BR122018071494B1 - INDOL CARBOXAMIDE COMPOUND USEFUL AS KINASE INHIBITORS, ITS USE AND PHARMACEUTICAL COMPOSITION INCLUDING IT - Google Patents

Abstract

Described are compounds of Formula (I): (I) or a salt thereof, wherein: X is CR4 or N; R1, R2, R3, R4, and A are defined here. Also described are methods of using such compounds as Bruton's tyrosine kinase (Btk) inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or delaying the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

Description

CROSS-REFERENCE TO RELATED ORDERS

[001] This order claims the benefit of the Order of the U.S. Serial No. 62/068,225, filed on October 24, 2014, which is hereby incorporated in its entirety.

DESCRIPTION

[002] The present invention generally relates to indole carboxamide compounds useful as kinase inhibitors, including the modulation of Bruton's tyrosine kinase (Btk) and other Tec family kinases, such as Itk. Provided herein are indole carboxamide compounds, compositions comprising such compounds, and methods of their use. The invention also concerns pharmaceutical compositions containing at least one compound according to the invention, which are useful for the treatment of conditions related to kinase modulation and methods of inhibiting the activity of kinases, including Btk and other kinase kinases. Tec family, such as Itk, in a mammal.

[003] Protein kinases, the largest family of human enzymes, encompass well over 500 proteins. Btk is a member of the Tec family of tyrosine kinases, and is a regulator of early B cell development as well as mature B cell activation, signaling and survival.

[004] B cell signaling through the B cell receptor (BCR) leads to a wide range of biological outcomes, which in turn depends on the stage of B cell development. The magnitude and duration of BCR signals should be precisely regulated. Aberrant BCR-mediated signaling can cause dysregulated B cell activation and/or the formation of pathogenic autoantibodies, leading to multiple autoimmune and/or inflammatory diseases. Btk mutation in humans results in X-linked agammaglobulinemia (XLA). This disease is associated with impaired B-cell maturation, decreased immunoglobulin production, compromised T-cell-independent immune responses, and marked attenuation of the prolonged calcium signal in BCR stimulation.

[005] Evidence for the role of Btk in allergic disorders and/or autoimmune disease and/or inflammatory disease has been established in Btk-deficient mouse models. For example, in preclinical murine models of systemic lupus erythematosus (SLE) patterns, Btk deficiency has been shown to result in an enhanced improvement of disease progression. Furthermore, Btk-deficient mice are also resistant to developing collagen-induced arthritis and are less susceptible to staphylococcal-induced arthritis.

[006] A large body of evidence supports the role of B cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapeutics such as rituximab, designed to deplete B cells, represent an important method for the treatment of various autoimmune and/or inflammatory diseases. Because of Btk's role in B cell activation, Btk inhibitors may be useful as inhibitors of B cell mediated pathogenic activity (such as autoantibody production).

[007] Btk is also expressed in mast cells and monocytes and has been shown to be important for the function of these cells. For example, Btk deficiency in mice is associated with IgE-mediated mast cell activation (enhanced decrease in TNF-alpha and other inflammatory cytokine release), and Btk deficiency in humans is associated with greatly reduced TNF-alpha production by activated monocytes.

[008] Thus, inhibition of Btk activity may be useful for the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases including, but not limited to: SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and hot agglutinin diseases, Evans syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathies (eg, Guillain-Barre syndrome), pemphigus vulgaris, and asthma.

[009] In addition, Btk has been reported to play a role in controlling B-cell survival in certain B-cell cancers. For example, Btk has been shown to be important for the survival of BCR-positive B-cell acute lymphoblastic leukemia cells abl. Thus, inhibition of Btk activity may be useful for the treatment of B-cell lymphoma and leukemia.

[0010] In view of the numerous conditions that are contemplated to benefit from treatment involving the modulation of protein kinases, it is immediately evident that new compounds capable of modulating protein kinases such as Btk, and methods of using these compounds should provide substantial therapeutic benefits to a wide variety of patients.

[0011] U.S. Patents Us. 8,084,620 and 8,685,969 describe tricyclic carboxamide compounds useful as kinase inhibitors, including modulation of Btk and other Tec family kinases.

[0012] There still remains a need for compounds useful as Btk inhibitors. Applicants have discovered potent compounds that have activity as Btk inhibitors. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important for this utility.

SUMMARY OF THE INVENTION

[0013] The present invention provides indole carboxamide compounds, including salts, solvates, and prodrugs thereof, which are useful as Btk inhibitors and are useful for the treatment of proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases.

[0014] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof.

[0015] The present invention also provides a method of inhibiting Btk activity, comprising administering to a mammal in need thereof at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof.

[0016] The present invention also provides a method for treating allergic disorders and/or autoimmune and/or inflammatory diseases, comprising administering to a mammal in need thereof at least one of the compounds of Formula (I) or salts, sol- vates, and prodrugs thereof.

[0017] The present invention also provides a method for treating proliferative diseases, such as cancer, comprising administering to a mammal in need thereof at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof same.

[0018] The present invention also provides a method of treating a disease or disorder associated with Btk activity, the method comprising administering to a mammal in need thereof at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof.

[0019] The present invention also provides processes and intermediates for preparing the compounds of Formula (I) including salts, solvates, and prodrugs thereof.

[0020] The present invention also provides at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof, for use in therapy.

[0021] The present invention also provides the use of at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof, for the manufacture of a medicament for the treatment or prophylaxis of Btk-related conditions, such as proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases.

[0022] The present invention also provides the use of at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof, for the manufacture of a medicament for the treatment of cancer.

[0023] The compounds of Formula (I) and compositions comprising the compounds of Formula (I) can be used in the treatment, prevention, or cure of various Btk-related conditions. Pharmaceutical compositions comprising these compounds are useful in treating, preventing, or delaying the progression of diseases or disorders in a variety of therapeutic areas, such as proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases.

[0024] These and other aspects of the invention will be mentioned in expanded form as the description continues.

DETAILED DESCRIPTION

[0025] The first aspect of the present invention provides at least one compound of Formula (I):

[0026] or a salt thereof, wherein:

[0027] X is CR4 or N;

[0028] A is:

[0029] (i)

[0030] (ii)

[0031] (iii)

[0032] (iv)

[0033] (v)

[0034] (vi) -CHR8(pyridinyl) wherein each pyridinyl is replaced by R6 and R9;

[0035] Q1 is -NR7Q2, -CR10R10NR7Q2, -C(O)NR7(C1-4 alkyl substituted by zero or 1 R11), -CH=CH2, -CH=C(CN)S(O)2CH3, -S (O)2CH=CR10R10, -NR7(dichlorotriazinyl), -NR7(quinazolin-4-yl substituted with zero or 1 R11), 3-methylenepyrrolidin-2-on-1-yl, or a cyclic group selected from 1H-pyrrole -2(5H)-on-1-yl, isoindolin-1-on-2-yl, quinazolin-4(3H)-on-3-yl, and quinazoline-2,4(1H, 3H)-dion-3 -yl, each cyclic group substituted with zero to two substituents independently selected from F, Cl, -CH3, -CN, and -OCH3;

[0036] Q2 is -CN, -C(O)(C1-4 alkyl substituted by zero or 1 R11), -C(O)(C3-6 cycloalkyl substituted by zero or 1 R11), -C(O)( C5-6 cycloalkenyl), -C(O)CR10=CR10R10, -C(O)C(R10)=CHCH2N(CH3)2, -C(O)C=CR7, -C(O)C=C (C1-3 hydroxyalkyl), -C(O)CsC(phenyl), -C(O)CHCS(CH3)3, or -S(O)2CH=CHRIO;

[0037] R1 is H, -CH3, -CF3, or phenyl substituted by zero or 1 R12;

[0038] R2 is H, -CH3, cyclopropyl, or phenyl substituted by zero or 1 R12, provided that zero or one of R1 and R2 is phenyl substituted by zero or 1 R12;

[0039] R3 is H, F, Cl, I, -CN, or -CH3;

[0040] R4 is H, F, -OH, -O(C1-4 alkyl), -O(C1-4 alkyl)-O-(C1-2 alkyl), -O(CH2)1-3(phenyl) , -O(CH2)1-3(methoxyphenyl), or -O(CH2)1-3(morpholinyl);

[0041] R5 is H, F, Cl, or -CH3;

[0042] R6 is H, F, Cl, -CF3, or C1-3 alkoxy;

[0043] each R6a is independently H or F;

[0044] R7, at each occurrence, is independently H, C1-4 alkyl, or cyclopropyl;

[0045] R8 is H or C1-4 alkyl;

[0046] R9 is -CH=CH2, -CH=CHCH2N(CH3)2, -C=CH, or -C=CCH3;

[0047] Ri0, at each occurrence, is independently H or -CH3;

[0048] Rii is F, Cl, -CN, -CF3, or C1-3 alkoxy; It is

[0049] Ri2 is F, Cl, -CN, -CF3, or C1-3 alkoxy.

[0050] The second aspect of the present invention provides at least one compound of Formula (I) wherein X is CR4, having the structure of Formula (Ia):

[0051] or a salt thereof, wherein:

[0052] A is:

[0053] (i)

[0054] (ii)

[0055] (iii)

[0056] (iv)

[0057] (v)

[0058] (vi) -CHRε(pyridinyl) wherein each pyridinyl is replaced by R6 and R9;

[0059] Qi is -NR7Q2, -CR10R10NR7Q2, -C(O)NR7(C1-4 alkyl substituted with zero or 1 R11), -CH=C(CN)S(O)2CH3, -S(O)2CH =CRWRW, -NR7(dichlorotriazinyl), -NR7(quinazolin-4-yl substituted with zero or 1 R11), 3-methylenepyrrolidin-2-on-1-yl, or a cyclic group selected from 1H-pyrrole-2(5H )-on-1-yl, isoindolin-1-on-2-yl, quinazolin-4(3H)-on-3-yl, and quinazoline-2,4(1H, 3H)-dion-3-yl, each cyclic group substituted by zero to two substituents independently selected from F, Cl, -CH3, -CN, and -OCH3;

[0060] Q2 is -CN, -C(O)(C1-4 alkyl substituted by zero or 1 R11), -C(O)(C3-6 cycloalkyl substituted by zero or 1 R11), -C(O)( C5-6 cycloalkenyl), -C(O)CR10=CR10R10, -C(O)C(R10)=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(CI -3 hydroxyalkyl), -C(O)CsC(phenyl), -C(O)CHCS(CH3)3, or -S(O)2CH=CHRiO;

[0061] R1 is H, -CH3, -CF3, or phenyl substituted by zero or 1 R12;

[0062] R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12;

[0063] as long as zero or one of R1 and R2 is phenyl substituted by zero or 1 R12;

[0064] R3 is H, F, Cl, -CH3, or -CN;

[0065] R4 is H, F, -OH, -O(C1-4 alkyl), -O(C1-4 alkyl)-O-(C1-2 alkyl), -O(CH2)1-3(phenyl) , -O(CH2)1-3(methoxyphenyl), or -O(CH2)1-3(morpholinyl);

[0066] R5 is H, F, Cl, or -CH3;

[0067] R6 is H, F, Cl, -CF3, or C1-3 alkoxy;

[0068] R7, at each occurrence, is independently H, C1-4 alkyl, or cyclopropyl;

[0069] R8 is H or C1-4 alkyl;

[0070] R9 is -CH=CH2, -CH=CHCH2N(CH3)2, -C1CH, or -CHCCH3;

[0071] R10, at each occurrence, is independently H or -CH3;

[0072] R11 is F, Cl, -CN, -CF3, or C1-3 alkoxy; It is

[0073] Ri2 is F, Cl, -CN, -CF3, or C1-3 alkoxy.

[0074] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is CR4; and R1, R2, R3, R4, and A are defined in the first aspect.

[0075] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N; and R1, R2, R3, and A are defined in the first aspect.

[0076] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: Q1 is -NR7Q2, -CR10R10NR7Q2, -C(O)NR7(C1-4 alkyl substituted with zero or 1 R11), - CH=CH2, -CH=C(CN)S(O)2CH3, -S(O)2CH=CR10R10, -NR7(dichlorotriazinyl), -NR7(quinazolin-4-yl substituted by zero or 1 R11), 3- methylenepyrrolidin-2-on-1-yl, or a cyclic group selected from 1H-pyrrol-2(5H)-on-1-yl, isoindolin-1-on-2-yl, quinazolin-4(3H)-on- 3-yl, and quinazoline-2,4(1H, 3H)-dion-3-yl, each cyclic group substituted with zero to two substituents independently selected from F, Cl, -CH3, -CN, and -OCH3.

[0077] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: Q1 is -NR7Q2, -CR10R10NR7Q2, -S(O)2CH=CR10R10, -NR7(dichlorotriazinyl), 1H-pyrrole-2 (5H)-on-1-yl, or 3-methylenepyrrolidin-2-on-1-yl; Q2 is -CN, -C(O)(C5-6 cycloalkenyl), -C(O)CH=CHR10, -C(O)CR10=CH2, -C(O)CR10=CHCH2N(CH3)2, -C (O)C=CR7, -C(O)C=C(C1-3 hydroxyalkyl), -C(O)CsC(phenyl), -C(O)C=CSi(CH3)3, or -S(O )2CH=CH2; R3 is H, F, or Cl; R4, when present, is H or F; and X, R1, R2, R5, R6, R7, R8, R9, R10, and A are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein X is CR4.

[0078] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: Q1 is -NR7Q2 or -S(O)2CH=CH2; Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O)CEC( C1-3 hydroxyalkyl), -C(O)C2CSi(CH3)3, or -S(O)2CH=CH2; R3 is H, F, or Cl; R4, when present, is H or F; and X, R1, R2, R5, R6, R7, R8, R9, R10, and A are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein X is CR4.

[0079] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is Ql; QI is -NR7Q2 or -S(O)2CH=CH2; Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O)CEC( C1-3 hydroxyalkyl), -C(O)C=CSi(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4, when present, is H or F; R5 is H, -CH3, F or Cl; R6 is H, F, Cl, -CF3 or C1-3 alkoxy; and R7 and R12 are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein X is CR4.

[0080] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0081] Q1 is -CH=CH2, -NR7Q2, or -S(O)2CH=CH2; Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)CsC(phenyl), -C(O)CEC(CI- 3-hydroxyalkyl), -C(O)C₁CSi(CH 3 ) 3 , or -S(O) 2 CH=CH 2 ; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4, when present, is H or F; R5 is H, -CH3, F or Cl; R6 is H, F, Cl, -CF3 or C1-3 alkoxy; and R7 and R12 are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein X is CR4.

[0082] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0083] Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)C=CR7, -C(O)Csθ(phenyl), -C(O )CEC(C1-3 hydroxyalkyl), -C(O)C=CSi(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4, when present, is H or F; R6 is H, F, Cl, -CF3 or C1-3 alkoxy; and R7 and R12 are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein X is CR4.

[0084] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0085] Qi is -CH=CH2, -NR7Q2, or -S(O)2CH=CH2; Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O)CsC( C1-3 hydroxyalkyl), -C(O)C2CSi(CH3)3, or -S(O)2CH=CH2; Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O)CsC( C1-3 hydroxyalkyl), -C(O)C=CSi(CH3)3, or -S(O)2CH=CH2; Ri is H, -CH3, -CF3, or phenyl substituted by zero or Ri2; and R2 is H, -CH3, cyclopropyl, or phenyl substituted by zero or -R12; provided that zero or one of R1 and R2 is phenyl substituted by zero or R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; R6 is H, F, Cl, -CF3 or C1-3 alkoxy; R6a is defined in the first aspect; and R7 and R12 are defined in either the first aspect or the second aspect.

[0086] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0087] Q2 is ˗C(O)CH=CH2, ˗C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O )CEC(C1-3 hydroxyalkyl), -C(O)C=CSi(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; R6 is H, F, Cl, -CF3 or C1-3 alkoxy; and R7 and R12 are defined either in the first aspect or in the second aspect.

[0088] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0089] Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O )CEC(C1-3 hydroxyalkyl), -C(O)CHCS(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; each R7 is independently H, C1-4 alkyl, or cyclopropyl; and R12 is defined in either the first aspect or the second aspect.

[0090] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0091] Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O )CEC(C1-3 hydroxyalkyl), -C(O)C=CSi(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; each R7 is independently H, C1-4 alkyl, or cyclopropyl; and R12 is defined either in the first aspect or in the second aspect.

[0092] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0093] Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O )CEC(C1-3 hydroxyalkyl), -C(O)CHCS(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; and R7 and R12 are defined in either the first aspect or the second aspect.

[0094] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0095] Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O )CEC(C1-3 hydroxyalkyl), -C(O)CHCS(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; and R7 and R12 are defined in either the first aspect or the second aspect.

[0096] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0097] Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O )CEC(C1-3 hydroxyalkyl), -C(O)CHCS(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; and R7 and R12 are defined in either the first aspect or the second aspect.

[0098] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[0099] Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)CEC(phenyl), -C(O)CEC (C1-3 hydroxyalkyl), -C(O)C=CSi(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; and R7 and R12 are defined in either the first aspect or the second aspect.

[00100] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[00101] Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(phenyl), -C(O )CEC(C1-3 hydroxyalkyl), -C(O)CHCS(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; each R7 is independently C1-4 alkyl or cyclopropyl; and R12 is defined in either the first aspect or the second aspect.

[00102] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is -CHR8(pyridinyl) wherein each pyridinyl is replaced by R6 and R9; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H or F; R6 is H; R8 is H or C1-4 alkyl; R9 is -CH=CH2, -CH=CHCH2N(CH3)2, -CHCH, or -C=CCH3; and R12 is defined in either the first aspect or the second aspect.

[00103] One embodiment provides a compound of Formula (I) or a salt thereof, wherein Ri is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; and R3, R4, R12 and A are defined in either the first aspect or the second aspect.

[00104] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R1 is H, -CF3 or -CH3; and R2 is H or -CH3: provided that one of R1 and R2 is -CH3 or -CF3 and the other of R1 and R2 is H; and R3, R4, and A are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein R1 is -CH3 and R2 is H. Also included in this embodiment are compounds wherein R1 is H and R2 is -CH3.

[00105] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R1 is -CH3; R2 is -CH3; and R3, R4, and A are defined in either the first aspect or the second aspect.

[00106] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R1 is -CF3; R2 is -CH3; and R3, R4, and A are defined in either the first aspect or the second aspect.

[00107] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R1 is -CH3; R2 is cyclopropyl; and R3, R4, and A are defined in either the first aspect or the second aspect.

[00108] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R1 is 4-fluorophenyl; R2 is -CH3; and R3, R4, and A are defined in either the first aspect or the second aspect.

[00109] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R1 is -CH3; R2 is 4-fluorophenyl; and R3, R4, and A are defined in either the first aspect or the second aspect.

[00110] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is H, F, Cl, I, -CN, or -CH3; and R1 , R2 , R4 , and A are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein R3 is H or F. Also included in this embodiment are compounds wherein R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3.

[00111] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 3 is H, F, or Cl; and R1, R2, R4, and A are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein R3 is H or F. Also included in this embodiment are compounds wherein R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3.

[00112] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 3 is F, Cl, or I; and R1, R2, R4, and A are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein R3 is F or Cl. Also included in this embodiment are compounds where R3 is F.

[00113] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R4 is H, F, -OH, -O(C1-2 alkyl), -OCH2CH2OCH3, -OCH2(phenyl), -OCH2 (methoxyphenyl), or -OCH2(morpholinyl); and R1, R2, R3, and A are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein R4 is H or F. Also included in this embodiment are compounds wherein R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; and R3 is H or F.

[00114] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is ; R5 is H, F, or -CH3; and R1, R2, R3, R4, and R6 are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein R6 is H. Also included in this embodiment are compounds wherein R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H or F; R4 is H or F; R6 is H; and R12 is defined in either the first aspect or the second aspect.

[00115] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R6 is H or F; and R1, R2, R3, R4, R5, and A are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein R6 is H. Also included are compounds wherein R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H or F; R4 is H or F; R5 is H, F, or -CH3; R6 is H or F; and R12 is defined in either the first aspect or the second aspect.

[00116] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R7, at each occurrence, is independently H or C1-2 alkyl; and R1, R2, R3, R4, and A are defined in either the first aspect or the second aspect.

[00117] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is -CHR8(pyridinyl) wherein each pyridinyl is replaced by R6 and R9; R8 is H or -CH3; and R1 , R2 , R3 , R4 , R6 , and R9 are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein Ri is H, -CH3, -CF3, or phenyl substituted by zero or Ri2; and R2 is H, -CH3, cyclopropyl, or phenyl substituted by zero or -R12; provided that zero or one of R1 and R2 is phenyl substituted by zero or R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H or F; R4 is H or F; R5 is H, F, or -CH3; R6 is H; R9 is -CH=CH2 or -C=CCH3; and R12 is defined in either the first aspect or the second aspect.

[00118] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is -CHR8(pyridinyl) wherein each pyridinyl is replaced by R6 and R9; R9 is -CH=CH2, -C1CH, or -CHCCH3; and R1 , R2 , R3 , R4 , R6 , and R8 are defined in either the first aspect or the second aspect. Included in this embodiment are compounds where R9 is -CH=CH2 or -C=CCH3.

[00119] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R11 is F, Cl, -CN, -CF3, or C1-3 alkoxy; and R1, R2, R3, R4, and A are defined in either the first aspect or the second aspect. Included in this embodiment are compounds wherein R11 is F or -CN.

[00120] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; and R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12; provided that zero or one of R1 and R2 is phenyl substituted with zero or 1 R12 and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H, F, -OH, -O(C1-2 alkyl), -OCH2CH2OCH3, -OCH2(phenyl), -OCH2(methoxyphenyl), or -OCH2CH2(morpholinyl); R5 is H, F, or -CH3; R6 is H or F; R7 is H or C1-3 alkyl; R8 is H or -CH3; R9 is -CH=CH2 or -C=CCH3; Qi is -N(CH3)C(O)CH=CH2, -N(CH3)S(O)2CH=CH2, -C(O)NHCH2CN, -C(CH3)2NHS(O)2CH=CH2, -CH2NHC (O)CH=CH2, -CH2NHS(O)2CH=CH2, -NHC(O)CH2CN, -NHC(O)CH2CH3, -NHC(O)CH=CH2, -NHC(O)C(CH3)=CH2 , -NHC(O)CH=C(CH3)2, -NHC(O)CH=CHCH3, -NHC(O)CH=CHCH2N(CH3)2, -NHC(O)(cyclohexenyl), -NHC( O)(cyclopropyl), -NHC(O)(cyanocyclopropyl), -NHS(O)2CH=CH2, -S(O)2CH=CH2, -CH=C(CN)S(O)2CH3, -NH(dichlorotriazinyl) ), -NH(fluoroquinazolin-4-yl), 3-methylenepyrrolidin-2-on-1-yl, or a cyclic group selected from 1H-pyrrol-2(5H)-on-1-yl, isoindolin-1-on -2-yl, quinazolin-4(3H)-on-3-yl, and quinazoline-2,4(1H, 3H)-dion-3-yl, each cyclic group substituted with zero to two substituents independently selected from F, Cl, -CH3, -CN, and -OCH3; Q2 is -CN, -C(O)CH=CH2, -S(O)2CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCH, -C(O)CHCCH3, -C(O)CHCCH2CH3, -C(O)CHCCH2CH2CH3, -C(O)CHC(CH3)2OH, -C(O)CHCS(CH3)3, -C(O)C=C(cyclopropyl), or - C(O)C=C(phenyl); and A and R12 are defined in either the first aspect or the second aspect.

[00121] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[00122] R1 is H, -CH3, -CF3, or 4-fluorophenyl; and R2 is H, -CH3, cyclopropyl, or 4-fluorophenyl; provided that zero or one of R1 and R2 is 4-fluorophenyl and also provided that at least one of R1 and R2 is -CH3; R3 is H, F, or Cl; R4 is H, F, -OH, -O(C1-2 alkyl), -OCH2CH2OCH3, -OCH2(phenyl), or -OCH2(morpholinyl); R5 is H, F, or -CH3; R6 is H; and Q1 is -N(CH3)C(O)CH=CH2, -N(CH3)S(O)2CH=CH2, -C(O)NHCH2CN, -C(CH3)2NHS(O)2CH=CH2, - CH2NHC(O)CH=CH2, -CH2NHS(O)2CH=CH2, -NHC(O)CH2CN, -NHC(O)CH2CH3, -NHC(O)CH=CH2, -NHC(O)C(CH3)= CH2, -NHC(O)CH=C(CH3)2, -NHC(O)CH=CHCH3, -NHC(O)CH=CHCH2N(CH3)2, -NHC(O)(cyclohexenyl), -NHC (O)(cyclopropyl), -NHC(O)(cyanocyclopropyl), -NHS(O)2CH=CH2, -S(O)2CH=CH2, -CH=C(CN)S(O)2CH3, -NH( dichlorotriazinyl), -NH(fluoroquinazolin-4-yl), 3-methylenepyrrolidin-2-on-1-yl, or a cyclic group selected from 1H-pyrrol-2(5H)-on-1-yl, isoindolin-1- on-2-yl, quinazolin-4(3H)-on-3-yl, and quinazoline-2,4(1H, 3H)-dion-3-yl, each cyclic group substituted by zero to two independently selected substituents of F, Cl, -CH3, -CN, and -OCH3. Included in this embodiment are compounds in which A is

[00123] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[00124] R1 is H, -CH3, -CF3, or 4-fluorophenyl; and R2 is H, -CH3, cyclopropyl, or 4-fluorophenyl; provided that zero or one of R1 and R2 is 4-fluorophenyl and also provided that at least one of R1 and R2 is -CH3; R3 is H or F; R4 is H or F; R6 is H or F; and Q2 is -CN, -C(O)CH=CH2, -C(O)CHCCH3, or -S(O)2CH=CH2. Included in this embodiment are compounds wherein R3 is F.

[00125] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[00126] R1 is H, -CH3, -CF3, or 4-fluorophenyl; and R2 is H, -CH3, cyclopropyl, or 4-fluorophenyl; provided that zero or one of R1 and R2 is 4-fluorophenyl and also provided that at least one of R1 and R2 is -CH3; R3 is H or F; R4 is H or F; R7 is H, -CH3, or -CH2CH3; and Q2 is -CN, -C(O)CH=CH2, -C(O)C^CH, -C(O)C=CCH3, -C(O)CHCCH2CH3, -C(O)CHCCH2CH2CH3, -C( O)C=C(CH3)2(OH), -C(O)CHCSi(CH3)3, -C(O)CπC(cyclopropyl), -C(O)CsC(phenyl), or -S(O) 2CH=CH2.

[00127] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[00128] R1 is H, -CH3, -CF3, or 4-fluorophenyl; and R2 is H, -CH3, cyclopropyl, or 4-fluorophenyl; provided that zero or one of R1 and R2 is 4-fluorophenyl and also provided that at least one of R1 and R2 is -CH3; R3 is H or F; R4 is H or F; and Q2 is -CN, -C(O)CH=CH2, -C(O)C=CCH3, or -S(O)2CH=CH2. Included in this embodiment are compounds where A is:

[00129] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is:

[00130] Ri is H, -CH3, -CF3, or 4-fluorophenyl; and R2 is H, -CH3, cyclopropyl, or 4-fluorophenyl; provided that zero or one of R1 and R2 is 4-fluorophenyl and also provided that at least one of R1 and R2 is -CH3; R3 is H or F; R4 is H or F; R7 is H; and Q2 is -CN, -C(O)CH=CH2, -C(O)=CH, -C(O)CHCCH3, -C(O)CH=CHCH2N(CH3)2, or -S(O)2CH =CH2.

[00131] One embodiment provides a compound of Formula (I) or a salt thereof, wherein A is -CHR8 (pyridinyl) wherein each pyridinyl is replaced by R6 and R9; Ri is H, -CH3, -CF3, or 4-fluorophenyl; and R2 is H, -CH3, cyclopropyl, or 4-fluorophenyl; provided that zero or one of R1 and R2 is 4-fluorophenyl and also provided that at least one of R1 and R2 is -CH3; R3 is F; R4 is H or F; R6 is H; R8 is H or -CH3; and R9 is -CH=CH2 or -C=CCH3.

[00132] One embodiment provides a compound of Formula (I) or a salt thereof, wherein: X is N; Ri is -CH3; R2 is -CH3; R3 is H, -CN, or -CH3; the is ; and Q2 is -C(O)C=CH2.

[00133] A compound that inhibits an enzyme by reacting with the enzyme to form a covalent bond may offer advantages over a compound that does not form such a covalent bond. (See, for example, Liu, Q. et al., Chem. Biol., 20:146 (2013); Barf, T. et al., J. Med. Chem., 55:6243 (2012); Kalgutkar, A. et al., Expert Opin. Drug Discov., 7:561 (2012); and Garuti, L. et al., Curr. Med. Chem., 18: 2981 (2011); and references cited here) . A compound that does not form a covalent bond can dissociate from the enzyme, releasing the enzyme from the resulting inhibition of its binding. Such reversible inhibition may require a relatively high and continuous concentration of the inhibitory compound to drive the binding equilibrium for sufficient enzyme occupancy by the inhibitor to obtain useful enzyme inhibition. A higher concentration of the compound may require administration of a greater dose of the compound to a mammal in need of such inhibition, and at a higher concentration, the inhibitor may have unwanted effects, due to the inhibition of other non-targeted enzymes. Such off-target inhibition may include toxicity. Additionally, more frequent dosing may be required, as the inhibitory compound, after dissociation from the target enzyme, may be removed from the body by metabolism and/or elimination, reducing the concentration available to achieve target enzyme inhibition.

[00134] In contrast, an inhibitor that forms a covalent bond with its target enzyme irreversibly inhibits the enzyme. Irreversible inhibition would result from slow or negligible dissociation of the inhibitor, since such dissociation would require the breaking of a covalent bond. If the affinity of such a covalent inhibitor for its target enzyme is large enough relative to the affinities for other off-target enzymes, the significantly lower concentration of the inhibitor can result in useful inhibition relative to a concentration required for reversible inhibition. The lower concentration may reduce the likelihood of unwanted off-target inhibition and potential toxicity. Furthermore, since the covalent inhibitor can bind essentially irreversibly to the target enzyme, the free (unbound) concentration of the inhibitor can become extremely low as unbound inhibitor is removed from the body by metabolism and/or elimination. , even when useful enzyme inhibition is maintained. This can reduce the likelihood of unwanted effects. Additionally, since the enzyme may be irreversibly inhibited, less frequent dosing may be required to obtain useful inhibition.

[00135] Certain reactive functional groups can be attached to a compound with good affinity for the target enzyme, which will allow covalent bond formation with a functional group on the target enzyme. For example, an electrophilic group, such as a vinylic or acetylenic group linked to an electron-withdrawing group, such as a ketone, amide, sulfone, sulfonamide, or an electron-withdrawing heterocyclic ring, such as a pyridyl ring, can react with a nucleophilic group present on the target enzyme, such as the thiol or thiolate group of a cysteine residue, to form a covalent bond. Such a reaction may be essentially irreversible under physiological conditions. In order for such a reaction to be obtained, the inhibitor compound must bind to the target enzyme and present the attached electrophilic group in a special correct orientation to allow favorable interaction with the binding nucleophile. If the orientation is not correct, the covalent bond may not easily form and the desired irreversible inhibition may not be achieved. In this case, the compound would behave as a reversible inhibitor and the benefits of irreversible inhibition could not be realized. Furthermore, if the orientation of the electrophile in the binding inhibitor is not suitable for reaction with the nucleophilic group of the target enzyme, the inhibitor will be capable of dissociating from the target enzyme, resulting in a higher concentration of the inhibitor and a greater probability that the reactive electrophilic group may react with other non-target nucleophiles and cause unwanted effects such as toxicity.

[00136] One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound covalently binds to the Btk enzyme.

[00137] One embodiment provides a compound of Formula (I) or a salt thereof, wherein Qi is -NR7Q2, -CR10R10NR7Q2, -CH=C(CN)S(O)2CH3, or -S(0)2CH= CRIORIO; Q2 is -C(O)CRio=CRioRio, -C(O)C(Rio)=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(C1-3 hydroxyalkyl), - C(O)CsC(phenyl), -C(O)C₁CSi(CH3)3, or -S(O)2CH=CHR10; and R1, R2, R3, R4, A, R7, R9, and R10 are defined in the first embodiment. Included in this embodiment are compounds wherein R3 is H, F, or Cl; R4 is H, F, -OH, -O(C1-2 alkyl), -OCH2CH2OCH3, -OCH2(phenyl), -OCH2(methoxyphenyl), or -OCH2CH2(morpholinyl); R5 is H, F, or -CH3; R6 is H or F; R7 is H or C1-3 alkyl; R8 is H or -CH3; and R9 is -CH=CH2 or -C=CCH3.

[00138] One embodiment provides a compound of Formula (I) or a salt thereof, wherein Q1 is -N(CH3)C(O)CH=CH2, -N(CH3)S(O)2CH=CH2, - C(CH3)2NHS(O)2CH=CH2, -CH2NHC(O)CH=CH2, -CH2NHS(O)2CH=CH2, -NHC(O)CH=CH2, -NHC(O)C(CH3)=CH2 , -NHC(O)CH=C(CH3)2, -NHC(O)CH=CHCH3, -NHC(O)CH=CHCH2N(CH3)2, -NHC(O)(cyclohexenyl), -NHS( O)2CH=CH2, -S(O)2CH=CH2, or -CH=C(CN)S(O)2CH3; and Q2 is -C(O)CH=CH2, -S(O)2CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCH, -C(O)CHCCH3, -C (O)CHCCH2CH3, -C(O)CHCCH2CH2CH3, -C(O)CHC(CH3)2OH, -C(O)C=CSi(CH3)3, -C(O)C^C(cyclopropyl), or - C(O)C=C(phenyl); and Ri, R2, R3, R4, and A are defined in the first mode. Included in this embodiment are compounds wherein R3 is H, F, or Cl; R4 is H, F, -OH, -O(C1-2 alkyl), -OCH2CH2OCH3, -OCH2(phenyl), -OCH2(methoxyphenyl), or -OCH2CH2(morpholinyl); R5 is H, F, or -CH3; R6 is H or F; R7 is H or C1-3 alkyl; R8 is H or -CH3; and R9 is -CH=CH2 or -C=CCH3.

[00139] One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is 4-(3-acrylamido-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide (1 ); 2,3-dimethyl-4-(3-(vinylsulfonyl)phenyl)-1H-indole-7-carboxamide (2); 5-fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (3); 2,3-dimethyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (4); 4-(3-acrylamido-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (5); (E)-4-(3-(but-2-enamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (6); 4-(3-acrylamido-2-methylphenyl)-2-methyl-1H-indole-7-carboxamide (7); (E)-4-(3-(but-2-enamido)-2-methylphenyl)-2-methyl-1H-indole-7-carboxamide (8); (E)-4-(3-(but-2-enamido)-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide (9); 2,3-dimethyl-4-(2-methyl-3-(3-methylbut-2-enamido)phenyl)-1H-indole-7-carboxamide (10); 2-methyl-4-(2-methyl-3-(3-methylbut-2-enamido)phenyl)-1H-indole-7-carboxamide (11); 3-methyl-4-(2-methyl-3-(3-methylbut-2-enamido)phenyl)-1H-indole-7-carboxamide (12); 2,3-dimethyl-4-(2-methyl-3-propionamidophenyl)-1H-indole-7-carboxamide (13); 4-(3-(cyclopropanecarboxamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (14); 4-(3-(1-cyanocyclopropanecarboxamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (15); (E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (16); 4-(3-methacrylamido-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (17); 4-(3-(cyclohex-1-enecarboxamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (18); 4-(3-(2-cyanoacetamido)-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide (19); 2,3-dimethyl-4-(2-methyl-3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (20); 4-(3-((cyanomethyl)carbamoyl)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (21); 4-(3-acrylamidophenyl)-2,3-dimethyl-1H-indole-7-carboxamide (22); 2,3-dimethyl-4-(2-methyl-3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (23); 3-methyl-4-(2-methyl-3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (24); 2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (25); 5-fluoro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (26); 5-chloro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (27); 3-methyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (28); 2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (29); 3-methyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (30); 3-methyl-4-(2-methyl-3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (31); 4-(2-fluoro-3-(N-methylacrylamido)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide (32); 3-methyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (33); 2,3-dimethyl-4-(2-methyl-3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (34); 2,3-dimethyl-4-(2-methyl-3-(3-methylene-2-oxopyrrolidin-1-yl)phenyl)-1H-indole-7-carboxamide (35); 2,3-dimethyl-4-(3-(3-methylene-2-oxopyrrolidin-1-yl)phenyl)-1H-indole-7-carboxamide (36); 5-Fluoro-2,3-dimethyl-4-(3-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-1H-indole-7-carboxamide (37); 4-(1-acryloylindolin-6-yl)-2,3-dimethyl-1H-indole-7-carboxamide (38); 2,3-dimethyl-4-(1-(vinylsulfonyl)indolin-6-yl)-1H-indole-7-carboxamide (39); 2,3-dimethyl-4-(3-(vinylsulfonamidomethyl)phenyl)-1H-indole-7-carboxamide (40); 4-(3-(acrylamidomethyl)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide (41); 2,3-dimethyl-4-(3-(2-(vinylsulfonamido)propan-2-yl)phenyl)-1H-indole-7-carboxamide (42); 4-(2-acrylamidopyridin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide (43); 4-(2-acrylamidopyridin-4-yl)-2-methyl-1H-indole-7-carboxamide (44); 4-(3-acrylamido-2-methylphenyl)-1H-indole-7-carboxamide (45); 4-(2-methyl-3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (46); 2,3-dimethyl-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-1H-indole-7-carboxamide (47); 4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (48); 2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (49); 4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (50); 4-(3-((5-fluoroquinazolin-4-yl)amino)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (51); 4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide (52); 4-(3-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide (53); 4-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide (54); 4-(3-(6-chloro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide (55); 4-(3-(8-methoxy-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide (56); 4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-1H-indole-7-carboxamide (57); 4-(3-(6-cyano-1-oxoisoindolin-2-yl)-2-methylphenyl)-1H-indole-7-carboxamide (58); 3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (59); 2-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (60); 6-((4-methoxybenzyl)oxy)-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (61 ); 4-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indol-7- carboxamide (62); 4-(3-(6-cyano-1-oxoisoindolin-2-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide (63 ); 4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indol-7- carboxamide (64); 4-(3-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indol-7- carboxamide (65); 4-(3-(8-methoxy-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indol-7- carboxamide (66); 4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydrodihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2,3-dimethyl-1H -indole-7-carboxamide (67); 2,3-dimethyl-4-(2-methyl-3-(1-methyl-2,4-dioxo-1,2-dihydrodihydroquinazolin-3(4H)-yl)phenyl)-1H-indol- 7-carboxamide (68); 4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (69); 4-(3-(2-cyano-2-(methylsulfonyl)vinyl)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide (70); 6-hydroxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (71); 6-ethoxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (72); 6-methoxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (73); 6-(benzyloxy)-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (74); 2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-6-(2-morpholinoethoxy)-1H-indole-7-carboxamide (75); 6-(2-methoxyethoxy)-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (76); 4-(3-((4,6-dichloro-1,3,5-triazin-2-yl)amino)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (77); (RS)-2,3-dimethyl-4-(3-(N-methylacrylamido)piperidin-1-yl)-1H-indole-7-carboxamide (78); 4-((1-acryloylpiperidin-4-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (79); 4-(1-acryloylpiperidin-3-yl)-2,3-dimethyl-1H-indole-7-carboxamide (80); (R)-4-(3-acrylamidopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (81); 4-(3-acrylamidopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (82); 4-(3-acrylamidopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (83); (S)-4-(3-acrylamidopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (84); (R)-4-(3-acrylamidopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (85); 4-((1-acryloylpyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (86); (R)-4-((1-acryloylpyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (87); (S)-4-((1-acryloylpyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (88); (S)-4-(3-acrylamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (89); 4-(1-acryloylpyrrolidin-3-yl)-2,3-dimethyl-1H-indole-7-carboxamide (90); 4-((1-acryloylpiperidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (91); 4-((1-acryloylpiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (92); 4-(1-acryloylpiperidin-3-yl)-3-methyl-1H-indole-7-carboxamide (93); (S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (94); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (95); (S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (96); 4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (97); cis-4-(5-acryloylhexahydropyrrolo [3,4-c]pyrrol-2(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (98); 4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (99); (S)-4-(3-acrylamidopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (100); 4-(2-acryloylisoindolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (101); (RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (102); (RS)-2,3-dimethyl-4-((1-propioloylpyrrolidin-3-yl)amino)-1H-indole-7-carboxamide (103); (RS)-4-(1-(but-2-inoyl)piperidin-3-yl)-3-methyl-1H-indole-7-carboxamide (104); 2,3-dimethyl-4-(3-(N-methylpropiolamido)piperidin-1-yl)-1H-indole-7-carboxamide (105); 2,3-dimethyl-4-((1-propioloylpiperidin-3-yl)amino)-1H-indole-7-carboxamide (106); 4-((1-(but-2-inoyl)piperidin-4-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (107); 2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (108); (S)-2,3-dimethyl-4-(3-(3-phenylpropiolamido)piperidin-1-yl)-1H-indole-7-carboxamide (109); (S)-2,3-dimethyl-4-(3-(3-(trimethylsilyl)propiolamido)piperidin-1-yl)-1H-indole-7-carboxamide (110); (S)-4-(3-(4-hydroxy-4-methylpent-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (111); (S)-2,3-dimethyl-4-(3-(pent-2-inamido)piperidin-1-yl)-1H-indole-7-carboxamide (112); (S)-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (113); 2,3-dimethyl-4-((1-propioloylpiperidin-4-yl)amino)-1H-indole-7-carboxamide (114); (S)-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide (115); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (116); (R)-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide (117); (R)-4-(3-(but-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (118); (R)-2,3-dimethyl-4-(3-propiolamidopyrrolidin-1-yl)-1H-indole-7-carboxamide (119); (R)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (120); 4-((1-(but-2-inoyl)pyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (121); 4-((1-(but-2-inoyl)piperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (122); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (123); (S,E)-4-((1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (124); (S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (125); (S)-5-fluoro-2,3-dimethyl-4-(3-(pent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (126); (S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylpent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (127); (S)-5-fluoro-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (128); 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (129) ; (S)-4-(3-(N-ethylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (130); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (131); (RS)-4-(2-acryloylisoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (132); (RS)-4-(2-(but-2-inoyl)isoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (133); 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (134) ; (S)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (135); (S)-4-(3-(3-cyclopropylpropiolamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (136); 4-(2-(but-2-inoyl)isoindolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (137); (RS)-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (138); 2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (139); 2,3-dimethyl-4-(3-(vinylsulfonamido)pyrrolidin-1-yl)-1H-indole-7-carboxamide (140); (S)-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (141); (R)-2,3-dimethyl-4-(3-(vinylsulfonamido)pyrrolidin-1-yl)-1H-indole-7-carboxamide (142); (R)-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (143); 2,3-dimethyl-4-((1-(vinylsulfonyl)pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide (144); 2,3-dimethyl-4-(4-(vinylsulfonyl)piperazin-1-yl)-1H-indole-7-carboxamide (145); (S)-5-fluoro-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (146); (S)-4-((1-cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (147); 4-(1-cyanopiperidin-3-yl)-2,3-dimethyl-1H-indole-7-carboxamide (148); 4-(1-cyanopyrrolidin-3-yl)-2,3-dimethyl-1H-indole-7-carboxamide (149); (S)-4-(3-cyanamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (150); 4-((1-cyanopiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (151); 4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (152); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (153 and 154); 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (155 and 156); 4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (157 and 158); cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, enantiomers single (159 and 160); cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indol-7- carboxamide, single diastereomers (161 to 164); 4-(5-acryloylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (165 and 166) ; 4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (167 and 168) ; 4-(2-acryloyl-4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single diastereomers (169 to 172); cis-4-(1-(but-2-inoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H- indole-7-carboxamide, single enantiomers (173 and 174); 4-(5-(but-2-inoyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (175 and 176); 4-(1-(but-2-inoyl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (177 and 178); cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, enantiomers single (179 and 180); 5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide (181); 5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carboxamide (182); 5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide, single enantiomers (183 and 184); 5-fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamide (185); (RS)-4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (186); 4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (187 and 188); (RS)-4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide ( 189); 4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (190 and 191); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (192); (RS)-4-(1-acryloylindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (193); (RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (194); 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (195 and 196); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide ( 197); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide, single enantiomers (198 and 199); (S)-4-(3-(N-cyclopropylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (200); 4-(4-(but-2-inoyl)piperazin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (201); 4-(4-acryloylpiperazin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (202); 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (203) ; (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (204); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (205 and 206); 4-(1-acryloylindolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (207); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (208); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide (209) ; 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide, single enantiomers (210 and 211); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indol-7- carboxamide (212); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide, single enantiomers (213 and 214); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indol-7- carboxamide (215); 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (216); (RS)-4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (217); 4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (218 and 219); (RS)-4-(1-(but-2-inoyl)piperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (220); 5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carboxamide (221); 5-fluoro-4-((5-fluoro-6-vinylpyridin-3-yl)methyl)-2,3-dimethyl-1H-indole-7-carboxamide (222); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (223); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iodo-2,3-dimethyl-1H-indole-7-carboxamide (224); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (225); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (226) ; 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (227 and 228); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-cyano-2,3-dimethyl-1H-indole-7-carboxamide (229); 4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (230); 4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (231 and 232); 4-(1-acryloyl-1,4,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (233); 4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (234); 4-(1-acryloyl-2,5-dihydro-1H-pyrrol-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (235); 4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (236); 4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (237); 4-(1-(but-2-inoyl)-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (238) ; 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide, racemate (239); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide, atropisomer A (240); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide (241); (S)-5-fluoro-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide (242); (R)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (243); 4-(6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (244); 4-(6-(but-2-inoyl)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide ( 245); 4-(7-acryloyl-2,7-diazaspiro[4,4]nonan-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (246); 4-(7-(but-2-inoyl)-2,7-diazaspiro[4,4]nonan-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (247) ; 5-fluoro-2,3-dimethyl-4-(2-vinylpyridin-3-yl)-1H-indole-7-carboxamide (248); 5-fluoro-3-methyl-2-(trifluoromethyl)-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide (249); 4-(1-acryloylpyrrolidin-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (250); 4-(1-acryloylpyrrolidin-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (251); 4-(1-acryloylpyrrolidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (252); 5-fluoro-2,3-dimethyl-4-(3-vinyl-5,6-dihydroisoquinolin-8-yl)-1H-indole-7-carboxamide (253); 4-(1-(but-2-inoyl)-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indol-7- carboxamide (254); 4-(1-acryloylctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (255); 4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indol-7 -carboxamide (256); 4-((1-acryloylpiperidin-4-ylidene)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (257); 4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (258); 4-((1-acryloylpyrrolidin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (259); 4-((1-(but-2-inoyl)piperidin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (260); 4-((1-(but-2-inoyl)piperidin-4-ylidene)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (261); 4-((1-(but-2-ynoyl)pyrrolidin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (262); 5-fluoro-4-(3-fluoro-2-vinylpyridin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide (263); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide, atropisomer B (264); or 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide (265 ).

