)-1H—indole ylate (0.65 mg, 1.41 mmol) in THF (10 mL), MeOH (2 mL) and water (2 mL) was added LiOH (0.17 mg, 7.04 mmol). The mixture was heated to reflux for about 4 h. After cooling to rt, the solvent was removed under reduced pressure and the aqueous layer was acidified with aqueous HCl (IN) to pH=4, extracted with EtOAc (10 mL), dried over NaZS O4, and concentrated under reduced pressure to provide 4-br0m0(1 -methyl-IH-pyrazolyl)((2-(trimethylsilyl)ethoxy)methyl)-1H-indole carboxylic acid (0.63 g, 99%): 1H NMR (CDC13) 5 7.90 (s, 1H), 7.81 (s, 1H), 7.80-7.79 (d, J =2.4 Hz, 1H), 7.54—7.52 (d, J :80 Hz, 1H), 6.84 (s, 1H), 5.95 (s, 2H), 4.18 (s, 3H), 3.25—3.20 (t, J =7.2 Hz, 2H), 0.82-0.78 (t, J=7.2 Hz, 2H), 0.00 (s, 9H).

Step E: 4-Br0m0(1-methyl-1H-pyrazolyl)((2-(trimethylsilyl)eth0xy)methyl)-lH-indole- 7-carb0xamide Br Br Br HO O H2N O H2N 0 TO a solution of 4-bromo( 1 -methyl- 1H-pyrazolyl)((2-(trimethylsilyl)ethoxy)methyl)- 1H-indole carboxylic acid (0.63 g, 1.4 mmol) in DMF (10 mL) was added PyBOP (1.46 g, 2.80 mmol), HOBt (0.43 g, 2.80 mmol), NH4Cl (0.11 g, 2.10 mmol) and DIEA (0.72 g, 5.60 mmol). The mixture was stirred at rt for about 2 h. Water (20 mL) was added to the e and extracted with EtOAc (30 mL). The c phase was dried over NaZSO4 and concentrated under reduced pressure to get a crude product, which was purified by column chromatography on silica gel (eluted with Pet EtOAc = 3:1) to provide crude 4-bromo(1-methyl-1H-pyrazolyl)((2- (trimethylsilyl)ethoxy)methyl)-1H-indolecarboxamide. It was dissolved in in anhydrous THF (10 mL) was added (2.02 g, 12.2 mmol) and ethane-1,2-diamine (2.20 g, 36.7 mmol) and heated to about 100 0C for about 2 h. After cooling to rt, water was added to dilute the mixture, extracted with EtOAc, the organic phase was dried over Na2S04, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc = 3:1) to provide 4-br0m0(1-methyl-IH-pyrazolyl)-1H-indolecarb0xamide (0.20 g, 51%): 1H NMR (CDCl3) 8 10.40 (br, 1 H), 7.87 (s, 1 H), 7.75 (s, 1 H), 7.30-7.28 (d, J: 8, 1 H), 7.20-7.18 (d, J = 8, 1 H), 6.64 (s, 1 H), 6.05 (br, 2 H), 3.99 (s, 3 H).

Preparation #11. 3-(2-(((tert-Butyldimethylsilyl)0xy)methyl)(4,4,5,5-tetramethyl-1,3,2- orolan-Z-yl)phenyl)flu0r0quinazolin—4(3H)-0ne Step A: (2-Aminebr0m0phenyl)methanol O OH OH HzNg/Br —> H2N Br The solution of 2-aminobromobenzoic acid (19.8 g, 91.7 mmol) in THF (190 mL) was added to the suspension of LiAlH4 (7.00 g, 183 mmol) in THF (190 mL) dropwise at about 0 0C. After the addition was te, the mixture was stirred at rt for about 4 h. Then the mixture was quenched with EtOAc (180 mL). The mixture was poured into H20 (1.1 L) and filtered. The filtrate was extracted with EtOAc (3 X 900 mL). The combined organic layer was dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc=50:1-5:1) to provide (2-amin0br0m0phenyl)methanol (10 g, 54%): 1H NMR (CDCl3) 8 1.77 (s, 1H), 4.34 (s, 2H), 4.92 (s, 2H), 6.64 (m, 1H), 6.95 (m, 2H).

Step B: 3-Bromo(((tert-butyldimethylsilyl)0xy)methyl)aniline OH OTBS HzNéBr —> H2N Br To the solution of nobromophenyl)methanol (3.02 g, 15 mmol) and imidazole (1.83 g, 27 mmol) in DMF (40 mL) was added TBSCl (3.39 g, 22.5 mmol) in portions at about 0 OC. Then the resulting e was stirred at rt overnight. The mixture was poured into H20 (80 mL), extracted with MTBE (3 X 80 mL). The combined organic phase was washed with brine, dried over Na2S04, filtered and trated under reduced pressure. The e was purified by column tography on silica gel (eluted with Pet ether:EtOAc=15:1) to give 3-br0m0(((tert- butyldimethylsilyl)0xy)methyl)aniline (4.2 g, 89%): 1H NMR (CDCl3) 5 0.00 (s, 6H), 0.80 (s, 9H), 4.38 (s, 2H), 4.85 (s, 2H), 6.48 (m, 1H), 6.79 (m, 2H).

Step C: 3-(3-Br0m0(((tert-butyldimethylsilyl)0xy)methyl)phenyl)flu0r0quinazolin-4(3H)- OTBS o H2N Br Fag: Br —> NJ/ OTBS The mixture of o(((tert-butyldimethylsilyl)oxy)methyl)aniline (3.5 g, 11 mmol), 2-amino fluoro-benzoic acid (1.7 g, 11 mmol) and CH(OMe)3 (1.8 g, 16.5 mmol) in THF (30 mL) was heated at about 120 0C in a sealed tube overnight. The mixture was cooled to rt and concentrated under reduced pressure. The residue was washed with EtOAc to afford 3-(3-br0m0(((tert- butyldimethylsilyl)0xy)methyl)phenyl)flu0r0quinazolin-4(3H)-0ne (1.3 g, 25%): 1H NMR (CDCl3) 0.00 (d, J = 8 HZ, 6H), 0.85 (s, 9H), 4.57 (d, J = 11.6 Hz, 1H), 4.98 (d, J = 11.6 Hz, 1H), 7.35 (m, 1H), 7.43 (t, J: 8 Hz, 1H), 7.62 (m, 1H), 7.83 (m, 2H), 8.06 (m, 2H). 2014/044247 Step D: 3-(2-(((tert-Butyldimethylsilyl)0xy)methyl)(4,4,5,5-tetramethyl-1,3,2-di0xab0rolan yl)phenyl)fluoroquinazolin—4(3H)-0ne :CCN /o B" —> (1:1 I i OTB8 OTBS he mixture of romo(((tert--butyldimethylsilyl)oxy)methyl)phenyl)--fluoroquinazolin- 4(3H)-one (4 g, 8.6 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2,2]b1[[1,3,2] dioxaborolanyl (2.6 g, 10.4 mmol), KOAC (1.7 g, 17.2 mmol) and f)C12 (0.8 g) in DMSO/1,4-dioxane (8 mL: 40 mL) was heated to about 110 0C under N2 atmosphere for about 2 h. The mixture was cooled to rt, d with EtOAc (100 mL), filtered and the filtrate was washed with H20 (30 mL) and brine (30 mL) successively. The organic phase was dried over Na2S04, filtered and concentrated to afford the crude product which was purified by column chromatography on silica gel (Pet ether/EtOAc, 30:1 to 5:1) to provide 3-(2 -(((tert-butyldimethylsilyl)oxy)methyl)(4, 4, 5, 5-tetramethyl-I , 3, Z-dioxaborolan-Z- yl)phenyl)flu0r0quinazolin-4(3H)-0ne (1.7 g, 38%): 1H NMR (CDCl3) 5 0.00 (d, J = 2 HZ, 6H), 0.92 (s, 9H), 1.52 (s, 12H), 4.70 (d, J: 1.6 Hz, 1H), 5.43 (d, J: 1.6 Hz, 1H), 7.63 (m, 1H), 7.70 (m, 2H), 7.93 (m, 1H), 8.16 (m, 3H).

Perparation #12: (R)(Piperidinyl)imidazo[1,2-a]pyrazin-8(7H)-0ne hydrochloride CIH.HI\©\ O Step A: (R)-tert-Butyl (1-benzylpiperidin—3-yl)carbamate H H N '1" To a solution of (R)-tert-butyl piperidinylcarbamate (40.0 g, 0.2 mol, 1.0 equiv) and TEA (22.22 g, 0.22 mol, 1.1 equiv) in DCM (500 mL) was added dropwise bromomethyl-benzene (37.62 g, 0.22 mol, 1.1 equiv) at 0 0C. After stirring overnight at about 25 0C, the solution was diluted with DCM and washed with water. The organic layer was dried and evaporated to afford (R)-tert-butyl (I- piperidin-S-yl)carbamate (58.0 g, 100%), which was used to the next step without further purification: 1H NMR (CDCl3) 7.15-7.26 (m, 5H), 4.92 (s, 1H), 3.67 (s, 1H), 3.39 (s, 2H), 2.16-2.45 (m, 4H), 1.41-1.61(m, 4H), 1.37 (s, 9H) Step B: (R)Benzylpiperidin—3-amine hydrochloride fl NH2_HC| (T Boc —> w H" To a solution of (R)-tert-butyl (1-benzylpiperidinyl)carbamate (58.0 g, 0.2 mol, 1.0 equiv) in MeOH (200 mL) was added HCl/MeOH (4.0 M, 200 mL) and the mixture was stirred for about 2 h.

The solvent was removed by vacuum to provide (R)-1 -benzylpiperidinamine hydrochloride (50 g): 1H NMR ( MeOD) 8 7.64 (d, J=2.4 Hz, 2H), 7.50 (s, 3H), 4.42-4.52 (q, 2H), 3.64-3.66 (d, J=10.8 Hz, 2H), 3.51-3.54 (d, J=12 Hz, 1H), 3.01-3.16 (m, 2H), 2.20-2.22 (d, J=11.2 Hz, 1H), 2.00-2.11 (m, 2H), 1.66-1.74 (m, 1H) Step C: (R)-N-(1-Benzylpiperidin—3-yl)-1H-imidazolecarboxamide o —’[W:—Q To a solution of 1H-imidazolecarboxylic acid (16.8 g, 0.15 mol) in DMF (500 mL) was added HATU (57 g, 0.15 mol) and the mixture was stirred for about 2 h at rt. Then (R)-tert-butyl (1- benzylpiperidinyl)carbamate (39.45 g, 0.15 mol) was added to the on and the mixture was stirred overnight. Additional 1H-imidazolecarboxylic acid (5.2 g, 46 mmol) and HATU (17.6 g, 46 mmol, 0.3 equiv) was added and the e was stirred at rt for 3 days. The solvent was removed and the residue was dissolved in EtOAc, washed with water, dried and concentrated. The residue was purified by column chromatograph on silica gel to provide crude (R)-N—(I -benzylpiperidinyl)-1H— imidazole-Z-carboxamide (50 g): LC/MS (Table 1, Method k) R = 1.15 min; MS m/Z: 285 (M+H)+.

Step D: (R)-N-(1-Benzylpiperidin—3-yl)(2,2-dieth0xyethyl)-1H-imidazolecarboxamide [EH0 _.§ M5\ | NHO N/Bn A mixture of (1-benzylpiperidinyl)imidazo[1,2-a]pyrazin-8(7H)-one (73.0 g, 150 mmol, crude), 2-bromo-1,1-diethoxy-ethane (30 g, 150 mmol), K2C03 (41.4 g, 300 mmol) and K1 (1 g) in DMF (500 mL) was heated to about 120 0C for 3 days. The t was removed. The residue was dissolved in DCM, washed with water, dried and ated to afford (R)-N-(1-benzylpiperidinyl)- 1-(2,Z-diethoxyethyl)-IH—imidazole-Z-carboxamide (30 g, 75 mmol) as an oil: LC/MS (Table 1, Method k) R = 1.81 min; MS m/Z: 401 (M+H)+.

Step E: (R)(1-Benzylpiperidinyl)imidaz0[1,2-a]pyrazin-8(7H)-0ne EtO/S Q0 —’Bn/N N Han NJKKN [H N\ \ NJ N O Bn A mixture of (R)-N—(1-benzylpiperidinyl)(2,2-diethoxyethyl)-1H-imidazolecarboxamide (30.0 g, 75 mmol, crude) in 2N HCl (200 mL) was heated to reflux overnight. The solvent was removed and the residue was d with water (50 mL) which was basified by saturated Na2C03 to pH 10. The aqueous phase was ted with DCM, dried and evaporated. The residue was purified by column chromatograph on silica gel to afford (R)(1-benzylpiperidinyl)imidazofl,2-a]pyrazin- 8(7H)-0ne (3.0 g, 9.7 mmol): 1H NMR (CDCl3) 8 7.44 , 7.17-7.24 (m, 7H), 7.01-7.02 (d, J=6 Hz, 1H), 5.00-5.05 (m, 1H), 3.45-3.47 (d, J=5.6 Hz, 2H), 2.78-2.80 (m, 1H), 2.55-2.58 (m, 1H), 2.31- 2.36 (m, 1H), 2.25 (s, 1H), 1.81 (s, 1H), 1.16-1.69 (m, 3H) Step F: (R)-tert-Butyl x0imidazo[1,2-a]pyrazin-7(8H)-yl)piperidinecarb0xylate NCLO B N , CLO K/NJ K/NJ To a solution of (R)(1-benzylpiperidinyl)imidazo[1,2-a]pyrazin-8(7H)-one (2.13 g, 6.9 mmol) in MeOH (40 mL) was added (Boc)20 (3.09 g, 13.8 mmol) and Pd/C (1.5 g). The e was hydrogenated under H2 balloon overnight and then filtrated. The filtrate was concentrated and purified by column chromatograph on silica gel to afford (R)-tert-butyl 3-(8-0x0imidaz0[1,2- a]pyrazin-7(8H)-yl)piperidine-I-carb0xylate (1.4 g, 64%): 1H NMR (MeOD) 5 7.69-7.70 (d, J=1.2 Hz, 1H), 7.52-7.54 (d, J=6.4 Hz, 1H), 7.50 (s, 1H), 7.12-7.14 (d, J=6Hz, 1H), 4.74-4.82 (m, 1H), 4.12- 4.15 (d, J=11.6 Hz, 1H), 4.04—4.05 (m, 1H), 3.05—3.11 (m, 1H), 2.83 (s, 1H), 1.91—2.02 (m, 2H), 1.86- 1.90 (m, 1H), 1.60-1.71 (m, 1H), 1.46 (s, 9H) Step G: (Piperidinyl)imidazo[1,2-a]pyrazin-8(7H)-0ne hloride BOCO‘NJYN0 o K/NJ —> CIH.H©\NJS¢N \ NJ To a solution of (R)-tert-butyl 3-(8-oxoimidazo[1,2-a]pyrazin-7(8H)-yl)piperidinecarboxylate (1.4 g, 4.4 mmol) in MeOH (10 mL) was added HCl/MeOH (4 M, 10 mL) and the mixture was stirred for about 1 h at rt. The solvent was removed to afford (R)(piperidinyl)imidaz0[1,2-a]pyrazin- 8(7H)-0ne hydrochloride (1.35 g, 100%): 1H NMR (DMSO-d6) 8 10.06 (s, 1H), 9.67 (s, 1H), 8.18- 8.21 (m, 1H), 8.00-8.03 (m, 1H), 7.89-7.93 (m, 1H), 7.69-7.74 (m, 1H), 5.12-5.18 (m, 1H), 3.20-3.34 (m, 3H), 2.82-2.90 (m, 1H), 2.02-2.08 (m, 1H), .93 (m,3H) Preparation #13: (Piperidinyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one hydrochloride CIH.HI\©\ O "$9N Step A: (R)-tert-Butyl 3-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)piperidine carboxylate O O \ NJ gm To a on of (R)(1-benzylpiperidinyl)imidazo[1,2-a]pyrazin-8(7H)-one (0.77 g, 2.5 mmol) in MeOH (20 mL) was added (Boc)20 (1.09 g, 5.0 mmol) and Pd(OH)2 (0.5 g). The mixture was hydrogenated under H2 balloon overnight and then filtrated. The filtrate was evaporated and purified by column Chromatograph on silica gel to afford (R)-tert-butyl 3-(8-0x0-5,6-dihydr0imidaz0[1,2- a]pyrazin-7(8H)-yl)piperidine-I-carb0xylate (0.5 g, 60%): 1H NMR (MeOD) 5 7.16 (s, 1H), 7.06 (s, 1H), 4.22-4.33 (m, 1H), 4.19-4.20 (m, 2H), 3.93-3.96 (m, 2H), 3.64-3.78 (m, 2H), 2.86-2.89 (m, 1H), 2.61 (s, 1H), 168-179 (m, 3H), 1.47-1.53 (m, 1H), 1.46 (s, 9H).

Step B: (Piperidinyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one hloride CL 0 0 BocN NJSéN —, CIH.HNCL Nj N)?!" To a solution of (R)-tert-butyl 3-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)piperidine carboxylate (0.5 g, 1.5 mol, 1 equiv) in MeOH (5 mL) was added HCl/MeOH (4.0 M, 5 mL) and the mixture was stirred for 1 h at rt. The solvent was removed to afford (R)(piperidinyl)-6,7- dihydroimidaz0[1,2-a]pyrazin-8(5H)-0ne hydrochloride (0.45 g, 100%): 1H NMR (MeOD) 5 7.75- 7.78 (q, J=9.6 Hz, 2H), 4.66-4.74 (m, 1H), 4.56-4.59 (q, z, 2H), 3.99—4.03 (t, J=6Hz, 2H), 3.32-3.45 (m, 3H), 2.96—3.03 (m, 1H), 1.85-2.14 (m, 4H).

Preparation #14: (Z)((3-(7-carbamoyl-1H-indolyl)phenyl)amino)oxobutenoic acid 0\ *Oxf —’ N O\N H H H2N 0 H2NO To a solution of 4-(3-amin0phenyl)-1H-indolecarb0xamide (0.25 g, 0.995 mmol, Preparation #A.1), 2,5-di0ne (0.117 g, 1.19 mmol), and N—ethyl-N—isopropylpropanamine (0.521 mL, 2.98 mmol) in DMF (10.0 mL) was added. The mixture is stirred at rt overnight. Solvent was removed under high vacuum and the e was purified by prep HPLC (Table 2, Method y) to provide ((3-(7-carbamoyl-1H—indolyl)phenyl)amin0)0x0buten0ic acid (0.32 g, 92%) as a solid. LC/MS (Table 1, Method g) R = 1.37 min; MS m/z 350 (M+H)+.

Preparation #15. tert-Butyl 3-(7-carbamoyl(2-methyl(4-oxoquinazolin-3(4H)-yl)phenyl)- 1H-indolyl)-2,5-dihydro-1H-pyrrolecarboxylate N,Boc H2N 0 Step A. Methyl 4-bromo(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrolyl)tosyl-1H- indolecarboxylate Br Br \ \ N I —» \ N\ N Ts Ts \oo \00 To a mixture of methyl 0—2-i0d0—1-t0syl-1H-ind01ecarb0xylate (1 g, 1.9 mmol, Preparation #1, Step D) in DME (20 mL)/water (5 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-2,5-dihydr0—1H-pyrrolecarb0xylate (0.72 g, 2.4 mmol), Na2C03 (0.6 g, 5.6 mmol) and Pd(dppf)C12 (0.2 g, 0.28 mmol). The reaction mixture was stirred at rt for 10 h under N2 atmosphere. After filtering, the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with hexanes:EtOAc = 5:1) to give methyl 4-br0m0(1-(tert-but0xycarb0nyl)-2,5-dihydr0-IH-pyrrol-S-yl)t0syl-IH—indole —114— carboxylate (0.6 g, 56%) as yellow solid: 1H NMR (CDCl3) 8 7.68-7.56 (d, J=8.22 HZ, 1H), 7.55- 7.54 (m, 1H), 7.14-7.05 (m, 4H), 6.45-6.37 (m, 2H), 4.37-4.31 (m, 2H), 4.05 (s, 3H), 3.89-3.84 (m, 2H), 2.38-2.34 (m, 3H), 1.53 (m, 9H).

Step B: 4-Br0m0(1-(tert-but0xycarbonyl)-2,5-dihydro-lH-pyrrolyl)-1H-indole carboxylic acid Br Br ’300 ,Boc \ N —> \ N \ \ N\T N \o 0 HO 0 To a solution of methyl 4-bromo(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrolyl)tosyl-1H— indolecarboxylate (2.5 g, 4.34 mmol) in THF (20 mL)/MeOH (5 mL)/ water (5 mL) was added LiOH'HzO (2.5 g, 59.5 mol) at rt. The reaction mixture was stirred at rt for about 3 h. The on was concentrated and residue was acidified by addition of 2N HCl to about pH 5 and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried and trated to give a solid, which was washed with EtOAc and MTBE to give 4-br0m0(1-(tert-but0xycarb0nyl)-2,5-dihydr0-IH- pyrrol-S-yl)-1H-indolecarb0xylic acid (1 g, 56.5%) as white solid: 1H NMR (CDCl3) 5 9.84 (m, 1 H), 7.77-7.75 (t, J=5.6 Hz, 1H), 7.34-7.32 (d, J=8 Hz, 1H), 6.54-6.49 (d, J=l6.8 Hz, 1H), .14 (d, J=18 Hz, 1H), 4.58-4.51 (d, J=30.4 Hz, 2H), 4.38-4.32 (d, J=22 Hz, 2H), 1.54 (s, 9H).

Step C: tert-Butyl3-(4-br0m0carbam0yl-1H-indolyl)-2,5-dihydr0-1H-pyrrole carboxylate Br Br HO 0 H2" 0 To a solution of o(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrolyl)-1H-indole carboxylic acid (1 g, 2. 5 mmol) in DMF (6 mL) was added PyBOP (2.6 g, 4.9 mmol), HOBt (0.75 g, 4.91 mmol), DIEA (1.7 mL, 9.82 mmol) and NH4Cl (0.2 g, 3.7 mmol). The reaction mixture was stirred at rt overnight. After quenching with water, the aqueous layer was extracted with EtOAc (3 x mL). The combined c layers were dried and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Table 1, Method ad) to give tert-butyl 3-(4-br0m0-7— carbamoyl-IH-indol-Z-yl)-2,5-dihydr0-1H-pyrrole-I-carb0xylate (0.6 g, 54%) as white solid: 1H NMR (CDCl3) 8 10.42 (s, 1 H), 7.26-7.25 (m, 2H), 6.48 (s, 1H), 6.19-6.13 (d, J=22.4 Hz, 1H), 4.55- 4.51 (d, J=16 Hz, 2H), 4.37-4.32 (d, J=18 Hz, 2H), 1.54 (s, 9H).

Step D: tert-Butyl 3-(7-carbam0yl(2-methyl(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol yl)-2,5-dihydr0-1H-pyrr01ecarb0xylate NVN I \ N N,Boc —> O \ H2N o H2N o A solution of tert-butyl 3-(4-bromocarbamoyl-1H-indolyl)-2,5-dihydro-1H-pyrrole carboxylate (0.6 g, 1.48 mmol), 3-(2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl)quinazolin-4(3H)-one (1 g, 2.95 mmol, WO 9857), K2C03 (0.816 g, 5.91 mmol) and Pd(dppi)C12 (0.22 g, 0.3 mmol) in THF (20 mL)/ MeOH (5 mL)/ water (5 mL) was stirred at about 60 0C for about 2 h under N2 atmosphere. The solvent was removed to give a residue, which was purified by column chromatography on silica gel (eluted with hexanes:EtOAc = 2:1) to give tert-butyl 3-(7-carbam0yl(2-methyl(4-0x0quinazolin-3(4H)-yl)phenyl)-1H—indol-Z-yl)-2, 5-dihydr0-IH- pyrrole-I-carboxylate (0.6 g, 72%) as a solid: 1H NMR (McOD) 5 10.44 (s, 1H), 8.40-8.38 (d, J =8 Hz, 1H), 8.15-8.10 (s, J =21.6 Hz, 1H), 7.83-7.81 (m, 2H), 7.59-7.35 (m, 5H), 7.09-6.98 (m, 1H), 6.31-6.11 (m, 4H), 4.49- 4.36 (m, 4H), 2.04 (s, 3H), 1.51 (s, 9H).

Preparation #16. tert-Butyl 4-(7-carbam0yl(2-methyl(4-oxoquinazolin-3(4H)-yl)phenyl)- 1H-indolyl)-5,6-dihydr0pyridine-1(2H)-carb0xylate NVN I O \ \ N—Boc H N2 O Step A: tert-Butyl 2-(4-br0m0carbam0yl-1H-ind01yl)benzylcarbamate Br Br \ \ | —> \ N—Boc N\ IZ H2N o H2N 0 To a on of nd methyl 4-bromoiodotosyl-1H-indole-7—carboxylate (2.4 g, 6.58 mmol, Preparation #1) and tert-butyl ,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6- dihydropyridine-1(2H)-carboxylate (2.0 g, 6.58 mmol) in THF (50 mL), MeOH (10 mL) and water (10 mL) were added Na2C03 (2.1 g, 19.73 mmol) and Pd(dppi)C12 (0.481 g, 0.658 mmol), the e was heated to about 80 0C for about 3 h. The resulting solution was diluted with EtOAc (100 mL), and washed with water (30 mL). The organic phase was dried over Na2S04, and concentrated under reduced re to give a crude product, which was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc = 1:1) to give utyl 4-(4-br0m0carbam0yl-IH—indol-Z-yl)-5,6- dihydropyridine-I(2H)-carb0xylate (2 g, 72%) as a solid: 1H NMR (DMSO-d6) 5 10.87 (s, 1H), 8.15 (s, 1H), 7.59-7.57 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.27-7.25 (d, J=8.0 Hz, 1H), 6.47 (s, 1H), 6.42 (s, 1H), 4.03 (s, 2H), 3.55 (s, 2H), 2.52 (s, 2H), 1.41 (s, 9H).

Step B: ten-Butyl 4-(7-carbamoyl(2-methyl(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol yl)-5,6-dihydr0pyridine-1(2H)-carb0xylate NVN I \ \ N—Boc —> O I? \ N—Boc N H H2N o H2N 0 To a solution of utyl 4-(4-bromocarbamoyl-1H-indolyl)-5,6-dihydropyridine-1(2H)- carboxylate (2 g, 4.76 mmol) and 3-(2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl)quinazolin-4(3H)-one (2.59 g, 7.14 mmol, WO 2011159857) in THF (40 mL), MeOH (10 mL) and water (10 mL) were added Na2C03 (1.513 g, 14.28 mmol) and Pd(dppi)C12 (0.348 g, 0.476 mmol). The mixture was heated to about 80 0C for about 4 h. The resulting solution was diluted with EtOAc (100 mL), and washed with water and brine (30 mL each). The organic phase was dried over Na2S04, and concentrated to give a crude product, which was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc = 1:1) to give tert-butyl 4-(7-carbam0yl(2-methyl(4- oxoquinazolin-3(4H)-yl)phenyl)-1H—indolyl)-5,6-dihydr0pyridine-I (2H)-carb0xylate (1.4 g, 51%) as a solid: 1H NMR (CDCl3) 10.43 (s, 1H), 8.42-8.40 (d, J=7.6 Hz, 1H), 8.15 (s, 1H), 7.85-7.83 (m, 2H), 7.61-7.59 (m, 1H), 7.49-7.45 (m, 3H), 7.37-7.34 (m, 1H), 7.04-7.01 (m, 1H), 6.20 (s, 2H), 3.65 (s, 2H), 2.55 (s, 2H), 2.00 (s, 3H), 1.76 (s, 2H), 1.50 (s, 9H). ation #17: 1-(Methylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)-1,2,3,6- ydropyridine O‘B’ 0.8,0 B —> —> N N N A H A4» 0 o 0’ ‘0 A solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)- carboxylate (4.03 g, 13.03 mmol, Carbocore) in HCl (4 M in dioxane, 19.55 mL, 78 mmol) was stirred at ambient temperature for about 2 h. The solution was concentrated under reduced pressure then dissolved in DCM (20.05 mL) and TEA added (12.72 mL, 91 mmol). The mixture was cooled to about 0 OC and methanesulfonyl chloride (1.83 mL, 23.5 mmol) added dropwise. The mixture was stirred at ambient temperature for about 2 h. To the mixture was added 1N HCl (60 mL) and the organic layer was extracted. The c layer was with saturated aqueous sodium bicarbonate (60 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was trituated with a mixture of EtOAc and heptanes, filtered and dried (1.477 g). The filtrate was concentrated and residue was trituated with a e of EtOAc and heptanes, filtered and dried to get second lot (0.940 g). Lots were combined to obtain 1 -(methylsulfonyl)(4,4, 5,5-tetramethyl-I,3,2-di0xab0rolanyl)- 1,2,3,6-tetrahydr0pyridine (2.41 g, 64%). LC/MS (Table 1, Method a) R = 2.18 min: MS m/Zi 288 (M+H)+. ation #18: 4-Br0m0(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)-1H-indole carboxamide Br Br \ I \ N_§_ —> \ N N ('5 H H H2N o H2N o A flask containing 1-(methylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,6- tetrahydropyridine (0.446 g, 1.55 mmol, Preparation #17), 4-bromoiodo-1H-indolecarboxamide (0.54 g, 1.48 mmol, Preparation #1), sodium carbonate (0.470 g, 4.44 mmol) and 1,1'— bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.108 g, 0.148 mmol) was purged with en. A mixture of THF (15.0 mL), MeOH (2.10 mL), and water (2.10 mL) was added. The mixture was stirred for about 2 h at about 70 OC. The mixture was filtered through Celite®, rinsing with EtOAc and concentrated under reduced pressure. The residue was trituated with DCM, ed, washed with DCM and EtOAc to afford a solid (0.315 g). The filtrate was trated and purified by column chromatography on silica gel (40-100% EtOAc/heptane). The resulting residue was triturated with DCM, filtered and dried to afford a solid(0. 125 g). The solids were combined to obtain 4-br0m0(1-(methylsulf0nyl)-I,2, 3, 6-tetrahydropyridinyl)-1H—indolecarb0xamide (0.44 g, 75%). LC/MS (Table 1, Method a) R, = 1.92 min: MS m/z: 400 (M+H)+.

Preparation #19: N-Methyl-N-(Z-methyl(4,4,5,5-tetramethyl-1,3,2-di0xab0rolan yl)phenyl)thiazolecarb0xamide do.s {be .. "I; O/B\O To ethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)thiazolecarboxamide (502 mg, 1.46 mmol, ation #4) in THF (10 mL) was added sodium hydride (70.0 mg, 1.75 mol) at about 0 0C and stirred for about 25 min. To the e was added iodomethane (0.363 mL, 5.83 mol) at about 0 0C. The reaction mixture was brought to rt and then stirred at rt for about 18 h. To mixture was added water, extracted twice with DCM and layers separated. Combined organic layers were evaporated and the e was purified using normal phase chromatography to provide N- methyl-N-(2-methyl(4, 4, 5, 5-tetramethyl-1 , 3, ab0rolanyl)phenyl)thiazole-Z-carboxamide (0.406 g, 59%). LC/MS (Table 1, Method f) R, = 1.97 min: MS m/z: 359 (M+H)+.

Preparation #20. (R)((2,2-Dimethyl-1,3-di0xolanyl)methyl)(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-Z-yl)-1H-pyrazole 0% W /N‘ J2 (I? 0‘ ,o —> L/N 0 >36) To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (1 g, 5.15 mmol) in DMF (25.8 mL) was added sodium hydride (0.206 g, 5.15 mmol). The mixture was stirred at rt for about 10 min under nitrogen. (S)-(+)-2,2-dimethyl-1,3-dioxolanylmethyl p-toluenesulfonate (1.62 g, 5.67 mmol) was added and the mixture was stirred at about 90 OC overnight under an nitrogen atmosphere. The reaction was cooled to rt, and partitioned n EtOAc and water. The aqueous layer was re-extracted with EtOAc (2x) and the organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was WO 10255 purified by column chromatography on silica gel with EtOAc/hexanes (30-75%) to provide (R)-1 - ((2, 2-dimethyl-1, 3-di0xolanyl)methyl)(4, 4, 5, 5-tetramethyl-1, 3, 2-di0xab0rolanyl)-1H- pyrazole (0.66 g, 42%): LC/MS (Table 1, Method f) R = 1.41 min; MS m/Z: 309 (M+H)+.

Preparation #21. (S)((2,2-Dimethyl-1,3-di0xolanyl)methyl)(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-Z-yl)-1H-pyrazole +0O/> ..n| O \O—# ‘ < > ,O —> 0 >35 To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (1.0 g, 5.2 mmol) in DMF (25.8 mL) was added sodium hydride (0.206 g, 5.15 mmol). The mixture was stirred at rt for about 10 min under en. (R)-(2,2-dimethyl-1,3-dioxolanyl)methyl 4-methylbenzenesulfonate (1.62 g, 5.67 mmol) was added and the mixture was d at about 90 OC overnight under an nitrogen atmosphere. The reaction was cooled to rt, partitioned between EtOAc and water. The aqueous layer was re-extracted with EtOAc (2x) and the organics were combined, washed with water, brine, dried over anhydrous MgSO4, ed and concentrated under reduced pressure. The e was purified by was column chromatography on silica gel with EtOAc/hexanes (30-75%) to provide (S)((2,2- dimethyl-1,3-dioxolanyl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (0.83 g, 52%): LC/MS (Table 1, Method f) R, = 1.35 min; MS m/z: 251 (M-(CH3)2CHO +H)+.

Preparation #22: N-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-Z-yl)phenyl)acrylamide —> B To a Vial was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (0.30 g, 1.37 mmol) in DCM (10 mL), and DIEA (0.72 mL, 4.11 mmol). The mixture was cooled to about 0 OC and acryloyl chloride (0.122 mL, 1.51 mmol) was added while stirring. The mixture was stirred for about 20 min while g to rt. The mixture was diluted with and additional DCM (10 mL) washed with water (2 x 10 mL), ed through a Biotage phase separator and concentrated under a warm stream of nitrogen to provide N—(3-(4,4,5,5-tetramethyl-I,3,2-di0xab0rolanyl)phenyl)acrylamide (0.375 g, 100%): LC/MS (Table 1, Method f) R, = 1.70 min; MS m/z: 274 (M+H)+.

Preparation #23: N-(transHydr0xypiperiodinyl)thiazolecarboxamide mixtureHof trans s Step A. Benzyl 4-(hydr0xyimin0)piperidinecarb0xylate O HO‘N 65 —> b N h" A e of benzyl 4-oxopiperidinecarboxylate (10 g, 42.9 mmol), NHZOH HCl (5.9 g, 86 mmol) and K2C03 (11.8 g, 86 mmol) in EtOH (45 mL) was heated at about 50 0C for about 0.5 h. Then the solvent was removed under reduced pressure. Water and EtOAc were added to the residue. The aqueous phase was extracted with EtOAc (3 X 75 mL). The organic layer was washed with brine and dried over NaZSO4, filtered and trated to provide benzyl 4-(hydroxyimino)piperidine-I- ylate (10 g, 94%). 1H NMR (CDCl3) 5 2.36 (br, 2H), 2.63 (br, 2H), 3.63-3.58 (m, 4H), 5.15 (s, 2H), 7.36-7.35 (m, 5H), 9.05 (br, 1H).

Step B. Benzyl 4-((tosyloxy)imino)piperidinecarb0xylate OrIN TsO\IN @ —> o "H "H Cbz Cbz To a solution of benzyl 4-(hydroxyimino)piperidinecarboxylate (12.2 g, 49.1 mmol) in pyridine (75 mL) was added TsCl (12.2 g, 64 mmol) slowly at about 0 OC. The reaction mixture was stirred at this temperature for about 0.5 h and stirred at rt for another 2 h. Then the solvent was removed under reduced pressure. Water and EtOAc were added to the residue. The aqueous phase was extracted with EtOAc (3 X 125 mL). The organic layer was washed with brine and dried over NaZSO4. The solvent was concentrated to give the crude product which was purified by column tography on silica gel (Pet ether:EtOAc = 15:1) to provide benzyl 4-((t0syloxy)imin0)piperidine-I-carb0xylate (5 g, 25.3%); 1H NMR (CDC13) 5 2.37 (br, 2H), 2.44 (s, 3H), 2.63 (br, 2H), 3.62—3.55 (m, 4H), 5.13 (s, 2H), 7.35—7.32 (m, 7H), 7.85 (d, J = 8.0 Hz, 2H).

Step C. Benzyl 3-amin00x0piperidinecarb0xylate hloride $O\N O I NH2 _, HCI w h" Na (28.6 mg, 1.243 mmol) was added to EtOH (6.5 mL) and the mixture was stirred until the Na was completely dissolved. MgSO4 (0.98 g) was added to the solution, then benzyl 4- ((tosyloxy)imino)piperidinecarboxylate (0.5 g, 1.242 mmol) was added to the solution at about 0 0C. After the reaction mixture was heated at about 30 0C for about 2 h, the mixture was filtered and 1 N HCl (6.5 mL) was added to the filtration. The filtration was stirred at rt for about 0.5 h and concentrated. The residue was mixed with EtOH (3 mL) and filtered. The filtration was concentrated to give crude benzyl 3-amin00x0piperidine-I-carb0xylate hydrochloride (200 mg, 0.702 mmol): 1H NMR (MeOD) 5 = 7.33 (m, 5 H), 5.12 (br. s., 2H), .95 (m, 1H), 3.6-3.7 (m, 1H), 3.5 (m, 2H), 3.1-3.2 (m, 1H), 1.95-2.10 (m, 1H), 1.7-1.8 (m, 1H).

Step D. Benzyl 4-0x0(thiazolecarboxamid0)piperidinecarb0xylate NH2 H ":3 HCI _> N fiNWKkSO Cbz I}! A solution of thiazolecarboxylic acid (189 mg, 14.6 mmol) and HATU (723 mg, 1.9 mmol) in DMF (20 mL) was stirred at rt for 0.5 h, then DIEA (945 mg, 7.31 mmol) and benzyl 3-amino oxopiperidinecarboxylate hydrochloride (500 mg, 1.76 mmol) was added to the mixture. The reaction solution was stirred at rt for about 4 h. Water was added to the mixture, extracted with EtOAc (3 X 45 mL). The combined c layer was washed with brine several times, dried over Na2S04, filtered and concentrated to give the crude t which was purified by Prep-HPLC (Table 1, Method ai) to provide benzyl 4-0x0(thiazole-Z-carb0xamid0)piperidine-I-carb0xylate (82 mg, 12%). 1H NMR (CDCl3) 8 2.68-2.62 (br, 2H), .86 (m, 1H), 3.16 (br, 1H), 4.7-5.9 (br, 2H), .05 (m, 1H), 5.31-5.22 (m, 2H), 7.43-7.38 (m, 5H), 7.60 (q, J: 1.2 Hz, 1H), 7.92-7.90 (m, 1H), 8.08 (s, 1H).

Step E. trans-Benzyl 4-hydr0xy(thiazolecarb0xamid0)piperidiNnecarb0xylate O N mixture of trans isomers To a solution of benzyl 4-oxo(thiazolecarboxamido)piperidinecarboxylate (6.9 g, 19.2 mmol) in MeOH (50 mL) was added NaBH4 (0.726 g, 0.019 mmol) in batches and the mixture was stirred at rt for about 0.5 h. Then water (50 mL) was added to the reaction mixture and extracted with DCM (3 X 60 mL). The organic layer was washed with brine and dried over Na2S04, filtered and concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel to provide trans-benzyl 4-hydr0xy(thiazolecarboxamid0)piperidine-I-carb0xylate (3 g, 43%). 1H NMR (MeOD) 8 1.56-1.51 (m, 1H), 2.00 (t, J: 5.2 Hz, 1H), 3.10-2.97 (m, 2H), 3.85-3.75 (m, 2H), 4.16-3.99 (m, 1H), 4.21-4.20 (m, 1H), 5.12 (s, 2H), 7.34-7.31 (m, 5H), 7.85 (q, J = 3.2 Hz, 1H), 7.94 (t, J: 3.2 Hz, 1H).

Step F. N-(transHydr0xypiperidinyl)thiazolecarb0xamide 9H N OH N Cbz H To a stirred solution of trans-benzyl 4-hydroxy(thiazolecarboxamido)piperidinecarboxylate (0.7 g, 1.937 mmol) in MeCN (15 mL) was added TMSI (1.55 O C, g, 775 mmol) slowly at about 0 then the mixture was d at rt for about 1 h. Water was poured into the e and MeCN was d under reduced pressure. 1 N HCl was added to the residue and the mixture was extracted with MTBE (3 X 30 mL). Then the aqueous phase was basified with NaOH (3 N) to about pH = 12 and extracted with DCM (6 X 45 mL). The c phase was washed with brine and dried over Na2S04, filtered and concentrated to give the crude product which was purified by Prep-TLC (1:1 MeOH/DCM) to provide N—(transhydr0xypiperidin-S-yl)thiazole-Z-carboxamide (50 mg, 11%): 1H NMR (MeOD) 8 1.86-1.77 (m, 1H), 2.28-2.22 (m, 1H), 3.29-309 (m, 2H), .44 (m, 2H), 4.84-3.90 (m, 2H), 7.88 (q, J: 3.2 Hz, 1H), 7.97 (q, J: 3.2 Hz, 1H).

Preparation #24: 4-Br0m0i0d0((2-(trimethylsilyl)eth0xy)methyl)-1H-indole carboxamide O NH2 Step A. 4-Br0m0i0d0((2-(trimethylsilyl)eth0xy)methyl)-1H-indolecarb0xylic acid Br Br \ I _> \ I "l "1 SEM SEM O OMe O OH To a solution of methyl 4-bromoiodo((2-(trimethylsilyl)ethoxy)methyl)-1H—indole carboxylate (10 g, 19.6 mmol, Preparation #10, step B) in MeOH (150 mL), THF (300 mL) and water (150 mL) was added lithium hydroxide hydrate (12 g, 286 mmol). The resulting mixture was heated at about 45 0C for about 3 h. Then the mixture was concentrated under reduced pressure to remove most solvent, the residue was dissolved in water. The aqueous mixture was ied by on of aqueous HCl (1N) to about pH 6. The itate was filtered, and the solid was dried to give 4- bromo-Z-iodo-I trimethylsilyl)ethoxy)methyl)-1H-indolecarb0xylic acid (9.1 g, 94%) as a solid: 1H NMR (CDCl3) 8 13.44 (br, 1H), 7.57-7.51 (m, 2H), 7.09 (s, 1H), 5.95 (s, 2H), 3.35-3.11 (t, J = 8.0 Hz, 2H), 0.87-0.83 (t, J: 8.0 Hz, 2H), 0.00 (s, 9H).

Step B. 4-Br0m0i0d0((2-(trimethylsilyl)eth0xy)methyl)-1H-indolecarb0xamide Br Br \ I \ I N. N.

SEM SEM 0 OH 0 NH2 A solution of 4-bromoiodo((2-(trimethylsilyl)ethoxy)methyl)-1H—indolecarboxylic acid (8 g, 16 mmol), EDCI (4.6 g, 24 mmol) and HOBt (3.7 g, 24 mmol) in THF (240 mL) and DCM (280 mL) was stirred at rt for about 1 h. The reaction mixture was then bubbled with NH3 gas for 15 min and stirred at rt overnight. Then the mixture was concentrated and ioned between aqueous NaHCO3 and EtOAc. The organic phase was washed with brine, dried and concentrated to give a residue, which was suspended in Pet ether and the solid was collected by filtration to e 4-br0m0i0d0- I -((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7—carb0xamide (7.2 g, 90%) as a white solid: 1H NMR ) 8 7.36-7.33 (m, 1H), 7.26-7.24 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 6.08 (br, 1H), 5.82 (br, 1H)5.82 (s, 2H), 3.48-3.41 (m, 2H), 0.90-0.86 (m, 2H), 0.00 (s, 9H).

Preparation #25: 4-(Difluoromethyl)-N-(2-methyl(4,4,5,5-tetramethyl-1,3,2-di0xab0rolan yl)phenyl)-N-(0xetanyl)benzamide H F 07 o o OH N ,B\ 07 o o if F o o A solution of 4-(difluoromethyl)benzoic acid (0.089 g, 0.519 mmol, Oakwood) in DCM (3.46 mL) under nitrogen was treated with sulfurous dichloride (0.075 mL, 1.037 mmol) and 1 drop DMF. The mixture was stirred at about 35 0C for about 16 h. The reaction was concentrated under reduced —124— 2014/044247 pressure, triturated e with heptane, and concentrated. The residue was dissolved in DCM (3.46 mL) and added N—(2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)oxetanamine (0.100 g, 0.346 mmol, prepared using H from 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)aniline -Blocks] and 3-oxetanone[(Molbridge]) and TEA (0.193 mL, 1.383 mmol). The mixture was stirred at ambient temperature for about 4 h then diluted with DCM (10 mL) and ed with saturated aqueous sodium bicarbonate (10 mL). The organics were combined and washed with 30 mL saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4, filtered and trated under reduced pressure to give the crude product which was purified by column chromatography on silica gel (0-40% EtOAc/heptane) to provide a yellow oil that solidified upon standing to afford 4-(difluoromethyl)-N—(2-methyl(4,4,5,5-tetramethyl-I,3,2-di0xab0rolan yl)phenyl)-N—(0xetanyl)benzamide (0.092 g, 60%). LCMS (Table 1, Method a) R = 2.51 min: MS m/z: 444 (M+H)+.

Preparation #26: yl(4-(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)-1H-pyrazol yl)pr0panol 0. Q @3er —»_N O’BWY_N OH To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (2.0 g, 10.31 mmol) in 2,2-dimethyloxirane (11.96 mL, 134 mmol) in a 30 mL microwave Vial was added cesium carbonate (0.521 g, 1.60 mmol). The mixture was heated in a microwave oven at about 120 0C for about 30 min.

The reaction was cooled and filtered. The resulting solution was evaporated to dryness to give 2- methyl-1 -(4-(4,4,5,5-tetramethyl-I,3,2-di0xab0rolanyl)-1H—pyrazol-I -yl)propan-Z-ol as a white solid. (2.7 g, 99%); (Table 1, Method g) R = 1.34 min.; MS m/z: 267 (M+H)+ Preparation #27: 4-Flu0r0i0d0t0syl-1H-indolecarb0nitrile \ / N—Ms CN TS Step A. 4-Flu0r0t0syl-1H-indolecarb0nitrile F F \ \ N N\ To a solution of 4-fluoro-1H—indolecarbonitrile (5.3 g, 33.1 mmol, Sinova) in DMF (92 mL) was added NaH (2.0 g, 49.6 mol) at 0 0C under N2 atmosphere and stirred for about 30 min. Then TsCl (9.46 g, 49.6 mmol) was added to the above e and stirred at rt for about 5 h. The mixture was poured into saturated aqueous NH4Cl solution (200 mL), extracted with EtOAc (100 mL X 3). The combined c phase was washed with brine, dried over Na2S04, ed and concentrated to afford the crude product which was washed with MTBE to provide 4-flu0r0-I-t0syl-1H-indole carbonitrile (7 g, 67.3%) as a solid: 1H NMR (CDCl3) 8 2.39 (s, 3H), 6.86 (d, J: 4 Hz, 1H), 6.99 (t, J: 8.4 Hz, 1H), 7.33 (d, J: 8.4 Hz, 2H), 7.62 (m, 1H), 7.84 (d, J: 3.6 Hz, 1H), 7.92 (d, J: 8.4 Hz, 2H).

Step B. 4-Flu0r0i0d0t0syl-lH-indolecarb0nitrile F F —> \ | N N \ \ CN TS Freshly prepared LDA (67 mL, 38.2 mmol) was added dropwise to a solution of 4-fluorotosyl-1H— indolecarbonitrile (10 g, 31.8 mmol) in THF (50 mL) at about -78 0C. After the addition was complete, the mixture was stirred for another 45 min. Then a solution of 12 (9.69 g, 38.2 mmol) in THF (50 mL) was added dropwise to the mixture at about -78 0C. After the on, the mixture was stirred for about another 1 h. The solution was poured into saturated aqueous Na2S203 (400 mL), extracted with EtOAc (100 mL X 3). The ed organic phase was washed with brine, dried over Na2S04, filtered and trated to afford the crude product which was washed with EtOAc to give 4-flu0r0i0d0t0syl-1H-indolecarb0nitrile (8.5 g, 61%) as a solid: 1H NMR (CDCl3) 8 2.45 (s, 3H), 7.01 (t, J: 8.4 Hz, 1H), 7.20 (s, 1H), 7.33 (d, J: 8.4 Hz, 2H), 7.64 (m, 1H), 8.05 (d, J: 8.4 Hz, 2H).

Step C. tert-Butyl 4-(7-cyan0flu0r0t0syl-lH-indol-Z-yl)-5,6-dihydr0pyridine-1(2H)- carboxylate F F \ | —> \ / N—Boc N. N.

TS TS CN CN To a solution of 4-fluoroiodotosyl-1H—indolecarbonitrile (2.92 g, 6.63 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)-carboxylate (2.05 g, 6.63 mmol) in the mixture of THF (20 mL), MeOH (4 mL) and water (4 mL) was added Na2C03 (2.108 g, 19.89 mmol) and PdC12(dppf) DCM (0.541 g, 0.663 mmol). The mixture was heated at about 80 0C for about 3 h. Then the reaction was cooled and diluted with EtOAc (30 mL) and washed with water (3 X 10 mL). The organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc = 10:1) to give tert-butyl yan0flu0r0t0syl-IH—indolyl)-5,6- opyridine-I(2H)-carb0xylate (2.5 g, 76%): 1H NMR (CDCl3) 5 1.25 (s, 2H), 1.52 (s, 9H), 2.38 (s, 3H), 3.63 (t, J: 5.6 Hz, 2H), 4.09 (d, J: 2.8 Hz, 2H), 5.83 (d, J: 2.8 Hz, 1H), 6.56 (s, 1H), 7.04 (t, J: 8.4 Hz, 1H), 7.20 (d, J: 8.0 Hz, 2H), 7.48 (s, 2H), 7.68 (q, J: 5.2 Hz, 1H).

Step D. 4-Flu0r0(1,2,3,6-tetrahydr0pyridinyl)t0syl-1H-indolecarb0nitrile hydrochloride F F \ / N—Boc —> \ / NHHCI N N CN TS CN TS To a solution of utyl 4-(7-cyanofluorotosyl-1H-indolyl)-5,6-dihydropyridine-1(2H)- carboxylate (2.7 g, 5.45 mmol) in EtOAc (30 mL) was added se HCI/EtOAc (30 mL) at about 0 0C, then the reaction was stirred at rt for about 3 h. The mixture was filtered and the filter cake was washed with EtOAc to give 4-flu0r0(1,2, 3,6-tetrahydropyridinyl)-1 -t0syl-1H—indole carbonitrile hydrochloride (1.96 g, 83%): 1H NMR (MeOD) 8 2.35 (s, 3H), 2.78 (s, 2H), 3.48 (t, J: .6 Hz, 2H), 3.94 (s, 2H), 6.04 (s, 1H), 6.86(s, 1H), 7.23-7.29 (m, 3H), 7.43 (d, J: 8.0 Hz, 2H), 7.84 (t, J: 5.2 Hz, 1H).

Step E. 4-Flu0r0(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridinyl)t0syl-1H-indole carbonitrile \ / NH HCI _> \ / N_MS Ts ‘ To a solution of tert-butyl 4-(7-cyanofluorotosyl-1H-indolyl)-5,6-dihydropyridine-1(2H)- carboxylate (1.96 g, 4.54 mmol) and TEA (1.84 g, 18.2 mmol) in DCM (30 mL) was added MsCl (0.623 g, 5.44 mmol), then the mixture was stirred at rt for about 24 h. Then water was added to the mixture and the reaction mixture was extracted with DCM (3 X 30 mL). The combined organic layer was washed with brine and dried over Na2S04, ed and concentrated under reduced pressure to give 4-flu0r0(1-(methylsulf0nyl)-1, 2, 3,6-tetrahydropyridinyl)t0syl-IH—indolecarb0nitrile (1.35g, 63%) which was used in the next step without any further cation. LC/MS (Table 1, Method f) R = 2.15 min; MS m/Z: 474 (M+H)+.

Preparation #28: 3-Bromo-N-(cyanomethyl)benzenesulfonamide 9/0 "40 S: S\ o \ a o N To a cooled (0 0C) on of 2-aminoacetonitrile hydrochloride (0.50 g, 5.40 mmol) in pyridine (27.0 mL) was slowly added 3-bromobenzenesulfonyl chloride (0.779 mL, 5.40 mmol). The mixture was slowly warmed to rt and stirred for about 16 h. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM and washed with 1N HCl, saturated sodium bicarbonate, brine and filtered h a Biotage Phase separator after each wash step. The organics were concentrated under reduced pressure afford the crude product. The crude product was purified by column chromatography on silica gel eluted heptane (0-40%) to provide 3-br0m0-N— (cyanomethyl)benzenesulfonamide (0.61 g, 41%): 1H NMR (DMSO-d6): 8 8.73 (br, 1H), 7.98 (t, J = 1.79, 1H), 7.91 (d, J: 8.02, 1H), 7.84 (d, J: 8.02, 1H), 7.60 (t, J: 7.92, 1H), 4.18 (s, 2H).

Preparation #29: 4-Cyclopropyl-N-(2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl)benzamide O\ / E3 —> H I ""2 o F To a solution of 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (0.350 g, 1.501 mmol) and HATU (0.856 g, 2.252 mmol) in DCM (2 mL) was added TEA (0.628 mL, 4.50 mmol) and 4-(difluoromethyl)benzoic acid (0.336 g, 1.952 mmol). The mixture was stirred at about rt for about 18h. The mixture was evaporated and the resulting e was purified by silica gel chromatography eluting with a gradient of 30-50% EtOAc in hexane to give 4-cyclopr0pyl-N—(2- methyl(4,4,5,5-tetramethyl-I,3,2-di0xab0rolanyl)phenyl)benzamide (0.52, 89%); LC/MS (Table 1, Method c) R = 2.10 min.; MS m/z: 388 (M+H)+ Preparation #30: (R)Fluoro(piperidin—3-yl)isoindolinone hydrochloride NflNH HCI Step A: Methyl 5-flu0r0methylbenzoate O O F@O"—’ C6"F To a solution of 5-fluoromethylbenzoic acid (20 g, 0.13 mol) in anhydrous MeOH (200 mL) was added SOCIZ (38.9 g, 0.33 mol) dropwise. The resulting mixture was stirred at rt ght. The solvent was evaporated to dryness to give methyl 5-flu0r0methylbenz0ate (24 g, 99%) as an oil. 1H NMR ): 8 7.62-7.59 (d, J = 9.6 Hz, 1H), 7.21-7.18 (d, J = 8.4 Hz, 1H), 7.12-7.09 (d, J = 8.0 Hz, 1H), 3.89 (s, 3 H), 2.55 (s, 3H).

