RU2775505C2 - Isoquinoline-3-yl carboxamides and their production and use - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to heterocyclic compounds with structures

,

, or to their pharmaceutically acceptable salt. The invention also relates to a pharmaceutical composition based on the above-mentioned compound and to a method for the treatment of malignant tumor.

EFFECT: new heterocyclic compounds are obtained, useful for the treatment of a disease caused by pathological activation or mutation of Wnt path.

6 cl, 8 tbl, 14 ex

Description

RELATED APPLICATIONS

[001] This application claims priority under Provisional Application US No. 62/328255, filed April 27, 2016, which is incorporated herein by reference in its entirety.

State of the art

Technical field

[002] The present invention relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins, as well as compositions containing them. More specifically, the present invention relates to the use of an isoquinoline compound, or salts or analogues thereof, in the treatment of disorders characterized by Wnt signaling activation (e.g., cancer, abnormal cell proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, and osteoarthritis), modulation cellular events mediated by Wnt signaling, as well as genetic diseases and neurological conditions/disorders/diseases caused by mutations or dysregulation of the Wnt pathway and/or one or more components of Wnt signaling. Methods for treating disease states associated with Wnt are also provided.

Description of the prior art

[003] The Wnt growth factor family includes more than 10 genes identified in mice and at least 19 genes identified in humans. Members of the Wnt family of signaling molecules mediate many important immediate and subsequent assembly processes during invertebrate and vertebrate development. The Wnt signaling pathway is known for its important role in the inductive interactions that regulate growth and differentiation, and also plays a role in the homeostatic maintenance of postembryonic tissue integrity. Wnt stabilizes cytoplasmic β-catenin, which stimulates the expression of genes including c-myc, c jun, fra-1, and cyclin D1. In addition, misregulation of Wnt signaling can cause developmental abnormalities and is implicated in the genesis of some human malignancies. Also, the Wnt pathway has been implicated in the maintenance of stem or progenitor cells in an expanding list of mature tissues, including skin, blood, gut, prostate, muscle, and nervous system.

The essence of the invention

[004] The present invention relates to methods and reagents, including contacting a cell with an agent, such as an isoquinoline compound, in a sufficient amount to antagonize Wnt activity, for example, to reverse or regulate an aberrant growth state or correct a genetic disorder due to mutations in Wnt-components. alarms.

[005] Some embodiments described herein include Wnt inhibitors containing an isoquinoline core. Other embodiments described herein include pharmaceutical compositions and methods of treatment using such compounds.

[006] One of the embodiments described herein includes a compound having the structure of Formula I :

as well as its prodrugs and pharmaceutically acceptable salts.

[007] In some embodiments of formula ( I ):

R ¹ , R ² , R ⁴ and R ⁵ are independently selected from the group consisting of H, halide, unsubstituted -(C _1-3 haloalkyl) and unsubstituted -(C _1-3 alkyl);

R ³ is a 5-membered heteroaryl optionally substituted with 1-4 R ⁴⁵ ;

R ⁶ is selected from the group consisting of -aryl substituted with 1-5 R ³⁶ and 6-membered heteroaryl optionally substituted with 1-6 R ³⁷ ;

each R ³⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl ), -XR ⁴² , -C(O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁷ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl ), -XR ⁴² , -C(O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁸ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁹ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴⁰ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴¹ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴² is independently selected from the group consisting of unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl), -(C _1-4 alkylene) _p aryl optionally substituted with 1-10 R ⁴⁶ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-12 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl, optionally substituted 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴³ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴⁴ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴⁵ is independently selected from the group consisting of unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, two adjacent R ⁴⁵ taken together form a ring selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R ⁴⁰ and -carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

each R ⁴⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴⁷ is independently selected from the group consisting of unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl);

each X is selected from the group consisting of O, S and NH; and

each p is independently 0 or 1.

[008] In another embodiment of formula ( I ):

R ¹ , R ² , R ⁴ and R ⁵ are independently selected from the group consisting of H, halide, unsubstituted -(C _1-3 haloalkyl) and unsubstituted -(C _1-3 alkyl);

R ³ is selected from the group consisting of:

where each of R ⁷ -R ³⁵ independently represents a substituent, as defined elsewhere herein, or a single bond linking R ³ to the isoquinoline ring; where only one of R ⁷ -R ¹⁰ (if present) is a bond, only one of R ¹¹ -R ¹⁴ (if present) is a bond, only one of R ¹⁵ -R ¹⁷ (if , if present) is a bond, only one of R ¹⁸ -R ²⁰ (if present) is a bond, only one of R ²¹ -R ²³ (if present) is a bond, only one of R ²⁴ -R ²⁶ (if present) is a bond, only one of R ²⁷ -R ²⁹ (if present) is a bond, only one of R ³⁰ -R ³¹ (if present) is is a bond, only one of R ³² -R ³³ (if present) is a bond, and only one of R ³⁴ -R ³⁵ (if present) is a bond; for purposes of clarification, any of the nitrogen atoms attached to R ⁷ , R ¹¹ , R ¹⁵ , R ¹⁸ or R ²¹ may serve as the point of attachment of R ³ to the isoquinoline ring; similarly, any of the carbon atoms attached to R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁶ , R ¹⁷ , R ¹⁹ , R ²⁰ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ or R ³⁵ may serve as the point of attachment of R ³ to the isoquinoline ring; thus:

when the nitrogen atom to which R ⁷ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ⁷ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ⁸ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ⁸ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ⁹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ⁹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁰ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁰ is a single bond linking R ³ to the isoquinoline ring;

when the nitrogen atom to which R ¹¹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹¹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹² is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹² is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹³ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹³ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁴ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁴ is a single bond linking R ³ to the isoquinoline ring;

when the nitrogen atom to which R ¹⁵ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁵ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁶ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁶ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁷ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁷ is a single bond linking R ³ to the isoquinoline ring;

when the nitrogen atom to which R ¹⁸ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁸ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁰ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁰ is a single bond linking R ³ to the isoquinoline ring;

when the nitrogen atom to which R ²¹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²¹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²² is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²² is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²³ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²³ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁴ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁴ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁵ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁵ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁶ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁶ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁷ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁷ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁸ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁸ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³⁰ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³⁰ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³¹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³¹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³² is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³² is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³³ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³³ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³⁴ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³⁴ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³⁵ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³⁵ is a single bond linking R ³ to the isoquinoline ring;

R ⁶ is selected from the group consisting of -aryl substituted with 1-5 R ³⁶ and 6-membered heteroaryl optionally substituted with 1-6 R ³⁷ ;

R ⁷ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl ), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ⁷ and R ⁸ , R ⁸ and R ⁹ , or R ⁹ and R ¹⁰ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ , and α-carbocyclyl, optionally substituted 1-12 R ⁴¹ ;

R ¹¹ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ¹² , R ¹³ and R ¹⁴ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl ), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ¹¹ and R ¹² , R ¹² and R ¹³ , or R ¹⁴ and R ¹¹ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ , and β-carbocyclyl, optionally substituted 1-12 R ⁴¹ ;

R ¹⁵ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ¹⁶ and R ¹⁷ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ¹⁵ and R ¹⁶ , or R ¹⁶ and R ¹⁷ , are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ , and β-carbocyclyl optionally substituted with 1-12 ^R41 ;

R ¹⁸ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ¹⁹ and R ²⁰ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ¹⁸ and R ¹⁹ or R ¹⁸ and R ²⁰ are taken together to form a heterocyclyl optionally substituted with 1-10 R ⁴⁰ ;

R ²¹ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ²² and R ²³ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, R ²² and R ²³ are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R ⁴⁰ and -carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl ), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ²⁴ and R ²⁵ , or R ²⁵ and R ²⁶ , are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ , and β-carbocyclyl optionally substituted with 1-12 ^R41 ;

R ²⁷ , R ²⁸ and R ²⁹ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl ), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, R ²⁷ and R ²⁸ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ and β-carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

R ³⁰ and R ³¹ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, R ³⁰ and R ³¹ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ and β-carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

R ³² and R ³³ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

R ³⁴ and R ³⁵ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, R ³⁴ and R ³⁵ are taken together to form a ring which is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R ⁴⁰ and -carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

each R ³⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl ), -XR ⁴² , -C(O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁷ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl ), -XR ⁴² , -C(O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁸ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁹ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴⁰ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴¹ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴² is independently selected from the group consisting of unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl), -(C _1-4 alkylene) _p aryl optionally substituted with 1-10 R ⁴⁶ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-12 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl, optionally substituted 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴³ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴⁴ is selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl) and -CN;

each R ⁴⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴⁷ is independently selected from the group consisting of unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl);

each X is selected from the group consisting of O, S and NH;

each Y is selected from the group consisting of O and S; and

each p is independently 0 or 1.