[00140] One embodiment provides a compound of Formula (I) or a salt thereof, wherein said compound is 4-(3-acrylamido-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide (1 ); 2,3-dimethyl-4-(3-(vinylsulfonyl)phenyl)-1H-indole-7-carboxamide (2); 5-fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (3); 2,3-dimethyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (4); 4-(3-acrylamido-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (5); 4-(3-acrylamido-2-methylphenyl)-2-methyl-1H-indole-7-carboxamide (7); (E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (16); 2,3-dimethyl-4-(2-methyl-3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (20); 4-(3-acrylamidophenyl)-2,3-dimethyl-1H-indole-7-carboxamide (22); 2,3-dimethyl-4-(2-methyl-3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (23); 3-methyl-4-(2-methyl-3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (24); 2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (25); 5-fluoro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (26); 5-chloro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (27); 3-methyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (28); 2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (29); 3-methyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide (30); 3-methyl-4-(2-methyl-3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (31); 4-(2-fluoro-3-(N-methylacrylamido)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide (32); 3-methyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (33); 2,3-dimethyl-4-(2-methyl-3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (34); 4-(1-acryloylindolin-6-yl)-2,3-dimethyl-1H-indole-7-carboxamide (38); 2,3-dimethyl-4-(1-(vinylsulfonyl)indolin-6-yl)-1H-indole-7-carboxamide (39); (RS)-2,3-dimethyl-4-(3-(N-methylacrylamido)piperidin-1-yl)-1H-indole-7-carboxamide (78); 4-((1-acryloylpiperidin-4-yl)amino)-2,3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (88); (S)-4-(3-acrylamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (89); 4-((1-acryloylpiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (92); 4-(1-acryloylpiperidin-3-yl)-3-methyl-1H-indole-7-carboxamide (93); (S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (94); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (95); (S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (96); 4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (97); cis-4-(5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (98); 4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (99); (S)-4-(3-acrylamidopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (100); (RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole - 7-carboxamide (102); (RS)-2,3-dimethyl-4-((1-propioloylpyrrolidin-3-yl)amino)-1H-indole-7-carboxamide (103); 2,3-dimethyl-4-(3-(N-methylpropiolamido)piperidin-1-yl)-1H-indole-7-carboxamide (105); 2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (108); (S)-2,3-dimethyl-4-(3-(3-phenylpropiolamido)piperidin-1-yl)-1H-indole-7-carboxamide (109); (S)-2,3-dimethyl-4-(3-(3-(trimethylsilyl)propiolamido)piperidin-1-yl)-1H-indole-7-carboxamide (110); (S)-4-(3-(4-hydroxy-4-methylpent-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (111); (S)-2,3-dimethyl-4-(3-(pent-2-inamido)piperidin-1-yl)-1H-indole-7-carboxamide (112); (S)-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (113); 2,3-dimethyl-4-((1-propioloylpiperidin-4-yl)amino)-1H-indole-7-carboxamide (114); (S)-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide (115); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (116); (R)-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide (117); (R)-4-(3-(but-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (118); (R)-2,3-dimethyl-4-(3-propiolamidopyrrolidin-1-yl)-1H-indole-7-carboxamide (119); (R)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (120); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (123); (S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (125); (S)-5-fluoro-2,3-dimethyl-4-(3-(pent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (126); (S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylpent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (127); (S)-5-fluoro-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (128); (S)-4-(3-(N-ethylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (130); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (131); (RS)-4-(2-acryloylisoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (132); (S)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (135); (S)-4-(3-(3-cyclopropylpropiolamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (136); (RS)-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (138); 2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (139); 2,3-dimethyl-4-(3-(vinylsulfonamido)pyrrolidin-1-yl)-1H-indole-7-carboxamide (140); (S)-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (141); (R)-2,3-dimethyl-4-(3-(vinylsulfonamido)pyrrolidin-1-yl)-1H-indole-7-carboxamide (142); (R)-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (143); 2,3-dimethyl-4-((1-(vinylsulfonyl)pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide (144); 2,3-dimethyl-4-(4-(vinylsulfonyl)piperazin-1-yl)-1H-indole-7-carboxamide (145); (S)-5-fluoro-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (146); (S)-4-((1-cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (147); (S)-4-(3-cyanamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (150); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (153 and 154); 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (155 and 156); cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, enantiomers single (159 and 160); cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indol-7- carboxamide, single diastereomers (161 and 164); 4-(5-acryloylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (165 and 166) ; 4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (167 and 168) ; 4-(2-acryloyl-4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single diastereomers (170 through 172); cis-4-(1-(but-2-inoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H- indole-7-carboxamide, single enantiomers (173 and 174); 4-(1-(but-2-inoyl) hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (177 and 178); 5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide (181); 5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carboxamide (182); 5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide, single enantiomers (183 and 184); 5-fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamide (185); (RS)-4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (186); 4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomer (188); (RS)-4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide ( 189); 4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomer (191 ); (RS)-4-(1-acryloylindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (193); (RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (194); 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (195 and 196); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide ( 197); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide, single enantiomer (199 ); (S)-4-(3-(N-cyclopropylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (200); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (204); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomer (206); 4-(1-acryloylindolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (207); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (208); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide (209) ; 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide, single enantiomer (211); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indol-7- carboxamide (212); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide, single enantiomer (213); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indol-7- carboxamide (215); 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (216); (RS)-4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (217); or 4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomer (219).

[00141] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is F and said compound is 5-fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl )-1H-indole-7-carboxamide (3); 5-fluoro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl)-1H-indole-7-carboxamide (26); 5-Fluoro-2,3-dimethyl-4-(3-(3-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)-1H-indole-7-carboxamide (37); (S)-4-((1-acryloylpyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (88); (S)-4-(3-acrylamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (89); 4-((1-acryloylpiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (92); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (95); (S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (96); 4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (97); cis-4-(5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (98); 4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (99); (S)-4-(3-acrylamidopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (100); 4-(2-acryloylisoindolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (101); (RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (102); 4-((1-(but-2-inoyl)piperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (122); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (123); (S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (125); (S)-5-fluoro-2,3-dimethyl-4-(3-(pent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (126); (S)-5-fluoro-2,3-dimethyl-4-(3-(N-methylpent-2-ynamido)piperidin-1-yl)-1H-indole-7-carboxamide (127); (S)-5-fluoro-4-(3-(hex-2-ynamido)piperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (128); 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (129) ; (S)-4-(3-(N-ethylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (130); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (131); (RS)-4-(2-acryloylisoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (132); (RS)-4-(2-(but-2-inoyl)isoindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (133); 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (134) ; (S)-4-(3-(but-2-ynamido)pyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (135); (S)-4-(3-(3-cyclopropylpropiolamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (136); 4-(2-(but-2-inoyl)isoindolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (137); (S)-5-fluoro-2,3-dimethyl-4-(3-(vinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide (146); (S)-4-((1-cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (147); (S)-4-(3-cyanamidopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (150); 4-((1-cyanopiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (151); 4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (152); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (153 and 154); 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (155 and 156); 4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (157 and 158); cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, enantiomers single (159 and 160); cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indol-7- carboxamide, single diastereomers (161 to 164); 4-(5-acryloylhexahydropyrrolo [3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (165 and 166) ; 4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (167 and 168) ; 4-(2-acryloyl-4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single diastereomers (169 to 172); cis-4-(1-(but-2-inoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H- indole-7-carboxamide, single enantiomers (173 and 174); 4-(5-(but-2-inoyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (175 and 176); 4-(1-(but-2-inoyl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (177 and 178); cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, enantiomers single (179 and 180); 5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide (181); 5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carboxamide (182); 5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide, single enantiomers (183 and 184); 5-fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamide (185); (RS)-4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (186); 4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (187 and 188); (RS)-4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide ( 189); 4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (190 and 191); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (192); (RS)-4-(1-acryloylindolin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (193); (RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (194); 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (195 and 196); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide ( 197); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide, single enantiomers (198 and 199); (S)-4-(3-(N-cyclopropylbut-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (200); 4-(4-(but-2-inoyl)piperazin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (201); 4-(4-acryloylpiperazin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (202); 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (203) ; (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (204); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (205 and 206); or 4-(1-acryloylindolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (207); One embodiment provides a compound of Formula (I) or a salt thereof, wherein R 3 is F and said compound is (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5 -yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide (212); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide, enantiomer single ros (213 and 214); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indol-7- carboxamide (215); 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (216); (RS)-4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (217); 4-(1-acryloylpiperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (218 and 219); (RS)-4-(1-(but-2-inoyl)piperidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (220); 5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carboxamide (221); or 5-fluoro-4-((5-fluoro-6-vinylpyridin-3-yl)methyl)-2,3-dimethyl-1H-indole-7-carboxamide (222).

[00142] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is F and said compound is (S)-4-(3-(but-2-ynamido)piperidin-1-yl )-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (223); 4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (230); 4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (231 and 232); 4-(1-acryloyl-1,4,5,6-tetrahydropyridin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (233); 4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (234); 4-(1-acryloyl-2,5-dihydro-1H-pyrrol-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (235); 4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (236); 4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (237); 4-(1-(but-2-inoyl)-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (238) ; (S)-5-fluoro-2,3-dimethyl-4-(3-propiolamidopiperidin-1-yl)-1H-indole-7-carboxamide (242); (R)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (243); 4-(6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (244); 4-(6-(but-2-inoyl)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide ( 245); 4-(7-acryloyl-2,7-diazaspiro[4,4]nonan-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (246); 4-(7-(but-2-inoyl)-2,7-diazaspiro[4,4]nonan-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (247) ; 5-fluoro-2,3-dimethyl-4-(2-vinylpyridin-3-yl)-1H-indole-7-carboxamide (248); 5-fluoro-3-methyl-2-(trifluoromethyl)-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide (249); 4-(1-acryloylpyrrolidin-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (250); 4-(1-acryloylpyrrolidin-2-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (251); 4-(1-acryloylpyrrolidin-3-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (252); 5-fluoro-2,3-dimethyl-4-(3-vinyl-5,6-dihydroisoquinolin-8-yl)-1H-indole-7-carboxamide (253); 4-(1-(but-2-inoyl)-2,5-dihydro-1H-pyrrol-3-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indol-7- carboxamide (254); 4-(1-acryloylctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (255); 4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indol-7 -carboxamide (256); 4-((1-acryloylpiperidin-4-ylidene)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (257); 4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (258); 4-((1-acryloylpyrrolidin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (259); 4-((1-(but-2-inoyl)piperidin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (260); 4-((1-(but-2-inoyl)piperidin-4-ylidene)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (261); 4-((1-(but-2-inoyl)pyrrolidin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (262); or 5-fluoro-4-(3-fluoro-2-vinylpyridin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide (263).

[00143] One embodiment provides a compound of Formula (I) or a salt thereof, wherein R3 is Cl and said compound is 5-chloro-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido)phenyl )-1H-indole-7-carboxamide (27); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide, racemate (239); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide, atropisomer A (240); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide, atropisomer B (264); or 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide (265 ).

[00144] The present invention may be represented in other specific ways without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is intended to be combined with any and all other elements of any embodiment to describe a further embodiment.

DEFINITIONS

[00145] The features and advantages of the invention may be more readily understood by those skilled in the art after reading the following detailed description. It should be appreciated that certain features of the invention which are, for clarity, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention which are, for the sake of brevity, described in the context of a single embodiment, may also be combined to form subcombinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[00146] Unless specifically stated otherwise herein, references made to the singular may also include the plural. For example, "um, a (a)" and "um, a (an)" can refer to one, or one, or more.

[00147] As used herein, the phrase "compounds" refers to at least one compound. For example, a compound of Formula (I) includes one compound of Formula (I) and two or more compounds of Formula (I).

[00148] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have enough hydrogen atoms to satisfy the valences.

[00149] The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and/or patent application publication incorporated herein by reference.

[00150] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific examples) either individually or as part of a larger group.

[00151] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable compounds and moieties.

[00152] According to a convention used in the art, is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[00153] The term "alkyl" as used herein, refers to both straight and branched chain, saturated, aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g. n-propyl and i-propyl), butyl (e.g. n-butyl, i-butyl, sec -butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscript after the "C" symbol, the subscript more specifically defines the number of carbon atoms a particular group can contain. For example, "C1-4 alkyl" denotes straight and branched chain alkyl groups having one to four carbon atoms.

[00154] The term "hydroxyalkyl" refers to both straight and branched chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and C1-4 hydroxyalkyl. "C1-4 hydroxyalkyl" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more hydroxyl groups.

[00155] As used herein, "alkylene" refers to a bivalent alkyl radical having the general formula -(CH2)n-, where n is 1 to 10. Non-limiting examples include methylene, dimethylene, trimethylene, tetramethylene, pen- tamethylene, and hexamethylene. For example, "C1-6 alkylene" denotes straight and branched chain alkylene groups having one to six carbon atoms. Also, for example, "C0-4 alkylene" denotes a bond and straight and branched chain alkylene groups having one to four carbon atoms.

[00156] The term "cyano" refers to the -CN group.

[00157] The term "cycloalkyl", as used herein, refers to a group derived from a monocyclic or polycyclic, non-aromatic hydrocarbon molecule by removal of a hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in a subscript after the "C" symbol, the subscript more specifically defines the number of carbon atoms a particular cycloalkyl group can contain. For example, "C3-6 cycloalkyl" denotes cycloalkyl groups having three to six carbon atoms.

[00158] The term "cycloalkenyl", as used herein, refers to a cyclic hydrocarbon ring having 1 double bond. For example, "C5-6 cycloalkenyl" denotes cyclopentenyl and cyclohexenyl.

[00159] The phrase "pharmaceutically acceptable" is used here to refer to those compounds, materials, compositions, and/or dosage forms that fall within the scope of safe medical diagnosis, suitable for use in contact with human tissues and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable risk/benefit ratio.

[00160] The compounds of Formula (I) can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds of Formula (I) as amorphous solids.

[00161] Certain compounds of Formula (I) can exist in a free form (without any ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is intended to include reference to the free form and salts thereof. The term "salt(s)" denotes acidic salts formed with inorganic and/or organic acids. Pharmaceutically acceptable (ie, physiologically acceptable, non-toxic) salts are preferred, such as, for example, salts in which the anion does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, for example, in isolation or purification steps that may be employed during preparation, and thus are contemplated within the scope of the invention. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) with an amount of acid, such as an equivalent amount, in a medium, such as one in which the salt precipitates itself or in an aqueous medium followed by lyophilization.

[00162] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trialloacetic acid, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), iodates, 2 -hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates , sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[00163] It should also be understood that solvates (eg hydrates) of the compounds of Formula (I) are also within the scope of the present invention. The term "solvate" means a physical association of a compound of Formula (I) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain cases, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both solution phase and isolatable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[00164] Various forms of prodrugs are well known in the art and are described in:

[00165] a) Wermuth, C.G. and another, The Practice of Medicinal Chemistry, Chapter 31, Academic Press (1996);

[00166] b) Bundgaard, H. ed., Design of Prodrugs, Elsevier (1985);

[00167] c) Bundgaard, H., chapter 5, "Design and Application of Prodrugs", A Textbook of Drug Design and Development, pp. 113-191, Krogsgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991); It is

[00168] d) Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism, Wiley-VCH (2003).

[00169] Furthermore, the compounds of Formula (I), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formula (I) ( "substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of Formula (I) are also contemplated herein as part of the present invention.

[00170] "Stable compound" and "stable structure" are intended to denote a compound that is sufficiently robust to survive isolation to a useful degree of purity from a feed mixture, and formulation into an effective therapeutic agent. The present invention aimed to represent stable compounds.

[00171] "Therapeutically effective amount" is intended to include an amount of a compound of the present invention alone or an amount of the combination of claimed compounds or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor for Btk, or effective to treat or prevent proliferative and/or autoimmune and/or inflammatory disease states such as multiple sclerosis and rheumatoid arthritis.

[00172] As used herein, "treat" or "treatment" encompasses treating a disease state in a mammal, particularly a human, and includes: (a) preventing the disease state from occurring in a mammal, in particular , when such mammal is predisposed to the disease state, but has not yet been diagnosed as having it; (b) inhibiting the disease state, ie, arresting its development; and/or (c) relieving the disease state, i.e., causing the disease state to regress.

[00173] The compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13C and 14C. The isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the unlabeled reagent otherwise employed. For example, methyl (-CH3) also includes deuterated methyl groups such as -CD3.

[00174] Compounds according to Formula (I) can be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or amount of compound of Formula (I) to be released .

[00175] Also encompassed in this invention is a class of pharmaceutical compositions comprising a compound of Formula (I) and one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as pharmaceutical materials). "vehicle") and, if desired, other active ingredients. The compounds of Formula (I) may be administered by any suitable routine, preferably in the form of a pharmaceutical composition adapted for such a routine, and in a dose effective for the intended treatment. The compounds and compositions of the present invention can, for example, be administered orally, mucosally, or parenterally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally in dosage unit formulations containing carriers, adjuvants, and vehicles. conventional pharmaceutically acceptable. For example, the pharmaceutical carrier can contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain further components such as a lubricating agent such as magnesium stearate and a disintegrating agent such as crospovidone. The carrier mixture can be filled into a gelatin capsule or compressed into a tablet. The pharmaceutical composition can be administered as an oral dosage form or an infusion, for example.

[00176] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a particular amount of the active ingredient. For example, the pharmaceutical composition can be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and most preferably from about 0. .5 to 100 mg. An adequate daily dose for a human or other mammal can vary widely depending on the patient's condition and other factors, but can be determined using routine methods.

[00177] Any pharmaceutical composition contemplated herein may, for example, be delivered orally by means of any suitable and acceptable oral preparations. Exemplary oral preparations include, but are not limited to, for example, tablets, troches, lozenges, oily and aqueous suspensions, dispersible powders or granules, emulsions, soft and hard capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration may be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition according to the invention can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, emollients, antioxidants, and preserving agents.

[00178] A tablet can, for example, be prepared by mixing at least one compound of Formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc. Additionally, a tablet can be unreacted, or reacted by known techniques to mask the bad taste of an unpleasant tasting drug, or to delay disintegration and absorption of the active ingredient in the gastrointestinal tract, thus sustaining the effects of the active ingredient over a longer period. Exemplary water soluble taste masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[00179] Hard gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one inert solid diluent, such as, for example, calcium carbonate; Calcium phosphate; and kaolin.

[00180] Soft gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one water-soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.

[00181] An aqueous suspension can be prepared, for example, by mixing at least one compound of Formula (I) with at least one excipient suitable for the manufacture of an aqueous suspension. Excipients suitable for making an aqueous suspension include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinyl -pyrrolidone, gum tragacanth, and gum acacia; wetting or dispersing agents, such as, for example, a naturally occurring phosphatide, for example lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long-chain aliphatic alcohols, such as, for example, heptadecaethyleneoxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension may also contain at least one preservative, such as, for example, ethyl n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including, but not limited to, for example, sucrose, saccharin, and aspartame.

[00182] Oily suspensions can, for example, be prepared by suspending at least one compound of Formula (I) in a vegetable oil, such as, for example, peanut oil, olive oil, sesame oil and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension may also contain at least one thickening agent, such as, for example, beeswax, hard paraffin and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described above, and/or at least one flavoring agent can be added to the oily suspension. An oily suspension may also contain at least one preservative, including, but not limited to, for example, an antioxidant, such as, for example, butylated hydroxyanisole and alpha-tocopherol.

[00183] Dispersible powders and granules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one wetting and/or dispersing agent; at least one suspending agent; and/or at least one condom. Suitable dispersing agents, wetting agents, and suspending agents are as already described above. Exemplary preservatives include, but are not limited to, for example, antioxidants, e.g., ascorbic acid. Furthermore, dispersible powders and granules may also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.

[00184] An emulsion of at least one compound of Formula (I) may, for example, be prepared as an oil-in-water emulsion. The oil phase of emulsions comprising compounds of Formula (I) may be constituted from known ingredients in known manner. The oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and peanut oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phrase can comprise only one emulsifier, it can comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally occurring phosphatides, for example, soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included along with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) prepare(s) the so-called emulsifying wax, and the wax together with the oil and fat prepare the so-called emulsifying ointment base which forms the oily dispersed phase of cream formulations. An emulsion may also contain a sweetening agent, a flavoring agent, a preservative, and/or an antioxidant. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.

[00185] The compounds of Formula (I) can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly by means of any suitable and pharmaceutically acceptable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and oleaginous or aqueous suspensions.

[00186] The formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules using one or more of the vehicles or diluents mentioned for use in the formulations for oral administration or using other suitable wetting or dispersing agents and suspending agents. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, gum tragacanth, and/or various buffers . Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable vehicles including saline, dextrose, or water, or with cyclodextrin (i.e., CAPTISOL®), co-solvent solubilization (i.e., propylene glycol), or micellar solubilization (i.e., , Tween 80).

[00187] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any white fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[00188] A sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one compound of Formula (I) in an oil phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining Formula (I) containing oil phase with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.

[00189] A sterile oleaginous or aqueous suspension can be prepared according to methods known in the art. For example, a sterile aqueous solution or suspension can be prepared with a non-toxic, parenterally acceptable diluent or solvent, such as, for example, 1,3-butane diol; and a sterile oleaginous suspension may be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, for example, synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.

[00190] Pharmaceutically acceptable vehicles, adjuvants, and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS ) such as d-alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tweens, polyethoxylated castor oil, such as CREMOPHOR® surfactant (BASF), or other similar polymeric release matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate , disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polymers of polyethylene-polyoxypropylene, polyethylene glycol and la-nolin block. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrins, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance the release of compounds of the formulas described here.

[00191] The pharmaceutically active compounds of this invention can be processed according to conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may undergo conventional pharmaceutical operations, such as sterilization, and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants such as wetting, sweetening, flavoring and perfuming agents.

[00192] The amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depend on a variety of factors, including age, weight, sex, medical condition of the subject, the type of disease, the severity of the disease, the routine and frequency of administration, and the particular compound employed. Thus, the dosage regimen can vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg/kg of body weight, preferably between about 0.0025 and about 50 mg/kg of body weight, and more preferably between about 0.005 to 10 mg/kg of body weight, can be appropriate. The daily dose can be administered in one to four doses per day. Other dosage ranges include one dose per week and one dose per two-day cycle.

[00193] For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated administration routine. If administered orally, the compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of acid phosphoric and sulfuric acid, gelatin, gum acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.

[00194] Pharmaceutical compositions of this invention comprise at least one compound of Formula (I) and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant and vehicle. Alternative compositions of this invention comprise a compound of Formula (I) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

UTILITY

[00195] The compounds of the invention modulate kinase activity, including modulation of Btk. Other types of kinase activity that can be modulated by the compounds of the present invention include, but are not limited to, the Tec family of kinases, such as BMX, Btk, ITK, TXK and Tec, and mutants thereof.

[00196] Consequently, compounds of Formula (I) have utility in the treatment of conditions associated with modulation of kinase activity, and particularly, selective Btk inhibition activity. Such conditions include B-cell mediated diseases in which cytokine levels are modulated as a consequence of intracellular signaling.

[00197] As used herein, the terms "treat" or "treatment" encompass either or both responsive and prophylactic measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a reduction all or part of the symptoms or disease state, and/or alleviate, ameliorate, reduce, or cure the disease or disorder and/or its symptoms.

[00198] In view of their activity as selective Btk inhibitors, compounds of Formula (I) are useful in the treatment of conditions associated with the cytokine including, but not limited to, inflammatory diseases such as Crohn's and colitis ulcerative disease, asthma, graft-versus-host disease, and chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus and psoriasis; destructive bone disorders such as bone-resorbing disease, osteoarthritis, osteoporosis, and bone disorder related to multiple myeloma; proliferative disorders such as acute myelogenous leukemia and chronic myelogenous leukemia; angiogenic disorders, such as solid tumors, ocular neovasculization, and infantile hemangiomas; infectious diseases, such as sepsis, septic shock, and shigellosis; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury, oncological and viral diseases such as metastatic melanoma, Ka-posi sarcoma, multiple myeloma, HIV infection, AIDS and CMV retinitis .

[00199] More particularly, specific conditions or diseases that can be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, arthritis rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren's syndrome, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel, ulcerative colitis, Crohn's disease, psoriasis, graft versus host disease, endotoxin-induced inflammatory reaction, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis , acute synovitis, pancreatic B-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy (CIDP), dermatomyositis, uveitis, anti-factor VIII disease, ankylosing spondylitis, myasthenia gravis, Goodpasture's disease, antiphospholipid syndrome, ANCA-associated vasculitis , dermatomyositis/polymyositis, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, bone resorptive disease, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, myeloid formation, scar tissue formation, ulcerative colitis , pyresis, influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovasculization, and infantile hemangiomas; viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; stroke, myocardial ischemia, ischemia in stroke heart attacks, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion damage, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock, conditions associated with prostaglandin endoperoxidase syndase-2, and pemphigus vulgaris.

[00200] Preferred methods of treatment are those where the condition is selected from Crohn's and ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, pemphigus vulgaris and multiple sclerosis. Alternative preferred methods of treatment are those in which the condition is selected from ischemia reperfusion damage, including cerebral ischemia reperfusion damage arising from stroke and cardiac ischemia reperfusion damage arising from myocardial infarction. Another preferred treatment method is one where the condition is multiple myeloma.

[00201] Furthermore, the Btk inhibitors of the present invention inhibit the expression of inducible proinflammatory proteins, such as prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2). Consequently, additional Btk-associated conditions include edema, analgesia, fever, and pain, such as neuromuscular pain, headache, cancer pain, dental pain, and arthritis pain. The inventive compounds can also be used to treat veterinary viral infections, such as lentivirus infections, including, but not limited to, equine infectious anemia viruses; or retrovirus infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.

[00202] When the terms "condition associated with Btk" or "disease or disorder associated with Btk" are used herein, each is intended to encompass all of the conditions identified above, when repeated throughout, as well as any other condition that is affected by Btk activity.

[00203] "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit Btk.

[00204] One embodiment provides methods of treating such conditions associated with Btk kinase, comprising administering to a subject in need thereof at least one compound of Formula (I). A therapeutically effective amount for treating such conditions can be administered. The methods of the present embodiment can be employed to treat conditions associated with Btk kinase, such as treatment of allergic disorders and/or autoimmune and/or inflammatory diseases including, but not limited to, SLE, rheumatoid arthritis, multiple vasculitides, purpura idiopathic thrombocytopenic (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold agglutinin diseases, and fever, Evans syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathies (eg, Guillain-Barre syndrome), pemphigus vulgaris, and asthma.

[00205] Methods of treating conditions associated with Btk kinase may comprise administering at least one compound of Formula (I) alone or in combination with each other and/or other suitable therapeutic agents in treatment of such conditions. Therapeutically effective amounts of at least one compound of Formula (I) and other therapeutic agents suitable for treating such conditions can be administered. Accordingly, "therapeutically effective amount" is also intended to include an amount of the combination of claimed compounds that is effective to treat conditions associated with Btk kinase. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou et al., Adv. Enzyme Regul., 22:27-55 (1984), occurs when the effect (in this case, Btk inhibition) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is more clearly demonstrated at suboptimal concentrations of the compounds. The synergy may be in terms of lesser cytotoxicity, increased anti-Btk effect, or some other beneficial effect of the combination compared to the individual components.

[00206] Examples of such other therapeutic agents include corticosteroids, rolipram, calfostine, cytokine suppressive anti-inflammatory drugs (CSAIDs), 4-substituted imidazo[1,2-a]quinoxalines, as described in United States Patent No. . 4,200,750; Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors such as deoxyspergualine (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib, and rofecoxib; steroids, such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®); cytotoxic drugs such as azathirine and cyclophosphamide; TNF-α inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or RAPA-MUNE®) or derivatives thereof.

[00207] The other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one skilled in the art. . In the methods of the present invention, such other therapeutic agents can be administered before, simultaneously with, or after the administration of the inventive compounds. The present invention also provides pharmaceutical compositions capable of treating conditions associated with the Btk kinase, including conditions mediated by IL-1, IL-6, IL-8, IFNY and TNF-α, as described above.

[00208] The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, to employ conventional solid or liquid carriers, as well as pharmaceutical additives of a type appropriate to the desired mode of administration (e.g., excipients, binders, preservatives, stabilizers, flavorings, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.

[00209] Another embodiment provides the compounds of Formula (I) for use in therapy. In the present embodiment, use in therapy can include administering a therapeutically effective amount of a compound of Formula (I).

[00210] The present invention also provides the use of the compounds of Formula (I) for the manufacture of a medicament for the treatment or prophylaxis of an allergic disorder and/or autoimmune and/or inflammatory disease. In the present embodiment, use for the manufacture of a medicament may include administering a therapeutically effective amount of a compound of Formula (I) for the prophylactic treatment of an allergic disorder and/or autoimmune disease and/or inflammation. kill.

[00211] The present invention also provides the use of the compounds of Formula (I) for the manufacture of a medicament for the treatment of cancer. The present embodiment may include use for the manufacture of a medicament which includes administering a therapeutically effective amount of a compound of Formula (I) for the prophylactic treatment of an allergic disorder and/or autoimmune and/or inflammatory disease .

[00212] Accordingly, the present invention also includes compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier.

[00213] A "pharmaceutically acceptable carrier" refers to means generally adopted in the art for delivering biologically active agents, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the skill of those skilled in the art. These include, without limitation, the type and nature of the active agent being formulated; the individual to whom the agent-containing composition is to be administered; the intended routine of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, for example, active agent stabilization, binders, etc., well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable vehicles, and factors involved in their selection, are found in a variety of readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 17th Edition (1985), which is incorporated herein by reference in its entirety.

[00214] The compounds of Formula (I) may be administered by any methods suitable for the condition being treated, which may depend on the site-specific need for treatment or amount of drug to be delivered. Topical administration is generally preferred for skin-related conditions, and systematic treatment preferred for cancerous or precancerous conditions, although other modes of delivery are contemplated. For example, the compounds can be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, in the form of solutions, suspensions, gels or ointments; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal infusion or injection techniques (for example, as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally, such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable carriers or diluents can be administered. The compounds can be administered in a form suitable for immediate release or sustained release. Immediate release or sustained release can be achieved with suitable pharmaceutical compositions or, particularly in the case of sustained release, with devices such as subcutaneous implants or osmotic pumps.

[00215] Examples of compositions for topical administration include a topical vehicle such as Plastibase (mineral oil gelled with polyethylene).

[00216] Examples of compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose to impart filler, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetening or flavoring agents , such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants, such as those known in the art . The inventive compounds may also be delivered orally by sublingual and/or buccal administration, for example, with molded, compressed, or freeze-dried tablets. Exemplary compositions may include rapidly dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. High molecular weight excipient compositions, such as celluloses (AVICEL®) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (eg, Gantrez); and agents to control release, such as polyacrylic copolymer (eg, Carbopol 934). Lubricants, glidants, flavorings, coloring agents and stabilizers can also be added for ease of manufacture and use.

[00217] Exemplary compositions for administration or inhalation or nasal spray include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents, such such as those versed in the art.

[00218] Examples of compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, a chloride solution isotonic sodium hydroxide, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[00219] Examples of compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but if liquefy and/or dissolve in the rectal cavity to release the drug.

[00220] The therapeutically effective amount of a compound of the present invention can be determined by one skilled in the art, and includes exemplary dosage amounts for a mammal of about 0.05 to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250mg/kg; 250-1000 mg/kg body weight of active compound per day, which may be administered in a single dose or in the form of single divided doses, such as 1 to 4 times daily. It will be understood that the specific dose level and frequency of dosing for any particular individual can be varied and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and time course of action of that compound, the species, age, body weight, general health, sex and diet of the subject, mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, more preferably mammalian species, such as humans, and domestic animals, such as dogs, cats, horses, and the like. Thus, when the term "patient" is used herein, this term is intended to include all individuals, most preferably mammalian species, who are affected mediated by Btk enzyme levels.

[00221] Examples of compounds of Formula (I) as specified in the "Examples" section below, were tested in one or more of the assays described below.

[00222] In one embodiment, the compounds of Formula (I) inhibit Btk enzymes with IC50 values of 10 nM or less, for example, from 0.001 to 10 nM, as measured by recombinant human Btk enzyme assay. Preferably, the compounds of Formula (I) inhibit Btk enzymes with IC50 values of 2 nM and less, for example from 0.001 to 2 nM. Other preferred compounds inhibit Btk enzymes with IC50 values of 1.0 nM and less, for example from 0.001 to 1.0 nM.

[00223] In one embodiment, the compounds of Formula (I) have useful potency in inhibiting intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 250 nM or less, e.g., 0 ,1 at 250 nM. More preferably, the compounds of Formula (I) have potency in inhibiting intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM with IC50 values of 160 nM or less, for example, from 0.1 to 160 nM; and with IC50 values of 100 nM or less, for example, from 0.1 to 100 nM.

[00224] In one embodiment, the compounds of Formula (I) inhibit Btk enzymes with IC50 values of 2 nM or less, for example, from 0.001 to 2 nM, when measured by the Recombinant Human Btk enzyme assay, and inhibit the intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 500 nM or less, for example, from 0.1 to 500 nM.

[00225] In one embodiment, the compounds of Formula (I) inhibit Btk enzymes with IC50 values of 2 nM or less, for example, from 0.001 to 2 nM, when measured by the Recombinant Human Btk enzyme assay, and inhibit the intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 150 nM or less, for example, from 0.1 to 150 nM.

[00226] In one embodiment, the compounds of Formula (I) inhibit Btk enzymes with IC50 values of 2 nM or less, for example, from 0.001 to 2 nM, when measured by the Recombinant Human Btk enzyme assay, and inhibit the intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 60 nM or less, for example, from 0.1 to 60 nM.

[00227] In one embodiment, compounds of Formula (I) inhibit Btk enzymes with IC50 values of 1 nM and less, for example, 0.001 to 1 nM, when measured by the Recombinant Human Btk enzyme assay, and inhibit the intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 500 nM or less, for example, from 0.1 to 500 nM.

[00228] In one embodiment, compounds of Formula (I) inhibit Btk enzymes with IC50 values of 1 nM and less, for example, 0.001 to 1 nM, when measured by the Recombinant Human Btk enzyme assay, and inhibit the intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 150 nM or less, for example, from 0.1 to 150 nM.

[00229] In one embodiment, the compounds of Formula (I) inhibit Btk enzymes with IC50 values of 1 nM or less, for example, from 0.001 to 1 nM, when measured by the Recombinant Human Btk enzyme assay, and inhibit the intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 60 nM or less, for example, from 0.1 to 60 nM.

[00230] In one embodiment, compounds of Formula (I) inhibit Btk enzymes with IC50 values of 0.5 nM and less, for example, 0.001 to 0.5 nM, when measured by the Recombinant Human Btk enzyme assay , and inhibit intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 500 nM or less, for example, from 0.1 to 500 nM.

[00231] In one embodiment, the compounds of Formula (I) inhibit Btk enzymes with IC50 values of 0.5 nM and less, for example, 0.001 to 0.5 nM, when measured by the Recombinant Human Btk enzyme assay , and inhibit intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 150 nM or less, for example, from 0.1 to 150 nM.

[00232] In one embodiment, the compounds of Formula (I) inhibit Btk enzymes with IC50 values of 0.5 nM or less, for example, from 0.001 to 0.5 nM, when measured by the Recombinant Human Btk enzyme assay , and inhibit intracellular calcium flux in RA1 Ramos B cells stimulated with anti-human IgM, with IC50 values of 60 nM or less, for example, from 0.1 to 60 nM.

PREPARATION METHODS

[00233] The compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, along with synthetic methods skilled in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in a solvent or solvent mixture appropriate for the reagents and materials employed and suitable for the transformations being carried out. It will be understood by those skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the proposed transformations. This will sometimes require diagnostics to modify the order of synthetic steps or to select a particular processing scheme over another in order to obtain a desired compound of the invention.

[00234] It will be recognized by one skilled in the art of organic synthesis that some functional groups present in intermediate compounds, or in compounds of Formula (I), may be unstable to, or otherwise unsuitable for, some of the reaction conditions used to prepare them or to convert them to other intermediates or to compounds of Formula (I). In these cases, the functional groups can be protected by conversion to alternative functional groups that are more stable to or suitable for the reaction conditions being employed. These protected functional groups can then be converted back to the original functional group at a later stage of the synthesis. Examples are the protection of a carboxylic acid such as a carboxylate ester, the protection of a primary or secondary amine such as a tert-butyloxycarbonyl (Boc) derivative or benzyloxycarbonyl (Cbz) derivative, or the protection of a nitrogen of indole as a 2-trimethylsilylethoxymethyl (SEM) derivative. The use of protecting groups is well known in the literature; an authoritative description describing the many alternatives to trained tractic is Wuts, P. et al., Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wiley-Interscience (2006).

[00235] Compound 3, representing certain compounds of Formula (I), can be prepared using methods shown in Scheme 1. Scheme 1

[00236] A substituted indolecarboxamide compound 1, where Y is a suitable group such as Br, Cl, or trifluoromethanesulfonyloxy, can be reacted with a boronic acid or boronic acid ester compound 2, where Ar represents one of the A groups of Formula (I) wherein the point of attachment to the indole moiety is located on a benzene or pyridine ring of A, to give compound 3. This reaction may be carried out using a suitable base such as potassium carbonate, cesium carbonate or sodium phosphate. tripotassium, and a suitable catalyst, such as tetracis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride, or 1,1'-bis(di-tert-butylphosphino)ferrocene palladium chloride (II), in a suitable solvent such as 1,4-dioxane, N,N-dimethylformamide or tetrahydrofuran, optionally with one or more suitable co-solvents, such as water or ethanol. Such coupling reactions are commonly known as Suzuki-Miyaura coupling reactions, and are well known in the chemical literature (see, for example, Heravi, M. et al., Tetrahedron, 68:9145 (2012), and references cited here). .

[00237] Alternatively, a substituted indolecarboxamide compound 1 can be converted to the corresponding boronic acid or boronic acid ester compound 4 using methods well known in the chemical literature (see, for example, Ishiyama, T. et al., Tetrahedron, 57:9813 (2001), and references cited therein). Examples of such methods are the reaction of a compound 1 with a reagent such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3, 2-dioxaborolane) or 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) in the presence of a base such as potassium acetate and a suitable catalyst such as chloride of 1,1'-bis(diphenylphosphino)ferrocene palladium(II) in a suitable solvent to provide a boronic acid ester compound 4. Alternatively, reaction of compound 1 where Y is Br with an organometallic reagent, such as butyl lithium chloride or isopropylmagnesium, followed by treatment with a boronic acid ester, such as trimethyl borate or triisopropyl borate, then followed by upon hydrolysis of the resulting boronic acid ester, can provide a boronic acid compound 4 (R = H). The reaction of a compound 4 with a suitable compound 5, wherein Ar represents one of the groups A of Formula (I) in which the point of attachment to the indole moiety is located on a benzene or pyridine ring of A, and Y is a group An appropriate compound such as Br, Cl, or trifluoromethanesulfonyloxy, using the Suzuki-Miyaura coupling reaction as described above, can also provide compound 3.

[00238] A compound 2 can be prepared from a compound 5 using the same method described for the preparation of a compound 4 from a compound 1.