Step B: Methyl 2-(br0m0methyl)flu0r0benzoate O O F F ()/_> 0/ To a solution of methyl 5-fluoromethylbenzoate (24 g, 0.14 mol) in CCl4 (250 mL) was added NBS (28 g, 0.16 mol) and BPO (1.7 g, 7.2 mmol). The reaction mixture was heated to reflux for about 18 h. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to give methyl 2- (bromomethyl)flu0r0benz0ate (35 g, crude), which was used in next step reaction ly without further purification. 1H NMR (DMSO-d6): 8 7.67-7.60 (m, 2H), 7.48-7.45 (d, J :84 HZ, 1H), 4.98 (s, 2H), 3.86 (s, 3H).

Step C: (R)-tert-Butyl 3-(6-flu0r00x0is0ind01inyl)piperidinecarb0xylate O O ’Boc Fdo —> CdeBr F / N To a solution of methyl 2-(bromomethyl)fluorobenzoate (35 g) in MeCN (400 mL) was added K2C03 (39 g, 0.29 mol) and 3-(R)-amino-piperidinecarboxylic acid tert-butyl ester (20 g, 0.10 mol). The reaction mixture was heated to reflux for about 3 h and then stirred at rt ght. The resulting suspension was filtered and the filtrate was trated under vacuum to give the residue which was dissolved in EtOAc (300 mL) and washed with brine (2X100 mL). The organic phase was dried over NaZSO4 and concentrated. The resulting residue was purified by column chromatography on silica gel (eluting with 15:1 petroleum ether: EtOAc) to give (R)-tert-butyl 3-(6-flu0r0 oxoisoindolin-Z-yl)piperidine-I-carb0xylate (12 g, 25%) as a solid: 1H NMR (CDCl3): 5 7.46-7.43 (d, J :76 Hz, 1H), 7.35-7.32 (d, J :80 Hz, 1H), 7.20-7.14 (m, 1H), .26 (m, 2H), 4.18 (m, 1H), .89 (m, 2H), 2.99-2.93 (m, 1H), 2.75 (s, 1H), 1.95-1.92 (m, 1H), 1.74-1.65 (m, 2H), 1.56-1.54 (m, 1H), 1.39 (s, 9H). 2014/044247 Step D: (R)Flu0r0(piperidinyl)is0indolin0ne hydrochloride 0 [Boc O F\©:l Preparation #31 : (R)(Piperidinyl)quinazolin-4(3H)-0ne Step A: (R)-tert-Butyl 3-(4-0x0quinazolin-3(4H)-yl)piperidinecarb0xylate o r/ OH —> NH2 h" To a solution of 2-aminobenzoic acid (7.5 g, 54.7 mmol) and 3-(R)-amino-piperidinecarboxylic acid tert-butyl ester (10.9 g, 54.7 mmol) in THF (20 mL) was added triethyl orthoformate (8.1 g, 54.7 mmol). The reaction mixture was heated to about 110 0C in a sealed tube overnight. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The combined c phase was washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to give a residue, which was ed by column tography on silica gel ng with 10:1 petroleum ether: EtOAc) to give (R)-tert-butyl 3-(4-0x0quinazolin-3(4H)-yl)piperidine-I-carb0xylate (7.5 g, 42%) as a yellow solid. 1H NMR (CDCl3): 8 8.34-8.32 (m, 1H), 8.11 (s, 1H), 7.80-7.71 (m, 2H), 7.55- 7.51 (m, 1H), 4.75 (br, 1H), 4.23-4.11 (br, 2H), .18 (t, 1H), 2.87 (br, 1H), 2.18-1.98 (m, 2H), 1.91-1.87 (br, 1H), 1.77-1.71 (m, 1H), 1.48 (s, 9H).

Step B: (R)(Piperidinyl)quinazolin-4(3H)-0ne The reaction solution of (R)-tert-butyl 3-(4-oxoquinazolin-3(4H)-yl)piperidinecarboxylate (12.5 g, 36 mmol) in 1M HCl/MeOH (150 mL) was stirred at about rt for about 2.5 h. The mixture was filtered. The solid was washed with EtOAc and dried to give (R)(piperidin-S-yl)quinazolin-4(3H)- one (10 g, 98%) as a white solid. LCMS (ESI+): m/Z 248 (M+H)+, RT: 1.90 min. 1H NMR (D20): 8 8.55-8.54 (d, J = 2.8 Hz, 1H), 7.80-7.77 (dd, J = 3.2 Hz, J = 2.8 Hz, 1H), 7.68-7.60 (m, 2H), 4.95- 4.89 (m, 1H), 3.61-3.57 (m, 1H), 3.46-3.43 (d, J: 12.4 Hz, 1H), 3.37-3.31 (t, 1H), 3.04-2.97 (m, 1H), 2.24-2.14 (m, 3H), 1.94-1.87 (m, 1H). ation #32 : (R)Flu0r0(piperidinyl)quinazolin-4(3H)-0ne hydrochloride H HCI Step A: (R)-tert-Butyl 3-(6-flu0r00x0quinazolin—3(4H)-yl)piperidinecarb0xylate o r/ FCW —> (7N NH2 1" The reaction on of 2-amino-5 -fluorobenzoic acid (7.5 g, 48.4 mmol), 3-(R)--amino-piperidine carboxylic acid tert-butyl ester (9.68 g, 48.4 mmol) and triethyl orthoformate (7.2 g, 48.4 mmol) in THF (20 mL) was heated to about 110 0C in a sealed tube overnight. After cooling to rt, the mixture was d with water. The aqueous layer was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluting with 10:1 petroleum ether: EtOAc) to give (R)-tert-butyl u0r00x0quinazolin-S(4H)-yl)piperidinecarb0xylate (6.25 g, 37%) as a solid. 1H NMR (CDCl3): 8 8.08 (s, 1H), 7.97-7.95 (m, 1H), 7.76-7.72 (m, 1H), 7.53-7.48 (m, 1H), 4.74 (br, 1H), 4.24-4.12 (br, 2H), 3.24-3.19 (t, 1H), 2.89 (br, 1H), .10 (m, 2H), .01 (m, 1H), 1.91-1.71 (m, 1H), 1.49 (s, 9H).

Step B: (R)Flu0r0(piperidinyl)quinazolin-4(3H)-0ne hydrochloride A solution of (R)-tert-butyl 3-(6-fluorooxoquinazolin-3(4H)-yl)piperidinecarboxylate (12.5 g, 36 mmol) in 1M HCl/MeOH (150 mL) was stirred at about rt about for about 2.5 h. The mixture was filtered and the solid was washed with EtOAc and dried to give (R)flu0r0(piperidin-S- yl)quinazolin-4(3H)-0ne hloride (10 g, 98%) as a solid. LC/MS (ESI+): m/Z 248 (M+H)+, RT: 1.90 min.1H NMR (D20): 8 8.55-8.54 (d, J = 2.8 Hz, 1H), 7.80-7.77 (dd, J = 3.2 Hz, J = 2.8 Hz, 1H), 7.68-7.60 (m, 2H), 4.95-4.89 (m, 1H), 3.61-3.57 (m, 1H), 3.46-3.43 (d, J: 12.4 Hz, 1H), 3.37-3.31 (t, 1H), 3.04-2.97 (m, 1H), .14 (m, 3H), 1.94-1.87 (m, 1H).

Preparation #33: 7-Cyclopropyl-S-flu0r0(piperidinyl)quinazolin-4(3H)-one hydrochloride (Ni/Om"F H HCI Step A: utyl 3-(7-br0m0flu0r00x0quinaz01in-3(4H)-yl)piperidinecarb0xylate N Br F o f/ of" H F Br NH2 '1" To a solution of 2-aminobromofluorobenzoic acid (7 g, 0.03 mol, prepared according to WO 2011075699) and 3-amino-piperidinecarboxylic acid tert-butyl ester (6.6 g, 0.033 mol) in THF (50 mL) was added triethyl orthoformate (6.6 g, 0.044 mol). The reaction mixture was heated at about 110 0C in a sealed tube overnight. After cooling to about rt, the mixture was diluted with water. The aqueous was extracted with EtOAC. The combined organic phase was washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced pressure to give a residue, which was purified by column tography on silica gel (eluting with 50:1 petroleum ether: EtOAC) to give tert-butyl 3- (7-br0m0flu0r00x0quinazolin-3(4H)-yl)piperidinecarb0xylate (6.4 g, 50%) as a solid. 1H NMR (CDCl3): 8 8.1 (s, 1H), 7.54-7.52 (dd, J = 2.4 Hz, 1H), 7.35-7.32 (dd, J = 2.8 Hz, 1H), 4.7 (br, 1H), 4.2-4.16 (br, 1H), 4.07-4.03 (br, 1H), .18 (t, 1H), 2.92-2.89 (br, 1H), 2.11-2.09 (br, 1H), 1.98-1.96 (br, 1H), 1.89-1.85 (br, 1H), 1.74-1.64 (br, 1H), 1.45 (s, 9H).

Step B: tert-Butyl 3-(7-cyclopropyl-S-fluor00x0quinazolin-3(4H)-yl)piperidinecarb0xylate r/N Br N (TN O F —’(TN 0 F I N Boo Boo To a mixture of tert-butyl 3-(7-bromofluorooxoquinazolin-3(4H)-yl)piperidinecarboxylate (20 g, 0.047 mol), Pd(OAc)2 (0.526 g, 0.002 mol), tricyclohexylphosphine (1.31 g, 0.005 mol), anhydrous K3PO4 (50 g, 0.236 mol) and water (40 mL) in toluene (200 mL) was added cyclopropylboronic acid (6.06 g, 0.07 mol). The reaction mixture was heated to reflux overnight under N2. After cooling to rt, the mixture was diluted with water. The aqueous layer was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaZSO4 and concentrated under reduced re to give a residue, which was ed by column chromatography on silica gel (eluting with 50:1 petroleum ether: EtOAc) to give tert-butyl 3-(7—cyclopr0pylflu0r0- 4-0x0quinazolin-3(4H)-yl)piperidine-I -carb0xylate (15 g, 83%) as a solid. 1H NMR (CDCl3): 5 7.96 (s, 1H), 7.07-7.04 (dd, J: 2.4 Hz, 1H), 6.71-6.67 (dd, J: 2.4 Hz, 1H), 4.68-4.65 (br, 1H), 4.16 (br, 1H), 4.06-4.02 (br, 1H), 3.37-3.33 (m, 1H), 3.08-3.02 (m, 1H), 2.82-2.76 (br, 1H), .01 (m, 1H), 1.90-1.69 (m, 2H), 1.64-1.60 (m, 1H), 1.40 (s, 9H), 1.20-1.06 (m, 2H), 0.712-0.608 (m, 2H).

Step C: 7-Cyclopropyl-S-flu0r0(piperidinyl)quinazolin(3H)-0ne hydrochloride m" m" (Nj/OF —> (Nj/OF H HCI A solution of tert-butyl yclopropylfluorooxoquinazolin-3(4H)-yl)piperidinecarboxylate (15 g, 0.039 mmol) in 1M HCl/MeOH (150 mL) was stirred at about rt for about 2.5 h. The mixture was filtered, the solid was washed with EtOAc and dried to give 7-cyclopr0pylflu0r0(piperidin- 3-yl)quinazolin-4(3H)-0ne hydrochloride (10 g, 91%) as a solid. LCMS (ESI+): m/Z 288 (M+H)+, Rt: 2.916 min. 1H NMR (D20): 8 8.56 (s, 1H), 6.99-6.96 (m, 1H), .82 (dd, J: 1.6 Hz, 1H), 4.87- 4.83 (m, 1H), 3.54-3.51 (m, 1H), 3.41-3.38 (d, 1H), 3.24-3.18 (t, 1H), 2.96-2.89 (t, 1H), .81 (m, 1H), 2.13-2.09 (m, 3H), 1.89-1.82 (m, 1H), 0.96-094 (br, 2H), 0.61 (br, 2H).

Preparation #34: 2-(Benzyloxy)(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)aniline Step A: 1-(Benzyloxy)br0m0nitr0benzene OH OBn N02 N02 Br Br To a solution of 4-bromonitrophenol (5 g, 22.9 mmol) in acetone (100 mL) was added (bromomethyl)benzene (4.7 g, 27.5 mmol) and K2C03 (6.3 g, 45.9 mmol). The mixture was refluxed overnight. After cooling to rt, the mixture was filtered. The filtrate was trated under d pressure to give a residue, which was washed with TBME to give I-(benzyloxy)br0m0 nitrobenzene (6.3 g, 89%): 1H NMR (CDCl3) 8 8.00 (d, J = 2.2 HZ, 1H), 7.60 (dd, J = 2.6, 8.8 HZ, 1H), 7.49-7.31 (m, 5H), 7.03 (d, J: 8.8 Hz, 1H), 5.24 (s, 2H).

Step B: 2-(Benzyloxy)br0m0aniline OBn OBn Br Br To a solution of 1-(benzyloxy)bromonitrobenzene (2 g, 6.5 mmol) in EtOH (80 mL) and water (20 mL) was added iron (1.8 g, 32.5 mmol) and NH4Cl (1.7 g, 32.5 mmol). The resulting mixture was refluxed for 3 h. The mixture was ed. The filtrate was d with water and extracted with EtOAc. The organic layer was concentrated to give 2-(benzyloxy)br0m0aniline (1.6 g, 89%): 1H NMR (CDCl3) 8 7.51 - 7.30 (m, 5H), 6.86 (d, J = 2.2 Hz, 1H), 6.83 - 6.76 (m, 1H), 6.74 - 6.66 (m, 1H), 5.07 (s, 2H), 3.91 (br, 2H) Step C: 2-(Benzyloxy)(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)aniline OBn NH2 Br 7L% —134— To a solution of 2-(benzyloxy)bromoaniline (2.0 g, 7.19 mmol) in DMSO (30 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.2 g, 8.6 mmol), Pd(dppf)C12 (0.53 g, 0.72 mmol) and potassium e (2.1 g, 21.6 mmol). The mixture was stirred at 80 OC ght under N2. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by column to give 2-(benzyloxy)(4,4,5,5-tetramethyl-1,3,2- orolan-Z-yl)aniline (1.5 g, 64%): 1H NMR (CDCl3) 8 7.55 - 7.29 (m, 5H), 7.23 - 7.12 (m, 2H), 6.86 (d, J: 7.9 Hz, 1H), 5.11 (s, 2H), 3.80 (br, 2H), 1.32 (s, 12H).

Preparation #35: 3-(Benzyloxy)(4,4,5,5-tetramethyl-1,3,2-di0xab0r01an—2-yl)aniline Step A: 3-Br0m0nitr0phenol MeO\©/NOZ —> HO\©/NOZ Br Br To a solution of 1-bromomethoxynitrobenzene (19 g, 82 mmol) in DCM (800 mL) was added dropwise BBr3 (27.9 mL, 295 mmol) in DCM (120 mL). The resulting mixture was heated to reflux overnight. After cooling in ice-water, the mixture was diluted by addition of water. Then the mixture was washed with brine. The organic phase was dried over Na2S04, trated under reduced re to give a residue, which was purified by column tography on silica gel to give 3- br0m0nitr0phenol (8 g, 44%) as a solid: 1H NMR (CDCl3) 8 7.89 (s, 1H), 7.57 (s, 1H), 7.27 (s, 1H), 5.27 (s, 1H).

Step B: 1-(Benzy10xy)br0m0nitr0benzene HO NO2 BnO N02 To a solution of 3-bromonitrophenol in acetone (50 mL) was added (bromomethyl)benzene (2.4 g, 13.8 mmol) and K2C03 (3.2 g, 22.9 mmol). The resulting mixture was heated to reflux overnight.

The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was washed with TBME to give I-(benzyloxy)br0m0nitr0benzene (1.3 g, 37%) as a solid: 1H NMR (CDCl3) 8 8.00 (s, 1H), 7.78-7.77 (m, 1H), 7.64-7.40 (m, 6H), 5.15 (s, 2H).

Step C: 3-(Benzyloxy)br0m0aniline Bn0\©/N02 BnO NH2 Br Br To a on of 1-(benzyloxy)bromonitrobenzene (1.3 g, 4.2 mmol) in EtOH (30 mL) and water (7.5 mL) was added iron (1.2 g, 21.1 mmol) and NH4Cl (1.1 g, 21.1 mmol). The e was heated to reflux overnight. The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was diluted by addition of water and extracted by EtOAc. The organic layer was concentrated under reduced pressure to give 3-(benzyloxy)br0m0aniline (1 g, 85%): 1H NMR (CDCl3) 8 7.33-7.31 (m, 5H), 6.48 (s, 1H), 6.39 (s, 1H), 6.14 (s, 1H), 4.92 (s, 2H), 3.63 (br, 2H).

Step D: 3-(Benzyloxy)(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)aniline BnO NH2 BnO NH2 Br j > 4 f To a solution of 3-(benzyloxy)bromoaniline (1 g, 3.6 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'— bi(1,3,2-dioxaborolane) (1.1 g, 4.3 mmol) in DMSO (1 mL) was added Pd(dppf)Clz (0.26 g, 0.36 mmol) and potassium acetate (1.1 g, 10.8 mmol). The mixture was heated to about 80 OC overnight under N2. After cooling to rt, the mixture was diluted by addition of water and extracted by EtOAc.

The organic layer was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to give 3-(benzyloxy)(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-Z-yl)aniline (1 g, 86%) as a solid: 1H NMR (CDCl3) 8 .31 (m, 5H), 6.87 (s, 1H), 6.77 (s, 1H), 6.43-6.42 (m, 1H), 5.05 (s, 2H), 3.64 (br, 2H), 1.34 (s, 12H). ation #36: 4-(Benzyloxy)br0m0nitr0benzene OH OBn N02 N02 Br Br To a solution of 4-bromonitrophenol (2 g, 9.17 mmol, Preparation #S. 1) in acetone (50 mL) was added BnBr (1.9 g, 11.0 mmol) and K2C03 (2.5 g, 18.4 mmol). The mixture was filtered. The filtrate was concentrated under reduced re to give a residue, which was washed with TBME to give 4- (benzyloxy)-1 -br0m0nitr0benzene (2.6 g, 92%): 1H NMR (CDCl3) 8 7.62 (d, J = 8.8 HZ, 1H), 7.48 (d, J: 2.6 Hz, 1H), 7.45 - 7.35 (m, 5H), 7.07 (dd, J: 2.9, 9.0 Hz, 1H), 5.12 (s, 2H).

Preparation #37: zyloxy)br0m0nitr0benzene 4 \‘ \ Step A: Methyl 2-(2-methoxy0x0ethyl)(4-meth0xybenzyl)-1H—pyrrolecarb0xylate \o "M" O NH O 0 / _ _ N O l / NH2 / o\ 0 A flask was charged with dimethyl 3-oxopentanedioate (77.0 g, 442 mol), (4- yphenyl)methanamine (60.1 mL, 460 mmol) and anhydrous NaOAc (72.5 g, 884 mmol) in dioxane (100 mL). The reaction mixture was d at about rt for about 30 min, then heated to about 50 OC and stirred for about 16 h. The reaction mixture was cooled to rt and dioxane (250 mL) was added. 2-chloroacetaldehyde (51.9 mL, 442 mmol) was added Via a dropping funnel. After about 7 h additional 2-chloroacetaldehyde (17.4 g, 221 mmol) was added and d for about 16 h. onal 2-chloroacetaldehyde (17.4 g, 221 mmol) was added and stirred for about 5 h, more 2- chloroacetaldehyde was added (25.9 mL, 221 mmol), the final portion of 2-chloroacetaldehyde (25.9 mL, 221 mmol) was added after about 2 h and left to stir for about 72 h. NaOAc (36.3 g, 442 mmol) was added and the solution and stirred for about 16 h. The reaction mixture was cooled under an ice bath and ice-water added to it (about 500 mL). The mixture was extracted with DCM (850 mL). The organic layer was washed with water (4 x 700 mL). The organic layer was dried over MgSO4, filtered and concentrated to give a Viscous oil. The crude material was purified Via flash chromatography (using heptane for 3 column volumes, 0-25% EtOAc/heptane over 4 column volumes, 20-35% over 4 column volumes). The pure fractions were combined and concentrated and minimal EtzO added to precipitate out a first batch of product which was collected Via filtration. The te was combined with the impure fractions, concentrated under vacuum and recrystallized from isopropanol to give a solid which was collected Via tion and combined with the first batch of product. The material was dried in a vacuum oven at about 70 0C for about 16 h to give methyl 2-(2-meth0xy0xoethyl) (4-meth0xybenzyl)-1H—pyrrolecarb0xylate (28.5 g, 20%): LC/MS (Table 1, Method as) R, = 2.20 min; MS m/z: 318 (M+H)+.

WO 10255 Step B: Methyl 2-(1-aminomethoxy0x0pr0penyl)(4-meth0xybenzyl)-1H-pyrrole carboxylate o’ o/ ) o o 7 N o/ _. N o/ l / | / \ O 0/ o o A flask was charged with NaH (23.3 g, 582 mmol) and THF (500 mL). The mixture was cooled to about 0 OC and methyl 2-(2-methoxyoxoethyl)(4-methoxybenzyl)-1H-pyrrolecarboxylate (28 g, 88 mmol) was added portion wise. The internal temperature measured below 10 0C during the addition. The suspension was stirred at about 0 0C for about 1 h. Methyl formate (7.62 mL, 124 mmol) was added. The reaction mixture was allowed to warm to rt and was stirred for about 16 h. onal methyl e (1.09 mL, 17.6 mmol) was added and the e stirred at rt for about 4 to 5 h, at which point all the starting material was consumed. The reaction was cooled on ice and quenched by the addition of MeOH (5 mL), and water was added carefully until effervescence stopped. The mixture was then acidified to pH of about 1 with aqueous 6N HCl, while keeping the flask on an ice bath. The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The aqueous layer was separated and extracted with EtOAc (3x50 mL). The combined organic layers were then dried over MgSO4 and ed. The solvent was evaporated to yield an oil consisting of two layers. The thinner top layer was clear and was separated using a pipette and discarded. The ing bottom layer was the crude intermediate, methyl 2-(1-hydroxymethoxyoxopropenyl)(4- methoxybenzyl)-1H-pyrrolecarboxylate. A flask was charged with this crude methyl 2-(1-hydroxy- 3-methoxyoxopropenyl)(4-methoxybenzyl)-1H-pyrrolecarboxylate (30 g, 87 mmol) and MeOH (300 mL). Ammonium acetate (33.5 g, 434 mmol) was added and the reaction mixture was refluxed for about 4 h and stirred at about 60 0C for about 72 h. The reaction mixture was concentrated under vacuum and diluted with water (200 mL) and EtOAc (200 mL). Part of the product precipitated out and was collected by filtration. The organic layer was separated. The aqueous layer was ted again with EtOAc (2x80 mL). The combined organic layers were dried over MgSO4, ed, and concentrated. The residue was suspended in EtzO (200 mL) and stirred for about 10 min and filtered to collect the product. This batch was combined with the us precipitate and dried in a vacuum oven at about 70 0C for about 4 h to give methyl 2-(1 -amin0 methoxy-S-oxoprop-I -enyl)-1 -(4-meth0xybenzyl)-1H—pyrrolecarb0xylate (25.7 g, 82%): LC/MS (Table 1, Method as) R, = 1.88 min; MS m/z: 345 (M+H)+.

WO 10255 Step C: Methyl eth0xybenzyl)0x0-4,5-dihydr0-1H-pyrrolo[3,2-c]pyridine carboxylate O |\ 0/ —> \ N /\NH2 \OOKQCi A flask was charged with methyl 2-(1-aminomethoxyoxopropenyl)(4-methoxybenzyl)- 1H-pyrrolecarboxylate (24.6 g, 71.4 mmol) and t-BuONa (6.87 g, 71.4 mmol) in DMA (100 mL).

The on was heated at about 150 0C for about 10 min, and cooled to rt. The solution was then poured onto ice-water (250 mL) and d with EtOAc (200 mL). The mixture was stirred at rt for about 45 min. The precipitate that formed was filtered and washed with water, then dried in a vacuum oven at about 70 0C for about 16 h to yield methyl I-(4-meth0xybenzyl)0x0-4,5-dihydr0-1H— pyrr010[3,2-c]pyridinecarb0xylate (18.9 g, 85%): LC/MS (Table 1, Method as) R, = 1.76 min; MS m/z: 313 (M+H)+.

Step D: Methyl 4-chlor0-1H-pyrr010[3,2-c]pyridinecarb0xylate 0 CI I \ N/ I \ A mixture of methyl 1-(4-methoxybenzyl)oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine carboxylate (24 g, 76 mmol) in phenyl phosphorodichloridate (30.8 mL, 206 mmol) was heated at about 150 0C for about 30 min. LCMS showed complete conversion to mixture of ester and acid.

The reaction mixture was cooled to about 0 OC and 50% aqueous NaOH was added slowly until pH of about 7. The reaction mixture was extracted with DCM (3x100 mL). The organic layers were combined and concentrated under reduced pressure. The residue was suspended in EtzO (100 mL), stirred at about 30 0C for about 1 h, cooled to rt and filtered. The filtrate was concentrated to give crude methyl 4-chloro(4-methoxybenzyl)-1H-pyrrolo [3,2-c]pyridinecarboxylate (22.5 g, 75%) as a black oil. A mixture of this crude methyl ro(4-methoxybenzyl)-1H-pyrrolo[3,2- c]pyridinecarboxylate (21.76 g, 65.8 mmol) and triflic anhydride (7.50 mL, 44.4 mmol) in TFA (50 mL) was stirred at about 50 0C for about 16 h. The reaction mixture was cooled to rt and added to ice cold NaHCO3 solution. Aqueous NaOH was slowly added to adjust the pH to about 9. The solid was ed and sonicated in EtzO. The precipitate was filtered of and the filtrate was concentrated to give 2014/044247 methyl 4-chlor0-IH—pyrrolo[3,2-c]pyridinecarb0xylate (9.4 g, 68% ): LCMS (Table 1, Method a) R, = 1.83 min; MS m/z: 211 (M+H)+.

Preparation #38: Methyl 4-(1-(tert-butoxycarbonyl)pyrrolidinyl)methyl-1H-indole carboxylate Step A: l-tert-Butyl 7-methyl 4-(1-(tert-butoxycarbonyl)pyrrolidinyl)methyl-lH-indole- 1,7-dicarb0xylate O O N N \ I \ N N Boc Boc \o o \o 0 To a solution of 1-tert-butyl 7-methyl 4-(1-(tert-butoxycarbonyl)pyrrolidinyl)iodo-1H-indole- 1,7-dicarboxylate (2.0 g, 3.5 mmol, Preparation #Y.1) in THF (35 mL) was added Zn(Me)2 (1 M in hexane, 21.04 mL, 21.04 mmol). The mixture was degassed using nitrogen and f)C12 (0.257 g, 0.351 mmol) was added in one portion and stirred at rt for about 19 h. The reaction was warmed to about 45 OC and stirred for about 22 h. The reaction mixture was carefully quenched by the addition of saturated aqueous NaHCO3 (50 mL) and d with EtOAc (50 mL) and brine (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2x50 mL). The combined organic extracts were washed with brine, dried over MgSO4, ed, concentrated under reduced pressure and purified by column chromatography on silica gel (0-50% EtOAc/heptane) to provide 1- tert-butyl 7-methyl tert-but0xycarbonyl)pyrrolidinyl)methyl-1H—indole-1,7-dicarb0xylate (1.45 g, 79%): LCMS (Table 1, Method ba) R, = 3.02 min; MS m/z: 476 (M+H)+. —140- Step B: Methyl 4-(1-(tert-butoxycarbonyl)pyrrolidinyl)methyl-1H-indolecarb0xylate N N \ \ N H \0 o \o o A solution of 1-tert-butyl 7-methyl 4-(1-(tert-butoxycarbonyl)pyrrolidinyl)methyl-1H-indole- 1,7-dicarboxylate (1.40 g, 3.05 mmol) in MeOH (7 mL) was added to a microwave reaction vial and the solution was heated to about 120 0C for about 30 min. The reaction mixture was adsorbed onto silica gel and purified using silica gel chromatography (0-50% EtOAc/heptane) to give methyl 4-(1- (tert-butoxycarbonyl)pyrrolidinyl)methyl-IH—indolecarb0xylate (1 g, 86%): LCMS (Table 1, Method as) R, = 2.58 min; MS m/z: 359 (M+NH4)+.

Preparation #39: Methyl 4-(1-(tert-but0xycarb0nyl)-1,2,5,6-tetrahydr0pyridinyl)t0syl-1H— indolecarb0xylate \ \ \ \ "1 "1 Ts Ts \o o \o o A flask was charged with methyl 4-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridinyl)tosyl- 1H-indolecarboxylate (2.00 g, 3.92 mmol, prepared using A from Preparation #1, step B with tert- butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)-carboxylate) in THF (39.2 mL). The solution was cooled to about -71 OC. LDA (1M solution in s/THF, 5.88 mL, .88 mmol) was added drop wise over about 5 min while ining the temperature below -65 OC.

The solution was stirred at about -72 0C for about 45 min. CH3I (0.367 mL, 5.88 mmol) was added.

The mixture was stirred at about -70 0C for a r 2.5 hours, and then quenched with a saturated aqueous Na2C03 on (150 mL). The mixture was ted with EtOAc (2 x 200 mL) and DCM (1 x 100 mL). The combined organic layers were dried over NaZSO4, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel % EtOAc/heptane) to provide methyl 4-(1 -(tert-butoxycarbonyl)-1 , 2, 5, 6-tetrahydr0pyridinyl)-1 -t0syl-IH—indole-7— carboxylate (1.67 g, 57%, 70% purity): LCMS (Table 1, Method as) R, = 2.88 min; MS m/z: 542 (M+NH4)+. —141— Preparation #40: tert-butyl 3-((7-carbamoyliodo-1H-indolyl)(methyl)amino)azetidine carboxylate N O \ L 4\ \ I H2N 0 Step A: Methyl 4-((1-(tert-butoxycarbonyl)azetidinyl)(methyl)amino)iodotosyl-1H- indolecarboxylate To a solution of methyl (tert-butoxycarbonyl)azetidinyl)(methyl)amino)tosyl-1H-indole carboxylate (4.00 g, 7.79 mmol, prepared using T from Preparation #1, step C with tert-butyl-S- aminoazetidinecarboxylate and J with CH3I ) in THF (60 mL) at about -78 0C was added slowly LDA (2M solution in THF, 5.84 mL, 11.7 mmol). The reaction was stirred at about -78 0C for about 1 h and a solution of 12 (2.97 g, 11.7 mmol) in THF (10 mL) was added slowly and the reaction stirred at about -78 0C for about 4 h. The cooling bath was removed to warm the reaction to rt and the reaction was quenched by the addition of saturated aqueous 3 (120 mL), extracted with additional EtOAc (2 X 150 mL) and washed with brine (2X150 mL). The combined organics were dried with ous , filtered and concentrated under reduced pressure to give the crude product, methyl 4-((I -(tert-butoxycarbonyl)azetidin-S-yl)(methyl)amino)i0d0-I -t0syl-IH—indole carboxylate (4.1 g, 80%): LC/MS (Table 1, Method aa) R, = 1.87 min; MS m/z: 640 (M+H)+. —142— Step B: 4-((1-(tert-Butoxycarbonyl)azetidin—3-yl)(methyl)amin0)i0d0-1H-indolecarb0xylic acid N o o N pk L" o \ N Né-o \ \o 4- 00 m To a solution of methyl 4-((1-(tert-butoxycarbonyl)azetidinyl)(methyl)amino)iodotosyl-1H- indolecarboxylate (15.5 g, 24.2 mmol) in MeOH (75 mL):THF (75 mL):water (30 mL) was added KOH (9.52 g, 170 mmol). The mixture was stirred at about 60 0C for about 16 h, cooled, and acidified with s 2N HCl. It was extracted with EtOAc (2 x 350 mL) and washed with brine (2 x 300 mL). The combined organics were dried with anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product 4-((I -(tert-butoxycarbonyl)azetidin-S-yl)(methyl)amin0) iodo-IH-indolecarb0xylic acid (11.4 g, 99 %): LC/MS (Table 1, Method aa) R, = 1.86 min; MS m/z: 416 (M +H-tBu)+.

Step C: tert-Butyl 3-((7-carbam0yli0d0-1H-ind01yl)(methyl)amin0)azetidine-l-carb0xylate O 0 L, JL i —> \ I \ I N Z N HO o H2N 0 4-((1-(tert-Butoxycarbonyl)azetidinyl)(methyl)amino)iodo-1H-indolecarboxylic acid (13.7 g, 29.1 mmol) and EDC (11.2 g, 58.1 mmol) were dissolved in DMF (260 , HOBt (8.90 g, 58.1 mmol) mL) and DIEA (25.4 mL, 145 mmol) was added. The mixture was stirred at rt for about 10 min and NH4Cl (12.4 g, 233 mmol) was added. The e was stirred at rt for about 16 h and saturated aqueous NH4Cl (1 L) was added. The solid was collected by filtration, washed with water, and dried to give the crude product tert-butyl carbam0yli0d0-IH—indolyl)(methyl)amin0)azetidine-I - ylate (13.4 g, 97%): LC/MS (Table 1, Method aa) R, = 1.81 min; MS m/z: 471 (M+H)+. —143- 2014/044247 Preparation #41: 4-(Azetidinyl(methyl)amino)(tetrahydrofuran—3-yl)-1H-indole carboxamide )1 NH \NLN O \NL _. o \ I N\ fl H o NH2 HZN o A reaction Vial was charged with tert-butyl 3-((7-carbamoyliodo-1H-indol thyl)amino)azetidinecarboxylate (0.050 g, 0.11 mmol, Preparation #40), (Z)-butene-1,4- diol (0.014 g, 0.16 mmol), NaHCO3 (10.7 mg, 0.128 mmol) and PdClZ (1.885 mg, 10.63 umol) in NMP (1.2 mL). The mixture was purged with nitrogen and heated at about 130 0C for about 1 h. It was extracted with EtOAc (2 x 20 mL) and washed with brine (2 x 20 mL). The combined organics were dried over anhydrous Na2S04, ed, concentrated under reduced pressure and purified by Prep TLC (EtOAc) to give crude tert-butyl 3-((7-carbamoyl(2,3-dihydrofuranyl)-1H-indol yl)(methyl)amino)azetidinecarboxylate (0.028 g, 39%). A mixture of tert-butyl 3-((7-carbamoyl (2,3-dihydrofuranyl)-1H-indolyl)(methyl)amino)azetidinecarboxylate (0.055 g, 0.081 mmol) in DCM (1.5 mL) was stirred at about 0 0C in an ice bath. Triethylsilane (0.014 g, 0.12 mmol) was added and then BF3.OEt2 (0.015 mL, 0.122 mmol) was added drop wise. The mixture was stirred at about 0 0C for about 1 h and quenched with a saturated aqueous solution of Na2C03 to a pH of about 8 then filtered. The te was purified by Prep HPLC (Table 1, method be) to give 4-(azetidin yl(methyl)amin0)(tetrahydrofuran-S-yl)-IH-indolecarb0xamide (0.008 mg, 28%): LC/MS (Table 1, Method av) R, = 1.03 min; MS m/z: 315 (M+H)+.

Preparation #42: Methyl 4-((1-(tert-but0xycarb0nyl)azetidinyl)(methyl)amin0)(3- hydroxyoxetanyl)t0syl-1H-ind01ecarb0xylate —* HO \ o No‘ S \ 0‘3 o \o o o \b To a cold on of methyl 4-((1-(tert-butoxycarbonyl)azetidinyl)(methyl)amino)tosyl-1H- indole-7—carboxylate (0.80 g, 1.56 mmol, prepared using T from Preparation #1, step C with tert- butylaminoazetidinecarboxylate and J with CH3I) in THF (12 mL) at about -78 0C was added slowly LDA (2M on in THF, 1.168 mL, 2.336 mmol). The reaction was stirred at about -78 0C for about 1 h, then a solution of oxetanone (0.168 g, 2.34 mmol) in THF (1 mL) was added slowly —144— 2014/044247 and the reaction e was stirred at about -78 0C for about 4 h. The cooling bath was removed and the reaction was quenched with saturated aqueous NH4CI solution. The mixture was extracted with EtOAc (2x50 mL) and washed with brine (2 x5 0 mL). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by Prep-TLC (1:1 EtOAc/pet. EtzO) to give methyl (tert-butoxycarbonyl)azetidinyl)(methyl)amin0)(3- hydroxyoxetan-S-yl)-I-t0syl-1H—indolecarb0xylate (0.55 g, 59%): LC/MS (Table 1, Method av) R, = 1.67 min; MS m/z: 586 (M+H)+.

Preparation #43: tert-Butyl 2-(7-cyan0t0syl-1H-indolyl)m0rph01inecarb0xylate Step A: 0t0syl-1H-ind01ecarb0nitrile \ _. NU/O H CN 043 A round bottom flask was charged with 4-bromo-1H-indolecarbonitrile (4.50 g, 20.4 mmol) and THF (75 mL). The solution was cooled to about 0 OC followed by the addition of NaH (60% dispersion in mineral oil, 1.22 g, 30.5 mmol). The solution was stirred at about 0 0C for about 40 min followed by the on of 4-methylbenzenesulfonyl chloride (4.66 g, 24.4 mmol). The ice bath was removed and the e was stirred at rt for about 15 h. The mixture was poured onto ice water (~150 mL) and the product was extracted with EtOAc (4x75 mL). The combined extracts were washed with water (75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 4-br0m0-I-t0syl-IH—indolecarb0nitrile (5.74 g, 75%): 1H NMR (400 MHZ, DMSO-d6) 5 8.21 (d, J = 3.9 Hz, 1H), 7.97 — 7.89 (m, 2H), 7.80 — 7.64 (m, 2H), 7.56 — 7.42 (m, 2H), 7.00 (d, J = 3.8 Hz, 1H), 2.38 (s, 3H).

Step B: 1-T0sylvinyl-1H-indolecarb0nitrile —145- A round bottom flask was charged with 4-bromotosyl-1H-indolecarbonitrile (8.54 g, 22.8 mmol), Na2C03 (7.24 g, 68.3 mmol) and dppf) (1.665 g, 2.276 mmol) followed by the addition of THF (70.2 mL): MeOH (10.03 mL): water (10.03 mL). The reaction mixture was purged with N2 for about 15 min, 4,4,5,5-tetramethylVinyl-1,3,2-dioxaborolane (4.63 mL, 27.3 mmol) was added and the mixture was heated to about 70 0C for about 5 h. The mixture was cooled to rt and DCM (75 mL) and water (50 mL) were added. The layers were separated and the s layer was extracted with DCM (50 mL). The combined extracts were dried over MgSO4, filtered, concentrated under reduced pressure and passed through a plug of silica gel, eluting with DCM, and concentrated under vacuum. The residue was suspended in a mixture of EtzO/EtOAc, filtered and then washed the itate with a small amount of EtOAc/EtZO. The material thus obtained was dried in vacuum oven to give 1-t0sylvinyl-IH-indolecarb0nitrile (5.62 g, 77%): LC/MS (Table 1, Method as) R, = 2.57 min; MS m/z: 323 (M+H) +.

Step C: 4-(Oxiranyl)t0syl-1H-indolecarb0nitrile _> \ TS N | 1 Ts N H To a suspension of 1-tosylVinyl-1H-indolecarbonitrile (0.40 g, 1.241 mmol) in dioxane (16 mL) and water (8 mL) was added AcOH (0.0710 mL, 1.24 mmol). The mixture was cooled to about 0 0C.

NBS (0.243 g, 1.36 mmol) was added in one portion. The reaction was allowed to warm to rt and stirred for about 2 h. NaOH (2M aqueous solution, 8.0 mL, 16 mmol) was added in one portion. The solid formed was collected by tion, washed with water and dried in a vacuum oven at about 60 0C for about 16 h to give 4-(oxiran-Z-yl)-1 -t0syl-IH—indolecarb0nitrile (0.29 g, 68% ): LC/MS (Table 1, Method as) R, = 2.36 min; MS m/z: 339 (M+H)+.

Step C: 4-(1-Hydr0xy((2-hydr0xyethyl)amin0)ethyl)t0syl-1H-indolecarb0nitrile HO H01 \ ’ \ \ N H ‘Ts N | | To a suspension of 4-(oxiranyl)tosyl-1H-indolecarbonitrile (0.285 g, 0.841 mmol) in IPA (8 mL) was added TEA (0.586 mL, 4.21 mmol) ed by oethanol (0.253 mL, 4.21 mmol).

The mixture was heated at about 75 0C for about 3 h and concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The mixture was extracted with EtOAc (2x10 mL). The combined organic layers were dried over NaZSO4, filtered, concentrated and dried under a vacuum pump to give 4-(1-hydr0xy((2-hydr0xyethyl)amin0)ethyl)t0syl-IH—indolecarb0nitrile (0.39 g, 94%): LC/MS (Table 1, Method as) R, = 1.53 min; MS m/z: 400 (M+H)+.

Step D: tert-Butyl (2-(7-cyan0t0syl-1H—indolyl)hydr0xyethyl)(2-hydr0xyethyl)carbamate HO "NOH Boc HO N/VOH __ \ N N.

I I Ts To a solution of 4-(1-hydroxy((2-hydroxyethyl)amino)ethyl)tosyl-1H-indolecarbonitrile (0.336 g, 0.673 mmol) in EtOAc (3 mL) was added DIEA (0.176 mL, 1.01 mmol) followed by drop wise addition of a solution of di-tert-butyl dicarbonate (0.220 g, 1.01 mmol) in EtOAc (1 mL) at rt.

THF (1 mL) was added to help solubilize the mixture and stirred at rt for about 2 h. Additional DIEA (0.060 mL, 0.34 mmol) and t-butyl dicarbonate (0.073 g, 0.34 mmol) were added. The mixture was stirred at rt for about another 2 h. The solvent was removed under reduced pressure and purified by flash chromatography (25-50 % heptane) then by HPLC (Table 1, Method bd) to give tertbutyl (2-(7—cyan0-I-t0syl-IH—indolyl)hydr0xyethyl)(2-hydr0xyethyl)carbamate (0.25 g, 74%): LC/MS (Table 1, Method as) R, = 2.22 min; MS m/z: 500 (M+H)+.

Step E: tert-Butyl 2-(7-cyan0t0syl-1H-indolyl)m0rph01inecarboxylate HO I °/°\/0H (\N N O \ —> Ts N\ I I Ts To a Vial charged with tert-butyl-(2-(7-cyanotosyl-1H-indolyl)hydroxyethyl)(2- yethyl)carbamate (0.50 g, 1.0 mmol) and PPh3 (0.315 g, 1.20 mmol) in toluene (10 mL) at about 0 0C was added TEA (0.367 mL, 2.63 mmol) followed by addition of DCAD (0.441 g, 1.20 mmol). The solution was stirred at about 0 0C for about 5 min and then d at about rt for about 16 h. onal PPh3 (0.131 g, 0.500 mmol) and DCAD (0.184 g, 0.500 mmol) were added at rt and the mixture was stirred at about rt for about 6 h. The reaction mixture was filtered and the filtrate was concentrated and ed by flash chromatography (0-30% EtOAc/heptane) to give tert-butyl 2-(7— cyano-I-tosyl-IH—indolyl)morpholinecarboxylate (0.41 g, 84%): LC/MS (Table 1, Method as) R, = 2.72 min; MS m/z: 499 (M+H20)+. —147— 2014/044247 Preparation #44: 2-Iod0-6,7-dihydro-4H—pyrazolo[5,1-c][1,4]0xazine / 0 Step A: 2-Nitr0-6,7-dihydr0-4H-pyrazolo[5,1-c][1,4]0xazine ' N\ \N" N / —> \N" / N/fi I, ARCH OI/ / O A mixture of (1-(2-bromoethyl)nitro-1H-pyrazolyl)methanol (4.0 g, 12 mmol) [Princeton] in NMP (7.7 mL) was heated at about 130 0C for about 16 h. The mixture was diluted with DCM and washed with water and brine. The organic layer was dried, concentrated and purified by chromatography on silica gel (0-5% MeOH/ DCM) to give 2-nitr0-6,7-dihydr0-4H—pyrazolo[5,1- c][1,4]0xazine (1 g, 49%): 1H NMR (400 MHZ, DMSO-ds) 8 6.88 (s, 1H), 4.83 (s, 2H), 4.24 (t, J = .2 Hz, 2H), 4.13 (dd, J: 5.9, 4.6 Hz, 2H).

Step B: 6,7-dihydr0-4H-pyrazolo[5,1-c][1,4]0xazinamine o" / O / O A flask was charged with Pd/C (10 wt%, 0.755 g, 0.709 mmol) under nitrogen before the on of a solution of 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (4.0 g, 24 mmol) in EtOAc (59.1 mL) and MeOH (59.1 mL). The reaction stirred at rt for about 16 h. The reaction mixture was filtered through a plug of Celite® and the filtrate was concentrated under reduced pressure to afford 6, 7- 0-4H-pyrazolo[5,1 -c][1,4]0xazinamine (3.2 g, 97%): LC/MS (Table 1, Method as) R, = 0.61 min; MS m/z: 140 (M+H)+.

Step C: 2-Iod0-6,7-dihydr0-4H-pyrazolo[5,1-c][1,4]0xazine A 50 mL round-bottom flask was charged with 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinamine (1.5 g, 11 mmol) and concentrated HCl (2.43 mL, 29.6 mmol).. The mixture was cooled to about 0 0C. A solution of NaNOZ (0.707 g, 10.2 mmol) in water (10 mL) was added and the reaction stirred for about 15 min. A solution of K1 (2.86 g, 17.3 mmol) in water (10 mL) was added lly and the reaction was stirred at about 0 0C for about 1 h and stirred at rt for about 30 min. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL) and then separated from the aqueous layer. The solution was purified Via chromatography on silica gel (0-50% EtOAc/heptane) to give -6,7— dihydro-4H—pyrazolo[5,I-c][1,4]0xazine (0.996 g, 37%): LC/MS (Table 1, Method as) R, = 1.58 min; MS m/z: 251 (M+H)+.

Preparation #45: Methyl 4-chlor0t0syl-1H-pyrrolo[3,2-c]pyridinecarb0xylate A round bottom flask was d with methyl 1H-pyrrolo[3,2-c]pyridinecarboxylate (14 g, 79 mmol) and THF (225 mL) ablock] and the on was cooled to about 5 OC followed by the addition of KHMDS (1M in THF, 79 mL, 79 mmol). The solution was then stirred for about 1 h followed by the addition of a solution of 4-methylbenzenesulfonyl chloride (15.2 g, 79.0 mmol) in THF (25 mL). The mixture was stirred for about 2 h at about 0 to 5 OC followed by the addition of saturated aqueous NH4Cl and DCM. The layers were separated and the organic solution was dried over MgSO4, filtered, concentrated under reduced re and purified by silica gel chromatography ( 0-50% EtOAc/DCM) to give methyl I-tosyl-IH—pyrrolo[3,2-c]pyridinecarb0xylate (18.8 g, 72%): LC/MS (Table 1, Method as) R, = 2.10 min; MS m/z: 331 (M+H)+.

Step B: 7-(Meth0xycarb0nyl)t0syl-lH-pyrrolo[3,2-c]pyridine 5-0xide NI \ \ _O‘N|+ \ \ 0 $0" (1 o w r; A round bottom flask was charged with methyl 1-tosyl-1H-pyrrolo[3,2-c]pyridinecarboxylate (16.0 g, 48.4 mmol) and EtOAc (150 mL). To the reaction solution was added a solution of 3- chlorobenzoperoxoic acid (14.2 g, 82 mmol) in EtOAc (80 mL) and stirred at rt for about 16 h. To the reaction mixture was added saturated aqueous Na2C03 (50 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2x30 mL) and DCM (2x30 mL). The combined extracts were dried over Na2S04, filtered and concentrated under reduced pressure to give a thick oil that was —149- dried on a vacuum pump to give 7-(methoxycarbonyl)-1 -t0syl-1H—pyrrolo[3,2-c]pyridine e (11.6 g, 69%): LC/MS (Table 1, Method as) R, = 1.73 min; MS m/z: 347 (M+H)+.

Step C: Methyl 4-chlor0t0syl-1H-pyrr010[3,2-c]pyridinecarb0xylate A round bottom flask was charged with 7-(methoxycarbonyl)tosyl-1H-pyrrolo[3,2-c]pyridine 5- oxide (11.6 g, 33.5 mmol) and PCl3 (26.5 mL, 285 mmol) and heated to about 60 0C for about 2 h.

The solution was cooled to rt and slowly poured into ice water with stirring and the resulting mixture was neutralized with the addition of saturated aqueous Na2C03. The aqueous mixture was extracted with EtOAc (3x40 mL) and the combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 4-chlor0-1 -t0syl-1H—pyrrolo[3,2-c]pyridinecarb0xylate (8.47 g, 69%): LC/MS (Table 1, Method as) R, = 2.46 min; MS m/z: 365 (M+H)+. ation #46: 7-Chlor0(1-methyl-1H-pyrazolyl)thiazolo[5,4-c]pyridinecarb0xamide Step A: (E)-Ethyl 3-(2-br0m0thiazolyl)acrylate in \O S /N A 1 L round-bottom flask was charged with ethyl 2-(triphenylphosphoranylidene)acetate (37.2 g, 107 mmol) in DCM (130 mL) to give a colorless solution. The solution was cooled to about 0 OC and a solution of 2-bromothiazolecarbaldehyde (20.5 g, 107 mmol) [ArkPharm] in DCM (500 mL) was added drop wise Via a dropping funnel. The reaction mixture was slowly warmed to rt and d for about 2 h then concentrated under reduced pressure. The e was taken up in EtzO (300 mL) and stirred at about 40 0C for about 30 min. It was then cooled, filtered and washed with EtzO (50 mL).

The itate was discarded and the filtrate was concentrated to half the volume. The precipitate formed was collected Via filtration to give the first batch of product. The filtrate was concentrated and EtzO was added (60 mL), the mixture was stirred at rt for about 20 min and the newly formed itate was filtered again to collect a second batch of product. The filtrate from this batch was concentrated under reduced pressure and purified silica gel chromatography (0-10% EtOAc/heptane).

The material thus ed was recrystallized from EtzO to give a third and final batch of product. All the batches were combined to give white crystalline al, (E)-ethyl 3-(2-br0m0thiaz01—4- yl)acrylate (20.1 g, 72%): LC/MS (Table 1, Method as) R, = 2.26 min; MS m/z: 262, 264 (M+H)+.

Step B: (E)-Ethyl 3-(2-(1-methyl-1H-pyrazolyl)thiazolyl)acrylate o) O O \ \ —> __ S / Br \\Ni\l A 500 mL round bottom flask was charged with 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole (20.7 g, 100 mmol), (E)-ethyl 3-(2-bromothiazolyl)acrylate (20.1 g, 77.0 mmol), Na2C03 (24.4 g, 230 mmol), dppf) (5.61 g, 7.67 mmol) and (E)-ethyl 3-(2-bromothiazol yl)acrylate (20.1 g, 77.0 mmol). To the solid mixture was added THF (150 mL): MeOH (21.00 mL): water (21 mL) and the suspension was degassed and purged with N2 for about 20 min. The reaction mixture was heated at about 75 0C for about 15 h. The reaction was filtered and washed with EtOAc (100 mL) and the filtrate was washed with water (70 mL). The aqueous layer was extracted with EtOAc (2x70 mL) and the combined organics were dried over MgSO4, ed and concentrated. To the residue was added DCM (50 mL) and heptane (150 mL). The entire suspension was filtered, washed with acetone and isopropanol and dried in a vacuum oven to give the first batch of product.

The filtrate was concentrated, dissolved in DCM (40 mL) and passed through a silica gel plug (eluent: 50% EtOAc/heptane). The filtrate was concentrated and refluxed in e (35 mL) and cooled. The precipitate was filtered, washed with isopropanol combined with the first batch and dried in a vacuum oven at about 70 0C for about 16 h to give (E)-ethyl 3-(2-(1-methyl-IH—pyrazolyl)thiazol- 4-yl)acrylate (15.2 g, 75%): LC/MS (Table 1, Method as) R, = 1.94 min; MS m/z: 264(M+H)+.

Step C: (E)(2-(1-Methyl-1H-pyrazolyl)thiazolyl)acrylic acid In a 20 mL reaction vial, (E)-ethyl 3-(2-(1-methyl-1H-pyrazolyl)thiazolyl)acrylate (15.2 g, 57.7 mmol) and LiOH (4.15 g, 173 mmol) in MeOH (60 mL): water (12 mL) were added. The reaction mixture was stirred at about 40 0C for about 2 h. The reaction mixture was concentrated, diluted with water (50 mL) and washed with DCM (50x3 mL). The aqueous layer was acidified with 1N HCl until no more itate . The precipitate was collected via filtration and dried in a vacuum oven at about 60 0C for about 16 h to give (E)(2-(1-methyl-IH-pyrazolyl)thiazolyl)acrylic acid (12.3 g, 91%): 1H NMR (400 MHZ, DMSO-d6) 8 12.42 (s, 1H), 8.38 (s, 1H), 7.94 (s, 2H), 7.56 (s, 1H), 6.56 (s, 1H), 3.90 (s, 3H).

Step D: (E)(2-(1-Methyl-1H-pyrazolyl)thiazolyl)acryloyl azide To a suspension of (E)(2-(1-methyl-1H-pyrazolyl)thiazolyl)acrylic acid (11.2 g, 47.4 mmol) in acetone (170 mL) was added TEA (6.61 mL, 47.4 mmol) and the mixture was cooled in an ice bath.

Isobutyl chloroformate (6.22 mL, 47.4 mmol) was added drop wise. After about 3.5 h a solution of NaN3 (3.85 g, 59.2 mmol) in water (15 mL) was added lly and the reaction was d for about 3 h at about 0 OC. The reaction mixture was poured over ice and stirred for about 5 min, filtered and washed with water (50 mL). The precipitate was dried in a vacuum oven at about 60 0C for about 16 h to give (E)(2-(1-methyl-IH—pyrazolyl)thiazolyl)acryloyl azide (9.6 g, 78%): LC/MS (Table 1, Method as) R, = 1.91 min; MS m/z: 261(M+H)+.