[009] In another embodiment of formula ( I ):

R ¹ , R ² , R ⁴ and R ⁵ are independently selected from the group consisting of H, halide, amino, unsubstituted -(C _1-3 haloalkyl) and unsubstituted -(C _1-3 alkyl);

R ³ is a 5-membered heteroaryl optionally substituted with 1-4 R ⁴⁵ ;

R ⁶ is selected from the group consisting of -phenyl substituted with 1-5 R ³⁶ , -(C _1-3 alkylene) _p pyridinyl optionally substituted with 1-6 R ³⁷ , and 6-10 membered heteroaryl optionally substituted with 1-6 R ³⁷ ; where the carbonyl of formula I is attached to the aromatic ring of heteroaryl; where -(C _1-3 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl ), -XR ⁴² , -C(=O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p N(R ⁵⁰ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1- 10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁷ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl ), -XR ⁴² , -C(=O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p N(R ⁵⁰ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1- 10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁸ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁹ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴⁰ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴¹ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴² is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p aryl optionally substituted with 1-10 R ⁴⁶ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1 -12 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴³ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN, -OH, -C(=O)R ⁵¹ , -N(R ⁵⁰ ) ₂ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴⁴ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴⁵ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl ), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene ) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, two adjacent R ⁴⁵ taken together form a ring selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R ⁴⁰ and -carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

each R ⁴⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴⁷ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl );

each R ⁴⁸ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl );

each R ⁴⁹ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl );

each R ⁵⁰ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), and -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁵¹ is heteroaryl optionally substituted with 1-6 R ⁵² ;

each R ⁵² is heterocyclyl optionally substituted with 1-10 R ⁴⁶ ;

each X is selected from the group consisting of O, S and NR ⁴⁸ ; and

each p is independently 0 or 1.

[010] In another embodiment of formula ( I ):

R ¹ , R ² , R ⁴ and R ⁵ are independently selected from the group consisting of H, halide, amino, unsubstituted -(C _1-3 haloalkyl) and unsubstituted -(C _1-3 alkyl);

R ³ is selected from the group consisting of:

where each of R ⁷ -R ³⁵ independently represents a substituent, as defined elsewhere herein, or a single bond linking R ³ to the isoquinoline ring; where only one of R ⁷ -R ¹⁰ (if present) is a bond, only one of R ¹¹ -R ¹⁴ (if present) is a bond, only one of R ¹⁵ -R ¹⁷ (if , if present) is a bond, only one of R ¹⁸ -R ²⁰ (if present) is a bond, only one of R ²¹ -R ²³ (if present) is a bond, only one of R ²⁴ -R ²⁶ (if present) is a bond, only one of R ²⁷ -R ²⁹ (if present) is a bond, only one of R ³⁰ -R ³¹ (if present) is is a bond, only one of R ³² -R ³³ (if present) is a bond, and only one of R ³⁴ -R ³⁵ (if present) is a bond; for purposes of clarification, any of the nitrogen atoms attached to R ⁷ , R ¹¹ , R ¹⁵ , R ¹⁸ or R ²¹ may serve as the point of attachment of R ³ to the isoquinoline ring; similarly, any of the carbon atoms attached to R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁶ , R ¹⁷ , R ¹⁹ , R ²⁰ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ or R ³⁵ may serve as the point of attachment of R ³ to the isoquinoline ring; thus:

when the nitrogen atom to which R ⁷ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ⁷ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ⁸ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ⁸ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ⁹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ⁹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁰ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁰ is a single bond linking R ³ to the isoquinoline ring;

when the nitrogen atom to which R ¹¹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹¹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹² is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹² is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹³ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹³ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁴ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁴ is a single bond linking R ³ to the isoquinoline ring;

when the nitrogen atom to which R ¹⁵ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁵ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁶ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁶ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁷ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁷ is a single bond linking R ³ to the isoquinoline ring;

when the nitrogen atom to which R ¹⁸ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁸ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ¹⁹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ¹⁹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁰ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁰ is a single bond linking R ³ to the isoquinoline ring;

when the nitrogen atom to which R ²¹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²¹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²² is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²² is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²³ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²³ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁴ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁴ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁵ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁵ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁶ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁶ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁷ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁷ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁸ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁸ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ²⁹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ²⁹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³⁰ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³⁰ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³¹ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³¹ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³² is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³² is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³³ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³³ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³⁴ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³⁴ is a single bond linking R ³ to the isoquinoline ring;

when the carbon atom to which R ³⁵ is attached serves as the point of attachment of R ³ to the isoquinoline ring, then R ³⁵ is a single bond linking R ³ to the isoquinoline ring;

R ⁶ is selected from the group consisting of -phenyl substituted with 1-5 R ³⁶ , -(C _1-3 alkylene) _p pyridinyl optionally substituted with 1-6 R ³⁷ , and 6-10 membered heteroaryl optionally substituted with 1-6 R ³⁷ ; where the carbonyl of formula I is attached to the aromatic ring of heteroaryl; where -(C _1-3 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ⁷ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl ), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ⁷ and R ⁸ , R ⁸ and R ⁹ , or R ⁹ and R ¹⁰ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ , and β-carbocyclyl, optionally substituted 1-12 R ⁴¹ ;

R ¹¹ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ¹² , R ¹³ and R ¹⁴ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl ), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ¹¹ and R ¹² , R ¹² and R ¹³ , or R ¹⁴ and R ¹¹ , are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ , and α-carbocyclyl , optionally substituted with 1-12 R ⁴¹ ;

R ¹⁵ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ¹⁶ and R ¹⁷ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ¹⁵ and R ¹⁶ , or R ¹⁶ and R ¹⁷ , are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ , and β-carbocyclyl optionally substituted with 1-12 ^R41 ;

R ¹⁸ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ¹⁹ and R ²⁰ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ¹⁸ and R ¹⁹ or R ¹⁸ and R ²⁰ are taken together to form a heterocyclyl optionally substituted with 1-10 R ⁴⁰ ;

R ²¹ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

R ²² and R ²³ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, R ²² and R ²³ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ and β-carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl ), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, one of R ²⁴ and R ²⁵ or R ²⁵ and R ²⁶ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ and α-carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

R ²⁷ , R ²⁸ and R ²⁹ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl ), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, R ²⁷ and R ²⁸ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ and β-carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

R ³⁰ and R ³¹ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, R ³⁰ and R ³¹ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ and β-carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

R ³² and R ³³ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

R ³⁴ and R ³⁵ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

alternatively, R ³⁴ and R ³⁵ are taken together to form a ring which is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 R ⁴⁰ and β-carbocyclyl optionally substituted with 1-12 R ⁴¹ ;

each R ³⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl ), -XR ⁴² , -C(=O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p N(R ⁵⁰ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1- 10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁷ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl ), -XR ⁴² , -C(=O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p N(R ⁵⁰ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1- 10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁸ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ³⁹ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴⁰ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴¹ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴² is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p aryl optionally substituted with 1-10 R ⁴⁶ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1 -12 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴³ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), -CN, -OH, -C(=O)R ⁵¹ , -N(R ⁵⁰ ) ₂ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁴⁴ is selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl) and -CN;

each R ⁴⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ) and -CN;

each R ⁴⁷ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl );

each R ⁴⁸ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl );

each R ⁴⁹ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl );

each R ⁵⁰ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl ), and -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

each R ⁵¹ is heteroaryl optionally substituted with 1-6 R ⁵² ;

each R ⁵² is heterocyclyl optionally substituted with 1-10 R ⁴⁶ ;

each X is selected from the group consisting of O, S and NR ⁴⁸ ;

each Y is selected from the group consisting of O and S; and

each p is independently 0 or 1.

[011] Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of formula ( I ). Some embodiments include pharmaceutically acceptable salts of a compound of formula ( I ).

[012] Some embodiments include prodrugs of a compound of formula ( I ).

[013] Some embodiments of the present invention include pharmaceutical compositions containing a compound of formula ( I ), as well as a pharmaceutically acceptable carrier, diluent or excipient.

[014] Other embodiments described herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins, by administering to a patient suffering from a disorder or disease in which aberrant Wnt signaling is involved, such as cancer. and other diseases associated with abnormal angiogenesis, cell proliferation, cell cycle and mutations in Wnt signaling components of the compound of formula ( I ). Accordingly, the compounds and compositions provided herein can be used to treat cancer, to attenuate or inhibit angiogenesis, to attenuate or inhibit cell proliferation, and to correct a genetic disorder due to mutations in Wnt signaling components.