[00239] Certain compounds of Formula (I), represented by 7, can be prepared using methods illustrated in Scheme 2. Scheme 2

[00240] These methods involve reacting a compound 6 carrying a primary or secondary amine (i.e. where XH represents an A group of Formula (I) where Q1 is replaced by NHR7 or C(R10)2NHR7, or where Q2 is replaced by H) with an appropriate reagent Q-Z, where Q represents Q2, an optionally substituted quinazoline-4-yl, or 4,6-dichloro-1,3,5-triazin-2-yl, or a precursor to such a group, and Z represents a leaving group, such as Cl or OH, to give compound 7, where XQ represents one of the A groups of Formula (I) resulting from such a reaction. Such amine reactions are well known in the literature. An example of such a reaction is acylation of the amine with a carboxylic acid chloride or a carboxylic acid anhydride, usually carried out in a suitable solvent such as tetrahydrofuran, ethyl acetate, acetonitrile, or dichloromethane, usually in the presence of a base. such as triethylamine, diisopropylethylamine, pyridine, or an aqueous solution of an inorganic base such as sodium hydroxide or potassium carbonate. Alternatively, a solvent such as pyridine can be used, in which case the solvent can also serve as a base.

[00241] Another example of a reaction shown in Scheme 2 is acylation of the amine of a compound 6 with a carboxylic acid using any of a number of amide coupling reagents well known in the literature, for example, hexafluorophosphate (benzotriazole-1 -yloxy)tris(dimethylamino)phosphonium (also known as BOP or Castro Reagent), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (also known as HATU) , or a reagent such as N,N-dicyclohexylcarbodiimide (also known as DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (also known as EDC) in the presence of a co-reagent such as 1- hydroxybenzotriazole (also known as HOBT) or 1-hydroxy-7-azabenzotriazole (also known as HOAT). Such reactions are usually carried out in a suitable solvent such as ethyl acetate, dichloromethane, tetrahydrofuran, N,N-dimethylformamide or N-methylpyrrolidin-2-one, in the presence of a suitable base such as triethylamine or diisopropylethylamine.

[00242] Another example of a reaction shown in Scheme 2, which can be used to prepare a compound 7, where Q is SO2CH=CHR10, is the treatment of the amine of a compound 6 with an appropriate 2-chloroethanesulfonyl chloride, in a suitable solvent such as dichloromethane or tetrahydrofuran, in the presence of a base such as triethylamine or diisopropylethylamine. In this case, a 2-chloroethanesulfonamide intermediate can be formed, which in the presence of base can undergo HCl loss to provide the desired ethylenesulfonamide.

[00243] Another example of a reaction shown in Scheme 2, which can be used to prepare a compound 7 where Q is 4,6-dichloro-1,3,5-triazin-2-yl or an optionally substituted quinazolin-4- yl, is the reaction of the amine of a compound 6 with cyanuric chloride or an optionally substituted 4-chloroquinazoline, respectively, in a suitable solvent such as tetrahydrofuran, in the presence of a suitable base such as potassium carbonate.

[00244] Another example of a reaction shown in Scheme 2, which can be used to prepare a compound 7 where Q is CN, is the reaction of the amine of a compound 6 with cyanogen bromide in a suitable solvent such as N,N -dimethylformamide, in the presence of a suitable base, such as cesium carbonate.

[00245] Certain compounds of Formula (I) can be prepared from certain other compounds of Formula (I) using methods shown in Scheme 3. Scheme 3

[00246] A compound 8 where R represents an optionally substituted benzyl group (which is an example of a compound of Formula (I)) can be converted into the corresponding hydroxy compound 9 (also an example of a compound of Formula (I) )) using methods well known in the literature, for example, by treatment with hydrogen in the presence of a suitable catalyst, such as palladium on charcoal in a suitable solvent, such as ethanol, or (when R is p-methoxybenzyl) by treatment with a strong acid, such as trifluoroacetic acid in an appropriate solvent. A compound 9 can be converted to another compound of Formula (I), represented by 10, by treatment with an alkylating agent, such as an optionally substituted alkyl bromide, alkyl chloride, alkyl iodide or alkyl sulfonate ester. alkyl, in a suitable solvent and in the presence of a suitable base such as potassium carbonate.

[00247] Certain intermediate compounds 6 of Scheme 2 can be prepared using methods analogous to those shown in Scheme 1, as shown in Scheme 4. Scheme 4

[00248] Reaction of a compound 1 with a boronic acid ester or boronic acid compound 11 (where XP is analogous to XH in Scheme 2; P can be either H or a suitable amine protecting group such as, for example, tert-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz), which are well known in the literature as protecting groups for amines), using the Suzuki-Miyaura coupling as described above (Scheme 1), can provide the corresponding compound 6 after removal of the group of P protection if necessary. If P in compound 11 represents H, compound 6 can be obtained directly.

[00249] By analogy to the methods illustrated in Scheme 1, an alternative method for preparing compound 6 of Scheme 2 is also shown in Scheme 4. Reaction of a boronic acid ester or boronic acid compound 4 of Scheme 1 with a compound 12 , where Y is a suitable leaving group, such as Br, Cl or trifluorosulfonyloxy, using the Suzuki-Miyaura coupling as described above, can also provide a compound 6. As described above, P can either be H, or a group of adequate protection in which case deprotection may provide compound 6.

[00250] Furthermore, a compound 11 can be prepared from a compound 12 using the same method described for the preparation of a compound 4 from a compound 1 (Scheme 1).

[00251] Compounds 15, which are examples of compounds 6 of Scheme 2, can be prepared using methods shown in Scheme 5. Scheme 5

[00252] Reaction of a compound 1 with a vinylic boronic acid ester or boronic acid compound 13, where P is a suitable amine-protecting group such as Boc or Cbz and m is 1 or 2, using the Suzuki- Miyaura as described above (see Scheme 1) can provide a compound 14. The double bond of the dihydropyrrole (m=1) or tetrahydropiperidine (m=2) ring of 14 can be reduced using methods well known in the literature, for example, by treatment with hydrogen in the presence of a suitable catalyst, such as palladium adsorbed on charcoal, in a suitable solvent such as methanol or ethanol, followed by removal of the protecting group using methods well known in the literature, to provide a compound 15. (If P represents a Cbz group, removal of the protecting group can be achieved in the same reaction as reduction of the double bond.) Alternatively, the order of steps for converting a compound 14 to a compound 15 can be reversed: a protecting group P can be removed using a suitable method, followed by hydrogenation of the double bond as described.

[00253] Compounds 19, representing certain compounds 6 of Scheme 2, can be prepared as shown in Scheme 6. Scheme 6

[00254] Reaction of a compound 1 with a dehydrating agent, such as phosphorus oxychloride, using methods well known in the literature, can provide a compound 16. Treatment of a compound 16 with a suitable mono-protected diamine, such as an aminopyrrolidine , an aminopiperidine, a piperazine, an octahydropyrrolopyrrole or an octahydropyrrolopyridine (represented by HN-X-NP, 17, where P may represent a suitable protecting group such as Cbz or Boc) can provide the corresponding compound 18. Conversion of a compound 16 into a compound 18 can be obtained using a suitable palladium catalyst, such as, for example, tris(dibenzylideneacetone)dipalladium, a linker such as, for example, 2,2'-bis(diphenylphosphine)-1,1 '-binaphthalene (also known as BINAP) or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (also known as Xantphos), and a base such as cesium carbonate or sodium tert-butoxide, in a suitable solvent such as 1,4-dioxane, toluene, N,N-dimethylacetamide or N-methylpyrrolidin-2-one. This reaction, commonly referred to as the Buchwald coupling, is well known in the literature (see, for example, Surry, D. et al., Angew. Chem., 47:6338 (2008), and references cited here). The nitrile moiety of a compound 18 can be hydrolyzed to the corresponding amide by treatment under suitable conditions, for example by heating with concentrated aqueous sulfuric acid, to provide compound 19, which is an example of a compound 6 of Scheme 2. A protecting group P, if present in a compound 18, can be removed during this reaction, or alternatively can be removed before or after the nitrile hydrolysis step using methods well known in the chemical literature.

[00255] Note that in some cases a compound 18 or 19 may possess a chiral center, for example when 17 represents a non-symmetric 3-aminopyrrolidine, 3-aminopiperidine, octahydropyrrolopyridine, or octahydropyrrolopyrrole. In these cases, a compound 18 or 19 can be prepared in racemic form using a racemic compound 17 in the Buchwald coupling step. Alternatively, a compound 18 or 19 having a chiral center can be prepared in enantiomerically pure or enantiomerically enriched form using an enantiomerically pure or enantiomerically enriched compound 17 during the Buchwald coupling step. Alternatively, in cases where a chiral center is present, an enantiomerically pure or enantiomerically enriched compound 18 or 19 can be prepared from a racemic compound 18 or 19, respectively, using optical resolution methods, well known in the literature, for example, by selective crystallization of a diastereomeric salt formed with an enantiomerically pure or enantiomerically enriched acid, or by chromatography on a stationary phase.

[00256] Compound 19, representing certain compounds 6 of Scheme 2, can also be prepared as shown in Scheme 7. Scheme 7

[00257] Conversion of a carboxylic acid 20 into an ester 21, such as a methyl ester (R = CH3) or ethyl ester (R = C2H5), can be achieved using well-known methods, such as treatment with an acid catalyst, such as sulfuric acid in a suitable alcoholic solvent such as methanol or ethanol. Using the Buchwald coupling procedure described for Scheme 6, a compound 21 can be converted to a compound 22. The carboxylic acid ester of a compound 22 can be converted to the corresponding amide, providing a compound 19 (with removal of the protecting group p if appropriate), using well known methods, such as hydrolysis of the ester, using a suitable base such as aqueous lithium hydroxide or sodium hydroxide, optionally in a suitable cosolvent, such as methanol, ethanol or tetrahydrofuran. The resulting carboxylic acid 22 (R=H) can then be converted to the amide 19, using methods well known in the literature, for example, by converting the carboxylic acid to the corresponding acid chloride, by treatment with oxalyl chloride or thionyl, followed by treatment with ammonia; or by treating the carboxylic acid with ammonia or ammonium chloride in the presence of a coupling reagent such as dicyclohexylcarbodiimide, or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole or 1-hydroxy -7- azabenzotriazole.

[00258] Certain compounds 23 (which are examples of compounds 6 of Scheme 2) can be prepared by a method shown in Scheme 8. Scheme 8

[00259] A compound 24 (where Z represents CN, which is an example of a compound 18 of Scheme 6; or where Z represents a carboxylic acid ester, which is an example of a compound 22 of Scheme 7; and m and n are selected to form an appropriate piperidine or pyrrolidine ring) can be converted to the corresponding compound 25 using methods known in the literature, such as alkylation with an appropriate alkyl halide, or by treatment with an appropriate aldehyde or ketone followed by reduction of the intermediate iminium compound, using a suitable reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride. The resulting compound 25 can then be converted to the corresponding compound 23 using the appropriate methods: for example, from Z is CN, using the method described for the conversion of a compound 18 to a compound 19 (Scheme 6); or if Z is a carboxylic acid ester, using the method described for converting a compound 22 into a compound 19 (Scheme 7).

[00260] Compounds 26, which are examples of compounds of Formula (I), can be prepared by a method shown in Scheme 9. A compound 27 (which can be prepared by installing a suitable protecting group such as trimethylsilylethoxymethyl on a compound 16 of Scheme 6) can be reacted with a suitable organozinc compound, such as 28, in the presence of a catalyst such as tetracis(triphenylphosphine)palladium, to provide compound 29. organozinc, commonly known as the Negishi coupling, is well known in the chemical literature (see, for example, Negishi, E. et al., Metal-Catalyzed Cross-Coupling Reactions, Second Edition, p. 815, by Meijere , A. et al., eds., Wiley-VCH (2004)). Removal of the protecting group from a compound 29 and reaction with an appropriate organostanane, such as R9Sn(CH2CH2CH2CH3)3 in the presence of a catalyst, such as tetracis(triphenylphosphine)palladium, can provide compound 30. Such a palladium-catalyzed coupling of compounds of organotin, commonly known as the Stille coupling, is well known in the chemical literature (see, for example, Stille, J., Angew. Chem., Int. Ed. Engl., 25:508 (1986)). Conversion of the nitrile of a compound 30 to the carboxamide by hydrolysis, using methods described in Scheme 6 or related methods, can provide a compound 26. In cases where R8 is not H, R8 may be present in the organozinc reagent 28. Alternatively, a compound 29 where R8 is H can be converted to the corresponding compound 29 where R8 is alkyl using methods well known in the literature, for example, by treatment with a suitable base, such as potassium bis(trimethylsilyl)amide, followed by treatment with a suitable alkylating agent, such as an iodoalkane. scheme 9

[00261] Compounds 1 (see Scheme 1) used in the preparation of compounds of Formula (I), and compounds 20 that can be used in the preparation of compounds 19 (see Scheme 7), can be prepared using procedures shown in Scheme 10 . Scheme 10

[00262] A substituted 2-aminobenzoic acid 31 (known in the literature, or prepared using procedures known in the literature) can be converted to the corresponding 2-hydrazinylbenzoic acid 32 as the hydrochloric acid salt, using methods well known in the literature, for example, by conversion to the corresponding diazonium salt by treatment with sodium nitrite in aqueous hydrochloric acid, followed by reduction with tin(II) chloride. Reaction of a compound 32 with a suitable ketone 33, such as 2-butanone or acetone, in a suitable solvent with a suitable catalyst, for example, ethanol with hydrochloric acid, toluene with p-toluenesulfonic acid or trifluoroacetic acid, or acetic acid ( in which case the solvent can also serve as the catalyst), can provide the corresponding substituted indole 20. This reaction is commonly known as the Fischer indole synthesis, and is well known in the chemical literature (see, for example, Hughes, D. , Org. Prep. Proc. Int., 25:607 (1993)). Alternatively, the Fischer indole synthesis can be carried out in two consecutive steps: a hydrazine 32 can be reacted with the appropriate ketone or aldehyde 33 under suitable conditions (such as in a suitable solvent such as ethanol or toluene, optionally with a suitable catalyst, such as p-toluenesulfonic acid) to form a hydrazone intermediate, which can be isolated and then reacted also under suitable conditions (e.g., ethanol with hydrochloric acid, aetic acid with zinc chloride, or toluene with trifluoroacetic acid) to provide a compound 20. The carboxylic acid of a compound 20 can be converted to the carboxamide of a compound 1 using methods described for the conversion of a compound 22 (R=H) to a compound 19 in Scheme 7.

[00263] An alternative method for preparing a compound 1 is shown in Scheme 11. Scheme 11

[00264] A dibromonitrobenzene 34 can be treated with an appropriate vinylic organomagnesium reagent 35 (Y' = Br or Cl) to provide a substituted indole 36. This method, commonly called the Bartoli indole synthesis, is well known in the chemical literature ( see, for example, Bartoli, G. et al., Tetrahedron Lett., 30:2129 (1989), and Dobson, D. et al., Synlett, 79 (1992)). A compound 36 can be converted to the corresponding compound 37 (P = H, a compound 20 of Schemes 7 and 9) by treatment with a suitable organolithium reagent, such as n-butyl lithium in a suitable solvent such as tetrahydrofuran , followed by treatment with carbon dioxide, then an aqueous acid to neutralize the intermediate carboxylate salt. Optionally, the indole nitrogen of compound 36 can be protected using methods well known in the literature, for example, by alkylation with 2-(trimethylsilyl)ethoxymethyl chloride to provide the corresponding 2-trimethylsilylethoxymethyl (SEM) derivative, followed by conversion into the corresponding carboxylic acid 37 (P = SEM) as described. The carboxylic acid of a compound 37 can then be converted to the carboxamide of a compound 1, using methods described for this transformation in Scheme 7. If the carboxamide thus obtained is derived from a compound 37 where P is a protecting group, deprotection using suitable methods known in the literature can then provide compound 1.

[00265] As shown in Scheme 12, a compound 38 can be converted into a compound 39, which is an example of a compound 2 of Scheme 1. Similarly, a compound 40 can be converted into a compound 41, which is an example of a compound 5 of Scheme 1. Scheme 12

[00266] In Scheme 12, Y represents a suitable group such as Br, Cl or trifluoromethanesulfonyloxy; (RO)2B represents a boronic acid or boronic acid ester; and XH represents a group A of Formula (I) linked to the indole moiety of Formula (I) via a linkage to a benzene or pyridine ring of A, however where Q1 (if present) is replaced by NHR7 or C( R10)2NHR7 or Q2 (if present) is replaced by H; and Q represents a group Q2, C(O)(C1-4 alkyl substituted by R6), C(O)(C3-6 cycloalkyl substituted by R6), dichlorotriazinyl or quinazolin-4-yl substituted by R6. Conversion of a compound 38 into a compound 39, and conversion of a compound 40 into a compound 41, can be carried out using the same methods described for the analogous transformations of a compound 6 into a compound 7 in Scheme 2. In addition, conversion of a compound 38 to a compound 40, and conversion of a compound 39 to a compound 41, can be carried out using the methods described for transforming a compound 1 into a compound 4 in Scheme 1.

[00267] Scheme 13 shows the preparation of compounds 42 and 43 (which are examples of compounds 5 of Scheme 1) and of compounds 44 and 45 (which are examples of compounds 2 of Scheme 1). Scheme 13

[00268] An isatoic anhydride 46 (where R' and R" represent optional substituents selected from F, Cl, CH3, CN and OCH3) can react with a substituted aniline 47 to produce an amide 48. Such reactions can be carried out under a variety of conditions, for example, by heating in a suitable solvent, or by heating in the presence of a reagent such as trimethylaluminium. A compound 48 can be converted to a substituted quinazolinedione 42, for example, by treatment in a suitable solvent with phosphate - gen or bis(trichloromethyl) carbonate (triphosgene) Optionally, a compound 42 can be converted to the corresponding compound 44, using methods described for converting a compound 1 to a compound 4 in Scheme 1. Alternatively, a compound 42 can optionally be converted to a compound 43 using methods well known in the chemical literature, for example by treatment with an alkylating agent such as iodomethane in the presence of a suitable base such as cesium carbonate. A compound 43 can then be converted to the corresponding compound 45 using the same methods described above. A compound 44 can also optionally be converted to the corresponding compound 45 by methods similar to those described for converting a compound 42 to a compound 43.

[00269] If R5 of a compound 42, 43, 44 or 45 is other than hydrogen, a compound 42, 43, 44 or 45 exhibits chirality, called atropisomerism, due to the prevented rotation around the single bond that connects the phenyl ring substituted to the quinazolinedione moiety, and exists as two enantiomers. These enantiomeric astropisomers can be isolated as separate compounds that are stable in interconversion under normal storage conditions. If desired, a compound 42, 43, 44 or 45 can be resolved into separate enantiomeric atropisomers, for example, by chromatography on a chiral stationary phase. A separated enantiomeric atropisomer of a compound 42 or a compound 43 can then optionally be converted to a stable enantiomeric atropisomer of a compound 44 or a compound 45, respectively, as described above.

[00270] An alternative synthesis of a compound 48 of Scheme 13 is shown in Scheme 14. A substituted 2-nitrobenzoic acid 49 can be converted into a compound 50 using well known amide formation reactions, for example by converting a compound 49 in the corresponding carboxylic acid chloride and reaction with a substituted aniline 47, or by direct reaction of a compound 49 and a compound 47 in the presence of a suitable coupling reagent, such as O-(7-azabenzotriazol-1-yl) hexafluorophosphate - 1,1,3,3-tetramethyluronium (HATU), or a mixture of 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole hydrate (HOBT), using methods well known in the literature. The nitro group of a compound 50 can then be reduced, using one of a wide variety of methods known in the literature, to provide a compound 48. Scheme 14

[00271] Other examples of compounds 2 and 5 of Scheme 1, and of compounds 11 and 12 of Scheme 4, are known in the literature, or can be prepared using methods known in the literature. For example, United States Patent No. US 8,084,620 describes preparation of a number of such compounds useful in the preparation of compounds of Formula (I).

[00272] Certain compounds of Formula (I) may exhibit impaired rotation about the bond joining the A group to the indole ring. In some cases, the impeded rotation may be such that two isomers around this bond, known as atropisomers, can be isolated as separate compounds that are stable to interconversion under ordinary storage and handling conditions. Cases where this impeded rotation can be observed are cases where R3 is not hydrogen and where A is a substituted pyridine or benzene ring carrying an R5 substituent which is also not hydrogen, or where R3 is not hydrogen and where A is, for example, a substituted 1,2,3,4-tetrahydroisoquinolin-5-yl group, a substituted 1,2,3,4-tetrahydroisoquinolin-8-yl, a 1a,2,3,7b-tetrahydro- A substituted 1H-cyclopropa[c]quinolin-7-yl, a substituted isoindolin-4-yl, a substituted 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl, a 3 a substituted ,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl, a substituted indolin-4-yl, or a 2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin-9-yl substituted. In these cases, the compounds of Formula (I) can be prepared in racemic or scalemic form, and the two atropisomers can be separated using methods known in the literature, for example by chromatography on a chiral stationary phase.

[00273] Likewise, a compound 6 of Schemes 2 and 4 may also exhibit prevented rotation about the bond joining the XH group to the indole ring, and may be isolated as separate compounds that are stable to interconversion under ordinary storage and handling conditions. Cases where this impeded rotation can be observed are where R3 is not hydrogen and where XH is a substituted benzene or pyridine anal carrying an R5 substituent which is also not hydrogen, or where R3 is not hydrogen and where XH is, for example, a optionally substituted 1,2,3,4-tetrahydroisoquinolin-5-yl group, one optionally substituted 1,2,3,4-tetrahydroisoquinolin-8-yl group, one optionally substituted 1a,2,3,7b-tetra - hydro-1H-cyclopropa[c]quinolin-7-yl, one optionally substituted isoindolin-4-yl, one optionally substituted 3,4-dihydro-2H-benzo[b][1,4]oxazin-8- yl, an optionally substituted 3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl, an optionally substituted indolin-4-yl, or an optionally substituted 2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-9-yl. In these cases, compound 6 can be prepared in racemic or scalemic form, as shown in Scheme 4, and the two atropisomers of 6 can be separated using methods known in the literature, for example by chromatographies on a chiral stationary phase. A separate enantiomeric atropisomer can then be converted into a single enantiomer of a compound 7, which represents certain compounds of Formula (I), as shown in Scheme 2.

[00274] In some cases, when the conversion of an intermediate compound into another intermediate compound or a compound of Formula (I) requires more than one synthetic reaction, the order of the individual steps may be changed. An example is shown in Scheme 12. Conversion of a compound 38 to a compound 41 can be done by (1) converting the amine of compound 38 to the substituted amine of a compound 39, followed by (2) conversion of the Y group of compound 39 to the boronic acid or boronic acid ester of compound 41. Alternatively, the same conversion of a compound 38 to a compound 41 can be accomplished by (1) converting the Y group of compound 38 to the boronic acid or boronic acid ester boronic acid of compound 40, followed by (2) conversion of the amine of compound 40 to the substituted amine of compound 41. Such cases will be recognized by one skilled in the art of organic synthesis.

EXAMPLES

[00275] Compounds of the present invention, and intermediates used in preparing compounds of the present invention, can be prepared using procedures shown in the following examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not intended to be limiting, but are intended to demonstrate how the compounds of the present invention can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or can be prepared using procedures described in the chemical literature. The invention is also defined by the following examples. It should be understood that the examples are given by way of illustration only. From the above description and examples, one skilled in the art can ascertain the essential features of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples mentioned here below, but rather defined by the claims appended thereto.

[00276] In the examples given, the phrase "dried and concentrated" generally refers to the removal of most residual water from a solution in an organic solvent, using either anhydrous sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtered (usually under reduced pressure and at a temperature suitable for the stability of the material being prepared). Column chromatography was usually performed using the flash chromatography technique (Still, W. et al., J. Org. Chem., 43:2923 (1978)), or with pre-packaged silica gel cartridges using an apparatus. of Isco medium pressure chromatography (Teledyne Corporation), eluting with the indicated solvent or solvent mixture. Preparative high pressure liquid chromatography (HPLC) was performed using a reversed phase column (Waters SunFire C18, Waters XBridge C18, PHENOMENEX® Axia C18, YMC S5 ODS or similar) of an appropriate size for the amount of material being used. being separated, usually eluting with a gradient of increasing concentration of methanol or acetonitrile in water, also containing 0.05% or 0.1% trifluoroacetic acid or 10 mM ammonium acetate, at an elution rate suitable for the column size and separation to be obtained. Supercritical fluid chromatography (SFC), a form of normal phase HPLC using a mobile phase containing CO2 from super- or subcritical fluid and polar organic modifiers such as alcohols, has been used to separate chiral compounds (White, C et al., J. Chromatography A, 1074:175 (2005)). Chiral SFC separation of enantiomers or diastereomers was performed using conditions described for the individual cases. Mass spectral data were obtained by liquid chromatography mass spectrometry using electrospray ionization. Chemical names were determined using CHEMDRAW® Ultra, version 9.0.5 (CambridgeSoft). The following abbreviations are used: AcCN acetonitrile BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BOP benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate DCM dichloromethane DDQ 2,3-dichloro-5, 6-dicyano-1,4-benzoquinone DIEA diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf EDC 1, 1'-bis(diphenylphosphino)ferrocene 1-[3-(dimethylamino)propyl]-3-ethyl- hydrochloride carbodiimide EtOAc ethyl acetate h hour (s) HATU O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOBT 1-hydroxybenzotriazole hydrate MeCN acetonitrile MeOH methanol min minute (s) NBS N-bromosuccinimide PdCl2(dppf) Pd2(dba)3 Pd(PPh3)4 TFA 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) tris-(dibenzylideneacetone)dipalladium tetracis(triphenylphosphine)palladium trifluoroacetic acid THF tetrahydrofuran HPLC high pressure liquid chromatography g gram (s) mL milliliter (s) µL microliter (s) mmol millimol (s) Intermediate 1 4-Bromo-2,3-dimethyl-1H-indole-7-carboxamide Intermediate 1A: 4-Bromo-2,3-dimethyl-1H-indole-7-carboxylic acid

[00277] A suspension of 4-bromo-2-hydrazinylbenzoic acid hydrochloride [prepared in accordance with United States Patent No. 8,084,620, Intermediate 46-1, Step 1] (5.87g, 21.9mmol) in acetic acid (73ml) at 75°C was treated with 2-butanone (9.8ml, 110mmol). The mixture was heated in an oil bath at 110 °C. After 18 hours, the mixture was concentrated under vacuum to provide a dark brown solid. The residue was suspended in EtOAc and the insoluble material was collected by filtration, washed with EtOAc and air dried. The filtrates were concentrated and the residue was resuspended in EtOAc. Additional solid was collected by filtration, washed with EtOAc and air dried. The two solids combined to give 4-bromo-2,3-dimethyl-1H-indole-7-carboxylic acid as a brown solid (4.63 g, 79% yield). LCMS (M+H)+ m/z 268, 270. 1H NMR (400 MHz, DMSO-d6) δ 13.29-12.97 (m, 1H), 10.87 (br.s., 1H), 7.48 (d, J=7.9 Hz, 1H), 7.20 (d, J=8.1 Hz, 2H), 2.40 (s, 3H), 2.36 (s, 3H).

Intermediate 1:

[00278] A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxylic acid (4.63 g, 17.3 mmol), EDC (4.97 g, 25.9 mmol) and HOBT (3.44 g, 22.5 mmol) in THF (276 mL) and DCM (69 mL) was stirred at room temperature for 1 h, then treated with 28% aqueous ammonium hydroxide (5.38 mL, 138 mL). mmol). The resulting suspension was stirred at room temperature for 4 days. The mixture was concentrated and the residue partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted again with EtOAc. The combined organic layers were washed with brine, dried and concentrated to give 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide as a yellow solid (3.34 g, 72% yield). Mass spectrum m/z 267, 269 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.01 (br. s., 1H), 7.48-7.31 (m, 2H), 7.14 (d , J=7.9 Hz, 1H), 2.39 (d, J=0.4 Hz, 3H), 2.34 (s, 3H). Intermediate 2 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Intermediate 2A: 4-bromo-2,5-difluorobenzoic acid

[00279] A solution of 1,4-dibromo-2,5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice - acetone bath was treated dropwise with 2 .5 M n-butyllithium in hexanes (1.04 mL, 2.59 mmol). The resulting solution was stirred at -78 °C for 30 minutes, then treated with a piece of dry ice. The cooling bath was removed after 5 minutes and the mixture was stirred for another 30 minutes while warming to room temperature. The mixture was diluted with EtOAc and water. The organic phase was separated and washed twice with saturated aqueous NaHCO3. The combined aqueous phases were acidified with 1M aqueous HCl, extracted twice with DCM, and the combined organic phases were dried and concentrated to give 4-bromo-2,5-difluorobenzoic acid as a white solid (297 mg, 53% income). Intermediate 2B: 4-Bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride

[00280] A mixture of 4-bromo-2,5-difluorobenzoic acid (2.50 g, 10.6 mmol) and hydrazine (3.81 mL, 121 mmol) in N-methyl-2-pyrrolidinone (2 mL) was heated at 95°C for 4 hours. The cooled mixture was poured into vigorously stirred 6M aqueous HCl (400 mL) which was cooled in an ice-NaCl bath. The resulting precipitate was collected by filtration, washed with 6M aqueous HCl (200 mL) and dried under vacuum to provide 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride as a yellow solid (1.88 g, 71 % purity, 44% yield), used without further purification.

Alternative synthesis of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride:

[00281] A suspension of 2-amino-4-bromo-5-fluorobenzoic acid (10.0 g, 42.7 mmol) in a mixture of 37% aqueous HCl (42.7 mL) and water (14.3 mL) mL), cooled with an ice-NaCl bath, was treated dropwise with a solution of sodium nitrite (3.24 g, 47.0 mmol) in water (15.7 mL). When the addition was complete, the mixture was stirred for an additional 30 minutes. A solution of tin(II) chloride dihydrate (28.9 g, 128 mmol) in 37% aqueous HCl (27.5 mL) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 45 minutes. The thick suspension was filtered and the collected precipitate was carefully washed with water and dried overnight under reduced pressure. The collected solid was triturated with MeOH with sonic wave treatment, and the precipitate was collected by filtration, washed with MeOH and dried. The filtrate was concentrated, and the residue was triturated with DCM. The resulting precipitate was collected by filtration and dried, and the two precipitate baths were combined to provide 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride as a white solid (5.37 g, 44% yield). Mass spectrum m/z 249, 251 (M+H)+. Intermediate 2C: 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid

[00282] A stirred suspension of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride (1.00 g, 3.50 mmol) in acetic acid (11.7 mL) was treated with 2-butanone (1, 26 mL, 14.0 mmol) at room temperature. The mixture was heated to 75 °C for 30 minutes, forming a brown solution, then heated again to 110 °C. After 16 hours the mixture was concentrated, and the residue was suspended in EtOAc. The precipitate was collected by filtration, washed with EtOAc and air dried. The filtrates were concentrated and the residue was suspended in EtOAc, forming additional precipitate which was collected by filtration, washed with EtOAc and air dried. The two collected precipitates were combined to provide 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid as a brown solid (0.515 g, 51% yield). Mass spectrum m/z 286, 288 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.84-12.75 (m, 1H), 10.96 (s, 1H), 7.45 (d, J=9.7 Hz, 1H), 2 .40 (s, 3H), 2.37 (s, 3H).

Intermediate 2:

[00283] Following the procedure used in the Final Step of the preparation of Intermediate 1, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid was converted to 4-bromo-5-fluoro-2 ,3-dimethyl-1H-indole-7-carboxamide in 75% yield. Mass spectrum m/z 285, 287 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.08 (br. s., 1H), 7.62-7.44 (m, 2H), 2.39 (s , 3H), 2.35 (s, 3H). Intermediate 3 4-Bromo-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide Intermediate 3A: 4-Bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride

[00284] Following the alternate procedure used for the preparation of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid HCl salt [Intermediate 2B], 2-amino-4-bromo-5-chlorobenzoic acid was converted to 4-bromo-5-chloro-2-hydrazinylbenzoic acid in 39% yield. Mass spectrum m/z 265, 267, 269 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (b, 1H), 7.86 (s, 1H), 7.58 (s, 1H). Intermediate 3B: 4-Bromo-2-(2-(butan-2-ylidene)hydrazinyl)-5-chlorobenzoic acid

[00285] A stirred suspension of 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride (1.50 g, 4.97 mmol) in acetic acid (16.6 mL) was treated at room temperature with 2-butanone (1.34 mL, 14.9 mmol). The mixture was heated in an oil bath at 75 °C for 30 minutes, then heated to 110 °C. After 16 hours the mixture was concentrated in vacuo and the residue suspended in EtOAc. The precipitate was collected by filtration, washed with EtOAc and air dried to give 4-bromo-2-(2-(butan-2-ylidene)hydrazinyl)-5-chlorobenzoic acid as a yellow solid (0.574 g, 36% performance). Mass spectrum m/z 319, 321, 323 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.59 (br.s., 1H), 10.66 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 2.33 (q, J=7.5 Hz, 2H), 1.89 (s, 3H), 1.09 (t, J=7.4 Hz, 3H). Intermediate 3C: 4-bromo-5-chloro-2,3-dimethyl-1H-indole-7-carboxylic acid

[00286] A mixture of 4-bromo-2-(2-(butan-2-ylidene)hydrazinyl)-5-chlorobenzoic acid (0.574 g, 1.80 mmol) and TFA (1.11 mL, 14.4 mmol ) in toluene (4.6 mL) was heated to 90 °C. After 21 hours, the mixture was concentrated in vacuo and the residue suspended in EtOAc. The precipitate was collected by filtration, washed with EtOAc and air dried to give 4-bromo-5-chloro-2,3-dimethyl-1H-indole-7-carboxylic acid as a dark colored solid (0.373 g, 69% income). Mass spectrum m/z 302, 304, 306 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.40 (br.s., 1H), 11.06 (s, 1H), 7.67 (s, 1H), 2.40 (s, 3H), 2.37 (s, 3H).

Intermediate 3:

[00287] Following the procedure used in the final step of the preparation of Intermediate 1, 4-bromo-5-chloro-2,3-dimethyl-1H-indole-7-carboxylic acid was converted to 4-bromo-5-chloro-2 ,3-dimethyl-1H-indole-7-carboxamide in 82% yield. Mass spectrum m/z 301, 303, 305 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.13 (br. s., 1H), 7.76 (s, 1H), 7.51 (br. s., 1H), 2.40 (s, 3H), 2.36 (s, 3H). Intermediate 4 4-Bromo-3-methyl-1H-indole-7-carboxamide Intermediate 4A: 4,7-Dibromo-3-methyl-1H-indole

[00288] A solution of 1,4-dibromo-2-nitrobenzene (4.60 g, 16.4 mmol) in THF (66 mL) cooled to -78 °C was treated for 10 minutes with 0.5 M bromide of (E)-prop-1-enylmagnesium in THF (98.2 mL, 49.1 mmol). The resulting mixture was stirred at -78 °C for 2 hours, then at room temperature for 2 hours. The mixture was treated with saturated aqueous NH 4 Cl (100 mL), then with water and 1 M aqueous HCl (to about pH 1 to 2), then extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (5 to 25% gradient), to provide 4,7-dibromo-3-methyl-1H-indole (1.75 g , 37% yield). 1H NMR (400 MHz, CDCl3) δ 8.16 (1H, br. s.), 7.16 (2H, s), 7.09 (1H, s), 2.57 (3H, d , J=1.1 Hz). Intermediate 4B: 4,7-Dibromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

[00289] A suspension of sodium hydride (60% in mineral oil, 0.254 g, 6.36 mmol) in THF (18.4 mL), cooled to 0 °C, was treated in portions with a solution of 4.7 -dibromo-3-methyl-1H-indole (1.75 g, 6.06 mmol) in THF (1.8 mL), then with 2-(trimethylsilyl)ethoxymethyl chloride (1.19 mL, 6.06 mL) mmol). The mixture became a light yellow solution which was stirred at room temperature for 3 hours. The mixture was then treated with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (0 to 5% gradient), to provide 4,7-dibromo-3-methyl-1-((2-(trimethylsilyl )ethoxy)methyl)-1H-indole as a light yellow oil (2.4 g, 95% yield). Mass spectrum m/z 417, 419, 421 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.217.16 (m, 1H), 7.14-7.09 (m, 1H), 6.99 (d, J=0.9 Hz, 1H), 5.79 (s, 2H), 3.50 (dd, J=8.6, 7.7 Hz, 2H), 2.53 (d, J=0.9 Hz, 3H), 0.92-0.86 ( m, 2H), -0.04 (s, 9H). Intermediate 4C: 4-Bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylic acid

[00290] A solution of 4,7-dibromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (2.30 g, 5.49 mmol) in THF (27.4 mL) at -78 °C was treated with 2.5 M n -butyllithium in hexanes (2.33 mL, 5.82 mmol). The mixture was stirred at -78 °C for 10 minutes, then bubbled with carbon dioxide for 15 minutes. The mixture was then warmed to room temperature, stirred for 4 hours, and treated with water. The pH was adjusted to 2 to 3 with 1M aqueous HCl and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried and concentrated to give crude 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylic acid as a brown oil (2.0 g, 95% yield), used without further purification. Intermediate 4D: 4-Bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

[00291] Following the procedure used in the final step of the preparation of Intermediate 1, 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylic acid was converted to 4 -bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide in 36% yield. Mass spectrum m/z 405, 407 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.47 (s, 1H), 7.37 (d, J=0.9 Hz, 1H), 7.26 (d , J=7.7 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 5.57 (s, 2H), 3.25 (dd, J=8.7, 7, 6 Hz, 2H), 2.47 (d, J=0.9 Hz, 3H), 0.77-0.71 (m, 2H), -0.09 (s, 9H).

Intermediate 4

[00292] A solution of 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide (0.72 g, 1.88 mmol), 1.0 M of tetra-n-butylammonium fluoride in THF (5.63 mL, 5.63 mmol) and ethylenediamine (0.761 mL, 11.3 mmol) in DMF (9.4 mL) was heated at 45 °C for 4 days . Additional tetra-n-butylammonium fluoride (2 mL) was added and the mixture was heated to 50 °C. After 5 days, additional ethylenediamine (4.0 mL) was added and the mixture was heated at 70°C for 5 hours. The mixture was cooled to room temperature, treated with water and 1M aqueous HCl and extracted with EtOAc. The organic phase was washed sequentially with saturated aqueous NaHCO 3 and brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (30 to 60% gradient), to provide 4-bromo-3-methyl-1H-indole-7-carboxamide as a solid. off-white (0.35 g, 74% yield). Mass spectrum m/z 253, 255 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.24 (br.s., 1H), 7.32-7.29 (m, 3H), 7.22-7.18 (m, 1H), 7.15 (d, J=1.1 Hz, 1H), 2.60 (d, J=1.1 Hz, 3H). Intermediate 5 4-Bromo-2-methyl-1H-indole-7-carboxamide

[00293] 4-Bromo-2-methyl-1H-indole-7-carboxamide was prepared following the procedures used to prepare Intermediate 4, but substituting prop-1-en-2-ylmagnesium chloride for (E)-chloride prop-1-enylmagnesium. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br.s., 1H), 8.04 (br.s., 1H), 7.49 (d, J=8.1 Hz, 1H) , 7.40 (br.s., 1H), 7.20 (d, J=8.1 Hz, 1H), 6.16 (dd, J=2.2, 0.9 Hz, 1H), 2 .44 (d, J=0.4Hz, 3H). Intermediate 6 4-Bromo-1H-indole-7-carboxamide Intermediate 6A: 4,7-Dibromo-1 H-indole

[00294] Following the procedure used in the preparation of Intermediate 4A, but replacing vinylmagnesium bromide with (E)-prop-1-enylmagnesium bromide, 1,4-dibromo-2-nitrobenzene was converted to 4,7-dibromo-1H -indole as a brown oil in 47% yield. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (br.s., 1H), 7.54 (t, J=2.9 Hz, 1H), 7.30-7.24 (m, 1H ), 7.22-7.16 (m, 1H), 6.53 (dd, J=3.1, 2.0 Hz, 1H). Intermediate 6B: 4-Bromo-1H-indole-7-carboxylic acid

[00295] Following the procedure used in the preparation of Intermediate 4C, 4,7-dibromo-1H-indole was converted to 4-bromo-1H-indole-7-carboxylic acid in 82% yield. Mass spectrum m/z 238, 240 (M-H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (br.s., 1H), 11.41 (br.s., 1H), 7.66 (d, J=8.1 Hz, 1H) , 7.49-7.47 (m, 1H), 7.35 (d, J=7.9 Hz, 1H), 6.52 (dd, J=3.1, 2.2 Hz, 1H).

Intermediate 6:

[00296] Following the procedure used in the final step of the preparation of Intermediate 1, 4-bromo-1H-indole-7-carboxylic acid was converted to 4-bromo-1H-indole-7-carboxamide in 71% yield. Mass spectrum m/z 239, 241 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.44 (br.s., 1H), 8.11 (br.s., 1H), 7.62 (d, J=7.9 Hz, 1H) , 7.497.41 (m, 2H), 7.30 (d, J=7.9 Hz, 1H), 6.45 (dd, J=3.1, 2.0 Hz, 1H). Intermediate 7 4-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

[00297] Following the procedures used in steps B to D of the preparation of Intermediate 4, 4,7-dibromo-1H-indole (Intermediate 6A) was converted to 4-bromo-1-((2-(trimethylsilyl)ethoxy)- methyl)-1H-indole-7-carboxamide as a solid. Mass spectrum m/z 369, 371 (M+H)+, 391, 393 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.50 (s, 1H), 7.33 (d , J=7.7 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H), 6.53 (d, J=3.3 Hz, 1H), 5.68 (s, 2H ), 3.30 (s, 2H), 3.29-3.24 (m, 2H), 0.82-0.69 (m, 2H), -0.09 (s, 9H). Intermediate 8 4-Bromo-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide Intermediate 8A: 2,5-Dibromo-1-fluoro-3-nitrobenzene

[00298] A mixture of copper(II) bromide (0.713 g, 3.19 mmol) and tert-butyl nitrite (0.556 mL, 4.68 mmol) in acetonitrile (5.67 mL) was heated to 60 °C for 10 minutes, then treated dropwise with a solution of 4-bromo-2-fluoro-6-nitroaniline (0.500 g, 2.13 mmol) in acetonitrile (8.51 mL). The mixture was stirred at 60°C for 30 minutes, then cooled to room temperature, treated with 1M aqueous HCl and extracted with EtOAc. The organic phase was washed sequentially with saturated aqueous NaHCO 3 and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (5%), to give 2,5-dibromo-1-fluoro-3-nitrobenzene as an off-white solid ( 0.534 g, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.25 (t, J=2.0 Hz, 1H), 8.15 (dd, J=8.4, 2.2 Hz, 1H). Intermediate 8B: 2,5-Dibromo-1-((4-methoxybenzyl)oxy)-3-nitrobenzene

[00299] A suspension of sodium hydride (60% in mineral oil, 0.637 g, 15.9 mmol) in THF (76 mL) was treated with (4-methoxyphenyl)methanol (1.89 g, 13.7 mmol) and stirred at room temperature for 30 minutes. The mixture was treated with 2,5-dibromo-1-fluoro-3-nitrobenzene (3.40 g, 11.4 mmol) and stirred at room temperature for 4 hours. Water and saturated aqueous NH4Cl were added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was crystallized from EtOAc-hexanes to give a yellow solid (0.879 g). The filtrate from the solid collection was concentrated and subjected to column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (5 to 20% gradient step) to provide, after crystallization from EtOAc-hexanes, a yellow solid additional (0.536 g). The filtrate was combined with additional impure material recovered from column chromatography effluent, and the crystallization was repeated three times, yielding additional yellow solids. All solids combined to give 2,5-dibromo-1-((4-methoxybenzyl)oxy)-3-nitrobenzene (2.28 g, 48%). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=2.0 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.42 (d, J =8.6 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 5.26 (s, 2H), 3.78 (s, 3H). Intermediate 8C: 4,7-Dibromo-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole

[00300] Following the procedure used to prepare Intermediate 4A, but replacing (E)-but-2-en-2-ylmagnesium bromide with (E)-prop-1-enylmagnesium bromide, 2,5-dibromo-1 -((4-methoxybenzyl)oxy)-3-nitrobenzene was converted to 4,7-dibromo-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole in 44% yield. Mass spectrum m/z 438, 440, 442 (M-H)+.