Step E: 2-(1-methyl-1H-pyrazolyl)thiazolo[5,4-c]pyridin—4(5H)-0ne 9?0 HN —" S /N S /N // N—N N’N / A 250 mL 3- neck round-bottomed flask was charged with tributylamine (6.10 mL, 25.6 mmol) in diphenylether (30 mL). The reaction e was heated to about 190 OC and a solution of (E)(2- (1-methyl-1H-pyrazolyl)thiazolyl)acryloyl aZide (5.60 g, 21.5 mmol) in diphenylether (80 mL) was added carefully and the reaction was stirred for about 5 h at about 190 OC. The on mixture was cooled and poured onto petroleum ether (300 mL) and stirred for about 5 min and filtered. The precipitate was dried in a vacuum oven at about 70 0C for about 30 min. The material was ded in EtzO (100 mL) and heated at about 50 0C for about 20 min. It was then filtered and washed with cold EtzO. The precipitate was dried in a vacuum oven at about 70 0C for about 10 h to give 2-(1- methyl-IH-pyrazolyl)thiazolo[5,4-c]pyridin-4(5H)-0ne (3.8 g, 76 %): LC/MS (Table 1, Method as) R, = 1.13 min; MS m/z: 233 (M+H)+.

Step F: 7-Chlor0(1-methyl-1H-pyrazolyl)thiaz010[5,4-c]pyridin-4(5H)-0ne S /N S ,N // % N-N N-N / / In a 250 mL round-bottom flask 2-(1-methyl-1H-pyrazolyl)thiazolo[5,4-c]pyridin-4(5H)-one (3.7 g, 16 mmol) in MeCN (80 mL) was added to give a suspension. The reaction mixture was heated with ng to about 80 0C. A solution of NCS (3.19 g, 23.9 mmol)) in MeCN (25 mL) was added drop wise via a dropping funnel, and the reaction was stirred for about 5 h at about 80 OC. The mixture was diluted with water (100 mL), filtered and washed with water (40 mL). The precipitate was dried in a vacuum oven at about 70 0C for about 16 h to give 7-chlor0(I-methyl-1H—pyrazol yl)thiazolo[5,4-c]pyridin-4(5H)-0ne (3.55 g, 84 %): LC/MS (Table 1, Method as) R, = 1.27 min; MS m/z: 267 (M+H)+.

Step G: 4-Br0m0chlor0(1-methyl-1H-pyrazolyl)thiazolo[5,4-c]pyridine CI CI / N \N / N I \ \ | —> I \ \ l s N\ N\ s N\ 0 Br In a 100 mL 3-neck round-bottom flask a mixture of ro(1-methyl-1H-pyrazol yl)thiazolo[5,4-c]pyridin-4(5H)-one (1.30 g, 4.87 mmol) and POBr3 (3.91 g, 13.6 mmol) was heated to about 70 0C for about 10 min then heated to to about 120 0C for about 45 min. Additional POBr3 (1.40 g, 4.87 mmol) was added and heated for about 50 min. The mixture was cooled on an ice bath and to it was added carefully a mixture of crushed ice and water (40 mL). The mixture was stirred at rt for about 16 h. To the suspension was added DCM (60 mL) and stirred for about 30 min, then filtered to remove some black solids. The DCM layer was separated and aqueous layer was extracted with DCM (2x20 mL). The combined organic layers were dried over MgSO4, filtered and adsorbed on silica gel (4-6 g). The material was purified by silica gel chromatography (1-3% EtOAc/heptane) to give 4-br0m0-7—chlor0(1-methyl-IH—pyrazolyl)thiazolo[5,4-c]pyridine (0.85 g, 53%): LC/MS (Table 1, Method as) R, = 2.20 min; MS m/z: 331 (M+H)+.

Step H: 7-Chlor0(1-methyl-1H-pyrazolyl)thiazolo[5,4-c]pyridinecarb0nitrile CI CI / N \N / N l \ \ I —> | \ \ I H2N o In a 50 mL round-bottom flask, 4-bromochloro(1-methyl-1H-pyrazolyl)thiazolo[5,4- c]pyridine (0.770 g, 2.13 mmol), Zn(CN)2 (0.168 g, 1.44 mmol) and Pd(PPh3)4 (0.174 g, 0.151 mmol) in DMF (10 mL) were added. The flask was degassed and purged with nitrogen then heated lly under nitrogen at about 110 0C to 120 0C for about 50 min. The on mixture was diluted with water (25 mL) and stirred for about 5 min, filtered and washed with water (6 mL). The precipitate was dried in a vacuum oven at about 70 0C for about 16 h to give crude 7-chloro(1- methyl-1H-pyrazolyl)thiazolo[5,4-c]pyridinecarbonitrile (0.67 g, 98%). To a flask charged with NaOH (1M aqueous solution, 7.29 mL, 7.29 mmol) in MeOH (12 mL) was added H202 (30% aqueous solution, 1.24 mL, 12.2 mmol). This solution was added to a flask containing 7-chloro(1-methyl- 1H-pyrazolyl)thiazolo[5,4-c]pyridinecarbonitrile (0.670 g, 2.43 mmol) and stirred at about 30 0C for about 5 min. The on e was diluted with water (51 mL) and stirred at rt for about 5 min and filtered. The precipitate was ated with EtzO, filtered and dried in a vacuum oven for about 16 h to give 7-chlor0(I l-1H—pyrazolyl)thiazolo[5,4-c]pyridinecarboxamide (0.597 g, 84%): LC/MS (Table 1, Method as) R, = 1.58 min; MS m/z: 294(M+H)+. —154— 2014/044247 Preparation #47: Methyl 4-((1R,3R)((tert-butoxycarbonyl)amino)cyclopentyl)tosyl-1H- indolecarboxylate NHBoc MeO 0 Step A: Methyl 4-(3-oxocyclopentenyl)tosyl-1H-indolecarboxylate Ox /0 B Q N\ 40 O \ 6’8 N (I) O MeO O A flask was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)tosyl-1H—indole- 7-carboxylate (1.74 g, 3.82 mmol, prepared using A from Preparation #1, step C with bis(pinacolato)diboron) in 2-methyl-THF(18.64 mL) and water (12.43 mL). The mixture was cooled to about 10 0C in a cold water bath. NaIO4 (1.23 g, 5.73 mmol) was added, the reaction was d for about 30 min and aqueous 1M HCl (8.41 mL, 8.41 mmol) was added drop wise. The mixture was stirred at rt for about 16 h. Additional 2-methyl-THF (50 mL) was added, the aqueous layer was separated and the organic layer was washed with 10% s Na2S203 (2x30 mL), ted aqueous NaHCO3 (30 mL) and brine (20 mL). The organic layer was then dried over Na2S04, filtered and trated to afford crude (7-(methoxycarbonyl)tosyl-1H—indolyl)boronic acid. In a 100 mL round-bottom flask the crude (7-(methoxycarbonyl)tosyl-1H-indolyl)boronic acid (1.59 g, 4.26 mmol) in e (17 mL) was added. A solution of Cs2C03 (3.47 g, 10.7 mmol) in water (4.26 mL) was added, the mixture was degassed with nitrogen followed by the addition of PdC12(PPh3)2 (0.209 g, 0.298 mmol) and 3-bromocyclopentenone (1.4 mL, 12.8 mmol) under inert atmosphere. The mixture was heated at about 80 0C for about 3 h then cooled to rt and added DCM (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2x50 mL). The combined organics were dried over MgSO4. The solvent was removed in vacuo and the residue was purified using silica gel chromatography (0-60% EtOAc/heptane) to afford methyl 4-(3-0x0cyclopent- I—en-I-yl)-I-t0syl-1H-indolecarb0xylate (1.2 g, 69%) : 1H NMR (400 MHZ, DMSO-dfi) 5 7.92 (d, J = 3.9 Hz, 1H), 7.71 (d, J: 7.9 Hz, 1H), 7.67 — 7.62 (m, 2H), 7.58 (d, J: 7.9 Hz, 1H), 7.39 — 7.31 (m, 2H), 7.23 (d, J = 3.9 Hz, 1H), 6.67 (t, J = 1.8 Hz, 1H), 3.83 (s, 3H), 3.12 (dt, J = 6.9, 1.9 Hz, 2H), 2.47 (dd, J: 4.9, 2.5 Hz, 2H), 2.33 (s, 3H). 2014/044247 Step B: thyl 4-(3-0x0cyclopentyl)t0syl-1H-indolecarb0xylate O O o\ a \ N N Ts Ts MeO O MeO O In a 40 mL reaction Vial, (2S,SS)benzylmethyl(5-methylfuranyl)imidazolidinone (0.190 g, 0.703 mmol) and methyl 4-(3-0x0cyclopent-I -en-I -yl)-1 -t0syl-IH—indole-7—carb0xylate (3.05 g, 7.45 mmol) in THF (5.67 mL) were added. The mixture was cooled to about 0 OC and degassed with nitrogen. Di-tert-butyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.05 g, 3.40 mmol) and oroacetic acid (0.071 mL, 0.70 mmol) were added under inert atmosphere. The on e was stirred at about 4 0C for about 16 h. Additional di-tert-butyl 2,6-dimethyl-1,4-dihydropyridine- 3,5-dicarboxylate (0.420 g, 1.36 mmol) was added, and reaction was stirred with cooling for about 72 h. The crude material was adsorbed onto silica gel and purified Via silica gel chromatography (0-45% EtAOc/heptane) to afford (R)-methyl 4-(3-0x0cyclopentyl)t0syl-IH—indolecarb0xylate (1 g, 79%). 1H NMR (400 MHZ, CDCl3-d) 8 7.67 — 7.58 (m, 2H), 7.58 — 7.45 (m, 2H), 7.23 — 7.10 (m, 3H), 6.75 (d, J: 4.2 Hz, 1H), 3.91 (s, 3H), 3.73 (tdd, J: 10.1, 7.6, 6.0 Hz, 1H), 2.73 — 2.61 (m, 1H), 2.51 — 2.24 (m, 7H), 2.16 — 1.98 (m, 1H).

Step C: Methyl 4-((1R,3S)hydr0xycyclopentyl)tosyl-1H-ind01ecarb0xylate O OH 7 9 \ \ N N Ts Ts MeO O MeO O In a 200 mL round-bottom flask, (R)-methyl 4-(3-oxocyclopentyl)tosyl-1H-indolecarboxylate (1.60 g, 3.89 mmol) in THF (32.4 mL) was added. The solution was cooled to about -78 0C. L- Selectride (7.78 mL, 7.78 mmol) was added drop wise over about 20 min and the mixture was stirred for about 16 h. The reaction mixture was cooled on an ice bath, saturated aqueous NH4Cl (60 mL) was added drop wise then EtOAc (100 mL) and water (20 mL) were added. The organic layer was separated, washed with brine, dried over Na2S04, filtered, concentrated and purified Via silica gel chromatography (0-65% EtOAc/heptane). The residue ed was purified using chiral chromatography (Table 2, Method 19) to give methyl 4-((1R,3S)hydr0xycyclopentyl)t0syl-1H— indole-7—carb0xylate ( 0.36 g, 22%): LC/MS (Table 1, Method a) R, = 2.21 min; MS m/z: 431(M+H20)+.

Step D: Methyl ,3R)((tert-butoxycarbonyl)amin0)cyclopentyl)t0syl-1H-indole carboxylate OH NHBoc "Ill H g H g _ _ \ \ N N \ \ Ts Ts MeO O MeO O In a 40 mL reaction Vial, methyl 4-((1R,3S)hydroxycyclopentyl)tosyl-1H—indolecarboxylate (0.35 g, 0.85 mmol) and PPh3 (0.266 g, 1.02 mmol) in THF (3.4 mL) were added. The solution was cooled to about 10 OC, DIEA (0.148 mL, 0.846 mmol) was added followed by drop wise addition of DIAD (0.197 mL, 1.02 mmol) and the reaction mixture was stirred for about 30 min. Diphenyl phosphorazidate (0.219 mL, 1.02 mmol) was added drop wise and stirred at rt for about 3 h. A solution of PPh3 (0.289 g, 1.10 mmol) in THF (0.6 mL) was added drop wise and the mixture was stirred for about 18 h. Water (0.183 mL, 10.2 mmol) was added and the mixture was heated at about 45 0C for about 72 h. To the reaction mixture was added DCM (10.7 mL, 166 mmol) and a solution of potassium hydrogenphosphate (0.737 g, 4.23 mmol) in water (2.14 mL, 119 mmol). A solution of di-tert-butyl dicarbonate (0.393 mL, 1.69 mmol) in DCM (2.14 mL, 33.2 mmol) was added drop wise and stirred at rt for about 1 h. Brine (2 mL) was added, the c layer was separated and washed with brine (3 mL), dried over , filtered, concentrated and purified Via silica gel chromatography (0-40% EtOAc/heptane) to afford methyl 4-((1R, ((tert- butoxycarbonyl)amin0)cyclopentyl)tosyl-IH-indole-7—carb0xylate (0.396 g, 59%): LC/MS (Table 1, Method a) R, = 2.72 min; MS m/z: 530 (M+H20)+.

Preparation #48: tert-Butyl 3-((7-carbam0yl(5-(morpholinomethyl)pyridinyl)-1H-indol yl)(methyl)amino)azetidine-l-carboxylate 0k 0k \ LN LNAO N \N ?:N\ I :Efg Nj/N H H2N 0 To a mixture of 4-((6-bromopyridinyl)methyl)morpholine (0.300 g, 1.17 mmol) in THF (5mL) was added n-BuLi (1.17 mL, 2.92 mmol). The mixture was stirred at about -78 0C for about 1 h, and then tributylchlorostannane (0.949 g, 2.92 mmol) was slowly added. The mixture was allowed to warm to rt over about 1 h, and a saturated solution of NH4Cl was added. The e was extracted with EtOAc and the combined organic layers were dried over Na2S04, ed and concentarted in vacuo to yield crude 4-((6-(tributylstannyl)pyridinyl)methyl)morpholine. A solution containing the tert- butyl 3-((7-carbamoyliodo-1H-indolyl)(methyl)amino)azetidinecarboxylate (0.300 g, 0.638 mmol, preparation #40) in DMF (2mL) was treated with LiCl (0.270 g, 6.38 mmol), PdC12(dppf)- CH2C12 adduct (0.156 g, 0.191 mmol) and 4-((6-(tributylstannyl)pyridinyl)methyl)morpholine (0.894 g, 1.91 mmol). The mixture was heated at about 100 0C for about 16 h, cooled, filtered through Celite® and partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (0-5% CM) to afford tert-butyl 3-((7—carbam0yl(5- olinomethyl)pyridinyl)-1H—indolyl)(methyl)amin0)azetidine-I-carb0xylate (0.172 g, 11%): LCMS (Table 1, Method av) R, = 1.24 min; MS m/z: 521 (M+H)+.

Preparation #49: tert-Butyl 6-(7-carbam0yl-1H-pyrr010[2,3-c]pyridinyl)-2,3-dihydr0-1,4- oxazepine-4(7H)-carb0xylate O/—\N’B°C oflN—Boc 2% ~ 2%N // / N‘ N / Ts H N H2N 0 To a solution of tert-butyl 6-(7-cyanotosyl-1H-pyrrolo[2,3-c]pyridinyl)-2,3-dihydro-1,4- oxazepine-4(7H)-carboxylate (0.973 g, 1.97 mmol, prepared using AG from tert-butyl 6- (((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (Preparation # W. 1) with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) and ation #AH. 1) in EtOH (3.93 mL) at about 0 0C was added NaOH (1N aqueous on, 7.87 mL, 7.87 mmol) followed by H202 (30% aqueous solution, 1.12 mL, 9.84 mmol). After about 10 min the ice bath was removed. After about 1 h additional NaOH (1N aqueous solution, 7 mL, 7 mmol) and H202 (30% aqueous solution, 1.00 mL, 8.82 mmol) and DCM (3 mL) were added. The on mixture was allowed to stir for about 1 h and concentrated down to about 15 mL and diluted with water (10 mL) and DCM (20 mL).

The suspension was filtered to remove any solids. The DCM layer was separated, dried over MgSO4, filtered, concentrated and purified Via silica gel chromatography to give tert-butyl 6-(7—carbam0yl- IH-pyrrolo[2,3-c]pyridinyl)-2,3-dihydr0-1,4-0xazepine-4(7H)-carb0xylate (0.138 g, 20%): LC/MS (Table 1, Method as) R, = 1.90 min; MS m/z: 359 (M+H)+.

General Procedure A: Suzuki Reaction of an aryl or heteroaryl halide with an aryl or heteroaryl boronic acid or boronate To a mixture of an aryl halide (preferably 1 equiv), a boronic acid or boronate ester (1 to 2 equiv, ably 1.1 equiv), and an inorganic base (such as, KF, Na2C03, K2C03 or Cs2C03, preferably Na2C03 or ) (1.1 to 16 equiv, preferably 2 equiv) in a solvent (such as THF, DME, DMF, 1,4- dioxane, 1 ,4-dioxane/water, DME/water, 1 ,4-dioxane/water, toluene/EtOH/water, 1,4- dioxane/EtOH/water or THF/MeOH/water preferably THF/MeOH/water, 1,4-dioxane/water, DME/water or 1,4-dioxane/EtOH/water) is added a palladium catalyst (for example Pd(OAc)2, szdba3, Pd(PPh3)4, bis(acetato)triphenylphosphinepalladium(II), polymer-bound FibreCat TM 1032, SiliaCat , dppf), (1,1’-bis(diphenylphosphino)ferrocene)dichloropalladium(II), or Pd(PPh3)2C12; preferably dppf), (1,1’-bis(diphenylphosphino)ferrocene)dichloropalladium(II), or at DPP-Pd 0.01 to 0.20 equiv, preferably 0.1 equiv) and a ligand (for example tricyclohexylphosphine, tri-tert-butyl-phosphine; preferably none or tricyclohexylphosphine; 0.01-1.0 equiv, preferably 0.16 equiv) is added optionally. The mixture is heated at about 40 to 120 OC (preferably about 70-85 0C) for about 1 to 48 h (preferably about 24 h) thermally, or at about 100 to 200 OC (preferably about 120 to 150 0C) for about 5 to 60 min (preferably about 20 to 45 min) in a microwave (preferably 5 min ramp time, 300 Watts max power, 250 psi max pressure). The mixture is allowed to cool to rt and is worked up using one of the following s. Method 1. For reactions containing water, the mixture may be diluted with an organic solvent (such as DCM or EtOAC). The layers are separated, the organic solution is ally washed with water and/or brine, dried over anhydrous MgSO4 or Na2S04, filtered, and the solvent is d under reduced pressure to give the d compound. Method 2. The mixture is concentrated under reduced pressure. Method 3. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure.

Illustration of General Procedure A Preparation #A.1: 4-(3-Aminophenyl)-1H-indolecarboxamide Br 3 N\—»o\ H N 0NH2 ONH2 A vessel was charged with 4-bromo-1H-indolecarboxamide (2.08 g, 8.70 mmol, ation #2), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (2.10 g, 9.57 mmol), sodium ate (2.77 g, 26.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.637 g, 0.870 mmol) and purged with nitrogen. A mixture of THF (71.4 mL), MeOH (10 mL), and water (10 mL) was added and the reaction was stirred at about 70 0C for about 24 h. The mixture was filtered through ®, the solvent was removed under reduced pressure and the residue was purified by column chromatograph on silica gel eluted With MeOH/DCM (0-10%) to provide a solid. The soid was triturated With ether to provide 4-(3-amin0phenyl)-1H—indolecarb0xamide (1.37 g, 63%): LC/MS (Table 1, Method f) R = 0.76 min; MS Hill: 293(M+MeCN+H)+.

Table A.1 Examples prepared from N-(2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan nyl)acrylamide (prepared using E from 2-methyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-Z-yl)aniline and acryloyl chloride) using l Procedure A Rt min Examp m/z ESI+ Btk Aryl Bromide Product (Table 1, le # (M+H)+ ICso Method) 4-bromo(3,5- dimethylisoxazolyl)- 1H-indole-7—carboxarnide (prepared using A from A11 2.84 (d) 415 Preparation #1 and 3,5- dimethylisoxazole boronic acid pinacol ester) 4-bromo(1-(tetrahydro- 2H-pyranyl)-1H- pyrazolyl)- ole- 7-carboxarnide (prepared using A from Preparation A12 2.87 (p) 470 #1 and1-(2- tetrahydropyranyl)- 1H- pyrazoleboronic acid pinacol ester) o(3,5-dimethyl- 1H-pyrazolyl)-1H- indole-7—carboxarnide (prepared using A from A13 2.51 (d) 414 Preparation #1 and 3,5- dimethylpyrazole c acid, pinacol ester) WO 10255 Rt min Examp m/z ESI+ Btk Aryl Bromide Product (Table 1, le # (M+H)+ IC50 4-bromo(1-isopropyl- 1H-pyrazoly1)- 1H- indole-7—carboxamide (prepared using A from A14 2.85 (d) 428 A Preparation #1 and1- isopropyl-1H-pyrazole boronic acid pinacol ester) 4-bromo(1 ,3-dimethy1— 1H-pyrazoly1)-1H- indole-7—carboxamide (prepared using A from A15 2.66 (d) 414 A Preparation #1 and1,3- dimethyl- 1H-pyrazole boronic inacol ester) 4-bromo(1-ethy1—1H- pyrazoly1)- 1H-indole- 7-Carboxamide (prepared using A from Preparation A16 2.74 (d) 414 A #1 and1-ethy1—1H- pyrazoleboronic acid, pinacol ester) 4-bromo(1-isobuty1— 1H-pyrazolyl)- 1H- indole-7—carboxamide red using A from Preparation #1 and1- A17 2.98 (d) 442 A isobuty1(4,4,5 ,5- tetramethyl-1,3,2- dioxaborolany1)- 1H- pyrazole) 4-bromo(1-(2- morpholinoethy1)- 1H- pyrazoly1)- 1H-indole- 7—Carboxamide (prepared A18 2.28 (d) 499 A using A from Preparation #1 and 1 -(2- linoethy1)- 1H- pyrazoleboronic acid, Rt min Examp m/z ESI+ Btk Aryl Bromide Product (Table 1, le # (M+H)+ IC50 Method) pinacol ester) 4-bromo-1H-indole-7— carboxamide (Preparation A19 1.31 (f) 320 B 4-bromo(pyrimidin yl)-1H-indole carboxamide (prepared using A from Preparation A110 2.56 (d) 398 A #1 and Pyrimidine-S- boronic acid pinacol ester) o(1-methyl-1H- pyrazol-S-y1)-1H-indole- 7-carboxamide (prepared using A from Preparation A111 2.66 (d) 400 A #1 and 1-methy1—1H- pyrazole-S-boronic acid pinacol ester) 4-bromo(pyridiny1)- ole-7—carboxamide red using A from A112 2.22 (d) 397 A Preparation #1 and 4- pyridineboronic acid pinacol ester) WO 10255 Rt min Examp m/z ESI+ Btk Aryl Bromide Product (Table 1, le # (M+H)+ IC50 Method) 4-bromo(2- methoxypyridinyl)-1H- indolecarboxamide (prepared using A from \0 A113 2.70 (d) 427 A Preparation #1 and 2- \ —N methoxy-pyridine \/ boronicacid) 4-bromo(3- o cyanophenyl) - 1H-indole- 7-carboxamide (prepared A114 3.03 (d) 421 A using A from Preparation #1 and 3-cyanophenyl- \O c acid) 2-(3-acetamidophenyl) bromo-1H-indole carboxamide (prepared A115 2.79 (d) 453 A using A from Preparation #1 and 3-acetamido- phenylboronic acid) u 4-bromo(6- fluoropyridiny1)- 1H- indolecarboxamide (prepared using A from A116 2.87 (d) 415 A Preparation #1 and 2- fluoropyridine-S-boronic acid) 2014/044247 Rt min Examp m/z ESI+ Btk Aryl Bromide Product (Table 1, le # (M+H)+ IC50 Method) 4-bromo(2- fluoropyridinyl)-1H- -7—carboxamide (prepared using A from A117 2.86 (d) 415 A Preparation #1 and 2- fluoropyridine-S-boronic acid) 4-bromo(2- methoxypyridin-S-yl)-1H- indole-7—carboxamide (prepared using A from A118 2.97 (d) 427 A Preparation #1 and 2- methoxy-pyridine-S- boronic acid pinacol ester) methyl 3-(4-bromo-7— carbamoyl-lH-indol yl)benzoate (prepared using A from Preparation A119 2.77 (0) 454 A #1 and 3- methoxycarbonylphenylb oronic acid) methyl romo-7— carbamoyl-lH-indol yl)benzoate (prepared using A from Preparation A120 2.77 (0) 454 A #1 and 4- methoxycarbonylphenylb oronic acid) Rt min Examp m/z ESI+ Btk Aryl Bromide Product (Table 1, le # (M+H)+ IC50 Method) 4-bromo(2,3- dihydrobenzofuran-S-yl)- 1H-indole-7—carboxamide red using A from A121 2.75 (0) 438 A Preparation #1 and 2,3- dihydrobenzofuran-S- boronic acid) H2N O 4-bromo(3- methoxyphenyl) - 1H- NH -7—carboxamide O red using A from A122 278(0) 426 A Preparation #1 and 3- methoxy-phenylboronic acid) H O NH2 4-bromo(4- methoxyphenyl) - 1H- indole-7—carboxamide (prepared using A from A123 276(0) 426 A Preparation #1 and 4- methoxy-phenylboronic acid) 4-bromo(6- methylpyridinyl)-1H- indole-7—carboxamide (prepared using A from A124 236 (d) 41 1 A Preparation #1 and 6- methylpyridine-S-boronic acid) Rt min Examp m/z ESI+ Btk Aryl e Product (Table 1, le # (M+H)+ IC50 Method) 4-bromo(3- carbamoylphenyl) - 1H- indole-7—carboxamide (prepared using A from A125 2.68 (d) 439 A Preparation #1 and 3- aminocarbonylphenylboro nic acid) 4-bromo(3- fluorophenyl)-1H-indole- 7-carboxamide red A126 2.82 (0) 414 A using A from Preparation #1 and 3- fluorophenylboronic acid) 4-bromo(3- (dimethylamino)phenyl)- 1H-indole-7—carboxamide (prepared using A from A127 2.24 (0) 439 A Preparation #1 and 3- (N,N— dimethylamino)pheny1bor onic acid) 4-bromo(2-methyl (pyrrolidin ylsulfonyl)pheny1)-1H- indole-7—carboxamide (prepared using A from A128 2.76 (0) 543 B Preparation #1 and 2- methyl-S-(pyrrolidin ylsulfonyl)pheny1boronic acid) WO 10255 Rt min Examp m/z ESI+ Btk Aryl Bromide Product (Table 1, le # (M+H)+ IC50 Method) o(2- fluorophenyl)-1H-indole- 7-carboxamide (prepared A129 2.80 (0) 414 A using A from Preparation #1 and 2- fluorophenylboronic acid) 4-bromo(6- morpholinopyridinyl)- 1H-indole-7—carboxamide (prepared using A from A130 2.64 (d) 482 A Preparation #1 and 6- (morpholiny1)pyridine- 3-boronic acid pinacol ester) 4-bromo(4-(4- methylpiperazine carbony1)pheny1)- 1H- -7—carboxamide (prepared using A from A131 2.34 (d) 522 A Preparation #1 and 3-(4- methyl piperazinylcarbonyl)benz eneboronic acid pinacol ester) 4-bromo(4- fluoropheny1)- 1H-indole- 7-carboxamide (prepared A132 2.80 (0) 414 A using A from Preparation #1 and 4- fluorophenylboronic acid) Rt min Examp m/z ESI+ Btk Aryl Bromide t (Table 1, le # (M+H)+ IC50 Method) 4-br0m0—2-phenyl- 1H- indole-7—carboxamide (Prepared "Sing A from A.1.33 2.77 (o) 396 A Preparation #1 and phenylboronic acid pinacol ester) 0—2-(2- lsulfonyl)phenyl)- 1H-indole-7—carboxamide (prepared using A from A134 2-85 (d) 474 B ation #1 and 2- (methylsulfonyl)phenylbo ronic acid) 4-br0m0—2-(4- (dimethylcarbamoyl)phen y1)- 1H-ind01e-7— carboxamide (prepared A135 2.76 (d) 467 A using A from Preparation #1 and 4-(N,N— dimethylaminocarbonyl)p henylboronic acid) 4-br0m0—2-(pyridinyl)- 1H-indole-7—carboxamide (prepared using A from A136 1.71 (a) 397 A Preparation #1 and 3- pyridineboronic acid pinacol ester) 4-br0m0—2-(4- (morpholine carbony1)phenyl)- 1H- indole-7—carboxamide A137 2.74 (d) 509 A (prepared using A from Preparation #1 and 4- (morpholine carbonyl)phenylb0ronic 2014/044247 Rt min Examp m/z ESI+ Btk Aryl Bromide Product (Table 1, le # (M+H)+ IC50 Method) acid pinacol ester) 4-bromo(4- (pyrrolidine carbony1)pheny1)- 1H- indolecarboxamide (prepared using A from A138 2.87 (d) 493 A Preparation #1 and 4-(1- pyrrolidinylcarbonyl)benZ eneboronic acid pinacol ester) 4-bromo(4-(4- methylpiperazine carbony1)pheny1)- 1H- indolecarboxamide (prepared using A from A139 2.31(d) 522 A Preparation #1 and 4-(4- methyl piperazinylcarbonyl)benz onic acid pinacol ester) 4-bromo(4- (methylsulfonyl)phenyl)- 1H-indolecarboxamide (prepared using A from A140 2.49 (0) 474 A Preparation #1 and 4- (methylsulfonyl)phenylbo ronic acid) 4-bromo(6- ypyridinyl)-1H- indolecarboxamide (prepared using A from A141 2.89 (d) 427 A Preparation #1 and 2-methoxy pyridineboronic acid) Rt min Examp m/z ESI+ Btk Aryl Bromide Product (Table 1, le # (M+H)+ IC50 Method) 4-bromo(4- cyanophenyl) - 1H-indole- 7—carboxamide (prepared A142 3.01(d) 421 A using A from Preparation #1 and 4- cyanophenylboronic acid) 4-bromo(2- methoxyphenyl) - 1H- indole-7—carboxamide (prepared using A from A143 3.10 (d) 426 A Preparation #1 and 2- y-phenylboronic acid) 4-bromo(4- (morpholinomethy1)pheny 1)-1H-indole amide (prepared using A from Preparation A144 2.37 (d) 495 A #1 and 4-(4- morpholinylmethyl)- benzeneboronic acid pinacol ester) 4-bromo(4- carbamoylphenyl) - 1H- indole-7—carboxamide (prepared using A from A145 2.61 (d) 439 A Preparation #1 and 4- aminocarbonylphenylboro nic acid) Table A.2 Examples prepared from N-(2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl)thiazolecarboxamide (Preparation #4) using General Procedure A R min m/z ESI+ Btk Aryl Bromide Product Example # (Table 1, (M+H)+ IC50 Method) 4-br0m0—2-(1-methyl- 6-0x0—1,6- S \ dihydropyridin-S-yl)- 1H-indole OYQ carboxamide (Prepared "Sing A 0 A.2.1 2.90 (d) 484 A from Preparation #1 / and yl-5 — O \ / (4,4,5,5-tetramethy1— H _ 1,3 xab0rolan-2— yl)pyridin-2(1H)-one (Preparation #5) 4-br0m0—2-(1-methyl- 0 1H-pyrazolyl)- 1H- A.2.2 2.87 (d) 457 A indole-7—carb0xamide (Preparation #10) O \ \T u N\ Table A.3 Examples prepared from 2-(1-acetyl-1,2,3,6-tetrahydropyridin—4-yl)bromo-1H— indolecarboxamide red using A with 4-bromoiodo-1H-indolecarboxamide (Preparation #1) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridin- 1(2H)-yl)ethanone [Combi-Blocks]) using General Procedure A R min Boronate Product e (Table 1, (15:11:)t IBék Method) 50 ethyl(4,4,5,5- ©YO tetramethyl-1,3,2- NVN dioxaborolan-Z- O A.3.1 1.89()g 518 A yl)phenyl)quinazolin- 4(3H)-0ne [WO 2011159857] HzN O R mint Boronate Product Exaanle (Table 1, (15:11:) IBék Method) 50 6-flu0r0—3-(2-methyl QfO (4,4,5,5-tetramethyl-1,3,2- _ NVN d10xab0rolan 0 A32 152 (g) 536 A yl)phenyl)quinazolin- 4(3H)-one[WO D; \ NJ< 9857] H 4-tert-buty1—N—(2-methyl-3 - >k©YO (4,4,5,5-tetramethyl-1,3,2- 0 A33 184%) 549 A d10xab0r01an o nyl)benzamide O \ NJ< [] HZN o N—(2-methyl(4,4,5,5- (:on tetramethyl-1,3,2- HN dioxaborolan 0 A34 151 (g) 500 A yl)phenyl)thiazole O \ \ amide (Preparation N_ F$0 \ \ / F F methylphenylboronic m 0 NH2 acid, pinacol ester 1,3-thiaz01ecarb0nyl Rt min m/z Btk Boronate Product Example # (Table 1, APCI+ IC50 ) (M+H)+ chloride [Maybridge- International]) N—(2-methyl(4,4,5,5- tetramethyl- l ,3 ,2- HN dioxaborolan O A.7.8 1.87 (a) 454 A yl)phenyl)thiazole O 0; carboxamide (Preparation F \‘N/ #4) O NH? Table A.8 Examples ed from 4-iodo(p-tolyl)-1H-indolecarboxamide (prepared using F from 1-(p-tolyl)ethanone) using General Procedure A Rt min m/z Btk c acid or Boronate Product Example # (Table 1, APCI+ IC50 Method) (M+H)+ pyrazoleb0ronic acid A.8.l 1.93 (a) 317 B 3 ,5 -dimethylisoxazole A.8.2 2.27 (a) 346 B boronic acid pinacol ester pyridineb0ronic acid A.8.3 2.15 (a) 328 B Rt min m/z Btk Boronic acid or Boronate Product Example # (Table 1, APCI+ IC50 Method) (M+H)+ pyridineb0r0nic acid A.8.4 2.27 (a) 328 B -acetylthi0phenylboronic A.8.5 0.92 (e) 375 B acid H2N o 4,4,5,5-tetramethyl-2— H (thiophenyl)-1,3,2_ O/ O A.8.6 0.97 (e) 333 B dioxaborolane H2N o 1-methy1(4,4,5,5- H tetramethyl-1,3,2- / O A.8.7 0.83 (e) 331 B orolan-Z-yl)-1H- pyrazole N—N H2N o 1H-pyraz01—3-ylb0r0nic acid Ox 0 A.8.8 0.81 (e) 317 B H2N o thiophen-Z-ylboronic acid O/ O A.8.9 0.97 (e) 333 B Rt min m/z Btk Boronic acid or Boronate Product Example # (Table 1, APCI+ IC50 Method) (M+H)+ H2N o thiophenylb0r0nic acid A.8.10 0.97 (e) 333 B Table A.9 Examples prepared from 4-iodo(p-tolyl)-1H-indolecarboxamide (prepared with F using 1-(4-fluorophenyl)ethanone) using General Procedure A R min m/z Btk Boronic acid or te Product Example # (Table 1, APCI+ IC50 Method) (M+H)+ pyrimidine-S-boronic acid 0 \ O A.9.1 1.82 (a) 333 B neb0r0nic acid A.9.2 2.05 (a) 332 A 3,5-dimethylisoxazole \ A.9.3 2.18 (a) 350 B boronic acid pinacol ester F pyridineb0ronic acid 0 A.9.4 2.15 (a) 332 B \ O F 2014/044247 Rt min m/z Btk Boronic acid or Boronate t Example # (Table 1, APCI+ IC50 Method) (M+H)+ pyrazoleb0r0nic acid A.9.5 1.87 (a) 321 B 6-flu0r0—2-(2-methyl (4,4,5,5-tetramethyl-1,3,2- dioxaborolan A.9.6 2.37 (a) 494 A yl)phenyl)isoindolinone N—(2-methyl(4,4,5,5- tetramethyl-1,3,2- dioxaborolanyl)phenyl)- 4,5 , 6,7- A.9.7 2.66 (a) 524 C tetrahydrobenz0[b]thiophene- 2-Carboxamide [WO 2006/099075] Table A.10 Examples prepared from 4-bromo(1-methyl-1H-pyrazolyl)-1H-indole carboxamide (prepared using A from 4-bromoiodo-1H-indolecarboxamide (Preparation #1) with 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole) using General ure A Rt min m/z Btk Boronate Product Example # (Table 1, APCI+ ICso Method) (M+H)+ 3-(2-methyl(4,4,5,5- tetramethyl-1,3,2- dioxaborolan A.10.1 2.11 (c) 475 yl)phenyl)quinazolin- 4(3H)-one [WO 201 1 159857] Rt min m/z Btk Boronate Product Example # (Table 1, APCI+ ICso Method) (M+H)+ 6-fluoro-3 -(2-mcthyl (4,4,5 ,5 -tetramcthyl- 1,3 ,2-dioxaborolan A.10.2 1.90 (a) 493 yl)phenyl)quinazolin- 4(3H)-one [US 2010/0160303] N—(3-(7—carbamoyl(1- methyl-1H-pyrazolyl)- olyl) methylphcnyl)-N— (oxctanyl)thiazolc carboxamide (prepared using H from 2-methyl(4,4,5,5- A.10.3 1.48 (g) 513 tetramethyl-1,3,2- dioxaborolanyl)aniline [Combi-Blocks] and 3- oxetanonc [Molbridgc]), E With thiazolc-Z- carbonyl de [Maybridch N-mcthyl-N-(2-mcthyl (4,4,5,5-tctramcthyl- 1,3 ,2-dioxaborolan A.10.4 1.52 (f) 471 nyl)thiazolc carboxamide (Preparation #19) N—(2-methyl(4,4,5,5- tetramethyl-1,3,2- dioxaborolan yl)phcnyl)-4,5,6,7— A.10.5 1.84 (g) 510 ydrobcnzo[b]thioph enccarboxamidc [WO 2006/099075] Table A.11: Examples ed from 4-bromo(3,6-dihydro-2H—pyranyl)-1H-indole carboxamide (prepared using A from 4-bromoiodo-1H-indolecarboxamide (Preparation #1) and 2-(3,6-dihydro-2H—pyranyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) using General Procedure A R min m/z Example Btk Boronate Product (Table 1, ESI+ # IC50 Method) (M+H)+ 3-(2-methyl(4,4,5,5- [2Y0 tetramethyl-1,3,2- NVN O dioxabordan'z' A.11.1 1.51 (g) 477 A nyl)quinazolin- 4(3H)-one[WO O \ 0 2011159857] 0—3-(2-methyl (4,4,5,5-tetramethyl- Q?) 1,3,2-dioxab0rolan O A.11.2 1.55 (g) 495 A yl)phenyl)quinazolin- 4(3H)-one[WO O \ \ 0 2011159857] E Table A.12: Examples prepared from 4-bromo(4-fluorophenyl)-1H-indolecarboxamide (prepared using A from 4-bromoiodo-1H-indolecarboxamide (Preparation #1) and 2-(4- fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) using General Procedure A R min m/z Exampl Btk Boronate Product (Table 1, ESI+ e # ICso Method) (M+H)+ ethyl(4,4,5,5- QYO tetramethyl-1,3,2- dioxaborolan-Z- A1 1-78 (g) 489 A yl)phenyl)qu1naz011n 4(3H). . _ _ O \ F one [WO 2011159857] H H2N o Table A.13: Examples prepared from 4-bromo(pyrimidinyl)-1H-indolecarboxamide (prepared using A from 4-bromoiodo-1H-indolecarboxamide (Preparation #1) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrimidine) using General ure A Rt min m/z Boronate Exampl Btk Product (Table 1, ESI+ e # ICso Method) (M+H)+ 3-(2-methyl(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxab0rolan A.13.1 1.52 (g) 473 yl)phenyl)quinazolin-4(3H)-0ne [WO 9857] 6-flu0r0—3-(2-methyl(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxab0rolan A.13.2 1.59 (g) 491 yl)phenyl)quinazolin-4(3H)-0ne [WO 2011159857] 4-(difluoromethyl)-N—(2-methyl- 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan A.13.3 1.64 (g) 498 yl)phenyl)benzamide (Preparation #29) 4-cyclopr0pyl-N—(2-methyl ,5-tetramethyl-1,3,2- dioxaborolan yl)phenyl)benzamide (prepared using B with 2- A.13.4 1.73 (g) 488 methyl(4,4,5,5- tetramethyl-1,3,2- dioxaborolanyl)aniline and 4-(2-cyan0pr0pan yl)benzoic acid) Table A.14: Examples prepared from 4-bromo(1-(2-hydroxymethylpropyl)-1H-pyrazol yl)-1H-indolecarboxamide (prepared using A from 4-bromoiodo-1H-indolecarboxamide (Preparation #1) and 2-methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazol yl)propanol (Preparation #26) using General ure A Rt min m/z Boronate Product Ex:r;1pl (Table 1, ESI+ IBék Method) (M+H)+ 5" 6-flu0r0—3-(2-methyl(4,4,5,5- ©YO tetramethyl-1,3,2- N\ N dioxaborolan O A.14.1 1.65 (g) 551 A yl)phenyl)quinazolin-4(3H)- 0 \ ‘N \ vaOH one [wo 2011159857] H H2N 0 Table A.15: Examples prepared from 2-(3-chloro(hydroxymethyl)phenyl)cyclopropyl fluoroisoquinolin-l(2H)-one [U.S. 20100222325] using l Procedure A R min Boronate Product Exaanle (Table 1, "1161 E51:- Btk( +H) ICSO 2-(1-methyl-lH-pyrazolyl) (4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1H-indole-7 - F carboxamide (prepared using A o from Preparation #1 with l— \ N O A151 2-77 (0) 548 A methyl—4—(4,4,5,5—tetramethyl— 1,3,2—dioxaborolan ON\ \\E\ —2—yl)—1H—pyrazole, and P with H HZN o 4,4,4',4',5,5,5',5'-octamethyl-2,2'— ,2-dioxab0rolane)) General Procedure B: Nucleophilic displacement of an aryl halide with an amine To a solution of an aryl halide or heteraryl halide and an appropriate organic solvent (such as DMSO, 1,4-di0xane, n-butanol, THF, pyridine, preferably DMSO or pyridine) was added an amine (1 to 10 equiv, preferably 1 equiv) and a base (such as TEA, pyridine, DIEA, K2C03, preferably TEA; 1 to 5 equiv, preferably 1 equiv.) The resulting solution is d at about 20 to 150 0C (preferably about 0 0C) thermally for a period of about 1 h to 72 h (preferably about 24 h) or in a microwave for about 5 min to 2 h (preferably about 30 min). The mixture is optionally concentrated in vacuo or under a warm en stream to give the intermediates or targeted compound or optionally filtered through a media (such as SiCO3 or Celite®) which is rinsed with an appropriate solvent (such as EtOAC, 1,4-dioxane, THF, MeCN, DCM, EtzO, MeOH, EtOH, DMSO, 1:1 MeOH/DMSO, 2:1 MeOH/DMSO) and then optionally concentrated in vacuo or under a warm en stream to give the targeted compound.

Illustration of General Procedure B Preparation #B.1: (R)-tert-Butyl 1-(7-cyano-1H-indolyl)piperidinylcarbamate BocHN,,,h BocHNMO O F N \ H \ N N CNH H A mixture of (R)-tert-butyl piperidinylcarbamate (1.501 g, 7.49 mmol) and 4-fluoro-1H-indole carbonitrile (0.6 g, 3.75 mmol) in ne (3.02 mL, 37.5 mmol) were heated at about 150 0C for about 30 min in a microwave oven. The mixture was evaporated to dryness and the resulting residue was purified by silica gel chromatography eluting with a gradient 30 to 100% of EtOAc in hexanes to give (R)-tert-butyl I-(7—cyan0-IH—indolyl)piperidinylcarbamate (0.4g, 31%); LC/MS (Table 1, Method g) R = 1.69 min.; MS m/z: 341 (M+H)+ General Procedure C: ysis of an ester to a carboxylic acid To a flask containing an ester rably 1 equiv) either neat or in an organic solvent (such as 1,4- dioxane, MeOH, or THF/MeOH, preferably 1,4-dioxane) is added an aqueous base (such as aqueous NaOH or LiOH; 1-10 equiV, preferably 2-6 equiV). The mixture is stirred at about 0 to 100 OC (preferably about 25 to 60 0C) for about 1 to 48 h (preferably about 4 to 24 h). The c solvent is ally be concentrated in vacuo. The mixture is then ied by the addition of a suitable aqueous acid (such as aqueous HCl). If a precipitate forms, it may be collected Via filtration to give product. The mixture or the filtrate if the solid is not product may optionally be concentrated in vacuo to give the target compound as a carboxylate salt. Alternatively, the e is optionally filtered through a media (such as silica gel or Celite®) which is rinsed with an appropriate t (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM, EtzO, MeOH, EtOH) and then optionally concentrated in vacuo to give a residue as the target compound. Either the residue or the solution may be optionally partitioned between water and an organic t (such as EtOAc, EtzO or DCM). The organic layer is isolated and may optionally be washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4C1) and/or s solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl, NaZSO3 or NaZSZO3). The organic on may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the target compound.

Illustration of General Procedure C Example #C.1: (E)((3-(7-Carbamoyl-1H-indolyl)phenyl)amino)oxobutenoic acid 0 o CO N O\N O\N H H HNO2 HNO2 (E)-Methyl 4-((3-(7-carbamoyl-1H-indolyl)phenyl)amino)oxobutenoate (0.610 g, 1.68 mmol, Example #D.1) was ded in 1,4-dioxane (8.39 mL). Lithium hydroxide (1M in water, 839 mL, 8.39 mmol) was added and the e was stirred at about 60 0C for about 1 h. The on was concentrated to about 8 mL and diluted with water (10 mL). The pH was adjusted to about 4 using 1N HCl. The solids were collected, washed with water, and dried under vacuum to provide (E)((3 - (7-carbamoyl-IH-indolyl)phenyl)amino)0x0buten0ic acid (0.45 g, 77%) as a solid. 50 mg of the crude product was further purified by preparative-HPLC (Table 1, Method af) to afford 30.9 mg to provide analytically pure (E)((3-(7-carbam0yl-IH—indolyl)phenyl)amin0)0x0buten0ic acid: LC/MS (Table 1, Method f) R = 1.64 min; MS Hill: 350 (M+H)+ (Btk IC50 = C) General Procedure D: Formation of an amide from an amine and a carboxylic acid To a flask is added in no particular order, a carboxylic acid or carboxylate salt (1 to 5 equiv, ably 1.1 to 1.5 equiv), an amine (1 to 5 equiv, preferably 1 to 1.5 equiv), an organic solvent (such as DCM, DCE, THF, or 1,4-dioxane, DMF, DMF/pyridine preferably DCM or DMF/pyridine), a peptide coupling reagent (such as BOP-Cl, HATU, EDC, DCI, PyBOP, or EDC'HCl, preferably HATU or EDC; 1 to 10 equiv, preferably 1 to 2.5 equiv), a base (such as TEA, DIEA, pyridine or DIEA, preferably DIEA; 1 to 20 equiv, preferably 1 to 5 equiv) and optionally HOBt (0 to 5 equiv, preferably 0 to 1 equiv). The mixture is then d at about 10 to 60 OC (preferably about 25 to 50 0C) for about 5 min to 48 h (preferably about 5 min to 24 h). ally, additional amounts of the reagents above can be added to drive the reaction to completion. The mixture is optionally concentrated in vacuo to give the targeted compound. The mixture is optionally filtered through a media (such as silica gel or ®) which is rinsed with an appropriate solvent (such as EtOAC, 1,4- dioxane, THF, MeCN, DCM, EtzO, MeOH, EtOH) and then optionally concentrated in vacuo to give a residue. Either the residue or the solution may be optionally partitioned between water and an organic solvent (such as EtOAC, EtzO or DCM). If the product does not partition, the e may be stirred for 5 min to 1 h (preferably 30 min) and the solid may be collected Via vacuum filtration.

Alternatively, the organic layer is isolated and may be optionally washed in no ular order with water and/or aqueous solutions containing an acid (such as HCl, ACOH or NH4C1) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl, NaZSO3 or Na2S203). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and trated in vacuo to give the targeted compound.

Illustration of General Procedure D: Example #D.1: (E)-Methyl 4-((3-(7-carbamoyl-1H-indolyl)phenyl)amino)oxobutenoate H2N N O o O Howo/ 0 \ O \ —.

N N H H HN2 o "N2 O To a solution of (E)methoxyoxobutenoic acid (0.43 g, 3.28 mmol) in DCM (40 mL) and DIEA (0.59 mL, 3.58 mmol) was added HATU (1.362 g, 3.58 mmol). The mixture was stirred at rt for 5 min then 4-(3-aminophenyl)-1H-indolecarboxamide (0.75 g, 2.98 mmol, ation #A.1) was added. The mixture was strired at rt for about 3 h. The mixture was concentrated and the e was suspended between water and EtOAc. The mixture was stirred at rt for about 30 min, filtered to collect the solid, which was washed with water and EtOAc, and dried under vacumm to provided (E)- methyl 4-((3-(7-carbamoyl-IH—indolyl)phenyl)amin0)0x0buten0ate (0.64 g, 59%): LC/MS (Table 1, Method f) R = 1.45 min; MS m/z: 364 (M+H)+ (Btk IC50 = A) Table D.1 es prepared from N-(3-(2-(2-(aminomethyl)phenyl)carbamoyl-1H—indol yl)methylphenyl)thiazolecarboxamide (Example #1) using General ure D R min m/z ESI+ Btk Acid Product Example # (Table 1, (M+H)+ IC50 Method) butynoic acid C 3.13 (d) 548 0 K D.1.1 Rt min m/z ESI+ Btk Acid Product Example # (Table 1, (M+H)+ IC50 acrylic acid D12 3.10 (d) 536 C 2-cyan0acetic acid D13 3.05 (d) 549 B (dimethylamino)pr0p D.1.4 2.64 (d) 581 B anoic acid HCl 3-(piperidin D.1.5 2.38 (0) 621 C yl)pr0pan0ic acid 2-phen0xyacetic acid D.1.6 3.06 (0) 616 C 2-(4- fluorophenoxy)acetic D.1.7 3.08 (0) 634 C acid Rt min m/z ESI+ Btk Acid t Example # (Table 1, (M+H)+ IC50 Method) butyric acid D.1.8 2.87 (0) 552 C (E)-buten0ic acid D.1.9 2.84 (0) 550 C methacrylic acid D.1.10 3.20 (d) 550 C propiolic acid D.1.11 3.10 (d) 534 B Table D.2 Examples prepared from an amine and 2-(3-oxobenzo[J_|isothiazol-2(3H)-yl)acetic acid [Matrix] using General Procedure D R min m/z ESI+ Btk Amine Product Example # (Table 1, (M+H)+ IC50 Method) min0phenyl)-1H- indole-7—carb0xamide 0 VS > (prepared using A from O )k/N\ 4-br0m0—1H-indole-7— amide O \ D.2.1 1.42 (f) 443 C (Preparation #2) and 2-(4,4,5,5-tetramethyl- 1,3 ,2-di0xab0rolan yl)aniline) Table D3 Examples prepared from N-(3-(3-aminocarbamoyl-1H-indolyl) methylphenyl)thiazolecarboxamide (Preparation #7) using General Procedure D R min m/z ESI+ Btk Acid Product e # (Table 1, (M+H)+ IC50 Method) @YOS 2-cyan0acetic acid HN D.3.1 2.58 (d) 459 C . . O \ acryl1c ac1d HN D.3.2 2.69 (d) 446 C —194— Rt min m/z ESI+ Btk Acid Product e # (Table 1, (M+H)+ IC50 Method) (E)-buten0ic acid D.3.3 2.82 (d) 460 C methacrylic acid D.3.4 2.89 (d) 460 C butyn0ic acid D.3.5 2.52 (d) 458 C 2-(4- fluorophenoxy)acetic D.3.6 3.09 (d) 544 C acid Table D4 Examples prepared from an (E)((3-(7-carbamoyl-1H-indolyl)phenyl)amino) oxobutenoic acid (Example #C.1) using l Procedure D Rt min m/z ESI+ Btk Amine Product Example # (Table 1, (M+H)+ ICso Method) Methylamine D.4.1 1.60 (f) 363 Dimethylamine D.4.2 1.66 (f) 377 ethanamine D.4.3 1.68 (f) 377 cyclopropanamine D.4.4 1.70 (f) 389 Table D5 Examples prepared from an acid and 2-(1-acetylpiperidinyl)(3-amino methylphenyl)-1H-indolecarboxamide (Example #L.1) using General Procedure D R min m/z ESI+ Btk Acid Product Example # (Table 1, (M+H)+ IC50 Method) 4-Cyclopr0pylbenzoic acid A0]? [Astra tech] 0 D.5.1 1.77 (f) 535 B Ok W Table D6 Examples ed from 4-(3-aminophenyl)-1H-indolecarboxamide (Preparation #A.1) using General Procedure B R min m/z ESI+ Btk Acid Product e # (Table 1, (M+H)+ IC50 Method) 2' H N\ thylamino)methyl)a O crylic acid (prepared using J from 2- D.6.1 2.24 (d) 363 A (bromomethyl)acrylic acid 0 H F%o and dimethylamine F hydrochloride) O ""2 ((dimethylamino)methyl)a O crylic acid (prepared using 0 D62 2.27 (d) 405 A J from 2- \ w (bromomethyl)acrylic acid o H F and morpholine) o NH2 Table D7: Examples prepared from 4-(3-aminomethylphenyl)(1-(methylsulfonyl)-1,2,3,6- tetrahydropyridinyl)-1H-indolecarboxamide (Example ) using General Procedure e Rt min m/z ESI+ Btk IC50 Acid Product # (M+H)+ H2N o (Z)methylbuten0ic ON / \ N‘fi=0 O D71 0.73 (e) 507 acid %0 OH H2N o 91 0 H2N O N | / \ H1 2-Ch10r0pr0pan01c a01d. . O O D.7.8 0.72 (e) 515 A CRHL 0 (E-but-Z-enoic acid D.7.9 0.71 (e) 493 A H 0 HZN o (Z)amin00X0but ON/ \ "15'." enoic acid D.7.10 0.62 (e) 522 A 2 O HKKMHo O 2N o ON | - / \ N'fi=° 2—(4-flu0r0philnoxy)acetlc ° 13.7.11 0.78 (e) 577 A 3( I'd 1 OH’ \ "'ISIIZO 1' pyrr01-1n- '_d 0 D.7.12 0.58 (e) 550 A y )propan01c a01 O «A O HZN o . O"/ \ Nfi‘o'= 2—(4-Cyan0phiiloxyhcetlc ° 13.7.13 0.75 (e) 584 A Example Rt min I’ll/Z ESI+ Btk IC50 Acid (M+H)+ 2-(pyridinyloxy)acetic D.7.14 0.58 (e) 560 A acid cyclopent D.7.15 0.75 (e) 519 A boxylic acid (E-Z-methylpent-Z-enoic D716 0.78 (e) 521 A acid (Z)ch10r0acrylic acid D717 0.70 (e) 513 A (E)meth0xy0X0but- D718 0.72 (e) 537 A 2-en0ic acid cyclohexenecarb0xylic D719 0.78 (e) 533 A acid (E)eth0xy0X0but D720 0.75 (e) 551 A enoic acid WO 10255 Example Rt min I’ll/Z ESI+ Btk IC50 Acid (M+H)+ 2-phen0xyacetic acid D721 0.79 (e) 559 A 2-flu0r0acetic acid D722 0.66 (e) 485 A (dimethylamino)pr0pan0i D723 0.58 (h) 524 A 0 acid 2-(pyridinyloxy)acetic D724 0.69 (e) 560 A acid (E)amin0—4-0X0but D725 0.59 (e) 522 A enoic acid 2-ch10r0butan0ic acid D726 0.74 (e) 529 A 3-(4-methy1piperazin D727 0.52 (e) 579 A yl)pr0pan0ic acid Example Rt min m/z ESI+ Btk IC50 Acid Product # (M+H)+ 2-(pyr1~13aém- _- O D.7.28 0.61 (e) 561 A yloxy)acetlc a01d O \ (RAH 0 . o O cyclohexanecarboxyhc O D 7 29 1 75 (e) 535 A acid 0N\ / N'%=° H N O 2-methylthiazole O / \ 7:0 carboxylic acid D.7.30 0.75 (ae) 550 A cyclopentanecarboxylic / \ N—‘sl‘=o acid D.7.31 0.75 (ae) 521 A -methylthiazole ylic acid D.7.32 0.77 (ae) 550 A tetrahydrO-ZH-pyran carboxylic acid D.7.33 0.65 (ae) 537 A methoxycyclohexanecarb D734 0-71 (ae) 565 A oxylic acid 2014/044247 Example Rt min m/z ESI+ Btk IC50 Acid Product # (M+H)+ 3-methy1butan0ic acid D 7 35 0 73 (ac) 509 A 1'methylpipefidine'4' D.7.36 0.56 (ae) 550 A carboxylic acid 1'methylpipefidine'3' D.7.37 0.57 (ae) 550 B carboxylic acid isothiazolecarb0xylic acid D.7.38 0.67 (ae) 536 A n _‘=0 / \ fl nicotinic acid D.7.39 0.59 (ae) 530 A / O ‘ N n/ N—‘1=O isobutyric acid M D.7.40 0.69 (ac) 495 A Example Rt min m/z ESI+ Btk IC50 Acid (M+H)+ propionic acid D.7.41 0.67 (e) 481 Table D.8: Compounds made from 4-(3-aminomethylphenyl)-1H-indolecarboxamide (Example #16) using General Procedure D.