[015] Non-limiting examples of diseases that can be treated with the compounds and compositions specified herein include various types of malignant tumors, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, osteochondrodysplasia, disease Alzheimer's disease, lung disease, bone fracture/osteoporotic fracture (wrist, spine, shoulder, and hip), articular cartilage defects (chondral), degenerative disc disease (or intervertebral disc degeneration), coli-polyposis, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy , retinal angiogenesis, early ischemic disease, tetra-amelia syndrome, Mullerian duct virilization and regression, SERKAL syndrome, type 2 diabetes mellitus, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel syndrome, odonto-onychodermal dysplasia, obesity, split cyst malformation and / foot, tail duplication syndrome, dental agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha thalassemia syndrome (ARTX), fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Norrie's disease, Rett's syndrome.

[016] Some embodiments of the present invention include methods for preparing compounds of formula ( I ).

[017] It is to be understood that both the foregoing general description and the following detailed description are illustrative and explanatory and are not intended to limit the present invention.

DETAILED DESCRIPTION

[018] Provided herein are compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins.

[019] Some embodiments provided herein relate to a method of treating a disease or disorder, including, but not limited to, malignant tumors, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer's disease, lung disease, osteoarthritis, bone fracture/osteoporotic fracture (wrist, spine, shoulder, and hip), articular cartilage (chondral) defects, articular cartilage (chondral) defects, degenerative disc disease (or degeneration of the intervertebral discs), coli-polyposis, defects in bone density and blood vessels in the eye (osteoporosis-pseudoglioma syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, Tetra-Amelia syndrome, virilization and regression of Müllerian ducts, SERKAL syndrome , type II diabetes, Furman's syndrome , Al-Awadi/Raas-Rothschild/Schinzel syndrome, odonto-onychodermal dysplasia, obesity, cleft hand/foot malformation, caudal duplication syndrome, dental agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, defects neural tube, alpha thalassemia syndrome (ARTX), fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Norrie's disease, Rett syndrome.

[020] In some embodiments, non-limiting examples of bone and cartilage diseases that can be treated with the compounds and compositions provided herein include bone spur (osteophytes), craniosynostosis, progressive fibrodysplasia ossificans, fibrous dysplasia, osteoblastoclastoma of bone, rupture of the acetabular lip hip, meniscus tear, bone fracture/osteoporotic fracture (wrist, spine, shoulder and hip), articular cartilage defects (chondral), degenerative disc disease (or degeneration of the intervertebral discs), osteochondritis dissecans, osteochondroma (swelling of the bone), osteopetrosis, relapsing polychondritis and Salter-Harris fracture.

[021] In some embodiments, pharmaceutical compositions are provided that are effective for treating a disease in an animal, such as a mammal, caused by pathological activation or mutation of the Wnt pathway. The composition includes a pharmaceutically acceptable carrier and a compound as described herein.

Definitions

[022] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as generally understood by a person skilled in the art to which the present invention pertains. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions of a term in this document, those in this section shall prevail unless otherwise noted.

[023] As used herein, the term "alkyl" refers to a branched or linear chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n- pentyl, isopentyl, sec-pentyl and neopentyl. Alkyl groups may be either unsubstituted or substituted with one or more substituents. In some embodiments, alkyl groups comprise 1 to 9 carbon atoms (eg, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[024] As used herein, the term "alkenyl" refers to a straight or branched chain chemical group containing only carbon and hydrogen, and containing at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. In various embodiments, the alkenyl groups may be either unsubstituted or substituted with one or more substituents. Typically, alkenyl groups will contain 2 to 9 carbon atoms (eg, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[025] As used herein, the term "alkynyl" refers to a straight or branched chemical group containing only carbon and hydrogen, and containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl, 2- butynyl and the like. In various embodiments, alkynyl groups may be either unsubstituted or substituted with one or more substituents. Generally, alkynyl groups will contain 2 to 9 carbon atoms (eg, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[026] As used herein, the term "alkylene" refers to a divalent straight or branched chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, s-butylene, tert-butylene , n-pentylene, isopentylene, sec-pentylene and neopentylene. The alkylene groups may be either unsubstituted or substituted with one or more substituents. Alkylene groups may be saturated or unsaturated (eg, containing -C=C- or -C≡C- subunits) at one or more positions. In some embodiments, the alkylene groups comprise 1 to 9 carbon atoms (eg, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[027] As used herein, the term "alkenylene" refers to a straight or branched bivalent chemical group containing only carbon and hydrogen, and containing at least one carbon-carbon double bond, such as ethenylene, 1-propenylene, 2-propenylene , 2-methyl-1-propenylene, 1-butenylene, 2-butenylene and the like. In various embodiments, the alkenylene groups may be either unsubstituted or substituted with one or more substituents. Typically, alkenylene groups will contain 2 to 9 carbon atoms (eg, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[028] As used herein, the term "alkynylene" refers to a divalent straight or branched chain chemical group containing only carbon and hydrogen, and containing at least one carbon-carbon triple bond, such as ethynylene, 1-propynylene, 1-butynylene , 2-butynylene and the like. In various embodiments, the alkynylene groups may be either unsubstituted or substituted with one or more substituents. Generally, alkynylene groups will contain 2 to 9 carbon atoms (eg, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[029] As used herein, the term "carbocyclyl" means a cyclic ring system containing only carbon atoms in the backbone of the ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include several fused rings. Carbocyclyls may be of any degree of saturation, provided that at least one ring in the ring system is non-aromatic. Carbocyclyl groups may be either unsubstituted or substituted with one or more substituents. In some embodiments, the implementation of carbocyclyl groups include from 3 to 10 carbon atoms, for example from 3 to 6 carbon atoms.

[030] As used herein, the term "aryl" means a mono-, bi-, tri-, or polycyclic group with only carbon atoms present in the ring skeleton, containing from 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and containing 6, 10 or 14 pi electrons, generalized in a cyclic group; where at least one ring in the system is aromatic. Aryl groups may be either unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl and other groups. In some embodiments, the aryl is phenyl.

[031] As used herein, the term "arylalkylene" means an aryl-alkylene group in which the aryl and alkylene moieties are as described above. In some embodiments, the arylalkylene groups contain a C _1-4 alkylene moiety. Examples of arylalkylene groups are benzyl and 2-phenethyl.

[032] As used herein, the term "heteroaryl" means a mono-, bi-, tri- or polycyclic group containing from 5 to 14 ring atoms, alternatively 5, 6, 9 or 10 ring atoms; and having 6, 10 or 14 pi electrons generalized in a cyclic group; where at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O and S. Heteroaryl groups may be either unsubstituted or substituted one or more substitutes. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzimidazolyl indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- d ]pyrimidinyl, pyrrolo[2,3- b ]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c ]pyridinyl, pyrazolo[ 3,4- b ]pyridinyl, pyrazolo[3,4- c ]pyridinyl, pyrazolo[4,3- c ]pyridine, pyrazolo[4,3- b ]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[ b ] [1,4]dioxin, benzo[ d ][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[ b ][1,4]oxathiine and others. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, pyranyl, pyrazinyl, and pyrimidinyl.

[033] As used herein, the term "halo", "halogen", or "halide" refers to radicals represented by chlorine, bromine, fluorine, or iodine atoms. In some embodiments, represents chlorine, bromine, or fluorine. For example, halide can be fluorine .

[034] As used herein, the term "haloalkyl" refers to a hydrocarbon substituent that is a linear or branched alkyl, alkenyl, or alkynyl substituted with one or more chlorine, bromine, fluorine, and/or iodine atoms. In some embodiments, haloalkyl are fluoroalkyls wherein one or more hydrogen atoms have been replaced by fluorine. In some embodiments, haloalkyls are 1 to about 3 carbons in length (eg, 1 to about 2 carbons in length or 1 carbon in length). The term "haloalkylene" denotes a diradical variant of a haloalkyl, and such diradicals may act as spacers between radicals, other atoms, or between a ring and another functional group.

[035] As used herein, the term "heterocyclyl" refers to a non-aromatic cyclic ring system containing at least one heteroatom in the backbone of the ring system. Heterocyclyls may include several fused rings. Heterocyclyls may or may not be substituted with one or more substituents. In some embodiments, heterocycles have 3-11 members. In six-membered monocyclic heterocycles, the heteroatom(s) is(are) selected from one to three O, N, or S, and where, in the case where the heterocycle is five-membered, it may have one or two heteroatoms selected from O, N, or S. Examples heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl and others. In some embodiments, heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

[036] As used herein, the term "monocyclic heterocyclyl" refers to a single non-aromatic cyclic ring containing at least one heteroatom in the backbone of the ring system. The heterocyclyl may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 3-7 members. In six-membered monocyclic heterocycles, the heteroatom(s) is(are) selected from one to three O, N, or S, and where, in the case where the heterocycle is five-membered, it may have one or two heteroatoms selected from O, N, or S. Examples heterocyclyls include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl and others.