Intermediate 8:

[00301] Following the procedures used to convert Intermediate 4B to Intermediate 4D, 4,7-dibromo-6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole was converted to 4-bromo -6-((4-methoxybenzyl)oxy)-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z 403, 405 (MH)+. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.71 (br.s., 1H), 7.59 (br.s., 1H), 7.45 (d, J=8.6 Hz, 2H), 7.14 (s, 1H), 6.97 (d, J=8.6 Hz, 2H), 5.22 (s, 2H), 3.77 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H). Intermediate 9 2,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide

[00302] A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 1] (0.79 g, 2.96 mmol), 4,4,4',4',5 ,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.751 g, 2.96 mmol), potassium acetate (0.581 g, 5.91 mmol), and PdCl 2 (dppf) DCM adduct (0.121 g, 0.148 mmol) in 1,4-dioxane (9.9 mL) was bubbled with nitrogen for 2 to 3 minutes, then heated to reflux under nitrogen. After 16 hours, the mixture was cooled to room temperature, filtered through CELITE®, and the solids were washed with a mixture of THF and EtOAc. The combined filtrates were concentrated and the residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (20 to 40% gradient), to provide 2,3-dimethyl-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide as a yellow glassy solid (0.798 g, 69% yield). Mass spectrum m/z 315 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.01 (br.s., 1H), 7.48 (d, J=7.5 Hz, 1H), 7.27 (d, J=7.7 Hz, 1H), 5.88 (br.s., 2H), 2.43 (s, 3H), 2.39 (d, J=0.4Hz, 3H), 1.44 (s, 12H). Intermediate 10 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide

[00303] Following the procedure used in the preparation of Intermediate 9, 4-bromo-2-methyl-1H-indole-7-carboxamide [Intermediate 5] was converted to 2-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide in 68% yield. Mass spectrum m/z 301 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (br.s., 1H), 8.03 (br.s., 1H), 7.53 (d, J=7.7 Hz, 1H) , 7.37 (br.s., 1H), 7.33 (d, J=7.5 Hz, 1H), 6.50 (dd, J=2.2, 0.9 Hz, 1H), 2 .44 (d, J=0.7 Hz, 3H), 1.33 (s, 12H). Intermediate 11 4-Bromo-2,3-dimethyl-1H-indole-7-carbonitrile

[00304] A suspension of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 1] (5.65 g, 21.2 mmol) in THF (151 mL) was treated slowly with sodium oxychloride phosphorus (13.8 mL, 148 mmol). The resulting mixture was stirred at room temperature for 23 hours, then concentrated. The residue was suspended in EtOAc and the precipitate was collected by filtration, washed sequentially with water, saturated aqueous NaHCO 3 and again with water, and air dried. The organic filtrate was concentrated, and the residue was suspended in water. The resulting precipitate was collected by filtration, washed sequentially with water, saturated aqueous NaHCO3 and again with water, and air-dried. The two precipitates together provided 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile as a yellow solid (4.68 g, 89% yield). Mass spectrum m/z 249, 251 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.89 (br.s., 1H), 7.35 (d, J=7.9 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 2.39 (s, 3H), 2.34 (s, 3H). Intermediate 12 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

[00305] Following the procedure used to prepare Intermediate 11, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 2] was converted to 4-bromo-5-fluoro-2 ,3-dimethyl-1H-indole-7-carbonitrile in 56% yield. Mass spectrum m/z 267, 269 (M+H)+. Intermediate 13 (S)-4-(3-Aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide (I-13) Intermediate 13A: (S )-benzyl (1-(7-cyano-2,3-dimethyl-1 H -indol-4-yl)piperidin-3-yl)carbamate

[00306] A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 11] (2.50 g, 10.0 mmol), (S)-benzyl piperidin-3-ylcarbamate (2.47 g, 10.5 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.312 g, 0.502 mmol), tris(dibenzylideneacetone)dipalladium (0.460 g, 0.502 mmol) and Cs2CO3 (4.58 g, 14.1 mmol) in 1,4-dioxane (143 mL) was flushed with nitrogen, then heated to 100 °C. After 16 hours, the mixture was cooled to room temperature, diluted with THF, filtered through CELITE®, and the solids washed with THF. The combined filtrates were concentrated and the residue was chromatographed on silica gel (80 g), eluting with EtOAc-hexanes (15 to 30% gradient), to provide (1-(7-cyano-2,3-dimethyl- (S)-benzyl 1H-indol-4-yl)piperidin-3-yl)carbamate as a light yellow solid (2.13 g, 53% yield). Mass spectrum m/z 403 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.407.26 (m, 7H), 6.62 (d, J=8.1 Hz, 1H), 5.08-4 .94 (m, 2H), 3.79-3.65 (m, 1H), 3.41 (d, J=10.1 Hz, 1H), 3.20 (d, J=11.0 Hz, 1H), 2.60 (t, J=10.7 Hz, 1H), 2.43-2.16 (m, 7H), 1.92 (d, J=9.5 Hz, 1H), 1, 86-1.78 (m, 1H), 1.71 (d, J=11.2 Hz, 1H), 1.40-1.26 (m, 1H).

Intermediate 13:

[00307] A suspension of (S)-benzyl (1-(7-cyano-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate (1.69 g, 3.44 mmol) in 80% aqueous H 2 SO 4 (11.3 mL, 172 mmol) was heated to 60 °C. After 2.5 hours the mixture was cooled to room temperature, then poured over ice. The pH of the mixture was adjusted to about 9 to 10 with concentrated aqueous KOH. The resulting mixture was extracted with 3:1 chloroform-isopropanol. The organic phase was dried and concentrated to afford (S)-4-(3-aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide as a brown solid (1.66 g, 50% purity, 99% yield) which was used without further purification. Mass spectrum m/z 287 (M+H)+. Intermediate 14 (R)-4-(3-Aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide

[00308] Following the procedures used to prepare Intermediate 13, but replacing (R)-benzyl piperidin-3-ylcarbamate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H - indole-7-carbonitrile [Intermediate 11] was converted to (R)-4-(3-aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z 287 (M+H)+. Intermediate 15 (RS)-4-(3-Aminopiperidin-1-yl)-2,3-dimethyl]-1H-indO-7-carboxamide

[00309] Following the procedures used to prepare Intermediate 13, but replacing (RS)-benzyl piperidin-3-ylcarbamate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H - indole-7-carbonitrile [Intermediate 11] was converted to (RS)-4-(3-aminopiperidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z 287 (M+H)+. Intermediate 16 (S)-4-(3-Aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[00310] Following the procedures used to prepare Intermediate 13, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12] was converted to (S)-4-(3- aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z 305 (M+H)+. Intermediate 17 2,3-Dimethyl-4-(piperidin-4-ylamino)-1H-indole-7-carboxamide

[00311] Following the procedures used to prepare Intermediate 13, but replacing benzyl 4-aminopiperidine-1-carboxylate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H-indole -7-carbonitrile [Intermediate 11] was converted to 2,3-dimethyl-4-(piperidin-4-ylamino)-1H-indole-7-carboxamide. Mass spectrum m/z 287 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.21-6.95 (m, 2H), 6 .08 (d, J=8.4 Hz, 1H), 4.87 (d, J=7.9 Hz, 1H), 3.89-3.76 (m, 1H), 3.46 (br. s., 1H), 3.00-2.85 (m, 2H), 2.672.54 (m, 2H), 2.37 (s, 3H), 2.26 (s, 3H), 1.94 ( d, J=9.5 Hz, 2H), 1.36 (d, J=9.0 Hz, 2H). Intermediate 18 5-Fluoro-2,3-dimethyl-4-(piperidin-4-ylamino)-1H-indole-7-carboxamide

[00312] Following the procedures used to prepare Intermediate 13, but replacing benzyl 4-aminopiperidine-1-carboxylate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-5-fluoro-2,3-dimethyl -1H-indole-7-carbonitrile [Intermediate 12] was converted to 5-fluoro-2,3-dimethyl-4-(piperidin-4-ylamino)-1H-indole-7-carboxamide. Mass spectrum m/z 305 (M+H)+. Intermediate 19 (RS)-2,3-Dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide

[00313] Following the procedures used to prepare Intermediate 13, but replacing (RS)-benzyl 3-aminopyrrolidine-1-carboxylate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl -1H-indole-7-carbonitrile [Intermediate 11] was converted to (RS)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide. Mass spectrum m/z 273 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.77-7.49 (m, 1H), 7.42 (d, J=7.9 Hz, 1H), 6 .85 (br. s., 1H), 6.05 (d, J=8.5 Hz, 1H), 5.12 (d, J=6.1 Hz, 1H), 4.00 (br. s. ., 1H), 3.11 (dd, J=11.0, 6.1 Hz, 1H), 3.02-2.96 (m, 1H), 2.86-2.81 (m, 1H) , 2.78 (dd, J=11.9, 3.4 Hz, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 2.17-2.09 (m, 1H ), 1.67 (d, J=5.5 Hz, 1H). Intermediate 20 (RS)-5-Fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide

[00314] Following the procedures used to prepare Intermediate 13, but replacing (RS)-benzyl 3-aminopyrrolidine-1-carboxylate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-5-fluoro-2 ,3-Dimethyl-1H-indole-7-carbonitrile [Intermediate 12] was converted to (RS)-5-fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide . Mass spectrum m/z 291 (M+H)+. Intermediate 21 (S)-5-Fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide Intermediate 21A: (S )-benzyl 3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidine-1-carboxylate

[00315] Following the procedure used to prepare Intermediate 13A, but substituting (S)-benzyl 3-aminopyrrolidine-1-carboxylate for (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-5-fluoro-2 ,3-Dimethyl-1H-indole-7-carbonitrile [Intermediate 12] was converted to 3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidin-1 - (S)-benzyl carboxylate in 39% yield. Mass spectrum m/z 407 (M+H)+.

Intermediate 21:

[00316] Following the procedure used to prepare Intermediate 13 from Intermediate 13A, 3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidine-1-carboxylate (S)-benzyl was converted to (S)-5-fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide in 77% yield. Mass spectrum m/z 291 (M+H)+. Intermediate 22 (RS)-4-(3-Aminopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide

[00317] Following the procedures used to prepare Intermediate 13, but replacing (RS):benzyl pyrrolidin:3:ylcarbamate with (S):benzyl piperidin:3:ylcarbamate, 4:bromo:2,3:dimethyl:1H : indole:7:carbonitrile [Intermediate 11] was converted to (RS):4:(3:aminopyrrolidin:1:yl):2,3:dimethyl:1H:indol:7:carboxamide. Mass spectrum m/z 273 (M+H)+. 1H NMR (400 MHz, DMSO:d6) δ 10.60 (s, 1H), 7.73 (dd, J=8.7, 5.6 Hz, 1H), 7.44 (d, J=8, 1 Hz, 1H), 6.96 (br.s., 3H), 6.44 (d, J=8.1 Hz, 1H), 3.56:3.46 (m, 1H), 3.26 :3.08 (m, 3H), 2.82 (dd, J=9.5, 5.3 Hz, 1H), 2.33 (s, 3H), 2.30 (s, 3H), 2. 19:2.11 (m, 1H), 1.61:1.50 (m, 1H). Intermediate 23 (R ):4:(3:Aminopyrrolidin-1:yl):2,3:dimethyl|:1H-indole-7-carboxamide

[00318] Following the procedures used to prepare Intermediate 13, but replacing (R)-benzyl pyrrolidin-3-ylcarbamate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl-1H - indole-7-carbonitrile [Intermediate 11] was converted to (R)-4-(3-aminopyrrolidin-1-yl)-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z 273 (M+H)+. Intermediate 24 (S)-4-(3-Aminopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[00319] Following the procedures used to prepare Intermediate 13, but replacing (S)-benzyl pyrrolidin-3-ylcarbamate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-5-fluoro-2,3 - dimethyl-1H-indol-7-carbonitrile [Intermediate 12] was converted to (S)-4-(3-aminopyrrolidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide . Mass spectrum m/z 291 (M+H)+. Intermediate 25 (RS)-2,3-Dimethyl-4-(piperidin-3-ylamino)-1H-indole-7-carboxamide

[00320] Following the procedures used to prepare Intermediate 13, but replacing (RS)-benzyl 3-aminopiperidine-1-carboxylate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-2,3-dimethyl -1H-indole-7-carbonitrile [Intermediate 11] was converted to (RS)-2,3-dimethyl-4-(piperidin-3-ylamino)-1H-indole-7-carboxamide. Mass spectrum m/z 287 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.94 (s, 1H), 7.56 (br.s., 1H), 7.41 (d, J=7 .9 Hz, 1H), 6.81 (br.s., 1H), 6.08 (d, J=8.5 Hz, 1H), 5.40-5.23 (m, 1H), 3. 77-3.56 (m, 2H), 3.06 (d, J=12.2 Hz, 1H), 2.78 (br. s., 1H), 2.70-2.61 (m, 2H ), 2.38 (s, 3H), 2.26 (s, 3H), 1.86-1.78 (m, 1H), 1.69-1.60 (m, 2H), 1.521.41 ( m, 1H). Intermediate 26 (S)-2,3-Dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide Intermediate 26A: (S)-tert-butyl 3-((7-cyano-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidine-1-carboxylate

[00321] A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 11] (0.400 g, 1.61 mmol), (S)-tert 3-aminopyrrolidine-1-carboxylate -butyl (0.336 g, 1.80 mmol) and 1,4-dioxane (15 mL) was bubbled with nitrogen for 5 minutes 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.050 g, 0.080 mmol ), tris(dibenzylideneacetone)dipalladium (0.074 g, 0.080 mmol) and Cs2CO3 (0.732 g, 2.25 mmol) were added, and the mixture was sealed under a nitrogen atmosphere and heated to 100 °C. After 19 hours, the mixture was cooled to room temperature. Water (50 mL) and EtO-Ac (50 mL) were added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes, to provide 3-((7-cyano-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidin-1- (S)-tert-butyl carboxylate as a pale yellow solid (0.47 g, 79% yield). Mass spectrum m/z 355 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.23 (d, J=8.4 Hz, 1H ), 5.36 (br.s., 1H), 4.25-4.08 (m, 1H), 3.69-3.57 (m, 1H), 3.48-3.37 (m, 1H), 3.38-3.31 (m, 1H), 3.27-3.16 (m, 1H), 2.34 (s, 3H), 2.24 (s, 3H), 2.22 -2.13 (m, 1H), 1.97-1.86 (m, 1H), 1.49-1.31 (m, 9H). Intermediate 26B: (S)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carbonitrile TFA salt

[00322] A mixture of (S)-tert-butyl 3-((7-cyano-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidine-1-carboxylate (0.470 g, 1.33 mmol) and DCM (5 mL) was cooled to 0 °C, treated with TFA (5 mL) and stirred for 1 hour. The mixture was concentrated to provide the crude TFA salt of (S)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carbonitrile, used without further purification. Mass spectrum m/z 255 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.93-8.72 (m, 1H), 7.27 (d, J=8.1 Hz, 1H), 6 .21 (d, J=8.6 Hz, 1H), 5.48 (br.s., 1H), 4.27 (br.s., 1H), 3.543.44 (m, 1H), 3. 42-3.33 (m, 1H), 3.31-3.17 (m, 2H), 2.38 (s, 3H), 2.362.28 (m, 1H), 2.26 (s, 3H) , 2.09-2.00 (m, 1H).

Intermediate 26:

[00323] A mixture of (S)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carbonitrile TFA salt (488 mg, 1.33 mmol) and aqueous H2SO4 at 80% (3 mL) was heated to 60 °C. After 2 hours, the mixture was cooled to room temperature, then slowly added to 10 M aqueous NaOH at 0 °C. The aqueous supernatant was removed from the resulting sticky brown solid by decantation. Water was added to the solid and the mixture was extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with brine, dried and concentrated to provide (S)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide as an orange solid (270 mg, 75% yield). Mass spectrum m/z 273 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.59 (br. s., 1H), 7.42 (d, J=8.4 Hz, 1H), 6, 85 (br.s., 1H), 6.05 (d, J=8.4 Hz, 1H), 5.07 (d, J=6.8 Hz, 1H), 3.993.89 (m, 1H) , 3.30 (br.s., 1H), 3.04 (dd, J=11.1, 6.1 Hz, 1H), 2.98-2.88 (m, 1H), 2.82- 2.67 (m, 2H), 2.36 (s, 3H), 2.26 (s, 3H), 2.10 (td, J=13.4, 7.5 Hz, 1H), 1.68 -1.53 (m, 1H). Intermediate 27 (R)-2,3-Dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide

[00324] Following the procedures used to prepare Intermediate 26, but substituting (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate for (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate, 4 - bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 11] was converted to (R)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide . Mass spectrum and 1H NMR were the same as for Intermediate 26. Intermediate 28 (S)-2,3-Dimethyl-4-(methyl(pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide

[00325] Following the procedures used to prepare Intermediate 26, but substituting (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate for (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate butyl, 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 11] was converted to (S)-2,3-dimethyl-4-(methyl(pyrrolidin-3-yl)amino)- 1H-indole-7-carboxamide. Mass spectrum m/z 287 (M+H)+. Intermediate 29 (RS-cis)-5-Fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3-dimethyl-1H-indol-7 -carboxamide Intermediate 29A: Ethyl 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate

[00326] A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid [Intermediate 2C] (2.00 g, 6.99 mmol) and concentrated H2SO4 (0.373 mL, 6.99 mmol) in ethanol (30 mL) was stirred at reflux for 6 days. The mixture was cooled to room temperature and concentrated. The residue was partitioned between EtOAc and water, and the organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (0 to 100% gradient) to afford ethyl 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate as an off-white solid (1.67 g, 72% yield). Mass spectrum m/z 314, 316 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.57 (br.s., 1H), 7.54 (d, J=9.4 Hz, 1H), 4.45 (q, J=7.2 Hz, 2H), 2.49 (d, J=0.5 Hz, 3H), 2.40 (s, 3H), 1.46 (t, J=7.2 Hz, 3H). Intermediate 29B: (RS) 6-(7-(ethoxycarbonyl)-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate -cis)-tert-butyl

[00327] Following the procedure used to prepare Intermediate 13A, but replacing (RS-cis)-tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate with ( Ethyl S)-benzyl, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylate was converted to 6-(7-(ethoxycarbonyl)-5-fluoro-2,3-dimethyl- (RS-cis)-tert-butyl 1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate as a light yellow glassy solid in 61% yield. Mass spectrum m/z 460 (M+H)+. Intermediate 29C: (1 S - cis )-4-(1-(tert-butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2 acid ,3-dimethyl-1H-indole-7-carboxylic acid

[00328] A mixture of 6-(7-(ethoxycarbonyl)-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate of (RS-cis)-tert-butyl (91 mg, 0.198 mmol) and 1M aqueous NaOH (1.98 mL, 1.98 mmol) in THF (1 mL) and MeOH (1 mL) was stirred at room temperature. environment at night. The mixture was treated with 1M aqueous HCl (to pH about 6) and extracted twice with EtOAc. The combined organic phases were dried and concentrated to give (RS-cis)-4-(1-(tert-butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl) acid -5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid as a yellow glassy solid (73 mg, 85% yield), used without further purification. Mass spectrum m/z 432 (M+H)+. Intermediate 29D: (RS-cis) 6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate )-tert-butyl

[00329] A solution of butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic acid (73 mg, 0.169 mmol), NH4Cl (45.2 mg, 0.846 mmol) and HATU (70.8 mg, 0.186 mmol) in DMF (1 mL) was treated with triethylamine (0.118 mL, 0.846 mmol) and stirred at room temperature environment for 2 hours. The mixture was diluted with DCM, washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (0 to 100% gradient), to provide 6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole - (RS-cis)-tert-butyl 4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate as a yellow gum (74.2 mg, 92% yield). Mass spectrum m/z 431 (M+H)+.

Intermediate 29:

[00330] A solution of 6-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate ( RS-cis)-tert-butyl (70 mg, 0.163 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (1.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated, and the residue was partitioned between DCM and saturated aqueous NaHCO 3 . The organic phase was dried and concentrated to afford (RS-cis)-5-fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3- dimethyl-1H-indole-7-carboxamide as a yellow glassy solid (53 mg, 99% yield), used without further purification. Mass spectrum m/z 331 (M+H)+.

Alternate Synthesis of Intermediate 29:

[00331] Following the procedures used to prepare Intermediate 26, but replacing (RS-cis)-tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate with 3-aminopyrrolidine-1-carboxylate of (S)-tert-butyl, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12] was converted to (RS-cis)-5-fluoro-4-( hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide. Intermediate 30 (RS-cis)-5-Fluoro-4-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide

[00332] Following the procedures used to prepare Intermediate 26, but replacing (RS-cis)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate with 3-aminopyrrolidine-1- (S)-tert-butyl, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile carboxylate [Intermediate 12] was converted to (RS-cis)-5-fluoro-4- (hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z 317 (M+H)+. Intermediate 31 (RS-cis)-5zFluoroz4z(hexazhydropyrrolo[314zb]pyrro4j(1H)-yl)-2,3zdimethylib 1H-indole-7-carboxamide

[00333] Following the procedures used to prepare Inter-26, but replacing (RS-cis)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate with 3-aminopyrrolidine-1 (S)-tert-butyl, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile -carboxylate [Intermediate 12] was converted to (RS-cis)-5-fluoro-4 -(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z 317 (M+H)+. Intermediate 32 cis -5-Fluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide

[00334] Following the procedures used to prepare Intermediate 26, but substituting cis-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate for (S )-tert-butyl, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12] was converted to cis-5-fluoro-4-(hexahydropyrrolo[3,4 - c]pyrrol-2(1H)-yl)-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z 317 (M+H)+. Intermediate 33 (S)-4-(3-(Ethylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[00335] Following the procedures used to prepare Intermediate 26, but substituting (S)-tert-butyl ethyl(piperidin-3-yl)carbamate for (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate, 4 -bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12] was converted to (S)-4-(3-(ethylamino)piperidin-1-yl)-5-fluoro- 2,3-dimethyl-1H-indole-7-carboxamide. Intermediate 34 2,3-Dimethyl-4-(piperazin-1-yl)-1H-indole-7-carboxamide Intermediate 34A: 2,3-Dimethyl-4-(piperazin-1-yl)-1H-indole-7-carbonitrile

[00336] A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 11] (100 mg, 0.401 mmol), piperazine (69.2 mg, 0.803 mmol), tris(dibenzylideneacetone) dipalladium (18.4 mg, 0.020 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (12.5 mg, 0.020 mmol) and CS2CO3 (183 mg, 0.562 mmol) in 1,4- dioxane (4 mL) in a sealed reaction vessel was subjected to three evacuate-charge cycles with nitrogen. The mixture was heated at 100 °C for 16 hours, then cooled to room temperature, filtered and the collected precipitate washed with EtOAc. The filtrate was concentrated and the residue was subjected to column chromatography on silica gel (12 g), eluting with MeOH-DCM (0 to 30% gradient), to provide 2,3-dimethyl-4-(piperazin-1- yl)-1H-indole-7-carbonitrile as a light brown solid (56 mg, 55% yield). Mass spectrum m/z 255 (M+H)+.

Intermediate 34:

[00337] A mixture of 2,3-dimethyl-4-(piperazin-1-yl)-1H-indole-7-carbonitrile (56 mg, 0.220 mmol) and 80% aqueous H 2 SO 4 (2 mL) was heated to 60°C °C for 3 hours. The mixture was poured over ice and the pH of the resulting mixture was adjusted to about 10 with solid KOH. The mixture was then extracted three times with a 3:1 mixture of DCM-isopropanol. The combined organic phases were washed with water, dried and concentrated to give 2,3-dimethyl-4-(piperazin-1-yl)-1H-indole-7-carboxamide as a yellow solid (35 mg, 58% yield) . Mass spectrum m/z 273 (M+H)+. Intermediate 35 (RS)-2,3-Dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide Intermediate 35A: ((flS)-tert-butyl 3-(((benzyloxy)carbonyl)(methyl)amino)piperidine-1-carboxylate

[00338] A solution of (RS)-tert-butyl 3-(methylamino)piperidine-1-carboxylate (1.60 g, 7.47 mmol) and DIEA (1.57 mL, 8.96 mmol) in DCM (29.9 mL) was cooled to 0 °C and slowly treated with benzyl chloroformate (1.08 mL, 7.54 mmol). The resulting mixture was stirred at room temperature for 1 hour, then concentrated. The residue was subjected to column chromatography on silica gel to afford (RS)-tert-butyl 3-(((benzyloxy)carbonyl)(methyl)amino)piperidine-1-carboxylate as a colorless oil (2.56 g, 98% yield). Mass spectrum m/z 371 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ 7.40-7.29 (m, 5H), 5.16 (s, 2H), 4.21-3.81 (m, 3H), 2.87 (s, 3H), 2.76 (t, J=10.9 Hz, 1H), 2.56 (t, J=11.9 Hz, 1H), 1.85 (d, J=12.3 Hz, 1H) , 1.78-1.70 (m, 1H), 1.66-1.60 (m, 1H), 1.45 (br.s., 10H). Intermediate 35B: (F S )-benzyl methyl(piperidin-3-yl)carbamate

[00339] A solution of (RS)-tert-butyl 3-(((benzyloxy)carbonyl)(methyl)amino)piperidine-1-carboxylate (2.56 g, 7.34 mmol) in DCM (14.7 mmol) mL) was cooled to 0 °C and slowly treated with TFA (2.80 mL, 36.7 mmol). The resulting mixture was stirred at room temperature for 16 hours, then concentrated. The residue was partitioned between 1M aqueous NaOH and EtOAc. The organic phase was washed with brine, dried and concentrated to give (RS)-benzyl methyl(piperidin-3-yl)carbamate as a pale yellow oil (1.71 g, 94% yield). Mass spectrum m/z 249 (M+H)+.

Intermediate 35:

[00340] Following the procedures used to prepare Intermediate 13, but replacing (RS)-benzyl methyl(piperidin-3-yl)carbamate with (S)-benzyl piperidin-3-ylcarbamate, 4-bromo-2,3 -dimethyl-1H-indole-7-carbonitrile [Intermediate 11] was converted to (RS)-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide. Mass spectrum m/z 301 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.81 (br. s., 1H), 7.47 (d, J=8.1 Hz, 1H), 7, 10 (br.s., 1H), 6.53 (d, J=8.4 Hz, 1H), 2.70 (br.s., 1H), 2.59 (br.s., 1H), 2.37-2.29 (m, 10H), 1.97 (d, J=10.4 Hz, 1H), 1.89 (s, 3H), 1.81-1.65 (m, 2H) , 1.13 (br.s., 1H). Intermediate 36 (S)-5-Fluoro-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide

[00341] Following the procedures used to prepare Intermediate 13, but replacing (S)-tert-butyl methyl(piperidin-3-yl)carbamate with (S)-benzyl, 4-bromo-5 piperidin-3-ylcarbamate -fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12] was converted to (S)-5-fluoro-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl )-1H-indole-7-carboxamide. Mass spectrum m/z 319 (M+H)+. Intermediate 37 (S)-5-Fluoro-2,3-dimethyl-4-(methyl(pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide Intermediate 37A: (S )-benzyl 3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)(methyl)amino)-pyrrolidine-1-carboxylate

[00342] A mixture of (S)-benzyl 3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)amino)pyrrolidine-1-carboxylate [Intermediate 21A] ( 0.114 g, 0.280 mmol), paraformaldehyde (0.025 g, 0.841 mmol), acetic acid (0.048 mL, 0.841 mmol), and sodium cyanoborohydride (0.035 g, 0.561 mmol) in MeOH (2.5 mL) was stirred at room temperature during the night. The mixture was then heated at 50°C for about 24 hours, then stirred at room temperature overnight. The mixture was diluted with EtOAc and washed sequentially with water and brine. The organic layer was collected, and the aqueous layers were sequentially extracted twice with EtOAc. The combined organic layers were dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexane (5%, 13%, and 20%, sequentially), to provide 3-((7-cyano-5-fluoro-2,3-dimethyl- (S)-Benzyl 1H-indol-4-yl)(methyl)amino)pyrrolidine-1-carboxylate as a colorless viscous oil (0.049 g, 42% yield). Mass spectrum m/z 421 (M+H)+.

Intermediate 37:

[00343] Following the procedure used in the last step of the preparation of Intermediate 13, 3-((7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)(methyl)amino)pyrrolidine-1 (S)-benzyl -carboxylate was converted to (S)-5-fluoro-2,3-dimethyl-4-(methyl(pyrrolidin-3-yl)amino)-1H-indole-7-carboxamide in 94% of performance. Mass spectrum m/z 305 (M+H)+. Intermediate 38 (RS)z213∑Dimethylz4z(piperidin∑3∑yl)z1H:indolz7zcarboxamidaisal of TFA Intermediate 38A: tert-butyl 3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[00344] A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 1] (175 mg, 0.655 mmol), 3-(4,4,5,5-tetramethyl-1, tert-Butyl 3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (203 mg, 0.655 mmol), 1,4-dioxane (5 mL) and water (1 mL) was bubbled with nitrogen for 5 min and treated with PdCl2(dppf) DCM adduct (32.1 mg, 0.039 mmol) and Cs2CO3 (640 mg, 1.97 mmol). The mixture was sealed under a nitrogen atmosphere and heated to 90 °C. After 15 hours the mixture was cooled to room temperature and diluted with EtOAc (15 mL) and water (15 mL). The layers were separated and the aqueous layer was extracted three times with EtO-Ac. The combined organic extracts were dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes, to provide 3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)-5,6-di- tert-butyl hydropyridine-1(2H)-carboxylate as a yellow solid (174 mg, 69% yield). Mass spectrum m/z 370 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.91 (br. s., 1H), 7.50 (d, J=7.7 Hz, 1H), 7, 23 (br.s., 1H), 6.75 (d, J=7.5 Hz, 1H), 6.62 (br.s., 1H), 3.62-3.56 (m, 2H) , 2.40-2.29 (m, 5H), 2.13 (s, 3H), 1.97-1.87 (m, 2H), 1.55-1.31 (m, 9H). tert-Butyl Intermediate 38B^(RS)z3z(7zcarbamoylz213zdimethylz1H:indolz4zyl)piperidine-1-carboxylate

[00345] A mixture of tert-butyl 3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (94 mg, 0.254 mmol), DMF (1 mL) and MeOH (5 mL) was treated with palladium on carbon (94 mg) and stirred at room temperature under an atmosphere of hydrogen. After 20 hours, additional palladium on carbon (94 mg) was added and stirring under an atmosphere of hydrogen was continued for a total of three days. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc, washed with water, and the aqueous layer was extracted three times with EtOAc. The organic extracts were combined, washed sequentially with saline and 10% aqueous LiCl, dried and concentrated to provide 3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)piperidine-1-carboxylate of (RS)-tert-butyl as a yellow solid (72.5 mg, 73% yield). Mass spectrum m/z 372 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.91 (br. s., 1H), 7.51 (d, J=7.9 Hz, 1H), 7, 22 (br.s., 1H), 6.87 (d, J=7.9 Hz, 1H), 4.15-4.06 (m, 1H), 3.50-3.38 (m, 1H ), 2.93-2.73 (m, 2H), 2.60 (s, 6H), 1.96-1.88 (m, 1H), 1.86-1.67 (m, 2H), 1.61-1.47 (m, 1H), 1.40 (s, 9H), 1.28-1.21 (m, 1H).

Intermediate 38:

[00346] A solution of (RS)-tert-butyl 3-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)piperidine-1-carboxylate (74 mg, 0.179 mmol) in DCM ( 2 mL) was cooled to 0 °C and slowly treated with TFA (2 mL). The mixture was stirred at room temperature for 2 hours, then concentrated to provide TFA (RS)-2,3-dimethyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide salt as a solid. yellow (76 mg, quantitative production). Mass spectrum m/z 272 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.93 (br. s., 1H), 7.54 (d, J=7.9 Hz, 1H), 7, 27 (br.s., 1H), 6.89 (d, J=7.9 Hz, 1H), 3.86-3.75 (m, 1H), 3.35 (d, J=11.9 Hz, 2H), 3.27-3.13 (m, 1H), 3.03-2.84 (m, 1H), 2.41-2.32 (m, 6H), 1.93 (d, J=11.9 Hz, 1H), 1.88-1.70 (m, 2H), 1.301.22 (m, 1H), 0.95 (d, J=7.0 Hz, 1H). Intermediate 39 (RS)-3zMethylz4z(piperidinz3zil)z1H-indolz7zcarboxamide Intermediate 39A: tert-butyl 3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[00347] Following the procedure used to prepare Intermediate 38A, 4-bromo-3-dimethyl-1H-indole-7-carboxamide [Intermediate 4] was converted to 3-(7-carbamoyl-3-methyl-1H-indole- tert-Butyl 4-yl)-5,6-dihydropyridine-1(2H)-carboxylate in 53% yield. Mass spectrum m/z 356 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.42-7.27 (m, 1H), 7.16-7.03 (m, 1H), 6.97-6.73 (m, 2H), 3.75-3.59 (m, 2H), 2.43 (br.s., 2H), 2.30 (s, 3H), 2.02 (br.s., 2H), 1.54- 1.37 (m, 9H). Intermediate 39B: 3-Methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide

[00348] Following the procedure used to prepare Intermediate 38 from Intermediate 38B, followed by neutralization of the resulting TFA salt, 3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-5,6-di tert-Butyl -hydropyridine-1(2H)-carboxylate was converted to 3-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide in 93% of yield. Mass spectrum m/z 256 (M+H)+.

Intermediate 39:

[00349] A solution of 3-methyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide (20 mg, 0.078 mmol) in MeOH (3 mL) was treated with palladium on charcoal (8.3 mg) and stirred under an atmosphere of hydrogen for 12 hours at room temperature. The mixture was filtered through CELITE® and the filtrate was concentrated to provide (RS)-3-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide as a white solid (20 mg, 99% income). Mass spectrum m/z 258 (M+H)+. Intermediate 40 (RS)-2,3-Dimethyl-4-(pyrrolidin-3-yl)-1H-indole-7-carboxamide

[00350] Following the procedures used to prepare Intermediate 38, but substituting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H tert-butyl-pyrrole-1-carboxylate by 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)- tert-butyl, 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide carboxylate [Intermediate 1] was converted to (RS)-2,3-dimethyl-4-(pyrrolidin-3-yl)- 1H-indole-7-carboxamide. Mass spectrum m/z 258 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.92 (br. s., 1H), 7.96 (s, 1H), 7.58 (d, J=7 .9 Hz, 1H), 7.29 (br.s., 1H), 6.99 (d, J=7.9 Hz, 1H), 4.35-4.17 (m, 1H), 3. 69-3.57 (m, 1H), 3.48-3.39 (m, 1H), 3.38-3.30 (m, 1H), 3.27-3.17 (m, 1H), 2.37 (s, 6H), 2.36-2.29 (m, 1H), 2.15-2.03 (m, 1H). Intermediate 41 4-(3-Amino-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide

[00351] A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 1] (0.25 g, 0.936 mmol), 2-methyl-3-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [prepared according to the procedure of United States Patent No. 8,084,620, Intermediate 50-1] (0.229 g, 0.983 mmol), and tetracis(triphenylphosphine)palladium (0.054 g, 0.047 mmol) in toluene (10.8 mL) and ethanol (3.6 mL) was sparged with argon for about 2 to 3 minutes. The mixture was treated with 2M aqueous Na 2 CO 3 (1.17 mL, 2.34 mmol), sparged with argon again, and the reaction vessel was sealed under argon and heated to 90 °C. After 16 hours the mixture was cooled to room temperature and partitioned between water and EtOAc. The organic phase was concentrated and the residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (50 to 70% gradient), to provide 4-(3-amino-2-methylphenyl)- 2,3-dimethyl-1H-indole-7-carboxamide as a light yellow solid (0.142 g, 52% yield). Mass spectrum m/z 294 (M+H)+. Intermediate 42 (RS)-5zFluoroz213zdimethylz4z(1J21314ztetrazhydroisoquinolinz5zyl)z1H-indole-7-carboxamide Intermediate 42A: tert-(RS)-5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate butyl

[00352] A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 2] (0.200 g, 0.701 mmol), 5-(4,4,5,5- tert-butyl tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.302 g, 0.842 mmol), 2M aqueous K3PO4 (1.05 mL, 2.10 mmol) and THF (4 mL) was subjected to 3 cycles of evacuate-charge with nitrogen. PdCl2(dppf) DCM adduct (0.023 g, 0.035 mmol) was added, and the mixture was subjected to 2 more cycles of evacuate-charge with nitrogen. The mixture was stirred at room temperature overnight, then diluted with EtOAc, washed sequentially with water and brine, dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes, to afford (RS)-5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)- tert-Butyl 3,4-dihydroisoquinoline-2(1H)-carboxylate as an off-white solid (0.307 g, quantitative yield). Mass spectrum m/z 438 (M+H)+.

Intermediate 42:

[00353] A mixture of (RS)-5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of tert-butyl (0.312 g, 0.713 mmol) and TFA (5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc, washed sequentially with 1.5M aqueous Na 2 HPO 4 and brine, dried and concentrated to give (RS)-5-fluoro-2,3-dimethyl-4 -(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide as an orange solid (0.241 g, quantitative yield). Mass spectrum m/z 338 (M+H)+. Intermediate 43 5-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroquinolin-6-yl)-1H-indole-7-carboxamide, TFA salt Intermediate 43A: tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

[00354] Following the procedure used to prepare Intermediate 9, tert-butyl 6-bromo-3,4-dihydroquinoline-1(2H)-carboxylate was converted to 6-(4,4,5,5- tert-butyl tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate as a white solid in 82% yield. Mass spectrum m/z 360 (M+H)+, 304 (M+H-C4H8)+. 1H NMR (400 MHz, CDCl3) δ 7.71-7.66 (m, 1H), 7.627.57 (m, 1H), 7.56 (s, 1H), 3.77-3.68 (m, 2H), 2.79 (t, J=6.6 Hz, 2H), 1.93 (dt, J=12.5, 6.4 Hz, 2H), 1.54 (s, 9H), 1, 36 (s, 12H).

Intermediate 43:

[00355] Following the procedures used to prepare Intermediate 42, but omitting the treatment with aqueous Na2HPO4 in the last step, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- tert-Butyl 3,4-dihydroquinoline-1(2H)-carboxylate was converted to 5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroquinolin-6-yl) -1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 338 (M+H)+. Intermediate 44 5-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-indole-7-carboxamide, TFA salt

[00356] Following the procedures used to prepare Intermediate 43, tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate was converted to 5-fluoro-2,3-dimethyl-4- (1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 338 (M+H)+. Intermediate 45 5-Fluoro-4-(isoindolin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide, TFA salt

[00357] Following the procedures used to prepare Intermediate 43, tert-butyl 4-bromoisoindoline-2-carboxylate was converted to 5-fluoro-4-(isoindolin-4-yl)-2,3-dimethyl-1H -indole-7-carboxamide, TFA salt. Mass spectrum m/z 324 (M+H)+. Intermediate 46 5-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-indole-7-carboxamide, TFA salt

[00358] Following the procedures used to prepare Intermediate 43, tert-butyl 7-bromo-3,4-dihydroquinoline-1(2H)-carboxylate was converted to 5-fluoro-2,3-dimethyl-4- (1,2,3,4-tetrahydroquinolin-7-yl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 338 (M+H)+. Intermediate 47 5-Fluoro-4-(isoindolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide, TFA salt

[00359] Following the procedures used to prepare Intermediate 43, tert-butyl 5-bromo-isoindoline-2-carboxylate was converted to 5-fluoro-4-(isoindolin-5-yl)-2,3-dimethyl-1H -indole-7-carboxamide, TFA salt. Mass spectrum m/z 324 (M+H)+. Intermediate 48 (RS-cis)-5-Fluoro-2,3-dimethyl-4-(1a,2,3,7b-tetrahydro-1Hcyclopropa[c]quinolin-7-yl)-1H-indol-7- carboxamide, TFA salt Intermediate 48A: (RS-cis)-tert-butyl 7-bromo-1a,2-dihydro-1H-cyclopropa[c]quinoline-3(7bH)-carboxylate

[00360] A solution of (RS-cis)-7-bromo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinoline [prepared according to procedures described in Example 9 of PCT Publication At the. WO 2012/149236] (700 mg, 3.12 mmol) and di-tert-butyl dicarbonate (1.08 mL, 4.69 mmol) in 1,4-dioxane (5.0 mL) was stirred at 80° C for 18. The cooled mixture was diluted with saturated aqueous NaHCO 3 (15 mL) and extracted with EtOAc (20 mL). The organic layer was dried and concentrated, and the residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes (0 to 50% gradient), to provide 7-bromo-1a,2-dihydro-1H (RS-cis)-tert-butyl-cyclopropa[c]quinoline-3(7bH)-carboxylate as a light brown gum (963 mg, 67% yield). Mass spectrum m/z 324, 326 (M+H-C4H8)+. 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J=8.0, 1.2 Hz, 1H), 7.25 (d, J=7.9 Hz, 1H), 6.95 (t , J=8.0 Hz, 1H), 4.51 (dd, J=13.0, 1.3 Hz, 1H), 2.94 (d, J=12.1 Hz, 1H), 2.44 (td, J=8.6, 4.5 Hz, 1H), 1.88 (dtq, J=8.0, 5.8, 1.9 Hz, 1H), 1.47 (s, 9H), 1.11 (td, J=8.3, 5.3 Hz, 1H), 0.74 (q, J=4.9 Hz, 1H).