Example Rt min I’ll/Z ESI+ Btk IC50 Acid Product (M+H)+ HZN o (E)eth0xy0X0but / enoic acid D.8.1 0.69 (ae) 392 A V0 \ O HN\ / (1-methyl-1H- O H [KN 0N / D.8.2 0.62 (ae) 400 B pyrazolyl)acrylic acid \ HZN o (E)(pyridin yl)acrylic acid D.8.3 0.55 (ae) 397 B (E-S-(pyridin-S- D.8.4 0.53 (ae) 397 B yl)acrylic acid —204— Example Rt min I’ll/Z ESI+ Btk IC50 Acid (M+H)+ (ID(thiaz01—2-yl)acrylic acid D.8.5 0.65 (ae) 403 B yclopropylacrylic D.8.6 0.69 (ae) 360 B acid 2-phenylacrylic acid D.8.7 0.75 (ae) 396 B (Emethylpenten0ic D.8.8 0.74 (ae) 362 B acid (E-but-Z-enoic acid D.8.9 0.64 (ae) 334 B Example Rt min I’ll/Z ESI+ Btk IC50 Acid t (M+H)+ methacrylic acid D.8.10 0.65 (ae) 334 C 2-methylenebutan0ic acid D.8.11 0.69 (ae) 348 C acetic acid D.8.12 0.56 (ae) 308 C 3-m0rph01in0pr0pan0ic D.8.13 0.50 (ae) 407 C acid 3-(pyrr01idin D.8.14 0.51 (ae) 391 C yl)pr0pan0ic acid Example Rt min m/z ESI+ Btk IC50 Acid t # (M+H)+ (Z)(ethylamino) D. 8. 15 0.62 (ae) 391 A oxobut-Z-enoic acid O \ fl HZN o Table D9 Examples prepared from (Z)((3-(7-carbamoyl-1H-indolyl)phenyl)amino) oxobutenoic acid (Preparation #14) using General Procedure D Rt min m/z ESI+ Amine Product Example # (Table 1, Btk IC50 (M+H)+ Method ) O "7‘:Oo n/VO\ 2-methoxyethylamine O D.9.1 1.42 (g) 407 B O "7‘: Ethanamine O D.9.2 1.41 (g) 377 A Table D.10. Examples prepared from propiolic acid with an amine using General Procedure D R min e m/z ESI+ Btk Amine Product (Table 1, # (M+H)+ IC50 Method) 4-(Azet1d1nyl(methyl)amino) NM methyl- 1H-1ndole-7—carboxamide hydrochloride (Prepared using A N from Preparation #40 with D. 10.1 1.35 (at) 311 A methylboronic acid and G with \ HCl) N H2N O General Procedure E: Formation of an amide from an amine and an acid halide or anhydride To a solution of an amine (1 to 3 equiv, preferably 1 to 3 equiv), optionally as a hydrochloride salt, in an organic solvent (such as DCM, DCE, DMF, DMA, NMP, THF, EtzO or 1,4-dioxane, preferably DMF, DMA, or DCM) is added a base (such as TEA, DIEA or pyridine; 1 to 4 equiv, preferably TEA or DIEA 1 to 3 equiv) and an acid halide or anhydride (1 to 4 equiv, preferably 1 to 4 equiv). The mixture is ally cooled to about 0 OC prior to addition of an acid halide or anhydride. The mixture is allowed to stir at about 0 to 60 OC (preferably about 0 to 50 0C) for about 5 min to 20 h (preferably about 20 min to 2 h). The mixture is ally neutralized with ACOH. The mixture is ally concentrated in vacuo to give the final nd. The mixture is optionally filtered through a media (such as silica gel or Celite®) which is rinsed with an riate solvent (such as EtOAC, 1,4-dioxane, THF, MeCN, DCM, EtzO, MeOH, EtOH) and then optionally concentrated in vacuo to give a residue. Either the e or the solution may be optionally partitioned between water and an organic solvent (such as EtOAC, EtzO or DCM). The organic layer is isolated and may be optionally washed in no ular order with water and/or s solutions containing an acid (such as HCl, ACOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl NaZSO3 or NaZSZO3). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and trated in vacuo to give the targeted compound. Alternatively, the residue from concentration of the reaction is suspended in water, sonicated, and collected Via vacuum filtration.

Illustration of General Procedure E: Example #E.1. 4-(3—Acrylamidomethylphenyl)(4,4-difluorocyclohexenyl)-1H—indole- 7-carboxamide H2N O HN N F H H H2N O H2N 0 To a Vial was added 4-(3-aminomethylphenyl)(4,4-diflu0rocyclohexenyl)-1H-indole carboxamide (0.189 g, 0.496 mmol, e #21) in DCM (5 mL), and DIEA (0.129 mL, 0.743 mmol). The mixture was cooled to about 0 OC and acryloyl chloride (0.044 mL, 0.545 mmol) was added while stirring. The mixture was warmed to rt over about 20 min, then concentrated and the residue was suspended in water (30 mL). The suspension was ted for about 5 min, filtered, washed with water, ether, and dried under vacumm. The crude product was added to a silica gel column and eluted with heptane/EtOAC (0-100%) to provide 4-(3-acrylamid0methylphenyl)(4,4- difluorocyclohex-I -en-1 -yl)-1H—indolecarb0xamide (0.16 g, 74%): LC/MS (Table 1, Method g) R = 3.02 min; MS Hill: 436 (M+H)+. (BTK IC50 = A) Table E.1. Examples prepared from acryloyl de using General Procedure E R min Example m/z ESI+ Btk Amine Product (Table 1, # (M+H)+ IC50 Method) 4-(2-(amin0methyl)phenyl) (1 ylsulf0nyl)- 1 ,2,3,6- tetrahydropyridinyl)-1H- indole-7—carb0xamide hydrochloride (prepared using 0 A from 0 NH 71 13.1.1 1.47m 479 A Preparation #18 and j 0 \ tert-butyl 2-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-Z- yl)benzylcarbamate [JW] and G with HCl Rt min Example m/z ESI+ Btk Amine Product (Table 1, # (M+H)+ IC50 Method) 4-(2-amin0phenyl)-1H- H indole-7—carb0xamide \ E2 1-32 (f) 306 C (Example #A.5. 1) N o NH2 N H \ \ / O 4-(2-amin0pyridinyl)-1H- indole-7—carb0xamide E13 0.96 (f) 307 A (Example #A.5.3) 4-(5-amin0pyridinyl)-1H- indole-7—carb0xamide E14 0.90 (f) 307 A (Example #A.5.4) 4-(3-(methylamin0)phenyl)- olecarb0xamide (prepared using A from 0 E.1.5 1.41 (f) 320 A ation #P.1 and 3-br0m0—N—methylaniline) \ H2N O 4-(2-methyl yo (methylamin0)phenyl)-1H- /N indole-7—carb0xamide (prepared using A from 13.1.6 1.45 (f) 334 B Preparation #P.1 and O \ 3-br0m0—N,2-dimethylaniline H [Beta Pharm]) Rt min Example m/z ESI+ Btk Amine Product (Table 1, (M+H)+ IC50 Method) ethyl-3 -(thiazol ylmethylamino)phenyl)(1 - (methylsulfonyl)-1,2,3,6- E.1.7 1.75 (g) 576 A tetrahydropyridinyl)- 1H- indolecarboxamide (Example #H.2. 1) 4-(3-amino methoxyphenyl) - 1H-indole carboxamide red using E.1.8 0.63 (ae) 336 B A from Preparation #P.1 and omethoxyaniline) 4-(3-aminomethylphenyl)- 1H-pyrrolo[3,2-c]pyridine carboxamide (prepared using A from Preparation #9 and E.1.9 1.94 (d) 321 A 2-methyl(4,4,5,5- tetramethyl-1,3,2- dioxaborolanyl)aniline [CombiBlocksD minomethylphenyl)- 1H-pyrrolo[3,2-c]pyridine carboxamide (prepared using E.1.10 2.04 (d) 307 A A from Preparation #9 and 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)aniline) (R)(3-aminopiperidin yl)(1-(methylsulfonyl)- 1,2,3,6-tetrahydropyridin yl)-1H-indolecarboxamide (prepared using B from E.1.11* 1.27 (f) 472 A Preparation #27 and (R)—tert—butyl piperidin—3— ylcarbamate, N with C82CO3, G With HCl, and Rt min Example m/z ESI+ Btk Amine t (Table 1, # (M+H)+ IC50 Method) 4-(3-amin0—4- (S: (benzyloxy)phenyl) - 1H- 71)1 indole-7—carb0xarnide F F 13.1.12 3.18(d) 412 C (prepared using A Preparation #2 and iF O \ Preparation #34) O HzN O 4-(3-amino(thiazol j oxy)phenyl) - 1H- O indole-7—carb0xarnide fir O Qi E 1 13 2 79 (d) 419 B red using R from Preparation #Q. 1, A from O i Preparation #P. 1) 4-(3-amino(thiazol Q ylmethoxy)phenyl) - 1H- Q indole-7—carb0xarnide O F 13.1.14 412 C (preparedusingA "Q4 280(0) Preparation #2 and O Preparation #35) 4-(3-amin0—5-(thiaz01—2- ylmethoxy)phenyl) - 1H- indole-7—carb0xarnide (prepared using S from s H OVE>\ 1-br0m0—3-meth0xy-5 - WM nitrobenzene With BBr3, Q Qg 5 27701) 419 B from thiaz01ylmethan01, R ° with Fe, P with " 4,4,4',4',5,5,5',5'— HEN o octamethy1—2,2'—bi(1,3,2— dioxaborolane), and A from Preparation #2 4-(2-an11n0—4-(th1az01—2-. . "\ S ylmethoxy)phenyl) - 1H- , indole-7—carb0xarnide 1 F (prepared using A from 0 1316 27701) 419 C O N 0:?4 Preparation #P.1 and 0 O \ Preparation #R. 1) H Rt min Example m/z ESI+ Btk Amine Product (Table 1, # (M+H)+ IC50 Method) 4-(2-arnin0—4- loxy)phenyl) - 1H- \ 0A0 indole-7—carb0xarnide l 0 (prepared using R from E.1.17 3.29 (d) 412 C Preparation #36 O \ N With Fe, and A from H Preparation #P. 1) 4-(3-arnin0phenyl)ethyl- 01e-7—carb0xarnide 1318 2-93 (d) 332 A (Example #20, Step C) 4-(3-arnin0—4-Ch10r0phenyl)- 61/ O 1H-ind01e-7—carb0xarnide (prepared using A from 9 0-67 (ae) 340 A Preparation #P.1 and 5- O bromo-Z-chloroaniline) 4-(3-arnin0—2,6- difluorophenyl)-1H-ind01e-7— O carboxamide(prepared using 1320 0-62 (ae) 342 A A from Preparation #P.1 and O 3-br0m0—2,4-diflu0r0aniline) 4-(5-arnin0—2,3- WM difluorophenyl)-1H-ind01e-7— carboxamide(prepared using 13.1.21 0.66 (ae) 342 A A from Preparation #P.1 and 3-br0m0—4,5-diflu0r0aniline) HZN o Rt min Example m/z ESI+ Btk Amine t (Table 1, (M+H)+ IC50 Method) 4-(5-arnino-2,4- difluorophenyl)-1H-indole-7— carboxarnide(prepared using E.1.22 0.62 (ae) 342 A A from Preparation #P.1 and -bromo-2,4-difluoroani1ine) rninofluorophenyl)- 1H-indole carboxarnide(prepared using E.1.23 0.62 (ae) 324 A A from Preparation #P.1 and -bromofluoroaniline) H2N o 4-(5-arninoChlorophenyl)- 1H-indole O carboxarnide(prepared using E.1.24 0.65 (ae) 340 A A from Preparation #P.1 and 3-bromochloroaniline) O / 12 4-(3-arninomethylphenyl)- 1H-indole carboxarnide(prepared using E.1.25 0.63 (ae) 320 A A from Preparation #P.1 and -bromomethylaniline) —214— WO 10255 Rt min e m/z ESI+ Btk Amine Product (Table 1, (M+H)+ IC50 Method) 4-(3-arnino-5 -cyanophenyl)- lH-indole-7—carboxarnide (prepared using A from E.l.26 0.63 (ae) 331 B Preparation #P.l and 3- bromocyano aniline) 4-(3-arninocyanophenyl)- lH-indole-7—carboxarnide (prepared using A from E127 0.58 (ae) 331 B Preparation #P.l and 3- bromo-ZCyano aniline) 4-(3-arnino methoxyphenyl) - 1H-indole-7— carboxarnide(prepared using E128 0.63 (ae) 336 B A from Preparation #P.l and 3-bromomethoxyaniline) 4-(3-arninomethylphenyl)- lH-indole carboxarnide(prepared using E129 0.65 (ae) 320 B A from Preparation #P.l and 3-bromomethylaniline) 4-(3-arnino methoxyphenyl) - 1H-indole-7— carboxamide 2 (prepared E.l.30 0.63 (ae) 336 B using A from Preparation #P.l and 3-bromo methoxyaniline) Rt min e m/z ESI+ Btk Amine Product (Table 1, (M+H)+ IC50 Method) 4-(3-arninocyanophenyl)- 1H-indole-7—carboxamide (prepared using A from E.1.31 0.59 (ae) 331 A Preparation #P.1 and 2- aminobromobenzonitrile) 4-(5-arninofluorophenyl)- 1H-indole-7—carboxamide (prepared using A from E.1.32 0.63 (ae) 324 B Preparation #P.1 and 3- bromofluoroaniline) 4-(3-arninofluorophenyl)- 1H-indole-7—carboxamide (prepared using A from E.1.33 0.62 (ae) 324 A Preparation #P.1 and 3- bromofluoroaniline) (cyclopentylmethyl)acrylarnid o)phenyl)-1H-indole E.1.34 0.79 (ae) 388 C carboxarnide (prepared using H from Preparation #A.1 and cyclopentanecarbaldehyde) 4-(3-(N— isobutylacrylamido)phenyl)- 1H-indole-7—carboxamide E.1.35 0.75 (ae) 362 B (prepared using H from ation #A.1 and isobutyraldehyde) Table E.2 Examples prepared from 4-(3-aminophenyl)-1H-indolecarboxamide (Preparation #A.1) using General ure E Rt min m/z ESI+ Btk Acid chloride Product Example # (Table 1, (M+H)+ ICso Method) methylisoxazole- E.2.1 2.61 (c) 361 4-carb0nyl chloride 1-methyl- 1,2,5,6- tetrahydropyridi necarb0nyl chloride E.2.2 1.36 (f) 375 hydrochloride [J . Med. Chem., 1980, 23 (8) 865] Table E.3. Examples prepared from 4-(2-aminophenyl)(1-(methylsulfonyl)-1,2,3,6- tetrahydropyridinyl)-1H-indolecarboxamide (Example #A.4.2) using l Procedure E R min Acid m/z ESI+ Btk Product Example # (Table 1, Chloride (M+H)+ ICso acetyl 0 chloride E.3.1 1.41 (f) 453 Table E.4 Examples prepared from N-(3-(2-(2-(aminomethyl)phenyl)carbamoyl-1H-indol yl)methylphenyl)thiazolecarboxamide (Example #1) using General Procedure E Acid Chloride Rt min m/z ESI+ Btk or Product Example # (Table 1, (M+H)+ 1C50 Anhydri Method) (:on 2- "Hg? chloroacetyl E.4.1 3.17 (d) 558 de O \ O {JYO propionyl WK E.4.2 3.10 (d) 538 chloride O \ O HN O o=< NH acetic E.4.3 3.01 (d) 524 anhydride \ H2N o Table E.5 Examples prepared from N-(3-(3-aminocarbamoyl-1H-indolyl) phenyl)thiazolecarboxamide (Preparation #7) using General Procedure E Rt min Acid Chloride or m/z ESI+ Btk Product Example # (Table 1, Anhydride (M+H)+ IC50 Method) 2-chlor0acetyl HN E.5.1 2.79(d) 468 C chloride O \ N HN2 o Table E.6. Examples prepared from ethyl o-chloridate using General Procedure E Rt min Example ESI+ Btk Amine Product (Table 1, # (M+H) IC50 Method) 2-(2,5-dihydro-1H- pyrrol-S-yl)(2- methyl(4- N oxoquinazolin- 0 E.6.1 2.74 (o) 534 A 3(4H)-yl)phenyl)- NJKOA 1H-indole carboxamide le #G. 1) 4-(2-methyl(4- oxoquinazolin- 3(4H)-yl)phenyl) NVN (1 ,2, 3 , 6- E62 2.82 (o) 548 A tetrahydropyridin- O 1H-indole \ N carboxamide ‘EO (Example #G.1.1) Table E.7 Examples prepared from 2-oxopropanoyl chloride (prepared from c aicd and 1,1-dichlorodimethyl ether [Synthesis, 1975, 3 163-164]) using General Procedure E Rt min Example m/z ESI+ Btk Amine Product (Table 1, # (M+H)+ ICso Method ) 4-(3-amin0phenyl)- 1H-indole- 7-carb0xamide (Preparation E.7.1 1.47 (g) 322 #A. 1) 4-(3-(amin0methyl)phenyl)- 1H-indole-7—carboxamide (prepared using A from (3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan E.7.2 1.41 (g) 336 nyl)methanamine hydrochloride with 4-br0m0— 1H-indole-7—carboxamide [Preparation #2]) Table E.8 Examples ed from acetyl chloride using General Procedure E Rt min m/z Example Acid Chloride Product (Table 1, ESI+ Btk IC50 Method) (M+H)+ 2-(2,5-dihydr0—1H-pyrr01—3- QYO yl)(2-methyl(4- 0 oxoquinazolin-3 (4H)- EL E.8.1 2.72 (d) 504 nyl)- 1H-indole-7— O \ N carboxamide (Example #G. 1) H H2 o 4-(2-methyl-3 -(4- QYO oxoquinazolin-3 (4H)- NV yl)phenyl)(1 ,2,3 , 6- NO E.8.2 1.78 (a) 518 tetrahydropyridinyl)- 1H- o indole-7—carb0xamide 0 N \H (Example #G. 1. 1) NH2 Table E.9. Examples prepared from acryloyl chloride with an amine using General Procedure E R min m/z e Btk Amine Product (Table 1, ESI+ # IC50 Method) (M+H)+ 4-(2- (Aminomethyl)phenyl)- 2-(1-(methylsulf0nyl)- 1,23,6- tetrahydropyridinyl)- ole O carboxamide hydrochloride oj/NH O \ fl E.9.1 1.47 (f) 479 A (prepared using A from Preparation #18 With 0 ""2 tert-butyl ,5,5- tetramethyl-1,3,2- dioxaborolan-Z- zylcarbamate [JW] and G with HCl) 4-(Azetidin yl(methyl)amin0) M cyclopropyl- 1H-indole- LN 7-carboxamide \N (prepared using A from 132 1-38 (33) 339 A Preparation #40 With Cyclopropylboronic acid [SCRC] and G O NH2 with HCl) 4-(Azetidin yl(methyl)amin0) (isochroman-7—yl)-1H- indole-7—carboxamide 0 (prepared using A from LNM Preparation #40 With N E93 1.44 (aa) 431 A 2-(isochromanyl)- 0 4,4,5,5-tetramethyl- 1,3,2-dioxab0rolane o NH2 [prepared using P and 7-br0m0isochr0man] and G With HCl) Rt min m/z Example Btk Amine Product (Table 1, ESI+ Method) (M+H)+ 4-(Azetidin yl(methyl)amino) ihydro-4H- pyrazolo[5,1- c][1,4]oxazinyl)-1H- indole-7—carboxamide (Prepared using P from preparation #40, Step A 13.9.4 1.46(a) 421 A With 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane, A With Preparation #44, C with LiOH, D with NH4C1 and G With HCl) 4-(Azetidin-3 - yl(methyl)amino) (4,4-difluorocyclohex- -yl)-1H-indole-7— carboxamide M (prepared using A from b2 Preparation #40 With 0/ E9.5 1.53 (aa) 415 A 2-(4,4- I2/ ‘n‘n difluorocyclohexen- 1-y1)-4,4,5,5- o NH2 ethyl-1,3,2- dioxaborolane [Syngene] and G With HCl) 4-(Azetidin-3 - yl(methyl)amino)(4- (methylsulfonyl)cycloh n-l-yl)-1H- indole-7—carboxamide o hydrochloride k? (prepared using A from \ L" Preparation #40 With ('3' E.9.6 1.44 (ab) 457 A 4,4,5,5-tetramethyl O . <4- H (methylsulfonyl)cycloh O NH2 eX-l-en-l-yl)-1,3,2- dioxaborolane (W02005/73206 A1) and G With HCl Rt min m/z Example Btk Amine Product (Table 1, ESI+ ICso ) (M+H)+ (S)Methyl idin-3 -yl)- 1H- indole-7—carboxarnide hydrochloride (prepared using X from Preparation #39 With E.9.7 1.58 (a) 312 A LiOH, D With NH4Cl, L With Pd/C, chiral separation (Table 2, Method 5) and G With HCl) (R)Methyl (piperidin-3 -yl)- 1H- -7—carboxarnide hydrochloride (prepared using X from Preparation #39 With E.9.8 1.64 (a) 312 A LiOH, D With NH4Cl, L With Pd/C, chiral H separation (Table 2, o NH2 Method 5) and G With HCl) 4-(Azetidin yl)(methyl)arnino) (6-morpholinopyridin- 3-yl)-1H-indole carboxarnide (Prepared using A from JOK// \NLN Preparation #40 With 4-(5-(4,4,5,5- _ E.9.10 1.22 (at) 461 A tetramethyl-1,3,2- N \N/ \_/ dioxaborolan H2N o yl)pyridin yl)morpholine and G With HCl) 4-(Azetidin yl(methyl)arnino) (7,8-dihydro-5H- pyrano[4,3-b]pyridin yl)- 1H-indole-7— carboxarnide E.9.11 1.48 (au) 432 A hydrochloride (Prepared using A from Preparation #40 With (7,8-dihydro-5H- pyrano[4,3-b]pyridin Rt min m/z Example Btk Amine Product (Table 1, ESI+ Method) (M+H)+ onic acid [Anichem]) and G With HCl) 4-(Azetidin yl(methyl)amino) (chromanyl)-1H- O indole-7—carboxamide M hydrochloride \ ,C/N (Prepared using P from E.9.12 1.51 (av) 431 A 7-bromochroman O \ O [Arkpharm] With H bis(pinacolato)diboron, A With Preparation #40 HZN O and G With HCl) tidin yl)(methyl)amino) (5- o (morpholinomethyl)pyr idinyl)-1H-indole-7— L carboxamide (Prepared _ 13.9.13 1.60 (aw) 475 A using \ \ / G from Preparation #48 fl N Wlth HCD N3 H2N 0 L0 4-(Azetidin yl(methyl)amino)(1- methyl-1H-pyrazol O yl)-1H-indole carboxamide \ LN hydrochloride (Prepared using A from / E.9.14 1.51 (aw) 379 A ation #40 With 1- methyl(4,4,5,5- tetramethyl-1,3,2- H2N O dioxaborolan-Z-yl)-1H- le and G With HCl) 4-(Azetidin yl(methyl)amino) (3,4-dihydro-2H- benzo[b] [1 ,4]oxazin [PM . HN y1)-1H-1ndole—7- X 13.9.15 1.37 (av) 432 A carboxamide dihydrochloride I (Prepared using A from Preparation #40 With tert-butyl 3-((7— —224— Rt min m/z Example Btk Amine Product (Table 1, ESI+ Method) (M+H)+ carbamoyl-Z-iodo- 1H- indol yl)(methyl)amino)azeti dine carboxylate[Arkpharmi no] and G With HCl) 4-(Azetidin-3 - yl(methyl)amino)(1- methyl- azol-5 - o yl)-1H-indole JV carboxannde. hydrochloride N (Prepared using A from E.9.16 1.28 (be) 379 A Preparation #40 With 1- methyl(4,4,5,5- H tetramethyl-1,3,2- H2N 0 dioxaborolan-Z-yl)-1H- pyrazole and G With HCl) 4-(Azetidin hyl)amino)(2- ethyl-1,234- tetrahydroisoquinolin- o 6-yl)-1H-indole / carboxamide \ LNJK/ hdeOChloride NJ 13.9.17 1.12 (av) 458 A (Prepared using A from 0 Preparation #40 With 1- methyl-S-(4,4,5,5- H2N o ethyl-1,3,2- dioxaborolan-Z-yl)-1H- pyrazole and G With HCl) 4-(Azetidin yl(methyl)amino) (1 ,3-dimethyl-1H- pyrazolyl)-1H- O indole-7—carboxamide NM hydrochloride \ L (Prepared using A from Preparation #40 1318 1-29 (3") 393 A With methyl \ N (4,4,5,5-tetramethyl- H \ 1,3 ,2-dioxaborolan yl)-1H-pyrazole and G with HCl) Rt min m/z Example Btk Amine Product (Table 1, ESI+ Method) (M+H)+ 4-(Azetidin yl(n1ethyl)amino) (1 , 1 -dioxidotetrahydro- opyranyl)-1H- indole-7—carboxamide 1 hydrochloride \ LN (Prepared using A from E.9. 19 1.41 (aw) 431 A Preparation #40 With 4- O \ I; (4,4,5,5-tetramethyl- " "0 1,3 xaborolan yl)-3,6-dihydro-2H- thiopyran 1,1-dioxide [Jtharmlab], L With Pd/C and G with HCl) 4-(Azetidin yl)(n1ethy1)amino) (1-propy1piperidin yl)-1H-indole carboxamide (Prepared using J from 1- \ LN opane With 4- E.9.20 1.10(av) 424 A (4,4,5,5-tetramethyl- \ N_/— 1,3 ,2-dioxaborolan N y1)-1,2,3,6- H2N o tetrahydropyridine [Arkpharminc], A With Preparation #40, L With Pd/C and G with HCl) tidin N yl)(n1ethy1)amino) \ L (tetrahydrofurany1)- E.9.21 1.28 (av) 369 A 1H-indole \ O carboxamide N (Preparation #41) H 4-(Azetidin O yl(n1ethyl)amino)(3- JV hydroxyoxetanyl)- 1H-indole LN carboxamide 2’22- Ho 13.9.22 1.18 (ay) 372 B trifluoroacetate \ 0 (Prepared using X from IZ Preparation # 42 With KOH, D with NH4C1 H2N O and G With TFA) WO 10255 Rt min m/z Example Btk Amine t (Table 1, ESI+ Method) (M+H)+ (R)(1-Methyl-1H- pyrazolyl) (morpholin-Z-yl)-1H- indole-7—carboxamide O hydrochloride V (Prepared us1ng Y pN from Preparation #43, A With 1-methyl E.9.23 1.40(a) 380 A \ \ N (4,4,5,5-tetramethyl- \ N 1,3 ,2-dioxaborolan H \ yl)-1H-pyrazole [Arkpharm], O, chiral separation (Table 2, Method 4) and G With HCl) (S)(1-Methyl- 1H- pyrazolyl) (morpholin-Z-yl)-1H- o indole-7—carboxamide V hydrochloride (\N (Prepared using Y from Preparation #43, A With _ 1324 136(3) 380 A 1-methyl(4,4,5,5- ethyl-1,3,2- N \ dioxaborolan-Z-yl)-1H- H2N O pyrazole arm], O, chiral separation (Table 2, Method 4) and G With HCl)) 4-(Azetidin O yl(methyl)amino) methyl-1H-indole carboxamide hloride E.9.25 1.30 (az) 313 A (Prepared using A from Preparation #40 With N methylboronic acid and H2N O G With HCl) (R)(6,7-Dihydro-4H- pyrazolo[5,1- c] [1 ,4]oxazinyl) (pyrrolidinyl)-1H- indole-7—carboxamide (Prepared using E926 1.58 (ba) 406 A P from Preparation #Y.1 with 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane, A With Preparation #44, 2014/044247 Rt min m/z Example Btk Amine Product (Table 1, ESI+ Method) (M+H)+ chiral separation (Table 2, Method 6), C With LiOH, D With NH3 and G With HCl) (S)(6,7-Dihydro-4H- pyrazolo[5,1- c] [1 ,4]oxazinyl) lidinyl)-1H- indole-7—carboxamide (Prepared using P from Preparation #Y.1 with E.9.27 1.58 (ba) 406 A 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane, A With Preparation #44, chiral separation (Table 2, Method 6), C With LiOH, D With NH3 and G With HCl) (R)(1-(Azetidin yl)ethyl)-1H- pyrrolo[3,2-c]pyridine- 7-carboxamide (prepared using AA from tert-butyl 3- acetylazetidine carboxylate [Jtharm] with NW N-(5-chlor0pyridin \/C/ yl)-1,1,1-trifluoro-N— ((trifluoromethyl)sulfon 1328 1-03 (a) 299 A yl)methane | sulfonamide, W With 4,4,4',4',5,5,5',5'— octamethyl-2,2'— O NHZ bi(1,3,2- dioxaborolane)], A With ation #37, L With Pd/C, C with LiOH, D With NH4Cl, chiral separation (Table 2, Method 7) and G With HCl) Rt min m/z Example Btk Amine Product (Table 1, ESI+ Method) (M+H)+ (S)(1-(Azetidin yl)ethyl)-1H- pyrrolo[3,2-c]pyridine- 7-carboxamide (prepared using AA from tert-butyl 3- acetylazetidine carboxylate [Jtharm] O With N—(5-chloropyridin NM yl)-1,1,1-triflu0ro-N— uoromethyl)sulfon 13.9.29 0.99 (a) 299 B yl)methane N sulfonamide, W With 4,4,4',4',5,5,5',5'— octamethyl-2,2'— O NH2 bi(1,3,2- dioxaborolane)], A With Preparation #37, L With Pd/C, C with LiOH, D With NH4Cl, chiral separation (Table 2, Method 7) and G With HCl) 4-((R)-1,4-Oxazepan 7a-dihydro-1H- pyrrolo[3,2-c]pyridine- fl 7-carboxamide O Nk; (prepared using V C from Preparation =\ 13.9.30 0.97 315 (a) A #AH.1 with LiOH, D N \ with NH4Cl, L with / N Pd(OH)2, chiral separation (Table 2, Method 8) and G With HCl) 4-((S)-1,4-Oxazepan yl)-7,7a-dihydro-1H- o[3,2-c]pyridine- O oxamide /_\ 0 Nk; (prepared using C from Preparation #AH.1 with LiOH, D E.9.31 0.97(as) 315 C with NH4C1, L with | Pd(OH)2, chiral separation (Table 2, H2N 0 Method 8) and G With HCl) Rt min m/z e Btk Amine Product (Table 1, ESI+ Method) (M+H)+ (Piperidinyl)- rolo[3,2- c]pyridine-7— carboxamide M hydrochloride O (prepared using Z from = E932 s) 299 A Preparation #AB. 1, NI \ chiral separation (Table / 2, Method 9) and G with HCl) H2N 0 (S)(Piperidin-3 -yl)- 1H-pyrrolo[3,2- O c]pyridine-7— NM carboxamide hydrochloride 13.9.33 1.04 (a) 299 B (prepared us1ng Z from NI \ Preparation #AB. 1, / chiral separation (Table H2" 0 2, Method 9) and G with HCl) 4-(Azetidin ylamino) - 1H- pyrrolo[2,3-c]pyridine- O 7-carboxamide M (prepared using 0 from LN Preparation #AD.1, T HN With E934 1.10 (ba) 286 A tert-butyl 3- N / aminoazetidine H carboxylate[arkpharm] O NH2 and G With HCl) tert-Butyl 3-((7— carbamoyl- 1H-indol yl)(methyl)amino)-3 - methylazetidine NM carboxylate \ i/ (Prepared using T from Preparation #1, Step C 1335 1-47 (a) 313 A and tert-butyl 3-amino- 3-methylazetidine IZ/ carboxylate [AKSCI], J withCH3I, X with O NH2 LiOH, D with NH4Cl and G With HCl) WO 10255 Rt min m/z e Btk Amine Product (Table 1, ESI+ Method) (M+H)+ (R)(1-Methyl-1H- pyrazolyl)-7— idin yl)thiazolo[5,4- c]pyridine carboxamide (Prepared using A from NM Preparation #46 With tert-buty13-(4,4,5,5- E.9.36 1.62 (as) 397 A tetramethyl-1,3,2- \ N dioxaborolanyl)-5,6- N / S\>_CN dihydropyridine- 1 (2H)- carboxylate, L With H2N O Pd/C, chiral separation (Table 2, Method 10) and G With HCl) (S)(1-Methyl-1H- pyrazolyl)-7— (piperidin yl)thiazolo[5 ,4- O c]pyridine )K// carboxamide (Prepared O using A from Preparation #46 with § 139.37 1.60 (as) 397 A utyl 3-(4,4,5,5- \ | N\ \N tetramethyl-1,3,2- N / \ N S \ dioxaborolanyl)-5,6- dihydropyridine-1(2H)- H2N O carboxylate, L With Pd/C, chiral separation (Table 2, Method 10) and G With HCl) (S)(1 ,4-Oxazepan yl)-1H-indole carboxamide (prepared using AA With O tert-butyl 6-oxo-1,4- /—\ oxazepane N4? carboxylate[Arkpharm] V and = E.9.38 1.34 (a) 314 A 1,1,1-trifluoro-N— \ phenyl-N— ((trifluoromethyl)sulfon yl)methane H2N O amide, A With Preparation #P. 1, L With Pd/C, chiral separation (Table 2, Rt min m/z Example Btk Amine Product (Table 1, ESI+ ICso Method) (M+H)+ Method 11) and G With HCl) (1,4-Oxazepan yl)-1H-indole carboxarnide (prepared using AA With tert-butyl 6-oxo-1,4- oxazepane carboxylate[Arkpharn1] 1,1,1-trifluoro-N— E.9.39 1.33 (a) 314 C ((trifluoromethyl)sulfon yl)methane sulfonarnide, A With Preparation #P. 1, L With Pd/C, chiral separation (Table 2, Method 11) and G With HCl) (S)Methyl (pyrrolidin-3 -yl)- 1H- indole-7—carboxarnide (Prepared using chiral separation (Table 2, E.9.40* 1.52 (ha) 298 B Method 3) from Preparation #38, C With LiOH, D With NH3 and G With HCl) (R)Methyl (pyrrolidin-3 -yl)- 1H- indole-7—carboxarnide (Prepared using chiral tion (Table 2, E.9.41* 1.60 (ba) 298 B Method 3) from Preparation #38, C With LiOH, D With NH3 and G With HCl) 4-((1S,SS)-3,6- icyclo[3.2.0]hept anyl)-1H-indole-7— carboxarnide (Prepared using A from 4-bromo- E.9.42 1.39 (ba) 311 B 1H-indole carboxarnide[Anthen1] With tert-butyl 3,6- diazabicyclo[3.2.0]hept anecarboxylate 2014/044247 Rt min m/z Example Btk Amine Product (Table 1, ESI+ Method) (M+H)+ [Arkpharm], chiral separation (Table 2, Method 13) and G With HCl) 4-((1R,5R)-3,6- Diazabicyclo[3.2.0]hept anyl)-1H-indole-7— O carboxamide (Prepared using A from 4-bromo- #4/ N H H 1H-indole CEII‘bOXElInid6[A1’lth6m] N 13.9.43 1.40 (ha) 31 1 B With tert-butyl 3,6- diazabicyclo[3.2.0]hept anecarboxylate N [Arkpharm], chiral separation (Table 2, Method 13) and G With HCl) 4-((3S,5R) (Hydroxymethyl)piperi dinyl)-1H-indole-7— carboxamide (Prepared 13.9.44 1.31(ba) 328 B using chiral tion (Table 2, Method 14) from Preparation #AE.1 and G With HCl) 4-((3S,SS) xymethyl)piperi dinyl)-1H-indole-7— carboxamide (Prepared E.9.45 1.29 (ha) 328 C using chiral separation (Table 2, Method 14) from Preparation #AE.1 and G With HCl) 4-(5- (Hydroxymethyl)piperi yl)-1H-indole-7— carboxamide (Prepared using chiral separation E.9.46 1.34(ba) 328 C (Table 2, Method 14) from Preparation #AE.1 and G With HCl) Rt min m/z Example Btk Amine Product (Table 1, ESI+ Method) (M+H)+ 4—(5- O (Hydroxymethyl)piperi dinyl)-1H-indole-7— carboxamide red using chiral separation E.9.47 1.30(ba) 328 B (Table 2, Method 14) from Preparation #AE.1 and G With HCl) (R)(1-Methyl-1H- pyrazolyl) (pyrrolidinyl)-1H- indole-7—carboxamide hydrochloride (Prepared using A from NH Preparation #Y.1 With l-methy1(4,4,5,5- E.9.48 1.39 (a) 364 A tetramethyl-1,3,2- \ / N dioxaborolanyl)-1H- / N le[arkpharm] , H chiral separation (Table H2N O 2, Method 17), C With LiOH, D With NH3 and G With HCl) (S)(1-Methyl- 1H- pyrazolyl) (pyrrolidinyl)-1H- -7—carboxamide 0 (Prepared using A from Preparation #Y.1 With QN 1-methyl(4,4,5,5- tetramethyl-ISQ- E.9.49 1.50 (ba) 364 B dioxaborolanyl)-1H- \ / N/ pyrazole[arkpharm] , chiral separation (Table H 2, Method 17), C With H2N O LiOH, D With NH3 and G With HCl) —234— Rt min m/z Example Btk Amine t (Table 1, ESI+ Method) (M+H)+ ,3R) 0 Aminocyclopentyl)-1H- fl indole-7—carboxamide 6 hydrochloride : (Prepared using C from _ 1350 143(3) 298 A Preparation #47 With LiOH, D with NH4C1 H and G With HCl) (S)(Piperidin-3 -yl)- 1H-pyrrolo[2,3- dine-7— carboxamide (Prepared using A from Example 0 #29, Step A with NJK/ tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2- H dioxaborolanyl)-5,6- E.9.51 1.42 (ba) 299 B dihydropyridine-1(2H)- | carboxylate, O, L With Pd/C, chiral separation (Table 2, Method 18) and G With acetyl chloride) (R)(Piperidinyl)- 1H-pyrrolo[2,3- c]pyridine-7— carboxamide red using A from Example #29, Step A With tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-Z-yl)-5,6- E952 1.43 (ba) 299 B dihydropyridine- 1 (2H)- carboxylate, O, L With Pd/C, chiral separation (Table 2, Method 18) and G With acetyl chloride) Table E.9.1. Examples prepared from acryloyl chloride with an amine using l Procedure Rt min m/z ESI+ Example Btk Amine Product (Table 1, (M+H20 # 1C50 Method) +H)+ 4-(Azetidin yl(methyl)amin0)(3- hydroxyoxetanyl)- lH-indole carboxamide 2,2,2- E.9.1.1 1.18 (ay) 353 B trifluoroacetate (Prepared using X from IZ/ ation # 42 With KOH, D with NH4Cl and G With TFA) Table E.10. es prepared from propionyl chloride with an amine using General Procedure E Rt min Example m/z ESI+ Btk Amine Product (Table 1, # (M+H)+ ICso Method) (R)Methyl(pyrrolidinyl)- lH-indolecarb0xamide M (Prepared using chiral separation (Table 2, Method 12) from E.10.1 1.64 (ha) 300 Preparation #38, C With LiOH, D % With NH3 and G With HCl) HZN o (S)Methyl(pyrrolidin-3 -yl)- NH lH-indolecarb0xamide (Prepared using chiral separation E.10.2 1.63 (ha) 300 (Table 2, Method 12) from \ Preparation #38, C With LiOH, D With NH3 and G With HCl) % H2N o General Procedure F: Formation of a 4-iodoindolecarboxamide To a solution of 2-aminonitrobenzoic acid (preferably 1 equiv) in MeOH is added slowly concentrated sulfuric acid (preferably 1 equiv). The resulting solution is heated at about 75 0C for about 3 days. After cooling, the on is neutralized by addition of aqueous NaOH solution until pH~10. The reaction is extracted with EtOAC, dried over anhydrous sodium sulfate, filtered and concentrated. To this intermediate (preferably 1 equiv) is added a methyl ketone (1-2 equiv, preferably 2 equiv) and an organic solvent (preferably dimethyl sulfoxide). The reaction is cooled to about -15 0C. A base (preferably potassium tert-butoxide 2 equiv) is added. After stirring for about 2.5 h at rt, the reaction is quenched with saturated aqueous ammonium de solution and then stirred for about 1 h at rt. The resulting suspension was ed, washed with water and the solid is dried under high vacuum. To this intermediate (preferably 1 equiv) is added ((1H- benzo[d] [1 ,2,3]triazol-1 y)tri(pyrrolidinyl)phosphonium hexafluorophosphate(V) (preferably 2 equiv), hydroxybenzotriazole hydrate (preferably 2 equiv) and ammonium chloride rably 1.5 equiv) and an organic solvent (preferably DMF). An organic base (preferably diisopropylethylamine, 4 equiv) is added. The reaction mixture is stirred at rt overnight. The mixture is poured into water and the resulting precipitate is ed, washed with water and EtOAC, and collected. To this ediate rably 1 equiv) is added an organic solvent (preferably MeOH), and the solution is purged with en. To this on is added 10% palladium on carbon (preferably 0.1 equiv). The ing suspension is treated with hydrogen (30 psi). After stirring overnight at rt, the reaction is filtered, and the solids are rinsed with MeOH. The filtrate is trated. A solution of sodium nitrite (preferably 2.2 equiv) in water is added to an ice cold suspension of this intermediate (preferably 1 equiv) in an organic solvent (preferably MeCN) and 2N HCl (preferably 5.4 equiv) with stirring, maintaining the temperature below about -5 0C. After stirring for about 30 min, a cold solution of aqueous potassium iodide (preferably 2.5 equiv) is added to the reaction and the resulting mixture was d at rt for about 30 min. The on is heated to about 85 0C for about 5 min. The reaction is cooled to rt and neutralized with saturated aqueous sodium bicarbonate to pH 8. The mixture is extracted with DCM.

The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by flash Chromatography (preferably silica gel, petroleum ether) to give the target compound. 2014/044247 Illustration of General Procedure F Example #F.1: 4-Iodo(pyridinyl)-1H-indolecarboxamide N02 N02 0%) N02 NH2 NH2 N o OH o o/ O OH NO2 NH2 | (EQQ a_N (EWQ a_N _N \ \ (EWQ\ H H H ONH2 ONH2 O NH2 To a solution of 2-amin0—4-nitr0benz0ic acid (102 g, 560 mmol) in MeOH (1.5 L) was added slowly concentrated sulfuric acid (0.030 L, 560 mmol). The resulting solution was heated at about 75 0C for about 3 days. After cooling, the product was neutralized by addition of aqueous NaOH solution until pH~10. The crude product was extracted with EtOAC, dried over ous sodium sulfate, filtered and concentrated to provide methyl 2-amin0—4-nitr0benz0ate (100 g, 91%). LC/MS (Table 1, Method ar) R = 1.85 min; MS Hill 197.1 (M+H)+. To a portion of this material (25 g, 127 mmol) and 1- inyl)ethan0ne (30.9 g, 255 mmol) in dimethyl sulfoxide (150 mL) at about -15 0C was added potassium tert-butoxide (28.6 g, 255 mmol). After stirring for about 2.5 h at rt, the reaction was quenched with saturated aqueous um chloride solution (100 mL) and then stirred for about 1 hr at rt. The resulting suspension was filtered, washed with water and dried under high vacuum to e 4-nitr0—2-(pyridinyl)-1H-indolecarb0xylic acid (22.4 g, 34%). LC/MS (Table 1, Method ab) R = 1.50 min; MS m/z 284.1 (M+H)+. To a mixture of this material (26.9 g, 95 mmol),((1H- benz0[d][1,2,3]triazolyl)0xy)tri(pyrrolidinyl)ph0sph0nium hexafluorophosphate(V) (99 g, 190 mmol), ybenzotriazole e (29.1 g, 190 mmol) and ammonium chloride (7.62 g, 142 mmol) in DMF (150 mL) was added diisopropylethylamine (66.3 mL, 380 mmol). The reaction mixture was stirred at rt overnight. The mixture was poured into 1000 mL water and the precipitate was filtered, washed with water and EtOAC, and collected to provide 4-nitr0—2-(pyridinyl)-1H- indolecarb0xamide (17.48 g, 56%). LC/MS (Table 1, Method ar) R = 1.44 min; MS m/z 283.1 (M+H)+. To a nitrogen-purged stirred on of this material (17.5 g, 52.6 mmol) in MeOH (1.5 L) was added 10% palladium on carbon (5.60 g, 5.26 mmol). The resulting suspension was d with hydrogen (30 psi). After stirring overnight at rt, the reaction was filtered, and the solids were rinsed with MeOH. The filtrate was concentrated to provide 4-amin0—2-(pyridinyl)-1H-indole carboxamide (10 g, 75%). LC/MS (Table 1, Method ar) R = 1.10 min; MS m/z 253.1 (M+H)+. A solution of sodium nitrite (7.82 g, 113 mmol) in water (20 mL) was added to an ice cold suspension of this material (13 g, 51.5 mmol) in MeCN (150 mL) and 2N hydrogen chloride (188 mL, 376 mmol) with stirring, maintaining the temperature below about -5 0C. After stirring for about 30 min, a cold solution of aqueous potassium iodide (21.4 g, 129 mmol) was added to the reaction and the resulting mixture was stirred at rt for about 30 min. The on was heated on a water bath (85 0C) for 5 min.

The reaction was cooled to rt and neutralized with saturated aqueous sodium bicarbonate to pH 8. The mixture was extracted with DCM. The organic layer was washed with brine, dried over sodium e, filtered and concentrated. The residue was purified by flash chromatography (silica gel, petroleum ether) to provide 4-i0d0(pyridinyl)-1H—indolecarb0xamide (2.0 g, 9%). LC/MS (Table 1, Method ab) R = 1.88 min; MS m/z 364.0 (M+H)+. (Btk IC50 = B) General Procedure G: Acidic cleavage of a otected amine To a solution of an N—Boc amine (1 equiv) in an organic solvent (such as DCM, DCE, l,4-dioxane, EtOAc, or MeOH, preferably DCM, EtOAc, or l,4-dioxane) is added an acid (such as TFA or HCl, preferably TFA; 2 to 35 equiv, preferably 15 to 25 equiV). The mixture is stirred at about 0 to 100 OC (preferably about 20 to 60 0C) for about 1 to 24 h (preferably about 1 to 6 h). Optionally, additional acid (2 to 35 equiV, preferably 20 to 25 equiV) may be added and the mixture stirred at about 0 to 100 OC (preferably about 15 to 60 0C) for about 1 to 24 h (preferably about 1 to 6 h). If a solid is present in the mixture, the mixture may be optionally filtered and the solid washed with an c solvent such as l,4-dioxane or EtzO. The resulting solid is then optionally dried under reduced pressure to give the targeted compound. Alternatively, the mixture may be optionally concentrated in vacuo to give final compound. atively, the mixture is optionally filtered through a media (such as silica gel or Celite®) which is rinsed with an appropriate solvent (such as EtOAc, l,4-dioxane, THF, MeCN, DCM, EtzO, MeOH, EtOH) and then optionally concentrated in vacuo to give a residue. Either the residue or the solution may be optionally ioned between water and an organic t (such as EtOAc, EtzO or DCM). The organic layer is isolated and may be optionally washed in no particular order with water and/or aqueous solutions ning an acid (such as HCl, AcOH or NH4Cl) and/or s solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an nic salt (such as NaCl NaZSO3 or Na2S203). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), ed and concentrated in vacuo to give the targeted compound.

Illustration of General Procedure G Example #G.1. 2-(2,5-Dihydro-1H-pyrrolyl)(2-methyl(4-oxoquinazolin—3(4H)- yl)phenyl)-1H-indolecarboxamide a ac ,Boc NH O\ N —>\ ON\ \ N H H2N 0 WO 10255 To a solution of tert-butyl 3-(7-carbamoyl(2-methyl(4-oxoquinazolin-3(4H)-yl)phenyl)-1H- indolyl)-2,5-dihydro-1H-pyrrolecarboxylate (0.6 g, 1 mmol, Preparation #15) in EtOAc (20 mL) was added HCl/EtOAc at rt. The reaction mixture was stirred at rt for 1 h. The solid was collected as a salt Via filtration and dried to give 2-(2,5-dihydr0-IH-pyrrol-S-yl)(2-methyl(4-0x0quinazolin- 3(4H)-yl)phenyl)-1H—indolecarb0xamide hydrochloride (0.5 g, 94%): LC/MS (Table 1, Method d) Rt = 2.39 min; MS m/Z: 462 (M+H)+ (Btk 1C50 = A).

Table G.1 Examples prepared using General Procedure G Rt min m/z ESI+ Btk N-Boc Amine t Example # (Table 1, (M+H)+ ICso tert-butyl 4-(7- carbamoyl(2- methyl(4- oxoquinazolin-3(4H)- yl)phenyl)- 1H-indol- G11 2.13 (o) 476 2-yl)-5,6- dihydropyridine- 1(2H)-carboxylate (Preparation #2) di-tert-butyl (2-((3- (7-carbamoyl-1H- indol yl)phenyl)carbamoyl) allyl)carbamate (prepared using J G12 2.17 (d) 335 from 2- (bromomethyl)acrylic acid and di-tert-butyl iminodicarboxylate, D from Preparation #A. 1) tert-butyl -(7- carbamoyl- 1H-indol- yl)phenyl)carbamoyl) allyl) yl)carbamate G13 2.20 (d) 349 (prepared using J from 2- (bromomethyl)acrylic acid and tert-butyl methylcarbamate, D —240- WO 10255 Example # (Table 1’ from Preparation #A. 1) General Procedure H: Reductive amination of an aldehyde or ketone with a primary or secondary amine An aldehyde or ketone (preferably 1.0 equiv to 1.3 equiv) and an amine or amine salt (preferably 1.0 to 2.2 equiv) are added in an organic solvent or mixture of organic solvents (such as DCM, DCE or MeOH, or a mixture of DCE and MeOH, preferably DCE, MeOH, or 1:1 MeOH/DCM) at about rt to about 80 0C (preferably about rt). If an amine salt is used, then an amine base (such as TEA or DIEA, 1.0 to 2.2 equiV) is ally added. ACOH (0.1 equiV to 5.0 equiV) is optionally added. The mixture is stirred at rt for about 1 to 90 min (preferably 5 to 30 min). A reducing agent (such as NaBH(OAC)3, Na(CN)BH3, NaBH4, MP-Cyanoborohydride from BiotageTM, 0.5 to 5.0 equiV, preferably 2.5-3.0 equiV of NaBH(OAC)3), is added as a solid or as a solution in an organic solvent (as DCM, DCE or MeOH, or a mixture of DCE and MeOH). The mixture is stirred at rt for about 30 min to 72 h (preferably 1 to 24 h). The crude mixture may be concentrated under reduced pressure or ally partitioned between water and an organic solvent (such as EtOAC, EtzO or DCM). The organic layer is isolated and may be optionally washed with water and/or aqueous solutions ning an acid (such as HCl, ACOH or NH4Cl) and/or s solutions containing a base (such as NaHCO3, , NaOH, KOH or NH4OH) and/or aqueous ons containing an inorganic salt (such as NaCl or ). The organic solution may then be optionally dried with a drying agent (such as MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the target compound.