[037] As used herein, the term "bicyclic heterocyclyl" refers to a non-aromatic bicyclic ring system containing at least one heteroatom in the backbone of the ring system. Bicyclic heterocyclyls may or may not be substituted with one or more substituents. In some embodiments, bicyclic heterocycles have 4-11 members with heteroatom(s) selected from one to five O, N, or S. Examples of bicyclic heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1 .0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[ c ]pyrrole , 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane etc.

[038] As used herein, the term "spirocyclic heterocyclyl" refers to a non-aromatic bicyclic ring system containing at least one heteroatom in the framework of the ring system, and with rings connected through only one atom. Spirocyclic heterocyclyls may or may not be substituted with one or more substituents. In some embodiments, spirocyclic heterocycles have 5-11 members with heteroatom(s) selected from one to five O, N, or S. Examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane , 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane , 2,5-diazaspiro[3.6]decane and the like.

[039] The term "substituted" refers to moieties having substituents replacing hydrogen with one or more non-hydrogen atoms in the molecule. It should be understood that "substitution" or "substituted" includes the implicit proviso that such substitution occurs according to the allowable valency of the atom being replaced and the substituent, and that the substitution provides a stable compound, e.g., which does not undergo spontaneous transformation such as rearrangement, cyclization, elimination, etc. d. Substituents may include, for example, -(C _1-9 alkyl) optionally substituted with one or more hydroxyl, -NH ₂ , -NH(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; -(C _1-9 haloalkyl); halide; hydroxyl; carbonyl [such as -C(O)OR and -C(O)R]; thiocarbonyl [such as -C(S)OR, -C(O)SR and -C(S)R]; -(C _1-9 alkoxy) optionally substituted with one or more halide, hydroxyl, -NH ₂ , -NH(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; -OPO(OH) ₂ ; phosphonate [such as -PO(OH) ₂ and -PO(OR') ₂ ]; -OPO(OR')Rʺ;-NRR';-C(O)NRR';-C(NR)NR'R';-C(NR')Rʺ;cyano;nitro;azido;-SH;-SR; -OSO ₂ (OR); sulfonate [such as -SO ₂ (OH) and -SO ₂ (OR)]; -SO ₂ NR'R'; and -SO ₂ R; wherein R, R' and R" are each independently selected from H; -(C _1-9 alkyl); C _6-10 aryl optionally substituted with 1-3 R'''; 5-10 membered heteroaryl having 1 -4 heteroatoms independently selected from N, O and S and optionally substituted with 1-3 R'''; C _3-7 carbocyclyl optionally substituted with 1-3 R'''; and a 3-8 membered heterocyclyl having 1 -4 heteroatoms independently selected from N, O and S and optionally substituted with 1-3 R'''; where each R''' is independently selected from -(C _1-6 alkyl), -(C _1-6 haloalkyl) , halide (for example, F), hydroxyl, -C(O)OR, -C(O)R, -(C _1-6 alkoxy), -NRR', -C(O)NRR' and cyano, each R and R' are independently selected from H and -(C _1-6 alkyl) In some embodiments, the substituent is selected from -(C _1-6 alkyl), -(C _1-6 haloalkyl), halide (e.g., F) , hydroxyl, -C(O)OR, -C(O)R, -(C _1-6 alkoxyl), -NRR', -C(O)NRR' and cyano, with each of R and R' independently selected from H and -(C _1-6 alkyl).

[040] As used herein, when two groups are "attached" or "bonded" to form a "ring", this should be understood to mean that a bond is formed between the two groups and may include replacing a hydrogen atom with one or two groups via a bond, whereby this forms a carbocyclyl, heterocyclyl, aryl or heteroaryl ring. Those skilled in the art will appreciate that such rings can and are easily formed by conventional chemical interactions. In some embodiments, such rings have from 3-7 members, such as 5 or 6 members.

[041] Those skilled in the art will appreciate that some of the structures described herein may be resonance forms or tautomers of compounds that, to a certain extent, may be represented by other chemical structures, even if kinetic; one skilled in the art will appreciate that such structures constitute only a small portion of a sample of such compound(s). Such compounds are expressly contemplated within the scope of the invention, although such resonance forms or tautomers are not presented here.

[042] The compounds described herein may include various stereochemical forms. The compounds also include diastereomers as well as optical isomers, for example, mixtures of enantiomers, including racemic mixtures, as well as individual enantiomers and diastereomers that result from structural asymmetries in some compounds. The separation of individual isomers or the selective synthesis of individual isomers is followed by the use of various methods that are well known to those skilled in the art. Unless otherwise indicated, when a described compound is designated or displayed by a structure without specification of stereochemistry, and it has one or more chiral centers, all possible stereoisomers of the compound are meant to be represented.

[043] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula I in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that prevails. in nature. Examples of isotopes suitable for inclusion in the compounds of the invention are, but are not limited to, isotopes of hydrogen such as ² H (deuterium) and ³ H (tritium), carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine, such as ³⁶ Cl, fluorine such as ¹⁸ F, iodine such as ¹²³ I and ¹²⁵ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P, and sulfur such as ³⁵ S.

[044] The term "use" or "administration" refers to a method of providing a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian, for example, orally, subcutaneously, intravenously, intralymphatic, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonary, vaginal, rectal, ontological, otoneurological, intraocular, subconjunctival, injection into the anterior chamber of the eyeball, introduction into the vitreous body, intraperitoneally, intrathecally, intracystically, intrapleurally, by washing the wound, intrabuccal, intraperitoneally, intraarticular, intraearly, intrabronchial, intracapsular, intrameningeally, by inhalation, endotracheal or endobronchial instillation, direct instillation into the lung cavity, intraspinal, intrasynovial, intrathoracic injection, lavage during thoracostomy, epidural, introduction into the tympanic cavity, intracisternally, intra ravascularly, intraventricularly, intraosseously, by lavage of infected bone, or by application as part of any mixture with a prosthesis. The route of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the area of the disease, the type of disease, and the severity of the disease.

[045] " Diagnostic", as used herein, is a compound, method, system, or device that helps identify or characterize a healthy or diseased condition. The diagnostic tool can be used in standard studies known from the prior art.

[046] The term "mammal" is used in its usual biological sense. Thus, it includes humans, cattle, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, goats, and non-human primates, but also includes many other species.

[047] The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable diluent", or "pharmaceutically acceptable excipient" includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, isotonic and absorbent delay agents, and the like, which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional vehicles or substances are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. Additional ingredients may also be included in the compositions. In addition, various adjuvants, such as those commonly used in the art, may be included. These and other similar compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, NJ. Analysis of the inclusion of various components in pharmaceutical compositions is described, for example, in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[048] The term "pharmaceutically acceptable salt" refers to salts that retain the biological efficacy and properties of the compounds provided herein, and which are not biologically or otherwise undesirable. In many cases, the compounds described herein are capable of forming acid and/or base salts due to the presence of amino groups and/or carboxyl groups or groups similar to them. Many such salts are known in the art, for example as described in WO 87/05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid , cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as, for example, isopropylamine, trimethylamine, diethylamine. , triethylamine, tripropylamine and ethanolamine.

[049] As used herein, the term "patient" refers to a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the patient is a human.

[050] A "therapeutically effective amount" of a compound as defined herein is one that is sufficient to achieve the desired physiological effect and may vary depending on the nature and severity of the disease state and the efficacy of the compound. A "therapeutically effective amount" also includes one or more compounds of Formula I in combination with one or more other substances that are effective in the treatment of the diseases and/or conditions described herein. The combination of compounds may be a synergistic combination. Synergy, as described, for example, in Chou and Talalay, Advances in Enzyme Regulation (1984), 22 , 27-55, occurs when the effect of the compounds administered in combination is greater than the additive effect of the compounds when administered singly as a separate tool. Typically, the synergistic effect is most pronounced at suboptimal concentrations of the compounds. It should be borne in mind that other concentrations can be used for prophylaxis than those used for the treatment of active disease. Such an amount may also depend on the patient's height, weight, sex, age and medical history.

[051] The therapeutic effect alleviates, to some extent, one or more symptoms of the disease.