Intermediate 48:

[00361] Following the procedures used to prepare Intermediate 43, (RS-cis)-tert-butyl 7-bromo-1a,2-dihydro-1H-cyclopropa[c]quinoline-3(7bH)-carboxylate was converted to (RS-cis)-5-fluoro-2,3-dimethyl-4-(1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-1H-indole- 7-carboxamide, TFA salt. Mass spectrum m/z 350 (M+H)+. Intermediate 49 4-(3,4-Dihydro-2H-benzo[ b ][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , TFA salt

[00362] Following the procedures used to prepare Intermediate 48, 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine [prepared according to procedures described in Example 10 of PCT Publication At the. WO 2012/149236] was converted to 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide, TFA salt. Mass spectrum m/z 340 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.01 (br. s., 1H), 7.45 (d, J=10.8 Hz, 1H), 7, 40 (br.s., 1H), 6.77-6.68 (m, 1H), 6.63 (dd, J=7.9, 1.7 Hz, 1H), 6.37 (dd, J =7.5, 1.6 Hz, 1H), 4.08-3.92 (m, 2H), 3.31-3.22 (m, 2H), 2.29 (s, 3H), 1, 62 (s, 3H). Intermediate 50 (1S)-5-Fluoro-4-(4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide, salt TFA Intermediate 50A: tert-butyl 5-bromo-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00363] A mixture of 5-bromo-2,3-dihydroisoquinolin-4(1H)-one hydrochloride (1.05 g, 4.00 mmol), di-tert-butyl dicarboxylate (1.02 mL , 4.40 mmol) and triethylamine (1.67 mL, 12.0 mmol) in MeOH (20 mL) was stirred at room temperature for 90 minutes. The mixture was concentrated and the residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes (0 to 30% gradient), to provide 5-bromo-4-oxo-3,4-dihydroisoquinoline tert-butyl -2(1H)-carboxylate as a gum (640 mg, 47% yield). Mass spectrum m/z 270, 272 (M+H-C4H8)+. 1H NMR (400 MHz, CDCl3) δ 7.67 (dt, J=7.9, 0.6 Hz, 1H), 7.40-7.32 (m, 1H), 7.31-7.26 ( m, 1H), 4.75 (s, 2H), 4.37 (s, 2H), 1.50 (s, 9H). Intermediate 50B: (1S)-tert-butyl 5-bromo-4-hydroxy-3,4-dihydroisoquinoline-2( 1H )-carboxylate

[00364] A solution of tert-butyl 5-bromo-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 0.460 mmol) in THF (3.0 mL) and MeOH ( 3.0 mL) was treated with sodium borohydride (17.4 mg, 0.460 mmol). The mixture was stirred at room temperature for 60 minutes and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes (0 to 100% gradient) to provide 5-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate. (RS)-tert-butyl as a white glassy solid (137 mg, 86% yield). Mass spectrum m/z 254, 256 (M+H-(H2O+C4H8))+. 1H NMR (400 MHz, CDCl3) δ 7.50 (dd, J=8.3, 0.6 Hz, 1H), 7.21-7.15 (m, 1H), 7.14-7.09 ( m, 1H), 5.02 (br.s., 2H), 4.48 (d, J=10.8 Hz, 1H), 4.26 (d, J=17.2 Hz, 1H), 3 .19 (d, J=12.3 Hz, 1H), 2.36 (br.s., 1H), 1.52 (s, 9H). Intermediate 50C: (1S)-tert-butyl 5-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00365] A solution of (RS)-tert-butyl 5-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (137 mg, 0.417 mmol) in DCM (5.0 mL ) at -78 °C was treated dropwise with diethylaminosulfur trifluoride [DAST] (0.331 mL, 2.51 mmol) and the mixture was stirred at -78 °C for 10 minutes. The mixture was treated with saturated aqueous NaHCO 3 (5.0 mL). The DCM layer was separated, dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0 to 100% gradient), to provide 5-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H) (RS)-tert-butyl-carboxylate as a colorless gum (100 mg, 69% yield). Mass spectrum m/z 254, 256 (M+H-(HF+C4H8))+. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=7.9 Hz, 1H), 7.25 (td, J=7.8, 2.1 Hz, 1H), 7.20-7 .13 (m, 1H), 5.95-5.64 (m, 1H), 5.25-4.91 (m, 1H), 4.69 (br.s., 1H), 4.26 ( br.s., 1H), 3.43-3.03 (m, 1H), 1.52 (s, 9H).

Intermediate 50:

[00366] Following the procedures used to prepare Intermediate 43, (RS)-tert-butyl 5-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate was converted to (RS) -5-fluoro-4-(4-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 356 (M+H)+. Intermediate 51 N-(3-Bromobenzyl)acrylamide

[00367] A solution of (3-bromophenyl)methanamine (0.500 g, 2.69 mmol) in DCM (13.4 mL) at 0 °C was treated with DIEA (0.939 mL, 5.37 mmol), then treated dropwise with acryloyl chloride (0.240 mL, 2.96 mmol). The mixture was stirred at room temperature for 3 hours, then concentrated. The residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (30 to 45% gradient), to provide N-(3-bromobenzyl)acrylamide as a white solid (0.476 g, 74% of income). Mass spectrum m/z 240, 242 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.47-7.40 (m, 2H), 7.25-7.19 (m, 2H), 6.35 (dd, J=16.9, 1.3 Hz, 1H), 6.17-6.09 (m, 1H), 5.84 (br.s., 1H), 5.71 (dd, J=10.2, 1.4Hz, 1H), 4.52 (d, J=5.9 Hz, 2H). Intermediate 52 1 -(6-Bromoindolin-1-yl)prop-2-en-1-one

[00368] Following the procedure used to prepare Intermediate 51, 6-bromoindoline [prepared according to the procedure of PCT Publication No. WO 2010/093949, Example 82, Step 1] was converted to 1-(6-bromoindolin-1-yl)prop-2-en-1-one in 94% yield. Mass spectrum m/z 252, 254 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (br.s., 1H), 7.21-7.19 (m, 2H), 6.79-6.66 (m, 1H), 6 .31 (dd, J=16.7, 2.2 Hz, 1H), 5.84 (dd, J=10.3, 2.2 Hz, 1H), 4.23 (t, J=8.6 Hz, 2H), 3.12 (t, J=8.5 Hz, 2H). Intermediate 53 N-(4-Bromopyridin-2-yl)acrylamide

[00369] Following the procedure used to prepare Intermediate 51, 4-bromo-2-aminopyridine was converted to N-(4-bromopyridin-2-yl)acrylamide in 50% yield after purification by preparative reverse phase HPLC. Mass spectrum m/z 227, 229 (M+H)+. Intermediate 54 6-Bromo-1-(vinylsulfonyl)indoline

[00370] A solution of 6-bromoindoline [prepared according to the procedure of PCT Publication No. WO 2010/093949, Example 82, Step 1] (0.290 g, 0.732 mmol) in DCM (3.7 mL) was cooled to 0 °C and treated with DIEA (0.205 mL, 1.17 mmol), then treated with dropwise with 2-chloroethanesulfonyl chloride (0.092 mL, 0.879 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue was chromatographed on silica gel (12 g), eluting with EtOAc-hexanes (5 to 20% gradient), to provide 6-bromo-1-(vinylsulfonyl)indoline as a solid. white (0.148 g, 70% yield). Mass spectrum m/z 288, 290 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J=1.1 Hz, 1H), 7.25-7.17 (m, 2H), 6.94 (dd, J=16, 3, 9.9 Hz, 1H), 6.32-6.18 (m, 2H), 3.94 (t, J=8.5 Hz, 2H), 3.06 (t, J=8.5 Hz, 2H). Intermediate 55 N-(3-Bromophenyl)ethenesulfonamide

[00371] Following the procedure used to prepare Intermediate 54, 3-bromoaniline was converted to N-(3-bromophenyl)ethenesulfonamide in 17% yield. 1H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 2H), 7.20 (t, J=7.9 Hz, 1H), 7.13-7.09 (m, 1H) , 6.57 (dd, J=16.4, 9.8 Hz, 1H), 6.37-6.31 (m, 2H), 6.02 (d, J=9.9 Hz, 1H). Intermediate 56 N-(3-Bromobenzyl)ethenesulfonamide

[00372] Following the procedure used to prepare Intermediate 54, (3-bromophenyl)methanamine was converted to N-(3-bromobenzyl)ethenesulfonamide in 41% yield. Mass spectrum m/z 298, 300 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ 7.50-7.43 (m, 2H), 7.29-7.21 (m, 2H), 6.51 (dd, J=16.5, 9.9 Hz, 1H), 6.28 (d, J=16.5 Hz, 1H), 5.96 (d, J=9.9 Hz, 1H), 4.64 (br.s., 1H), 4 .20 (d, J=6.2 Hz, 2H). Intermediate 57 N-(2-(3-Bromophenyl)propan-2-yl)ethenesulfonamide

[00373] Following the procedure used to prepare Intermediate 54, 2-(3-bromophenyl)propan-2-amine was converted to N-(2-(3-bromophenyl)propan-2-yl)ethenesulfonamide in 74% yield . Mass spectrum m/z 326, 328 (M+Na)+. 1H NMR (400 MHz, CDCl3) δ 7.60 (t, J=1.9 Hz, 1H), 7.42 (dddd, J=7.9, 4.9, 1.9, 1.0 Hz, 2H), 7.267.21 (m, 1H), 6.37 (dd, J=16.5, 9.7 Hz, 1H), 6.04 (d, J=16.5 Hz, 1H), 5, 72 (d, J=9.7 Hz, 1H), 4.64 (s, 1H), 1.73 (s, 6H). Intermediate 58 1-(3-Bromophenyl)-3-methylenepyrrolidin-2-one Intermediate 58A: 1-(3-Bromophenyl)pyrrolidin-2-one

[00374] A mixture of dihydrofuran-2(3H)-one (1.51 mL, 19.7 mmol), 3-bromoaniline (1.79 mL, 16.5 mmol), and concentrated aqueous HCl (0. 70 mL) was heated to 160 °C. After 16 hours the mixture was cooled to room temperature. Additional dihydrofuran-2(3H)-one (0.5ml) was added and heating was resumed at 160°C. After a total of 36 hours the mixture was cooled to room temperature and partitioned between water and EtOAc. The organic phase was washed with brine and concentrated. The residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (40 to 50% gradient), to provide 1-(3-bromophenyl)pyrrolidin-2-one as a solid (4. 16 g, quantitative production). Mass spectrum m/z 240, 242 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.80 (t, J=2.0 Hz, 1H), 7.65-7.60 (m, 1H), 7.30-7.27 (m, 1H) , 7.26-7.20 (m, 1H), 3.85 (t, J=7.0 Hz, 2H), 2.63 (t, J=8.0 Hz, 2H), 2.23- 2.10 (m, 2H). Intermediate 58B: Ethyl 2-(1-(3-bromophenyl)-2-oxopyrrolidin-3-yl)-2-oxoacetate

[00375] A stirred mixture of sodium hydride (60% in mineral oil, 1.84 g, 46.0 mmol) in THF (43.8 mL) was slowly treated with a solution of 1-(3-bromophenyl)pyrrolidin -2-one (4.15 g, 16.4 mmol) and diethyl oxalate (4.45 mL, 32.8 mmol) in THF (21.9 mL). The mixture was heated to reflux for 6 hours, then cooled to room temperature and stirred for 16 hours. Acetic acid (1.03 mL, 18.1 mmol) was added dropwise and the mixture stirred at room temperature for 1 hour, then partitioned between EtOAc and water. The pH of the aqueous layer was adjusted to 2 to 3 with 1M aqueous HCl and the layers were separated. The organic phase was washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (20 to 30% gradient), to provide a white viscous solid. This was suspended in EtOAc and the precipitate was collected by filtration to give ethyl 2-(1-(3-bromophenyl)-2-oxopyrrolidin-3-yl)-2-oxoacetate as a white solid (1.71 g, 31 % yield). Mass spectrum m/z 340, 342 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.08-8.05 (m, 1H), 7.67 (dt, J=7.0, 2.2 Hz, 1H), 7.44-7.39 (m, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.97 (t, J=7.0 Hz, 2H), 3. 07 (t, J=6.9 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).

Intermediate 58:

[00376] A suspension of ethyl 2-(1-(3-bromophenyl)-2-oxopyrrolidin-3-yl)-2-oxoacetate (1.71 g, 5.03 mmol) and diethylamine (1.57 mL, 15.1 mmol) in water (10.1 mL) at 0°C was slowly treated with 36.5% aqueous formaldehyde (1.52 mL, 20.1 mmol). The mixture was stirred at room temperature for 21 hours, forming a sticky solid. The supernatant was decanted off, and the residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (20 to 30% gradient), to provide 1-(3-bromophenyl)-3- methylenepyrrolidin-2-one as a white solid (0.497 g, 39% yield). Mass spectrum m/z 252, 254 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.92 (t, J=1.9 Hz, 1H), 7.76-7.71 (m, 1H), 7.33-7.29 (m, 1H) , 7.28-7.23 (m, 1H), 6.19-6.15 (m, 1H), 5.50-5.46 (m, 1H), 3.88-3.81 (m, 2H), 2.92 (tt, J=6.9, 2.6Hz, 2H). Intermediate 59 Mixture of 3-methylene-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one, and 3-methyl-1 -(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrol-2(5H)-one

[00377] A mixture of 1-(3-bromophenyl)-3-methylenepyrrolidin-2-one [Intermediate 58] (0.22 g, 0.873 mmol), 4,4,4',4,,5,5,5 ,,5,-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.233 g, 0.916 mmol), potassium acetate (0.171 g, 1.745 mmol), and PdCl2(dppf) DCM adduct ( 0.036 g, 0.044 mmol) in 1,4-dioxane (2.18 mL) was bubbled with nitrogen for about 2 to 3 minutes, then heated to 90 °C under a nitrogen atmosphere. After 2 hours, the mixture was cooled to room temperature and filtered through CELITE®. The solids were washed with EtOAc, MeOH and acetone, and the combined filtrates were concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with EtOAc-hexanes (20 to 30% gradient), to give a mixture of 3-methylene-1-(3-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one and 3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenyl)-1H-pyrrol-2(5H)-one as a colorless oil. Mass spectrum m/z 300 (M+H)+. Intermediate 60 1-(3-Bromo-2-methylphenyl)-3-methylenepyrrolidin-2-one

[00378] Following the procedures used to prepare Intermediate 58, 3-bromo-2-methylaniline was converted to 1-(3-bromo-2-methylphenyl)-3-methylenepyrrolidin-2-one. Mass spectrum m/z 266, 268 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J=7.6, 1.7 Hz, 1H), 7.19-7.08 (m, 2H), 6.17-6.10 ( m, 1H), 5.51-5.43 (m, 1H), 3.76-3.68 (m, 2H), 2.98 (tt, J=6.8, 2.6Hz, 2H) , 2.30 (s, 3H). Intermediate 61 N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide

[00379] A solution of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [prepared in accordance with United States Patent No. 8,084,620, Intermediate 50-1] (0.200 g, 0.858 mmol), EDC (0.296 g, 1.54 mmol), HOBT (0.236 g, 1.54 mmol), methacrylic acid (0.073 mL, 0.867 mmol), and DIEA ( 0.420 mL, 2.40 mmol) in THF (7.2 mL) and DCM (7.2 mL) was stirred at room temperature for 4 days. The mixture was concentrated and subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (10 to 30% gradient), to provide N-(2-methyl-3-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide as an off-white solid (0.164 g, 64% yield). Mass spectrum m/z 302 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 7.50 (dd, J=7.4, 1.4 Hz, 1H), 7.347.29 (m, 1H), 7 .20-7.14 (m, 1H), 5.84 (s, 1H), 5.50-5.47 (m, 1H), 2.32 (s, 3H), 1.96 (s, 3H ), 1.31 (s, 12H). Intermediate 62 N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohex-1-enecarboxamide

[00380] Following the procedure used to prepare Intermediate 61, but replacing cyclohex-1-enecarboxylic acid with methacrylic acid, 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)aniline [prepared in accordance with U.S. Patent No. 8,084,620, Intermediate 50-1] was converted to N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohex-1-enecarboxamide in 55% yield. Mass spectrum m/z 342 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.48 (dd, J=7.5, 1.3 Hz, 1H), 7.31 (dd, J=7, 8, 1.2 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 6.73-6.68 (m, 1H), 2.31 (s, 3H), 2, 29-2.23 (m, 2H), 2.18 (dd, J=5.9, 2.2 Hz, 2H), 1.68-1.54 (m, 4H), 1.30 (s, 12H). Intermediate 63 2-Cyano-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

[00381] Following the procedure used to prepare Intermediate 61, but replacing 2-cyanoacetic acid with methacrylic acid, 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline [prepared in accordance with U.S. Patent No. 8,084,620, Intermediate 50-1] was converted to 2-cyano-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide in 89% yield. Mass spectrum m/z 301 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.52-7.47 (m, 1H), 7.43-7.38 (m, 1H), 7.18 ( t, J=7.6 Hz, 1H), 3.91 (s, 2H), 2.34 (s, 3H), 1.30 (s, 12H). Intermediate 64 1-Cyano-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide

[00382] Following the procedure used to prepare Intermediate 61, but replacing 1-cyanocyclopropanecarboxylic acid with methacrylic acid, 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline [prepared in accordance with U.S. Patent No. 8,084,620, Intermediate 50-1] was converted to 1-cyano-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxa- measured at 60% yield. Mass spectrum m/z 327 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.54 (dd, J=7.5, 1.3 Hz, 1H), 7.30 (dd, J=7, 9, 1.3 Hz, 1H), 7.22-7.15 (m, 1H), 2.31 (s, 3H), 1.72-1.66 (m, 2H), 1.66-1 .60 (m, 2H), 1.31 (s, 12H). Intermediate 65 N-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide Intermediate 65A: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[00383] A mixture of 3-bromoaniline (1.00 g, 5.81 mmol), 4,4,4',4,,5,5,5,,5,-octamethyl-2,2,-bi( 1,3,2-dioxaborolane) (1.55 g, 6.10 mmol) and potassium acetate (1.14 g, 11.6 mmol) in 1,4-dioxane (14.5 mL) was flushed with nitrogen for 10 minutes. The mixture was treated with PdCl 2 (dppf) DCM adduct (0.114 g, 0.140 mmol) and bubbled with nitrogen for an additional 5 minutes. The mixture was heated to reflux for 2.75 hours, then cooled to room temperature and filtered through CELITE®. The solids were washed with EtOAc and THF. The combined filtrates were concentrated and the residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (10 to 25% gradient), to provide 3-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)aniline as an off-white solid (1.27 g, quantitative yield). Mass spectrum m/z 220 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.24-7.13 (m, 3H), 6.82-6.77 (m, 1H), 3.64 (br.s., 2H), 1.35 (s, 12H).

Intermediate 65:

[00384] A solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.300 g, 1.37 mmol) and DIEA (0.311 mL, 1.78 mmol) in DCM (9.1 mL) was cooled in an ice bath and treated with acryloyl chloride (0.117 mL, 1.44 mmol). The mixture was stirred at room temperature for 40 minutes, then concentrated and the residue was column chromatographed on silica gel (24 g), eluting with EtOAc-hexanes (15 to 40% gradient), to provide N- (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide as a white solid (0.292 g, 78% yield). Mass spectrum m/z 270 (M+H)+. Intermediate 66 N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[00385] Following the procedure used to prepare Intermediate 65, 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [prepared according to the Patent of the United States No. 8,084,620, Intermediate 50-1] was converted to N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide in 80% yield . Mass spectrum m/z 288 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.01 (br.s., 1H), 7.64 (d, J=5.9 Hz, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.07 (br.s., 1H), 6.48-6.40 (m, 1H), 6.32 (br.s., 1H), 5.78 (d, J=9, 5Hz, 1H), 2.49 (s, 3H), 1.36 (s, 12H). Intermediate 67 (E) - N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide

[00386] Following the procedure used to prepare Intermediate 65, but replacing (E)-but-2-enoyl chloride with acryloyl chloride, 2-methyl-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)aniline [prepared in accordance with U.S. Patent No. 8,084,620, Intermediate 50-1] was converted to (E)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but- 2-enamide in 85% yield. Mass spectrum m/z 302 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 7.46 (d, J=7.5 Hz, 2H), 7.15 (t, J=7.7 Hz, 1H ), 6.83-6.66 (m, 1H), 6.21 (d, J=14.7 Hz, 1H), 2.34 (s, 3H), 1.86 (dd, J=6, 9, 1.2Hz, 3H), 1.30 (s, 12H). Intermediate 68 3-Methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide

[00387] Following the procedure used to prepare Intermediate 65, but replacing 3-methylbut-2-enoyl chloride with acryloyl chloride, 2-methyl-3-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)aniline [prepared in accordance with U.S. Patent No. 8,084,620, Intermediate 50-1] was converted to 3-methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but- 2-enamide in 85% yield. Mass spectrum m/z 316 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.44 (d, J=7.3 Hz, 2H), 7.14 (t, J=7.6 Hz, 1H ), 5.95 (br.s., 1H), 2.33 (s, 3H), 2.12 (d, J=1.1 Hz, 3H), 1.86 (s, 3H), 1. 30 (s, 12H). Intermediate 69 N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide

[00388] Following the procedure used to prepare Intermediate 65, but replacing cyclopropanecarbonyl chloride with acryloyl chloride, 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline [prepared in accordance with U.S. Patent No. 8,084,620, Intermediate 50-1] was converted to N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide in 71% yield . Mass spectrum m/z 302 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (br.s., 1H), 7.43 (dd, J=10.0, 7.8 Hz, 2H), 7.13 (t, J =7.6 Hz, 1H), 2.35 (s, 3H), 1.87 (d, J=6.6 Hz, 1H), 1.30 (s, 12H), 0.79-0.74 (m, 4H). Intermediate 70 N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamide

[00389] Following the procedure used to prepare Intermediate 65, but replacing propionic anhydride with acryloyl chloride, 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )aniline [prepared in accordance with U.S. Patent No. 8,084,620, Intermediate 50-1] was converted to N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamide in 88% yield . Mass spectrum m/z 290 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 7.52-7.34 (m, 2H), 7.14 (t, J=7.6 Hz, 1H), 2 .37-2.30 (m, 5H), 1.30 (s, 12H), 1.10 (t, J=7.6 Hz, 3H). Intermediate 71 (E)-4-(Dimethylamino)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2- enamide

[00390] A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (0.300 g, 1.81 mmol) and a catalytic amount of DMF (7 μL, 0.091 mmol) in THF (22, 6 mL) was cooled to 0 °C. Oxalyl chloride (0.153 mL, 1.81 mmol) was added dropwise and the mixture was warmed to room temperature and stirred for 2 hours, then heated at 50 °C for 30 minutes. The solution was cooled to 0 °C, treated sequentially with DIEA (0.633 mL, 3.62 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline [prepared according to the procedure of United States Patent No. 8,084,620, Intermediate 50-1] (0.380 g, 1.63 mmol), and the resulting mixture was stirred at room temperature. After 30 minutes, the mixture was partitioned between saturated aqueous NaHCO 3 and EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc containing increasing amounts of 2 M NH 3 in MeOH (sequentially 0%, 5% and 10%), to give (E)-4-( dimethylamino)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide as a brown syrup (88 mg, 14% yield). Mass spectrum m/z 345 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.53-7.42 (m, 2H), 7.15 (t, J=7.6 Hz, 1H), 6 .70 (dt, J=15.4, 5.9 Hz, 1H), 6.35 (d, J=15.2 Hz, 1H), 3.05 (d, J=5.3 Hz, 2H) , 2.34 (s, 3H), 2.17 (s, 6H), 1.30 (s, 12H). Intermediate 72 N-Methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide Intermediate 72A: N,2-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[00391] A mixture of 3-bromo-N,2-dimethylaniline (1.90 g, 9.50 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2 ,2'-bi(1,3,2-dioxaborolane) (2.53 g, 9.97 mmol) and potassium acetate (1.86 g, 19.0 mmol) in 1,4-dioxane (23.7 mL) was bubbled with nitrogen for 10 minutes. The mixture was treated with PdCl 2 (dppf) DCM adduct (0.194 g, 0.237 mmol) and the mixture was bubbled with nitrogen for another 5 minutes, then heated to reflux. After 2.75 hours, the mixture was cooled to room temperature, filtered through CELITE®, and the solids washed with EtOAc. The combined filtrates were concentrated and the residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (5 to 15% gradient), to provide N,2-dimethyl-3-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as an off-white waxy solid (2.26 g, 96% yield). Mass spectrum m/z 249 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.21-7.12 (m, 2H), 6.72 (dd, J=6.5, 2.8 Hz, 1H), 3.63 (br. s. , 1H), 2.90 (s, 3H), 2.36 (s, 3H), 1.35 (s, 12H).

Intermediate 72:

[00392] Following the procedure used to prepare Intermediate 51, N,2-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was converted to N- methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide as a white solid in 98% yield. Mass spectrum m/z 302 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J=7.3, 1.3 Hz, 1H), 7.25-7.16 (m, 2H), 6.37 (dd, J= 16.8, 2.1 Hz, 1H), 5.90 (dd, J=16.9, 10.3 Hz, 1H), 5.47 (dd, J=10.3, 2.2 Hz, 1H ), 3.25 (s, 3H), 2.38 (s, 3H), 1.37 (s, 12H). Intermediate 73 N-Methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide Intermediate 73A: N-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[00393] Following the procedure used in the preparation of Intermediate 72A, 3-bromo-N-methylaniline was converted to N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)aniline in quantitative production. Mass spectrum m/z 234 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.25-7.15 (m, 2H), 7.07 (d, J=2.4 Hz, 1H), 6.73 (ddd, J=7.7, 2.6, 1.3 Hz, 1H), 4.02-3.43 (b, 1H), 2.87 (s, 3H), 1.35 (s, 12H).

Intermediate 73:

[00394] Following the procedure used in the preparation of Intermediate 72, N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was converted to N-methyl- N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide in 88% yield. Mass spectrum m/z 288 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=7.3 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.42 (t, J=7 .7 Hz, 1H), 7.26-7.23 (m, 1H), 6.37 (dd, J=16.7, 2.0 Hz, 1H), 6.06 (dd, J=16, 7, 10.6 Hz, 1H), 5.51 (dd, J=10.3, 2.0 Hz, 1H), 3.36 (s, 3H), 1.36 (s, 12H). Intermediate 74 N-(2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methylacrylamide Intermediate 74A: 2N-(3-Bromo-2-methylphenyl)formamide

[00395] A solution of 3-bromo-2-fluoroaniline (1.00 g, 5.26 mmol) in formic acid (1.99 mL, 52.6 mmol) was heated at 90°C for 16 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was washed sequentially with saturated aqueous NaHCO 3 and brine, dried and concentrated to provide N-(3-bromo-2-fluorophenyl)formamide as a beige solid (1.02 g, 89% yield) . Mass spectrum m/z 218, 220 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.40-8.17 (m, 1H), 7.53-7.41 (m, 1H), 7.31 (ddd, J=8.0, 6.6, 1.4Hz, 1H), 7.05 (td, J=8.2, 1.4Hz, 1H). Intermediate 74B: 3-Bromo-2-fluoro-N-methylaniline

[00396] A solution of N-(3-bromo-2-fluorophenyl)formamide (1.00 g, 4.59 mmol) in THF (15 mL) was cooled to 0 °C, treated dropwise with borane complex - methyl sulfide (6.88 mL, 13.8 mmol) and heated at 70 °C for 2 hours. The mixture was cooled to room temperature and treated with MeOH, stirred at room temperature for 30 minutes, then slowly treated with 1M aqueous HCl. The mixture was heated to 70 °C for 1 hour, then cooled to room temperature. room temperature, treated with 1M aqueous NaOH and extracted with EtOAc. The organic extract was washed with saline, dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes, to provide 3-bromo-2-fluoro-N-methylaniline as a colorless oil (0.800 g, 85% yield). Mass spectrum m/z 204, 206 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.92-6.86 (m, 1H), 6.84-6.78 (m, 1H), 6.63-6.56 (m, 1H), 4, 03 (br.s., 1H), 2.88 (d, J=4.6 Hz, 3H). Intermediate 74C: 2-Fluoro-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[00397] Following the procedure used in the preparation of Intermediate 72A, 3-bromo-2-fluoro-N-methylaniline was converted to 2-fluoro-N-methyl-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)aniline in 71% yield. Mass spectrum m/z 252 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J=7.3 Hz, 2H), 6.85-6.73 (m, 1H), 4.07-3.85 (m, 1H) , 2.86 (s, 3H), 1.38-1.32 (m, 12H).

Intermediate 74:

[00398] Following the procedure used in the preparation of Intermediate 72, 2-fluoro-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was converted to N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methylacrylamide in 56% yield. 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.33-7.27 (m, 1H), 7.22-7.06 (m, 1H), 6.37 (d, J=16.7 Hz, 1H), 6.16-5.87 (m, 1H), 5.52 (d, J=10.1 Hz, 1H), 3.30 (s, 3H), 1, 38 (s, 12H). Intermediate 75 N-Methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) ethenesulfonamide

[00399] A solution of N,2-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [Intermediate 72A] (0.500 g, 2.02 mmol ) in DCM (10.1 mL), cooled to 0 °C, was treated with DIEA (0.530 mL, 3.03 mmol), then 2-chloroethanesulfonyl chloride (0.254 mL, 2.43 mmol) was added dropwise to drop. The mixture was stirred at room temperature for 3 hours, then concentrated. The residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (10 to 20% gradient), to provide N-methyl-N-(2-methyl-3-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide as a white waxy solid (0.432 g, 63% yield). Mass spectrum m/z 338 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J=7.3, 1.3 Hz, 1H), 7.27-7.23 (m, 1H), 7.21-7.15 ( m, 1H), 6.62 (dd, J=16.5, 9.9 Hz, 1H), 6.23 (d, J=16.7 Hz, 1H), 6.02 (d, J=9 .9Hz, 1H), 3.15 (s, 3H), 2.61 (s, 3H), 1.35 (s, 12H). Intermediate 76 N-Methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide

[00400] Following the procedure used to prepare Intermediate 75, N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [Intermediate 73A] was converted to N-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide in 61% yield. Mass spectrum m/z 324 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.62-7.54 (m, 2H), 7.51-7.37 (m, 2H), 6.86 (dd, J=16.4, 10 .0 Hz, 1H), 6.14 (d, J=10.1 Hz, 1H), 6.02 (d, J=16.5 Hz, 1H), 3.18 (s, 3H), 1, 30 (s, 12H). Intermediate 77 N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide

[00401] Following the procedure used to prepare Intermediate 75, 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [prepared according to procedure United States Patent No. 8,084,620, Intermediate 46-1, Step 1] was converted to N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide in 49 % yield. Mass spectrum m/z 324 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.527.47 (m, 1H), 7.27 (d, J=6.6 Hz, 1H), 7.19-7 .13 (m, 1H), 6.83 (dd, J=16.5, 9.9 Hz, 1H), 5.99-5.89 (m, 2H), 2.44 (s, 3H), 1.30 (s, 12H). Intermediate 78 N-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide

[00402] Following the procedure used to prepare Intermediate 75, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [Intermediate 65A] was converted to N-(3 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethenesulfonamide in 40% yield. Mass spectrum m/z 310 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=7.0 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.44-7.40 (m , 1H), 7.40-7.34 (m, 1H), 6.57 (dd, J=16.5, 9.9 Hz, 1H), 6.34-6.26 (m, 2H), 5.97 (d, J=9.9 Hz, 1H), 1.36 (s, 12H). Intermediate 79 4,4,5,5-Tetramethyl-2-(3-(vinylsulfonyl)phenyl)-1,3,2-dioxaborolane Intermediate 79A: (3-Bromophenyl)(2-chloroethyl)sulfane

[00403] A mixture of 3-bromobenzenethiol (1.09 mL, 10.6 mmol), 1-bromo-2-chloroethane (1.76 mL, 21.2 mmol) and K2CO3 (1.46 g, 10.6 mmol) in DMF (10.6 mL) was heated at 60°C for 5 hours. The mixture was cooled to room temperature and stirred overnight. After 16 hours, the mixture was partitioned between water and ether. The organic phase was washed with brine, dried and concentrated to give (3-bromophenyl)(2-chloroethyl)sulfane as a colorless oil (2.63 g, 99% yield), used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.53 (t, J=1.8 Hz, 1H), 7.38 (ddd, J=8.0, 1.8, 1.0 Hz, 1H), 7 .31 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 7.22-7.15 (m, 1H), 3.65-3.60 (m, 2H), 3 .27-3.22 (m, 2H). Intermediate 79B: 1-Bromo-3-((2-chloroethyl)sulfonyl)benzene

[00404] A solution of (3-bromophenyl)(2-chloroethyl)sulfane (2.63 g, 10.5 mmol) in DCM (10.5 mL) was cooled to 0 °C and treated portionwise with a solution of m-chloroperoxybenzoic acid (6.01 g, 26.1 mmol) in DCM (40 mL). The resulting suspension was stirred at 0°C for 4 hours. The mixture was diluted with DCM, treated with saturated aqueous NaHCO 3 and sodium thiosulfate. The organic phase was separated, washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (5 to 30% gradient), to provide 1-bromo-3-((2-chloroethyl)sulfonyl)benzene as a solid. white (2.93 g, 99% yield). Mass spectrum m/z 283, 285 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.08 (t, J=1.9 Hz, 1H), 7.86 (dddd, J=14.5, 7.9, 1.8, 1.1 Hz, 2H), 7.49 (t, J=7.9 Hz, 1H), 3.81-3.76 (m, 2H), 3.59-3.52 (m, 2H).

Intermediate 79:

[00405] A mixture of 1-bromo-3-((2-chloroethyl)sulfonyl)benzene (0.500 g, 1.76 mmol), 4,4,4',4,,5,5,5,,5, -octamethyl-2,2,-bi(1,3,2-dioxaborolane) (0.470 g, 1.85 mmol), potassium acetate (0.346 g, 3.53 mmol) and PdCl2(dppf) DCM adduct (0.036 g, 0.044 mmol) in 1,4-dioxane (4.41 mL) was bubbled with nitrogen for about 2 to 3 minutes, then heated to reflux. After 2.5 hours, the mixture was cooled to room temperature and filtered through CELITE®. The solids were washed with EtOAc, and the combined filtrates were concentrated. The residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (10 to 25% gradient), to provide 4,4,5,5-tetramethyl-2-(3-(vinylsulfonyl) phenyl)-1,3,2-dioxaborolane as a pale yellow waxy solid (0.196 g, 80% purity, 30% yield), used without further purification. Mass spectrum m/z 295 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.09-8.02 (m, 1H), 8.01-7.95 (m, 1H), 7.60-7, 51 (m, 1H), 6.736.63 (m, 1H), 6.48 (d, J=16.5 Hz, 1H), 6.04 (d, J=9.7 Hz, 1H), 1, 36 (s, 12H). Intermediate 80 N-(Cyanomethyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide Intermediate 80A: 3-Bromo-N-(cyanomethyl)-2-methylbenzamide

[00406] A solution of 3-bromo-2-methylbenzoic acid (0.500 g, 2.33 mmol), EDC (0.669 g, 3.49 mmol), HOBT (0.534 g, 3.49 mmol), and DIEA (1 .22 mL, 6.98 mmol) in THF (14.5 mL) and DCM (14.5 mL) was stirred at room temperature for 30 minutes, then treated with 2-aminoacetonitrile hydrochloride (0.237 g, 2, 56mmol). The mixture was stirred at room temperature for 5 hours, then partitioned between saturated aqueous NaHCO 3 and EtOAc. The organic phase was dried and concentrated, and the residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient 20 to 40%) to give 3-bromo-N-(cyanomethyl )-2-methylbenzamide as a white solid (0.554 g, 94% yield). Mass spectrum m/z 253, 255 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J=8.0, 1.0 Hz, 1H), 7.30 (dd, J=7.7, 0.9 Hz, 1H), 7 .14-7.08 (m, 1H), 6.14 (br.s., 1H), 4.38 (d, J=5.9 Hz, 2H), 2.48 (s, 3H).

Intermediate 80:

[00407] Following the procedure used to prepare Intermediate 65A, 3-bromo-N-(cyanomethyl)-2-methylbenzamide was converted to N-(cyanomethyl)-2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide as a yellow solid in 91% yield. Mass spectrum m/z 301 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (t, J=5.6 Hz, 1H), 7.69 (dd, J=7.5, 1.5 Hz, 1H), 7.37 (dd, J=7.6, 1.4 Hz, 1H), 7.30-7.18 (m, 1H), 4.28 (d, J=5.5 Hz, 2H), 2.45 ( s, 3H), 1.31 (s, 12H). Intermediate 81 8-Fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4( 1H ,3H)-dione Intermediate 81A: 2-Amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide

[00408] A solution of 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2.00 g, 11.0 mmol) and 3-bromo-2-methylaniline (4, 11 g, 22.1 mmol) in 1,4-dioxane (20 mL) in a sealed reaction vessel was heated at 110 °C for 4 days. The mixture was cooled to room temperature and treated with 10% aqueous K 2 CO 3 and stirred for 30 minutes. The mixture was extracted three times with DCM, and the combined organic phases were washed with water, dried and concentrated. The residue was triturated with ether, and the precipitate was collected by filtration to give a gray solid (2.50g). The filtrate was concentrated and the residue was triturated again with ether to give a gray solid (230 mg). The two solids combined to give 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide as a gray solid (2.73 g, 78% yield). Mass spectrum m/z 323, 325 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=7.9 Hz, 1H), 7.65 (br.s., 1H), 7.50-7.46 (m, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.19-7.11 (m, 2H), 6.73-6.64 (m, 1H), 5.69 (br.s. , 2H), 2.44 (s, 3H).

Alternative Synthesis of 2-Amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide:

[00409] A suspension of 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (3.00 g, 16.6 mmol) in xylenes (50 mL) was treated with 3- bromo-2-methylaniline (3.08 g, 16.6 mmol) and heated to reflux. After 6 hours the mixture was allowed to cool to room temperature overnight. The resulting suspension was diluted with hexanes and the precipitate was collected by filtration, rinsed with hexanes and air dried to provide 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide as a white solid (4. 50 g, 84% yield). Intermediate 81B: 3-(3-Bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H ,3H)-dione

[00410] A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide (5.70 g, 17.6 mmol) in THF (100 mL) was treated with bis(trichloromethyl carbonate ) [triphosgene] (6.28 g, 21.2 mmol) at room temperature and stirred for 15 minutes. The mixture was diluted with EtOAc, carefully treated with saturated aqueous NaHCO 3 and stirred at room temperature until gas evolution ceased. The organic phase was separated and washed sequentially with saturated aqueous NaHCO 3 , water and brine, dried and concentrated. The residue was triturated with ether to give 3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as an off-white solid (6.00 g, 97% yield ). Mass spectrum m/z 349, 351 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=17.6 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.70 (dd, J=7 .8, 1.2 Hz, 1H), 7.54-7.43 (m, 1H), 7.28-7.21 (m, 2H), 7.21-7.17 (m, 1H), 2.28 (s, 3H). Intermediate 81C: 3-(3-Bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione

[00411] A solution of 3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione (4.80 g, 13.8 mmol) in DMF (25 mL) was treated with Cs2CO3 (13.4 g, 41.2 mmol). The suspension was stirred at room temperature and treated rapidly dropwise with iodomethane (4.30 mL, 68.7 mmol) and stirred rapidly at room temperature for 1 hour. The mixture was diluted with EtOAc and water (200 mL). The organic phase was separated and washed sequentially with water and brine, then dried and concentrated to give 3-(3-bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H) - dione as a brown glassy solid (4.80 g, 96% yield). Mass spectrum m/z 363, 365 (M+H)+.

Intermediate 81:

[00412] A mixture of 3-(3-bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione (4.80 g, 13.2 mmol), 4, 4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.36 g, 17.2 mmol), potassium acetate (3.89 g, 39.6 mmol) and PdCl 2 (dppf) DCM adduct (0.540 g, 0.661 mmol) in 1,4-dioxane (65 mL) was heated to reflux for 2 hours. After cooling to room temperature, the mixture was filtered through CELITE® and the solids were rinsed with EtOAc. The filtrate was diluted with EtOAc, washed with water, dried and concentrated. The residue was subjected to column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (20 to 50% gradient), to provide 8-fluoro-1-methyl-3-(2-methyl-3 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione as a white solid (4.61 g, 85% income). Mass spectrum m/z 411 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.14-8.08 (m, 1H), 7.93 (dd, J=7.5, 1.3 Hz, 1H), 7.48 (ddd, J= 14.0, 8.0, 1.5 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.27-7.20 (m, 2H), 3.88 (d , J=7.9 Hz, 3H), 2.36 (s, 3H), 1.36 (s, 12H). Intermediate 82 1-Methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4( 1H , 3H)-dione Intermediate 82A: 2-Amino-N-(3-bromo-2-methylphenyl)benzamide

[00413] A solution of 2-aminobenzoic acid (5.00 g, 36.5 mmol) and thionyl chloride (8.68 g, 72.9 mmol) in toluene (50 mL) was heated to reflux for 60 minutes. The mixture was concentrated and the residue suspended in THF (50 mL), cooled in an ice-water bath and treated with 3-bromo-2-methylaniline (20.35 g, 109 mmol). The resulting suspension was heated to reflux for 2 hours. The mixture was cooled to room temperature and treated with 10% aqueous K 2 CO 3 (50 mL), stirred vigorously for 15 minutes, and extracted with EtOAc. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel to provide 2-amino-N-(3-bromo-2-methylphenyl)benzamide as a light yellow solid (4.70 g, 42% yield). Mass spectrum m/z 305, 307 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=7.9 Hz, 1H), 7.67 (br.s., 1H), 7.54 (dd, J=8.3, 1 .2 Hz, 1H), 7.48 (dd, J=7.9, 0.9 Hz, 1H), 7.367.31 (m, 1H), 7.15 (t, J=8.0 Hz, 1H ), 6.81-6.73 (m, 2H), 5.59 (br.s., 2H), 2.45 (s, 3H).

Alternative Synthesis of 2-Amino-N-(3-bromo-2-methylphenyl)benzamide:

[00414] A suspension of 1H-benzo[d][1,3]oxazine-2,4-dione (5.00 g, 30.7 mmol) and 3-bromo-2-methylaniline (5.70 g, 30 .7 mmol) in xylenes (50 mL) was heated to reflux for 8 hours. The solvent was distilled off and the residue was purified by column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (0 to 50% gradient), to give 2-amino-N-(3-bromo- 2-methylphenyl)benzamide as an off-white solid (2.30 g, 24% yield). Intermediate 82B: 3-(3-Bromo-2-methylphenyl)quinazoline-2,4( 1H ,3 H)-dione

[00415] A solution of 2-amino-N-(3-bromo-2-methylphenyl)benzamide (2.00 g, 6.55 mmol) in THF (50 mL) was treated with bis(trichloromethyl) carbonate [triphosgene ] (2.92 g, 9.83 mmol) and heated to reflux for 60 minutes. The mixture was cooled to room temperature and treated with saturated aqueous NaHCO 3 , extracted with EtOAc, and the combined organic layers were washed twice with saturated NaHCO 3 , then with water, dried and concentrated. The residue was triturated with DCM to give a white solid which was collected by filtration. The residue from the filtrate concentration was triturated with DCM to provide an additional white solid which was collected by filtration. The two solids were combined to provide 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione as a white solid (2.10 g, 97% yield). Mass spectrum m/z 331, 333 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 8.07 (dd, J=7.92, 1.32 Hz, 1H), 7.65-7.75 (m, 2H), 7.21-7, 32 (m, 4H), 2.20 (s, 3H). 1H NMR (400 MHz, CDCl3) δ 9.38 (br.s., 1H), 8.19 (dd, J=7.9, 1.1 Hz, 1H), 7.76-7.69 (m , 1H), 7.69-7.60 (m, 1H), 7.35-7.17 (m, 3H), 7.04-6.97 (m, 1H), 2.28 (s, 3H ). Intermediate 82C: 3-(3-Bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione

[00416] A suspension of 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (23.02 g, 69.5 mmol) and Cs2CO3 (34.0 g, 104 mmol ) in DMF (70 mL) cooled in an ice-water bath was treated portionwise with iodomethane (5.22 mL, 83 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between EtOAc and water, forming a precipitate which was collected by filtration. The collected solid was washed with water and dried overnight under vacuum to give a white solid. The organic phase of the filtrate was separated, washed three times with 10% aqueous LiCl, then washed twice with water, dried and concentrated to give an additional solid. The two solids were combined to give 3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione as a white solid (15.56 g, 92% yield) . Mass spectrum m/z 345, 347 (M+H)+.