Illustration of General Procedure H Example #H.1. 2-(1-Methyl-2,5-dihydro-1H-pyrrolyl)(2-methyl(4-oxoquinazolin-3(4H)- yl)phenyl)-1H-indolecarboxamide [1,0 NVNO V0 O\ NH —> o\ \N N\ n H2NO HNO2 To a solution of 2-(2,5-dihydro-1H-pyrrolyl)(2-methyl(4-oxoquinazolin-3(4H)-yl)phenyl)- 1H-indole-7—carboxamide (50 mg, 0.1 mmol, Example #G.1) in MeOH (1 mL) was added (CH20)n —241— (1.6 mg, 0.054 mol) at rt. After stirring at rt for 1 h under N2 here, NaBH(OAc)3 (60 mg, 0.27 mmol) was added. The ing mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure to give a residue, which was purified by prep-HPLC to give 2-(1-methyl-2,5- o-IH—pyrrolyl)(2-methyl(4-0x0quinazolin-3(4H)-yl)phenyl)-1H—indole-7—carb0xamide (15 mg, 32%): LC/MS (Table 1, Method o) R = 2.05 min; MS Hill: 476 (M+H)+ (Btk IC50 A).

Table H.1 Examples prepared from 4-(2-methyl(4-oxoquinazolin—3(4H)-yl)phenyl)(1,2,3,6- tetrahydropyridinyl)-1H-indolecarboxamide (Example #G.1.1) using General Procedure H Rt min m/z ESI+ Btk Aldehyde Product Example# (Table 1, (M+H)+ IC50 Method) paraformaldehyde H.1.1 2.08 (o) 490 A ON\ \ N_ H2N o Table H.2 Examples prepared from 4-(3—aminomethylphenyl)(1-(methylsulfonyl)-1,2,3,6- tetrahydropyridinyl)-1H-indolecarboxamide (Example #A.4.5) using General Procedure H Rt min m/z ESI+ Btk Aldehyde Product Example# (Table 1, (M+H)+ IC50 Method) <1 "o thiazole-Z- O 0 H21 1.74 (g) 522 A carbaldehyde N\ \ 0 H2N o General Procedure 1: Formation of a sulfonamide from an amine and a sulfonyl chloride To a flask is added an amine (1.0 equiv), optionally as a hydrochloride salt, a solvent or mixture of solvents (such as DCM, DCE, EtOAc, THF, 1,4-dioxane, ne, DME, or pyridine/DCM, preferably THF, optionally with a base (such as TEA, DIEA, preferably DIEA; 1 to 5 equiv, ably 1-2 equiv) and a sulfonyl chloride (0.9 to 2.0 equiv, preferably 1.0 to 1.25 equiv). The mixture is stirred at about 0 to 80 0C (preferably about 0 to 35 0C) for about 1 h to 24 h (preferably 5 to 16 h). The e may ally be concentrated in vacuo to give a residue as the target compound. Either the residue or the solution may be optionally partitioned between water and an organic solvent (such as EtOAc, EtzO or DCM). The organic layer is isolated and may optionally be —242— 2014/044247 washed in no particular order with water and/or aqueous solutions ning an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl NaZSO3 or 3). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the target compound.

Illustration of General Procedure I Example #I.1: 4-(3-(Vinylsulfonamido)phenyl)-1H-indolecarboxamide oNH2 o N‘S— ©\ —»N o\ HZN o H2N 0 To a mixture of 4-(3-aminophenyl)-1H-indolecarboxamide (0.11 g, 0.438 mmol, Preparation #A.1), THF (4 mL) and DIEA (0.152 mL, 0.876 mol) at about 0 0C (ice bath) was added ethenesulfonyl chloride (0.058 g, 0.460 mmol, FCH Group). The ice bath was removed and mixture was stirred for about 6 h at rt. The reaction mixture was concentrated under reduced re and the residue was dissolved in DCM and washed water (2x), brine, and passed through a Biotage Phase separator. The mixture was concentrated under reduced pressure and the residue was purified on silica gel using a gradient of 0-10% MeOH in DCM to provide a solid. The solid was triturated with ether (3x, sonicating after each addition of ether). The solid was dried over night under d pressure at 75 0C to provide 4-(3-(vinylsulfonamido)phenyl)-1H—indolecarb0xamide (29 mg, 19%): LC/MS (Table 1, Method c) R = 2.34 min; MS m/z 342 (M+H)+. (Btk IC50 = A) General Procedure J: Substitution of an alkyl halide with an amine nucleophile A flask is charged with an alkyl halide (preferably 1 equiV) and an organic solvent (such as THF, MeCN, DMF, DMA, NMP or DMSO; ably THF or MeCN). To the flask are added in no particular order the amine nucleophile (1 to 25 equiV, preferably 1.2-20 equiV) and an optionally a base (such as LiHMDS, NaH, K2C03, NaHMDS, NaOt-Bu, KHMDS or KOt-Bu, preferably none, NaH or K2C03; 1 to 5 equiV, preferably 1-3 equiV). The mixture is d at about 0 to 100 0C (preferably about 0-40 0C) for about 1 to 24 h (preferably about 3 to 20 h). The mixture may optionally be concentrated in vacuo to give a residue as the target compound. Either the residue or the solution may be optionally ioned n water and an organic solvent (such as EtOAc, EtzO or DCM). The organic layer is ed and may optionally be washed in no particular order with water and/or aqueous solutions ning an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions —243- containing an inorganic salt (such as NaCl NaZSO3 or NaZSZO3). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), ed and concentrated in vacuo to give the target compound. Alternatively, the residue from concentrating the reaction mixture may be suspended in water, sonicated and collected Via vacuum filtration.

Illustration of l Procedure J Example #J.1: (E)(3-(4-(Dimethylamino)butenamid0)methylphenyl)-1H-indole amide —> O \ o\ N N H H H2N O H2N 0 To a solution of (E)(3-(4-bromobutenamido)methylphenyl)-1H-indolecarboxamide (1.4 g, 3.40 mmol, prepared using E from 4-(3-aminomethylphenyl)-1H-indolecarboxamide (Example #16) and (E)bromobutenoyl chloride [J. Org. Chem. 2011, 76, 4467]) in THF (24 mL) at 0 0C was added 2 M dimethylamine in THF (34.0 mL, 67.9 mmol). The mixture was d for 3 h while warming to rt. The mixture was concentrated under reduced pressure and water (15 mL) was added to the residue. The e was sonicated for about 20 min at rt, filtered, washed with water and dried under reduced pressure. The residue was added to a silica gel column and was eluted with MeOH/DCM (0-15%,) to provide the crude product (0.650 g). The crude product was dissolved in DMA (5 mL) and water (100 mL) added while stirring for 20 min at rt. The mixture was filtered, washed with water (50 mL x 3), and dried under d pressure to provide (E)(3-(4- (dimethylamino)but-Z-enamido)methylphenyl)-1H—indolecarb0xamide (0.40 g, 31%): LC/MS (Table 1, Method f) R = 1.05 min; MS m/z 377 (M+H)+. (Btk IC50 B) —244— WO 10255 Table J.1 Examples prepared from an (E)(3-(4-bromobutenamido)methylphenyl)-1H- indolecarboxamide (prepared using E from 4-(3-aminomethylphenyl)-1H-indole carboxamide (Example #16) and (E)bromobutenoyl chloride [J. Org. Chem. 2011, 76, 4467]) using General Procedure J Rt min m/z ESI+ Btk Amine Product e# (Table 1, (M+H)+ IC50 Method) ONT 0NN / piperidine O \ J.1.1 1.13m 417 B H2N o (tetrahydrofur an_2_ Alternatively the solvent is removed under reduced pressure to give the desired compound.

Illustration of General Procedure K: Example #K.1 *: 2-( 1 -((R)-2,3-Dihydroxypropyl)- azolyl)(2-methyl(4-oxoquinazolin- 3(4H)-yl)phenyl)- 1H-indole-7—carboxamide NVN O Que NVN O OI? ); O \ \\l\l\il\/k/OH o NH2 0 NH2 To a solution of 2-(1-(((R)-2,2-dimethyl-1,3-dioxolanyl)methyl)-1H-pyrazolyl)(2-methyl (4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indolecarboxamide (0.047 g, 0.082 mmol, ed using A from 4-bromoiodo-1H-indole-7—carboxamide and (R)((2,2-dimethyl-1,3-dioxolan yl)methyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (Preparation #20), A from 3- (2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)quinazolin-4(3H)-one [PCT Int.

Appl., WO 2011159857]) in THF (5 mL) was added 4 M HCl in 1,4-dioxane (0.5 mL). The mixture was stirred at rt for about 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (Table 1, Method af) to provide 2-(1-((R)-2,3-dihydr0xypr0pyl)- IH—pyrazolyl)(2-methyl(4-0x0quinazolin-3(4H)-yl)phenyl)-1H—indole-7—carb0xamide (0.035 g, 80%): LC/MS (Table 1, Method a) R = 1.65 min; MS m/z 535. (Btk IC50 = A) —247— Table K.1 Examples prepared from an acetonide using General Procedure K R min m/z Example Btk Acetonide t (Table 1, ESI+ # IC5° Method) (M+H)+ 2-(1-(((S)-2,2- dimethyl- 1 ,3-dioxolan- ethyl)-1H- pyrazolyl)(2- methyl(4- nazolin-3(4H)- yl)phenyl)-1H-indole- 7—Carboxamide ©Yo (prepared using A "v" O from 4-bromoiodo- K1 1-64 (a) 535 A 1H-indole-7— O carboxamide and o N N2|:z/ Preparation #21, A from 3-(2-methyl (4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan yl)phenyl)quinazolin- 4(3H)-one [WO 2011159857]) General Procedure L: Hydrogenation of an alkene A round bottom flask is charged With a palladium catalyst, such as Pd/C or Pd(OH)2 (10 or 20 wt%, about 0.005 to 1.0 equiv, preferably 0.5 to 1.0 equiv). The flask is evacuated then flushed With nitrogen 2 to 5 times (preferably 3 times) prior to addition of an organic solvent or mixture of solvents (such as EtOAC, MeOH, EtOH or MeOH/ACOH, preferably MeOH/ACOH) under a nitrogen here. To the mixture is added an alkene (preferably 1 equiv), neat or optionally as a solution in an organic solvent or mixture of solvents (such as EtOAC, MeOH, EtOH or MeOH/ACOH, preferably MeOH). The mixture is stirred under a hydrogen atmosphere (about 30 to 50 psi) for about 1 to 60 h (preferably about 4 to 5 h). ally the reaction may be performed using an H-cube instrument With either Pd/C or Pd(OH)2 cartridges (10 or 20 wt%) and the starting material is passed through the system as a solution in the preferred solvent/s. In cases Where the reaction does not proceed to completion as monitored by TLC, LC/MS, or HPLC, the mixture can be optionally heated to about 30 to 80 OC rably about 50 0C) for about 1 to 24 h (preferably about 16 h) and in cases Where the H-cube is used to m the reaction, the pressure may be increased (25 to 50 bar, preferably 40 to 50 bar). The mixture is then filtered and the filter cake is rinsed With an c solvent (such as EtOAc, MeOH or EtOH, preferably the reaction solvent) and the filtrate is concentrated under reduced pressure to give the crude product.

Illustration of General Procedure L Example #L.1: 2-(1-Acetylpiperidinyl)(3-aminomethylphenyl)-1H-indole carboxamide H2N O H2N I O 0 o N 4< N H H H H2N O H2N o 2-(1-Acetyl-1,2,3,6-tetrahydropyridinyl)(3-aminomethylphenyl)-1H-indolecarboxamide (300 mg, 0.772 mmol, prepared using A with 4-bromoiodo-1H-indolecarboxamide (Preparation #1) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridin-1(2H)-yl)ethanone [Combi-Blocks], A with 3-aminomethylphenylboronic acid, pinacol ester [Combi-Blocks]) and solvent MeOH (72 mL) were added to 20 wt% Pd/C (60.0 mg, 0.564 mmol) in a 250 mL stainless steel pressure bottle and stirred for about 4.5 h at 30 psi then at about 50 0C for about 16 h. The on was ed, concentrated in vacuo and the residue was purified on silica gel using a gradient of 0-10% MeOH in DCM to provide 2-(1-acetylpiperidinyl)(S-amino-Z-methylphenyl)-1H— -7—carb0xamide (77.1 mg, 0.197 mmol): LC/MS (Table 1, Method f) R = 1.06 min; MS m/z 391. (Btk IC50 = B) l Procedure M: Removal of a silyl group from an 0-silyl ether Method 1: To a solution of an 0-silyl-ether (1 equiv) in an c solvent (such as DMF, 1,4-dioxane, or DCM, preferably DCM) is added an acid (such as TFA or HCl, 5 to 50 equiv, preferably 30 equiv) and the mixture is stirred at about 0 to 50 OC (preferably about 15 to 25 0C) for about 1 to 48 h (preferably about 4 to 16 h). Alternatively, additional acid (5 to 20 equiV, preferably 10 equiV) may be added and the mixture is heated to about 30 to 100 OC rably about 50 to 80 0C) for about 0.5 to 10 h (preferably about 1 to 5 h).

Method 2: To a on of an 0-silyl ether (1 equiV) in an organic solvent (such as DMF, 1,4-dioxane, or DCM, preferably DMF) is added a fluoride source such as HF, TBAF (1 to 10 equiV, preferably 4 equiV), and the mixture is stirred at about 20 to 110 OC (preferably about 25 to 60 0C) for about 1 to 20 h (preferably about 2 to 8 h).

For either method, the ed compound may optionally be isolated by cooling the mixture and filtering the precipitate. Alternatively, the mixture is optionally concentrated in vacuo to give the —249- targeted compound. Alternatively, the mixture is ally filtered through a media (such as silica gel or Celite®) which is rinsed with an appropriate solvent (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM, EtzO, MeOH, or EtOH) and then optionally concentrated in vacuo to give a residue. Either the residue or the solution may be optionally partitioned between water and an organic solvent (such as EtOAc, EtzO or DCM). The organic layer is isolated and may be optionally washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4Cl) and/or s solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl, NaZSO3 or NaZSZO3). The organic on may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the targeted compound.

Illustration of General Procedure M: Example #M.1: N-(3-(7-carbam0yl(1-methyl-1H-pyrazolyl)-1H-indolyl) (hydroxymethyl)phenyl)thiazolecarboxamide as CS "It; Myo HO O TBSO O \ {10,} W N N \ \ H o NH? To a on of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)(7-carbamoyl(1-methyl-1H—pyrazol- 4-yl)-1H-indolyl)phenyl)thiazolecarboxamide (100 mg, 0.170 mmol, prepared using D from thiazolecarboxylic acid and 2-((tert-butyldimethylsilyloxy)methyl)(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)aniline [Matrix], A and Preparation # 10) in oxane (2 mL) was added 3 N aqueous HCl (2 mL, 6.00 mmol) and the mixture was stirred at about 25 0C for about 3 h. The resulting solution was diluted with EtOAc (5 mL) and washed with water (3 mL). The organic phase was dried over NaZSO4 and concentrated to give a crude product, which was purified by LC (DCM:MeOH=20:1) to e N—(3-(7—carbam0yl(I-methyl-1H-pyrazolyl)-1H-indolyl) (hydroxymethyl)phenyl)thiazole-Z-carboxamide (36 mg, 45%): 1H NMR (DMSO-d6) 5 11.16 (s, 1H), 10.92 (s, 1H), 8.32 (s, 1H), 8.27-8.25 (d, J=8.4 Hz, 1H), 8.14-8.07 (m, 3H), 7.94 (s, 1H), 7.67- 7.65 (d, J :64 Hz, 1H), .43 (m, 2H), 7.14-7.12 (d, J :76 Hz, 1H), 6.96-6.94 (d, J :76 Hz, 1H), 6.31 (s, 1H), 5.78 (s, 1H), 4.54-4.47 (m, 2H), 3.82 (s, 3H). LC/MS (Table 1, Method 0) R = 2.73 min; MS Hill: 473 (M-H)+. (Btk IC50 = A) Table M.1 Examples prepared from an 0-silyl ether using General Procedure M R min m/z ESI+ Btk 0-silyl ether Product Example # (Table 1, (M+H)+ IC50 4-(2-(((tert- butyldimethylsilyl)oxy )methyl)(6-fluoro oxoquinazolin-3 (4H)- yl)phenyl)(1- methyl-1H-pyrazol M.1.1 3.22 (v) 509 A yl)-1H-indole carboxamide (prepared using A from Preparation #10 and Preparation #11) 4-bromo(1-(2-(tert- butyldimethylsilyloxy) ethyl)-1H-pyrazol yl)-1H-indole carboxamide (prepared using J from 4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan -pyrazole With ©YO A With NV" 0 (2-bromoethoxy)-tert- M2 1-70 (a) 505 A imethylsilane, FXKO \ \ ,‘quH 4-bromoiodo-1H- F O NH? indolecarboxamide, A With 3-(2-methyl(4,4,5,5- tetramethyl-1,3,2- dioxaborolan yl)phenyl)quinazolin- 4(3H)-one [WO 2011159857]) General Procedure N: Hydrolysis of a sulfonamide To a flask containing a sulfonamide, for example, a sulfonyl-protected indole, (preferably 1 equiv) in an organic t (such as 1,4-dioxane, MeOH, or THF/MeOH, preferably 1,4-dioxane) is added an base (such as K2C03, Cs2C03, s Na2C03 or aqueous NaOH, 1-30 equiv; preferably 1-5 equiV for ,). The mixture is stirred at about 25-100 OC (preferably about 60 0C) for about 1-72 h (preferably about 1-18 h). In cases Where the reaction does not proceed to completion as red by TLC, LC/MS, or HPLC, additional base (such as K2C03, Cs2C03, aqueous Na2C03 or aqueous NaOH, preferably 1-5 equiv for Cs2C03,) and/or a cosolvent (such as EtOH) is added. The reaction is continued at about 25-100 OC (preferably about 60 0C) for about 0.25-3 h (preferably about 1-2 h). In any case where an additional base labile group is t (for example, an ester or a cyano group), this group may also be hydrolyzed. The reaction is worked up using one of the following s.

Method 1. The organic solvent is optionally removed under reduced pressure and the s solution is neutralized with the addition of a suitable s acid (such as aqueous HCl). A suitable organic solvent (such as EtOAc or DCM) and water are added, the layers are separated, and the organic solution is dried over anhydrous NaZSO4 or MgSO4, filtered, and trated to dryness under reduced pressure to give the target compound. Method 2. The organic solvent is optionally removed under reduced pressure a suitable organic solvent (such as EtOAc or DCM) and water are added, the layers are separated, and the c solution is dried over anhydrous NaZSO4 or MgSO4, ed, and concentrated to dryness under reduced pressure to give the target compound. Method 3.

The reaction mixture is concentrated under reduced pressure and directly purified by one of the subsequent methods.

Illustration of General Procedure N: Preparation #N.1: : (R)(3-(4-Oxoquinazolin-3(4H)-yl)piperidinyl)-1H—indole carbonitrile. ; ‘fo E :L ,O N N V MO N NVNfio E?) N N ooN TS CN H To a mixture of (R)(3-(4-oxoquinazolin-3(4H)-yl)piperidinyl)tosyl-1H-indolecarbonitrile (0.12 g, 0.229 mmol, prepared using B from 4-fluorotosyl-1H-indole-7—carbonitrile (Preparation #27, step A) and (piperidinyl)quinazolin-4(3H)-one (Preparation #31) in THF (2 mL) and MeOH (1 mL) was added cesium carbonate (0.128 mL, 1.60 mmol) and stirred at rt for about 18 h.

The reaction was d with water (60 mL) and stirred for another 20 min. The mixture was extracted into DCM, dried by passing through a Biotage phase separator to remove residual water and evaporated to dryness to give (3-(4-0x0quinazolin-3(4H)-yl)piperidin-1 -yl)-1H—indole carbonitrile (0.044g, 52%); LC/MS (Table 1, Method g) R = 1.50 min.; MS m/z: 370 (M+H)+ General Procedure 0: Hydrolysis of a e to a primary amide To a flask containing a nitile, (preferably 1 equiV) in an organic solvent (such as MeOH, EtOH, DMSO, DMSO/MeOH, or DMSO/EtOH, preferably DMSO/EtOH) is added a base (such as KOH, aqueous KOH or aqueous NaOH, 1-30 equiV, preferably 3-5 equiV for KOH, preferably 10-15 equiV WO 10255 for aqueous NaOH). The e is stirred at about rt for about 1-30 min (preferably about 1-10 min) then 30% H202 (5-30 equiv preferably 9-27 equiv) was added to the mixture slowly and the reaction mixture was stirred at rt for about 10-30 min. In cases where the reaction does not proceed to completion as monitored by TLC, LC/MS, or HPLC, the reaction is continued at rt for about 0.25-1 h (preferably about 0.25-0.5 h). The reaction is worked up using one of the following methods.

Method 1. The mixture is diluted with saturated NH4Cl and water, stirred at about rt for about 1-30 min. The resulting suspension is collected by filtration, washed with a suitable solvent (such as MeOH, EtOH, or water), and the cake is dried under vacuum to give the target compound.

Method 2. The organic solvent is optionally removed under reduced pressure a suitable organic solvent (such as EtOAc or DCM) and water are added, the layers are separated, and the organic solution is dried over anhydrous NaZSO4 or MgSO4, filtered, and concentrated to dryness under d pressure to give the target compound. Method 3. The reaction mixture is concentrated under reduced re and directly purified by one of the uent methods Illustration of General Procedure 0: Example #O.1: ns(7-carbam0yl(1-(methylsulf0nyl)-1,2,3,6-tetrahydropyridin—4-yl)- olyl)hydroxypiperidinyl)thiazolecarboxamide \ \ Nu OH mixture of transIsomers mixture of trans'Isomers To a stirred solution of N—(trans(7-cyano(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridinyl)- 1H-indolyl)hydroxypiperidinyl)thiazolecarboxamide (36 mg, 0.068 mmol, prepared using B Preparation #27 and ation #23, N with Cs2C03) in DMSO (0.8 mL) was added EtOH (4.8 mL) and KOH (12.81 mg, 0.228 mmol). The mixture was stirred at rt for about 10 min, then 30% H202 (0.070 mg, 0.615 umol) was added to the mixture slowly and the reaction mixture was stirred at rt for about 15 min. Then water (6 mL) was added to the mixture and the solution was ted with EtOAc (3 X 20 mL). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the crude product which was purified by flash chromatography to provide N- (trans(7-carbam0yl(1-(methylsulf0nyl)-1, 2, 3, 6-tetrahydropyridinyl)-1H—indolyl) hydroxypiperidin-S-yl)thiazole-Z-carboxamide (15 mg, 40%): LC/MS (Table 1, Method d) R, = 2.52 min.; MS m/z: 545 (M+H)+. (Btk IC50 = A) Table 0.1 Examples prepared using General Procedure 0 Rt min Example m/z ESI+ Btk Nitrile Product (Table 1, # (M+H)+ IC50 Method) N—(3-(7—cyan0—1H-indol- 4-yl)methylphenyl) (difluoromethyl)benzami (prepared using A from 4-br0m0—1H-indole-7— carbonitrile 0.1.1 1.69 (f) 420 B 2-methyl(4,4,5,5- tetramethyl-1,3,2- dioxaborolan yl)aniline [Combi- BlocksD, N with Cs2C03 4-(2-methyl(oxetan ylamino)phenyl) - 1H- indole-7—carb0nitrile (prepared using A from 0—1H-indole-7— itrile 0.1.2 1.72 (f) 322 C 2-methyl(4,4,5,5- tetramethyl-1,3,2- dioxaborolan yl)aniline [CombiBlocks]), H from oxetanone, N with Cs2C03 (R)(1- (methylsulfonyl)-1,2,3,6- tetrahydropyridinyl)- 8-oxo-5,6- dihydroimidazofl ,2- a]pyrazin-7(8H)- 013* 0.99 (f) 538 A yl)piperidinyl)- 1H- indole-7—carb0nitrile (prepared using B from ation #27 and Preparation #13, N with Cs2C03 —254— Rt min Example m/z ESI+ Btk Nitrile Product (Table 1, (M+H)+ IC50 Method) (R)(1- lsulfonyl)-1,2,3,6- tetrahydropyridinyl)- 4-(3-(8-oxoimidazo[1,2- a]pyrazin-7(8H)- eridiny1)- 1H- 014* 1.18 (f) 536 A indolecarbonitri1e (prepared using B from Preparation #27 and ation #12, N With Cs2C03 (R)-N—(1-(7-cyano(1- (methylsulfonyl)-1,2,3,6- tetrahydropyridinyl)- 1H-indoly1)piperidin- 3-y1)methyloxazole carboxamide (prepared using B from Preparation #27 and 015* 1.43 (f) 527 A (R)—tert—buty1 piperidin—3— ylcarbamate, G with HCl, and D with 2-methyloxazole carboxylic acid, N With C82CO3 (1-(7-cyano- 1H- indoly1)piperidin 0 yl)methyloxazole N 016* 1.08 (g) 368 carboxamide \ (Preparation #V. 1) , N N with Cs2C03 o NH2 (R)(1-(7-cyano-1H- SYN indoly1)piperidin-3 - y1)-3 - (thiazoly1)urea (prepared using V With 017* 0.72 (g) 385 C thiazoly1carbamic acid and Preparation #B.1, N Wlth C82CO3 Rt min Example m/z ESI+ Btk Nitrile Product (Table 1, (M+H)+ IC50 Method) (R)-N—(1-(7-cyano-1H- indoly1)piperidin y1) (trifluoromethy1)benzami de (prepared using V 018* 1.62 (g) 431 C With 4- (trifluoromethy1)benzoic acid and Preparation H2N O #B.1, N with Cs2C03 (R)-N—(1-(7-cyano-1H- indoly1)piperidin yl)methoxybenzamide (prepared using V With 019* 1.30 (g) 393 C 4-methoxybenzoic acid and Preparation #B. 1, N with Cs2C03 (R)tert-buty1—N-(1 -(7- cyano-1H-indol y1)piperidin yl)isoxazole carboxamide (prepared 0110* 1.70 (g) 410 C using V With butylisoxazole carboxylic acid and Preparation #B.1, N With Cs2C03 (R)(3-aminopiperidin- 1-y1)-1H-indole carboxamide red using V With 0111* 1.55 (g) 419 C 4-tert-buty1benzoic acid and Preparation #B. 1, N with Cs2C03 (R)(3-(4- oxoquinazolin-3 (4H)- y1)piperidiny1)- 1H- 0112* 1.28 (g) 388 C -7—carbonitri1e (Preparation #N. 1) Rt min Example m/z ESI+ Btk Nitrile Product (Table 1, (M+H)+ IC50 Method) 4-(3-(7-cyclopropy1 fluorooxoquinazolin- 3(4H)-y1)piperidiny1) - 1H-indolecarbonitri1e F O N 0.1.13 1.63 (g) 446 C (prepared using B from Preparation #27, step A N and ation #33, N H H2N O with Cs2C03 (R)(4-fluoropheny1)- 4-(3-(4-oxoquinazolin- 3(4H)-y1)piperidiny1) - olecarbonitri1e (prepared using A from Preparation #27, step B NVNI,O N 0114* 1.69 (g) 482 B and 2-(4-fluorophenyl)- 4,4,5,5-tetramethyl- o\ F 1,3,2-dioxaborolane, B from Preparation #31, N Wlth C82CO3 (R)(3-(6-fluoro oxoquinazolin-3(4H)- yl)piperidiny1)(4- fluoropheny1)- 1H- indolecarbonitri1e (prepared using A from Preparation #27, step B 0115* 1.75 (g) 500 C and uorophenyl)- 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane, B from Preparation #32, N Wlth C82CO3 (R)(1-methy1—1H- pyrazoly1)(3-(4- nazolin-3(4H)- yl)piperidiny1)- 1H- indolecarbonitri1e (prepared using A from Preparation #27, step B 0116* 1.39 (g) 468 B and 1-methy1—4-(4,4,5,5- tetramethy1-1 ,3,2- dioxaborolany1)- 1H- pyrazole, B from Preparation #31, N With C82CO3 2014/044247 Rt min Example m/z ESI+ Btk Nitrile Product (Table 1, (M+H)+ IC50 Method) (3-(6-fluoro oxoisoindolin yl)piperidiny1)(1- methyl-1H-pyrazol y1)- 1H-indole carbonitrile (prepared using A from Preparation #27, step B 0118* 1.48 (g) 473 C and 1-methy1—4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolany1)-1H- pyrazole, B from Preparation #30, N With C82CO3 (R)tert-butyl-N-(1-(7- cyano(1-methyl-1H- pyrazoly1)-1H-indol- 4-y1)piperidin zamide (prepared using A from ation #27, step B and 1-methy1—4-(4,4,5,5- 0119* 1.73 (g) 499 A tetramethyl-1,3,2- dioxaborolany1)-1H- pyrazole, B from (R)- H2N o tert-butyl piperidin ylcarbamate, V With 4- tert-butylbenzoic acid, N With C82CO3 (R)-N—(1-(7-cyano(1- methyl-1H-pyrazol yl)-1H-indol y1)piperidiny1) methoxybenzamide (prepared using A from Preparation #27, step B and 1-methy1—4-(4,4,5,5- 0120* 1.32 (g) 473 B tetramethyl-1,3,2- dioxaborolany1)-1H- pyrazole, B With (R)- tert-butyl piperidin ylcarbamate, V With 4- methoxybenzoic acid, N With C82CO3 Rt min Example m/z ESI+ Btk Nitrile Product (Table 1, (M+H)+ IC50 Method) (R)-N—(1-(7-cyan0—2-(1- methyl-1H-pyraz01—4- yl)-1H-ind01—4- y1)piperidiny1) (trifluoromethy1)benzami de methoxybenzamide (prepared using A from Preparation #27, step B 0 0.1.21* 1.65 (g) 511 B and 1-methy1—4-(4,4,5,5- \ ‘N tetramethyl-1,3,2- \ N\ di0xab0r01anyl)- 1H- H H2N O pyrazole, B With (R)- tert-butyl piperidin ylcarbamate, V With 4- (trifluoromethyl)benz0ic acid, N With Cs2C03 (R)-N—(1-(7-cyan0—2-(1- methyl-1H-pyraz01—4- yl)-1H-ind01—4- y1)piperidiny1) (difluoromethyl)benzami (prepared using A from Preparation #27, step B O 0.1.22* 1.51 (g) 493 B and 1-methy1—4-(4,4,5,5- \ ‘N tetramethyl-1,3,2- \ N\ di0xab0r01anyl)- 1H- H H2N o pyrazole, B With (R)- tert-butyl piperidin amate, V With 4- (difluoromethyl)benz0ic acid, N With Cs2C03 (R)-N—(1-(7-cyan0—2-(1- methyl-1H-pyraz01—4- yl)-1H-ind01—4- eridiny1)(2- ropan zamide (prepared using A from Preparation #27, step B and 1-methy1—4-(4,4,5,5- 0.1.23* 1.28 (g) 528 B tetramethyl-1,3,2- di0xab0r01anyl)- 1H- H2N o pyrazole, B With (R)- tert-butyl piperidin amate, V With 4- (1 -amin0—2-methyl 0X0pr0panyl)benzoic acid, N With Cs2C03 Rt min Example m/z ESI+ Btk Nitrile Product (Table 1, (M+H)+ IC50 Method) (1-(7-cyan0—2-(1- methyl-1H-pyraz01—4- yl)-1H-ind01—4- y1)piperidiny1) (trifluoromethoxy)benza mide (prepared using A from Preparation #27, step B 0124* 1.68 (g) 527 B and 1-methy1—4-(4,4,5,5- tetramethyl-1,3,2- di0xab0r01anyl)- 1H- pyrazole, B With (R)- tert-butyl piperidin ylcarbamate, V With 4- (trifluoromethoxy)benz0i c acid, N With Cs2C03 (R)-N—(1-(7-cyan0—2-(1- -1H-pyraz01—4- yl)-1H-ind01—4- y1)piperidiny1) ropylbenzamide (prepared using A from Preparation #27, step B and 1-methy1—4-(4,4,5,5- 0.1.25* 1.40 (g) 483 A tetramethyl-1,3,2- di0xab0r01anyl)- 1H- pyrazole, B With (R)- tert-butyl piperidin ylcarbamate, V With 4- cyclopropylbenzoic acid, N Wlth C82CO3 tert-buty1—N—(1 -(7- cyan0(pyridiny1)- 1H-ind01—4-y1)piperidin- 3-yl)benzamide (prepared using A from Preparation #27, step B 0.1.26 1.56 (g) 496 A and pyridiny1b0r0nic acid, B With (R)-tert- butyl piperidin ylcarbamate, V With 4- tert-butylbenzoic acid, N With C82CO3 Rt min Example m/z ESI+ Btk Nitrile Product (Table 1, # (M+H)+ IC50 Method) (R)(3-(4- oxoquinazolin-3(4H)- yl)piperidinyl) (pyridin-3 -yl)- 1H- QYO indolecarbonitrile NvNI"O (prepared using A from N O. 127* 1.22 465 B Preparation #27, step B —N and pyridinylboronic \ / acid with Cs2C03, B H from Preparation #31 With C82CO3 General ure P: Formation of a boronate from an aryl halide or aryl halide To a mixture of an halide, for example, a bromo indole (preferably 1 equiv), 4,4,4',4',5,5,5',5'— octamethyl-2,2'—bi(1,3,2-dioxabor olane) (1 to 3 equiv, preferably 1.2 equiv), potassium acetate (2 to 5 equiv, ably 3 equiv), and in a solvent (such as THF or 1,4-dioxane; preferably 1,4-dioxane) is added a palladium catalyst (for example szdba3 or (1,1’- bis(diphenylphosphino)ferrocene)dichloropalladium(II) complex with DCM; preferably 1,1’- phenylphosphino)ferrocene)dichloropalladium(II) complex with DCM, 0.01 to 0.20 equiv, ably 0.1 equiv). The mixture is heated at about 40 to 120 OC (preferably about 80 0C) for about 1 to 24 h (preferably about 16 h). The mixture is allowed to cool to rt and is worked up using one of the following methods. Method 1. The e may be d with an organic solvent (such as DCM or EtOAC) and the organic solution is optionally washed with water and/or brine, dried over anhydrous MgSO4 or NaZSO4, filtered, and the solvent is d under reduced pressure to give the desired compound. Method 2. The mixture is concentrated under reduced pressure and optionally purified using one or more of the Purification Methods described above to give the desired compound.

Method 3. The catalyst is d by filtration and the filtrate is concentrated under d pressure.

Illustration of General Procedure P Preparation #P.1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)-1H-indolecarboxamide H \ H2N o H H2N o A mixture of 4-bromo-1H-indolecarboxamide (5 g, 20.9 mmol, Preparation #2), 4,4,4',4',5,5,5',5'— octamethyl-2,2'—bi(1,3,2-dioxaborolane) (6.37 g, 25.1 mmol), potassium acetate (6.16 g, 62.7 mmol) and Pd(dppf)C12-DCM (0.85 g, 1.05 mmol) in 1,4-dioxane (2 mL) was heated at about 80 0C under N2 ght. The solvent was removed under reduced pressure to get a residue, which was purified by column chromatography on silica gel to afford 4-(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)- IH-indole-7—carb0xamide (3 g, 50%): 1H NMR (CDCl3) 8 10.30 (br, 1H), 7.64-7.62 (d, J: 8 HZ, 1H), .38 (m, 2H), 7.08-7.07 (m, 1H), 1.42 (s, 12H).

General Procedure Q: Mitsunobu reaction of an alcohol To an l (preferably 1 equiv) in an organic solvent (such as THE, benzene, toluene, or 1,4- dioxane, preferably toluene or 1,4-dioxane) is added a suitably acidic reactant (such as a carboxylic acid, a phenol or a heteroaryl l, 1-3 equiv, preferably 1 , followed by tri-n- butylphosphine, triphenylphosphine or polymer bound triphenylphosphine (preferably triphenylphosphine, 1-3 equiV, preferably 1.2 equiv), and TMAD, azodicarbonyl)dipiperidine, DIAD or DEAD (preferably DEAD, 1-3 equiV, preferably 1.2 equiV) is added dropwise at about 0- 120 OC (preferably 0-25 OC). The reaction mixture is stirred at about 25-120 0C for about 5-48 h (preferably about 16 h). Alternatively, after about 01-24 h additional ine reagent (0.2-2 equiV) and TMAD, 1,1'-(azodicarbonyl)dipiperidine, DIAD or DEAD (0.2-1 equiV) are added to drive the reaction to completion. Method 1. When polymer bound reagent is used, the reaction mixture is filtered and washed with a mixture of solvents such as DCM, EtOAc and MeOH (preferably DCM then MeOH). The filtrate is concentrated under reduced re. Method 2. When no polymer bound reagent is used, the on mixture is optionally d with an organic solvent such as DCM or EtOAc and then washed with water, saturated aqueous NaHCO3, brine and dried over anhydrous NaZSO4 or MgSO4, filtered, and concentated under reduced pressure. Alternatively, the reaction mixture is directly concentrated under reduced pressure.

Illustration of General Procedure Q Preparation #Q.1: 2-((4-Bromonitrophenoxy)methyl)thiazole 0" I N02 —> To a solution of 4-bromonitrophenol (2 g, 9.17 mmol, Preparation #S.1), thiazolylmethanol (1.01 g, 9.17 mmol) and triphenylphosphine (2.9 g, 11.01 mmol) in anhydrous toluene (50 mL) was added DEAD (1.7 mL, 11.01 mol) at about 0 0C under N2. Then the mixture was heated to reflux overnight. After cooling to rt, the e was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to give 2-((4-br0m0 nitrophenoxy)methyl)thiazole (2 g, 69%): 1H NMR (CDCl3) 5 7.83 (d, J = 3.1 HZ, 1H), 7.63 (d, J = 8.8 HZ, 1H), 7.53 (d, J: 3.1 HZ, 1H), 7.42 (d, J: 3.1 HZ, 1H), 7.12 (dd, J: 3.1, 8.8 HZ, 1H), 5.43 (s, 2H).

General Procedure R: Reduction of a nitro group to an amine using Fe To a mixture of a containing compound in a solvent (such as MeOH, EtOH, MeOH/water or EtOH/water, preferably EtOH/water) is added Fe (3 to 5 equiv, ably 5 equiv) and NH4Cl (3 to 5 equiv, preferably 5 equiv). The mixture is heated at about 40 to 100 OC (preferably about 80 0C) for about 2 to 24 h (preferably about 16 h). The e is allowed to cool to rt and is worked up using one of the following methods. Method 1. The mixture may be diluted with an organic solvent (such as DCM or EtOAC) and the organic solution is optionally washed with water and/or brine, dried over anhydrous MgSO4 or Na2S04, filtered, and the solvent is removed under reduced pressure to give the desired compound. Method 2. The mixture is concentrated under d pressure and ally purified using one or more of the Purification Methods described above to give the desired compound.

Method 3. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. Intermediates and final compounds prepared Via this General Procedure can be optionally purified using one or more of the Purification Methods described above. ration of General Procedure R Preparation #R.1: 2-Bromo(thiazolylmethoxy)aniline /=\ /=\ s,N S/N I I O 0 N02 NH2 Br Br To a solution of bromonitrophenoxy)methyl)thiazole (1 g, 3.2 mmol) in EtOH (40 mL) and water (20 mL) was added iron (0.88 g, 15.8 mmol) and NH4Cl (0.85 g, 15.8 mmol). The e was heated to reflux overnight. The mixture was filtered and the filtrate was concentrated under d pressure to get a residue, which was diluted by addition of water and extracted by EtOAC. The organic layer was concentrated under reduced pressure to provide 2-br0m0(thiazol oxymmline (0.7 g, 77%): LC/MS (Table 1, Method l) R = 1.46 min; MS m/z 285 (M+H)+.

General Procedure S: Demethylation of aryl methyl ether To a mixture of a methoxy compound in a t (such as DCM, DCE, THF, benzene, toluene, or 1,4-dioxane, preferably DCM) is slowly added BBr3 (2 to 24 equiV, preferably 2.5 equiv). The mixture is heated at about 30 to 110 OC (preferably about 45 0C) for about 2 to 24 h (preferably about 4-24 h). The mixture is allowed to cool to 0 - 10 OC (preferably about 0 OC) and is d with water.

The mixture may be diluted with an organic solvent (such as DCM or EtOAc) and the organic on is optionally washed with water and/or saturated NaHCO3 and/or brine, dried over anhydrous MgSO4 or Na2S04, filtered, and the solvent is d under reduced pressure to give the d compound.

Illustration of General Procedure S Preparation #S.1: 4-Bromonitrophenol O/ OH N02 —> : ‘N02 Br Br To a solution of 1-bromomethoxynitrobenzene (20 g, 82 mmol) in DCM (800 mL) was added dropwise BBr3 (19 mL, 207 mmol) in DCM (120 mL). The resulting mixture was heated to reflux overnight. The mixture was cooled in ice-water and was diluted by on of water. Then the mixture was washed with saturated NaHCO3 and brine. The organic phase was dried over Na2S04, concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to provide 4-br0m0nitr0phenol (6 g, 31%) as a solid: 1H NMR (CDCl3): 8 7.57 (d, J = 8.8 Hz, 1H), 7.35 (d, J: 2.6 Hz, 1H), 6.94 (dd, J: 2.9, 8.6 Hz, 1H), 5.90 (br., 1H).

General Procedure T: Buchwald reaction of an aryl halide or a heteroaryl halide with an amine A mixture of an aryl halide or heteroaryl halide (1.0 , an amine (1 to 2.2 equiv, preferably 1 to 1.2 equiv), a ium catalyst (such as Pd2dba3 or Pd(OAc)2, preferably Pd2dba3; 0.01 to 1.0 equiV, preferably 0.04 to 0.1 equiV), a ligand (such as X-phos, Xanthphos or tert-butyl-X-phos, preferably tert-butyl-X-phos or X-Phos, 0.01 to 2.0 equiV, preferably 0.04 to 0.1 equiV) and a base (such as K2C03, Na2C03, CszCO3, K3PO4, NaOt-Bu, , KOAc, KOH, preferably K2C03; 1 to 5 equiV, preferably 1 to 3 equiV) are added to a solvent (such as oxane, , preferably t-BuOH).

The mixture is degassed under an inert atmosphere (such as nitrogen or argon, preferably nitrogen) and heated with conventional heating at about 80 to 100 0C (preferably about 85 to 95 0C) for about 2 to 24 h (preferably about 18 h) or with microwave heating at about 100-150 0C for about 30 min to 2 h. The mixture is cooled to rt. The mixture is optionally filtered through a media (such as silica gel or Celite®) which is rinsed with an appropriate solvent (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM, EtzO, MeOH, EtOH, DMSO, 1:1 MeOH/DMSO or 2:1 MeOH/DMSO, preferably MeOH/DMSO) and then the filtrate is optionally concentrated in vacuo or under a warm en stream to give a residue. 2014/044247 Illustration of General Procedure T Preparation #T.1: 4-(1-Methyl-1H-pyrazolylamino)p-tolyl-1H-indolecarboxamide HZN o 4-Iodo(p-tolyl)-1H-indolecarboxamide (99 mg, 0.26 mmol, prepared using F with 1-(ptolyl )ethanone), 1-methyl-1H-pyrazolylamine (27 mg, 0.26 mmol, Maybridge-Int), X-Phos (7.53 mg, 0.016 mmol), K2C03 (44 mg, 0.316 mmol), and szdba3 (14 mg, 0.016 mmol) were combined in t-BuOH (1.32 mL) in a sealed microwaved tube. The tube was degassed and purged with N2 and heated at about 85 0C for 18 h. The reaction was cooled to rt and filtered through Celite®. The filtrate was extracted twice with DCM. The combined organic layers were concentrated. The residue product was purified on a normal phase column (18 mg, 20%): LC/MS (Table 1, Method f) R = 1.48 min; MS m/z 346 (M+H)+. (Btk IC50 = B) Table T.1 Examples prepared from 4-iodo(p-tolyl)-1H-indolecarboxamide (prepared using F with 1-(p-tolyl)ethanone) using l ure T R min m/z ESI+ Btk Amine Product Example # (Table 1, (M+H)+ IC50 Method) methoxybenz / yl)-1H- T.1.1 1.77 (f) 452 B pyrazol O amine General Procedure U: Negishi cross-coupling reaction of an aryl halide or a heteroaryl halide with an organozinc A mixture of an aryl halide or heteroaryl halide (preferably 1.0 equiv) an organic t or mixture of solvents (such as THF, EtzO or 1,4-dioxane, preferably THF), an organozinc compound (0.67 to 1.5 equiv, preferably 0.9 to 1.2 equiv), a ium catalyst (such as 3)4, 0.01 to 1.0 equiv, preferably 0.025 to 0.10 equiv) is stirred at about rt to 90 0C (preferably about 85 0C) for about 1 to 24 h rably about 18 h). The mixture is cooled to rt. The mixture is optionally filtered through a media (such as silica gel or Celite®) which is rinsed with an appropriate solvent (such as EtOAC, 1,4- dioxane, THF, MeCN, DCM, EtzO, MeOH, EtOH) and then optionally concentrated in vacuo to give WO 10255 a residue. Either the residue or the solution may be optionally partitioned between water and an organic solvent (such as EtOAc, EtzO or DCM). The organic layer is isolated and may be optionally washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl, NaZSO3 or Na2S203). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and trated in vacuo to give the targeted compound.

Illustration of General ure U Preparation #U.1: 4-(2-Chlorofluorobenzyl)p-tolyl-1H-indolecarboxamide HZN o 4-Iodo(p-tolyl)-1H-indolecarboxamide (97 mg, 0.258 mmol, prepared using F from 1-(p- tolyl)ethanone), (2-chlorofluorobenzyl)zinc(II) bromide (0.77 mL, 0.387 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) were dissolved in THF (0.82 mL) in a sealed ave tube and heated thermally at 85 0C for about 18 h. The reaction was cooled to rt and filtered through Celite®. The filtrate was concentrated to give a e. The residue was purified on a normal phase column eluting with EtOAc in hexane to give 4-(2-chlor0flu0r0benzyl)p- tolyl-IH-indolecarb0xamide (30 mg, 30%): LC/MS (Table 1, Method f) R = 2.09 min; MS m/z 393 (M+H)+.

Table U.1 es prepared from (p-tolyl)-1H—indolecarboxamide (prepared using F with 1-(p-tolyl)ethanone) using General Procedure U R min m/z ESI+ Btk Organozinc Product Example # (Table 1, (M+H)+ IC50 Method) (2,6- C dichlorobenzyl)zinc(II) O U.1.1 2.13 \ O (f) 409 C bromide u 2-Thiazolylzinc U.1.2 1.76 (f) 334 A bromide 2-Pyridylzinc bromide U.1.3 1.34 (g) 328 B l Procedure V: Formation of an amide from a Boc-protected amine and a carboxylic acid To a solution of an N—Boc amine (1 equiv) in an organic solvent (such as DCM, DCE, 1,4-dioxane or MeOH, ably DCM or 1,4-dioxane) is added an acid (such as TFA or HCl, ably TFA; 2 to 100 equiv, preferably 25 to 50 equiv). The mixture is stirred at about 0 to 100 OC rably about 20 to 60 0C) for about 0.5 to 24 h rably about 0.5 to 6 h). Optionally, additional acid (2 to 35 equiV, preferably 20 to 25 equiv) may be added and the mixture stirred at about 0 to 100 OC rably about 20 to 60 0C) for about 1 to 24 h (preferably about 1 to 6 h). If a solid is t in the mixture, the mixture may be optionally filtered and the solid washed with an organic solvent such as 1,4-dioxane or EtzO. The resulting solid is then optionally dried under reduced pressure.

Alternatively, the reaction miture is concentrated under reduced pressure. To the residue in a flask is added in no particular order, a carboxylic acid or ylate salt (1 to 5 equiV, preferably 1.1 to 1.5 equiV) an organic solvent (such as DCM, DCE, DMF, THF, or 1,4-dioxane, preferably DCM or DMF), a peptide coupling reagent (such as BOP-Cl, IBCF, HATU, DCI, PyBOP, or EDC'HCl, preferably HATU; 1 to 10 equiV, preferably 1 to 2 equiV), a base (such as TEA, DIEA, pyridine or DIEA, preferably DIEA; 1 to 20 equiV, preferably 1 to 5 equiV) and optionally HOBt (0 to 5 equiV, preferably 0 to 1 equiV). The mixture is then stirred at about 10 to 60 OC (preferably about 25 to 50 0C) for about 15 min to 48 h (preferably about 15 min to 24 h). Optionally, additional amounts of the reagents above can be added to drive the reaction to completion. The mixture is optionally trated in vacuo to give the targeted compound. The mixture is optionally filtered h a media (such as silica gel or Celite®) which is rinsed with an appropriate solvent (such as EtOAC, 1,4- dioxane, THF, MeCN, DCM, EtzO, MeOH, EtOH) and then optionally concentrated in vacuo to give a residue. Either the residue or the solution may be ally partitioned between water and an organic solvent (such as EtOAC, EtzO or DCM). The organic layer is isolated and may be optionally washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl, NaZSO3 or NaZSZO3). The organic solution may then be optionally dried with a drying agent (such as ous MgSO4 or NaZSO4), filtered and trated in vacuo to give the targeted compound.

Illustration of General Procedure V Preparation #V.1: (R)-N-(1-(7-cyano-1H-indolyl)piperidinyl)methyloxazole carboxamide Mo OH ’Wo N OYL O \ o N N CNH CNH To a solution of (R)-tert-butyl 1-(7-cyano-1H-indolyl)piperidinylcarbamate ( 0.11 g, 0.333 mmol, Preparation #B.1) in DCM (1 mL) was added TFA (1 mL) and the solution stirred at about 25 0C for about 30 min. The mixture was evaporated to dryness followed by the addition of DMF (2 mL), TEA (0.139 mL, 0.999 mmol), HATU (190 mg, 0.499 mmol) and 2-methyloxazolecarboxylic acid (0.055g, 0.433 mmol) The mixture was d at about rt for about 18 h. The reaction was evaporated and the resulting residue was purified by silica gel chromatography eluting with a nt of 30-100% EtOAc in hexane to (R)-N-(1-(7—cyan0-IH—indolyl)piperidinyl)methyloxazole carboxamide (0.092g, 79%); LC/MS (Table 1, Method g) R = 1.35 min.; MS m/z: 350 (M+H)+ General Procedure W: Conversion of a vinyl e to a vinyl boronate or boronic acid To a mixture of a boronic acid or te (1 to 2 equiv, ably 1.1 equiv) a palladium catalyst (for example Pd(OAc)2, Pd2dba3, Pd(PPh3)4, bis(acetato)triphenylphosphinepalladium(II), PdC12(dppf), bis(diphenylphosphino)ferrocene)dichloropalladium(II), or Pd(PPh3)2C12; preferably PdC12(dppf) or 3)2C12; 0.01 to 0.20 equiV, preferably 0.05 to 0.1 equiV), a base (such as KF, KOAc, Na2C03, K2C03 or Cs2C03, preferably K2C03 or KOAc) (1.1 to 16 equiV, preferably 1.5 to 2 equiV) and optionally a phosphine additive (preferably PPh3; 0.01 to 0.1 equiV, preferable 0.06 equiV) in an organic solvent (such as dioxane, DME or DCE, preferably dioxane) is added a Vinyl triflate (1 equiV). The mixture is heated under inert atmosphere at about 60 to 90 OC (preferably 70 to 80 0C) for about 1 to 20 h (preferably 8 to 16 h). The mixture is optionally trated in vacuo to give the targeted compound. Alternatively, the mixture is optionally filtered through a media (such as silica gel or Celite®) which is rinsed with an appropriate solvent (such as EtOAc, 1,4- dioxane, THF, ACN, DCM, EtzO, MeOH, or EtOH) and then ally concentrated in vacuo to give a residue. Either the residue or the solution may be optionally partitioned between water and an WO 10255 organic solvent (such as EtOAc, EtzO or DCM). The organic layer is isolated and may be optionally washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl, NaZSO3 or Na2S203). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the targeted compound. ration of General Procedure W Preparation #W.1: tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2-yl)-2,3-dihydro-1,4- oxazepine-4(7H)-carboxylate TfO W o- lo \ B N—Boc AN-Boc A 100 mL 3 neck round-bottomed flask was charged with 4,4,4',4',5,5,5',5'-octamethyl-2,2'—bi(1,3,2- dioxaborolane) (1.10 g, 4.34 mmol, Preparation #AA.1), PPh3 (0.062 g, 0.24 mmol), 3)2C12 (0.138 g, 0.197 mmol) and K2C03 (0.818 g, 5.92 mmol). To this mixture was added a solution of tert- butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (1.37 g, 3.94 mmol) in dioxane (30 mL). The entire mixture was degassed for about 5 min and purged with nitrogen. The mixture was heated at about 75 0C for about 15 h. The mixture was d with EtOAc (30 mL) and water (30 mL). The organic layer was separated, dried over MgSO4, filtered and trated. The resulting mixture was purified silica gel chromatography % EtOAc/heptane) to give tert-butyl 6-(4,4, 5,5-tetramethyl-I,3,2-di0xab0rolanyl)-2,3-dihydr0-I,4-0xazepine-4(7H)- carboxylate (0.57 g, 44%): LC/MS (Table1, Method as) R, = 2.65 min; MS m/z: 226 (M+H-Boc)+ General Procedure X: Hydrolysis of an ester to a carboxylic acid under basic conditions and removal of a tosyl group from an N-tosyl protected heteroaryl ring To a flask containing a nd with and ester functionality and a tosyl-protected heteroaromatic ring (1 equiv) either neat or in an organic solvent (such as 1,4-dioxane, MeOH, or THF/MeOH, ter/MeOH ably THF/water/MeOH) is added a base or combination of bases (such as aqueous or solid Na2C03, KOH, Cs2C03, K2C03, NaOH or LiOH, preferably LiOH, or KOH; 1 to 10 equiV, preferably 5 to 10 equiv). The mixture is d at about 0 to 100 OC (preferably about 40 to 85 0C) for about 1 to 48 h (preferably about 1 to 24 h). Optionally, more base is added (such as aqueous or solid , KOH, Cs2C03, K2C03, NaOH or LiOH, preferably LiOH or NaOH, 1 to 10 equiV, preferably 2 to 6 equiV) and the mixture is stirred at about 0 to 100 OC (preferably about 10 to 100 0C) for about 1 to 48 h (preferably about 4 to 24 h). The mixture is then acidified with the addition of a 2014/044247 suitable aqueous acid (such as aqueous HCl, AcOH or citric acid, preferably citric acid). The mixture is optionally concentrated in vacuo to give the targeted compound. Alternatively, the mixture is optionally filtered through a media (such as silica gel or Celite®) which is rinsed with an appropriate solvent (such as EtOAc, 1,4-dioxane, THF, ACN, DCM, EtzO, MeOH, or EtOH) and then optionally concentrated in vacuo to give a residue. Either the residue or the solution may be ally partitioned between water and an organic solvent (such as EtOAc, EtzO or DCM). The organic layer is isolated and may be optionally washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions ning a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl, NaZSO3 or NaZSZO3). The organic solution may then be optionally dried with a drying agent (such as ous MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the targeted compound. ration of General Procedure X Preparation #X.1: 4-(1-(tert-Butoxycarbonyl)-1,2,5,6-tetrahydropyridinyl)methyl-1H- indolecarboxylic acid N,Boc O OH A round bottom flask was charged with methyl 4-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridin- 2-methyltosyl-1H-indolecarboxylate (1.67 g, 2.30 mmol, Preparation #39) in THF (12 mL), water (4 mL) and MeOH (4 mL). LiOH (monohydrate, 0.468 g, 11.1 mmol) was added. The mixture was stirred at about 60 0C. After about 7 h additional LiOH (monohydrate, 0. 234 g, 5.57 mmol) was added and the mixture was allowed to stir for about 24 h at about 60 OC. The mixture was diluted with 5% citric acid (200 mL) and extracted with DCM (2 x 100 mL) and 3:1, CHCl3: isopropanol (100 mL). The combined organic layers were washed with water (50 mL) and dried over NaZSO4, filtered and concentrated under reduced pressure to give 4-(1-(tert-but0xycarb0nyl)-1,2,5,6- tetrahydropyridin-S-yl)methyl-IH—indolecarb0xylic acid (1.16 g, 93 %): LC/MS (Table 1, Method as) R, = 2.33 min; MS m/z: 355 (M-H)".