[052] As used herein, the terms "treat", "treatment", or "treating" refer to the administration of a compound or pharmaceutical composition of the present invention for therapeutic purposes. The term "therapeutic treatment" refers to the administration of a treatment to a patient already suffering from a disease to thereby bring about a therapeutically beneficial effect, such as alleviating the intensity of existing symptoms, reducing the underlying metabolic causes of the symptoms, delaying or preventing the further development of the disorder, and/or reducing the severity of the symptoms that develop. will be expected or expected.

Connections

[053] The compounds and compositions described herein can be used as antiproliferative agents, for example, antitumor and antiangiogenesis agents, and/or as inhibitors of the Wnt signaling pathway, for example, to treat diseases or disorders associated with aberrant Wnt - signaling. In addition, the compounds can be used as inhibitors of one or more kinases, kinase receptors or kinase complexes. Such compounds and compositions are also useful in controlling cell proliferation, cell differentiation and/or apoptosis.

[054] Some embodiments of the present invention include compounds of formula I :

or their salts, pharmaceutically acceptable salts or prodrugs.

[055] In some embodiments, R ¹ , R ² , R ⁴ and R ⁵ are independently selected from the group consisting of H, halide, unsubstituted -(C _1-3 haloalkyl) and unsubstituted -(C _1-3 alkyl);

[056] In some embodiments, R ¹ , R ² , R ⁴ and R ⁵ are independently selected from the group consisting of H, halide, amino, unsubstituted -(C _1-3 haloalkyl) and unsubstituted -(C _1-3 alkyl) .

[057] In some embodiments, R ¹ , R ² , R ⁴ and R ⁵ are independently selected from the group consisting of H and a halide.

[058] In some embodiments, R ¹ , R ² , R ⁴ and R ⁵ are independently selected from the group consisting of H and F.

[059] In some embodiments, R ¹ , R ² , R ⁴ , and R ⁵ are each H.

[060] In some embodiments, R ¹ is F and R ² , R ⁴ and R ⁵ are each H.

[061] In some embodiments, R ² is F and R ¹ , R ⁴ and R ⁵ are each H.

[062] In some embodiments, R ⁴ is F and R ¹ , R ² and R ⁵ are each H.

[063] In some embodiments, R ⁵ is F and R ¹ , R ² and R ⁴ are each H.

[064] In some embodiments, R ³ is a 5-membered heteroaryl ring, optionally substituted as defined elsewhere herein.

[065] In some embodiments, R ³ is a 5-membered heteroaryl ring optionally substituted with 1-4 (eg, 1-3, 1-2, 1) R ⁴⁵ ;

[066] In some embodiments, R ³ is selected from the group consisting of: furanyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R ⁴⁵ , thiophenyl optionally substituted with 1-4 (e.g., 1 -3, 1-2, 1) R ⁴⁵ , pyrrolyl, optionally substituted with 1-4 (eg 1-3, 1-2, 1) R ⁴⁵ ,

where each m is independently 1 to 4 (eg, 1-3, 1-2, 1).

[067] In some embodiments, R ³ is selected from the group consisting of:

where each of R ⁷ -R ³⁵ independently represents a substituent, as defined elsewhere in this document, or a single bond linking R ³ to the isoquinoline ring; where only one of R ⁷ -R ¹⁰ (if present) is a bond, only one of R ¹¹ -R ¹⁴ (if present) is a bond, only one of R ¹⁵ -R ¹⁷ (if , if present) is a bond, only one of R ¹⁸ -R ²⁰ (if present) is a bond, only one of R ²¹ -R ²³ (if present) is a bond, only one of R ²⁴ -R ²⁶ (if present) is a bond, only one of R ²⁷ -R ²⁹ (if present) is a bond, only one of R ³⁰ -R ³¹ (if present) is is a bond, only one of R ³² -R ³³ (if present) is a bond, and only one of R ³⁴ -R ³⁵ (if present) is a bond; for purposes of clarification, any of the nitrogen atoms attached to R ⁷ , R ¹¹ , R ¹⁵ , R ¹⁸ or R ²¹ can serve as the point of attachment of R ³ to the isoquinoline ring; similarly, any of the carbon atoms attached to R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁶ , R ¹⁷ , R ¹⁹ , R ²⁰ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ or R ³⁵ may serve as the point of attachment of R ³ to the isoquinoline ring.

[068] In some embodiments, R ⁶ is selected from the group consisting of α-aryl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R ³⁶ , and 6-membered heteroaryl optionally substituted 1-6 (eg 1-5, 1-4, 1-3, 1-2, 1) R ³⁷ .

[069] In some embodiments, R ⁶ is selected from the group consisting of -phenyl substituted with 1-5 R ³⁶ , -(C _1-3 alkylene) _p pyridinyl optionally substituted with 1-6 R ³⁷ , and 6-10 membered heteroaryl optionally substituted with 1-6 R ³⁷ ; where the carbonyl of formula I is attached to the aromatic ring of heteroaryl; where -(C _1-3 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein;

[070] In some embodiments, R ⁷ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1 -4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[071] In some embodiments, R ⁷ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , - (C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[072] In some embodiments, R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1 -8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[073] In some embodiments, R ⁸ , R ⁹ and R ¹⁰ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C( =O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[074] In some embodiments, one of R ⁷ and R ⁸ , R ⁸ and R ⁹ , or R ⁹ and R ¹⁰ are taken together to form a ring that is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 (e.g. , 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴¹ .

[075] In some embodiments, R ¹¹ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1 -4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[076] In some embodiments, R ¹¹ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , - (C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[077] In some embodiments, R ¹² , R ¹³ and R ¹⁴ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1 -8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[078] In some embodiments, R ¹² , R ¹³ and R ¹⁴ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C( =O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[079] In some embodiments, one of R ¹¹ and R ¹² , R ¹² and R ¹³ , or R ¹⁴ and R ¹¹ are taken together to form a ring that is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 (e.g. , 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ and -carbocyclyl optionally substituted with 1-12 (for example, 1 -11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴¹ .

[080] In some embodiments, R ¹⁵ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1 -4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[081] In some embodiments, R ¹⁵ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , - (C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[082] In some embodiments, R ¹⁶ and R ¹⁷ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6 , 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[083] In some embodiments, R ¹⁶ and R ¹⁷ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O) N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[084] In some embodiments, one of R ¹⁵ and R ¹⁶ or R ¹⁶ and R ¹⁷ are taken together to form a ring that is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1- 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10 , 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴¹ .

[085] In some embodiments, R ¹⁸ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1 -4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[086] In some embodiments, R ¹⁸ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , - (C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[087] In some embodiments, R ¹⁹ and R ²⁰ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6 , 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[088] In some embodiments, R ¹⁹ and R ²⁰ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O) N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[089] In some embodiments, one of R ¹⁸ and R ¹⁹ , or R ¹⁸ and R ²⁰ , are taken together to form a heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ .

[090] In some embodiments, R ²¹ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1 -4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[091] In some embodiments, R ²¹ is selected from the group consisting of a single bond, H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene)OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , - (C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[092] In some embodiments, R ²² and R ²³ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6 , 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[093] In some embodiments, R ²² and R ²³ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O) N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[094] In some embodiments, R ²² and R ²³ are taken together to form a ring that is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8 , 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴¹ .

[095] In some embodiments, R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1 -8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[096] In some embodiments, R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C( =O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[097] In some embodiments, one of R ²⁴ and R ²⁵ or R ²⁵ and R ²⁶ are taken together to form a ring that is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1- 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴¹ .

[098] In some embodiments, R ²⁷ , R ²⁸ and R ²⁹ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1 -8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[099] In some embodiments, R ²⁷ , R ²⁸ and R ²⁹ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C( =O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0100] In some embodiments, R ²⁷ and R ²⁸ are taken together to form a ring that is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8 , 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴¹ .

[0101] In some embodiments, R ³⁰ and R ³¹ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6 , 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0102] In some embodiments, R ³⁰ and R ³¹ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O) N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0103] In some embodiments, R ³⁰ and R ³¹ are taken together to form a ring that is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8 , 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴¹ .

[0104] In some embodiments, R ³² and R ³³ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6 , 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0105] In some embodiments, R ³² and R ³³ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O) N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0106] In some embodiments, R ³⁴ and R ³⁵ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6 , 1-5, 1-4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0107] In some embodiments, R ³⁴ and R ³⁵ are independently selected from the group consisting of single bond, H, halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O) N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ , and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0108] In some embodiments, R ³⁴ and R ³⁵ are taken together to form a ring that is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8 , 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴¹ .

[0109] In some embodiments, each R ³⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -XR ⁴² , -C(O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1- 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 (for example , 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0110] In some embodiments, each R ³⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -XR ⁴² , -C(=O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p N(R ⁵⁰ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0111] In some embodiments, each R ³⁷ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -XR ⁴² , -C(O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1- 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 (for example , 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0112] In some embodiments, each R ³⁷ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -XR ⁴² , -C(=O)N(R ⁴⁷ ) ₂ , -(C _1-4 alkylene) _p N(R ⁵⁰ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0113] In some embodiments, each R ³⁸ is selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted - (C _1-5 haloalkyl), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 (e.g. 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0114] In some embodiments, each R ³⁹ is selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted - (C _1-5 haloalkyl), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 (e.g. 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0115] In some embodiments, each R ⁴⁰ is selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted - (C _1-5 haloalkyl), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 (e.g. 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0116] In some embodiments, each R ⁴¹ is selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted - (C _1-5 haloalkyl) and -CN.

[0117] In some embodiments, each R ⁴² is selected from the group consisting of unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl), ), -(C _1-4 alkylene) _p aryl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1-4 , 1-3, 1-2, 1) R ⁴⁶ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-12 (e.g. 1-11, 1-10, 1-9, 1-8, 1 -7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 (e.g. 1- 11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0118] In some embodiments, each R ⁴² is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl), -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p aryl optionally substituted with 1-10 R ⁴⁶ , -(C _1-4 alkylene ) _p heterocyclyl optionally substituted with 1-12 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0119] In some embodiments, each R ⁴³ is selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted - (C _1-5 haloalkyl), -CN and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 (e.g. 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0120] In some embodiments, each R ⁴³ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl), -CN, -OH, -C(=O)R ⁵¹ , -N(R ⁵⁰ ) ₂ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-12 R ⁴⁴ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0121] In some embodiments, each R ⁴⁴ is selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted - (C _1-5 haloalkyl) and -CN.

[0122] In some embodiments, each R ⁴⁵ is independently selected from the group consisting of H, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 (e.g. 1-9, 1-8, 1-7, 1-6, 1-5, 1- 4, 1-3, 1-2, 1) R ³⁸ , and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6 , 1-5, 1-4, 1-3, 1-2, 1) R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0123] In some embodiments, each R ⁴⁵ is independently selected from the group consisting of halide, unsubstituted -(C _1-9 alkyl), unsubstituted -(C _2-9 alkenyl), unsubstituted -(C _2-9 alkynyl), unsubstituted -(C _1-9 haloalkyl), -(C _1-4 alkylene) _p N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p OR ⁴⁹ , -C(=O)N(R ⁴⁸ ) ₂ , -(C _1-4 alkylene) _p heterocyclyl optionally substituted with 1-10 R ³⁸ and -carbocyclyl optionally substituted with 1-12 R ³⁹ ; where each -(C _1-4 alkylene) is independently optionally substituted with one or more substituents as defined elsewhere herein.

[0124] In some embodiments, two adjacent R ⁴⁵ groups are taken together to form a ring that is selected from the group consisting of α-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1- 6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴⁰ and -carbocyclyl optionally substituted with 1-12 (for example, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R ⁴¹ .

[0125] In some embodiments, each R ⁴⁶ is independently selected from the group consisting of halide, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl) and -CN.

[0126] In some embodiments, each R ⁴⁷ is independently selected from the group consisting of unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -( C _1-5 haloalkyl).

[0127] In some embodiments, each R ⁴⁷ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl).

[0128] In some embodiments, each R ⁴⁸ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl).

[0129] In some embodiments, each R ⁴⁹ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), and unsubstituted -(C _1-5 haloalkyl).

[0130] In some embodiments, each R ⁵⁰ is independently selected from the group consisting of H, unsubstituted -(C _1-5 alkyl), unsubstituted -(C _2-5 alkenyl), unsubstituted -(C _2-5 alkynyl), unsubstituted -(C _1-5 haloalkyl) and -(C _1-4 alkylene)N(R ⁴⁸ ) ₂ ; where -(C _1-4 alkylene) is optionally substituted with one or more substituents as defined elsewhere herein.

[0131] In some embodiments, each R ⁵¹ is heteroaryl optionally substituted with 1-6 R ⁵² .

[0132] In some embodiments, each R ⁵² is heterocyclyl optionally substituted with 1-10 R ⁴⁶ .

[0133] In some embodiments, heterocyclyl in -(C _1-4 alkylene) _p heterocyclyl is optionally substituted with 1-10 R ³⁸ .

[0134] In some embodiments, -(C _1-4 alkylene) in -(C _1-4 alkylene) _p heterocyclyl is optionally substituted with 1-10 R ³⁸ .

[0135] In some embodiments, heterocyclyl in -(C _1-4 alkylene) _p heterocyclyl is optionally substituted with 1-10 R ⁴³ .

[0136] In some embodiments, -(C _1-4 alkylene) in -(C _1-4 alkylene) _p heterocyclyl is optionally substituted with 1-10 R ⁴³ .

[0137] In some embodiments, the carbocyclyl in -(C _1-4 alkylene) _p carbocyclyl is optionally substituted with 1-12 R ⁴⁴ .

[0138] In some embodiments, -(C _1-4 alkylene) in -(C _1-4 alkylene) _p carbocyclyl is optionally substituted with 1-12 R ⁴⁴ .

[0139] In some embodiments, the aryl in -(C _1-4 alkylene) _p aryl is optionally substituted with 1-10 R ⁴⁶ .

[0140] In some embodiments, -(C _1-4 alkylene) in -(C _1-4 alkylene) _p aryl is optionally substituted with 1-10 R ⁴⁶ .

[0141] In some embodiments, -(C _1-4 alkylene) is optionally substituted with 1-5 halides or 1-5 unsubstituted -(C _1-3 alkyl).

[0142] In some embodiments, -(C _1-4 alkylene) is substituted with 1-2 fluorine atoms.

[0143] In some embodiments, -(C _1-4 alkylene) is substituted with 1-2 methyls.

[0144]

[0145] In some embodiments, each X is selected from the group consisting of O, S, and NH.

[0146] In some embodiments, each X is selected from the group consisting of O, S and NR ⁴⁸ .

[0147] In some embodiments, each X is selected from the group consisting of O and S.

[0148] In some embodiments, each X is selected from the group consisting of O and NH.

[0149] In some embodiments, X is O.

[0150] In some embodiments, X is S.

[0151] In some embodiments, X is NH.

[0152] In some embodiments, X is NR ⁴⁸ .

[0153] In some embodiments, X is NMe.

[0154] In some embodiments, each Y is selected from the group consisting of O and S.

[0155] In some embodiments, Y is O.

[0156] In some embodiments, Y is S.

[0157] In some embodiments, each m is independently 1 to 4 (eg, 1-3, 1-2, 1).

[0158] In some embodiments, each n is independently 1 to 3 (eg, 0-2, 0-1, 0).

[0159] In some embodiments, each p is independently 0 or 1.

[0160] In some embodiments, each q is independently 0 to 12 (e.g., 0-11, 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0).

. [0161] In some embodiments, R ³ is

.

[0162] In some embodiments, R ⁹ is a single bond linking R ³ to an isoquinoline ring, i.e. R ³ has the following formula:

.

.

, и n равно 1-3. [0163] In some embodiments, R ³ is

, and n is 1-3.

[0164] In some embodiments, R ⁷ is selected from the group consisting of H, unsubstituted -(C _1-3 alkyl), unsubstituted -(C _1-2 haloalkyl), and -(C _3-4 carbocyclyl), optionally substituted with 1- 2 R ³⁹ .

[0165] In some embodiments, R ⁷ is selected from the group consisting of H, methyl, -CF ₃ and cyclopropyl optionally substituted with 1-2 R ³⁹ .

[0166] In some embodiments, R ⁷ is selected from the group consisting of H and methyl.

[0167] In some embodiments, R ⁷ is methyl.

[0168] In some embodiments, R ⁷ is -CD ₃ .

[0169] In some embodiments, R ⁸ is selected from the group consisting of H, halide, unsubstituted -(C _1-2 alkyl), unsubstituted -(C _1-2 haloalkyl), and -(C _1-2 alkylene)OR ⁴² .

[0170] In some embodiments, R ⁸ is selected from the group consisting of H, F, methyl, -CF ₃ , -(CH ₂ )OH, and -(CH ₂ )OMe.

[0171] In some embodiments, R ⁸ is selected from the group consisting of H, F, methyl, and -CF ₃ .