Intermediate 82:

[00417] A mixture of 3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1 H ,3 H)-dione (36.39 g, 105 mmol), 4,4,4, ,4,,5,5,5,,5,-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (40.2 g, 158 mmol), PdCl 2 (dppf) DCM adduct (4 .30 g, 5.27 mmol) and potassium acetate (31.0 g, 316 mmol) in 1,4-dioxane (500 mL) and DMSO (50 mL) was heated to reflux for 24 hours. Additional PdCl 2 (dppf) DCM adduct (1.47 g) was added and the mixture heated at reflux for a further 6 hours. The cooled mixture was filtered through CELITE® and the filtrate was concentrated. The residue was diluted with EtOAc, stirred with water, and both layers were filtered through CELITE® to remove a black precipitate. The organic phase of the filtrate was separated, washed sequentially with water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (2330 g columns), eluting with EtOAc-hexanes (20 to 100% gradient). The product-containing effluent concentration residue was triturated with EtOAc to give a solid which was collected by filtration. The filtrate was concentrated and crystallized from EtOAc to provide an additional solid. The mother liquor from this crystallization was concentrated and the residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (20 to 50% gradient), to provide an additional solid. The three solids were combined to give 1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4 (1H,3H)-dione as a white solid (21.2 g, 51% yield). Mass spectrum m/z 393 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=7.9 Hz, 1H), 7.64 (ddd, J=8.5, 7.3, 1.5 Hz, 1H), 7 .59 (dd, J=7.4, 1.4 Hz, 1H), 7.33-7.27 (m, 1H), 7.24-7.17 (m, 1H), 7.12 (d , J=8.1 Hz, 2H), 3.55 (s, 3H), 1.59 (s, 3H), 1.39 (s, 12H). Intermediate 83 5-Fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide

[00418] Following the procedure used to prepare Intermediate 9, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 2] was converted to 5-fluoro-2,3-dimethyl -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide in 38% yield. Mass spectrum m/z 333 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.27 (d, J=10.1 Hz, 1H), 2.39 (s, 3H), 2.24 (s, 3H), 1.44 (s , 12H). Intermediate 84 ((flS)-5-Fluoro-2,3-dimethyl-4-(2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-1H-indol- 7-carboxamide, TFA salt

[00419] Following the procedures used to prepare Intermediate 48, 9-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine [prepared according to procedures described in Example 13 of PCT Publication At the. WO 2012/149236] was converted to (RS)-5-fluoro-2,3-dimethyl-4-(2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl) -1H-indole-7-carboxamide. Mass spectrum m/z 354 (M+H)+. Intermediate 85 ((1S)-5-Fluoro-4-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide, salt TFA Intermediate 85A: Ethyl 2-bromo-4-fluorophenethylcarbamate

[00420] A mixture of 3-(2-bromo-4-fluorophenyl)propanoic acid (2.00 g, 8.10 mmol), EtOH (0.945 mL, 16.2 mmol), TEA (3.38 mL, 24 .3 mmol) and diphenylphosphoryl azide (2.45 g, 8.90 mmol) in anhydrous THF (20 mL) was heated at 80°C for 18 hours. The mixture was concentrated and the residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes (0 to 100% gradient) to provide ethyl 2-bromo-4-fluorophenethylcarbamate as a colorless gum (2.03 g , 82% yield). Mass spectrum m/z 290, 292 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J=8.3, 2.5 Hz, 1H), 7.24-7.16 (m, 1H), 6.99 (td, J= 8.3, 2.6 Hz, 1H), 4.68 (br.s., 1H), 4.19 4.06 (m, 2H), 3.43 (q, J=6.6 Hz, 2H ), 2.95 (t, J=6.9 Hz, 2H), 1.30-1.19 (m, 3H). Intermediate 85B: Ethyl 5-bromo-7-fluoro-3,4-dihydroisoquinoline-2( 1H )-carboxylate

[00421] A solution of ethyl 2-bromo-4-fluorophenethylcarbamate (1.30 g, 4.48 mmol) in acetic acid (9.00 mL, 157 mmol) and sulfuric acid (3.00 mL, 56 .3 mmol) was stirred at 0 °C and treated with paraformaldehyde (0.148 g, 4.93 mmol). The mixture was stirred at room temperature for three days, then diluted with water (50 mL) and extracted with EtOAc. The organic layer was washed sequentially with saturated aqueous NaHCO 3 and 1M aqueous HCl, dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0 to 30% gradient) to provide 5-bromo-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate. ethyl as a white solid (334 mg, 23% yield). Mass spectrum m/z 302, 304 (M+H)+. Intermediate 85C: 5-Bromo-7-fluoro-1,2,3,4-tetrahydroisoquinoline

[00422] A solution of ethyl 5-bromo-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (350 mg, 1.16 mmol) in ethylene glycol (7.0 mL) was treated with a solution of KOH (5.85 g, 104 mmol) in water (5.6 mL) and the mixture was stirred at 90°C for 18 hours. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried and concentrated to give 5-bromo-7-fluoro-1,2,3,4-tetrahydroisoquinoline, used without further purification. Mass spectrum m/z 230, 232 (M+H)+.

Intermediate 85:

[00423] Following the procedures used to prepare Intermediate 48, 5-bromo-7-fluoro-1,2,3,4-tetrahydroisoquinoline was converted to (RS)-5-fluoro-4-( 7-Fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 356 (M+H)+. Intermediate 86 5-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-indole-7-carboxamide, TFA salt

[00424] Following the procedures used to prepare Intermediate 48, 6-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride was converted to 5-fluoro-2,3-dimethyl-4-(1,2, 3,4-tetrahydroisoquinolin-6-yl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 338 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.42 (d, J=10.6 Hz, 1H), 7.377.27 (m, 3H), 4.48 (s, 2H), 3.59 (td , J=6.4, 2.3 Hz, 2H), 3.25-3.18 (m, 2H), 2.36 (s, 3H), 1.65 (s, 3H). Intermediate 87 (RS)-5-Fluoro-4-(indolin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide, TFA salt

[00425] Following the procedures used to prepare Intermediate 48, 4-bromoindoline was converted to (RS)-5-fluoro-4-(indolin-4-yl)-2,3-dimethyl-1H-indole-7-carboxamide , TFA salt. Mass spectrum m/z 324 (M+H)+. Intermediate 88 (RS)-4-(314-Di:hydro-2H-benzo[bJ[1,4]thiazi4-8-yl)∑5-fluoro-2,3-dimethyl,∑1H-indole-7-carboxamide, TFA salt

[00426] Following the procedures used to prepare Intermediate 48, 8-bromo-3,4-dihydro-2H-benzo[b][1,4]thiazine [prepared according to procedures described in Example 331 of PCT Publication At the. WO 2012/149236] was converted to (RS)-4-(3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl -1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 356 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.38 (d, J=10.4 Hz, 1H), 7.11-7.02 (m, 1H), 6.87 (dd, J=8, 1, 1.3 Hz, 1H), 6.76 (dd, J=7.4, 1.2 Hz, 1H), 3.63 (dtd, J=8.1, 6.0, 1.9 Hz , 2H), 3.05 (dt, J=6.6, 4.0 Hz, 2H), 2.35 (s, 3H), 1.67 (s, 3H). Intermediate 89 (S)-4-(3-(Cyclopropylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Intermediate 89A: (S )-tert-butyl 3-(cyclopropylamino)piperidine-1-carboxylate

[00427] A solution of (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.00 g, 4.99 mmol), (1-ethoxycyclopropoxy)trimethylsilane (0.870 g, 4.99 mmol) and acid Acetic acid (2.86 mL, 49.9 mmol) in MeOH (15 mL) was treated with sodium cyanoborohydride (0.471 g, 7.49 mmol) and the mixture was stirred at 60°C for 14 hours. The mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO 3 , dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes (0 to 100% gradient) to provide (S)-tert-butyl 3-(cyclopropylamino)piperidine-1-carboxylate as an oil. colorless (180 mg, 15% yield). Mass spectrum m/z 241 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 4.19-4.09 (m, 1H), 3.84 (d, J=12.8 Hz, 1H), 2.83 (ddd, J=13, 5, 10.9, 3.1 Hz, 1H), 2.71-2.60 (m, 2H), 2.18 (tt, J=7.0, 3.6 Hz, 1H), 2.05 -1.96 (m, 1H), 1.75-1.66 (m, 1H), 1.52-1.40 (m, 11H), 1.371.27 (m, 1H), 0.53-0 .47 (m, 2H), 0.38-0.33 (m, 2H). Intermediate 89B: (S)-tert-butyl 3-(((benzyloxy)carbonyl)(cyclopropyl)amino)piperidine-1-carboxylate

[00428] A solution of (S)-tert-butyl 3-(cyclopropylamino)piperidine-1-carboxylate (180 mg, 0.749 mmol) and benzyl (2,5-dioxopyrrolidin-1-yl)carbonate (560 mg, 2.25 mmol) in THF (2 mL) was treated with TEA (313 µL, 2.25 mmol) and the mixture was stirred at room temperature for 14 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO 3 , dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtO-Ac-hexanes (0 to 100% gradient), then purified by followed by preparative reverse phase HPLC to afford 3-(((benzyloxy)carbonyl (S)-tert-butyl)(cyclopropyl)amino)piperidine-1-carboxylate as a colorless viscous oil (200 mg, 71% yield). 1H NMR (400 MHz, MeOH-d4) δ 7.44-7.26 (m, 5H), 5.12 (s, 2H), 4.00 (d, J=11.4 Hz, 2H), 3 .62-3.45 (m, 1H), 3.10 (t, J=11.9 Hz, 1H), 2.722.50 (m, 2H), 2.10 (qd, J=12.5, 3 .9 Hz, 1H), 1.89 (d, J=11.7 Hz, 1H), 1.74 (d, J=13.6 Hz, 1H), 1.55-1.38 (m, 10H ), 0.90-0.77 (m, 2H), 0.740.61 (m, 2H). Intermediate 89C: (S )-benzyl cyclopropyl(piperidin-3-yl)carbamate

[00429] A solution of (S)-tert-butyl 3-(((benzyloxy)carbonyl)(cyclopropyl)amino)-piperidine-1-carboxylate (200 mg, 0.534 mmol) in DCM (1 mL) was treated with TFA (0.50 mL, 6.49 mmol) and the mixture was allowed to stand at room temperature for 30 minutes. The solution was concentrated and the residue was dissolved in DCM, washed with saturated aqueous NaHCO 3 , dried and concentrated to give (S)-benzyl cyclopropyl(piperidin-3-yl)carbamate as a colorless oil (140 mg, 96% yield ). Mass spectrum m/z 275 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.43-7.16 (m, 5H), 5.11 (s, 2H), 3.66 (dtd, J=11.7, 7.9, 4 .0 Hz, 1H), 2.96-2.86 (m, 3H), 2.56-2.49 (m, 1H), 2.41 (td, J=12.7, 2.9 Hz, 1H), 2.10-1.98 (m, 1H), 1.87 (dd, J=12.3, 3.1 Hz, 1H), 1.81-1.72 (m, 1H), 1 .60-1.46 (m, 1H), 0.83-0.76 (m, 2H), 0.70-0.62 (m, 2H).

Intermediate 89:

[00430] Following the procedures used to prepare Intermediate 13, (S)-benzyl cyclopropyl(piperidin-3-yl)carbamate and 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12] were converted to (S)-4-(3-(cyclopropylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide. Mass spectrum m/z 345 (M+H)+. Intermediate 90 5-Fluoro-2,3-dimethyl-4-(piperazin-1-yl)-1H-indole-7-carboxamide Intermediate 90A: tert-Butyl 4-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperazine-1-carboxylate

[00431] A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12] (0.200 g, 0.749 mmol), tert-butyl piperazine-1-carboxylate (0.146 g, 0.786 mmol), Cs2CO3 (0.488 g, 1.50 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.023 g, 0.037 mmol), and tris(dibenzylideneacetone)dipalladium (0.034 g , 0.037 mmol) in 1,4-dioxane (5 mL) was bubbled with nitrogen and heated overnight at 95 °C. The mixture was cooled to room temperature, filtered through CELITE® and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0 to 100% gradient), to provide 4-(7-cyano-5-fluoro-2,3-dimethyl-1H-indole-4 tert-Butyl-yl)piperazine-1-carboxylate as a yellow solid (0.194 g, 70% yield). Mass spectrum m/z 373 (M+H)+.

Intermediate 90:

[00432] A mixture of tert-butyl 4-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperazine-1-carboxylate (0.195 g, 0.524 mmol), chloro- trimethylsilane (5.00 mL, 39.1 mmol), and water (2.50 mL, 139 mmol) was stirred at room temperature for two days. The upper layer was decanted off and the remaining aqueous layer was concentrated to provide 5-Fluoro-2,3-dimethyl-4-(piperazin-1-yl)-1H-indole-7-carboxamide HCl salt as a brown solid (166 mg, 97% yield), used without further purification. Mass spectrum m/z 291 (M+H)+. Intermediate 91 4-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide

[00433] 4-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide was prepared following the procedures used to prepare Intermediate 2, substituting 1,1,1-trifluoro-2 -butanone to 2-butanone. Mass spectrum m/z 339, 341 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.75 (d, J=9.7 Hz, 1H), 2.70 (q, J=1.7 Hz, 3H). Intermediate 92 (1S)-5-Fluoro-3-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-2-(trifluoromethyl)-1H-indole-7-carboxamide, salt of TFA

[00434] Following the procedures used to prepare Intermediate 42, 4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide [Intermediate 91] was converted to (RS)-5 -fluoro-3-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-2-(trifluoromethyl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 392 (M+H)+. Intermediate 93 (RS)-5-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-8-yl)∑1H: indole-7-carboxamide, TFA salt

[00435] Following the procedures used to prepare Intermediate 48, 8-bromo-1,2,3,4-tetrahydroisoquinoline HCl salt was converted to (RS)-5-fluoro-2,3-dimethyl-4- (1,2,3,4-tetrahydroisoquinolin-8-yl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 338 (M+H)+. Intermediate 94 5-Fluoro-4-(indolin-6-yl)-2,3-dimethyl-1H-indole-7-carboxamide, TFA salt

[00436] Following the procedures used to prepare Intermediate 48, 6-bromoindoline was converted to 5-fluoro-4-(indolin-6-yl)-2,3-dimethyl-1H-indole-7-carboxamide, TFA salt . Mass spectrum m/z 324 (M+H)+. Intermediate 95 4-Bromo-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[00437] Following the procedures used to prepare Intermediate 2 from Intermediate 2A, 4-bromo-2,6-difluorobenzoic acid was converted to 4-bromo-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide . Mass spectrum m/z 285, 287 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.08 (d, J=12.0 Hz, 1H), 2.44 (d, J=0.5 Hz, 3H), 2.36 (s, 3H ). Intermediate 96 6-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide, TFA salt

[00438] Following the procedures used to prepare Intermediate 42, 4-bromo-6-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 95] was converted to 6-fluoro-2,3-dimethyl -4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 338 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.45-7.38 (m, 1H), 7.37-7.31 (m, 1H), 7.29 (d, J=7.3 Hz, 1H), 6.64 (d, J=13.0 Hz, 1H), 4.48 (d, J=2.9 Hz, 2H), 3.48-3.39 (m, 2H), 2. 82-2.60 (m, 2H), 2.33 (s, 3H), 1.57 (d, J=0.5 Hz, 3H). Intermediate 97 4-Bromo-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide

[00439] Following the procedures used to prepare Intermediate 2 from Intermediate 2B, 1-cyclopropylpropan-2-one was converted to 4-bromo-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide. Mass spectrum m/z 312, 314 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.49 (d, J=9.5 Hz, 1H), 2.49 (s, 3H), 1.93 (br.s., 1H), 1, 04 (d, J=6.5 Hz, 2H), 0.68 (d, J=4.3 Hz, 2H). Intermediate 98 ((1S)-3-Cyclopropyl-5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide, TFA salt

[00440] Following the procedures used to prepare Intermediate 42, 4-bromo-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide [Intermediate 97] was converted to (RS)-3-cyclopropyl -5-fluoro-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 364 (M+H)+. Intermediate 99 4-Bromo-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide

[00441] Following the procedures used to prepare Intermediate 2 from Intermediate 2B, 1-(4-fluorophenyl)propan-2-one was converted to 4-bromo-5-fluoro-3-(4-fluorophenyl)-2-methyl -1H-indole-7-carboxamide. Mass spectrum m/z 365, 367 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.51 (d, J=9.9 Hz, 1H), 7.38-7.30 (m, 2H), 7.18-7.09 (m, 2H), 2.31 (s, 3H). Intermediate 100 (1S)-5-Fluoro-3-(4-fluorophenyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide , TFA salt

[00442] Following the procedures used to prepare Intermediate 42, 4-bromo-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide [Intermediate 99] was converted to (RS) -5-fluoro-3-(4-fluorophenyl)-2-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 418 (M+H)+. Intermediate 101 4-Bromo-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indole-7-carboxamide

[00443] Following the procedures used to prepare Intermediate 2 from Intermediate 2B, 1-(4-fluorophenyl)propan-1-one was converted to 4-bromo-5-fluoro-2-(4-fluorophenyl)-3-methyl -1H-indole-7-carboxamide. Mass spectrum m/z 365, 367 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.67-7.61 (m, 2H), 7.56 (d, J=9.9 Hz, 1H), 7.31-7.24 (m, 2H), 2.64 (s, 3H). Intermediate 102 (1S)-5-Fluoro-2-(4-fluorophenyl)-3-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide , TFA salt

[00444] Following the procedures used to prepare Intermediate 42, 4-bromo-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indole-7-carboxamide [Intermediate 101] was converted to (RS) -5-fluoro-2-(4-fluorophenyl)-3-methyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 418 (M+H)+. Intermediate 103 5-Fluoro-2,3-dimethyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide, TFA salt Intermediate 103A: tert-butyl 3-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

[00445] A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 2] (120 mg, 0.421 mmol), 3-(4,4,5,5- tert-butyl tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (130 mg, 0.421 mmol), K3PO4 (179 mg, 0.842 mmol) and 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (13.7 mg, 0.021 mmol) in THF (2 mL) and water (0.2 mL) was purged with nitrogen and stirred at 60° C overnight. The mixture was cooled to room temperature, filtered through CELITE® and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0 to 50% gradient), to provide 3-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indole-4 tert-butyl-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow gum (135 mg, 74% yield). Mass spectrum m/z 388 (M+H)+.

Intermediate 103:

[00446] A solution of tert-butyl 3-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (69 mg, 0.178 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (1.5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated to provide 5-fluoro-2,3-dimethyl-4-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide TFA salt as a solid. light brown (70 mg, 88% yield). Mass spectrum m/z 288 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.37 (d, J=11.1 Hz, 1H), 6.01 (tt, J=3.9, 1.9 Hz, 1H), 4.03 -3.80 (m, 2H), 3.57-3.39 (m, 2H), 2.72-2.62 (m, 2H), 2.40-2.36 (m, 3H), 2 .22 (s, 3H). Intermediate 104 (RS)-5zFluoro-213-dimethyl-4z(piperidin-3-yl)-1H:indo∑7-carboxamide TFA salt

[00447] Following the procedures used to prepare Intermediate 38, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 2] was converted to (RS)-5-fluoro-2 ,3-dimethyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide, TFA salt. Mass spectrum m/z 290 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.39-7.32 (m, 1H), 4.11-3.99 (m, 1H), 3.68-3.58 (m, 1H), 3.55-3.44 (m, 2H), 3.16-3.03 (m, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.23-1, 86 (m, 4H). Intermediates 105 and 106 5-Fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide (single enantiomers) Intermediates 105A and 106A: tert-Butyl 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (single enantiomers)

[00448] A sample of 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (RS) -tert-butyl [Intermediate 42A] (754 mg) was separated by chiral super critical fluid chromatography (Column: AD-H (3 x 25 cm, 5 µm); mobile phase: CO2-MeOH (85:15) at 150 mL/min; sample preparation: 37.7 mg/mL in MeOH-DCM (1:1); injection: 1 mL).

[00449] The first peak eluting from the column provided an enantiomer of 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2 tert-butyl (1H)-carboxylate [Intermediate 105A] as a white solid (249 mg). Mass spectrum m/z 438 (M+H)+.

[00450] The second peak eluting from the column provided the other enantiomer of 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline- tert-butyl 2(1H)-carboxylate [Intermediate 106A] as an off-white solid (232 mg). Analytical chiral supercritical fluid chromatography indicated 1.5% contamination of the first enantiomer. Chiral supercritical fluid chromatographic separation was repeated to provide the second enantiomer [Intermediate 106A] as a white solid (203 mg). Mass spectrum m/z 438 (M+H)+.

[00451] An alternative chiral supercritical fluid chromatographic separation of 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H) (RS)-tert-butyl-carboxylate [Intermediate 42A] (754 mg) used similar conditions, but with a mobile phase consisting of CO 2 -MeOH (75:25) containing 0.1% aqueous NH 4 OH. The second peak eluting from the column provided Intermediate 106A as a white solid.

[00452] The absolute stereochemistries of Intermediates 105A and 106A have not been assigned.

Intermediate 105:

[00453] A mixture of a single enantiomer of 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of tert-butyl [Intermediate 105A] (0.249 g, 0.569 mmol) and TFA (3 mL) was stirred at room temperature for 45 minutes. The mixture was concentrated and the residue was dissolved in EtOAc, washed twice with 1.5M aqueous Na 2 HPO 4 then brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated to provide a single enantiomer of 5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5- yl)-1H-indole-7-carboxamide as a pale yellow solid (0.192 g, 100% yield). Mass spectrum m/z 338 (M+H)+. Absolute stereochemistry has not been designated.

Intermediate 106:

[00454] Following the procedure used to prepare Intermediate 105, a single enantiomer of 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline tert-Butyl-2(1H)-carboxylate [Intermediate 106A] (0.203 g, 0.464 mmol) was converted to a single enantiomer of 5-fluoro-2,3-dimethyl-4-(1,2,3,4- tetrahydroisoquinolin-5-yl)-1H-indole-7-carboxamide as a pale yellow solid (0.157 g, 96% yield). Mass spectrum m/z 338 (M+H)+. Absolute stereochemistry has not been designated. Intermediate 107 (1S)-5-Fluoro-2,3-dimethyl-4-(2,7-diazaspiro[4,4]nonan-2-yl)-1H-indole-7-carboxamide

[00455] Following the procedures used to prepare Intermediate 26, but substituting 7-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-2,7-diazaspiro[4,4 (RS)-tert-butyl]nonane-2-carboxylate to (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate, 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7 -carbonitrile [Intermediate 12] was converted to (RS)-5-fluoro-2,3-dimethyl-4-(2,7-diazaspiro[4,4]nonan-2-yl)-1H-indole-7-carboxamide . Mass spectrum m/z 331 (M+H)+. Intermediate 108 5-Fluoro-2,3-dimethyl-4-(1,4,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide, TFA salt

[00456] Following the procedures used to prepare Intermediate 26, 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydropyridine-1(2H tert-butyl)-carboxylate was converted to 5-fluoro-2,3-dimethyl-4-(1,4,5,6-tetrahydropyridin-3-yl)-1H-indole-7-carboxamide, salt TFA. Mass spectrum m/z 288 (M+H)+. Intermediate 109 Ethyl 4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylate Intermediate 109A: 4-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylic acid

[00457] A mixture of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid, HCl (5.0 g, 17.51 mmol), and 1,1,1-trifluoro-2-butanone (6.62 g, 52.5 mmol) in TFA (8.0 mL) was stirred at reflux for 18 hours. The mixture was concentrated. The crude product was added to DCM and the precipitate was collected by filtration and dried under high vacuum. Production was 4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylic acid (3.86 g, 10.22 mmol, 58.3% yield) as a white solid . 1H NMR (400MHz, methanol-d4) δ 7.75 (d, J=9.3 Hz, 1H), 2.69 (q, J=1.7 Hz, 3H). LCMS: 1.07 min, M+H non-ionized product.

Intermediate 109:

[00458] A mixture of 4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylic acid (3.86 g, 11.35 mmol) and sulfuric acid (0.605 mL, 11.35 mmol) in EtOH (80 mL) was stirred at reflux for three days. The mixture was concentrated. The mixture was diluted with EtOAc (65 mL) and washed with 1.0 M aqueous HCl (65 mL) and saturated aqueous sodium bicarbonate solution (2 x 65 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (100:0 to 0:100 silica gel/hexane-EtOAc gradient). Production was ethyl 4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxylate (1.80 g, 4.65 mmol, 40.9% yield) as a solid white. 1H NMR (400MHz, methanol-d4) δ 7.81 (s, 1H), 4.49 (d, J=7.1 Hz, 2H), 2.76-2.65 (m, 3H), 1, 46 (t, J=7.2 Hz, 3H). LCMS: 1.26 min, M+H non-ionized product. Example 1 4-(3-Acrylamido-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide

[00459] A mixture of 4-bromo-3-methyl-1H-indole-7-carboxamide [Intermediate 4] (0.030 g, 0.119 mmol), N-(2-methyl-3-(4,4,5,5 - tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide [Intermediate 66] (30.4 mg, 0.130 mmol), and tetracis(triphenylphosphine)palladium (6.85 mg, 5.93 µmol) in toluene (2.22 mL) and ethanol (741 µL) was bubbled with nitrogen for about 2 to 5 minutes. The mixture was treated with 2M aqueous Na2CO3 (148 µL, 0.296 mmol), bubbled again with nitrogen, and the vessel was sealed and heated to 90 °C. After 16 hours, the mixture was cooled to room temperature and concentrated. The residue was dissolved in DMF-MeOH, filtered, and purified by preparative reverse phase HPLC to give 4-(3-acrylamido-2-methylphenyl)-3-methyl-1H-indole-7-carboxamide (21.9 mg, 61% yield). Mass spectrum m/z 438 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.04 (br. s., 1H), 7.67 (d, J=7.4 Hz, 1H), 7, 33 (br.s., 1H), 7.06 (s, 1H), 6.92 (t, J=7.7 Hz, 1H), 6.73-6.64 (m, 2H), 6. 39 (d, J=6.4 Hz, 1H), 4.87 (s, 2H), 1.71 (s, 3H), 1.63 (d, J=1.0 Hz, 3H). Example 2 2,3-Dimethyl-4-(3-(vinylsulfonyl)phenyl)-1H-indole-7-carboxamide

[00460] A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 1] (30.0 mg, 0.112 mmol), 4,4,5,5-tetramethyl-2-( 3-(vinylsulfonyl)phenyl)-1,3,2-dioxaborolane [Intermediate 79] (43.4 mg, 0.118 mmol), and palladium dichloride 1,1'-bis(di-tert-butylphosphino)ferrocene (3, 66 mg, 5.62 µmol) in THF (3 mL) was bubbled with nitrogen, treated with 2M aqueous K3PO4 (0.168 mL, 0.336 mmol), bubbled again with nitrogen, and heated to 50 °C under nitrogen. After 16 hours, the mixture was cooled to room temperature and concentrated. The residue was dissolved in DMF, filtered, and purified by preparative reverse phase HPLC to give 2,3-dimethyl-4-(3-(vinylsulfonyl)phenyl)-1H-indole-7-carboxamide (12.7 mg , 30% yield). Mass spectrum m/z 355 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.07 (br. s., 1H), 7.93-7.89 (m, 1H), 7.80-7 .72 (m, 3H), 7.63 (d, J=7.4 Hz, 1H), 7.40 (br.s., 1H), 7.21 (dd, J=16.3, 9, 9 Hz, 1H), 6.87 (d, J=7.4 Hz, 1H), 6.38 (d, J=16.8 Hz, 1H), 6.23 (d, J=9.9 Hz , 1H), 2.35 (s, 3H), 1.63 (s, 3H). Example 3 5-Fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide

[00461] A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 2] (29.0 mg, 0.102 mmol), N-methyl-N-(3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide [Intermediate 73] (32.1 mg, 0.112 mmol), and Cs2CO3 (83.0 mg, 0.254 mmol ) in 6 : 1 THF - water (3.39 mL) was bubbled with nitrogen, then treated with PdCh(dppf) DCM adduct (4.15 mg, 5.09 µmol). The mixture was bubbled with nitrogen again, then heated to 50 °C under nitrogen. After 16 hours, the mixture was cooled to room temperature and concentrated. The residue was dissolved in DMF, filtered, and purified by preparative reverse phase HPLC to provide 5-fluoro-2,3-dimethyl-4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide ( 27 mg, 73% yield). Mass spectrum m/z 366 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.09 (br. s., 1H), 7.57-7.52 (m, 2H), 7.49 (br. s., 1H), 7.38-7.33 (m, 2H), 7.29 (d, J=1.5 Hz, 1H), 6.22-6.06 (m, 2H), 5 .63-5.55 (m, 1H), 3.29 (s, 3H, 2.31 (s, 3H), 1.58 (s, 3H). Example 4 2,3-Dimethyl-4-(3 -(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide

[00462] A mixture of 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide [Intermediate 9] ( 35.0 mg, 0.0890 mmol), N-(3-bromophenyl)ethenesulfonamide [Intermediate 55] (25.7 mg, 0.0980 mmol) and Cs2CO3 (72.6 mg, 0.223 mmol) in 4 : 1 of THF-water (2.97 mL) was bubbled with nitrogen, then treated with PdCh(dppf) DCM adduct (3.64 mg, 4.46 μmol). The mixture was bubbled again with nitrogen, then heated to 50 °C under nitrogen. After 16 hours, the mixture was cooled to room temperature and concentrated. The residue was dissolved in DMF, filtered, and purified by preparative reverse-phase HPLC to afford 2,3-dimethyl-4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (12 mg, 36% performance). Mass spectrum m/z 370 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.08 (s, 1H), 8.02 (br. s., 1H), 7.58 (d, J=7 .9 Hz, 1H), 7.40-7.32 (m, 2H), 7.22-7.18 (m, 1H), 7.12 (s, 1H), 7.08 (d, J= 7.4 Hz, 1H), 6.84-6.73 (m, 2H), 6.11-6.01 (m, 2H), 2.33 (s, 3H), 1.66 (s, 3H ).

[00463] Additional examples that were prepared by procedures described in Examples 1 to 4 or similar procedures, using the indicated starting materials, are shown in Table 1. (Starting materials prepared using literature procedures are indicated in footnotes to the Table.) Table 1 (a) Intermediate 50-8, (b) Intermediate 50-5, (c) Intermediate 50-24, (d) Intermediate 50-27, (e) Intermediate 50-55, (f) Intermediate 5060, (g) Intermediate 50-48, Intermediate 50-26, (i) Intermediate 5051, and (j) Intermediate 50-9, each of US Pat. 8,084,620. Example 69 4-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide Example 69A: 4-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indol-7- carboxamide

[00464] A solution of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide [Intermediate 7] (0.50 g, 1.35 mmol), 3-( 2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one [prepared according to US Patent procedures States No. 8,084,620, Intermediate 50-24] (0.515 g, 1.42 mmol), tetracis(triphenylphosphine)palladium (0.078 g, 0.068 mmol), 2.0 M aqueous Na 2 CO 3 (1.69 mL, 3.38 mmol) in 5:1 toluene-ethanol (16.9 mL) was heated under a nitrogen atmosphere at 90 °C for 16 h. The mixture was cooled to room temperature and partitioned between EtOAc and saturated aqueous NaHCO 3 . The organic phase was washed with brine, dried and concentrated. The residue was combined with that from another identical reaction, and the material was purified by column chromatography over silica gel (40 g), eluting with EtOAc-hexanes, to give 4-(2-methyl-3-(4-oxoquinazolin- 3(4H)-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indole-7-carboxamide as a glassy solid (1.40 g, 94% yield). Mass spectrum m/z 525 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (1H, br.s.), 8.35 (1H, br.s.), 8.08 (1H, br.s.), 8.08 (1H, br.s.), 7.98-8.06 (1H, m), 7.90 (1H, d, J=7.9 Hz), 7.74 (1H, t, J=7.5 Hz), 7, 52-7.70 (5H, m), 7.50 (1H, d, J=7.3 Hz), 7.17 (1H, d, J=7.5 Hz), 6.19- 6.46 (1H, m), 5.83 (2H, d, J=7.3 Hz), 2.10 (1H, s), 1.96 (3H, s), 0.86 (2H, dd, J=9.4, 6.9 Hz), -0.04-0.03 (9H, m).

Example 69:

[00465] A solution of 4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7- carboxamide (40 mg, 0.076 mmol), 1.0 M tetra-n-butylammonium fluoride in THF (229 µL, 0.229 mmol) and 1,2-diaminoethane (31 µL, 0.457 mmol) in DMF (762 µL) was heated to 60 °C. After 17 h, more tetra-n-butylammonium fluoride solution (0.25 mL) was added and heating was continued for another day. The mixture was cooled to room temperature and treated with 1.0M aqueous HCl and the mixture was stirred for 4 days. The mixture was concentrated and the residue was subjected to preparative reverse phase HPLC to afford 4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide (1 .1 mg, 4% yield). Mass spectrum m/z 395 (M+H)+. 1H NMR (500 MHz, MeOH-d4) δ 8.38 (d, J=8.0 Hz, 1H), 8.24 (d, J=19.7 Hz, 1H), 7.95-7.87 (m, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.68-7.62 (m, 1H) , 7.52 (q, J=7.8 Hz, 2H), 7.43-7.36 (m, 2H), 7.09 (d, J=15.0 Hz, 1H), 6.416.24 ( m, 1H), 1.99 (br.s., 3H). Example 70 4-(3-(2-Cyano-2-(methylsulfonyl)vinyl)phenyl)-2,3-dimethyl-1H-indole-7-carboxamide Example 70A: 4-(3-Formylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide

[00466] A mixture of 4-bromo-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 1] (50 mg, 0.187 mmol), (3-formylphenyl)boronic acid (33.7 mg, 0.225 mmol ), 2.0 M aqueous K3PO4 (0.187 mL, 0.374 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (6.1 mg, 9.36 µmol) in THF (2 mL ) in a sealed tube was subjected to 3 nitrogen evacuate-charge cycles. The mixture was stirred at room temperature for three days, then concentrated. The residue was subjected to column chromatography on silica gel (12 g), eluting with EtOAc-hexanes (0-100% gradient), to provide 4-(3-formylphenyl)-2,3-dimethyl-1H- indole-7-carboxamide as an off-white solid (36 mg, 66% yield). 1H NMR (400 MHz, CDCl3) δ 10.17 (br.s., 1H), 10.12 (s, 1H), 7.98-7.93 (m, 2H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 1H), 7.36 (d, J=7.7 Hz, 1H), 6.96 (d, J=7.7 Hz, 1H) , 2.41 (s, 3H), 1.76 (s, 3H).

Example 70:

[00467] A solution of 4-(3-formylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (26 mg, 0.089 mmol) and 2-(methylsulfonyl)acetonitrile (42.4 mg, 0.356 mmol) in ethanol (1 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.054 mL, 0.356 mmol). The mixture was stirred at room temperature for 2 h, then combined with the reaction mixture from an identical reaction using 4-(3-formylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide (7.7 mg, 0.026 mmol), 2-(methylsulfonyl)acetonitrile (12.6 mg, 0.105 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.016 mL, 0.105 mmol). The combined mixtures were diluted with EtOAc, washed once with 1M aqueous HCl and twice with water, dried and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with EtOAc-hexanes (10-100% gradient), to give 4-(3-(2-cyano-2-(methylsulfonyl)vinyl )phenyl)-2,3-dimethyl-1H-indole-7-carboxamide as a yellow solid (24 mg, 91% yield). Mass spectrum m/z 394 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.44 (s, 1H), 8.12-8.08 (m, 2H), 8.04 (br. s. , 1H), 7.737.70 (m, 2H), 7.64 (d, J=7.7 Hz, 1H), 7.36 (br.s., 1H), 6.86 (d, J=7 .7Hz, 1H), 2.36 (s, 3H), 1.70 (s, 3H). Example 71 6-Hydroxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide

[00468] A solution of 6-(4-methoxybenzyloxy)-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-7- carboxamide [Example 61] (218 mg, 0.390 mmol) and thioanisole (369 µL, 3.12 mmol) in DCM (4.13 mL) was treated with TFA (2.07 mL) and the mixture was stirred at room temperature for 3.5 h. The mixture was concentrated and partitioned between EtOAc and 1M aqueous NaOH combined with saturated aqueous NaHCO 3 (pH about 9). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes, to give 6-hydroxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3- 4H)-yl)phenyl)-1H-indole-7-carboxamide as a pale yellow glassy solid (124 mg, 73% yield). Mass spectrum m/z 439 (M+H)+. Example 72 6-Ethoxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide

[00469] A mixture of 6-hydroxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide [Example 71 ] (20 mg, 0.046 mmol), iodoethane (7 µL, 0.091 mmol), K2CO3 (37.8 mg, 0.274 mmol) and acetone (0.91 mL) was heated at 60 °C for 80 min. The mixture was cooled to room temperature and subjected to preparative reverse phase HPLC to provide 6-ethoxy-2,3-dimethyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl) -1H-indole-7-carboxamide (12.7 mg, 59% yield). Mass spectrum m/z 467 (M+H)+. 1H NMR (500 MHz, MeOH-d4) δ 10.45 (2s, 1H), 8.41-8.32 (m, 1H), 8.22-8.12 (2s, 1H), 7.94- 7.86 (m, 1H), 7.82 (t, J=7.4 Hz, 1H), 7.69-7.61 (m, 1H), 7.54-7.44 (m, 2H) , 7.43-7.35 (m, 1H), 6.72-6.57 (2s, 1H), 4.35-4.23 (m, 2H), 2.33 (s, 3H), 1 .89 (2s, 3H), 1.74-1.58 (2s, 3H), 1.54 (t, J=6.9 Hz, 3H) (rotamer mixture).

[00470] Additional examples that were prepared from Example 71 by the procedure described in Example 72 or similar procedures, using the indicated alkylating agent, are shown in Table 2. Table 2 Example 77 4-(3-((4,6-Dichloro-1,3,5-triazin-2-yl)amino)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide

[00471] A suspension of cyanuric chloride (0.026 mL, 0.187 mmol) and K2CO3 (59.0 mg, 0.426 mmol) in THF (1 mL) was stirred over an ice water bath and treated dropwise with a solution of 4 -(3-amino-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 41] (50.0 mg, 0.170 mmol) in THF (1 mL). The mixture was stirred at room temperature for 2.25 h, then filtered and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with EtOAc-hexanes (1080% gradient), to give 4-(3-((4,6-dichloro-1,3,5-triazine -2-yl)amino)-2-methylphenyl)-2,3-dimethyl-1H-indole-7-carboxamide as an off-white solid (56.8 mg, 74% yield). Mass spectrum m/z 441, 443, 445 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.75 (s, 1H), 8.00 (br.s., 1H), 7.61 (d, J=7 .7 Hz, 1H), 7.39-7.25 (m, 3H), 7.16 (dd, J=7.2, 1.7 Hz, 1H), 6.72 (d, J=7, 5 Hz, 1H), 2.31 (s, 3H), 1.82 (s, 3H), 1.55 (s, 3H). Example 78 (RS)-213zDimethylz4z(3z(N:methylacrylamido)piperidinz1zyl)z1H-indolez7z carboxamide

[00472] A solution of (RS)-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide [Intermediate 35] (60.0 mg, 0.114 mmol ) in 1:1 DCM-THF (2.08 mL) was cooled to 0°C and treated with DIEA (33.8 µL, 0.194 mmol). Acryloyl chloride (13.0 µL, 0.159 mmol) was added slowly and the mixture was stirred at 0 °C. After 1 h, the mixture was concentrated and the residue was subjected to column chromatography on silica gel (4 g), eluting with EtOAc-hexanes (50-70% gradient), to afford (RS)-2,3-dimethyl -4-(3-(N-methylacrylamido)piperidin-1-yl)-1H-indole-7-carboxamide as a solid (23 mg, 53% yield). Mass spectrum m/z 355 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.17-9.93 (m, 1H), 7.24 (br.s., 1H), 6.766.52 (m, 2H), 6.34 (d, J =16.7 Hz, 1H), 6.08-5.57 (m, 3H), 5.07-4.14 (m, 1H), 3.43 (br.s., 2H), 3.00 (d, J=6.8 Hz, 3H), 2.80-2.56 (m, 1H), 2.542.43 (m, 3H), 2.38 (s, 3H), 1.95 (br. s., 3H), 1.83-1.60 (m, 2H).

[00473] Additional examples that were prepared by procedure described in Example 78 or similar procedures, using the indicated starting material, are shown in Table 3. Table 3 Example 103 (RS)-2,3-Dimethyl-4-((1-propioloylpyrrolidin-3-yl)amino)-1H-indole-7-carboxamide

[00474] A solution of (RS)-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide [Intermediate 19] (35 mg, 0.096 mmol), HATU (73 mg, 0.19 mmol), DIEA (51 µL, 0.29 mmol) and propiolic acid (7.4 mg, 0.11 mmol) in DMF (1.4 mL) was stirred at room temperature. After 4 h, the mixture was filtered and purified by preparative reverse phase HPLC to afford (RS)-2,3-dimethyl-4-((1-propioloylpyrrolidin-3-yl)amino)-1H-indole-7-carboxamide (7.1 mg, 23% yield). Mass spectrum m/z 325 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.64 (br.s., 1H), 7.44 (d, J=8.5Hz, 1H), 6, 88 (br.s., 1H), 6.15 (dd, J=18.9, 7.9 Hz, 1H), 5.20 (br.s., 1H), 4.52-4.40 ( m, 1H), 4.294.17 (m, 1H), 4.11 (br.s., 1H), 3.83-3.51 (m, 3H), 2.38-2.19 (m, 7H ), 2.12-1.98 (m, 1H). Example 104 (RS)-4-(1-(But-2-inoyl)piperidin-3-yl)-3-methyl-1H-indole-7-carboxamide

[00475] A solution of (RS)-3-methyl-4-(piperidin-3-yl)-1H-indole-7-carboxamide [Intermediate 39] (10.0 mg, 0.039 mmol), BOP (20.6 mg, 0.047 mmol), DIEA (68 µL, 0.39 mmol) and but-2-ynoic acid (6.5 mg, 0.078 mmol) in THF (2 mL) was stirred at room temperature. After 2 h, the mixture was filtered and purified by preparative reverse phase HPLC to afford (RS)-4-(1-(but-2-inoyl)piperidin-3-yl)-3-methyl-1H-indol-7 -carboxamide (2.8 mg, 21% yield). Mass spectrum m/z 324 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.84 (d, J=15.3 Hz, 1H), 7.99 (br.s., 1H), 7.63 (t, J=8.5 Hz, 1H), 7.28 (br.s., 1H), 7.12 (d, J=12.8 Hz, 1H), 6.96 (dd, J=19.8, 7.6 Hz, 1H), 4.50-4.39 (m, 2H), 4.36 (t, J=11.3 Hz, 2H), 3.37 (br.s., 1H), 3.32-3, 25 (m, 1H), 3.24-3.15 (m, 1H), 2.81-2.70 (m, 2H), 2.05 (s, 3H), 1.92 (s, 3H) .