General Procedure Y: Iodination of a 1H- indole or a 1H—aza indole ring to give a 2-iodo-1H— indole or a 2-iodo-1H—azaindole ring To a on of an indole or azaindole (1 equiV) in an organic solvent (such as THF or EtzO, preferably THF) at about -60 to -78 OC (preferably about -70 to -78 0C) is added a base (such as BuLi or LDA, preferably LDA; 1 to 2 equiv, preferably 1.1 to 1.5 equiv). The reaction mixture is then stirred for about 30 to 45 min and iodine (1 to 2 equiv, preferably 1.4 to 1.6 equiv) is then added. The reaction mixture is stirred for about 10 to 60 min (preferably about 10 to 30 min). The mixture is optionally quenched with NaZSZO3. The mixture is optionally concentrated in vacuo to give the targeted compound. Either the residue or the solution may be optionally partitioned between water and an organic solvent (such as EtOAc, EtzO or DCM). The organic layer is isolated and may be optionally washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, , NaOH, KOH or NH4OH) and/or s solutions containing an inorganic salt (such as NaCl, NaZSO3 or NaZSZO3). The c on may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the ed compound.

Illustration of General Procedure Y Preparation #Y.1: 1-tert-Butyl 7-methyl 4-(1-(tert-butoxycarbonyl)pyrrolidinyl)iodo-1H- -1,7-dicarboxylate N N \ \ I N N Boo Boo MeO O MeO O A solution of anhydrous 1-tert-butyl 7-methyl 4-(1-(tert-butoxycarbonyl)pyrrolidinyl)-1H-indole- 1,7-dicarboxylate (10.0 g, 22.5 mmol, (Preparation #Z.1) in THF (136 mL) was cooled to about -78 OC and LDA (1M in THF, 33.7 mL, 33.7 mmol) was added drop wise. After about 45 min, a solution of iodine (7.99 g, 31.5 mmol) in THF (15 mL) was added drop wise while ining the temperature at about -71 OC. The reaction e was then quenched by pouring into an aqueous on of NaZSZO3 and NaHCO3 (10:1, 150 mL). The mixture was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give methyl 4-(1-(tert-but0xycarb0nyl)-2,5-dihydr0-1H—pyrrolyl)-IH- indole-7—carb0xylate (10.4 g, 97%): LC/MS (Table 1, Method as) R, = 2.90 min; MS m/z: 588 (M+NH4) +.

General Procedure Z: Formation of an N-Boc protected amine To a solution of an amine or amine salt (preferably 1 equiv) in an organic solvent (such as ACN, 1,4- dioxane, DCM, DMF or THF, ably DCM) is added an aqueous base such as Na2C03, NaOH, K2C03 or NaHCO3, preferably Na2C03 (2 to 20 equiv, preferably 2 to 10 equiv) or an organic base such as TEA or DIEA, ably TEA (1 to 5 equiv, preferably 1 to 2 equiv) followed by addition of a Boo transfer reagent such as BoCZO, Boo ON, Boc-azide or Boc-OSu preferably B0020 (1 to 4 equiv, preferably 1 to 2 equiv). Optionally, an additive, such as DMAP (0.01 to 0.1 equiv, preferable 0.05 equiv) may be added. The on of base is optional if an amine salt is not used. The mixture is stirred at about 0 to 40 OC (preferably about 0 to 25 OC ) for about 2 to 24 h (preferably about 2 to 16 h). The mixture may optionally be concentrated in vacuo to give the target compound.

Alternatively, the mixture is optionally filtered through a media (such as silica gel or Celite®) which is rinsed with an appropriate solvent (such as EtOAC, 1,4-dioxane, THF, ACN, DCM, EtzO, MeOH, EtOH) and then optionally concentrated in vacuo to give a e as the target compound. Either the residue or the on may be optionally partitioned between water and an c solvent (such as EtOAC, EtzO or DCM). The organic layer is isolated and may optionally be washed in no particular order with water and/or aqueous ons containing an acid (such as HCl, ACOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl NaZSO3 or 3). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or ), filtered and concentrated in vacuo to give the target compound.

Illustration of l Procedure Z Preparation #Z.1: -Butyl 7-methyl 4-(1-(tert-butoxycarbonyl)pyrrolidinyl)-1H-indole- 1,7-dicarboxylate O O N N \ \ H N MeO O MeO O In a 200 mL round-bottomed flask, methyl 4-(1-(tert-butoxycarbonyl)pyrrolidinyl)-1H-indole-7— carboxylate (12.4 g, 36.0 mmol, prepared using A from methyl 4-bromo-1H-indolecarboxylate [Anthem] with tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2,5-dihydro-1H-pyrrole carboxylate [AKSCI] and L with Pd/C) and di-tert-butyl dicarbonate (9.43 g, 43.2 mmol)) in ACN (100 mL) were added. DMAP (0.22 g, 1.8 mmol) was added, the reaction mixture was stirred at rt for about 18 h, TEA (10 mL, 72 mmol) and di-tert-butyl dicarbonate (1.60 mL, 6.87 mmol) were added.

The reaction mixture was stirred at rt for about 16 h. The mixture was extracted with dilute acetic acid and EtOAc. The combined c layers were dried over MgSO4, concentrated under d pressure and purified using silica gel chromatography (0-25% EtOAC/heptane) to give -butyl 7- methyl 4-(1-(tert-but0xycarbonyl)pyrrolidinyl)-1H—indole-1,7-dicarb0xylate (12.5 g, 70%, 89% purity): LC/MS (Table 1, Method as) R, = 2.79 min; MS m/z: 462 (M+NH4)+.

General Procedure AA: Conversion of a cyclic ketone to a cyclic vinyl triflate A solution of a ketone (1 equiv) in an organic solvent (such as THF, dioxane or ether preferably THF) is cooled to about -60 to -78 OC (preferably about -65 to -75 OC ). A base is then added slowly (such as LiHMDS, KHMDS or NaHMDS preferably KHMDS). After about 20 to 60 min (preferably 60 min) a solution of a triflating reagent is added, such as, N—(5-Chloro pyridyl)bis(trifluoromethanesulfonimide)) or 1 1 1 -trifluoro-N—phenyl-N— , , ((trifluoromethyl)sulfonyl)methanesulfonamide in THF. The reaction mixture is then d to warm to rt over about 1 to 1.5 h. The reaction mixture may then be quenched with a saturated solution of NH4Cl or water and diluted with an organic solvent (such as DCM or EtOAc). The layers are separated, the organic solution is optionally washed with water and/or brine, dried over anhydrous MgSO4 or Na2S04, filtered, and the solvent is removed under d pressure to give the desired compound.

Illustration of General Procedure AA Preparation #AA.1: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine- 4(7H)-carboxylate O TfO (SEN—«OX —> A< To a solution of tert-butyl 1,4-oxazepanecarboxylate (5.00 g, 23.2 mmol) [Arkpharm] in THF (51.6 mL) at about -78 0C was added KHMDS (1M in THF, 30.2 mL, 302 mmol) drop wise maintaining internal temperature of about -72 to -74 0C. The mixture was then stirred at about -77 0C for about 1 h. A solution of 1 1 1 -trifluoro-N—phenyl-N— , , ((trifluoromethyl)sulfonyl)methanesulfonamide (7.88 g, 22.1 mmol) in THF (25.8 mL) was added drop wise. The mixture was lly warmed to about 0 0C over about 1 to 2 h. The reaction e was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2x75 mL). The combined c layers were washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure and passed through a plug of neutral alumina (EtOAc/heptane as eluent) to yield (((trifluoromethyl)sulf0nyl)oxy)-2,3-dihydr0-1,4-0xazepine-4(7H)-carb0xylate (5.1 g, 63.2 %); 1H NMR (400 MHZ, DMSO-dfi) 8 7.17 (s, 1H), 4.41 (s, 2H), 3.77 (q, J = 2.3 HZ, 4H), 1.45 (s, 9H).

General ure AB: ion of a double bond and removal of a CBZ group from a CBZ protected amine A round bottom flask is charged with a palladium st, such as Pd/C or Pd(OH)2 (10 or 20 wt%, about 0.005 to 1.0 equiv, preferably 0.5 to 1.0 equiv). The flask is evacuated then flushed with nitrogen 2 to 5 times (preferably 3 times) prior to addition of an organic solvent or mixture of solvents (such as EtOAC, MeOH, EtOH or MeOH/ACOH, preferably MeOH/ACOH) under a nitrogen atmosphere. To the mixture is added a compound with an alkene functionality and an N—CBZ protected amine (preferably 1 equiv), neat or optionally as a solution in an organic solvent or mixture of solvents (such as EtOAC, MeOH, EtOH or MeOH/ACOH, preferably MeOH). The mixture is d under a hydrogen atmosphere (about 30 to 50 psi) for about 1 to 60 h (preferably about 4 to 5 h). ally the reaction may be performed using an H-cube instrument with either Pd/C or 2 dges (10 or 20 wt%) and the starting material is passed h the system as a solution in the red solvent/s. In cases where the reaction does not proceed to completion as monitored by TLC, LC/MS, or HPLC, the mixture can be optionally heated to about 30 to 80 OC (preferably about 50 0C) for about 1 to 24 h (preferably about 16 h) and in cases where the H-cube is used to perform the reaction, the pressure may be increased (25 to 50 bar, preferably 40 to 50 bar). The mixture is then filtered and the filter cake is rinsed with an organic solvent (such as EtOAC, MeOH or EtOH, preferably the reaction solvent) and the filtrate is concentrated under reduced pressure to give the crude product.

Illustration of General Procedure AB ation #AB.1: 4-(Piperidinyl)-1H—pyrrolo[3,2-c]pyridinecarboxamide JL NH —>N\\ N\\ | I/ /N N H ONH2 ONH2 A round bottom flask was charged with Pd(OH)2 (20 wt %, 0.336 g, 0.478 mmol) followed by the slow addition of a solution of benzyl 3-(7-carbamoyl-1H-pyrrolo[3,2-c]pyridinyl)-5,6- dihydropyridine-1(2H)-carboxylate (1.8 g, 4.8 mmol, prepared using A from Preparation #45 and benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)-carboxylate [Arkpharm], Y with LiOH and D with NH4Cl) in MeOH (30 mL) and ACOH (10 mL). The flask was purged with N2, then filled with H2 using a balloon. The reaction mixture was then heated at about 45 —274— 0C for about 3 h. The reaction e was cooled to rt and filtered h a pad of Celite®, washing with MeOH. The filtrate was concentrated under reduced pressure, dissolved in MeOH and then d with MP-carbonate beads by stirring at rt for about 2 h. The beads were filtered off and the filtrate was concentrated under reduced pressure to give 4-(piperidinyl)-1H—pyrrolo[3,2-c]pyridine- 7-carb0xamide (0.84 g, 72%): LC/MS (Table 1, Method as) R, = 0.58 min.; MS m/z: 245 (M+H)+.

General Procedure AC: N-Oxidation of an N containing hetero ic ring A solution of an N—containing hetero aromatic nd (1 equiv) in an organic solvent (such as DCE, DME, DCM or EtOAc, preferably DCM) is cooled to about 0 OC and an oxidizing reagent such as 3-chlorobenzoperoxoic acid or magnesium monoperoxyphthalate hexahydrate (1 to 3 equiv, ably 2 equiv). The solution is stirred at rt for about 2 to 24 h (preferably about 10 to 16 h). The mixture is optionally filtered to give the desired product or optionally concentrated in vacuo to give a residue, either the residue or the solution may be optionally partitioned between water and an organic solvent (such as EtOAc, EtzO or DCM). The organic layer is isolated and may optionally be washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4Cl) and/or aqueous ons containing a base (such as , Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl NaZSO3 or Na2S203).

The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and trated in vacuo to give the target compound.

Illustration of General Procedure AC Preparation #AC.1: 4-Bromo-1H-pyrrolo[2,3-c]pyridine 6-oxide Br Br |\\_. N|\\ N/N e’/N A flask was charged with 4-bromo-1H-pyrrolo[2,3-c]pyridine (10.0 g, 50.8 mmol) [Combiblocks] and dissolved in EtOAc (254 mL). The flask was cooled to about 0 OC and a solution of 3- chlorobenzoperoxoic acid (10.5 g, 60.9 mmol) in EtOAc (254 mL) was slowly added. The reaction was stirred warming to rt for about 16 h. The precipitate that had formed was collected Via filtration and dried in vacuum oven to afford 4-br0m0-1H—pyrrolo[2,3-c]pyridine 6-0xide (0.85 g, 79 %): LC/MS (Table 1, Method as) R, = 1.18 min; MS m/z: 213, 215(M+H)+. l Procedure AD: Cyanation of an N-oxide containing heteroaryl ring A flask is charged with an N—oxide heteroaromatic compound (1 equiV) in an appropriate organic t, such as ACN. TEA is added (1 to 2 equiV, preferably 1.5 equiV). TMSCN (2 to 5 equiV, preferable 3 to 4 equiV) is then added using a syringe. The on mixture is refluxed until complete 2014/044247 consumption of ng material is observed either Via TLC or LC/MS. The reaction mixture is cooled to rt and quenched appropriately, preferable with an aqueous solution of NaOH and extracted with an organic solvent, such as DCM or EtOAC. The organic layer is isolated and may ally be washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions containing a base (such as , , NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl NaZSO3 or NaZSZO3). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the target compound.

Illustration of l Procedure AD Preparation #AD.1: 4-Bromo-1H-pyrrolo[2,3-c]pyridinecarbonitrile '6) \ —>N/N H II A flask was charged with o-lH-pyrrolo[2,3-c]pyridineoxide 3-chlorobenzoate (6.25 g, 16.91 mmol, Preparation #AC.l) in ACN (97 mL) and TEA (3.56 mL, 25.4 mmol). TMSCN (9.02 mL, 67.6 mmol) was added in one portion Via syringe the mixture was refluxed for about 45 min. The reaction was quenched by careful addition of 50 mL of aqueous l M NaOH solution, transferred to a separatory funnel and diluted with aqueous lM NaOH solution (200 mL) and EtOAc (200 mL). The layers were separated and the organic phase was washed again with 50 mL of aqueous l M NaOH solution. The combined aqueous extracts were washed with EtOAc (4 x 75 mL) and then with l M NaOH (2 x 20 mL) and brine (l x 50 mL), dried over NaZSO4, filtered and the solvent was removed to afford 4-br0m0-1H—pyrrolo[2,3-c]pyridinecarb0nitrile (3.84 g, 93%): 1H NMR (400 MHZ, DMSO-dg) 8 8.27 (s, 1H), 7.90 (d, J = 2.8 Hz, 1H), 6.60 (d, J = 2.8 Hz, 1H).

General Procedure AE: Reduction of an ester to form an alcohol To a solution of an ester in an appropriate organic t (such as THF, dioxane, DCM or EtOAc, preferably THF) is ally added water (1 to 4 equiV, preferably 2 equiv). The mixture is then cooled to about 0 OC and a reducing agent is added (such as LiBH4 or LAH, preferably LiBH4; 2 to 12 equiV, preferably 6 equiv). The reaction mixture is stirred for about 5 to 24 h until complete consumption of the ester. Additional ng agent may be ally added as required. The reaction mixture is then quenched with an aqueous solution of NH4Cl. The organic layer is isolated and may ally be washed in no particular order with water and/or aqueous solutions containing an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl NaZSO3 or NaZSZO3). The organic solution may then be ally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the target compound.

Illustration of l Procedure AE Preparation #AE.1: tert-Butyl 3-(7-carbamoyl-1H-indolyl)(hydroxymethyl)piperidine carboxylate Boc HO N,Boc \O N, N H o NH2 0 NH2 In a 500 mL round-bottomed flask, 1-tert-butyl 3-methyl 5-(7-carbamoyl-1H-indolyl)piperidine- 1,3-dicarboxylate (6.75g, 16.8 mmol, prepared using Z from Preparation #AF. 1) in THF (150 mL) was added. The reaction mixture was cooled to about 0 OC and water (0.606 mL, 33.6 mmol) was added. LiBH4 (2.93 g, 135 mmol) was added and on mixture stirred at rt for about 12 h.

Additional LiBH4 (2.93 g, 135 mmol) was added and reaction mixture was stirred for about 3 h. The reaction mixture was carefully added to a saturated s solution of NH4Cl (800 mL) at about -10 OC. The mixture was extracted with DCM (500 mL). The DCM layer was dried over MgSO4, filtered and concentrated to give crude tert-butyl arbamoyl-IH—indolyl) (hydroxymethyl)piperidine-I-carb0xylate (6.35 g, 101 %): LC/MS (Table 1, Method as) R, = 1.74 min; MS m/z: 374 (M+H)+. l Procedure AF: Reduction of a pyridine ring to a piperiding ring To a solution of the pyridine (1 equiv) in acetic acid is added a reducing reagent (such as PtOZ, Pd(OH)2 or Pd/C, preferably PtOZ; 0.05 to 0.5 equiv, preferable 0.1 to 0.2 equiv). The reaction mixture is heated at about 50 0C at about 20 to 50 psi (preferably about 30 psi) for about 6 to 12 h rably about 10 h). The reaction mixture is concentrated under reduced pressure to give the desired compound.

Illustration of General Procedure AF Preparation #AF.1: Methyl 5-(7-carbamoyl-1H-indolyl)piperidinecarboxylate o o \o |\N \0 NH \ \ N N H H o NH2 0 NH2 Methyl 5-(7-carbamoyl-1H-indolyl)nicotinate (6.25 g, 23.7 mmol, prepared using A from Preparation # P1 with methyl 5-bromonicotinate) and ACOH (70 mL) were added to PtOZ (1.26 g, .55 mmol) in a 50 mL pressure bottle and shaken for about 10 h at about 50 0C at about 30 psi. The resulting black solution was concentrated under reduced pressure and filtered through a plug of Celite® and washed with DCM. The filtrate was then trated to a thick s black oily residue. This material was dissolved in 15% MeOH/EtOAC and passed through a large silica gel plug.

The plug was flushed with 10% MeOH/EtOAC (250 mL), then 35-40% MeOH/EtOAC (1.5 L) to afford methyl 5-(7-carbamoyl-IH—indolyl)piperidinecarb0xylate (6.3 g, 79 %): LC/MS (Table 1, Method a) R, = 0.96 min; MS m/z: 302 (M+H)+.

General Procedure AG: One pot borylation of a triflate and Suzuki reaction of the in situ formed boronate with an aryl halide To a mixture of a Vinyl triflate (preferably 1 equiv), a boronic acid or boronate ester (1 to 2 equiv, ably 1.1 equiv), and an inorganic base (such as KF, Na2C03, K2C03 or , preferably Na2C03 or Cs2C03; 1.1 to 16 equiv, preferably 2 equiV) in a solvent (such as THF, DME, DMF, 1,4- dioxane, 1,4-dioxane, preferably dioxane) is added a ium catalyst (for example Pd(OAc)2, szdba3, Pd(PPh3)4, bis(acetato)triphenylphosphinepalladium(II), polymer-bound FibreCat TM 1032, SiliaCat DPP-Pd, PdC12(dppf) or Pd(PPh3)2C12; preferably PdC12(dppf) or Pd(PPh3)2C12; 0.01 to 0.20 equiv, preferably 0.05 to 0.1 equiv) and a ligand (for example tricyclohexylphosphine, tri-tert-butyl- phosphine; preferably none or PPh3; 0.01 t01.0 equiv, preferably 0.01 to 0.03 equiv) is added optionally. The mixture is heated at about 40 to 120 OC (preferably about 70 to 85 0C) for about 1 to 48 h (preferably about 2 to 4 h) thermally, or at about 100 to 200 OC (preferably about 120 to 150 0C) for about 5 to 60 min (preferably about 20 to 45 min) in a microwave (preferably 5 min ramp time, 300 Watts max power, 250 psi max pressure). The mixture is optionally allowed to cool to rt and filtered. To the reaction mixture is added the aryl halide (1 to 2 equiv), water (about 1/3 to 1/4 the volume of the original organic solvent used) and ally additional catalyst, base and ligand is added rably the same ones used in the first on) and heated at the same ature for about 3 to 24 h (preferably about 8 to 10 h) and is worked up using one of the following methods.

Method 1. For reactions containing water, the e may be diluted with an organic solvent (such as DCM or EtOAc). The layers are separated, the organic solution is optionally washed with water and/or brine, dried over ous MgSO4 or NaZSO4, filtered, and the solvent is removed under reduced pressure to give the desired compound. Method 2. The mixture is concentrated under reduced pressure. Method 3. The st is d by filtration and the te is concentrated under reduced pressure Illustration of General Procedure AG Preparation #AG.1: tert-Butyl 6-(7-(methoxycarbonyl)-1H-pyrrolo[3,2-c]pyridinyl)-2,3- dihydro-l,4-oxazepine-4(7H)-carboxylate o NaBoc TfO i350 / #N-Boc —> A —> NI : \ N-Boc fl 0 O A 40 mL microwave reaction Vial was charged with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (0.995 g, 3.92 mmol), PPh3(0.056 g, 0.214 mmol), 3)2C12 (0.125 g, 0.178 mmol) and K2C03 (0.738 g, 5.34 mmol). To this mixture was added a solution of tert-butyl 6- (((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (1.24 g, 3.56 mmol, Preparation #AA. 1) in dioxane (13 mL). The entire e was degassed for about 5 min and purged with nitrogen. The mixture was heated at about 75 0C for about 2 h. To the reaction mixture was added methyl 4-chloro-1H-pyrrolo[3,2-c]pyridinecarboxylate (0.600 g, 2.85 mmol), Pd(PPh3)2C12 (125 mg, 0.178 mmol) and water (3.25 mL). The entire suspension was , K2C03 (0.492 g, 3.56 mmol) degassed with nitrogen for about 10 min and heated at about 75 0C for about 8 h. The reaction mixture was cooled, filtered over a plug of Celite® and MgSO4, concentrated and purified Via silica gel chromatography (0-40% EtOAc/heptane) to give tert-butyl 6-(7-(methoxycarbonyl)-1H— pyrrolo[3,2-c]pyridinyl)-2,3-dihydr0-1,4-0xazepine-4(7H)-carb0xylate (0.3 g, 23%): LC/MS (Table 1, Method as) R, = 2.04 min; MS m/z: 374(M+H)+.

General ure AH: Formation of an N-tosyl protected heteroaromatic ring A solution of a compound with an N—heteroaromatic ring, such as an indole or azaindole (1 equiv) in an appropriate organic solvent (such as THF, DMF, DCE, toluene or dioxane, preferably THF) is optionally cooled to about 0 OC and a base (such as NaH, KOH or NaOH, preferable NaH; 1 to 2 equiv, preferable 1.1 to 1.3 equiv) is added. The reaction mixture is d for about 10 to 30 min and 4-methyl-benzenesulfonyl chloride (1 to 3 equiV, preferable 1 to 1.5 equiV) is added. The reaction mixture is optionally allowed to warm to rt if cooled or ally heated at about 30 to 90 0C until complete ption of the starting N—heteroaromatic compound. Additional base and tosylating reagent may be optionally added as required. The reaction mixture is quenched by the addition of water and extracted with an c solvent (such as EtOAc or DCM). The organic layer is isolated and may optionally be washed in no particular order with water and/or aqueous solutions ning an acid (such as HCl, AcOH or NH4Cl) and/or aqueous solutions containing a base (such as NaHCO3, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl NaZSO3 or 3). The c solution may then be optionally dried with a drying agent (such as anhydrous MgSO4 or NaZSO4), filtered and concentrated in vacuo to give the target compound.

Illustration of General Procedure AH Preparation #AH.1: 4-Bromotosyl-1H-pyrrolo[2,3-c]pyridinecarbonitrile A flask is charged with 4-bromo-1H-pyrrolo[2,3-c]pyridinecarbonitrile (0.985 g, 4.44 mmol, Preparation # AD.1) in THF (30 mL). NaH (60% dispersion in mineral oil, 0.213 g, 5.32 mmol) was added portion wise at about 0 OC. The mixture was allowed to stir for about 15 min, then 4-methyl- esulfonyl chloride (0.930 g, 4.88 mmol) was added in one portion and the reaction was allowed to warm to room temperature and stirred or about 16 h. Additional NaH (60% dispersion in mineral oil, 0.355 g, 0.89 mmol) and 4-methylbenzenesulfonyl chloride (0.254 g, 1.33 mmol) were added in sequence and stirred at rt for about 1 h. The reaction e was diluted with water (30 mL) and extracted with EtOAc (60 mL). The organic layer was dried over MgSO4, filtered, trated and purified using silica gel chromatography (0-35% EtOAc/heptane) to give 4-br0m0t0syl-1H— pyrrolo[2,3-c]pyridinecarb0nitrile (1.35 g, 81 %): LC/MS (Table 1, Method as) R, = 2.51 min; MS m/z: 376, 378(M+H)+.

Example #1: tert-Butyl 2-(4-bromocarbamoyl-1H-indolyl)benzylcarbamate methylphenyl)thiazolecarboxamide C ‘I2 Step A: tert-Butyl r0m0carbam0yl-1H-ind01yl)benzylcarbamate Boc\ Br NH \ | N —> H oN H2N o H2N 0 To a solution of 4-bromoiodo-1H-indolecarboxamide (2.5 g, 6.8 mmol, Preparation #1) in THF (185 mL), MeOH (25 mL) and water (25 mL) was added tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2- orolanyl)benzylcarbamate (2.7 g, 8.2 mmol, JW), Pd(dppi)C12 (0.5 g, 0.7 mmol) and Na2C03 (2.2 g, 20.6 mmol). The mixture was stirred at about 80 OC overnight under nitrogen. The solvent was removed under reduced pressure to give a residue, which was purified by column chromatography on silica gel to provide crude tert-butyl 2-(4-br0m0carbam0yl-1H-indol yl)benzylcarbamate (2.5 g, 5.6 mmol).

Step B: tert-Butyl 2-(7-carbam0yl(2-methyl(thiazole-Z-carboxamid0)phenyl)-1H-indol yl)benzylcarbamate [1Y0N Boc\ 3 H2N 0 To a solution of 2-(4-bromocarbamoyl-1H—indolyl)benzylcarbamate (2.5 g, 5.6 mmol) in THF (185 mL), MeOH (25 mL) and water (25 mL) was added ethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)phenyl)thiazolecarboxamide (2.3 g, 6.8 mmol, Preparation #4), Pd(dppi)C12 (0.4 g, 0.6 mmol) and Na2C03 (1.8 g, 16.9 mmol). The mixture was stirred at about 80 OC overnight under en. The solvent was removed under reduced re to give a residue, which was purified by column chromatograph on silica gel to provide tert-butyl 2-(7—carbam0yl(2-methyl(2-0x0 (thiazol-Z-yl)ethyl)phenyl)-1H-indolyl)benzylcarbamate (3 g, 92%): 1H NMR (CDCl3) 5 10.57 (s, 1H), 9.25 (s, 1H), 8.22-8.20 (d, J = 7.6 Hz, 1H), 7.92-7.91 (d, J = 3.2 Hz, 1H), 7.64-7.63 (d, J = 3.2 Hz, 1H), 7.50-7.45 (m, 3H), 7.37-7.35 (m, 3H), 7.26-7.24 (m, 2H), 7.04-7.02 (d, J: 3.6 Hz, 1H), 6.32 (s, 1H), 4.43 (s, 2H), 2.25 (s, 3H), 1.38 (s, 9H).

Step C: N-(3-(2-(2-(aminomethyl)phenyl)carbam0yl-1H-indolyl)methylphenyl)thiazole- 2-carb0xamide H2N o H2N o A solution of tert-butyl 2-(7-carbamoyl(2-methyl(2-oxo(thiazolyl)ethyl)phenyl)-1H-indol- 2-yl)benzylcarbamate (3 g, 5.2 mmol) in DCM (50 mL) and TFA (10 mL) was stirred at about 25 0C for about 6 h. The solvent was removed by reduced pressure. Water was added and the solution was basified by addition of saturated aqueous NaHCO3 to pH 9. The mixture was extracted with EtOAc.

The c phase was concentrated to provide 2-(2-(amin0methyl)phenyl)carbam0yl-1H— indolyl)methylphenyl)thiazole-Z-carboxamide (2.2 g, 89%): LC/MS (Table 1, Method b) R = 2.53 min; MS Hill: 482(M+H)+. (Btk IC50 = B) Example #2: 4-(3-Amin0methylphenyl)-1H-pyrrolo[2,3-c]pyridinecarboxamide Step A: 4-Br0m0chlor0-1H-pyrr010[2,3-c]pyridine I N| \ —> / N02 H To a solution of 5-bromochloronitropyridine (10 g, 0.042 mol) in anhydrous THF (150 mL), a solution of Vinylmagnesium bromide (17 g, 0.127 mol) in THF was added dropwise at -30 to -50 OC.

The reaction mixture was stirred at -30 to -40 0C for 2 h. Then the reaction e was poured into saturated aqueous NH4Cl solution and the mixture was extracted with EtOAc (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, ed and concentrated under reduced pressure and the residue was purified by column chromatography to provide 0chlor0-IH—pyrrolo[2,3-c]pyridine ( 3 g, 31%): 1H NMR: d6) 5 12.45 (s, 1H), 8.04 (s, 1H), 7.79-7.78 (m, 1H), 6.59-6.58 (d, J: 2.0, 1H).

Step B: 3-(7-Chloro-lH-pyrrolo[2,3-c]pyridinyl)methylaniline N/N —> |\\ CI /N To a e of 4-bromochloro-1H—pyrrolo[2,3-c]pyridine x] (5 g, 21.6 mmol), 2-methyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (7.55 g, 32.4 mmol, CombiBlocks) and sodium carbonate (1.6 g, 64.8 mmol) in THF (80 mL), MeOH (80 mL) and water (20 mL), f)C12 (1.6 g, 2.16 mmol) was added and the mixture was degassed several times and heated to about 70 OC overnight under N2. The reaction mixture was filtered through Celite® and concentrated under reduced pressure and the residue was ed by column chromatography to provide 3-(7—chlor0-1H- pyrrolo[2,3-c]pyridinyl)methylaniline (2.2 g, 40%): 1H NMR (DMSO-d6) 5 12.05 (s, 1H), 7.71 (s, 1H), 7.64 (d, J: 2.4, 1H), 6.99-6.96 (m, 1H), 6.72-6.70 (d, J: 8.0, 1H), 6.48 (d, J: 6.8, 1H), 6.2 (d, J: 2.8, 1H), 4.95 (s, 2H), 1.82 (s, 3H).

Step C: Methyl 4-(3-aminomethylphenyl)-1H-pyrr010[2,3-c]pyridinecarb0xylate | \ |\\—» N/N N/N H OOMe To a solution of 3-(7-chloro-1H—pyrrolo[2,3-c]pyridinyl)methylaniline (800 mg, 3.1 mmol) in anhydrous MeOH (80 mL), Et3N (3.1 g, 31 mmol) and Pd(dppf)C12 (0.45 g, 0.62 mmol) were added and the reaction mixture was heated to about 130 0C for about 24 h under CO. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column to provide methyl 4-(3-amin0methylphenyl)-1H-pyrrolo[2,3-c]pyridinecarb0xylate (0.60 g, 69%): 1H NMR (DMSO-d6): 811.65 (br. s., 1 H), 8.09 (s, 1 H) 7.65 (s, 1 H) 7.02 (t, J = 7.72 Hz, 1 H), 6.74 (d, J = 7.94 Hz, 1 H), 6.52 (d, J = 7.50 Hz, 1 H) 6.26 (d, J = 2.65 Hz, 1 H), 5.02 (s, 2 H), 4.0 (s, 3 H), 1.83 (s, 3 H) Step D: 4-(3-Amin0methylphenyl)-1H-pyrr010[2,3-c]pyridinecarb0xamide H N2 \ |\ | \ H2N o o OMe To a solution of methyl 4-(3-aminomethylphenyl)-1H—pyrrolo[2,3-c]pyridinecarboxylate (600 mg, 2.13 mmol) in MeOH (10 mL), ammonia (2 mL) was added and the reaction mixture was stirred overnight at rt. The mixture was concentrated and the residue was purified by prep-TLC (30:1 DCM/MeOH) to provide 4-(3-amin0methylphenyl)-1H-pyrrolo[2,3-c]pyridinecarb0xamide (320 mg, 56%): 1H NMR (DMSO-d6): 8 11.56 (s, 1H), 8.2 (s, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.0-6.97 (m, 1H), 6.71 (d, J = 7.6, 1H), 6.50 (d, J = 4.4, 1H), 6.17 (s, 1H), 4.97 (s, 2H), 1.82 (s, 3H); (Table 1, Method d) R = 1.95 min; MS m/Z: 267 (M+H)+. (BtkICso = C) Example #3: N-(3-(7-carbam0ylmethyl-1H-indolyl)methylphenyl)thiazole carboxamide (71" O \ N H2N O Step A: Methyl 4-br0m0f0rmyl-1H-ind01ecarb0xylate Br Bro H —> \ H H o o \o o POCl3 (2.4 mL, 26 mmol) was added into DMF (60 mL) solution dropwise at 0 OC and stirred for about 30 min. Then a solution of methyl 4-bromo-1H—indolecarboxylate (5 g, 13 mmol, Preparation #1, step B) in DMF (60 mL) was added dropwise into the above on mixture at about 0 OC and stirred for about 20 min. The ing reaction mixture was heated to about 90 0C for about 3 h. After cooling to rt, the mixture was poured into ice water and basified by addition of aqueous NaOH solution to pH = 8 to 9. The aqueous e was extracted with EtOAc. The combined c phase was washed with brine, dried over , filtered and concentrated under reduced pressure to get a residue, which was purified by column chromatography on silica gel to provide methyl 4-br0m0f0rmyl-IH-indolecarb0xylate (3.5 g, 95%): 1H NMR (DMSO-d6): 5 12.33 (br, 1H), 10.69 (s, 1H), 8.20 (d, J = 2.0 HZ, 1H), 7.76-7.74 (d, J = 8.0 HZ, 1H), 7.61-7.59 (d, J = 8.4 HZ, 1H), 3.94 (s, 3H).

Step B: Methyl 4-br0m0(((4-meth0xybenzyl)amin0)methyl)-1H-indolecarb0xylate Br Br H NHPMB \ —, \ N N H H \o o o 0 To a on of methyl 4-bromoformyl-1H—indolecarboxylate (3.5 g, 12.4 mmol) in anhydrous DCE (50 mL) was added (4-methoxyphenyl)methanamine (2.6 g, 18.6 mmol) and a catalyst amount of AcOH. The reaction mixture was d at rt for about 1 h. Then NaBH(OAc)3 (13.2 g, 62 mmol) was added in portions and stirred at rt overnight. When the reaction was completed, water was added to quench the reaction. The aqueous phase was extracted with DCM. The combined organic phase was concentrated under reduced pressure to get a residue, which was purified by column chromatography on silica gel to provide methyl 4-br0m0(((4-meth0xybenzyl)amin0)methyl)-1H- -7—carb0xylate (4 g, 80%): 1H NMR (DMSO-d6): 8 11.25 (br, 1H), 7.61-7.59 (d, J = 8.4 HZ, 1H), 7.41 (s, 1H), .23 (m, 3H), .83 (d, J = 8.4 Hz, 2H), 4.02 (s, 2H), 3.90 (s, 3H), 3.70- 3.69 (m, 5H), 1.88 (s, 1H).

Step C: 4-Br0m0(((4-meth0xybenzyl)amin0)methyl)-1H-indolecarb0xylic acid Br NHPMB Br NHPMB \ \ N N H H \o 0 Ho 0 To a solution of methyl 4-bromo(((4-methoxybenzyl)amino)methyl)-1H—indolecarboxylate (5.4 g, 13.4 mmol) in THF (250 mL), MeOH (50 mL) and water (50 mL) was added LiOH (1.6 g, 67.0 mmol) and heated to reflux for about 6 h. After cooling to rt, the organic solvent was removed under reduced pressure. The aqueous phase was acidified with 1 N HCl to pH=5 to 6. Then the suspension was filtered and the filter cake was washed with water and dried to afford 4-br0m0(((4- methoxybenzyl)amino)methyl)-1H-indole-7—carb0xylic acid (4 g, 77%): 1H NMR (DMSO-d6) 5 11.40 (br, 1H), 7.58-7.56 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.40-7.38 (d, J = 8.4 Hz, 2H), 7.27-7.25 (d, J = 8.0 Hz, 1H), 6.94-6.92 (d, J = 8.4 Hz, 2H), 4.31 (s, 2H), 3.98 (s, 2H), 3.74 (s, 3H).

Step D: 4-Br0m0(((4-meth0xybenzyl)amin0)methyl)-1H-indolecarb0xamide Br NHPMB Br NHPMB \ \ N N H H HO o HZN 0 A mixture of 4-bromo(((4-methoxybenzyl)amino)methyl)-1H—indolecarboxylic acid (9.3 g, 23.9 mmol), EDCI (5.5 g, 28.7 mmol) and HOBt (4.4 g, 28.7 mmol) in THF (350 mL) and DCM (420 mL) was stirred at rt for about 1 h. Then the on mixture was d with ammonia gas for about 15 min at about -60 0C, then warmed to rt and stirred overnight. The solvent was removed under reduced pressure and MeOH was added. The suspension was filtered and the filtrated was concentrated under reduced re to get a residue, which was purified by Prep-HPLC (Table 1, Method s) to provide 4-br0m0(((4-meth0xybenzyl)amin0)methyl)-1H-indolecarb0xamide (2.1 g, 23%): LC/MS (Table 1, Method d) R = 2.31 min; MS m/Z: 388 (M+H)+ Step E: N-(3-(7-carbam0yl(((4-methoxybenzyl)amin0)methyl)-1H-indolyl) methylphenyl)thiazolecarb0xamide <71" Br NHPMB O NHPMB H2N o H H2N 0 To a solution of 4-bromo(((4-methoxybenzyl)amino)methyl)-1H—indolecarboxamide (100 mg, 0.26 mmol), N—(2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)thiazole carboxamide (116 mg, 0.39 mmol, Preparation #4) and CsF (39 mg, 0.26 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was added Pd(PPh3)4 (29.8 mg, 0.03 mmol). Then the reaction mixture was heated to about 100 0C under nitrogen for about 12 h. After cooling to rt, water was added and extracted with EtOAc. The combined organic phase was washed with brine, dried over NaZSO4, filtered and trated under d pressure to get a crude product, which was purified by Prep- HPLC (Table 1, Method r) to provide N—(3-(7-carbam0yl(((4-meth0xybenzyl)amin0)methyl)-1H- indolyl)methylphenyl)thiazole-Z-carboxamide (10 mg, 8%): 1H NMR (DMSO-d6): 5 11.05 (br, 1H), 10.23 (br, 1H), 8.14-8.10 (m, 3H), 7.72-7.65 (m, 2H), 7.27 (br, 1H), 7.26-7.24 (m, 2H), 7.11- 7.09 (m, 1H), 7.02-7.00 (d, J = 8.8 Hz, 2H), 6.77-6.71 (m, 3H), 3.63 (s, 3H), 3.24-3.21 (m, 4H), 1.88 (s, 3H), 1.83 (s, 1H) Step F: N-(3-(7-carbam0ylmethyl-1H-ind01yl)methylphenyl)thiazolecarboxamide H N H N O O NHPMB —> O\N O\N H H H2NO H2NO To a solution of N—(3-(7-carbamoyl(((4-methoxybenzyl)amino)methyl)-1H—indolyl) methylphenyl)thiazolecarboxamide (10 mg, 0.02 mmol) in ous MeOH (5 mL) was added dry Pd/C (5 mg) and stirred at rt under hydrogen (50 Psi) overnight. Then the reaction mixture was filtered and the ted was concentrated under reduced pressure to get a residue, which was purified by PLC (Table 1, Method q) to provide N-(3-(7—carbam0ylmethyl-IH-indolyl) methylphenyl)thiazole-Z-carboxamide (1.1 mg, 15%): LC/MS (Table 1, Method j) R = 3.05 min; MS Hill: 391 (M+H)+. (Btk IC50 = B) Example #4: N-(3-(7-carbam0ylmethyl-1H-ind01—4-yl)methylphenyl)thiazole carboxamide H2N 0 Step A: 5-Br0m0nitr0indoline NH NH Br Br To a solution of 5-bromoindoline (12.33 g, 83 mmol) in H2SO4 (60 mL) was added KNO3 (7.55 mL, 74.7 mol) at about 0 OC. The solution was stirred at 0-10 0C for about 1 h, and then the mixture was stirred overnight at rt. The mixture was poured into ice water, basified with NaCO3 to about pH 8.

The mixture was ted with EtOAc (300 mL X 3), the organic phase was dried with NaSO4, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (Pet ether: EtOAc=20:1) to provide 5-br0m0nitr0indoline (12.3 g, 81%): 1H NMR (CDCl3) 8 7.25 (s, 1H), 6.91 (s, 1H), 3.98 (s, 1H), 3.66-3.56 (m, 2H), 3.08-2.96 (m, 2H).

Step B: tert-Butyl 5-br0m0nitr0indolinecarb0xylate NH /Boc To a solution of 5-bromonitroindoline (7.5 g, 30.9 mmol) in DCM (750 mL) was added (Boc)20 (13.47 g, 61.7 mol) at 0 OC. Then Et3N (9.37 g, 93 mmol) and DMAP g, 3.09 mmol) were added to the mixture. The mixture was stirred overnight at rt. The reaction mixture was poured into water, extracted with DCM (300 mL X 3) and the organic phase was dried with NaSO4, trated under reduced pressure and the residue was purified by silica gel column (Pet ether : EtOAc = 30:1) to provide tert-butyl 5-br0m0nitr0indoline-I-carb0xylate (6.7 g, 63%): 1H NMR (CDCl3) 5 8.29 (s, 1H), 7.42 (s, 1H), 4.06 (s, 2H), .13 (m, 2H) 1.57 (s, 9H).

Step C: tert-Butyl 5-br0m0-2,3-dihydr0pyrr010[2,3-e]indole-1(6H)-carb0xylate [Boo N NO2 H To a mixture of tert-butyl 5-bromonitroindolinecarboxylate (4 g, 11.66 mmol ) in THF (60 mL) was added vinylmagnesium e (6.43 g, 49.0 mol) at -40 to 50 0C, then the resulting mixture was stirred at -20 to -30 0C for about 2 h, and then overnight at rt. The mixture was poured into saturated NH4Cl soution and extracted with EtOAc (100 mL X 3). The c phase was dried with NaSO4, concentrated under reduced pressure and the residue was purified by gel chromatography silica (Pet ether:EtOAc=50:1) to provide tert-butyl 5-br0m0-2,3-dihydr0pyrrolo[2,3-e]indole-1 (6H)- ylate (0.7 g, 18%): 1H NMR (CDCl3) 8 8.17 (s, 1H), 7.13-7.10 (m, 2H),7.07 (m, 1H), 4.05- 4.00 (t, J = 8.4 Hz, 2H), 3.07-3.03 (t, J = 8.4 Hz, 2H), 1.5 (s, 9H).

Step D: 1,2,3,6-Tetrahydropyrrolo[2,3-e]indole-S-carbonitrile / NH \ _.

H H To the solution of tert-butyl 5-bromo-2,3-dihydropyrrolo[2,3-e]indole-1(6H)-carboxylate (60 mg, 0.178 mmol) in DMF (2 mL) was added Zn(CN)2 (12.53 mg, 0.107 mmol) and Pd(PPh3)4 (20.56 mg, 0.018 mmol). The solution was heated at about 145 0C for about 50 min by microwave under N2.

The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (Table 1, Method aj) to provide 1,2,3,6-tetrahydr0pyrrolo[2,3-e]indolecarb0nitrile (20 mg, 61%): 1H NMR (MeOD): 8 7.34 (s, 1H), 7.30 (d, J = 3.2, 1H), 6.51 (d, J = 3.2, 1H), .78 (t, J = 8 Hz, 2H), 3.23-3.18 (t, J: 8.4 Hz, 2H).

Step E: 1,2,3,6-Tetrahydropyrrolo[2,3-e]indole-S-carboxamide \ \ N I2 CN H2N 0 To a on of 1,2,3,6-tetrahydropyrrolo[2,3-e]indolecarbonitrile (160 mg, 0.873 mmol) in DMSO (4 mL), K2C03 (300 mg, 2.171 mmol) was added, then H202 (4 mL, 39.2 mmol) was added dropwise at rt. And the reaction mixture was d overnight at rt. The mixture was poured into water, extracted with EtOAc (20 mL X 3) and the organic phase was washed by saturated aqueous Na2S203, dried and concentrated and the residue was purified by prep-HPLC (Table 1, Method ak) to provide I,2,3,6-tetrahydr0pyrrolo[2,3-e]indolecarb0xamide (70 mg, 40%): LC/MS (Table 1, Method d) R = 1.43 min; MS m/Z: 202 (M+H)+.

Step F: 1-Acryloyl-1,2,3,6-tetrahydropyrrolo[2,3-e]indole-S-carboxamide NH M —> \ H N H2N o H2N 0 To a solution of 1,2,3,6-tetrahydropyrrolo[2,3-e]indolecarboxamide (15 mg, 0.075 mmol) in DCM (10 mL), Et3N (1 mL, 7.17 mmol) was added, and then a solution of acryloyl chloride (10 mg, 0.11 mmol) in DCM (0.5 mL) was added se at 0 OC. The on mixture was stirred overnight ar rt. The reaction solution was concentrated under reduced pressure and the residue was purified by prep-HPLC (Table 1, Method t) to e 1-acryloyl-1,2,3,6-tetrahydr0pyrrolo[2,3-e]indole carboxamide (12 mg, 63%): 1H NMR: (DMSO-d6) 811.13 (s, 1H), 7.93 (s, 1H), 7.61 (s, 1H), 7.21 (s, 2H), 68-673 (m, 2H), 6.34-6.30 (m, 1H), 5.84-5.82 (d, J: 10.4, 1H), 4.25-4.21 (t, J: 8.0, 2H), 3.21- 3.13 (m, 2H); LC/MS (Table 1, Method d) R = 2.39 min; MS m/z: 256 (M+H)+. (Btk IC50 = B) Example #5: lamid0-lH-indolecarb0xamide HNJV H2N o Step A: 4-Amin0t0syl-lH-indolecarb0nitrile F NH2 N N To a solution of 4-fluorotosyl-1H—indolecarbonitrile (500 mg, 1.59 mmol, Preparation #27, step A) in 1,4-dioxane (5 mL), ammonia (2.5 mL, 116 mmol) was added. The mixture was d at about 120 OC overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column to provide 4-amin0t0syl-IH-indolecarb0nitrile (100 mg, 20%): 1H NMR (DMSO-d6): 8 7.86-7.84 (m, 2H), 7.77-7.76 (d, J = 4, 1H), .44 (d, J = 8, 2H), 7.37-7.35 (d, J: 8, 1H), 7.12 (s, 1H), 6.70 (s, 2H), 6.46-6.44 (d, J: 8, 1H), 2.37 (s, 3H).

Step B: 4-Amin0-1H-indolecarb0nitrile NH2 NH2 \ \ N m || II N N To a solution of 4-aminotosyl-1H—indolecarbonitrile (90 mg, 0.289 mmol) in THF (2 mL), MeOH (1 mL) and water (1 mL) was added LiOH (69 mg, 2.89 mmol). The mixture was stirred at about 40 OC ght. The reaction mixture was concentrated under reduced pressure, water was added, and extracted with EtOAc (20 mL X 3) The combined organics were dried over NaZSO4, filtered, and concentrated under reduced re to provide 4-amin0-1H-indolecarb0nitrile (40 mg, 88%): 1H NMR (DMSO-d6): 8 11.43 (s, 1H), 7.21-7.19 (d, J: 8, 1H), 7.13-7.12 (m, 1H), 6.67- 6.62 (m, 1H), 6.20-6.18 (d, J: 8, 1H).

Step C: 4-Amin0-lH-indolecarb0xamide NH2 NH2 IZ I2 To a solution of 4-amino-1H—indolecarbonitrile (40 mg, 0.254 mmol) in DMSO (2 mL), K2C03 (52.8 mg, 0.382 mmol) and 30% H202 (2 mL) were added at rt. The reaction mixture was stirred at rt for 5 h. Water was added to the on mixture and the mixture was extracted with EtOAc (20 mL X 3) and the organic phase was dried over Na2S04, concentrated under reduced pressure and the residue was purified by prep-TLC (DCM:MeOH=15:1) to provide 4-amin0-1H-indolecarb0xamide (30 mg, 67%): 1H NMR (DMSO-d6) 8 10.79 (s, 1H), 7.43-7.41 (d, J: 8, 1H), 7.04 (s, 1H), 6.52 (s, 1H), 6.10-6.08 (d, J: 8, 1H), 5.83 (s, 2H).

Step D: 4-Acrylamid0-1H-ind01ecarb0xamide NH2 HNM —> \ H N H2N o H2N 0 To a solution of 4-amino-1H—indolecarboxamide (30 mg, 0.171 mmol) in DCM (3 mL), DIEA (0.060 mL, 0.342 mmol) and acroyloyl chloride (18.60 mg, 0.205 mmol) were added and the reaction mixture was stirred overnight at rt. Then the on e was trated under reduced re and the residue was purified by prep-HPLC (Table 1, Method u) to provide 4-acrylamid0- IH-indolecarb0xamide (17 mg, 43%): LC/MS (Table 1, Method d) R = 2.10 min; MS m/z: 230 (M+H)+. (Btk IC50 = C) Example #6: 4-Acrylamid0-1H-indolecarb0xamide \ N—s=o N I H2N 0 Step A: 4-(3-Acrylamid0amin0phenyl)(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)- lH-indolecarb0xamide tfo tfo HN 0N02 HN l NH2 O 0 o \ N—s"=o ' O \ \ N—s"=o \ \ N N H2N 0 2014/044247 To a round bottom flask was added 4-(3-acrylamidonitrophenyl)(1-(methylsulfonyl)-1,2,3,6- tetrahydropyridinyl)-1H-indolecarboxamide (0.175 g, 0.343 mmol, prepared using A from 4- bromo(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridinyl)-1H-indolecarboxamide (Preparation #18) and 3-aminonitrophenylboronic acid hydrochloride [CombiBlocks], E and acryloyl chloride) in NMP (2 mL) and HCl, 37% (0.222 mL) to give a red suspension. The reaction was heated to about 85 0C and tin (II) chloride (0.600 g, 0.316 mmol) was added. The on was stirred at about 85 0C for about 1.5 h. Additional tin (II) chloride (2.39 g, 1.26 mmol) was added and the reaction was further stirred at about 85 0C for about 2 h. The reaction was cooled to rt and DCM (30 mL), MeOH (10 mL), and 1N NaOH (15 mL) were added. The mixture was stirred usly for about 2 h, filtered, and the filtrate extracted with DCM (3x). The organic layers were combined and the solvent removed under vacuum. Water and EtOAc was added to the e and extracted with EtOAc (4x).

The organic layers were combined and washed with water and brine. The organic layers were combined and solvent removed under vacuum. The crude product was added to a silica gel column and was eluted with 0-10% MeOH in DCM. The material was further purified by prep-HPLC (Table 1, Method ag) to provide 4-(3-acrylamidoamin0phenyl)(1-(methylsulf0nyl)-I,2,3,6- tetrahydropyridinyl)-1H—indolecarb0xamide (20 mg, 12%): LC/MS (Table 1, Method g) R, = 1.12 min.; MS m/z: 480 (M+H)+.

Step B: 4-(3-Acrylamid0(thiazolylmethylamin0)phenyl)(1-(methylsulf0nyl)-1,2,3,6- ydropyridinyl)-1H-indolecarb0xamide To a stirring solution of 4-(3-acrylamidoaminophenyl)(1-(methylsulfonyl)-1,2,3,6- tetrahydropyridinyl)-1H-indolecarboxamide (20 mg, 0.042 mmol) and lecarbaldehyde (4.03 uL, 0.046 mmol) in MeOH (1 mL) was added MP-Cyanoborohydride (88 mg, 0.167 mmol) and acetic acid (9.55 uL, 0.167 mmol). The slurry was stirred at about 40 0C for about 40 h. The suspension was filtered and the resin washed with DCM and MeOH. The filtrate was passed through a plug of Si-carbonate. The filtrate was trated under d pressure and the residue was purified by Prep-TLC (10% MeOH/DCM) follow by a second purification by Prep-TLC (5% MeOH/DCM) to provide 4-(3-acrylamid0(thiazolylmethylamin0)phenyl)(1-(methylsulf0nyl)- I,2,3,6-tetrahydropyridinyl)-1H—indolecarb0xamide (7.2 mg, 25%): LC/MS (Table 1, Method g) R, = 1.56 min.; MS m/z: 577 (M+H)+. (Btk IC50 = A) e #7. (3-(2-Cyanohydr0xybutenamid0)phenyl)-1H-indolecarb0xamide N\OH H2N o A mixture of N—(3-(7-carbamoyl-1H-indolyl)phenyl)methylisoxazolecarboxamide (0.060 g, 0.166 mmol, Example #E.2.1) and NaOH (0.008 g, 0.200 mmol) in MeOH (1.9 mL) was heated in a vial at about 60 0C. After about 2 h, the reaction was cooled to rt and 1N aqueous HCl was added to acidify. The resulting precipitate was collected via vacuum filtration to provide (E)(3-(2-cyan0 hydroxybut-Z-enamid0)phenyl)-1H—indolecarb0xamide (0.047 g, 78%) as a solid after drying under vacuum at about 55 OC: LC/MS (Table 1, Method c) R, = 2.79 min.; MS m/z: 361 . (Btk IC50 = C) Example #8. Acrylamid0cyclohexyl)-1H-indolecarb0xamide and Example #9. 4- (transAcrylamid0cyclohexyl)-1H-ind01ecarb0xamide H H 0 orN.\\\\ \ .-\\‘ Nr\ \ \ N N H H o NH2 0 NH2 Step A: tert-Butyl (3-(7-carbam0yl-1H-indolyl)cyclohexen—1-yl)carbamate and tert-Butyl (3-(7-carbam0yl-1H-indolyl)cyclohexenyl)carbamate H H ON\ B00 ’ N\Boc \ \ \ —> O N N O H H H O NH2 0 NH2 0 NH2 To a solution of 4-bromo-1H-indolecarboxamide (296 mg, 1.237 mmol, Preparation #2), a mixure of [3-(4,4,5,5-tetramethyl[l,3,2]dioxaborolanyl)-cyclohexenyl]-carbamic acid tert-butyl ester and [3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolanyl)-cyclohexenyl]-carbamic acid tert-butyl ester (400 mg, 1.237 mmol, US. 2009/0197864), Na2C03 (328 mg, 3.09 mmol), PdC12(dppf)-DCM Adduct (101 mg, 0.124 mmol) in THF:MeOH:H20 (Ratio: 4:22, 20 mL) under N2 atmosphere, the mixture was heated at about 100 OC overnight. The reaction mixture was filtered through a pad of Celite®.