[0172] In some embodiments, R ⁸ is selected from the group consisting of H, F, and methyl.

[0173] In some embodiments, R ⁸ is H.

[0174] In some embodiments, R ¹⁰ is selected from the group consisting of H and a halide.

[0175] In some embodiments, R ¹⁰ is selected from the group consisting of H and F.

[0176] In some embodiments, R ¹⁰ is H.

. [0177] In some embodiments, R ³ is

.

[0178] In some embodiments, R ¹² is a single bond linking R ³ to an isoquinoline ring, that is, R ³ has the following formula:

.

.

, и n равно 1-3. [0179] In some embodiments, R ³ is

, and n is 1-3.

[0180] In some embodiments, R ¹¹ is selected from the group consisting of H, unsubstituted -(C _1-3 alkyl), unsubstituted -(C _1-2 haloalkyl), and -(C _3-4 carbocyclyl), optionally substituted with 1- 2 R ³⁹ .

[0181] In some embodiments, R ¹¹ is selected from the group consisting of H, methyl, -CF, and cyclopropyl optionally substituted with 1-2 R ³⁹ .

[0182] In some embodiments, R ¹¹ is selected from the group consisting of H and methyl.

[0183] In some embodiments, R ¹¹ is methyl.

[0184] In some embodiments, R ¹¹ is -CD ₃ .

[0185] In some embodiments, R ¹³ is selected from the group consisting of H and a halide.

[0186] In some embodiments, R ¹³ is selected from the group consisting of H and F.

[0187] In some embodiments, R ¹⁴ is selected from the group consisting of H, halide, unsubstituted -(C _1-2 alkyl), and unsubstituted -(C _1-2 haloalkyl).

[0188] In some embodiments, R ¹⁴ is selected from the group consisting of H, F, methyl, and -CF ₃ .

[0189] In some embodiments, R ¹⁴ is selected from the group consisting of H and methyl.

[0190] In some embodiments, R ¹¹ and R ¹⁴ are both methyl.

. [0191] In some embodiments, R ³ is

.

, и Y представляет собой S. [0192] In some embodiments, R ³ is

, and Y is S.

, и Y представляет собой O. [0193] In some embodiments, R ³ is

, and Y is O.

[0194] In some embodiments, R ²⁷ is a single bond linking R ³ to an isoquinoline ring, that is, R ³ has the following formula:

.

.

. [0195] In some embodiments, R ³ is

.

. [0196] In some embodiments, R ³ is

.

[0197] In some embodiments, R ²⁸ is selected from the group consisting of H and a halide.

[0198] In some embodiments, R ²⁸ is selected from the group consisting of H and F.

[0199] In some embodiments, R ²⁹ is selected from the group consisting of H, halide, unsubstituted -(C _1-2 alkyl), and unsubstituted -(C _1-2 haloalkyl).

[0200] In some embodiments, R ²⁹ is selected from the group consisting of H, F, methyl, and -CF ₃ .

. [0201] In some embodiments, R ³ is

.

, и Х представляет собой S. [0202] In some embodiments, R ³ is

, and X is S.

, и Х представляет собой O. [0203] In some embodiments, R ³ is

, and X is O.

[0204] In some embodiments, R ³³ is a single bond linking R ³ to an isoquinoline ring, that is, R ³ has the following formula:

.

.

. [0205] In some embodiments, R ³ is

.

. [0206] In some embodiments, R ³ is

.

[0207] In some embodiments, R ³² is selected from the group consisting of H, halide, unsubstituted -(C _1-2 alkyl), unsubstituted -(C _1-2 haloalkyl), and -N(R ⁵³ ) ₂ .

[0208] In some embodiments, R ³² is selected from the group consisting of H, F, methyl, -CF ₃ , -NHMe, and -NMe ₂ .

[0209] In some embodiments, R ³² is selected from the group consisting of H and methyl.

[0210] In some embodiments, R ³² is methyl.

. [0211] In some embodiments, R ³ is

.

[0212] In some embodiments, R ²⁰ is a single bond linking R ³ to an isoquinoline ring, that is, R ³ has the following formula:

.

.

. [0213] In some embodiments, R ³ is

.

[0214] In some embodiments, R ¹⁶ is a single bond linking R ³ to an isoquinoline ring, that is, R ³ has the following formula:

.

.

[0215] In some embodiments, R ¹⁷ is a single bond linking R ³ to an isoquinoline ring, that is, R ³ has the following formula:

.

.

[0216] In some embodiments, R ¹⁵ is selected from the group consisting of H and unsubstituted -(C _1-2 alkyl).

[0217] In some embodiments, R ¹⁵ is selected from the group consisting of H and methyl.

[0218] In some embodiments, R ¹⁵ is methyl.

[0219] In some embodiments, R ¹⁵ is -CD ₃ .

, и n равно 1-3. [0220] In some embodiments, R ³ is

, and n is 1-3.

[0221] In some embodiments, R ¹⁸ is selected from the group consisting of H, unsubstituted -(C _1-3 alkyl), unsubstituted -(C _1-2 haloalkyl), and -(C _3-4 carbocyclyl), optionally substituted with 1- 2 R ³⁹ .

[0222] In some embodiments, R ¹⁸ is selected from the group consisting of H, methyl, -CF ₃ and cyclopropyl optionally substituted with 1-2 R ³⁹ .

[0223] In some embodiments, R ¹⁹ is selected from the group consisting of H, halide, unsubstituted -(C _1-2 alkyl), and unsubstituted -(C _1-2 haloalkyl).

[0224] In some embodiments, R ¹⁹ is selected from the group consisting of H, F, methyl, and -CF ₃ .

[0225] In some embodiments, R ³⁹ is selected from the group consisting of halide, unsubstituted -(C _1-3 alkyl), and unsubstituted -(C _1-2 haloalkyl).

[0226] In some embodiments, R ³⁹ is selected from the group consisting of F, methyl, and -CF ₃ .

[0227] In some embodiments, R ⁴⁰ is selected from the group consisting of H and unsubstituted -(C _1-2 alkyl).

[0228] In some embodiments, R ⁴⁰ is selected from the group consisting of H and methyl.

[0229] In some embodiments, R ⁶ is selected from the group consisting of α-aryl substituted with 1-5 R ³⁶ and 6-membered heteroaryl optionally substituted with 1-6 R ³⁷ .

[0230] In some embodiments, R ⁶ is selected from the group consisting of -phenyl substituted with 1-5 R ³⁶ and -pyridinyl optionally substituted with 1-4 R ³⁷ .

[0231] In some embodiments, R ⁶ is -phenyl substituted with one R ³⁶ .

[0232] In some embodiments, R ⁶ is -pyridinyl substituted with one R ³⁷ .

[0233] In some embodiments, R ⁶ is -pyridin-2-yl substituted with one R ³⁷ .

[0234] In some embodiments, R ⁶ is -pyridin-3-yl substituted with one R ³⁷ .

[0235] In some embodiments, R ⁶ is -pyridin-4-yl substituted with one R ³⁷ .

[0236] In some embodiments, R ³⁶ is selected from the group consisting of halide, unsubstituted -(C _1-3 alkyl), unsubstituted -(C _1-3 haloalkyl), -OR ⁴² , -NHR ⁴² , -C(O) N(C _1-3 alkyl) ₂ , -C(O)NH(C _1-3 alkyl), -heterocyclyl optionally substituted with 1-2 R ⁴³ , -(CH ₂ )heterocyclyl optionally substituted with 1-2 R ⁴³ , -(C _3-4 carbocyclyl) optionally substituted with 1-2 R ⁴⁴ , and -(CH ₂ )(C _3-4 carbocyclyl) optionally substituted with 1-2 R ⁴⁴ .

[0237] In some embodiments, R ³⁷ is selected from the group consisting of halide, unsubstituted -(C _1-3 alkyl), unsubstituted -(C _1-3 haloalkyl), -OR ⁴² , -NHR ⁴² , -C(O) N(C _1-3 alkyl) ₂ , -C(O)NH(C _1-3 alkyl), -heterocyclyl optionally substituted with 1-2 R ⁴³ , -(CH ₂ )heterocyclyl optionally substituted with 1-2 R ⁴³ , -(C _3-4 carbocyclyl) optionally substituted with 1-2 R ⁴⁴ , and -(CH ₂ )(C _3-4 carbocyclyl) optionally substituted with 1-2 R ⁴⁴ .

[0238] In some embodiments, heterocyclyl is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl.