[00476] Additional examples that were prepared by procedures described in Examples 103 and 104 or similar procedures, using the indicated starting material and the appropriate carboxylic acid, are shown in Table 4. Table 4 Example 138 (RS)-2,3-Dimethyl-4-(3-(N-methylvinylsulfonamido)piperidin-1-yl)-1H-indole-7-carboxamide

[00477] A solution of (RS)-2,3-dimethyl-4-(3-(methylamino)piperidin-1-yl)-1H-indole-7-carboxamide [Intermediate 35] (60 mg, 0.11 mmol ) in 1:1 DCM-THF (2.08 mL) was cooled to -20°C and treated with DI-EA (40 µL, 0.23 mmol). A solution of 2-chloroethanesulfonyl chloride (21 µL, 0.21 mmol) in DCM (296 µL) was added slowly and the mixture was stirred at 0 °C. After 1 hour, the mixture was concentrated. The residue was subjected to column chromatography on silica gel (4 g), eluting with EtOAc-hexanes (2550% gradient), to afford (RS)-2,3-dimethyl-4-(3-(N-methylvinylsulfonamido) piperidin-1-yl)-1H-indole-7-carboxamide as a solid (20 mg, 44% yield). Mass spectrum m/z 391 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.81 (br. s., 1H), 7.48 (d, J=8.1 Hz, 1H), 7, 12 (br.s., 1H), 6.84 (dd, J=16.4, 10.0 Hz, 1H), 6.59 (d, J=7.9 Hz, 1H), 6.14- 5.99 (m, 2H), 4.00-3.84 (m, 1H), 3.21 (d, J=10.8 Hz, 2H), 2.74 (s, 4H), 2.55 (br.s., 1H), 2.33 (d, J=12.3 Hz, 6H), 1.88-1.58 (m, 4H).

[00478] Additional examples that were prepared by procedure described in Example 138 or similar procedures, using the indicated starting materials, are shown in Table 5. Table 5 *Alternative Preparation of Example 34. Example 147 (S)-4-((1-Cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[00479] A mixture of (S)-5-fluoro-2,3-dimethyl-4-(pyrrolidin-3-ylamino)-1H-indole-7-carboxamide [Intermediate 21] (0.041 g, 0.127 mmol) and Cs2CO3 (0.166 g, 0.508 mmol) in DMF (1.5 mL) was cooled to 0°C and treated with 5M cyanogen bromide in acetonitrile (0.028 mL, 0.140 mmol). The mixture was stirred at 0 °C for 60 min, then at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed twice with 10% aqueous LiCl, then with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (50-75% gradient), to afford (S)-4-((1-cyanopyrrolidin-3-yl)amino)-5-fluoro -2,3-dimethyl-1H-indole-7-carboxamide as a yellow solid (0.007 g, 17% yield). Mass spectrum m/z 316 (M+H)+.

[00480] Additional examples that were prepared by procedures described in Example 147 or similar procedures, using the indicated starting material, are shown in Table 6. Table 6 Examples 153 and 154 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (single enantiomers)

[00481] A sample of (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indol-7- carboxamide [Example 95] (42 mg) was separated by chiral supercritical fluid chromatography (Column: IC (3 x 25 cm, 5 µm); mobile phase: CO 2 -MeOH (55:45) at 150 mL/min; sample preparation: 5.83 mg/mL in MeOH-DCM (4:1; injection: 2 mL).

[00482] The first peak eluting from the column provided an enantiomer of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide [Example 153] as a pale yellow solid (18 mg). Mass spectrum m/z 392 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.08 (br. s., 1H), 7.53 (d, J=10.7 Hz, 1H), 7, 48 (br.s., 1H), 7.33-7.28 (m, 2H), 7.15-7.10 (m, 1H), 6.93 (dd, J=16.7, 10, 5 Hz, 0.4H), 6.80 (dd, J=16.6, 10.5 Hz, 0.6H), 6.14 (d, J=16.6 Hz, 1H), 5.73 ( d, J=10.7 Hz, 0.4H), 5.67 (dd, J=10.5, 1.9 Hz, 0.6H), 4.87 (s, 1H), 4.77 (d , J=3.8 Hz, 1H), 3.78-3.62 (m, 1H), 3.603.52 (m, 1H), 2.44-2.31 (m, 2H), 2.31- 2.24 (m, 3H), and 1.43-1.38 (m, 3H).

[00483] The second peak eluting from the column provided the other enantiomer of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl- 1H-indole-7-carboxamide [Example 154] (18 mg). Mass spectrum m/z 392 (M+H)+. NMR: same as Example 153.

[00484] The absolute stereochemistry of Examples 153 and 154 have not been assigned.

[00485] Alternative preparation of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (single enantiomer ) [Example 153]:

[00486] Following the procedure used to prepare Example 78, a single enantiomer of 5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indol- 7-carboxamide [Intermediate 105] (20 mg, 0.059 mmol) was converted into a single enantiomer of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2 ,3-dimethyl-1H-indole-7-carboxamide in 91% yield.

[00487] Alternative preparation of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (single enantiomer ) [Example 154]:

[00488] Following the procedure used to prepare Example 78, a single enantiomer of 5-fluoro-2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-indol- 7-carboxamide [Intermediate 106] (2.85 g, 8.45 mmol) was converted into a single enantiomer of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5 -fluoro-2,3-dimethyl-1H-indole-7-carboxamide in 78% yield. Examples 155 and 156 4-(4-Acryloyl-3,4-dihydro-2H-benzo[ b ][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H- indole-7-carboxamide (single enantiomers)

[00489] A sample of (RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3 -dimethyl-1H-indole-7-carboxamide [Example 102] (25 mg) was separated by chiral supercritical fluid chromatography (Column: CHIRALPAK® IC, 3 x 25 cm, 5 µm; mobile phase: CO2-MeOH 55 :45 to 150 mL/min, 35 °C; sample preparation: dissolved in 1:1 MeOH-DCM; injection 1.0 mL).

[00490] The first peak eluting from the column provided an enantiomer of 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro- 2,3-dimethyl-1H-indole-7-carboxamide [Example 155] as an off-white solid (10.4 mg). Mass spectrum m/z 394 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.04 (br. s., 1H), 7.60-7.38 (m, 3H), 7.08-6 .95 (m, 2H), 6.82 (dd, J=16.8, 10.4 Hz, 1H), 6.30 (dd, J=16.8, 2.1 Hz, 1H), 5, 91-5.80 (m, 1H), 4.17 (t, J=4.6 Hz, 2H), 4.08-3.95 (m, 1H), 3.83 (dt, J=13, 6, 4.9 Hz, 1H), 2.29 (s, 3H), 1.57 (s, 3H).

[00491] The second peak eluting from the column provided the other enantiomer of 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5 -fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Example 156] (11 mg). Mass spectrum m/z 394 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.04 (br. s., 1H), 7.57-7.35 (m, 3H), 7.05-6 .95 (m, 2H), 6.82 (dd, J=16.7, 10.3 Hz, 1H), 6.30 (dd, J=16.9, 2.0 Hz, 1H), 5, 90-5.80 (m, 1H), 4.17 (t, J=4.6 Hz, 2H), 4.01 (dt, J=13.7, 4.4 Hz, 1H), 3.83 (dt, J=13.5, 4.9 Hz, 1H), 2.29 (s, 3H), 1.57 (s, 3H).

[00492] The absolute stereochemistry of Examples 155 and 156 have not been assigned. Examples 157 and 158 4-(2-Cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (single enantiomers)

[00493] A sample of (RS)-4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indol-7- carboxamide [Example 152] (25 mg) was separated by chiral supercritical fluid chromatography (Column: AD-H (3 x 25 cm, 5 µm); mobile phase: CO2-MeOH (65:35) at 150 mL/ min; 100 bar, 40 °C; sample preparation: 4.39 mg/mL in MeOH; injection: 1 mL).

[00494] The first peak eluting from the column provided an enantiomer of 4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide [Example 157] as an off-white solid (11 mg). Mass spectrum m/z 363 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.08 (br. s., 1H), 7.54 (d, J=10.7 Hz, 1H), 7, 49 (br.s., 1H), 7.34-7.29 (m, 1H), 7.23 (d, J=7.0 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 4.52 (s, 2H), 3.38 (t, J=6.3 Hz, 2H), 2.39 (t, J=5.9 Hz, 2H), 2.29 ( s, 3H), and 1.43 (s, 3H).

[00495] The second peak eluting from the column provided the other enantiomer of 4-(2-cyano-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl- 1H-indole-7-carboxamide [Example 158] (18 mg). Mass spectrum m/z 363 (M+H)+. NMR: same as Example 157.

[00496] The absolute stereochemistry of Examples 157 and 158 have not been assigned. Examples 159 and 160 cis -4-(1-Acryloylhexahydro-1 H-pyrrolo[3,4-b ]pyridin-6(2 H)-yl)-5-fluoro-2,3-dimethyl-1 H- indole-7-carboxamide (single enantiomers)

Example_J59A:_JRS}-cis-4-[1-Acrylojhexahydro-1H-pjiTolo]34zb]piljdin 6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[00497] Following the procedures used to prepare Example 78, 5-fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2,3-dimethyl-1H -indole-7-carboxamide [Intermediate 29] was converted to (RS)-cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5- fluoro-2,3-dimethyl-1H-indole-7-carboxamide as a yellow solid in 57% yield. Mass spectrum m/z 385 (M+H)+. 1H NMR (500 MHz, MeOH-d4) complex due to a mixture of rotamers. At 60 °C: δ 7.36 (d, J=13.6 Hz, 1H), 6.80 (br.s., 1H), 6.18 (d, J=16.5 Hz, 1H), 5.75 (br.s., 1H), 2.43 (s, 3H), 2.36 (s, 3H). Complex of methine and methylene protons, but consistent with expected structure.

Examples 159 and 160:

[00498] A sample of (RS)-cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl -1H-indole-7-carboxamide (30 mg) was separated by chiral supercritical fluid chromatography (Column: OJ (3 x 25 cm, 5 μm); mobile phase: CO2-MeOH (85:15) at 170 mL /min; 100 bar, 40 °C; sample preparation: 2.5 mg/mL in MeOH-DCM).

[00499] The first peak eluting from the column provided an enantiomer of cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2, 3-dimethyl-1H-indole-7-carboxamide [Example 159] as an off-white solid (10.7 mg). The second peak eluting from the column provided the other enantiomer of cis-4-(1-acryloylhexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3- dimethyl-1H-indole-7-carboxamide [Example 160] as an off-white solid (11.8 mg). Mass spectrum and NMR spectrum for both enantiomers were the same as those observed for the racemic mixture.

[00500] The absolute stereochemistry of Examples 159 and 160 have not been assigned. Examples 161 to 164 cis -4-(3-Acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl -1 H-indole-7-carboxamide (single diastereomers)

Example 161A: cis -4-(3-Acryloyl-1α,2,3,7b-tetrahydro-1H-cyclopropa[ c ]quinolin-7-yl)-5-fluoro-2,3-dimethyl- 1H-indole-7-carboxamide (mixture of four diastereomers)

[00501] Following the procedures used to prepare Example 78, (RS-cis)-5-fluoro-2,3-dimethyl-4-(1a,2,3,7b-tetrahydro-1H-cyclopropa) TFA salt [c]quinolin-7-yl)-1H-indole-7-carboxamide [Intermediate 48] was converted to cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c] ]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, a mixture of four diastereomers, as a gum in 86% yield. Mass spectrum m/z 404 (M+H)+.

Examples 161 to 164:

[00502] A sample of cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl- 1H-indole-7-carboxamide, mixture of four diastereomers (29 mg) was separated by chiral supercritical fluid chromatography (Column: AS-H, 5 x 25 cm, 5 µm; mobile phase: CO2-MeOH (72: 28) at 280 mL/min, 100 bar; sample preparation: 2.9 mg/mL in MeOH).

[00503] The first peak eluting from the column was subjected to column chromatography on silica gel, eluting with 10% MeOH/EtOAc-hexanes (gradient 0-100%), to provide a diastereomer of cis-4-( 3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Example 161] (1.09 mg).

[00504] The second peak eluting from the column provided a second diastereomer of cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)-5- fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Example 162] (5.46 mg).

[00505] The third peak eluting from the column provided a third diastereomer of cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl)- 5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Example 163] (5.72 mg).

[00506] The fourth peak eluting from the column provided a fourth diastereomer of cis-4-(3-acryloyl-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinolin-7-yl )-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Example 164] (5.37 mg).

[00507] The absolute stereochemistry of Examples 161 to 164 have not been assigned. The mass spectrum for all four was the same as that of Example 161A.

[00508] Additional examples that were prepared by procedures described for Examples 159 to 164 or similar procedures, using the indicated starting material, are shown in Table 7. Table 7 Examples 173 and 174 cis -4-(1-(But-2-inoyl)hexahydro-1 H -pyrrolo[3,4-b ]pyridin-6(2 H)-yl)-5-fluoro-2, 3-dimethyl-1 H-indole-7-carboxamide (single enantiomers)

Example 173A: (RS)-cis-4-(1-(But-2-inoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2 ,3-dimethyl-1H-indole-7-carboxamide

[00509] Following the procedures used to prepare Example 103, but replacing but-2-ynoic acid with propiolic acid, 5-fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H )-yl)-2,3-dimethyl-1H-indole-7-carboxamide [Intermediate 29] was converted to (RS)-cis-4-(1-(but-2-inoyl)hexahydro-1H-pyrrole [3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide as a yellow gum in 75% yield. Mass spectrum m/z 397 (M+H)+. 1H NMR (500 MHz, MeOH-d4) complex due to rotamer mixing.

Examples 173 and 174:

[00510] A sample of (RS)-cis-4-(1-(but-2-inoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5- fluoro-2,3-dimethyl-1H-indole-7-carboxamide (32 mg) was separated by chiral supercritical fluid chromatography (Column: OJ-H (3 x 25 cm, 5 µm); mobile phase: CO2- MeOH (85:15) at 150 mL/min; 40 °C; sample preparation: 3.2 mg/mL in MeOH).

[00511] The first peak eluting from the column provided an enantiomer of cis-4-(1-(but-2-inoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl) -5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Example 173] as a white solid (9.2 mg). The second peak eluting from the column provided the other enantiomer of cis-4-(1-(but-2-inoyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5 -fluoro-2,3-dimethyl-1H-indole-7-carboxamide [Example 174] as an off-white solid (9.8 mg). Mass spectrum and NMR spectrum for both enantiomers were the same as those observed for the racemic mixture.

[00512] The absolute stereochemistry of Examples 173 and 174 have not been assigned.

[00513] Additional examples that were prepared by procedures described for Examples 173 and 174 or similar procedures, using the indicated starting material, are shown in Table 8. Table 8 Examples 179 and 180 cis -4-(1-Cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indol- 7-carboxamide (single enantiomers)

Example 179A: (RS)-cis-4-(1-Cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H-indol- 7-carboxamide

[00514] Following the procedures used to prepare Example 147, (RS-cis)-5-fluoro-4-(hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2 ,3-Dimethyl-1H-indole-7-carboxamide [Intermediate 29] was converted to (RS)-cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl )-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide as a brown gum in 34% yield. Mass spectrum m/z 356 (M+H)+.

Examples 179 and 180:

[00515] A sample of (RS)-cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl-1H -indole-7-carboxamide (12 mg) was separated by chiral supercritical fluid chromatography (Column: CHIRALPAK® AS-H 5 x 25 cm, 5 µm; mobile phase CO2-MeOH 75:25 at 280 mL/min, 30° C; sample preparation: dissolved in MeOH; injection: 1 mL).

[00516] The first peak eluting from the column provided an enantiomer of cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3- dimethyl-1H-indole-7-carboxamide [Example 179] as a white solid (4.2 mg). Mass spectrum m/z 356 (M+H)+. The second peak eluting from the column provided the other enantiomer of cis-4-(1-cyanohexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-5-fluoro-2,3-dimethyl- 1H-indole-7-carboxamide [Example 180] as a white solid (4.5 mg). Mass spectrum m/z 356 (M+H)+.

[00517] The absolute stereochemistry of Examples 179 and 180 have not been assigned. Example 181 5-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carboxamide, TFA salt Example 181A: 4-Bromo-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

[00518] A solution of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Intermediate 12] (1.50 g, 5.62 mmol) in THF (15 mL) at - 78 °C was treated with 1.0 M lithium bis(trimethylsilyl)amide in THF (6.74 mL, 6.74 mmol) and the mixture was stirred at -78 °C for 15 min. (2-(Chloromethoxy)ethyl)trimethylsilane (0.983 g, 5.90 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (45 mL), washed sequentially with saturated aqueous NaHCO 3 (2 x 45 mL) and 1.0 M aqueous HCl (45 mL), dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0-30% gradient), to provide 4-bromo-5-fluoro-2,3-dimethyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile as a white solid (1.92 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=8.4 Hz, 1H), 5.77 (s, 2H), 3.68-3.60 (m, 2H), 2.52 (d, J=0.5 Hz, 3H), 2.43 (s, 3H), 0.95 (dd, J=8.7, 7.7 Hz, 2H), -0.01 (s, 9H ). Example 181B: 4-((6-Chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

[00519] A suspension of 4-bromo-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile (238 mg, 0.599 mmol) in THF (5.0 mL) was treated with 0.5 M (2-chloro-5-pyridyl)methylzinc chloride in THF (1.32 mL, 0.659 mmol) and palladium tetracis(triphenylphosphine) (25.6 mg, 0.022 mmol) and the mixture was stirred at reflux for 18 h. The mixture was diluted with EtOAc (15 mL), washed twice with saturated aqueous NaHCO 3 , dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0-60% gradient), to provide 4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3 -dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile as a colorless gum (201 mg, 72% yield). Mass spectrum m/z 444, 446 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=2.1 Hz, 1H), 7.31-7.25 (m, 2H), 7.23-7.18 (m, 1H) , 5.78 (s, 2H), 4.44 (s, 2H), 3.73-3.59 (m, 2H), 2.41 (s, 3H), 2.26 (d, J=0 .4 Hz, 3H), 0.97 (dd, J=8.6, 7.6 Hz, 2H), -0.01 (s, 9H). Example 181C: 4-((6-Chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

[00520] A solution of 4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7 -carbonitrile (200 mg, 0.450 mmol) in THF (2.0 mL) was treated with a 1.0 M solution of tetra-n-butylammonium fluoride in THF (4.50 mL, 4.50 mmol), and the mixture was heated at reflux for 18 h. The cooled mixture was diluted with EtOAc and washed twice with saturated aqueous NaHCO 3 , dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0-30% gradient), to provide 4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3 -dimethyl-1H-indole-7-carbonitrile as a white solid (90 mg, 61% yield). Mass spectrum m/z 314, 316 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.37 (br.s., 1H), 8.25 (d, J=2.3 Hz, 1H), 7.33 (ddd, J=8.2, 2 .5, 0.6 Hz, 1H), 7.25-7.16 (m, 2H), 4.43 (s, 2H), 2.41 (s, 3H), 2.26 (d, J= 0.4Hz, 3H). Example 181D: 5-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carbonitrile

[00521] A mixture of 4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (28 mg, 0.089 mmol), tri-n- butyl(vinyl)stannane (85 mg, 0.268 mmol), LiCl (11.4 mg, 0.268 mmol) and tetracis(triphenylphosphine)palladium (10.3 mg, 8.92 µmol) in DMF (1.0 mL) under a nitrogen atmosphere was heated at 90 °C for 18 h. The cooled mixture was diluted with EtOAc, washed twice with saturated aqueous NaHCO 3 , dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0-30% gradient) to provide 5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl )methyl)-1H-indole-7-carbonitrile as a white solid (22 mg, 77% yield). Mass spectrum m/z 306 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=2.0 Hz, 1H), 8.38 (br. s., 1H), 7.32 (dd, J=8.1, 1 .7 Hz, 1H), 7.25-7.22 (m, 1H), 7.20 (d, J=9.5 Hz, 1H), 6.79 (dd, J=17.5, 10, 9 Hz, 1H), 6.15 (dd, J=17.5, 1.2 Hz, 1H), 5.44 (dd, J=10.8, 1.3 Hz, 1H), 4.45 ( s, 2H), 2.40 (s, 3H), 2.26 (d, J=0.2 Hz, 3H).

Example 181:

[00522] 5-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indole-7-carbonitrile (22 mg, 0.072 mmol) was cooled in an ice bath and treated with chlorotrimethylsilane (921 µL, 7.20 mmol), then with water (65 µL, 3.60 mmol) and the mixture was stirred at room temperature for 18 h. The supernatant was removed and the residue was dissolved in DMF and purified by preparative HPLC, eluting with MeOH-water containing 0.1% TFA (20-100% gradient). The appropriate effluent fractions were lyophilized from 1:1 water-acetonitrile (10 mL) to provide 5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-3-yl)methyl)-1H-indol-7 - carboxamide, TFA salt, as an off-white powder (15.8 mg, 48% yield). Mass spectrum m/z 324 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 8.43 (d, J=1.3 Hz, 1H), 8.25-8.16 (m, 1H), 8.14-8.07 (m, 1H), 7.43 (d, J=11.0 Hz, 1H), 6.95 (dd, J=17.6, 11.2 Hz, 1H), 6.48 (d, J=17.6 Hz, 1H), 6.01 (d, J=11.2 Hz, 1H), 4.67 (s, 2H), 2.38 (s, 3H), 2.26 (s, 3H). Example 182 5-Fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carboxamide, TFA salt Example 182A: 5-Fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole-7-carbonitrile

[00523] Following the procedure used to prepare Example 181D but replacing tri-n-butyl(prop-1-yn-1-yl)stannane with tri-n-butyl(vinyl)stannane, 4-((6-chloropyridin-3 -yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile [Example 181C] was converted to 5-fluoro-2,3-dimethyl-4-((6-(prop-1 -yn-1-yl)pyridin-3-yl)methyl)-1H-indol-7-carbonitrile in 44% yield. Mass spectrum m/z 318 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.46-8.37 (m, 2H), 7.25 (d, J=1.3 Hz, 2H), 7.20 (d, J=9.4 Hz , 1H), 4.44 (d, J=1.6 Hz, 2H), 2.40 (s, 3H), 2.24 (d, J=0.4 Hz, 3H), 2.07 (s , 3H).

Example 182:

[00524] Following the procedure used to convert Example 181D to Example 181, 5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl) -1H-indole-7-carbonitrile was converted to 5-fluoro-2,3-dimethyl-4-((6-(prop-1-yn-1-yl)pyridin-3-yl)methyl)-1H-indole -7-carboxamide, TFA salt, in 48% yield. Mass spectrum m/z 336 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 8.41 (d, J=1.6 Hz, 1H), 8.00 (dd, J=8.3, 2.1 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.43 (d, J=11.0 Hz, 1H), 4.64 (s, 2H), 2.39 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H). Examples 183 and 184 5-Fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carboxamide, TFA salt (single enantiomers) Example 183A: (RS)-4-(1-(6-Chloropyridin-3-yl)ethyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indole-7-carbonitrile

[00525] A solution of 4-((6-chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7 -carbonitrile [Example 181B] (91 mg, 0.205 mmol) in THF (5.0 mL) at -78 °C was treated with 1.0 M potassium bis(trimethylsilyl)amide in THF (0.615 mL, 0.615 mmol) , then with iodomethane (0.038 mL, 0.615 mmol). The mixture was stirred at -78 °C for 1 h, then warmed to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO 3 , dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0-30% gradient), to afford (RS)-4-(1-(6-chloropyridin-3-yl)ethyl) -5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile as a colorless gum (90 mg, 91% yield). Mass spectrum m/z 458, 460 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=2.2 Hz, 1H), 7.53 (ddd, J=8.3, 1.7, 0.9 Hz, 1H), 7 .25 (d, J=8.3 Hz, 1H), 7.14 (d, J=11.1 Hz, 1H), 5.79 (s, 2H), 5.15 (q, J=6, 9 Hz, 1H), 3.75-3.62 (m, 2H), 2.46 (s, 3H), 2.45 (s, 3H), 1.82 (dd, J=7.2, 1 .5Hz, 3H), 0.97 (dd, J=8.7, 7.8Hz, 2H), 0.00 (s, 9H). Example 183B: (RS)-5-Fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl)-1H-indole-7-carbonitrile

[00526] Following the procedures used to convert Example 181B to Example 181D, (RS)-4-(1-(6-chloropyridin-3-yl)ethyl)-5-fluoro-2,3-dimethyl-1-(( 2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile was converted to (RS)-5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl) -1H-indole-7-carbonitrile in 65% yield (two steps). Mass spectrum m/z 320 (M+H)+.

Examples 183 and 184:

[00527] A sample of (RS)-4-(1-(6-chloropyridin-3-yl)ethyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl) -1H-indole-7-carbonitrile (45 mg) was separated by chiral supercritical fluid chromatography (Column: AD-H, 3 x 25 cm, 5 µm; mobile phase: CO2-MeOH (70:30) at 150 mL/ min; 35 °C, 100 bar; sample preparation: 4.5 mg/mL; injection: 2.0 mL).

[00528] Concentration of the first peak eluting from the column provided a residue (14 mg) which was converted into an enantiomer of 5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3-yl)ethyl) -1H-indole-7-carboxamide, TFA salt, as a white powder [Example 183] (11.6 mg) following the procedure used to convert Example 181D to Example 181. Mass spectrum m/z 338 (M+H )+. 1H NMR (400 MHz, MeOH-d4) δ 8.58 (s, 1H), 8.41 (dd, J=8.6, 2.0 Hz, 1H), 8.17 (d, J=8, 6 Hz, 1H), 7.31 (d, J=12.7 Hz, 1H), 7.00 (dd, J=17.6, 11.2 Hz, 1H), 6.52 (d, J= 17.6 Hz, 1H), 6.06 (d, J=11.2 Hz, 1H), 5.37 (q, J=6.8 Hz, 1H), 2.48 (s, 3H), 2 .45 (s, 3H), 1.92 (dd, J=7.2, 1.0 Hz, 3H).

[00529] Concentration of the second peak eluting from the column provided a residue (14 mg) that was similarly converted into the other enantiomer of 5-fluoro-2,3-dimethyl-4-(1-(6-vinylpyridin-3 -yl)ethyl)-1H-indole-7-carboxamide, TFA salt, as a white powder [Example 184] (10.6 mg) following the procedure used to convert Example 181D to Example 181. Mass Spectrum and NMR: same as those of Example 183. Example 185 5-Fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamide Example 185A: 4-((6-Chloropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

[00530] Chlorotrimethylsilane (2.7 μL, 0.021 mmol) and 1,2-dibromoethane (3.2 μL, 0.043 mmol) were added to a suspension of zinc (84 mg, 1.28 mmol) in THF (1.5 mL) and the mixture was stirred at 65 °C for 20 min. The mixture was cooled to 0 °C, treated dropwise with a solution of 2-chloro-4-(chloromethyl)pyridine (139 mg, 0.856 mmol) in THF (0.5 mL) and stirred for 20 min. A solution of 4-bromo-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile [Example 181A] (170 mg, 0.428 mmol) and 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (27.9 mg, 0.043 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 1 h. The mixture was heated at 60 °C overnight, then cooled to room temperature and filtered through a pad of CELITE®. The filtrate was diluted with DCM, washed sequentially with saturated aqueous NaHCO 3 and water, and dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0-50% gradient), to provide 4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2 ,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile as a yellow glassy solid (168.5 mg, 75% yield). Mass spectrum m/z 444, 446 (M+H)+. Example 185B: 4-((2-Chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

[00531] A mixture of 4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7 -carbonitrile (130 mg, 0.293 mmol) and tetra-n-butylammonium fluoride (1M in THF) (2.93 mL, 2.93 mmol) in THF (1 mL) was stirred at 70 °C for 3 h. The mixture was diluted with EtOAc, washed twice with saturated aqueous NaHCO 3 , dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0-100% gradient) to afford 4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3- dimethyl-1H-indole-7-carbonitrile as a yellow solid (38 mg, 29% yield). Mass spectrum m/z 314, 316 (M+H)+. Example 185C: 4-((2-Chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, TFA salt

[00532] A mixture of 4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (45 mg, 0.143 mmol), chlorotrimethylsilane (2, 5 mL, 19.6 mmol) and water (1 mL, 55.5 mmol) was stirred at room temperature overnight. The upper layer was decanted off and the lower aqueous layer was concentrated. The residue was purified using preparative reverse phase HPLC to afford 4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, TFA salt, as a white solid (18.7 mg, 29% yield). Mass spectrum m/z 332, 334 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 8.21 (d, J=5.1 Hz, 1H), 7.41 (d, J=11.0 Hz, 1H), 7.17-7.07 (m, 2H), 4.51 (s, 2H), 2.37 (s, 3H), 2.19 (s, 3H).

Example 185:

[00533] Following the procedure used to convert Example 181C to Example 181D, 4-((2-chloropyridin-4-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, salt TFA, was converted to 5-fluoro-2,3-dimethyl-4-((2-vinylpyridin-4-yl)methyl)-1H-indole-7-carboxamide in 74% yield. Mass spectrum m/z 324 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 8.31 (d, J=5.3 Hz, 1H), 7.41 (d, J=10.9 Hz, 1H), 7.27 (s, 1H ), 6.98 (dd, J=5.3, 1.1 Hz, 1H), 6.74 (dd, J=17.6, 11.0 Hz, 1H), 6.05 (dd, J= 17.6, 1.1 Hz, 1H), 5.45 (dd, J=11.0, 1.0 Hz, 1H), 4.51 (s, 2H), 2.36 (s, 3H), 2.19 (d, J=0.2 Hz, 3H).

[00534] Additional examples that were prepared by procedures described above, using the indicated starting material(s) and procedures, are shown in Table 9. Table 9 (a) Prepared following the procedure used to prepare Example 78 or similar procedures. (b) Prepared by supercritical fluid chromatography of the racemic compound. Absolute setting is not assigned. (c) Prepared following the procedure used to prepare Example 103 or similar procedures. Example 221 5-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carboxamide Example 221A: 5-Fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-indole-7-carbonitrile

[00535] Following the procedure used to prepare Intermediate 9, 4-bromo-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile [Example 181A ] was converted to 5-fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-indole-7-carbonitrile as a white solid in 45% yield. Mass spectrum m/z 445 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J=8.6 Hz, 1H), 5.76 (s, 2H), 3.58 (dd, J=8.6, 7.6 Hz , 2H), 2.41 (s, 3H), 2.26 (s, 3H), 1.45 (s, 12H), 0.95-0.88 (m, 2H), -0.03 (s , 9H). Example 221B: 4-((6-Chloropyridin-2-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile

[00536] A mixture of 2-(bromomethyl)-6-chloropyridine hydrochloride (19.1 mg, 0.079 mmol), 5-fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile (35 mg, 0.079 mmol), 1,1'-bis dichloride Palladium (di-tert-butylphosphino)ferrocene (2.6 mg, 3.94 µmol) and K3PO4 (67 mg, 0.315 mmol) in THF (300 µL) and water (150 µL) was stirred at room temperature under nitrogen. After 18 h, the mixture was diluted with EtOAc (2 mL), dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with EtOAc-hexanes (0-30% gradient) to afford 4-((6-chloropyridin-2-yl)methyl)-5-fluoro-2, 3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbonitrile as a colorless gum (29 mg, 79% yield). Mass spectrum m/z 444, 446 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J=7.8 Hz, 1H), 7.29-7.24 (m, 1H), 7.16 (dd, J=7.9, 0.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 5.76 (s, 2H), 4.62 (d, J=1.3 Hz, 2H), 3 .69-3.62 (m, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 1.00-0.91 (m, 2H), -0.02 (s, 9H). Example 221C: 5-Fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrile

[00537] Following the procedure used to convert Example 181C to Example 181D, 4-((6-chloropyridin-2-yl)methyl)-5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-indole-7-carbonitrile was converted to 5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-((6-vinylpyridin-2-yl) methyl)-1H-indole-7-carbonitrile as a colorless gum in 74% yield. Mass spectrum m/z 436 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.49 (t, J=7.8 Hz, 1H), 7.31-7.24 (m, 1H), 7.17 (d, J=7.6 Hz , 1H), 6.82 (dd, J=17.5, 10.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.19 (dd, J=17, 5, 1.5 Hz, 1H), 5.78 (s, 2H), 5.47 (dd, J=10.8, 1.3 Hz, 1H), 4.65 (d, J=1.7 Hz, 2H), 3.71-3.61 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 1.03-0.92 (m, 2H), - 0.01 (s, 9H). Example 221D: 5-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrile

[00538] Following the procedure used to convert Example 181B to Example 181C, 5-fluoro-2,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-((6-vinylpyridin-2-yl )methyl)-1H-indole-7-carbonitrile was converted to 5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrile as a white solid at 49% yield. Mass spectrum m/z 306 (M+H)+.

Example 221:

[00539] Following the procedure used to convert Example 181D to Example 181, 5-fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carbonitrile was converted to 5-Fluoro-2,3-dimethyl-4-((6-vinylpyridin-2-yl)methyl)-1H-indole-7-carboxamide as a white powder in 30% yield. Mass spectrum m/z 324 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.94 (br.s., 1H), 7.47 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.10 (d, J=10.4 Hz, 1H), 6.85 (dd, J=17.5, 10.9 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.22 (dd, J=17.5, 1.3 Hz, 1H), 5.49 (dd, J=10.8, 1.3 Hz, 1H), 4.67 (d , J=1.6 Hz, 2H), 2.37 (s, 3H), 2.30 (s, 3H). Example 222 5-Fluoro-4-((5-fluoro-6-vinylpyridin-3-yl)methyl)-2,3-dimethyl-1H-indole-7-carboxamide Example 222A: 4-((6-Chloro-5-fluoropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[00540] Following the procedure used to convert Example 221A to Example 221B, 5-fluoro-2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-7-carboxamide [Intermediate 83] and 5-(bromomethyl)-2-chloro-3-fluoropyridine [prepared according to the procedure of US Pat. 8,188,292, Example VII Step 1] were converted to 4-((6-chloro-5-fluoropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide as a colorless gum in 60% yield. Mass spectrum m/z 350, 352 (M+H)+.

Example 222:

[00541] Following the procedure used to convert Example 181C to Example 181D, 4-((6-chloro-5-fluoropyridin-3-yl)methyl)-5-fluoro-2,3-dimethyl-1H-indol-7- carboxamide was converted to 5-fluoro-4-((5-fluoro-6-vinylpyridin-3-yl)methyl)-2,3-dimethyl-1H-indole-7-carboxamide as a white powder in 22% yield. Mass spectrum m/z 342 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.43 (d, J=11.0 Hz, 1H), 7.20 (d, J=11.2 Hz, 1H), 6.94 (ddd, J=17.5, 11.2, 1.1 Hz, 1H), 6.29 (dd, J=17.5, 1.7 Hz, 1H), 5.57 (dd, J=11.2, 1.5 Hz, 1H), 4.54 (s, 2H), 2.39 (s, 3H), 2.26 (s, 3H). Example 223 (S)-4-(3-(But-2-ynamido)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Intermediate 223A:4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

[00542] To a homogeneous solution of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (3.43 g, 12.0 mmol) in tetrahydrofuran (25 mL) at room temperature phosphoryl trichloride (2.24 mL, 24.1 mmol) was added dropwise via syringe. The reaction mixture was stirred for 3.5 days. The heterogeneous reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the resulting solid was collected by vacuum filtration, washed with ethyl acetate, and dried to give 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7- carbonitrile (2.56 g, 9.58 mmol, 80% yield) as a yellow solid. The product had a UPLC retention time = 1.31 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 min.); Solvent A = 10% AcCN, 90% H2O, 0.1% TFA; Solvent B = 90% AcCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 268.2. Intermediate 223B: (S)-Benzyl (1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate

[00543] A mixture of 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (2.37 g, 8.86 mmol), (S)-benzyl piperidin-3-ylcarbamate (2.49 g, 10.6 mmol), and (S)-benzyl piperidin-3-ylcarbamate (2.49 g, 10.6 mmol) in dioxane (50 mL) was degassed with vacuum and nitrogen (3x) . BINAP (0.276 g, 0.443 mmol) was added followed by Pd2(dba)3 (0.405 g, 0.443 mmol), and the mixture was degassed (3x). The reaction mixture was immersed in a 103 °C oil bath and stirred for ~36 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, and washed with brine. The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane to give (1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3 (S)-benzyl-yl)carbamate (1.08 g, 2.57 mmol, 29% yield) as a pale yellow solid. The product had a UPLC retention time = 1.40 min. - Column: PHENOME-NEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 min.); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 421.5. Intermediate 223C: (S)-4-(3-Aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[00544] A mixture of (S)-benzyl (1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate (1.00 g , 2.38 mmol) and 90% aqueous sulfuric acid (14.1 ml, 238 mmol) was immersed in a 60 °C oil bath and stirred for 60 min. To the reaction mixture, cooled to 0 °C, sodium hydroxide (10 M) (47.6 ml, 476 mmol) was added dropwise with stirring. A few more drops of sodium hydroxide solution were added until the pH was ~7. The mixture was extracted with ethyl acetate, resulting in a suspension. The mixture was filtered under reduced pressure, and the solid was washed well with water. Drying under reduced pressure provided (S)-4-(3-aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (0.724 g, 2.37 mmol, 99% yield) as a brown solid. The product had a UPLC retention time = 0.767 min. - Column: PHE-NOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% AcCN, 90% H2O, 0.1% TFA; Solvent B = 90% AcCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 305.2.

Example 223:

[00545] A mixture of (S)-4-(3-aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (0.171 g, 0.562 mmol), but- 2-inoyl (0.094 g, 1.124 mmol), HATU (0.470 g, 1.24 mmol), and Hunig's base (0.343 mL, 1.97 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 60 min. HPLC analysis indicated that the reaction was complete. The mixture was diluted with ethyl acetate, washed with water, washed with 10% aqueous lithium chloride (2x), washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate in hexane provided (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro- 2,3-dimethyl-1H-indole-7-carboxamide (0.130 g, 0.351 mmol, 63% yield) as a white solid. The product had a UPLC retention time = 1.00 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 371.4. 1H NMR (500 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.46 (d, J=6.3 Hz, 1H), 7.90 (br.s., 1H), 7, 42-7.37 (m, 1H), 7.31 (br.s., 1H), 3.96-3.84 (m, 1H), 3.13 (d, J=7.6 Hz, 1H ), 3.05-2.93 (m, 2H), 2.80 (br.s., 1H), 2.36 (s, 3H), 2.33-2.29 (m, 3H), 1 .93 (s, 3H), 1.87 (d, J=8.5 Hz, 1H), 1.71 (br.s., 2H), and 1.32 (br.s., 1H). Alternative Preparation of Example 223 Intermediate 223D: 4-Bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile

[00546] To a 100 mL 3-neck flask were added 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (40.4 g, 142 mmol) and dichloromethane (810 mL) . To the resulting heterogeneous mixture were added pyridine (50 g, 2.5 eq) and phosphoryl trichloride (19.8 ml, 213 mmol) dropwise at room temperature over 2 minutes. The reaction mixture was stirred for 20 min. The solvent was removed under reduced pressure, water was added to the residue, and the mixture was stirred for 30 min. The precipitate was collected by filtration and dried to provide 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (35 g, 131 mmol, 92% yield) as a brown solid. Intermediate 223E: (S)-tert-butyl (1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate

[00547] A mixture of (S)-tert-butyl piperidin-3-ylcarbamate (33.9 g, 169 mmol), 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carbonitrile (41.13 g, 154 mmol), cesium carbonate (100 g, 308 mmol), and BINAP (9.59 g, 15.40 mmol) in 1,4-dioxane (1380 mL) was degassed by bubbling nitrogen for 5 min. To the mixture was added Pd2(dba)3 (7.05 g, 7.70 mmol), and the reaction mixture was stirred at reflux for 24 h. The reaction mixture was diluted with ethyl acetate (750 mL) and washed with water (1000 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure provided the crude product as a brown solid, which was passed through a pad (5") of silica gel with ethyl acetate (900 mL) to remove any inorganics. The reddish crude product was then purified by recrystallization of acetonitrile to provide two crops of (S)-tert-butyl (1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate (53 g, 108 mmol, 86% yield) Intermediate 223F: (S)-4-(3-Aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide

[00548] To a 100 mL 3-necked flask was added sulfuric acid (90 g). The solution was heated to 60°C. (S)-tert-butyl (1-(7-cyano-5-fluoro-2,3-dimethyl-1H-indol-4-yl)piperidin-3-yl)carbamate (21 g, 54.3 mmol) was added portionwise over a period of 1.5 h. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was added to ice and warmed to room temperature with stirring. The water phase was extracted with dichloromethane (3x) to remove organic impurities. The water phase was adjusted to pH 8, and the solution was extracted with ethyl acetate (2x). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford (S)-4-(3-aminopiperidin-1-yl)-5-fluoro-2, 3-dimethyl-1H-indole-7-carboxamide (13.6 g, 44.7 mmol, 82% yield) as a yellow solid.

Example 223:

[00549] To a 500 mL 3-neck flask were added (S)-4-(3-aminopiperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (33, 2 g, 109 mmol) in N,N-dimethylformamide (364 mL), but-2-ynoic acid (11.9 g, 142 mmol), HATU (62.2 g, 164 mmol), and Hunig's base (38 .1 mL, 218 mmol) (temperature rose to 35 °C). The resulting solution was stirred at room temperature for 1.5 h. The mixture was diluted with ethyl acetate (250ml) and washed with water (500ml). The organic phase was separated, and the aqueous layer was extracted with ethyl acetate (2 x 250 mL) (layer separation was aided by adding small amount of NaCl). The combined organic extracts were washed with water (with a small amount of NaCl) (4 x 500 mL), washed with brine (500 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure furnished the crude product, which was purified by recrystallization from ethyl acetate to afford (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-5-fluoro-2,3 -dimethyl-1H-indole-7-carboxamide (31 g, 83 mmol, 76% yield) as a white solid. Example 224 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iodo-2,3-dimethyl-1H-indole-7-carboxamide Intermediates 224A-1 and 224A-2: Mixture of 5-((2R,3R)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl and tert-butyl 5-((2R,3S)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00550] To a solution of tert-butyl 5-(7-carbamoyl-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (650 mg , 1.549 mmol) in dichloromethane (20 mL) were added sodium cyanoborohydride (487 mg, 7.75 mmol) and acetic acid (1.77 mL, 31.0 mmol). The resulting mixture was stirred at room temperature for 12 h. Purification by reverse phase preparative HPLC provided tert-butyl 5-((2R,3R)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)carboxylate (350 mg, 53.6% yield) and 5-((2R,3S)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of tert-butyl (250 mg, 38.3% yield) as white solids.