The resulting mixture was diluted with EtOAc (30 mL), washed with H20 (20 mL X 2), dried with Na2SO4, concentrated under reduced pressure and the residue was ed by prep-HPLC (Table 1, Method X) to provide a mixture of tert-butyl (3-(7-carbamoyl-1H-indolyl)cyclohex-Z-en-I- yl)carbamate and tert-butyl (3-(7-carbam0yl-IH—indolyl)cyclohex-S-en-I-yl)carbamate (300 mg, 68%): LC/MS (Table 1, Method l) R = 1.67 min; MS m/Z: 356 (M+H)+.

Step B: utyl (3-(7-carbam0yl-1H-ind01—4-yl)cyclohexyl)carbamate H H NHBoc O \ \ O \ —> N N H O NH2 0 NH2 0 NH2 To a solution of tert-butyl (3-(7-carbamoyl-1H-indolyl)cyclohexenyl)carbamate and tert- butyl (3-(7-carbamoyl-1H-indolyl)cyclohexenyl)carbamate (300 mg, 0.844 mmol) in THF (20 mL), Pd/C (44.9 mg, 0.422 mmol) was added and the reaction mixture was stirred at rt for about 3 h under H2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give crude product tert-butyl (3-(7-carbamoyl-IH—indolyl)cyclohexylkarbamate (290 mg, 96%), which was used to next step directly. LC/MS (Table 1, Method l) R = 1.53 min; MS m/Z: 358 (M+H)+.

Step C: min0cyclohexyl)-1H—indolecarb0xamide NHBoc NH2 \ \ u N o NH2 0 NH2 To a solution of tert-butyl (3-(7-carbamoyl-1H-indolyl)cyclohexyl)carbamate (220 mg, 0.615 mmol) in MeOH (10 mL), Cl (10 mL) was added at about 0 0C, then the reaction mixture was stirred at rt for about 3 h. The reaction mixture was concentrated under reduced pressure to give crude product 4-(3-amin0cyclohexyl)-IH-indolecarb0xamide (100 mg, 63%), which was used to next step ly. LC/MS (Table 1, Method l) R = 0.54 min; MS m/Z: 258 (M+H)+. —294— Step D: 4-(cisAcrylamid0cyclohexyl)-1H-ind01ecarb0xamide and 4-(trans Acrylamidocyclohexyl)-1H-ind01ecarb0xamide NH2 H o rNx" \ ..\\\ Nr\ \ \ , \ o NH2 0 NH2 0 NH2 To a solution of 4-(3-aminocyclohexyl)-1H-indolecarboxamide (120 mg, 0.466 mmol) in DCM (3 mL), DIEA (120 mg, 0.933 mmol) was added, acryloyl chloride (42.2 mg, 0.466 mmol) was added at about 0 OC dropwise and the mixture was stirred at about 0 0C for about 10 min, then concentrated under reduced pressure and the e was purified by prep-HPLC (Table 1, Method y) to provide 4- (cisacrylamidocyclohexyl)-1H-indolecarb0xamide (27 mg, 19%) 1H NMR: (MeOD) 8 7.59 (d, J = 8, 1H), 7.33 (d, J = 3.2, 1H), 6.95 (d, J = 8, 1H), 6.64 (d, J = 4, 1H), 6.26-6.17 (m, 2H), 5.67-5.58 (m, 1H), 4.01-3.96 (m, 1H), 3.22-3.13 (m, 1H), 2.19-1.97 (m, 4H), 1.65-1.59 (m, 3H),1.37-1.34 (m, 1H); LC/MS (Table 1, Method d) R = 2.56 min; MS Hill: 312 (M+H)+. (Btk IC50 = A) and 4-(trans- 3-acrylamidocyclohexyl)-1H-indolecarb0xamide (33 mg, 23%): 1H NMR: (MeOD) 8 7.58 (d, J = 8, 1H), 7.31 (d, J: 3.2, 1H), 6.98 (d, J: 8, 1H), 6.59 (d, J: 2.8, 1H), 6.52-6.46 (m, 1H), 6.28-6.24 (m, 1H), 5.69-5.64 (m, 1H), 4.35 (s, 1H), 3.42-3.36 (m, 1H), 2.13-1.72 (m, 8H); LC/MS (Table 1, Method d) R = 2.56 min; MS m/z: 312 (M+H)+. (Btk IC50 = B) e #10 and #11: 4-(cisAcrylamid0cyclopentyl)-1H-ind01ecarb0xamide and 4-(trans- lamid0cyclopentyl)-1H-ind01ecarb0xamide H H .\\\\N \ "\an U if 0 \ \ NH2 0 o NH2 Example #10 Example #11 Step A: rt-But0xycarb0nyl)amin0)cyclopentenyl trifluoromethanesulfonate and 4- ((tert-but0xycarb0nyl)amino)cyclopentenyl trifluoromethanesulfonate H H H N N N q\ \ BOC Q/ \ BOC g BOC O OTf OTf To a y prepared LDA solution (2M in THF, 9.38 mL) was added tert-butyl (3- oxocyclopentyl)carbamate (2.00 g, 10.0 mmol) in THF (4 mL) at about -780 C dropwise. The mixture was warmed to rt for about 30 min and then cooled to about -78 OC again. A solution of 1,1,1- trifluoro-N—phenyl-N—((trifluoromethyl)sulfonyl)methanesulfonamide (5.38 g, 15.1 mmol) in THF (10 mL) was added dropwise to the reaction mixture at about -780 C. The resulting mixture was warmed to rt and stirred for another 3 h. Treated with EtOAc (30 mL), the mixture was washed with H20 (20 mL X 3) and brine (10 mL), dried with Na2S04, concentrated under reduced pressure and the residue was purified by tography on silica gel to provide a e of 3-((tert- butoxycarbonyl)amin0)cyclopent-I-enyl trifluoromethanesulfonate and 4-((tert- butoxycarbonyl)amin0)cyclopent-I-enyl trifluoromethanesulfonate (0.82 g, 25%), which was used in next step t r purificaiton.

Step B: tert-Butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxab0r01anyl)cyclopenten yl)carbamate and tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxab0r01anyl)cyclopenten yl)carbamate wo0 Z I N ZI B00 \B00 —> / B O \O o’ \o A mixture of 3-((tert-butoxycarbonyl)amino)cyclopentenyl trifluoromethanesulfonate and 4- ((tert-butoxycarbonyl)amino)cyclopentenyl trifluoromethanesulfonate (720 mg, 2.173 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2' -bi(1,3,2-dioxaborolane) (662 mg, 2.61 mmol), PdC12(dppf)-DCM adduct (177 mg, 0.217 mmol) and KOAc (427 mg, 4.35 mmol) in 1,4-dioxane (20 mL) under N2 atmosphere was heated at about 100 OC overnight. The resulting mixture was diluted with DCM (30 mL), washed with H20 (20 mL X 2), trated under reduced pressure and the residue was purified by silica gel to give crude mixture of tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)cyclopentenyl)carbamate and tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan lopentenyl)carbamate (0.42 g, 63%), which was used directly in the next step without further purification.

Step C: tert-Butyl (3-(7-carbam0yl-1H-indolyl)cyclopentenyl)carbamate and utyl (3-(7-carbam0yl-1H-ind01yl)cyclopentenyl)carbamate N\ H ’ \BOC B. C N N H H H o NH2 0 NH2 0 NH2 To a on of 4-bromo-1H-indolecarboxamide (325 mg, 1.36 mmol, Preparation #2), tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclopentenyl)carbamate and tert-butyl (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclopentenyl)carbamate (420 mg, 1.36 mmol), Na2C03 (360 mg, 3.4 mmol), PdC12(dppf)-DCM Adduct (111 mg, 0.136 mmol) in THF:MeOH:H20 (Ratio: 4:22, 15 mL) under N2 atmosphere, the mixture was stirred at about 100 OC ght. The reaction mixture was filtered to remove Pd x. The resulting mixture was diluted with EtOAc (30 mL), washed with H20 (20 mL X 2), dried with Na2S04, concentrated and purified by PLC (Table 1, Method y) to provide a mixture of tert-butyl (3-(7-carbamoyl-1H-indolyl)cyclopenten- I—yl)carbamate and tert-butyl (3-(7-carbam0yl-IH—indolyl)cyclopenten-I-yl)carbamate (0.32 g, 69%): LC/MS (Table 1, Method l) R = 1.65 min; MS m/z: 342 (M+H)+.

Step D: utyl (3-(7-carbam0yl-1H-indolyl)cyclopentyl)carbamate H N'Boc H H o NH2 0 NH2 0 NH2 To a solution of tert-butyl (3-(7-carbamoyl-1H-indolyl)cyclopentenyl)carbamate and tertbutyl (3-(7-carbamoyl-1H-indolyl)cyclopentenyl)carbamate (300 mg, 0.844 mmol) in THF (20 mL), Pd/C (44.9 mg, 0.422 mmol) was added and the the mixture was stirred for about 3 h at rt under H2. The mixture was filtered and concentrated under reduced pressure to provide crude tert- butyl (3-(7-carbamoyl-IH—indolyl)cyclopentyl)carbamate (0.29 g, 96%), which was used to next step directly without further purification. LC/MS (Table 1, Method l) R = 1.50 min; MS Hill: 344 (M+H)+.

Step E: 4-(cisAmin0cyclopentyl)-1H-ind01ecarb0xamide and nsaminocyclopentyl)- lH-indolecarb0xamide "(\NHZ U UTA N‘Boc \ —> \ N N H H \ MeOH/HCI ""2 O NH2 —> Example#10 fl "NHZ o NH2 Nw \ _> u \ O NH2 N O NH2 Example #11 To a solution of tert-butyl (3-(7-carbamoyl-1H—indolyl)cyclopentyl)carbamate (250 mg, 0.728 mmol) in MeOH (10 mL), MeOH/HCl (10 mL) was added at about 0 OC and the mixture was stirred for about 3 h at rt. The mixture was concentrated under d pressure and the residue was ed by prep-HPLC (Table 1, Method t) to provide 4-(transamin0cyclopentyl)-1H-indole carboxamide (10 mg, 6%) and 4-(cis-S-aminocyclopentyl)-1H-indolecarb0xamide (50 mg, 28%).

To a solution of 4-(cisaminocyclopentyl)-1H—indolecarboxamide (50 mg, 0.206 mmol) in DCM (3 mL), DIEA (53 mg, 0.411 mmol) was added, then acryloyl chloride (18.60 mg, 0.206 mmol) was added dropwise at about 0 0C, the mixture was stirred at about 0 0C for about 10 min, then concentrated under reduced pressure and the e was purified by prep-HPLC (Table 1, Method 2) to give 4-(cisacrylamid0cyclopentyl)-1H-indolecarb0xamide (20 mg, 33%): 1H NMR (MeOD) 8 7.59 (d, J = 7.2, 1H), 7.33 (s, 1H), 7.02 (d, J = 8, 1H), 6.64 (s, 1H), 6.30-6.20 (m, 2H), 5.64 (d, J = 8.8, 1H), 4.51-4.40 (m, 1H), 3.60-3.58 (m, 1H), 2.56-2.51 (m, 1H), 2.26-2.21 (m, 2H), 2.07-2.02 (m, 1H), 1.86-1.78 (m, 2H): LC/MS (Table 1, Method d) R = 2.48 min; MS m/z: 298 (M+H)+. (Btk IC50 = A) To a solution of 4-(transaminocyclopentyl)-1H—indolecarboxamide (10 mg, 0.041 mmol) in DCM (1 mL), DIEA (11 mg, 0.082 mmol) was added, then acryloyl chloride (3.72 mg, 0.041 mmol) was se added, the mixture was stirred at about 00C for about 10 min, concentrated and purified by prep-HPLC (Table 1, Method 2) to give 4-(transacrylamid0cyclopentyl)-1H-indole carboxamide (1.1 mg, 9%): 1H NMR (MeOD) 8 7.60 (d, J: 7.6, 1H), 7.33 (d, J: 2.8, 1H), 7.00 (d, J = 7.6, 1H), 6.62 (d, J: 3.2, 1H), 6.33-6.20 (m, 2H), 5.67-5.64 (m, 1H), 4.50-4.49 (m, 1H), .72 (m, 1H), 2.34-2.28 (m, 3H), 2.26-2.23 (m, 1H), 2.07-1.89 (m, 1H), 1.88-1.74 (m, 1H); LC/MS (Table 1, Method d) R = 2.47 min; MS m/z: 298 (M+H)+. (BtkIC50= A) e #12*: (R)(1-(Methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)(2-0X0-1,3'- bipiperidin—l'-yl)-1H-ind01ecarb0xamide H2N 0 Step A: (R)(1-(Methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)(2-0X0-1,3'-bipiperidin-1'- yl)t0syl-1H-indolecarb0nitrile 0’NZ?o F a \ 9 o" \ + \ ,9 9 \ N- 3:0 N \ o o O ‘ N\ N n NC T5 NC Ts 02‘0 To a solution of (R)-tert-butyl 2-oxo-1,3'—bipiperidine-1'-carboxylate (100 mg, 0.354 mmol, WO 2011/029046) in DCM (4 mL) was added TFA (1.000 mL). The reaction was stirred for about 4 h at rt. The solvent was stripped off and a e of 4-fluoro(1-(methylsulfonyl)-1,2,3,6- tetrahydropyridinyl)tosyl-1H-indolecarbonitrile (168 mg, 0.354 mmol, Preparation #27) and TEA (0.197 mL, 1.417 mmol) in DMSO (2 mL) was added. The vial was sealed and the reaction was heated in a microwave at about 120 0C for about 30 min. Water (20 mL) was added and extracted into DCM then washed with brine and passed through a phase tore to remove residual water.

Evaporated and chromatographed on silica to eluting with a gradent of 0-100% EtOAc/hexane to provide crude (R)(1-(methylsulf0nyl)-1,2,3,6-tetrahydropyridinyl)(2-0x0-1,3 '-bipiperidin-I '- yl)-I-t0syl-IH—indolecarb0nitrile (0.041 g, 18.21%).

Step B: (R)(1-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)(2-0X0-1,3'-bipiperidin-1'- yl)-1H-ind01ecarb0xamide O \ N-S/’=O \ 4. \ \ N-S—O N N H CN H2N O A mixture of Cs2C03 (20.50 mg, 0.063 mmol) and (R)(1-(methylsulfonyl)-1,2,3,6- tetrahydropyridinyl)(2-oxo-1,3'-bipiperidin-1'—yl)tosyl-1H-indolecarbonitrile (40 mg, 0.063 mmol) in THF (2 mL) and MeOH (1.000 mL) were stired at rt overnight. The solution was diluted with water (15 mL) and stirred for about 20 min. DCM was added to dissolve the suspension and the mixture was filtered through a Biotage phase separator. The organics were collected and concentrated. The intermediate was dissolved in t-butanol (1 mL) and DMSO (0.500 mL) and NaOH (0.377 mL, 0.755 mmol) and hydrogen peroxide (0.175 mL, 1.699 mmol) were added. The mixture was stirred for about 20 min at rt and saturated NH4Cl (1 mL) was added. The mixture was diluted with water (15 mL) and stirred for about15 min. The solids were collected by filtration washing several times with water and dried under vaccum and purified by PLC (Table 1, Method aq).

The samples were returned and dissolved in DCM. The organics were combined and washed wirh saturated sodium bicarbonate, filtered through a Biotage phase separator, and concentrated to provide (R)(1-(methylsulf0nyl)-1,2,3,6-tetrahydropyridinyl)(2-0x0-1,3'-bipiperidin-I '-yl)-1H—indole- 7-carb0xamide (3 mg, 9.54%): LC/MS (Table 1, Method f) R = 1.37 min; MS m/Z: 500 (M+H)+.

(Btk IC50 = B) Example #13*: (1-(Methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)(3-(1-0x0-3,4- dihydroisoquinolin-2(1H)-yl)piperidinyl)-1H-indolecarb0xamide Step A: (R)-Methyl-N-(piperidinyl)benzamide —’ UNO" A mixture of (R)-tert-butyl 3-(2-methylbenzamido)piperidinecarboxylate (19.0 g, 59.7 mmol, prepared using D from rt-butyl 3-aminopiperidinecarboxylate and 2-methylbenzoic acid) in HCl (2 N in MeOH, 300 mL, 600 mmol) was d at rt for about 4 h, then concentrated under d re to provide crude (R)methyl-N—(piperidin-S-yl)benzamide (20.0 g), which was used ly for the next step without further purification.

Step B: (R)-N-(1-Benzylpiperidin—3-yl)methylbenzamide @"fi H H (TNT; : N '1 To a solution of (R)methyl-N—(piperidinyl)benzamide (20.0 g, crude) and TEA (30.1 g, 298.5 mmol) in DCM (260 mL) was added dropwise BnBr (11.2 g, 65.7 mol) at rt over about 30 min.

Then the mixture was stirred at rt overnight. After completion, DCM (1 L) was added, and the mixture was washed with H20 (3 X 100 mL) The organic phase was dried over anhydrous NaZSO4 and concentrated under reduced pressure to provide (R)-N-(1-benzylpiperidinyl) methylbenzamide (12.0 g, 65% over two steps): LC/MS (Table 1, Method l) R = 0.91 min; MS m/Z: 309 (M+H)+.

Step C: (R)(1-Benzylpiperidinyl)is0quinolin-1(2H)-0ne : N : E —> 0’I; w w Bn Bn To the on of (R)-N—(1-benzylpiperidinyl)methylbenzamide (12.0 g, 38.9 mmol) in THF was added dropwise n-BuLi (2.5 M, 32.7 mL) between -22 and -14 0C, over about 30 min. The resulting deep red solution was stirred at about -22 0C for about 30 min and DMF was added below about -14 OC (internal). After the addition was completed, the on was stirred at about -22 0C for about 30 min. Then HCl (6 N aqueous, 25 mL, 150 mmol) was slowly added, keeping the temperature below 5 OC. The mixture was basified by addition of saturated NaOH at about 0 0C to pH 14 and ted with DCM (3 X 500 mL). The organic phase was dried over NaZSO4 and concentrated under reduced pressure to provide (R)(1-benzylpiperidinyl)isoquinolin-I(2H)-0ne (12.0 g as a solid: LC/MS (Table 1, Method l) R = 1.35 min; MS m/Z: 319 (M+H)+. , 97%) Step D: (R)(Piperidinyl)-3,4-dihydr0is0quinolin-1(2H)-0ne O" —> O)"f : 0 o l m A mixture of (R)(1-benzylpiperidinyl)isoquinolin-1(2H)-one (12 g, 37.7 mmol) and Pd(OH)2 (0.5 g) in MeOH was stirred at about 50 0C under H2 atmosphere (50 psi) ght. Then the mixture was filtrated through Celite®, and the filtrate was concentrated. The crude product was purified by flash chromatography to afford 6.3 g of the crude product which was tallized in a mixture of 2014/044247 MTBE (15 mL) and OH (5 mL) to provide (R)(piperidinyl)-3,4-dihydr0is0quinolin- 1(2H)-0ne (HCl salt) as a solid (2.1 g, 21%): 1H NMR (MeOD) 7.95 (d, J = 8, 1H), 7.51-7.47 (m, 1H), 7.38-7.34 (m, 1H), 7.29 (d, J = 7.6, 1H), 4.86-4.80 (m, 1H), 3.61-3.58 (m, 2H), 3.39-3.35 (m, 2H), 3.28-3.22 (m, 1H), 3.03-2.95 (m, 3H), 2.12-1.87 (m, 4H); LC/MS (Table 1, Method d) R = 2.05 min; MS m/Z: 231 (M+H)+.

Step E: (R)(1-(Methylsulf0nyl)-1,2,3,6-tetrahydr0pyridin—4-yl)(3-(1-0x0-3,4- dihydrois0quin01in-2(1H)-yl)piperidinyl)t0syl-1H-indolecarb0nitrile \ ,9 \ N-S=O o N N NC T5 0 \ N—s"=o CN TS A mixture of 4-fluoro(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridinyl)tosyl-1H-indole carbonitrile (318 mg, 0.672 mmol, Preparation #27), (piperidinyl)-3,4-dihydroisoquinolin- 1(2H)-one hydrochloride (179 mg, 0.672 mmol) and TEA (0.374 mL, 2.69 mmol) in DMSO (4 mL) were heated in a microwave at about 120 0C for about 20 min. The reaction was heated in a microwave at about 120 0C for an additional 30 min. Water (50 mL) was added and extracted into DCM. The solution was washed with brine and passed through a phase separator to remove residual water. The organics were concentrated and chromatographed on silica to eluting with a t of 0- 100% EtOAc/hexane to provide crude (R)(I-(methylsulf0nyl)-1,2,3,6-tetrahydropyridinyl)(3- (I -0x0-3,4-dihydr0is0quinolin-2(1H)-yl)piperidin-I -yl)-I -t0syl-I -indolecarb0nitrile (110 mg, 24%). The material was used without further purification.

Step F: (R)(1-(Methylsulf0nyl)-1,2,3,6-tetrahydr0pyridin—4-yl)(3-(1-0x0-3,4- dihydroisoquinolin-2(1H)-yl)piperidinyl)-1H-indolecarb0xamide A...O "'0 \ ,9 \ ,9 \ N—s=o \ N-S=O N N H CN TS H2N O A mixture of Cs2C03 (51.9 mg, 0.159 mmol) and (R)(1-(methylsulfonyl)-1,2,3,6- ydropyridinyl)(3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidinyl)tosyl-1H- indolecarbonitrile (109 mg, 0.159 mmol) in THF (2 mL) and MeOH (1.000 mL) were stirred at rt overnight. The mixture was diluted with water (15 mL) and stirred for about 20 min. The itate was collected by filtration and the filter cake was washed with water. The filter cake was dissolved in t-butanol (1 mL) and DMSO (0.500 mL) was added NaOH (0.956 mL, 1.91 mmol) and hydrogen peroxide (0.444 mL, 4.30 mmol). The mixture was stirred for about 20 min at rt and saturated NH4Cl (1 mL) was added. The mixture was diluted with water (15 mL) and stirred for about 15 min. The solids were ted by filtration washing several times with water and dried under vaccum. The resulting solids were purified by prep-HPLC (Table 1, Method ap). The samples were returned and dissolved in DCM. The organics were combined and washed wirh saturated sodium bicarbonate, ed h a Biotage phase separator, and concentrated. The residue was further dried in a vacuum oven at about 50 0C for about 48 h to afford (R)(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)(3-(1-0x0-3,4-dihydr0is0quinolin-2(1H)-yl)piperidin-I-yl)-IH-indole amide (30 mg, 34%): LC/MS (Table 1, Method f) R = 1.63 min; MS m/Z: 548 (M+H)+. (Btk IC50 = A) Example #13A*: (1-(7-Carbamoyl-Z-(l-(methylsulfonyl)-1,2,3,6-tetrahydropyridin—4-yl)- 1H-indolyl)piperidinyl)thiazolecarb0xamide rs H N/ N///,, ogé WO 10255 Step B: (R)-N-(Piperidinyl)thiazolecarboxamide (Tle?NH \ N H \ —> (j,"m"? 0 o N N Boc H To a solution of (R)-tert-butyl 3-(thiazolecarboxamido)piperidinecarboxylate (1.9 g, 6.1 mmol) in EtOAc (20 mL) was added HCl/EtOAc (20 mL) dropwise at about 0 0C, then the reaction was d at rt for about 3 h. The mixture was filtered and the filter cake was hygroscopic. The filter cake was dissolved into water and saturated s NaHCO3 solution. The mixture was extracted with DCM (3 X 50 mL) and the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to provide (R)-N—(piperidin-S-yl)thiazole-Z-carboxamide (1.2 g, 5.68 mmol, 93%): 1H NMR (CDClS) 8 1.79-1.66 (m, 3H), 1.92-1.86 (m, 1H), 2.04 (s, 1H), 2.87-2.70 (m, 3H), 3.15-2.88 (m, 1H), .06 (m, 1H), 7.54-7.53 (m, 2H), 7.84 (t, J: 2.8 Hz, 1H).

Step C: (1-(7-Cyan0(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin—4-yl)t0syl-1H— indolyl)piperidinyl)thiazolecarboxamide O ",3 CN \ / N_MS A mixture of 4-fluoro(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridinyl)tosyl-1H-indole carbonitrile (200 mg, 0.422 mmol, Preparation #27), (R)-N—(piperidinyl) thiazolecarboxamide (178 mg, 0.842 mmol) and TEA (170 mg, 1.680 mmol) in DMSO (2 mL) was heated under microwave condition at about 120 0C for about 1 h. Water (10 mL) was added to the mixture and extracted with DCM (3 X 20 mL). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated under reduced re to give the crude product which was purified by Prep-TLC (DCM:MeOH = 75:1) to provide (R)-N-(1-(7-cyan0(1-(methylsulf0nyl)-1,2,3,6- tetrahydropyridinyl)-1 -t0syl-IH—indolyl)piperidin-S-yl)thiazole-Z-carboxamide (20 mg, 7%): LC/MS (Table 1, Method m) R = 2.24 min; MS m/Z: 665 (M+H)+. —304— Step D: (R)-N-(1-(7-Carbamoyl-Z-(l-(methylsulf0nyl)-1,2,3,6-tetrahydr0pyridinyl)-1H-indol- 4-yl)piperidinyl)thiazolecarboxamide (Ni,NH O’NH —> N \ / \ N-Ms N-Ms N N CN ‘TS H2N o A mixture of (R)-N—(1-(7-cyano(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridinyl)tosyl-1H- indolyl)piperidinyl)thiazolecarboxamide (76 mg, 0.114 mmol), NaOH (54.9 mg, 1.37 mmol) and 30% H202 (350 mg, 3.09 mmol) in the mixture of DMSO (1 mL) and n-butanol (2 mL) was stirred at rt for about 24 h. Then saturated s NH4Cl (2 mL) was added and diluted with water (30 mL) and stirred for 30 min. The solid was collected by filtration and washed several times with water and the crude product was purified by Prep-TLC (50:1 DCM/MeOH) to provide (R)-N-(1-(7- carbamoyl-Z-(I -(methylsulf0nyl)-1, 2, 3, 6-tetrahydropyridinyl)-1H-indolyl)piperidin yl)thiazole-Z-carboxamide (32 mg, 53%): LC/MS (Table 1, Method d) R = 2.90 min; MS m/Z: 529 (M+H)+. (Btk IC50 = A) Example #14: 2-(1-Methyl-1H-pyrazolyl)(2-methyl(4-0x0quinaz01in-3(4H)-yl)phenyl)- 1H-benzo[J]imidazolecarb0xamide H2N 0 Step A: 3-(3-(7-Br0m0benz0[c][1,2,5]thiadiazolyl)methylphenyl)quinazolin-4(3H)-0ne Br N /N\ O N C\/N Br 18 To a on of bromobenzo[c][1,2,5]thiadiazole (1.029 g, 3.5 mmol) and 3-(2-methyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)quinazolin-4(3H)-one (1.141 g, 3.15 mmol, WO 2011159857) in the mixture of toluene (40 mL), MeOH (10 mL) and water (10 mL) were added 2014/044247 Na2C03 (0.742 g, 7.00 mmol) and Pd(PPh3)4 (0.081 g, 0.070 mmol). The mixture was heated to about 100 0C for 24 h. The resulting solution was cooled to rt and diluted with EtOAc, washed with water and brine, dried over NaZSO4, filtered and concentrated to give a crude product, which was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc=5:1 to 1:1) to afford 3-(3-(7— bromobenz0[c][1,2,5]thiadiazolyl)methylphenyl)quinazolin-4(3H)-0ne (1.0 g, 64%): 1H NMR (CDCl3) 5 8.40-8.38 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 7.95-7.93 (d, J=7.6 Hz, 1H), 7.82-7.80 (m, 2H), .56 (m, 1H), .46 (m, 3H), 7.41-7.39 (t, J=4.8 Hz, 1H), 1.95 (s, 3H).

Step B: 7-(2-Methyl(4-0x0quinazolin-3(4H)-yl)phenyl)benzo[c][1,2,5]thiadiazole carbonitrile r/N r/N N N O O O o /N\ /N\ N N Br CN To a solution of 3-(3-(7-bromobenzo[c][1,2,5]thiadiazolyl)methylphenyl)quinazolin-4(3H)-one (0.449 g, 1 mmol) in DMF (12 mL) were added Zn(CN)2 (0.076 g, 0.650 mmol) and Pd(PPh3)4 (0.046 g, 0.040 mmol). The mixture was heated to about 160 0C for about 15 min under N2 atmosphere in a microwave reactor. The resulting solution was diluted with EtOAc, and washed with brine (4 x). The organic phase was dried over NaZSO4, filtered and concentrated to give a crude product, which was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc=5:1 to 1:1) to provide 7-(2-methyl(4-0x0quinazolin-3(4H)-yl)phenyl)benz0[c][1, 2, 5]thiadiazolecarbonitrile (0.3 g, 76%): 1H NMR ) 5 .03 (d, J :80 Hz, 1H), 8.10-8.06 (t, J :72 Hz, 2H), .74 (m, 2H), 7.63-7.61 (t, J=7.2 Hz, 1H), 7.53-7.45 (m, 3H), 7.39-7.37 (d, J=7.2 Hz, 1H), 1.90 (s, 3H).

Step C: 2,3-Diamin0-2'-methyl-3'-(4-0x0quinazolin—3(4H)-yl)-[1,1'-biphenyl]carb0nitrile N N N N O o O fooo 0/N\ NH2 N ONH2 ON ON To a solution of 2,3-diamino-2'-methyl-3'-(4-oxoquinazolin-3(4H)-yl)-[1,1'-biphenyl]carbonitrile (0.53 mg, 1.34 mmol) in AcOH (50 mL) was added Zinc (1.75 g, 26.8 mmol), the mixture was heated to about 120 0C for about 2 h. The solvent was concentrated and the residue was taken up into EtOAc, washed with saturated aqueous NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give a crude product, which was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc=1:1 to 0:1) to provide 2,3-diamin0-2’- methyl-3 '-(4-0x0quinazolin-3(4H)-yl)-[1,1'-biphenyl]carb0nitrile (0.4 g, 81%): LC/MS (Table 1, Method l) R = 1.33 min; MS m/Z: 368 (M+H)+.

Step D: 2-(1-Methyl-1H-pyrazolyl)(2-methyl(4-0x0quinazolin-3(4H)-yl)phenyl)-1H- benz0[d]imidazolecarb0nitrile r/N r/N N N O o O 0 01 / ON ON To a solution of 2,3-diamino-2'-methyl-3'-(4-oxoquinazolin-3(4H)-yl)-[1,1'-biphenyl]carbonitrile (400 mg, 1.09 mmol) in DMF (15 mL) were added 1-methyl-1H-pyrazolecarbaldehyde (240 mg, 2.18 mmol) and TMSCl (0.417 mL, 3.27 mmol). The mixture was heated to about 100 0C for about min in a microwave reactor. The resulting on was diluted with EtOAc, and washed with brine (4 x). The organic phase was dried over Na2SO4, filtered and concentrated to give a crude t, which was purified by column chromatography on silica gel (eluted with Pet ether:EtOAc=1:1 then MeOH=50:1) to provide 2-(1-methyl-1H—pyrazolyl)(2-methyl (4-0x0quinazolin-3(4H)-yl)phenyl)-1H—benz0[d]imidazolecarb0nitrile (200 mg, 40%): LC/MS (Table 1, Method m) R = 1.78 min; MS m/Z: 458 (M+H)+.

Step E: 2-(1-Methyl-1H-pyrazolyl)(2-methyl(4-0x0quinazolin-3(4H)-yl)phenyl)-1H- benzo[J_|imidazolecarb0xamide 0\ wN / N\ m /N N CN H2N 0 To a solution of 2-(1-methyl-1H-pyrazolyl)(2-methyl(4-oxoquinazolin-3(4H)-yl)phenyl)-1H- benzo[d]imidazolecarbonitrile (278 mg, 0.608 mmol) in the e of butanol (6 mL) and DMSO (3 mL) were added NaOH (292 mg, 7.29 mmol) and H202 (1.68 mL, 16.4 mmol). The mixture was d for about 24 h at about 25 OC. The resulting solution was quenched with saturated aqueous NH4Cl solution, extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated to give a crude product, which was purified by prep-HPLC (Table 1, Method 11) to provide 2 -(I l-IH-pyrazolyl)(2-methyl(4-0x0quinazolin-3(4H)-yl)phenyl)-1H- benz0[d]imidazolecarb0xamide (140 mg, 48%): LCMS (Table 1, Method d) R = 2.53 min; MS m/z: 476 (M+H)+. (Btk IC50 = B) Example #15: 4-(3-Acrylamid0phenyl)-lH-indazolecarb0xamide 0 MN 0 NH2 Step A: 3-(7-Carbamoyl-1H-ind01yl)benzoic acid Br 0 OH Iz\ / H2N o H H2NO A mixture of 4-bromo-1H-indolecarboxamide (0.5 g, 2.091 mmol, Preparation #2), (3- (methoxycarbonyl)phenyl)boronic acid (0.565 g, 3.14 mmol), sodium carbonate (2.61 mL, 5.23 mmol) in DME (10.00 mL) was degassed and purged with nitrogen for about 5 min, then is(triphenylphosphine)palladium(0) (0.121 g, 0.105 mmol) was added. The reaction vessel was sealed and heated with ave (Biotage Initiator) at about 1100C for about 45 min. The mixture was cooled to rt, followed by on of about 50 mL of water. The precipitate is filtered, air-dried and used without further purification. This crude was then dissolved in THF (25 mL) and treated with lithium hydroxide (0.250 g, 10.46 mmol) solution in water (25 mL). The reaction mixture was stirred at rt overnight. THF was d and the aqueous layer was extracted with DCM to remove triphenylphosphine oxide. The aqueous phase was then acidified with 1N HCl solution to about pH 2.

The precipitate was filtered and dried to give 0.58 g of crude 3-(7-carbamoyl-IH—indolyl)benzoic acid as a solid. LC/MS (Table 1, Method g) R = 1.37 min; MS m/z 281 (M+H)+.

Step B: 4-(3-((Cyanomethyl)carbamoyl)phenyl)-1H-indolecarb0xamide 0 o o o. o \ / 0 / O N N H2N 0 0 NH2 A e of 3-(7-carbamoyl-1H-indolyl)benzoic acid (0.1 g, 0.357 mmol), TBTU (0.172 g, 0.535 mmol) and DIEA (0.249 mL, 1.43 mmol) in DMF (5.0 mL) was stirred at rt for about 5 min, followed by addition of 2-aminoacetonitrile,hydrochloric acid (0.040 g, 0.43 mmol). The reaction mixture was stirred at the same temperature overnight. Water was added and the aqueous phase was extracted with EtOAc. Organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was dried and the crude was ed by prep HPLC (Table 1, Method i) to give cyanomethyl)carbamoyl)phenyl)-IH-indole-7—carb0xamide (0.065 g, 57%) as a solid. LC/MS (Table 1, Method g) R = 1.30 min; MS m/z 319 (M+H)+ (Btk IC50 = C) Example #16: 4-(3-Amin0methylphenyl)-1H-indolecarb0xamide Br 0 \ —.

H2" 0 H2N o A mixture of 4-bromo-1H-indolecarboxamide (1.28 g, 5.35 mmol, Preparation #2), 2-methyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (1.37 g, 5.89 mmol, Combi-Blocks), Na2C03 (1.70 g, 16.06 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.392 g, 0.535 mmol) in THF (41.8 mL), MeOH (5.86 Ll), and water (5.86 mL) was stirred at about 70 0C for about 16 h under a en atmosphere. The mixture was filtered through Celite® and concentrated under reduced pressure. The crude product was purified by silica gel column with 0-10% MeOH in DCM to e the crude product. The residue was ated with DCM (2 x with sonication for about 5 min), filtered, was washed with DCM and dried under reduced pressure to provide 4-(3- amino-Z-methylphenyl)-IH-indolecarb0xamide (0.86 g, 61%): LC/MS (Table 1, Method g) R = 1.03 min; MS m/z: 266 (M+H)+. (Btk IC50 = C) Example #17: 4-(3-Acrylamid0methylphenyl)-1H-pyrrolo[2,3-c]pyridinecarboxamide H2N W" \ \ \ —> | \ N/ N N / H2N O H2N 0 To a solution of 4-(3-aminomethylphenyl)-1H-pyrrolo[2,3-c]pyridinecarboxamide (3.0 g, 11.3 mmol, Example #2) and TEA (3.14 mL, 22.5 mmol) in THF (113 mL) was slowly added acryloyl chloride (1.01 mL, 12.4 mol) at 0 OC. The reaction was stirred at about 0 0C for about 20 min. The mixture was concentrated under reduced pressure and water (100 mL) was added and the suspension was sonicated for 30 min, filtered, wahed with water (100 mL), ether (100 mL) and dried to give 4-(3- acrylamido-Z-methylphenyl)-1H—pyrrolo[2,3-c]pyridinecarb0xamide (3.05 g, 85%): LC/MS (Table 1, Method 0 Rt = 1.27 min; MS Hill: 321 (M+H)+. (Btk 1C50 = A) Example #18: 4-(3-Acrylamid0phenyl)-1H-indazolecarb0xamide H2N 0 Step A: Methyl 2-aminochlor0methylbenz0ate CI CI NH2 NH2 HO O O 0 To a e of 2-aminochloromethylbenzoic acid (5.0 g, 26.9 mmol, e) and cesium carbonate (13.2 g, 40.4 mmol) in DMF (100 mL) was added iodomethane (1.77 mL, 28.3 mmol). The mixture was then d at rt for about 16 h. Water was added and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was trated and purified by chromatography on silica gel (5-60% EtOAc in heptane) to provide methyl 2-amin0chlor0methylbenz0ate (4.48 g) as a solid. LC/MS (Table 1, Method g) R = 1.74 min; MS m/z 200 (M+H)+.

Step B: Methyl 4-chlor0-1H-indaz01ecarboxylate CI CI NH2 N To a solution of methyl 2-aminochloromethylbenzoate (4.5 g, 22.5 mmol) in CHCl3 (100 mL) was added acetic anhydride (4.89 mL, 51.8 mmol). The e was then stirred at rt for about 2 h, followed by addition of isopentyl nitrite (6.68 mL, 49.6 mmol) and potassium acetate (0.664 g, 6.76 mmol). The reaction mixture was heated at refluxed for about 18 h. The reaction was diluted with DCM and washed with saturated sodium bicarbonate and dried over magnesium sulfate. The te is concentrate to provide crude methyl 4-chlor0-1H—indazolecarb0xylate (4.46 g): LC/MS (Table 1, Method g) R, = 1.47 min; MS m/z 211 (M+H)+.

Step C: 4-Chloro-1H-indazolecarb0xamide CI CI \IN \ —> N N N H H \o o H2N 0 To a sion of methyl 4-chloro-1H-indazolecarboxylate (4.3 g, 20.4 mmol) in oxane (75 mL) was added a solution of KOH (1.69 g, 26.5 mmol) in water (75 mL). The reaction mixture was then stirred at rt for about 16 h to give a clear solution. Solvent was removed and the residue wais treated with 1N HCl to precipitate the crude acid, which was used without further purification. A mixture of this crude acid (0.5 g, 2.54 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane- 1,3-diamine hydrochloride (0.731 g, 3.82 mmol) and HOBt (0.584 g, 3.82 mmol) in DMF (15 mL) was stirred at rt for about 60 min, then ammonia (0.5 N solution in 1,4-dioxane, 50.9 mL, 25.4 mmol) was added. The reaction mixture was stirred at rt for about 6 h. The suspension was filtered and washed with EtOAc. The filtrate was concentrated and treated with water. The precipitate was filtered, washed with water and ied to provide 4-chlor0-1H—indazolecarb0xamide (0.43 g) as a solid; LC/MS (Table 1, Method g) R = 1.00 min; MS m/z 196 (M+H)+.

Step D: 4-(3-Amin0phenyl)-1H-indazolecarboxamide CI 0 / —> N\ \ N N H N H2N O O NH2 A suspension of ro-1H—indazolecarboxamide (0.15 g, 0.767 mmol), utyl (3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)phenyl)carbamate (0.367 g, 1.15 mmol), cesium carbonate (0.75 g, 2.3 mmol) in DME (4.0 mL) and water (2.0 mL) was degassed and purged with nitrogen for 5 min.

Then tris(dibenzylideneacetone)dipalladium(0) (0.07 g, 0.077 mmol) and 2-(dicyclohexylphosphino)- 2',4',6'-triisopropylbiphenyl (0.037 g, 0.077 mmol) were added. The on vessel was sealed and heated using Biotage Initiator at about 140 0C for about 30 min. The mixture was cooled to rt and filtered through a pad of Celite®. The filtrate was ioned between water and EtOAc. Organic layer was washed with brine, dried over magnesium e and filtered. The filtrate was concentrated and purified by chromatography on silica gel (30-100% EtOAc/heptane). This product was then dissolved in DCM (2 mL) and treated with TFA (5 mL, 64.9 mmol). The reaction mixture ws stirred at rt overnight. Excess TFA and solvent were removed to provide crude 4-(3-amin0phenyl)-1H- le-7—carb0xamide, trifluoroacetic acid (0.195 g) as a solid. LC/MS (Table 1, Method g) R = 0.25 min; MS m/z 253(M+H)+.

Step E: 4-(3-Acrylamid0phenyl)-1H-indazolecarboxamide ONH2 0 NHo O —. \ 0 H2" 0 H2N o A suspension of 4-(3-aminophenyl)-1H—indazolecarboxamide, TFA (0.1 g, 0.27 mmol), DIEA (0.143 mL, 0.819 mmol) in THF (2.5 mL) was cooled in an ice bath and acryloyl chloride (0.026 mL, 0.31 mmol) is added slowly. After 30 min, the reaction was treated with MeOH and stirred for about min. Solvent was then removed under vacuum and the residue was triturated with DCM to provide 4-(3-acrylamid0phenyl)-IH-indazolecarb0xamide (56 mg) as a solid: 1H NMR (d-DMSO-d6) 5 13.17 (s, 1 H) 10.34 (s, 1 H) 8.28 (s, 1 H) 8.21 (s, 1 H) 8.17 (s, 1 H) 8.00 (d, J: 7.48 Hz, 1 H) 7.73 (d, J: 7.70 Hz, 1 H) 7.40 - 7.59 (m, 3 H) 7.30 (d, J: 7.59 Hz, 1 H) 6.39 - 6.58 (m, 1 H) 6.17 - 6.36 (m, 1 H) 5.60 - 5.97 (m, 1 H). (Btk IC50 = A) Example #19: 4-(3-Acrylamid0phenyl)-1H-indazolecarb0xamide Step A: Methyl 4-br0m0methyl((2-(trimethylsilyl)eth0xy)methyl)-1H-indolecarb0xylate B r Br \ \ N N \ \ sEM 5EM MeO O MeO 0 To a solution of diisopropylamine (1.45 mL 10.1 mmol) and anhydrous THF (30 mL), a solution of t- BuLi (11 mL, 11.7 mmol) in pentane was added at about -78 0C under nitrogen atmosphere reaction mixture was d for about 30 min. Then a on of methyl 4-bromo((2- (trimethylsilyl)ethoxy)methyl)-1H-indolecarboxylate (3 g, 7.81 mmol, Preparation #10, step A) in anhydrous THF (10 mL) was added at about -78 0C. After about 2 h, a on of iodomethane (2.216 g, 15.61 mmol) in anhydrous THF (10 mL) was added at about -78 OC. The mixture continued to stir for about 2 h at about -78 OC. The reaction mixture was quenched with aqueous NH4Cl, extracted with EtOAc (500 mL X 3). The c phase was dried over Na2S04, concentrated under d pressure, and the residue was ed by prep-HPLC (Table 1, Method a0) to provide methyl 4-br0m0methyl-I-((2-(trimethylsilyl)ethoxy)methyl)-1H-indolecarb0xylate (1 g, 32%) as a solid: 1H NMR (CDCl3) 8 7.51-7.49 (d, J = 8.0, 1H), 7.39-7.37 (d, J = 8, 1H), 6.55 (s, 1H), 5.77 (s, 2H), 4.06 (s, 3H), 3.31-3.27 (m, 2H), 2.60 (s, 3H), 0.87-0.83 (m, 2H), 0.00 (s, 9H).

Step B: 4-Br0m0methyl((2-(trimethylsilyl)eth0xy)methyl)-1H-indolecarb0xylic acid Br Br \ \ N N \ \ sEM 8EM MeO O HO 0 To a solution of methyl 4-bromomethyl((2-(trimethylsilyl)ethoxy)methyl)-1H—indole carboxylate (0.6 g, 1.5 mmol) in MeOH (3 mL), THF (6 mL) and water (3 mL), LiOH (0.361 g, 15.1 mmol) was added and the reaction mixture was heated to about 45 0C for about 3 h. The reaction mixture was adjusted to pH < 3 by the addition of 1N HCl, then extracted with EtOAc (300 mL X 3), and the organic phase was concentrated under reduced pressure to provide 4-br0m0methyl((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-7—carb0xylic acid (0.5 g, 86%) as a solid: 1H NMR (DMSO- d6) 8 13.32 (s, 1H), 7.53-7.42 (m, 2H), 6.56 (s, 1H), 5.86 (s, 2H), 3.36-3.32 (m, 2H), 2.63 (s, 3H), 0.90-0.82 (m, 2H), 0.00 (s, 9H).

Step C: 4-Br0m0methyl((2-(trimethylsilyl)eth0xy)methyl)-1H-indolecarb0xamide Br Br \ \ N N ‘s EM 8EM HO 0 H2N 0 To a solution of 4-bromomethyl((2-(trimethylsilyl)ethoxy)methyl)-1H—indole-7—carboxylic acid (0.5 g, 1.30 mmol) in THF (10 mL) and DCM (12 mL), HOBt (0.299 g, 1.95 mmol) and EDCI (0.374 g, 1.95 mmol) were added at about 0 OC. Then the reaction e was stirred for about 1 hour at rt, then bubbled with NH3 gas for about 20 min, and stirring continued overnight at rt. Aqueous NaHCO3 was added and the mixture was extracted with EtOAc (200 mL X 3), and the organic phase was dried over Na2S04, trated under reduced pressure to provide 4-br0m0methyl((2- (trimethylsilyl)ethoxy)methyl)-1H-indolecarb0xamide (0.45 g, 90%) as a solid: 1H NMR (DMSO- d6) 8 8.10 (s, 1H), 7.67 (s, 1H), 7.36-7.34 (d, J: 8, 1H), 7.20-7.18 (d, J: 8, 1H), 6.46 (s, 1H), 5.74 (s, 2H), 3.46-3.38 (m, 2H), 2.56 (s, 3H), 0.90-0.83 (m, 2H), 0.00 (s, 9H).

Step D: 4-Br0m0methyl-1H-indolecarb0xamide Br Br N\ IZ H2N o H2N 0 To a solution of 4-bromomethyl((2-(trimethylsilyl)ethoxy)methyl)-1H—indolecarboxamide (350 mg, 0.913 mmol) in THF (15 mL) was added TBAF (2.4 g, 9.13 mmol) and ethane-1,2-diamine (1.1 g, 18.3 mmol). The e was refluxed ght. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column to provide 4-br0m0 -IH-indolecarb0xamide (180 mg, 78%) as a solid: 1H NMR (DMSO-d6) 5 11.18 (s, 1H), 8.05 (s, 1H), 7.48-7.42 (m, 2H), 7.20-7.18 (d, J: 8, 1H), 6.14 (s, 1H), 2.41 (s, 3H).

Step E: 4-(3-Amin0phenyl)methyl-1H-indolecarb0xamide ONH2 -314— To a solution of 4-bromomethyl-1H-indolecarboxamide (180 mg, 0.711 mmol) in THF (8 mL) and water (4 mL) and MeOH (4 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)aniline (187 mg, 0.853 mmol), Pd(dppi)C12 (104 mg, 0.142 mmol) and Na2C03 (226 mg, 2.13 mmol), and the solution was heated at about 90 0C for about 2 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column to e 4-(3-amin0phenyl)- Z-methyl-IH-indolecarb0xamide (80 mg, 42%) as a solid: 1H NMR (MeOD) 5 10.92 (s, 1H), 7.99 (s, 1H), 7.66-7.63 (d, J: 12, 2H), 7.61 (s, 1H), 7.13-7.09 (m, 1H), 6.99-6.97 (d, J: 8, 1H), 6.88 (s, 1H), 6.78-6.73 (m, 2H), 6.58-6.56 (d, J: 8, 1H), 6.29 (s, 1H), 2.42 (s, 3H).

Step F: 4-(3-Acrylamid0phenyl)methyl-1H-indolecarb0xamide 0NH2 0 NWo O \ —’ O \ N fl H H2N o H2N 0 To a on of 4-(3-aminophenyl)methyl-1H—indolecarboxamide (80 mg, 0.302 mmol) in DCM (6 mL), acryloyl chloride (40.9 mg, 0.452 mmol) and DIEA (0.105 mL, 0.603 mmol) were added at about 0 OC. The mixture was stirred for about 1 hour at rt. The on mixture was concentrated under reduced pressure and the residue was ed by prep-HPLC (Table 1, Method an) to give 4-(3-acrylamid0phenyl)methyl-1H-indolecarb0xamide (10 mg, 11%) as a solid: LC/MS (Table 1, Method j) R = 2.07 min; MS m/z: 320 (M+H)+. (Btk IC50 = A) Example #20: 4-(3-Acrylamid0phenyl)ethyl-1H-indolecarb0xamide \ | H2N o H2N 0 To a solution of 4-bromoiodo((2-(trimethylsilyl)ethoxy)methyl)-1H—indolecarboxamide ((1.5 g, 3.03 mmol, Preparation #24) in THF (20 mL), TBAF (15.84 g, 60.6 mmol) and ethane-1,2-diamine (1.82 g, 30.3 mmol) were added, and the solution was heated at reflux overnight. The solution was concentrated under reduced pressure and water (30 mL) and EtOAc (30 mL) were added, and the organic phase was dried and concentrated under d pressure. The residue was purified by column chromatography (Pet ether:EtOAc = 10: 1 to 1:1) to provide 4-br0m0i0d0-IH-indole carboxamide (700 mg, 63%): LC/MS (Table 1, Method k) R = 1.91 min; MS m/Z: 367 (M+H)+.

Step B: 4-Br0m0vinyl-1H-indolecarb0xamide \ —>| H2N 0 H2N O To a solution of 4-bromoiodo-1H—indolecarboxamide (0.630 g, 1.726 mmol) in 1.4-dioxane (4.5 mL) and water (0.5 mL), CsF (0.787 g, 5.18 mmol), Pd(PPh3)2C12 (0.242 g, 0.345 mmol) and potassium trifluoro(Vinyl)borate (254 mg, 1.899 mmol) were added. The reaction mixture was heated to about 90 0C for about 2 h under N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was ed by column chromatography to e 4-br0m0vinyl-IH- indole-7—carb0xamide (0.140 g, 31%): 1H NMR (CDCl3) 8 10.36 (s, 1H), 72-712 (m, 2H), 6.72- 6.65 (m, 1H) = 17.6, 1H), 5.33 (d, J = 10.8, 1H). , 6.50 (s, 1H), 6.25-5.78 (m, 2H), 5.69 (d, J Step C: 4-(3-Amin0phenyl)vinyl-1H-indolecarb0xamide 0NH2 Br \ / N \ / H2N o H H2N 0 To a solution of oVinyl-1H—indolecarboxamide (0.12 g, 0.45 mmol) in THF (10 mL), water (5 mL) and MeOH (5 mL), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (119 mg, 0.543 mmol), PdC12(dppf) (66.2 mg, 0.091 mmol) and Na2C03 (144 mg, 1.358 mmol) were added.

The reaction mixture was heated at about 90 0C for about 2 h. The mixture was concentrated under reduced pressure and the residue was ed by column chromatography on silica gel to provide 4- (3-amin0phenyl)vinyl-1H-indolecarb0xamide (80 mg, 75%): LC/MS (Table 1, Method l) R = 1.06 min; MS m/Z: 278 (M+H)+.

Step C: 4-(3-Amin0phenyl)ethyl-1H-indolecarb0xamide ONHZ ONHZ O\ / —> O\N N H H H2N o H2N 0 To a solution of 4-(3-aminophenyl)vinyl-1H-indolecarboxamide (46 mg, 0.116 mmol) in THF (10 mL), Pd/C (10 mg, 0.094 mmol) was added. The mixture was stirred for about 1.5 h at rt. The mixture was filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure to e 4-(3-amin0phenyl)ethyl-IH—indolecarb0xamide (40 mg, 70%), which was used to next step directly: LC/MS (Table 1, Method l) R = 1.21 min; MS Hill: 280 (M+H)+.