[00551] The cis product had a UPLC retention time = 1.17 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. MS (E+) m/z: 546.2 (M+H). 1H NMR (400 MHz, chloroform-d) δ 7.27-7.18 (m, 3H), 7.15-7.02 (m, 2H), 4.73 (dd, J=16.7, 5 .8 Hz, 2H), 4.58 (d, J=16.8 Hz, 1H), 3.95-3.84 (m, 2H), 3.69-3.58 (m, 1H), 3 .46-3.22 (m, 2H), 3.02-2.92 (m, 1H), 2.90-2.78 (m, 1H), 2.67 (dd, J=6.8, 5.3 Hz, 1H), 2.62-2.40 (m, 2H), 2.01-1.89 (m, 2H), 1.40-1.24 (m, 5H), 0.86 (d, J=6.8 Hz, 2H), and 0.76 (d, J=7.0 Hz, 2H).

[00552] The trans product had a UPLC retention time = 1.23 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. MS (E+) m/z: 546.2 (M+H). 1H NMR (400 MHz, chloroform-d) δ 7.27-7.17 (m, 3H), 7.14-7.02 (m, 2H), 6.57 (dd, J=8.0, 2 .3 Hz, 2H), 4.73 (dd, J=16.7, 6.2 Hz, 2H), 4.58 (d, J=16.9 Hz, 2H), 3.72-3.60 (m, 2H), 3.022.93 (m, 1H), 2.68 (d, J=1.5 Hz, 1H), 2.62-2.42 (m, 2H), 1.40-1, 34 (m, 3H), 1.32 (d, J=6.4 Hz, 2H), 0.86 (d, J=6.8 Hz, 2H), and 0.76 (d, J=7, 0Hz, 2H). Intermediate 224B: tert-butyl 5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00553] To a suspension of tert-butyl 5-((2R,3R)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate ( 350 mg, 0.830 mmol) in tetrahydrofuran (5 mL) was added N-iodosuccinimide (280 mg, 1.25 mmol) and a drop of pyridine (0.201 mL, 2.49 mmol). The resulting mixture was stirred at 70 °C for 1 h. Purification by reverse phase preparative HPLC provided tert-5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. -butyl (150 mg, 0.275 mmol, 33% yield) as a white solid. The product had a UPLC retention time = 1.38 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. MS (E+) m/z: 546.2 (M+H). 1H NMR (400 MHz, chloroform-d) δ 7.82 (s, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H ), 7.02 (d, J=7.3 Hz, 1H), 4.69 (s, 2H), 3.57 (br. s., 2H), 2.49-2.23 (m, 5H ), 1.50 (br.s., 9H), and 1.43-1.35 (m, 3H).

Intermediate 224B: Alternative Preparation

[00554] To a suspension of tert-butyl 5-((2R,3S)-7-carbamoyl-2,3-dimethylindolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate ( 300 mg, 0.712 mmol) in tetrahydrofuran (5 mL) was added N-iodosuccinimide (240 mg, 1.07 mmol) and a drop of pyridine (0.20 mL, 2.49 mmol). The resulting mixture was stirred at room temperature for 1 h, then DDQ (188 mg, 0.830 mmol) was added, stirring was continued for a further 1 h. Purification by reverse phase preparative HPLC provided tert 5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. -butyl (100 mg, 0.183 mmol, 26% yield) as a white solid. The product had a UPLC retention time = 1.38 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. MS (E+) m/z: 546.2 (M+H). Intermediates 224C-1 and 224C-2: 5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of tert-butyl (Atropisomers 1 and 2)

[00555] tert-butyl 5-(7-Carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg , dissolved in 12 mL of 9:1 MeOH/CH2Cl2) was resolved into its corresponding enantiomers using chiral supercritical fluid chromatography (SFC) with the following conditions: Column, CHIRALPAK®-IC, 3 cm x 25 cm, 5 µM; mobile phase, 45% MeOH/CO2; flow rate, 120 mL/min; detection, UV (220 nM). Column temperature: 35 °C, pressure: 100 bars BPR.

Example 224-Atropisomer 1:

[00556] A solution of tert-butyl 5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Atropisomer 1; 10 mg, 0.018 mmol) in trifluoroacetic acid (0.5 mL, 6.49 mmol) was stirred at room temperature for 10 min. Trifluoroacetic acid was removed under reduced pressure. The resulting mixture was dissolved in tetrahydrofuran (1 mL), and to the solution were added DIEA (9.61 µL, 0.055 mmol) and acryloyl chloride (1.99 mg, 0.022 mmol). The reaction mixture was stirred at room temperature for an additional 10 min. Purification by reverse phase preparative HPLC provided 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iodo-2,3-dimethyl-1H-indole-7-carboxamide ( Atropisomer 1; 6 mg, 66% yield) as a white solid. The product had a UPLC retention time = 1.08 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. MS (E+) m/z: 500.2 (M+H). 1H NMR (400 MHz, methanol-d4) δ 8.07 (s, 1H), 7.43-7.28 (m, 2H), 7.07-6.99 (m, 1H), 6.78 ( dd, J=16.8, 10.6 Hz, 1H), 6.33-6.21 (m, 1H), 5.87-5.68 (m, 1H), 3.86-3.68 ( m, 3H), 2.57-2.27 (m, 5H), 1.96-1.83 (m, 1H), and 1.43-1.31 (m, 3H).

Example 224-Atropisomer 2:

[00557] The title compound was prepared in a similar manner to that of the preparation of Example 1. The product had a UPLC retention time = 1.08 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. MS (E+) m/z: 500.2 (M+H). 1H NMR (400 MHz, methanol-d4) δ 8.07 (s, 1H), 7.43-7.27 (m, 2H), 7.07-6.98 (m, 1H), 6.78 ( dd, J=16.8, 10.6 Hz, 1H), 6.26 (d, J=16.8 Hz, 1H), 5.89-5.69 (m, 1H), 4.954.89 (m , 1H), 3.78 (q, J=6.2 Hz, 2H), 2.56-2.27 (m, 6H), and 1.45-1.33 (m, 3H). Example 225 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide Intermediate 225A: 4-Bromo-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine

[00558] A 0.5 M tetrahydrofuran solution of (E)-but-2-en-2-ylmagnesium bromide (295 ml, 147 mmol) was added at -70 °C to a stirred solution of 5 -bromo-2-chloro-3-nitropyridine (10 g, 42.1 mmol) in tetrahydrofuran (80 mL). The reaction mixture was allowed to come to -35°C over 30 min. and then quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and dried over magnesium sulfate. The crude product was purified by ISCO flash chromatography (gradient 100:0 to 0:100 silica gel/hexane-EtOAc) followed by trituration with hexanes-ether to provide 4-bromo-7-chloro-2,3-dimethyl- 1H-pyrrolo[2,3-c]pyridine (1 g, 3.85 mmol, 9.2% yield) as a pink solid. LC/MS M+1 = 261.1 and 263.1. Intermediate 225B: 5-(7-Chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00559] A mixture of 4-bromo-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (0.500 g, 1.927 mmol), 5-(4,4,5,5- tert-butyl tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.831 g, 2.31 mmol), tripotassium phosphate (2 M in water) (2.89 mL, 5.78 mmol), and tetrahydrofuran (10 mL) was degassed with vacuum and nitrogen (3x). 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.063 g, 0.096 mmol) was added, and the reaction mixture was degassed (2x). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure, followed by purification by ISCO flash chromatography (40 g column; gradient: 0%-100% ethyl acetate in hexane) provided 5-(7-chloro-2,3-dimethyl-1H-pyrrolo[ tert-Butyl 2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.681 g, 1.65 mmol, 86% yield) as a yellow solid. The product had a UPLC retention time = 1.17 min. Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (1.5 minute gradient); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 412.5 and 414.5. Intermediate 225C: tert 5-(7-cyano-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate -butyl

[00560] A mixture of 5-(7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate of tert-butyl (0.300 g, 0.728 mmol), zinc cyanide (0.051 g, 0.437 mmol), zinc (5.71 mg, 0.087 mmol), and 1,1'-bis(diphenylphosphine)ferrocene (DPPF) (0.048 g, 0.087 mmol) in N,N-dimethylacetamide (4 mL) was degassed well with vacuum and nitrogen (3x). To the mixture was added tris(dibenzylideneacetone) dipalladium(0) (0.040 g, 0.044 mmol), with degassing, and the reaction mixture was immersed in an oil bath at 130 °C for 6.5 h. The reaction was then cooled and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with 10% aqueous lithium chloride (2x), and washed with brine. The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure, followed by purification by ISCO flash chromatography (24 g column; gradient: 0%-100% ethyl acetate in hexane) provided 5-(7-cyano-2,3-dimethyl-1H-pyrrolo[ tert-Butyl 2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.153 g, 0.380 mmol, 52% yield) as a yellow film. The product had a UPLC with a retention time = 1.29 min. Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (1.5 minute gradient); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 403.5. Intermediate 225D: 2,3-Dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

[00561] A mixture of 5-(7-cyano-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H) tert-butyl-carboxylate (0.152 g, 0.378 mmol) and 90% aqueous sulfuric acid (4.47 ml, 76 mmol) was immersed in an oil bath at 60 °C and stirred for 60 min. To the reaction mixture, cooled to 0 °C, an aqueous solution of sodium hydroxide (10 M) (15.1 mL, 151 mmol) was added dropwise with stirring. A few more drops of sodium hydroxide solution were added until the pH was ~9. The resulting suspension was stirred overnight. The precipitate was collected by vacuum filtration and washed well with water and dried to give 2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3 -c]pyridine-7-carboxamide (0.097 g, 0.288 mmol, 76% yield) as a brown solid. The product had a UPLC retention time = 0.698 min. - Column: PHENO-MENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 324.2.

[00562] The filtrate was extracted with dichloromethane (3x), and the organic layer was dried over anhydrous sodium sulfate to give 2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl )-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (0.024 g, 0.074 mmol, 20% yield) as a pale yellow solid.

Example 225:

[00563] To a mixture of 2,3-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (0.097 g, 0.303 mmol) and Hunig's base (0.212 mL, 1.21 mmol) in tetrahydrofuran (2.0 mL) at room temperature was added acryloyl chloride (0.025 mL, 0.303 mmol). The reaction mixture was stirred for 20 min. The reaction mixture was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure, followed by purification by ISCO flash chromatography (12 g column; gradient: 0%-5% methanol in dichloromethane) provided 4-(2-acryloyl-1,2,3,4- tetrahydroisoquinolin-5-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (0.039 g, 0.103 mmol, 34% yield) as a pale yellow solid. The product had a UPLC retention time = 0.807 min. - Column: PHENOME-NEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 375.1. 1H NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.82 (s, 1H), 7.60 (d , J=1.8 Hz, 1H), 7.32 (d, J=7.2 Hz, 2H), 7.18-7.11 (m, 1H), 6.966.73 (m, 1H), 6 .13 (d, J=16.6 Hz, 1H), 5.76-5.63 (m, 1H), 4.93-4.81 (m, 1H), 4.77 (s, 1H), 3.76-3.55 (m, 2H), 2.45-2.38 (m, 1H), 2.37 (s, 3H), 2.33 (br.s., 1H), and 1. 56-1.49 (m, 3H). Example 226 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide ( mixture of atropisomers) Intermediate 226A: 4-Bromo-7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine

[00564] To a stirred solution of 3-bromo-6-chloro-2-methyl-5-nitropyridine (2.00 g, 7.95 mmol) in tetrahydrofuran (16 mL) at -78 °C was added bromide of (E)-but-2-en-2-ylmagnesium (0.5 M in THF) (55.7 mL, 27.8 mmol). The reaction mixture was allowed to warm to ~-35 °C over 30 min. and was then quenched with a saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution, washed with brine, and dried over anhydrous sodium sulfate. The organic layer was collected, and the aqueous layers were sequentially washed, extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate, and the resulting residue was purified by ISCO flash silica gel chromatography (24 g column; gradient: 0%-100 ethyl acetate in hexane) to provide 4-bromo- 7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine (0.402 g, 1.47 mmol, 19% yield) as a yellow solid. The product had a UPLC retention time = 1.14 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 273.2 and 275.2. Intermediate 226B: 5-(7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[00565] A mixture of 4-bromo-7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine (0.400 g, 1.46 mmol), 5-(4,4, tert-Butyl 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.630 g, 1.76 mmol), tripotassium phosphate (2M in water) (2.19 mL, 4.39 mmol), and tetrahydrofuran (8 mL) was degassed with vacuum and nitrogen (3x). 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.048 g, 0.073 mmol) was added, and the reaction mixture was degassed (2x). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by ISCO flash chromatography (40 g column; gradient: 0% - 100% ethyl acetate in hexane) provided 5-(7-chloro-2,3,5-trimethyl-1H- tert-butyl pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.331 g, 0.777 mmol, 53% yield) as a yellow solid. The product had a UPLC retention time = 1.09 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 426.5 and 428.4. Intermediate 226C: 5-(7-cyano-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[00566] A mixture of 5-(7-chloro-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H) tert-butyl-carboxylate (0.331 g, 0.777 mmol), zinc cyanide (0.055 g, 0.466 mmol), zinc (6.10 mg, 0.093 mmol), and 1,1'-bis(diphenylphosphine) ferrocene (DPPF) (0.052 g, 0.093 mmol) in N,N-dimethylacetamide (4 mL) was degassed well with vacuum and nitrogen (3x). To the mixture was added tris(dibenzylideneacetone)dipalladium(0) (0.043 g, 0.047 mmol), with degassing, and the reaction mixture was immersed in an oil bath at 130 °C for 6 h. The mixture was then stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous lithium chloride (2x), and washed with brine. The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by ISCO flash chromatography (24 g column; gradient: 0%-100% ethyl acetate in hexane) provided 5-(7-cyano-2,3,5-trimethyl-1H- tert-butyl pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.164 g, 0.394 mmol, 51% yield) as a yellow film. The product had a UPLC retention time = 1.21 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 417.5. Intermediate 226D: 2,3,5-Trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

[00567] A mixture of 5-(7-cyano-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H) tert-butyl-carboxylate (0.164 g, 0.394 mmol) and 90% aqueous sulfuric acid (4.66 ml, 79 mmol) was immersed in an oil bath at 60 °C and stirred for 60 min. UPLC and LCMS indicated that the reaction was complete. To the reaction mixture cooled to 0 °C was added sodium hydroxide (10 M) (15.8 mL, 157 mmol) dropwise with stirring. A few more drops of sodium hydroxide solution were added until the pH was ~9. The resulting solid was collected by vacuum filtration and washed with water, washed with ethyl acetate, and dried to provide 2,3,5-trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl )-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (0.043 g, 0.129 mmol, 33% yield) as a yellow solid. The ethyl acetate layer was collected and washed with saline. The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide 2,3,5-trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2 ,3-c]pyridine-7-carboxamide (0.026 g, 0.078 mmol, 20% yield) as a pale yellow solid. The product had a UPLC retention time = 0.708 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 335.4.

Example 226:

[00568] To a mixture of 2,3,5-trimethyl-4-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (0.043 g, 0.129 mmol) and Hunig's base (0.090 mL, 0.514 mmol) in tetrahydrofuran (1 mL) at room temperature was added acryloyl chloride (0.686 mL, 8.45 mmol). The reaction mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water, washed with brine, and dried over anhydrous sodium sulfate. The product mixture was concentrated under reduced pressure, and the residue was purified by ISCO flash chromatography (4 g column; gradient: 0%-5% methanol in dichloromethane) to give 4-(2-acryloyl-1,2, 3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (0.025 g, 0.064 mmol, 50% yield) as a pale yellow solid. The product had a UPLC retention time = 0.798 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 389.6. Examples 227 and 228 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine-7- carboxamide (mixture of atropisomers)

[00569] A sample of 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,3,5-trimethyl-1H-pyrrolo[2,3-c]pyridine- 7-carboxamide (Intermediate 2E, mixture of two atropisomers) was separated by chiral supercritical fluid chromatography using the following preparative conditions to provide two stable and isolated atropisomers.

[00570] Preparative Chromatographic Conditions: Instrument: Thar350; Column: Cellulose-4 (3 x 25 cm; 5 µm); BPR pressure: 100 bars; Temperature: 35°C; Flow rate: 150 mL/min; mobile phase: CO2/MeOH (55/45); detector wavelength: 220 nm; injection: 2.5 mL; sample preparation: 21 mg/7 mL MeOH, 3 mg/mL.

[00571] Atropisomer 1 (Peak 1): The product was >99% pure by UPLC with a retention time = 0.793 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 389.4. 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.03 (d, J=2.8 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H ), 7.32 (d, J=5.7 Hz, 2H), 7.09-7.05 (m, 1H), 6.93 (dd, J=16.3, 10.4 Hz, 0. 4H), 6.78 (dd, J=16.8, 10.4 Hz, 0.6H), 6.13 (d, J=16.8 Hz, 1H), 5.76-5.63 (m , 1H), 4.88 (br.s., 1H), 4.77 (s, 1H), 3.74-3.57 (m, 2H), 2.31 (s, 3H), 3.32 (s, 3H), 2.29-2.21 (m, 2H), and 2.19 (s, 2H).

[00572] Atropisomer 2 (Peak 2): The product had a UPLC retention time = 0.803 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC/MS M+1 = 389.3. 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.03 (d, J=2.6 Hz, 1H), 7.58 (d, J=2.7 Hz, 1H ), 7.36-7.27 (m, 2H), 7.10-7.04 (m, 1H), 6.93 (dd, J=16.6, 10.6 Hz, 0.4H), 6.78 (dd, J=16.6, 10.5 Hz, 0.6H), 6.13 (d, J=16.6 Hz, 1H), 5.76-5.63 (m, 1H) , 4.88 (br.s., 1H), 4.77 (s, 1H), 3.74-3.58 (m, 2H), 3.30 (s, 3H), 2.31 (s, 3H), 2.28-2.22 (m, 2H), and 2.19 (s, 3H). Example 229 4-(2-Acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-cyano-2,3-dimethyl-1H-indole-7-carboxamide Intermediate 229A: tert-butyl 5-(7-carbamoyl-5-cyano-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00573] A mixture of tert-butyl 5-(7-carbamoyl-5-iodo-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (25 mg, 0.046 mmol) and zinc cyanide (5.38 mg, 0.046 mmol) in N,N-dimethylformamide (1 mL) was degassed well with vacuum and nitrogen (3x). To the mixture, Pd(PhβP)4 (5.30 mg, 4.58 μmol) was added, the yellow heterogeneous solution was degassed (3x), immersed in an oil bath at 100 °C, and stirred for 12 h. During the reaction, the mixture changed from a yellow heterogeneous solution to a dark homogeneous solution. Purification by reverse phase preparative HPLC provided 5-(7-carbamoyl-5-cyano-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (15 mg, 0.034 mmol, 74% yield) as a white solid. The product had a UPLC retention time = 1.24 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. MS (E+) m/z: 445.3 (M+H).

Example 229:

[00574] A solution of tert-butyl 5-(7-carbamoyl-5-cyano-2,3-dimethyl-1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (10 mg, 0.022 mmol) in trifluoroacetic acid (0.5 mL, 6.49 mmol) was stirred at room temperature for 10 min., then concentrated in vacuo to remove TFA. Also dried in a vacuum pump. The resulting mixture was dissolved in tetrahydrofuran (1 mL), and to the solution were added DIEA (0.012 mL, 0.067 mmol), BOP (11.9 mg, 0.027 mmol), and but-2-ynoic acid (2.27 mg, 0.027 mmol). The reaction mixture was stirred at room temperature for an additional 10 min. Purification by reverse phase preparative HPLC provided 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-cyano-2,3-dimethyl-1H-indole-7-carboxamide ( 6.4 mg, 71% yield) as a white solid. The product had a UPLC retention time = 0.980 min. - Column: PHENOMENEX® Kinetex C18 2.1 x 50 mm (gradient of 1.5 minutes); Solvent A = 10% MeCN, 90% H2O, 0.1% TFA; Solvent B = 90% MeCN, 10% H2O, 0.1% TFA. MS (E+) m/z: 399.3 (M+H). 1H NMR (400 MHz, methanol-d4) δ 7.82 (s, 1H), 7.43-7.27 (m, 2H), 7.09-7.01 (m, 1H), 6.78 ( dd, J=16.8, 10.6 Hz, 1H), 6.28 (m, 1H), 5.89-5.69 (m, 1H), 4.95-4.89 (m, 1H) , 3.78 (q, J=6.2 Hz, 2H), 2.55-2.27 (m, 6H), and 1.44-1.32 (m, 3H). Example 230 4-((1-Acryloylpiperidin-4-yl)methyl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide Intermediate 230A: tert-butyl 4-((7-carbamoyl-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indol-4-yl)methylene)piperidine-1-carboxylate

[00575] A mixture of 4-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (100 mg, 0.295 mmol), tert-butyl 4-methylenepiperidine-1-carboxylate (116 mg, 0.590 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (19.22 mg, 0.029 mmol), N,N-dicyclohexylmethylamine (0.094 mL, 0.442 mmol) and sodium chloride Tetrabutylammonium (8.20 mg, 0.029 mmol) in degassed DMA (2.0 mL) under nitrogen was stirred in a sealed vial at 80°C for 18 hours. The mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (PHENOMENEX®, Luna 5 µ 30 x 250 mm, flow rate = 30 ml/min., gradient = 20% A to 100% B in 30 min., A = H2O/ MeOH/TFA (90:10:0.1), B = H2O/MeOH/TFA (10:90:0.1) Production of 4-((7-carbamoyl-5-fluoro-3-methyl-2- tert-Butyl (trifluoromethyl)-1H-indol-4-yl)methylene)piperidine-1-carboxylate (108 mg, 0.225 mmol, 76% yield) as white solid.1H NMR (400 MHz, methanol-d4) δ 7.75-7.65 (m, 1H), 6.89-6.72 (m, 1H), 3.86-3.70 (m, 1H), 3.51-3.39 (m, 1H) ), 3.25-3.03 (m, 2H), 2.61 (d, J=1.6 Hz, 4H), 2.49-2.39 (m, 1H), 1.96-1, 81 (m, 1H), 1.76-1.60 (m, 1H), 1.51 (s, 9H) LCMS: 1.21 min., M+H 456.

Example 230:

[00576] To a solution of tert-butyl 4-((7-carbamoyl-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indol-4-yl)methylene)piperidine-1-carboxylate (15 mg, 0.033 mmol) and triethyl silane (0.263 mL, 1.647 mmol) in DCM (1.0 mL) was added TFA (0.254 mL, 3.29 mmol), the mixture was stirred at room temperature for 30 min. The mixture was concentrated to provide crude 5-fluoro-3-methyl-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)-1H-indole-7-carboxamide, TFA salt.

[00577] To a solution of 5-fluoro-3-methyl-4-(piperidin-4-ylmethyl)-2-(trifluoromethyl)-1H-indole-7-carboxamide, TFA salt and TEA (0.023 mL, 0.165 mmol ) in DMF (0.3 mL) and DCM (1.0 mL) a solution of acryloyl chloride (2.68 µL, 0.033 mmol) in DCM (0.3 mL) was added, the mixture was stirred at room temperature for 30 min. The mixture was concentrated. The crude product was purified by preparative HPLC (PHENOMENEX®, Luna 5 µ 30 x 250 mm, flow rate = 30 ml/min., gradient = 20% A to 100% B in 30 min., A = H2O/ MeOH/TFA (90:10:0.1), B = H2O/MeOH/TFA (10:90:0.1)). Production of 4-((1-acryloylpiperidin-4-yl)methyl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide (3.8 mg, 8.78 µmol, 26 .6% yield). 1H NMR (500 MHz, DMSO-d6) δ 11.12 (br.s., 1H), 8.27 (br.s., 1H), 7.81 (d, J=10.9 Hz, 1H) , 7.70 (br.s., 1H), 6.79 (dd, J=16.7, 10.5 Hz, 1H), 6.08 (dd, J=16.7, 2.2 Hz, 1H), 5.65 (dd, J=10.5, 2.2 Hz, 1H), 4.40 (d, J=13.5 Hz, 1H), 4.02 (d, J=12.7 Hz, 1H), 3.06-2.86 (m, 3H), 1.84 (br.s., 1H), 1.64 (d, J=12.5 Hz, 2H), 1.32- 1.10 (m, 3H). LCMS: 0.93 min., M+H 412. Examples 231 and 232 (atropisomers) 4-(2-Acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)- 5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Intermediate 231A: Ethyl 2-(2-chloro-6-methylphenyl)-2,2-difluoroacetate

[00578] To a suspension of copper (1.057 g, 16.63 mmol) and 1-chloro-2-iodo-3-methylbenzene (1.50 g, 5.94 mmol) in DMSO (5.0 mL) was added Ethyl 2-bromo-2,2-difluoroacetate (1.206 g, 5.94 mmol), the mixture was stirred at 55°C for 18 hours. The mixture was poured into a cold solution of saturated NH 4 Cl in water (100 mL) and extracted with EtOAc (70 mL). The EtOAc was then washed with a 1.0 N aqueous HCl solution (2 x 50 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (gradient 100:0 to 70:30 silica gel/hexane-EtOAc). Production of ethyl 2-(2-chloro-6-methylphenyl)-2,2-difluoroacetate (1.26 g, 4.81 mmol, 81% yield) as clear oil. 1H NMR (400 MHz, chloroform-d) δ 7.33-7.24 (m, 2H), 7.23-7.11 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 2.58 (t, J=5.9 Hz, 3H), 1.411.30 (m, 3H). Intermediate 231B: Ethyl 2-(2-(bromomethyl)-6-chlorophenyl)-2,2-difluoroacetate

[00579] A mixture of ethyl 2-(2-chloro-6-methylphenyl)-2,2-difluoroacetate (1.26 g, 5.07 mmol), NBS (0.947 g, 5.32 mmol), and peroxide of benzoyl (0.123 g, 0.507 mmol) in CCl 4 (15 mL) was stirred at reflux for 4 hours. The mixture was cooled to room temperature. The precipitate was filtered and the filtrate was concentrated. Crude yield of ethyl 2-(2-(bromomethyl)-6-chlorophenyl)-2,2-difluoroacetate (1.81 g, 4.42 mmol, 87% yield) as light brown gum. 1H NMR (400 MHz, chloroform-d) δ 7.45-7.39 (m, 2H), 7.33-7.26 (m, 1H), 4.74 (t, J=2.1 Hz, 2H), 4.43-4.37 (m, 2H), 1.37-1.33 (m, 3H). Intermediate 231C: Ethyl 2-(2-(azidomethyl)-6-chlorophenyl)-2,2-difluoroacetate

[00580] A mixture of ethyl 2-(2-(bromomethyl)-6-chlorophenyl)-2,2-difluoroacetate (1.81 g, 5.53 mmol) and sodium azide (0.718 g, 11.05 mmol ) in DMF (15 mL) was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc (35 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 35 mL) and 1.0 M aqueous HCl (35 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (gradient 100:0 to 0:100 silica gel/hexane-EtOAc). Production of ethyl 2-(2-(azidomethyl)-6-chlorophenyl)-2,2-difluoroacetate (1.36 g, 4.46 mmol, 81% yield) as clear gum. 1H NMR (400 MHz, chloroform-d) δ 7.51-7.41 (m, 3H), 4.69 (t, J=3.1 Hz, 2H), 4.44-4.34 (m, 2H), 1.39-1.30 (m, 3H). Intermediate 231 D: 5-Chloro-4,4-difluoro-1,2-dihydroisoquinolin-3(4H)-one

[00581] A mixture of ethyl 2-(2-(azidomethyl)-6-chlorophenyl)-2,2-difluoroacetate (1.25 g, 4.32 mmol) and platinum (IV) oxide (0.098 g, 0.432 mmol) in MeOH (10 mL) was hydrogenated in 1 atm of hydrogen for 2 hours. Platinum was filtered and the filtrate was concentrated. Production of 5-chloro-4,4-difluoro-1,2-dihydroisoquinolin-3(4H)-one (950 mg, 4.15 mmol, 96% yield) as white solid. 1H NMR (400 MHz, methanol-d4) δ 7.59-7.52 (m, 2H), 7.35 (d, J=4.6 Hz, 1H), 4.70 (t, J=3, 5Hz, 2H). Intermediate 231E: tert-butyl 5-chloro-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00582] To a solution of hydroisoquinolin-3(4H)-one (950 mg, 4.37 mmol) in THF (5.0 mL) was added 1.0M borane tetrahydrofuran complex in THF (24.01 mL, 24.01 mmol), the mixture was stirred at reflux for 2 hours. The mixture was cooled to room temperature and the mixture was quenched with 1.0M aqueous HCl solution (17.46 mL, 17.46 mmol). The mixture was stirred at reflux for 2 hours and cooled to room temperature. The mixture was concentrated. The mixture was washed with ethyl ether (2 x 80 mL). A 10 N aqueous NaOH solution was added until pH 10 and extracted with EtOAc (2 x 50 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to provide 5-chloro-4,4-difluoro-1,2,3,4-tetrahydroisoquinoline.

[00583] To a solution of 5-chloro-4,4-difluoro-1,2,3,4-tetrahydroisoquinoline in THF (15 mL) was added BOC2O (1.014 mL, 4.37 mmol), the mixture was stirred at room temperature for 60 min. The mixture was concentrated. The crude product was subjected to ISCO flash chromatography (gradient from 100:0 to 0:100 silica gel/hexane-EtOAc). Production of tert-butyl 5-chloro-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (960 mg, 3.00 mmol, 68.8% yield) as clear gum. 1H NMR (400 MHz, chloroform-d) δ 7.36 (d, J=12.8 Hz, 2H), 7.17-7.07 (m, 1H), 4.68 (br.s., 2H ), 4.06 (t, J=12.0 Hz, 2H), 1.51 (s, 9H). Intermediate 231F: Intermediate 231F: 4,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H) tert-butyl carboxylate

[00584] A mixture of bis(pinacolato) diboron (881 mg, 3.47 mmol), tert-butyl 5-chloro-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate ( 527 mg, 1.735 mmol), potassium acetate (511 mg, 5.21 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (56.5 mg, 0.087 mmol) in dioxane (6 .0 mL) under nitrogen was stirred at 90°C for 18 hours. The mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous sodium bicarbonate solution (15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (gradient 100:0 to 70:30 silica gel/hexane-EtOAc). Production of tert 4,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate -butyl (160 mg, 0.385 mmol, 22.16% yield) as light brown gum. Intermediate 231G: 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[00585] A mixture of 4,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H) tert-butyl -carboxylate (160 mg, 0.405 mmol), 4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (115 mg, 0.405 mmol), 1,1'-dichloride bis(di-tert-butylphosphino)ferrocene palladium (13.19 mg, 0.020 mmol) and tribasic potassium phosphate (258 mg, 1.214 mmol) in THF (3.0 mL) and water (1.500 mL) was stirred at 50 °C in a sealed vial under nitrogen for 4 hours. EtOAc (5.0 mL) was added to extract the product. The EtOAc layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (gradient 100:0 to 50:50 silica gel/hexane-10% MeOH/EtOAc). Production of tert 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4,4-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate -butyl (125 mg, 0.238 mmol, 58.7% yield) as a light brown foam. Mass spectrum m/z 474 (M+H)+.

Examples 231 and 232:

[00586] A mixture of 5-(7-carbamoyl-5-fluoro-2,3-dimethyl-1H-indol-4-yl)-4,4-difluoro-3,4-dihydroisoquinoline-2(1H) tert-Butyl -carboxylate (125 mg, 0.264 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature for 30 min. The mixture was then concentrated to give 4-(4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indol-7- carboxamide.

[00587] To a solution of 4-(4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide and TEA (0.110 mL, 0.792 mmol) in DCM (3.0 mL) at 0 °C was added a solution of acryloyl chloride (23.89 mg, 0.264 mmol) in DCM (0.30 mL), the mixture was stirred at 0 °C for 30 min. The mixture was diluted with DCM (5ml) and washed with saturated aqueous sodium bicarbonate solution (5ml). The DCM layer was dried over sodium sulfate and concentrated. The crude product was subjected to ISCO flash chromatography (gradient 100:0 to 0:100 silica gel/hexane-10% MeOH/EtOAc). Production of 4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide ( 76 mg, 0.169 mmol, 64.0% yield) as light brown gum.

[00588] 4-(2-Acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide was separated by chiral supercritical fluid chromatography (CHIRALCEL® OJ (3 x 25 cm, 5 μm); mobile phase: 20% MeOH in CO2 at 120 mL/min; 100 bar, 30 °C; sample preparation: 76 mg in 7 mL of MeOH). The first peak eluting from the column provided one enantiomer of 4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl- 1H-indole-7-carboxamide [Intermediate 1] as a white powder (33 mg). The second peak eluting from the column provided the other enantiomer of 4-(2-acryloyl-4,4-difluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl -1H-indole-7-carboxamide as a white powder (30 mg).

[00589] Additional examples were prepared by the procedures described above or procedures similar to those known in the art, using the starting materials, are shown in Table 10. Table 10

[00590] Additional examples that were prepared by the procedures described above or procedures similar to those known in the art, using the appropriate starting materials, are shown in Table 11. Table 11

BIOLOGICAL TESTS

[00591] The pharmacological properties of the compounds of this invention can be confirmed by various biological assays. The following exemplified biological assays were performed with compounds of the invention.

Recombinant Human Btk Enzyme Assay

[00592] Test compounds, human recombinant Btk (1 nM, Invitrogen Corporation), fluoresceinated peptide (1.5 μM), ATP (20 μM), and assay buffer (HEPES a 20 mM, pH 7.4, 10 mM MgCl2, 0.015% Brij 35 surfactant and 4 mM DTT in 1.6% DMSO), with a final volume of 30 µL. After incubation at room temperature for 60 minutes, the reaction was terminated by adding 45 µL of 35 mM EDTA to each sample. The reaction mixture was analyzed on a LABCHIP® 3000 Caliper (Caliper, Hopkinton, MA) by electrophoretic separation of fluorescent substrate and phosphorylated product. Inhibition data were calculated by comparing control reactions with no enzyme (for 100% inhibition) and controls with no inhibitor (for 0% inhibition). Dose-response curves were generated to determine the concentration required for 50% inhibition of Btk activity (IC50). Compounds were dissolved to 10 mM in DMSO and evaluated at eleven concentrations.

Ramos FLIPR Assay

[00593] Ramos RA1 B cells (ATCC CRL-1596) at a density of 2 x 106 cells/mL in RPMI minus phenol red (Invitrogen 11835-030) and 50 mM HEPES (Invitrogen 15630-130) containing 0.1% of BSA (Sigma A8577) were added to half the volume of Calcium Loading Buffer (BD Volume Kit for Probenecid Sensitive Assays, #640177) and incubated at room temperature in the dark for 1 hr. Pigment-loaded cells were pelleted (Beckmann GS-CKR, 1200 rpm, room temperature, 5 min) and resuspended at room temperature in RPMI minus phenol red with 50 mM HEPES and 10% FBS at a density of 1 x 106 cells/mL. Aliquots of 150 μL (150,000 cells/well) were seeded in 96-well assay plates, coated with poly-D-lysine (BD 35 4640) and briefly centrifuged (Beckmann GS-CKR 800 rpm, 5 min., no control) . Then, 50 µL compound dilutions in 0.4% DMSO/RPMI minus phenol red + 50 mM HEPES + 10% FBS were added to the wells and the plate was incubated at room temperature in the dark for 1 hour. The assay plate was briefly centrifuged as above before measuring calcium levels. Using FLIPR1 (Molecular Devices), cells were stimulated by adding goat anti-human IgM (Invitrogen AHI0601) at 2.5 µg/ml. Changes in intracellular calcium concentrations were measured over 180 seconds and percent inhibition was determined relative to peak calcium levels in the presence of stimulation alone.

[00594] Table 12 below lists the Btk and Ramos IC50 values for the following examples of this invention measured in the recombinant human Btk enzyme assay and the Ramos FLIPR assay. The compounds of the present invention, as exemplified by the following examples, showed Btk IC50 values of less than 700 nM. Table 12

[00595] The compounds of the present invention have activity as Btk inhibitors, and therefore, can be used in the treatment of diseases associated with Btk activity.

Collagen-induced arthritis in mice:

[00596] Male DBA/1 mice (8-10 weeks old; Harlan) were immunized subcutaneously at the base of the tail on Day 0 and again on Day 21 with 200 μg bovine collagen type II mixed with recombinant Sigma Adjuvant System (SAS ; Sigma-Aldrich). Daily oral dosing was immediately started with example 223 or methotrexate (1 mg/kg) in PEG400:water (80:20) and continued until the end of the study (38 days).

[00597] Following the booster immunization, the mice were monitored three times a week for the development and severity of paw inflammation. Each paw was visually classified according to the following scheme: +0 = normal; +1 = one (or more) inflamed joints in the fingers; +2 = mild-moderate paw inflammation and modestly increased paw thickness; +3 = moderate-severe inflammation of the plantar surface of the paw and significantly increased paw thickness; +4 = ankle joint ankylosis (joint movement significantly reduced in flexion/extension). Paw clinical scores for all four paws were summed for each mouse, and the average was calculated for each treatment group.

Results:

[00598] Treatment with example 223 provided dose-responsive inhibition of clinically evident disease, with 21%, 83%, and 93% inhibition of mean clinical scores at the end of the study at doses of 0.1, 0.5 , and 2.5 mg/kg orally QD, respectively. In contrast, treatment with methotrexate at 1 mg/kg, the standard of care in rheumatoid arthritis, showed only 58% inhibition of clinical scores.

NZB/W Lupus Prone Mice:

[00599] Female NZB/WF1 mice, aged 24 weeks, were dosed by oral gavage, once a day, for 16 weeks and included in the following treatment groups: Example 223 at 0.2, 0.5 and 1 .5 mg/kg in vehicle (80:20 PEG400:water), vehicle alone, or prednisolone 10 mg/kg. Proteinuria was measured using a colorimetric assay for albumin (Siemens Albustix Reagent Strips for Uri-nalysis).

[00600] At the end of the study, the kidneys were collected in 10% Neutral Buffered Formalin for histological evaluation. Tissues from the fixed kidneys were routinely processed and paraffin embedded. Kidney sections were stained with periodic acid Schiff and hematoxylin (PASH) and hematoxylin and eosin (H&E) to assess the severity of nephritis. Blinded to treatment group, severity of nephritis was assessed using the following criteria. For glomerular damage: 1- mesangial matrix thickening and/or mesangial cell proliferation; 2 - Growing formation-cellular deposits/casts in Bowman's space; 3 - Cellular infiltration - composed of mononuclear cells in glomerular tufts; 4 - Bowman's capsule fibrosis. For tubular damage: 1 - Infiltration of mononuclear cells; 2 - Severity of tubular epithelial cell damage; 3- protein templates. For tubulointerstitial damage: 1 - Fibrosis; 2 - Infiltration of mononuclear cells. A score from 0 to 4 was assigned to each subcategory. The total score for each mouse was the sum of the 9 subcategories mentioned above.

Results:

[00601] Treatment with Example 223 showed dose-dependent inhibition of severe proteinuria, a measure of underlying nephritis, at study completion, with 42%, 17%, and 8% of mice showing severe proteinuria (> 300 mg/dL ) at doses of 0.2, 0.5 and 1.5 mg/kg, respectively. In comparison, 75% of vehicle control animals showed severe proteinuria. Histological evaluation of kidneys from vehicle control mice showed advanced nephritis, with mesangial hypertrophy of the glomeruli, prominent/increasing cell projections, and capsular fibrosis. Tubular epithelial cells were frequently damaged and protein templates were numerous. In addition, there was a prominent mononuclear cell infiltrate present in the interstitium of many of the examined kidneys. The results of the present study show that the Total Nephritis Histology Severity Scores for the three groups of mice treated with 0.2, 0.5 and 1.5 mg/kg of Example 223 were 6.4, 7.5 , and 5.0, respectively. In comparison, groups of mice treated with prednisolone or vehicle alone had Total Nephritis Histology Severity Scores of 7.8 and 21.0, respectively. In summary, the results of the present study indicate that treatment with Example 223 at all doses provided protection against glomerular and tubulointerstitial nephritis, as well as inflammatory infiltration. Table 13 Effect of Example 223 on Nephritis in NZB/W Lupus-Prone Mice

Claims (10)

1. Compound, characterized by the fact that it has Formula (I): Or a salt thereof, in which: X is CR4; A is: Q2 is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)CHCR7, -C(O)C=C(C1_3 hydroxyalkyl), -C(O)CsC (phenyl), -C(O)CHCS(CH3)3, or -S(O)2CH=CH2; R1 is H, -CH3, -CF3, or phenyl substituted with zero or 1 R12; R2 is H, -CH3, cyclopropyl, or phenyl substituted with zero or 1 R12, provided that at least one of R1 and R2 is -CH3; R3 is F or Cl; R4 is H or F; R6 is H, F, Cl, -CF3, or C1-3 alkoxy; R7, at each occurrence, is independently H, C1-4 alkyl, or cyclopropyl; and R12 is F, Cl, -CN, -CF3, or C1-3 alkoxy. 2. Compound, according to claim 1, or a salt thereof, characterized in that: R3 is F, or Cl; and Q2 is -C(O)CH=CH2, -S(O)2CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)C^CH, -C(O)CHCCH3, -C(O)CHCCH2CH3, -C(O)CHCCH2CH2CH3, -C(O)CHC(CH3)2OH, -C(O)C=CSi(CH3)3, -C(O)C=C(cyclopropyl), or -C(O)CEC(phenyl). 3. Compound, according to claim 1, characterized by the fact that it has the structure: 4. Compound according to claim 1, or a salt thereof, characterized in that said compound is selected from: (RS)-4-(2-acryloyl-1,2,3,4-tetra- hydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (95); 4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (97); 4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (99); (RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (102); 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (129) ; 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (131); 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (134) ; 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (153 and 154); 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (155 and 156); (RS)-4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (186); 4-(5-acryloyl-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-9-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (187 and 188); (RS)-4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide ( 189); 4-(2-acryloyl-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (190 and 191); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (192); (RS)-4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole -7-carboxamide (194); 4-(4-acryloyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide , single enantiomers (195 and 196); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide ( 197); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-methyl-2-(trifluoromethyl)-1H-indole-7-carboxamide, single enantiomers (198 and 199); 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (203) ; (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide (204); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide, single enantiomers (205 and 206); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide (209) ; 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-cyclopropyl-5-fluoro-2-methyl-1H-indole-7-carboxamide, single enantiomers (210 and 211 ); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7- carboxamide (212); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-3-(4-fluorophenyl)-2-methyl-1H-indole-7-carboxamide, single enantiomers (213 and 214); (RS)-4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-fluoro-2-(4-fluorophenyl)-3-methyl-1H-indol-7- carboxamide (215); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide (239); 4-(2-acryloyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide, single atropisomers (240 and 264); and 4-(2-(but-2-inoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,3-dimethyl-1H-indole-7-carboxamide (265 ). 5. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 6. Compound, according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that it is for use in therapy in the treatment of autoimmune disease or chronic inflammatory disease. 7. Compound or a pharmaceutically acceptable salt thereof, according to claim 6, characterized in that said autoimmune disease or chronic inflammatory disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), and Sjogren's syndrome. 8. Use of a compound, as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a drug for the treatment of autoimmune disease or chronic inflammatory disease. 9. Use according to claim 8, characterized in that said autoimmune disease or chronic inflammatory disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), and Sjogren's syndrome. 10. Compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that it is for use in therapy.