Step D: 4-(3-Acrylamid0phenyl)ethyl-1H-indolecarb0xamide ONH2 H 0 wo O \ O \ H2" 0 H2N 0 To a on of 4-(3-aminophenyl)ethyl-1H-indolecarboxamide (20 mg, 0.072 mmol) in DCM (15 mL), TEA (29 mg, 0.288 mmol) and acryloyl chloride (13.05 mg, 0.144 mmol) were added at about 0 OC. The on was stirred overnight at rt. The solution was concentrated under d pressure, and the residue was purified by pre-HPLC (Table 1, Method am) to provide 4-(3- acrylamidophenyl)ethyl-1H—indolecarb0xamide (9 mg, 38%): LC/MS (Table 1, Method d) R = 2.91 min; MS m/z: 334 (M+H)+. (Btk IC50 = A) Example #21: 4-(3-Amin0methylphenyl)(4,4-diflu0r0cyclohexenyl)-1H-indole carboxamide HZNO "\FN F H2NO WO 10255 Step A: 4-Bromo(4,4-difluor0cyclohexenyl)-1H-indolecarb0xamide Br Br A mixture of 2-(4,4-difluorocyclohexenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.267 g, 1.09 mmol, Syngene), 4-bromoiodo-1H-indolecarboxamide (0.363 g, 0.995 mmol, Preparation #1), Na2C03 (0.316 g, 2.98 mmol) in THF (7 mL), MeOH (0.98 mL), and water (0.98 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.073 g, 0.099 mmol). The mixture was bubbled with nitrogen and the vessel was sealed and heated at about 80 0C for about 4 h. The reaction was cooled to rt, filtered h Celite® and concentrated under reduced pressure. The residue was purified by silica gel column with EtOAc/hexanes (30-100%) to provide crude product which was further ed by silica gel column eluting with a gradent of 30-70% EtOAc/hexanes to provide 4-br0m0(4,4-diflu0r0cyclohex-I-enyl)-IH-indole-7—carb0xamide (0.25 g, 71%): LC/MS (Table 1, Method f) R = 1.82 min; MS m/Z: 357 (M+H)+.

Step B: 4-(3-Amin0methylphenyl)(4,4-diflu0r0cyclohexenyl)-1H-indolecarb0xamide HZN O o\ oF o H2N o H2N o A mixture of 4-bromo(4,4-difluorocyclohexenyl)-1H-indolecarboxamide (0.48 g, 0.622 mmol), 2-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (0.203 g, 0.870 mmol, Combi-Blocks), Na2C03 (0.198 g, 1.865 mmol) and [1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.045 g, 0.062 mmol) in THF (5 mL), MeOH (0.700 mL), and water (0.700 mL) was stirred at about 70 0C for about 16 h under a nitrogen atmosphere. The e was filtered through ® and concentrated under reduced pressure. The residue was passed through a silica gel column with EtOAc/heptane (50-75%) to provide the crude product. The crude product was triturated with DCM (2 x with sonication for about 5 min), filtered, washed with DCM and dried under reduced pressure to provide 4-(3-amin0methylphenyl)(4,4- difluorocyclohex-I-enyl)-1H—indolecarb0xamide (134 mg, 57%): LC/MS (Table 1, Method f) R = 1.36 min; MS m/z: 382 (M+H)+. (Btk IC50 = A) Example #22: 4-(3—Acrylamid0phenyl)(2-eth0xyethyl)-1H-ind01ecarb0xamide O OEt H2N 0 Step A: (E)Br0m0(2-eth0xyvinyl)((2-(trimethylsilyl)eth0xy)methyl)-1H-indole carboxamide / OEt \ | —> N\ SEM SEM H2N o H2N 0 Five reaction vessels were charged with a solution of 4-bromoiodo((2- (trimethylsilyl)ethoxy)methyl)-1H-indolecarboxamide (1 g, 2.02 mmol, ation #24) in e (100 mL) was added (E)-tributyl(2-ethoxyvinyl)stannane (1.09 g, 3.03 mmol), Pd(PPh3)2C12 (0.142 g, 0.202 mmol) and LiCl (0.428 g, 10.1 mmol). The mixtures were heated at about 90 OC overnight under N2 atmosphere. All five reaction mixtures were combined, concentrated under reduced pressure, and the residue was purified by silica gel column to provide (E)br0m0(2-eth0xyvinyl)- I -((2-(trimethylsilyl)ethoxy)methyl)-1H-indolecarb0xamide (2 g, 45%) as a yellow solid: 1H NMR (DMSO-d6) 8 8.11 (s, 1H), 7.69 (s, 1H), 7.37-7.35 (d, J = 8, 1H), 7.17-7.15 (d, J = 8, 1H), 6.96 (s, 1H), 6.78-6.76 (d, J = 8, 1H), 5.80-5.78 (d, J = 8, 2H), 5.69-5.68 (d, J = 4, 1H), 4.24-4.08 (m, 2H), 3.42-3.36 (m, 2H), 1.43-1.34 (m, 3H), 0.86-0.82 (m, 2H), 0.00 (s, 9H).

Step B: (E)(3-Amin0phenyl)(2-eth0xyvinyl)((2-(trimethylsilyl)eth0xy)methyl)-1H- indolecarb0xamide Br 0 H2N 0 To a solution of (E)bromo(2-ethoxyvinyl)((2-(trimethylsilyl)ethoxy)methyl)-1H—indole-7— carboxamide (1.5 g, 3.41 mmol) in THF (20 mL), water (10 mL) and MeOH (10 mL) was added 3- ,5-tetramethyl-1,3,2-dioxaborolanyl)aniline (0.897 g, 4.10 mmol), Pd(dppf)C12 (0.5 g, 0.683 mmol) and Na2C03 (1.085 g, 10.24 mmol). The solution was heated at about 90 0C for about 2 h.

The reaction mixture was concentrated under d pressure and purified by silica gel column to provide (E)(3-amin0phenyl)(Z-ethoxyvinyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7— carboxamide (0.80 g, 52%): 1H NMR (DMSO-d6) 8 8.06 (s, 1H), 7.62 (s, 1H), 7.30-7.22 (m, 2H), 7.15 (s, 1H), 7.10-7.08 (d, J: 8, 1H), 6.93 (s, 1H), 6.83-6.81 (d, J: 8, 1H), 6.68-6.65 (m, 2H), 5.82- .80 (d, J: 8, 2H), 5.67-5.66 (d, J: 4, 1H), 5.28 (s, 2H), .06 (m, 2H), 3.43-3.37 (m, 2H), 1.39- 1.33 (m, 3H), 0.86-0.82 (m, 2H), 0.00 (s, 9H).

Step C: 4-(3-Aminophenyl)(2-eth0xyethyl)((2-(trimethylsilyl)eth0xy)methyl)-1H-indole carboxamide O\ /OEt—> O\ OEt N N H2N o NH2 0 Two on vessels were charged with a solution of (E)(3-aminophenyl)(2-ethoxyvinyl)((2- thylsilyl)ethoxy)methyl)-1H-indolecarboxamide (400 mg, 0.886 mmol) in MeOH (60 mL), and Pd/C (400 mg, 10%). The es were stirred for about 1 h at rt under H2 (14 psi) atmosphere.

The two reaction mixtures were combined, filtered and concentrated under reduced pressure to provide 4-(3-amin0phenyl)(Z-ethoxyethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7— carboxamide (600 mg, 75%) as a solid, which was used directly for the next step: 1H NMR (DMSO- d6) 8 8.05 (s, 1H), 7.61 (s, 1H), 7.32-7.31 (d, J: 4, 1H), 7.23-7.09 (m, 2H), 6.90 (s, 1H), 6.81-6.79 (d, J: 8, 1H), 6.68-6.66 (d, J: 8, 1H), 6.58 (s, 1H), 5.78 (s, 2H), 5.26 (s, 2H), 3.79-3.76 (m, 2H), 3.55- 3.52 (m, 2H), 3.45-3.41 (m, 2H), 3.15-3.12 (m, 2H), 1.26-1.15 (m, 3H), 0.87-0.83 (m, 2H), 0.01 (s, 9H).

Step D: 4-(3-Amin0phenyl)(2-eth0xyethyl)-1H-indolecarb0xamide O NH2 0NH2 0 \ OEt O \ OEt N N NH2 0 H2N 0 To a solution of 4-(3-aminophenyl)(2-ethoxyethyl)((2-(trimethylsilyl)ethoxy)methyl)-1H- indolecarboxamide (500 mg, 1.10 mmol) in THF (20 mL) was added TBAF (2.88 g, 11.0 mmol) and -1,2-diamine (1.33 g, 22.0 mmol). The mixture was stirred for about 5 h at about 80 OC.

The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column to provide 4-(3-amin0phenyl)(2-eth0xyethyl)-1H-indolecarb0xamide (267 mg, 75%) as a solid: 1H NMR d6) 8 11.09 (s, 1H), 8.12 (s, 1H), 7.76-7.74 (d, J = 8, 1H), 7.46-7.44 (d, J: 8, 1H), 7.24-7.19 (m, 1H), 7.09-7.07 (d, J = 8, 1H), 6.96 (s, 1H), 6.87-6.85 (d, J = 8, 1H), 6.67- 6.66 (d, J = 4, 1H), 6.45 (s, 1H), 5.25 (s, 2H), 3.76-3.73 (m, 2H), 3.59—3.54 (m, 2H), 3.13—3.09 (m, 2H), 1.27—1.23 (m, 3H).

Step E: crylamid0phenyl)(2-eth0xyethyl)-1H-indolecarb0xamide N ONH2 0 10A\ 0 OEt —> \ O OEt N N H H NH2 0 NH2 0 Two reaction vessels were d with a solution of 4-(3-aminophenyl)(2-ethoxyethyl)-1H- indolecarboxamide (60 mg, 0.186 mmol) in DCM (2 mL). DIEA (0.065 mL, 0.371 mmol) and acryloyl chloride (25.2 mg, 0.278 mmol) were added and the mixtures were stirred for about 1 h at rt.

The two reaction mixtures were combined, concentrated under reduced pressure, and the residue was purified by prep-HPLC (Table 1, Method w) to provide 4-(3-acrylamid0phenyl)(2-eth0xyethyl)- IH-indole-7—carb0xamide (21.6 mg, 26.4%) as a solid: LC/MS (Table 1, Method d) R = 2.95 min; MS m/Z: 378 (M-H)". (Btk IC50 = A) Example #23: 4-(3-Acrylamid0phenyl)(2-hydr0xyethyl)-1H-indolecarb0xamide 0N7AO C OH H2N 0 Step A: min0phenyl)(2-hydr0xyethyl)-1H-indolecarb0xamide O \ OEt —> OH N O \ N H H H2N o H2N 0 Two reaction vessels were charged with a solution of minophenyl)(2-ethoxyethyl)-1H- carboxamide (100 mg, 0.309 mmol, Example #22, Step D) in DCM (10 mL) was added dropwise tribromoborane (387 mg, 1.55 mol) at about -78 OC. The mixtures were stirred for about 2 h at about 0 OC. The two reaction mixtures were combined and aqueous NaHCO3 was added and the mixture was extracted with DCM (100 mL X 3). The organic phase was dried over Na2S04, concentrated under reduced pressure to give 4-(3-amin0phenyl)(2-hydr0xyethyl)-IH-indole carboxamide (160 mg, 88%) as a yellow solid: 1H NMR (DMSO-d6) 8 10.96 (s, 1H), 8.04 (s, 1H), 7.67-7.65 (d, J: 8, 1H), 7.38-7.34 (d, J: 16, 1H), 7.16-7.12 (m, 1H), .99 (d, J: 8, 1H), 6.91 (s, 1H), 6.81-6.80 (d, J = 4, 1H), 6.62-6.59 (d, J = 12, 1H), 6.36 (s, 1H), 5.33 (s, 2H), 4.87 (s, 1H), .70 (m, 2H), 2.96-2.93 (m, 2H).

Step B: 4-(3-Amin0phenyl)(2-hydr0xyethyl)-1H-indolecarb0xamide NH2 "W H2N o H2N 0 To a solution of 4-(3-aminophenyl)(2-hydroxyethyl)-1H—indole-7—carboxamide (40 mg, 0.135 mmol) in pyridine (4 mL) was added EDCI (31 mg, 0.163 mmol) and acrylic acid (9.8 mg, 0.135 mmol). The mixture was stirred for about 3 h at about 110 OC. The reaction mixture was concentrated under reduced pressure and the residue was ed by prep-HPLC (Table 1, Method al) to provide 4-(3-acrylamid0phenyl)(2-hydr0xyethyl)-1H-indolecarb0xamide (4.5 mg, 10%) as a solid: LC/MS (Table 1, Method j) R, = 2.46 min; MS Hill: 350 (M+H)+. (Btk IC50 = A) Example #24: 4-((1-Acryloylazetidinyl)(methyl)amino)-1H-indolecarb0xamide VLNAN/ H2N 0 Step A: tert-Butyl- 3-((7-cyan0-1H-ind01yl)amino)azetidine-l-carboxylate Br >LO N X041!" @ _> \:\\NH \lNHz M \ CN IZ In a 4 mL reaction Vial, 4-bromo-1H—indolecarbonitrile (200 mg, 0.905 mmol, Sinova), chloro[2- (dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl][2-(2-amino- ethyl)phenyl]palladium(II) (9.03 mg, 0.011 mmol), and dicyclohexyl(2',4',6'-triisopropyl-3,6- dimethoxy-[1,1'-biphenyl]yl)phosphine (6.07 mg, 0.011 mmol) were added. The solid mixture was evacuated and backfilled with nitrogen. Lithium bis(trimethylsilyl)amide (2.17 mL, 2.17 mmol) was added ed by tert-butylaminoazetidinecarboxylate (170 pl, 1.09 mmol). The reaction mixture was heated at about 65 0C for about 2.5 h. The reaction mixture was quenched with a few drops of 1N HCl and d with EtOAc (10 mL). The EtOAc layer was washed with a saturated aqueous solution of NaHCO3 and dried over MgSO4, filtered and concentrated under vacuum. The crude al was purified Via flash chromatography, using a gradient of 5-40% EtOAc in heptane to give tert-butyl((7-cyan0-1H—indolyl)amin0)azetidine-I -carb0xylate (160 mg, 57%); LC/MS (Table 1, Method as) R,= 2.13 min.; MS m/z 311 (M-H).

Step B: tert-Butyl (tert-butoxycarbonyl)azetidinyl)amino)cyan0-1H-indole carboxylate B0C \ B\ocN \ N N CN #0 H 0 CN )V In a 100 mL round-bottomed flask, tert-butyl 3-((7-cyano-1H-indolyl)amino)azetidine carboxylate (200 mg, 0.640 mmol) in MeCN (5 mL) was added to give a brown solution. DMAP (15.6 mg, 0.128 mmol) and BOCZO (419 mg, 1.92 mmol) were added. Reaction mixture was stirred for about 18 h at rt. Reaction mixture was diluted with water (2 mL) and EtOAC (3 mL). The entire suspension was filtered and washed with EtOAc (5 mL). The white itate ted was dried in a vacuum oven at about 70 0C for about 2 h to give tert-Butyl 4-((1-(tert-but0xycarbonyl)azetidin yl)amin0)cyan0-1H—indolecarb0xylate (154 mg, 58.3%). LC/MS (Table 1, Method as) R, = 2.54 min.; MS m/z: 411 (M-H)".

Step C: tert-Butyl((1-(tert-but0xycarb0nyl)azetidinyl)(methyl)amino)cyan0-1H-indole carboxylate Boc\N\j\ BOC\ CN 0 CN 0 In a 4 mL reaction vial, sodium hydride (23.9 mg, 0.598 mmol, 60% disp in mineral oil) in DMF (1 mL) was added to give a white suspension. Reaction mixture was cooled to about 0 OC and tert-butyl 4-((1-(tert-butoxycarbonyl)azetidinyl)amino)cyano-1H-indolecarboxylate (145 mg, 0.352 mmol) was added as a solution in DMF (4 mL). After about 30 min, iodomethane (33 ul, 0.528 mmol) was added. Stirring was continued at 0 0C for about 1 h. The reaction was quenched with water (15 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO4, filtered and concentrated. The material was purified Via flash chromatography using a gradient of 0-25% EtOAc/heptane over 5 min, then held at 25% EtOAc/heptane for 5 min, to give crude tert-Butyl(U - butoxycarbonyl)azetidinyl)(methyl)amino)-7—cyan0-IH—indole-I -carb0xylate (148 mg, 71.1%); LC/MS (Table 1, Method as) R,= 2.71 min.; MS m/z: 427 (M+H).

Step D: tert-Butyl 3-((7-carbam0yl-1H-ind01yl)(methyl)amino)azetidine-l-carb0xylate To a solution of tert-butyl 4-((1-(tert-butoxycarbonyl)azetidinyl)(methyl)amino)cyano-1H- indolecarboxylate (148 mg, 0.250 mmol) in ethanol (2 mL)/DMSO (0.500 mL) was added hydrogen peroxide (0.515 mL, 5.04 mmol) and NaOH (1M, 0.515 mL, 0.515 mmol). The reaction mixture was stirred at rt for about 2 h. To the reaction mixture was added water (5 mL) and the precipitate was collected Via filtration, washed with water (5 mL) and dried in a vacuum oven at about 70 0C for about 2 h to give tert-Butyl 3-((7-carbam0yl-IH—indolyl)(methyl)amino)azetidine-I - carboxylate (60 mg, 52%); LC/MS (Table 1, Method as) R, = 1.97 min.; MS m/z: 345 (M+H)+.

Step E: 4-(Azetidin—3-yl(methyl)amino)-1H-indolecarb0xamide \ LNXO HZN o In a 4 mL reaction Vial, tert-butyl carbamoyl-1H-indolyl)(methyl)amino)azetidine carboxylate (60mg, 0.129 mmol) in oxane (2 mL) was added to give an off-white solution. 4M HCl in e (0.129 mL, 0.516 mmol) was added. Reaction was d at rt for about 2 h. It was the warmed to about 50 0C for about 2 h. Additional 4M HCl in dioxane (0.129 mL, 0.516 mmol) was added and stirring was continued at about 50 0C for about 45 min. Reaction mixture was filtered and -324— washed with DCM to give a precipitate. The precipitate was dissolved in water (2 mL) and basified with a few drops of 5N aqueous NaOH solution. The aqueous layer was then extracted with DCM (2 x 7 mL) and EtOAC (2 x 8 mL). The organic layers were combined and dried over MgSO4, filtered and concentrated to give 4-(azetidin-S-yl(methyl)amino)-IH-indolecarb0xamide (29 mg, 66%); LC/MS (Table 1, Method as) R,= n.; MS m/z: 245 (M+H)+.

Step F: 4-((1-Acryloylazetidinyl)(methyl)amino)-1H-ind01ecarb0xamide \N/C/NH A flask was d with 4-(azetidinyl(methyl)amino)-lH-indolecarboxamide (28mg, 0.083 mmol) and N—ethyl-N—isopropylpropanamine (65 ul, 0.373 mmol) in DCM (5 mL). The mixture was cooled to 0 0C on an ice-bath. Acryloyl chloride (7.38 ul, 0.091 mmol) was added and the mixture stirred to about 20 min. Reaction mixture was concentrated. The material was ed via flash chromatography using a gradient of 1.0 - 3.3% MeOH/DCM over 7 min then held at 3.3% for 5 min to give 4-((I -Acryloylazetidinyl)(methyl)amino)-1H—indole-7—carb0xamide (10.5 mg, 43%); LC/MS (Table 1, Method a) R, = 1.31 min.; MS m/z: 299 (M+H) +. (Btk IC50 = A) Example #25 : 4-(1-Acryloylpiperidinyl)-1H-ind01ecarb0xamide H2N 0 Step A: tert-Butyl 3-(7-carbam0yl-1H-indolyl)-5,6-dihydr0pyridine-1(2H)-carb0xylate ,Boc ,B\ N \ O O H 9 Q N H2N O H H2N O A 20 mL Vial was charged with 4-bromo-lH-indolecarboxamide (300 mg, 1.255 mmol), tert-butyl 3-(4,4,5 ,5-tetramethyl- l ,3 xaborolanyl)-5,6-dihydropyridine- l (2H)-carboxylate (466 mg, 1.506 mmol), is(diphenylphosphino)ferrocene)dichloropalladium (92 mg, 0.125 mmol) and sodium carbonate (399 mg, 3.76 mmol). To the solid mixture was added THF (6 mL):MeOH (0.840 2014/044247 mL):Water (0.840 mL). The suspension was sparged with nitrogen for about 5 min. The reaction mixture was heated at about 70 OC overnight. Reaction mixture was filtered over a pad of Celite®, concentrated and purified by silica gel column (30-60% EtOAc/heptane) to give tert-butyl 3-(7— carbamoyl-IH—indolyl)-5,6-dihydr0pyridine-I(2H)-carb0xylate (355 mg, 83%); LC/MS (Table 1, Method as) R, = n.; MS m/z: 340 .

Step B: tert-Butyl3-(7-carbam0yl-1H-ind01yl)piperidinecarb0xylate N,Boc N,Boc \ \ N N H H H2N O H2N O A flask was charged tert-butyl 3-(7-carbamoyl-1H-indolyl)-5,6-dihydropyridine-1(2H)-carboxylate (355 mg, 1.04 mmol) and palladium (55.3 mg, 0.520 mmol). Ethyl acetate (10 mL) was added under vacuum and the mixture was stirred under H2 balloon at rt for about 5 h. The reaction e was filtered over a pad of Celite® and washed with MeOH (20 mL) and EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give tert-Butyl 3-(7-carbamoyl-IH-indolyl)piperidine-I- carboxylate (357 mg, 100%); LC/MS (Table 1, Method as) R, = 2.14 min.; MS m/z: 342 (M-H)".

Step C: 4-(Piperidinyl)-1H-indolecarb0xamide N,Boc NH \ \ H N H2N o H2N O A flask was charged with ol (5 mL) and cooled to 0 OC. Acetyl chloride (0.828 mL, 11.6 mmol) was added drop wise, and the ice bath was removed. The mixture was stirred at rt for about 25 min. The solution was then added to tert-butyl 3-(7—carbamoyl-1H-indolyl)piperidine carboxylate (100 mg, 0.291 mmol) and the reaction mixture was stirred at rt for about 4 h. The mixture was concentrated under vacuum. The residue was dissolved in water (10 mL) and washed with EtOAc (7 mL). The aqueous layer was basified with a few of drops of 50% w/w NaOH solution and extracted with EtOAC (12 mL). The EtOAc layer was dried over MgSO4, filtered and concentrated to give 4-(Piperidinyl)-1H—indolecarb0xamide (40 mg, 56%); the material was used crude in the next step t further characterization.

Step D: cryloylpiperidinyl)-1H-indolecarb0xamide NH NM H2N o H2N o A flask was charged with 4-(piperidinyl)-1H-indolecarboxamide (40 mg, 0.164 mmol) and N- ethyl-N—isopropylpropanamine (43 uL, 0.247 mmol) in DCM (5 mL). The mixture was cooled to 0 OC. Acryloyl chloride (14.69 uL, 0.181 mmol) was added and the mixture stirred for about 20 min.

Reaction mixture was concentrated. The material was purified by silica gel column using a nt of 1.0 - 5.5% MeOH/CH2Cl2 over 10 min; to give cryloylpiperidin-S-yl)-1H—indole carboxamide (41 mg, 84%); LC/MS (Table 1, Method a) R, = 1.53min.; MS m/z: 298 (M+H)+. (Btk IC50 = B) Example #26: 4-(1-Acryloylpiperidin 3-yl)(1-methyl-1H-pyrazolyl)-1H-indole carboxamide H2N 0 Step A: tert-Butyl 3-(7-carbam0yl(1-methyl-1H-pyrazolyl)-1H-indolyl)-5,6- opyridine-l(2H)-carb0xylate ,Boc ,B00 Br \ N\ _, \ ,B\ N \ [T] o o H \ N N\ 9 Q H2N O H H2N O A 20 mL Vial was charged with 4-bromo(1-methyl-1H-pyrazolyl)-1H-indolecarboxamide (216 mg, 0.677 mmol, Preparation #10), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- ,6-dihydropyridine-1(2H)-carboxylate (251 mg, 0.812 mmol), (1,1- phenylphosphino)ferrocene)dichloropalladium(1:1) complex with DCM (55.3 mg, 0.068 mmol) and sodium carbonate (215 mg, 2.03 mmol). To the solid mixture was added THF (3 mL):MeOH (0.420 mL):Water (0.420 mL). The suspension was sparged with N2 for about 5 min. The reaction mixture was heated at about 70 OC overnight. Reaction mixture was filtered over a pad of celite, concentrated and was purified by silica gel column (0-2% MeOH/DCM) to give tert-butyl 3-(7— carbamoyl-Z-(I -methyl-1H-pyrazolyl)-IH-indolyl)-5, 6-dihydr0pyridine-I (2H)-carb0xylate (227 mg, 80%); LC/MS (Table 1, Method as) R, = 2.09 min.; MS m/z: 422 (M+H)+.

Step B: tert-butyl 3-(7-carbam0yl(1-methyl-1H-pyrazolyl)-1H-ind01yl)piperidine carboxylate N,Boc N,Boc N N\ N N\ H H H2N O H2N O A flask was charged with tert-butyl 3-(7-carbamoyl(l-methyl-lH-pyrazolyl)-lH—indolyl)- ,6-dihydropyridine-l(2H)-carboxylate (227 mg, 0.539 mmol) and 10% palladium on carbon (28.7 mg, 0.027 mmol). Ethyl acetate (5 mL) was added under vacuum and the mixture was stirred under H2 balloon at rt for about 5 h. The reaction mixture was filtered over a pad of Celite® and washed with MeOH (20 mL) and EtOAc (30 mL). The filtrate was trated under reduced pressure to give the title compound (177 mg, 78%); LC/MS (Method as) R, = 2.08 min.; MS m/z: 424 (M+H)+.

Step C: 2-(1-Methyl-1H-pyrazolyl)(piperidinyl)-1H-ind01ecarb0xamide N,Boc NH \ \N —’ \ \w \ N \ N N \ N \ H H H2N o H2N O A flask was charged with MeOH (2 mL) and cooled to 0 OC. Acetyl chloride (0.151 mL, 2.12 mmol) was added drop wise, and the ice bath was removed. The mixture was d at rt for about 25 min.

The solution was then added to tert-butyl 3-(7-carbamoyl(l-methyl-lH—pyrazolyl)-lH—indol eridine-l-carboxylate (30 mg, 0.071 mmol) and the reaction mixture was stirred at rt ght.

The mixture was concentrated under . The residue was dissolved in water (3 mL) and washed with DCM (3 mL). The aqueous layer was basified with a few drops of 5N NaOH to give a suspension, to which was added DCM. The DCM layer was separated. The aqueous layer formed a precipitate which was collected Via filtration and washed with a mixture of DCM/EtOAC/MeOH (1:1:1) (6 mL). This filtrate was combined with the DCM layer and concentrated under vacuum to give 2-(1-methyl-1H-pyrazolyl)(piperidinyl)-1H-indolecarb0xamide (18 mg, 79%); LC/MS (Table 1, Method as) R, = 1.03 min.; MS m/z: 324 (M+H)+.

Step D: 4-(1-Acryloylpiperidin 3-yl)(1-methyl-1H-pyrazolyl)-1H-indolecarb0xamide NH NM ‘ ' \N H "\ \ H2N o A flask was charged with ethyl-1H-pyrazolyl)(piperidinyl)-1H-indolecarboxamide (18mg, 0.056 mmol) and N—ethyl-N—isopropylpropanamine (0.044 mL, 0.250 mmol) in DCM (5 mL). The mixture was cooled to 0 0C on an ice-bath. Acryloyl chloride (4.97 ul, 0.061 mmol) was added and the mixture stirred for about 20 min. Reaction mixture was concentrated. The material was purified by silica gel column (2.0 - 6.5% MeOH/DCM) to give 4-(1-acryloylpiperidin 3-yl)(1- methyl-IH-pyrazolyl)-IH-indolecarb0xamide (9 mg, 43%); LC/MS (Table 1, Method a) R, = 1.56 min.; MS m/z: 378 . (Btk IC50 = A) Example #27: 4-((1-Acryloylazetidinyl)0xy)-1H-ind01ecarb0xamide Step A: tert-butyl 3-(4-br0m0nitrophenoxy)azetidine-l-carboxylate LNJkO OH O 4\ N02 N02 Br Br Cesium carbonate (2.038 g, 6.26 mmol) was added in DMF (12 mL) to give a white suspension. lar sieves (410%, 8-12 mesh, beads, 100 mg) 4-bromonitrophenol (1 g, 4.59 mmol) and tert- butyl 3-((methylsulfonyl)oxy)azetidinecarboxylate (1.048 g, 4.17 mmol) were added, and the mixture was heated at about 85 0C for about 18 h. The crude e was partitioned between EtOAc (50 mL) and saturated aqueous ammonium chloride solution (30 mL). The organic layer was washed by brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford tert-butyl 3-(4-br0m0- 3-nitr0phen0xy)azetidine-I-carb0xylate (0.799 g, 2.14 mmol, 46.7 % : LC/MS (Table 1, Method a) R = 2.62 min; MS m/z 373, 375 (M+H)+.

Step B: tert-butyl 3-((7-br0m0-1H—ind01—4-yl)0xy)azetidine-l-carboxylate O O Hi #1 N02 N Br Br A 100 mL round-bottom flask was degassed with nitrogen and cooled to about -700 C in a dry- ice/acetone bath. A solution of Vinylmagnesium bromide in THF (1.0 M, 21.59 mL, 21.59 mmol) was added into the flask. Then a solution of tert-butyl 3-(4-bromonitrophenoxy)azetidinecarboxylate (2.65 g, 5.40 mmol) in yl-THF (18 mL) was added dropwise over 8 min, the mixture was stirred at about -70 0C for about 1 h, and the reaction mixture was quenched by saturated aqueous ammonium chloride solution (22 mL) at about -60 OC. The resulting mixture was warmed to rt and EtOAc (50 mL) and water (40 mL) were added. The layers were ted, the aqueous layer was extracted with EtOAc (50 mL), the combined c layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford an orange oil, which was purified by silica gel chromatography eluting with a gradient of 0 to 40% EtOAc/heptane to afford tert-butyl 3-((7—br0m0- IH—indolyl)0xy)azetidine-I-carb0xylate (0.87 g, 2.37 mmol, 43.9 % yield): LC/MS (Table 1, Method a) R = 2.52 min; MS m/z 367, 369 (M+H)+.

Step C: tert-butyl 3-((7-cyan0-1H—ind01—4-yl)0xy)azetidine-l-carboxylate In a 20 mL microwave reaction Vial, tert-butyl 3-((7-bromo-1H-indolyl)oxy)azetidine carboxylate (0.8 g, 2.178 mmol), Zinc cyanide (0.512 g, 4.36 mmol) and DMF (12 mL) were added to give a yellow suspension. The Vial was degassed with en, tetrakis(triphenylphosphine)palladium(0) (0.755 g, 0.654 mmol) was added. The mixture was degassed with nitrogen, and then the on mixture was heated in a Biotage® microwave reactor at about 160 0C for about 30 min (2psi maximum pressure, 235 max watts). The resulting orange suspension was filtered through Celite®, washed with DMF (10 mL) and yl-THF (3x10 mL), the filtrate was concentrated in vacuo to remove most DMF, then it was partitioned between 2- methyl-THF (50 mL) and saturated aqueous ammonium chloride solution (50 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford an orange oil, which was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc/heptane to afford tert-butyl 3-((7-cyan0-1H—indolyl)0xy)azetidine-I - carboxylate (0.28 g, 0.894 mmol, 41.0 % yield): LC/MS (Table 1, Method a) R = 2.29 min; MS m/z 314 .

Step D: 4-((1-acryloylazetidinyl)0xy)-1H—ind01ecarb0xamide JK Jk 0L 4N o 0L 2%N 0 || H2N o A mixture of tert-butyl cyano-lH-indolyl)oxy)azetidine-l-carboxylate (0.28 g, 0.894 mmol) and potassium ate (0.309 g, 2.234 mmol) in DMSO (2.98 mL) was cooled to about 10 0C by ice-cold water bath, then hydrogen peroxide (0.091 ml, 0.894 mmol) was added dropwise. The on mixture was stirred at rt for about 18 h, hydrogen peroxide (0.023 mL, 0.225 mmol) was added. The reaction mixutre was stirred at rt for about an additional 9 h. Water (30 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the crude tert-butyl 3-((7— carbamoyl-IH—indolyl)0xy)azetidine-I-carb0xylate, which was used directly in the next step.

To a suspension of utyl 3-((7-carbamoyl-1H-indolyl)oxy)azetidinecarboxylate (0.27 g, 0.815 mmol) in MeOH (4.45 mL) was added hydrogen chloride (4.0 M in dioxane, 4.07 mL, 16.30 mmol) se, the mixture was stirred at rt for about 30 min, then the mixture was concentrated in vacuo to afford the crude 4-(azetidinyloxy)-1H-indolecarboxamide hydrochloride, which was used directly in the next step.

The suspension of tidinyloxy)-1H-indolecarboxamide hydrochloride (0.218 g, 0.815 mmol) in DCM (13.0 mL) was cooled to about -10 0C in an ice/sodium chloride bath, TEA (0.568 mL, 4.08 mmol) was added dropwise; then a solution of acryloyl de (0.075 mL, 0.897 mmol) in DCM (3.26 mL) was added dropwise Via syringe and the reaction mixture was stirred for about 30 min. The reaction mixture was concentrated in vacuo, the crude al was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH/DCM to afford acryloylazetidin )-1H—indolecarb0xamide (0.16 g, 0.555 mmol, 68.1 % yield): LC/MS (Table 1, Method a) R = 1.37 min; MS m/z 286 (M+H)+. (Btk IC50 = A) Example #28*: (S)(1-(1-Acryloylazetidinyl)ethyl)-1H-indolecarb0xamide and (R)(1- (1-acryloylazetidinyl)ethyl)-1H-ind01ecarb0xamide Step A: tert-butyl 3-(1-(((triflu0r0methyl)sulfonyl)0xy)vinyl)azetidine-l-carboxylate and tert- butyl 3-(1-(((trifluoromethyl)sulfonyl)0xy)ethylidene)azetidine-l-carb0xylate N/j2K o o F H |I,/o F\i/S\ ,S F // N \FK o N/j/§ #5 <7 —> Y 0 CY r $0 To a solution of diisopropylamine (0.646 mL, 4.57 mmol) in THF (3.8 mL) at about 0 0C was added a solution of n-butyllithium (2 M in hexanes) (2.28 mL, 4.57 mmol) dropwise (internal temperature maintained below about 3 0C). The reaction mixture was stirred at about 0 0C for about 30 min, and was cooled down to about -78 0C. A solution of tert-butyl 3-acetylazetidinecarboxylate (0.758 g, 3.81 mmol) in THF (7.6 mL) was added dropwise (keeping the internal temperature below about -70 0C), and reaction mixture was then stirred at about -78 0C for about 30 min. A solution of 1,1,1- trifluoro-N—phenyl-N—((trifluoromethyl)sulfonyl)methanesulfonamide (1.42 g, 4.00 mmol) in THF (7.6 mL) was added dropwise (keeping the internal temperature below about -70 0C). After addition, the mixture was allowed to warm to about 0 0C over about 4 h, and the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc ( 3 x 50 mL), trated and purified by silica gel chromatography eluting with a gradient of 0-15% EtOAc/heptane to afford a mixture of tert-butyl 3- (I -(((trifluoromethyl)sulfonyl)0xy)vinyl)azetidine-I -carb0xylate and tert-butyl 3-(1- (((trifluoromethyl)sulfonyl)0xy)ethylidene)azetidine-I-carb0xylate as a yellow oil (0.398 g, 31%):1H NMR (400 MHZ, CDCl3) tert-butyl 3-(1-(((trifluoromethyl)sulfonyl)0xy)vinyl)azetidine-I-carb0xylate: 8 5.32 (d, J: 4.2 Hz, 1H), 5.16 (dd, J: 4.2, 1.0 Hz, 1H), 4.15 (t, J: 8.8 Hz, 2H), 3.93 (dd, J: 8.8, 6.1 Hz, 2H), 3.49 — 3.37 (m, 1H), 1.44 (s, 9H); tert-butyl 3-(1- (((trifluoromethyl)sulfonyl)0xy)ethylidene)azetidine-I-carb0xylate: 8 4.58 — 4.53 (m, 2H), 4.52 — 4.49 (m, 2H), 1.98 — 1.94 (m, 3H), 1.45 (s, 9H) Step B: utyl 3-(1-(7-carbam0yl-1H-ind01yl)vinyl)azetidine-l-carb0xylate and tert-butyl 3-(1-(7-carbam0yl-1H-indolyl)ethylidene)azetidine-l-carboxylate OTf W 0\ ,O Boc OYN / o —> \fi + N \ \ OTf N N H2N o H H o N H2N O H2N o To a Vial charged with a mixture of tert-butyl 3-(1-(((trifluoromethyl)sulfonyl)oxy)Vinyl)azetidine carboxylate and tert-butyl 3-(1-(((trifluoromethyl)sulfonyl)oxy)ethylidene)azetidinecarboxylate (0.388 g, 1.17 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H—indolecarboxamide (0.279 g, 0.975 mmol) and sodium carbonate (0.31 g, 2.93 mmol) , Pd(dppf)C12 (0.043 g, 0.059 mmol) was added 1,4-dioxane (3 mL) and water (1 mL). The reaction e was evacuated and filled with nitrogen (repeated 3 times). The e was then heated at about 80 0C for about 1 h. The reaction mixture was concentrated and d with MeOH/DCM. The mixture was filtered and washed with MeOH/DCM and the filtrate was concentrated to dryness. The crude product was purified by silica gel chromatography eluting with a gradient of 0-3% MeOH/DCM to give a mixture of tert-butyl 3-(1- (7-carbamoyl-IH-indolyl)vinyl)azetidine-I-carb0xylate and tert-butyl 3-(1-(7-carbam0yl-IH-indol- thylidene)azetidine-I-carb0xylate (0.277 g, 83 %) as a yellow oil: LC/MS (Table 1, Method a) R, = 2.08, 2.13 min.; MS m/z: 340 (M-H)‘.

Step C: tert-butyl 3-(1-(7-carbam0yl-1H-ind01yl)ethyl)azetidine-l-carb0xylate ,BOC ,Boc N N,Boc N N N H H H H2N O H2N o H2N 0 To a flask charged with 10 wt% Pd/C (0.026 g, 0.024 mmol) was added a solution of tert-butyl 3-(l- (7-carbamoyl-lH-indolyl)Vinyl)azetidine-l-carboxylate and tert-butyl 3-(l-(7—carbamoyl-1H- indolyl)ethylidene)azetidine-l-carboxylate (0.26 g, 0.76 mmol) in EtOAc (10 mL) and about 2 drops of MeOH. The mixture was hydrogenated with a hydrogen balloon at about rt for about 2 h. The reaction e was filtered through a pad of Celite® and washed with EtOAc. The filtrate was trated to dryness to give tert-butyl 3-(1-(7-carbam0yl-IH-indolyl)ethyl)azetidine-I- carboxylate (0.212 g, 81 %) as a light yellow foam: LC/MS (Table 1, Method a ) R, = 2.08 min; MS m/z: 342 (M-H)".

Step D: (S)(1-(1-acryloylazetidinyl)ethyl)-1H-ind01ecarb0xamide and (R)(1-(1- ylazetidin—3-yl)ethyl)-1H-ind01ecarb0xamide , Boc , Boc , Boc N N a 1,, N IZ/ HN oH H2N O IZ/ 2 H2N O tert-Butyl 3-(l-(7-carbamoyl-lH-indolyl)ethyl)azetidine-l-carboxylate (0.17g, 0.495 mmol) was purified by preparative chiral HPLC (Table 2, Method 1) to give (S)(I -(I oylazetidin yl)ethyl)-IH—indolecarb0xamide (0.063 g, 37%) (R = 12.339 min, or = positive) and (R)(I-(I- acryloylazetidin-S-yl)ethyl)-1H—indole-7—carb0xamide (0.066 g, 39%) (R = 18.959 min, or = negative). —334— Step E.1: (S)(1-(1-acryloylazetidin—3-yl)ethyl)-1H-indolecarb0xamide N’BOC NH NM —> HCI —> \ \ N N N H H H H2N o H2N o H2N 0 To a Vial charged with (S)-tert-butyl 3-(1-(7-carbamoyl-1H-indolyl)ethyl)azetidinecarboxylate (0.063 g, 0.183 mmol) and MeOH (1 mL) was added hydrogen chloride (4 M in dioxane, 0.92 mL, 3.67 mol) at about rt. The mixture was stirred for about 30 min, then the mixture was concentrated in vacuo to afford the crude (S)-tert-butyl 3-(1-(7-carbamoyl-1H-indolyl)ethyl)azetidine ylate hydrochloride that was used without additional cation.

To a suspension of (S)(1-(azetidinyl)ethyl)-1H-indole-7—carboxamide hydrochloride (0.051, 0.183 mmol) in THF (2 mL) and DCM (1 mL) at about 0 0C was added N—ethyl-N—isopropylpropan amine (0.096 mL, 0.550 mmol) ed by acryloyl de (0.017 mL, 0.202 mmol). The mixture was stirred at about 0 0C for about 30 min. The mixture was quenched with MeOH, and the volatiles were removed under reduced pressure. The residue was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was concentrated, and the crude product was purified by silica gel chromatography g with a gradient of 0-5 % MeOH/DCM to afford (S)(1-(1- acryloylazetidin-S-yl)ethyl)-1H—indole-7—carb0xamide (0.039 g, 69.9 %) as a white solid: LC/MS (Table 1, Method a) R, = 1.50 min.; MS m/z: 298 (M+H)+. (Btk IC50 = B) Step E.2: (R)(1-(1-acryloylazetidin—3-yl)ethyl)-1H-indolecarb0xamide ,Boc NH NM —> HCI —> \ \ N N H H H2N O H2N 0 To a Vial charged with rt-butyl 3-(1-(7-carbamoyl-1H-indolyl)ethyl)azetidinecarboxylate (0.066 g, 0.192 mmol) and MeOH (1 mL) was added hydrogen chloride (4 M in dioxane, 0.96 mL, 3.84 mol) at about rt. The mixture was stirred at rt for about 1 h, then the mixture was concentrated in vacuo to afford the crude rt-butyl 3-(1-(7-carbamoyl-1H-indolyl)ethyl)azetidine carboxylate hydrochloride that was used without additional purification.

To a suspension of (R)(1-(azetidinyl)ethyl)-1H—indolecarboxamide hydrochloride (0.054 g, 0.192 mmol) in THF (2 mL) and DCM (1 mL) at about 0 0C was added N—ethyl-N—isopropylpropan amine (0.1 mL, 0.577 mmol) followed by dropwise on of acryloyl chloride (0.018 mL, 0.212 mmol). The mixture was stirred at about 0 0C for about 30 min. The mixture was quenched with MeOH, and the volatiles were removed under reduce pressure. The residue was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was concentrated, and the crude product was purified by silica gel chromatography eluting with a gradient of 0-5 % MeOH/DCM to afford (R) (I-(1-acryloylazetidinyl)ethyl)-IH-indolecarb0xamide (0.042 g, 73.2 %) as a white solid.

LC/MS (Table 1, Method a) R, = 1.50 min.; MS m/z: 298 (M+H)+. (Btk IC50 = A) Example #29: 4-((1-Acryloylazetidin—3-yl)(methyl)amino)-1H-pyrrolo[2,3-c]pyridine carboxamide Step A: 4-br0m0-lH-pyrrolo[2,3-c]pyridinecarb0nitrile Br Br |\\ —> |\\ N/N N/N H H To a solution of 4-bromo-1H—pyrrolo[2,3-c]pyridine [ChemTec] (10.4 g, 52.8 mmol) in DCM (66.0 mL) and DME (66.0 mL) was added 3-chlorobenzoperoxoic acid (21.29 g, 95 mmol, 77% by weight) in one portion and the mixture was allowed to stir for about 16 h. The c solvents were removed under reduced re, the solid triturated with DCM and the solid filtered to yield a mixture of both t and benzoic acid. The filtrate still contained additional product and it was concentrated further under reduced pressure to enable a second filtration. The combined filtercakes were dried and transferred to a 1 L round bottom flask containing a magnetic stir bar. MeCN (264 mL) and TEA (14.8 mL, 106 mmol) were added to give an ite slurry. Trimethylsilyl cyanide (24.64 mL, 185 mmol) was added in one portion Via syringe and the mixture was heated to reflux. After about 2 h of heating the e was allowed to cool to rt. The reaction was quenched by the on of 100 mL of 1 M NaOH, diluted with 100 mL of EtOAc, transferred to a tory funnel and further diluted with 100 mL of 1 M NaOH and 100 mL of EtOAc. The layers were separated and the aqueous phase was ted with EtOAc (3 x 150 mL). The combined c extracts were washed with at 1:1 mixture of brine and 1 M NaOH (2 x 50 mL), dried over Na2S04, filtered and the solvent was removed to afford 4-br0m0-1H-pyrrolo[2,3-c]pyridinecarb0nitrile as a brown-yellow solid (10.28 g, 80%). 1H NMR (400 MHZ, DMSO) 8 8.44 (s, 1H), 7.96 (d, J = 3.1 Hz, 1H), 6.71 (d, J = 3.1 Hz, 1H).

Step B: 4-br0m0-1H-pyrr010[2,3-c]pyridinecarb0xamide Br Br |\ \ —> |\ \ N/ N / N N H H M O NH2 To a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridinecarbonitrile (10.2 g, 45.9 mmol) in EtOH (104 mL) were added a 1 M aqueous solution of NaOH (115 mL, 115 mmol) and 30% hydrogen peroxide (80 mL, 781 mmol) and the reaction mixture was heated to about 45 OC and stirred for about 30 min.

The organic solvent was removed under reduced pressure. The mixture was diluted with 30 mL of water and filtered to afford 4-br0m0-1H—pyrrolo[2,3-c]pyridine-7—carb0xamide as a light yellow solid (9.87 g, 83%). LC/MS (Table 1, Method as) : R, = 1.81 min; MS m/z: 240, 242 (M+H)+.

Step C: tert-butyl carbam0yl-lH-pyrrolo[2,3-c]pyridinyl)(methyl)amino)azetidine carboxylate Br \N \ \ | \ —> | \ N / N / N N H H o NH2 0 NH2 4-Bromo-1H-pyrrolo[2,3-c]pyridinecarboxamide (580 mg, 2.416 mmol) was dissolved in 12 mL of anhydrous dioxane and dried for about 1 h over . The solution was then filtered into an oven- dried 75 mL re vessel and the drying agent washed using 3 mL of e. The solution was degassed using a stream of argon and tert-butyl 3-(methylamino)azetidinecarboxylate hydrochloride (0.969 g, 4.35 mmol, Synthonix) was added followed by chloro(2- dicyclohexylphosphino-2’,4’,6 ’-triisopropyl- 1 , 1 ’-biphenyl) [2-(2-aminoethyl)phenyl)]palladium(II) (0.089 g, 0.12 mmol) and X-Phos (0.057 g, 0.12 mmol). The mixture was degassed for about 10 min and LiHMDS (1 M in THF, 10.87 mL, 10.87 mmol) was added dropwise Via syringe, the Vial sealed and heated to about 90 0C for about 19 h. The reaction was cooled to rt and quenched by addition of s NaHCO3 (20 mL) and diluted with EtOAc (50 mL). Further dilution using water (10 mL) and brine (10 mL) led to te dissolution and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with 1:1 brine and aqueous NaHCO3 (20 mL), dried over Na2S04, filtered and the solvent was d under reduced pressure. The crude material was deposited onto silica and purified using a silica column (40 g), eluting with 0-5% of MeOH/DCM. The fractions containing product were concentrated under reduced pressure to afford tert-butyl 3-((7-carbam0yl-IH—pyrrolo[2,3-c]pyridinyl)(methyl)amin0)azetidine- I-carboxylate as a light-yellow solid (0.61 g, 69%). 1H NMR (400 MHZ, DMSO) 8 11.41 (bs, 1H), 7.90 (bs, 1H), 7.48 — 7.43 (m, 1H), 7.43 — 7.39 (m, 2H), 6.60 (dd, J = 3.1, 2.0 Hz, 1H), 4.61 — 4.51 (m, 1H), 4.23 — 4.14 (m, 2H), 3.86 (dd, J: 8.9, 5.2 Hz, 2H), 3.06 (s, 3H), 1.38 (s, 9H).

Step D: 4-(azetidinyl(methyl)amino)-lH-pyrrolo[2,3-c]pyridinecarboxamide hydrochloride ,Boc //:lN NH HCI N \ L | \ —> \ 1 \ N N / H H O NH2 0 NH2 To a 50 mL round bottom flask containing a magnetic stir bar and MeOH (1.97 mL) was added acetyl chloride (1307 ul, 18.38 mol) at about 0 OC Via syringe. After about 10 min, the mixture was warmed to rt and stirred for about 1 h. Then, a solution of tert-butyl 3-((7-carbamoyl-1H—pyrrolo[2,3- c]pyridinyl)(methyl)amino)azetidinecarboxylate (127 mg, 0.368 mmol) in MeOH (1970 uL) and DCM (657 uL) was added dropwise Via syringe and the reaction stirred for about 5 h at rt. The ts were removed under reduced pressure to afford 4-(azetidin-S-yl(methyl)amin0)-1H- o[2,3-c]pyridinecarb0xamide hydrochloride (128 mg, 99%) .LC/MS (Table 1, Method at) : R, = 0.93 min.; MS m/z: 246 (M+H)+.

HCI N" \NLNH \N/C/ \ \ | \ —> | \ N N / H H 0 NH2 0 NH2 Step E: acryloylazetidinyl)(methyl)amino)-1H-pyrrolo[2,3-c]pyridinecarboxamide To a cooled solution of the 4-(azetidinyl(methyl)amino)-1H—pyrrolo[2,3-c]pyridinecarboxamide hydrochloride (101 mg, 0.36 mL) in DCM (5760 uL) and ethyldiisopropylamine (258 uL, 1.440 mmol) was added a solution of acryloyl chloride (50 mg, 0.552 mmol) in DCM (1440 uL) dropwise Via e g the internal temperature at or below at -4 OC. The mixture was allowed to stir for min. The reaction was quenched by addition of 0.3 mL of water, the solvent volume reduced to 1.5 mL and the mixture loaded onto 4 g of silica. The material was purified using a 24 g silica column, 0- % MeOH/DCM. The fractions containing product were concentrated under reduced pressure to afford 4-((I -acryloylazetidinyl)(methyl)amin0)-1H-pyrrolo[2,3-c]pyridinecarb0xamide as a white solid (89 mg, 78%). 1H NMR (400 MHZ, DMSO) 8 11.43 (bs, 1H), 7.98 - 7.88 (m, 1H), 7.49 - 7.44 (m, 2H), 7.42 (s, 1H), 6.64 - 6.58 (m, 1H), 6.40 - 6.29 (m, 1H), 6.11 (dd, J = 17.0, 2.2 Hz, 1H), WO 10255 2014/044247 .68 (dd, J = 10.2, 2.2 Hz, 1H), 4.72 — 4.62 (m, 1H), 4.60 — 4.52 (m, 1H), 4.31 — 4.18 (m, 2H), 3.97 (dd, J = 10.5, 5.2 Hz, 1H), 3.08 (s, 3H); MS m: 300 (M+H)+. (Btk 1C50 = A) Example #30*: (R)(1-Acryloylpiperidinyl)-1H-indolecarboxamide and (S)(1- acryloylpiperidinyl)-1H-indolecarboxamide N N N HZN O H2N o H2N o A sample of 4-(1-acryloylpiperidinyl)-1H-indolecarboxamide (0.03 g, 0.10 mmol) was purified via preparative chiral HPLC (Table 2, Method 2) to give (R)(1-acryloylpiperidinyl)-IH-indole- 7-carb0xamide (0.012 g, 40%) (R = 17.14 min, or = positive) (Btk IC50 = B) and (S)(1- acryloylpiperidin-S-yl)-1H—indole-7—carb0xamide (0.013 g, 43%) (R = 20.46 min, or = negative) (Btk IC50 = A): LC/MS (Table 1, Method a) R, = 1.47 min.; MS m/z: 298 (M+H)+.

Table 3. Examples prepared from an acryloyl amide using chiral method: Table 2, Method 4 Rt min Example m/z ESI+ Btk Acryloyl amide Product (Table 1, # (M+H)+ IC50 Method) 4-(Azetidin \ LN yl)(methyl)amino) N hydrofuranyl)-1H- 5-1 1-37 (3X) 369 A \ O indolecarboxamide (Example #E.9.21) H o NH2 4-(Azetidin yl)(methyl)amino) LNM (tetrahydrofuranyl)-1H- \N indolecarboxamide 5.2 1.37 (ax) 369 A \ OO (Example #E.9.21) o NH2 Table 4. Examples prepared from an acryloyl amide using chiral method: Table 2, Method 15 Rt min Example m/z ESI+ Btk Acryloyl amide t (Table 1, # (M+H)+ ICso Method) 4-(1,4-Oxazepanyl)-1H- pyrrolo[2,3-c]pyridine-7— carboxamide (Prepared using L With ation #49 and 3.1 1.27 (as) 315 Pd(OH)2, G with HCl and E With acryloyl chloride) 4-(1,4-Oxazepanyl)-1H- pyrrolo[2,3-c]pyridine-7— carboxamide red using L With Preparation #49 and 3.2 1.26 (as) 315 Pd(OH)2, G with HCl and E With acryloyl chloride) Table 5. Examples prepared from an acryloyl amide using chiral method: Table 2, Method 16 R min e m/z ESI+ Btk yl amide Product (Table 1, # (M+H)+ ICso Method) 2-(1-Methyl-1H-pyrazol yl)(piperidinyl)-1H- indole-7—carboxamide hydrochloride (Prepared using A from Preparation # 10 With tert-butyl 5-(4,4,5,5- tetramethyl-1,3,2- 4.1 1.54 (ha) 378 dioxaborolanyl)-3,4- dihydropyridine- 1 (2H)- carboxylate [Anisyn], L With Pd/C, G With acetyl chloride, E With acryloyl chloride) —340— Rt min Example m/z ESI+ Btk Acryloyl amide Product (Table 1, (M+H)+ ICso Method) 2-(1-Methyl- 1H-pyrazol yl)(piperidinyl)- 1H- -7—carboxarnide hydrochloride (Prepared using A from Preparation #10 with tert-butyl 5-(4,4,5 ,5- tetramethyl-1,3,2- 4.2 1.58 (ha) 378 dioxaborolan-Z-yl)-3 ,4- opyridine- 1 (2H)- carboxylate [Anisyn], L with Pd/C, G with acetyl chloride, E with acryloyl chloride) -341—

Claims (2)

WE CLAIM :

1. (S)(1-acryloylpiperidinyl)-1H-indolecarboxamide.

2. A pharmaceutically acceptable salt of (S)(1-acryloylpiperidinyl)-1H-indole carboxamide. AbbVie Inc. By the eys for the Applicant SPRUSON & FERGUSON Per: 29624684