[0239] In some embodiments, R ⁴² is selected from the group consisting of unsubstituted -(C _1-3 alkyl) and unsubstituted -(C _1-3 haloalkyl), -CH ₂ phenyl, optionally substituted with 1-2 halides, -heterocyclyl, optionally substituted with one -(C _1-3 alkyl), -CH ₂ heterocyclyl, optionally substituted with one -(C _1-3 alkyl), unsubstituted -carbocyclyl and unsubstituted -CH ₂ carbocyclyl.

[0240] In some embodiments, R ⁴² is selected from the group consisting of methyl, ethyl, propyl, isopropyl, -CHF ₂ , -CF ₃ and -heterocyclyl optionally substituted with one Me.

и

. [0241] In some embodiments, R ⁴² is selected from the group consisting of methyl, ethyl, propyl, isopropyl, -CHF ₂ , -CF ₃ ,

and

.

[0242] In some embodiments, R ⁴³ is selected from the group consisting of halide, unsubstituted -(C _1-2 alkyl), unsubstituted -(C _1-2 haloalkyl), and -carbocyclyl optionally substituted with 1-2 halides.

[0243] In some embodiments, R ⁴³ is selected from the group consisting of F, methyl, ethyl, -CF ₃ and cyclopropyl.

[0244] In some embodiments, R ⁴⁴ is selected from the group consisting of halide, unsubstituted -(C _1-2 alkyl), and unsubstituted -(C _1-2 haloalkyl).

[0245] In some embodiments, R ⁴⁴ is selected from the group consisting of F, methyl, ethyl, -CF ₃ .

[0246] In some embodiments, R ³⁶ is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, -O(C _1-3 alkyl), -O(C _1-3 haloalkyl),

[0247] In some embodiments, R ³⁷ is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, -O(C _1-3 alkyl), -O(C _1-3 haloalkyl),

[0248] In some embodiments, R ³ is selected from the group consisting of:

и

,

and

,

where Y is S or O and R ⁶ is -aryl substituted with 1-5 R ³⁶ .

[0249] In some embodiments, R ³ is selected from the group consisting of:

и

,

and

,

where Y is S or O and R ⁶ is a 6-membered heteroaryl optionally substituted with 1-6 R ³⁷ .

[0250] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -фенил, замещенный 1-5 R³⁶.

and

, and R ⁶ is -phenyl substituted with 1-5 R ³⁶ .

[0251] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -пиридинил, необязательно замещенный 1-4 R³⁷.

and

, and R ⁶ is -pyridinyl optionally substituted with 1-4 R ³⁷ .

[0252] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -фенил, замещенный одним R³⁶.

and

, and R ⁶ is -phenyl substituted with one R ³⁶ .

[0253] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -пиридин-2-ил, замещенный одним R³⁷.

and

, and R ⁶ is -pyridin-2-yl substituted with one R ³⁷ .

[0254] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -пиридин-3-ил, замещенный одним R³⁷.

and

, and R ⁶ is -pyridin-3-yl substituted with one R ³⁷ .

[0255] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -пиридин-4-ил, замещенный одним R³⁷.

and

, and R ⁶ is -pyridin-4-yl substituted with one R ³⁷ .

[0256] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -фенил, замещенный одним R³⁶; и R³⁶ выбран из группы, состоящей из F, метила, этила, н-пропила, изопропила, -O(C_1-3 алкил), -O(C_1-3 галогеналкил),

и

.

and

, and R ⁶ is -phenyl substituted with one R ³⁶ ; and R ³⁶ is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, -O(C _1-3 alkyl), -O(C _1-3 haloalkyl),

and

.

[0257] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -пиридин-2-ил, замещенный одним R³⁷; и R³⁷ выбран из группы, состоящей из F, метила, этила, н-пропила, изопропила, -O(C_1-3 алкил), -O(C_1-3 галогеналкил),

и

.

and

, and R ⁶ is -pyridin-2-yl substituted with one R ³⁷ ; and R ³⁷ is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, -O(C _1-3 alkyl), -O(C _1-3 haloalkyl),

and

.

[0258] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -пиридин-3-ил, замещенный одним R³⁷; и R³⁷ выбран из группы, состоящей из F, метила, этила, н-пропила, изопропила, -O(C_1-3 алкил), -O(C_1-3 галогеналкил),

и

.

and

, and R ⁶ is -pyridin-3-yl substituted with one R ³⁷ ; and R ³⁷ is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, -O(C _1-3 alkyl), -O(C _1-3 haloalkyl),

and

.

[0259] In some embodiments, R ³ is selected from the group consisting of:

и

, и R⁶ представляет собой -пиридин-4-ил, замещенный одним R³⁷; и R³⁷ выбран из группы, состоящей из F, метила, этила, н-пропила, изопропила, -O(C_1-3 алкил), -O(C_1-3 галогеналкил),

и

.

and

, and R ⁶ is -pyridin-4-yl substituted with one R ³⁷ ; and R ³⁷ is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, -O(C _1-3 alkyl), -O(C _1-3 haloalkyl),

and

.

[0260] In some embodiments, R ³ is selected from the group consisting of:

, R⁶ представляет собой -фенил, замещенный одним R³⁶; и R³⁶ выбран из группы, состоящей из F, метила, -O(C_1-3 алкил), -O(C_1-3 галогеналкил),

и

.

, R ⁶ is -phenyl substituted with one R ³⁶ ; and R ³⁶ is selected from the group consisting of F, methyl, -O(C _1-3 alkyl), -O(C _1-3 haloalkyl),

and

.

[0261] In some embodiments, R ³ is selected from the group consisting of:

, R⁶ представляет собой -пиридин-2-ил, замещенный одним R³⁷; и R³⁷ выбран из группы, состоящей из

, R ⁶ is -pyridin-2-yl substituted with one R ³⁷ ; and R ³⁷ is selected from the group consisting of

и

.

and

.

[0262] In some embodiments, R ³ is selected from the group consisting of:

, R⁶ представляет собой -пиридин-3-ил, замещенный одним R³⁷; и R³⁷ выбран из группы, состоящей из

, R ⁶ is -pyridin-3-yl substituted with one R ³⁷ ; and R ³⁷ is selected from the group consisting of

и

.

and

.

[0263] In some embodiments, R ³ is selected from the group consisting of:

, R⁶ представляет собой -пиридин-4-ил, замещенный одним R³⁷; и R³⁷ выбран из группы, состоящей из

и

.

, R ⁶ is -pyridin-4-yl substituted with one R ³⁷ ; and R ³⁷ is selected from the group consisting of

and

.

, R⁶ представляет собой -пиридин-3-ил, замещенный одним R³⁷; и R³⁷ выбран из группы, состоящей из [0264] In some embodiments, R ³ is selected from the group consisting of:

, R ⁶ is -pyridin-3-yl substituted with one R ³⁷ ; and R ³⁷ is selected from the group consisting of

и

.

and

.

[0265] In some embodiments, R ³ is selected from the group consisting of:

, R⁶ представляет собой -пиридин-4-ил, замещенный одним R³⁷; и R³⁷ выбран из группы, состоящей из

и

.

, R ⁶ is -pyridin-4-yl substituted with one R ³⁷ ; and R ³⁷ is selected from the group consisting of

and

.

, R⁶ выбран из группы, состоящей из -фенила, необязательно замещенного 1-2 R³⁶, и -(C_1-2алкилен)_pпиридинила, необязательно замещенного 1-2 R³⁷. [0266] In some embodiments, R ³ is selected from the group consisting of:

, R ⁶ is selected from the group consisting of -phenyl optionally substituted with 1-2 R ³⁶ and -(C _1-2 alkylene) _p pyridinyl optionally substituted with 1-2 R ³⁷ .

, R⁶ выбран из группы, состоящей из -фенила, замещенного 1-2 R³⁶, и -пиридинила, замещенного 1-2 R³⁷, и R³⁶ выбран из группы, состоящей из -XR⁴², -(C_1-4 алкилен)_pгетероциклила, необязательно замещенного 1-2 R⁴³, и -(C_1-4 алкилен)_pкарбоциклила, необязательно замещенного 1-2 R⁴⁴, и R³⁷ выбран из группы, состоящей из -XR⁴², -(C_1-4 алкилен)_pгетероциклила, необязательно замещенного 1-2 R⁴³, и -(C_1-4 алкилен)_pкарбоциклила, необязательно замещенного 1-2 R⁴⁴. [0267] In some embodiments, R ³ is selected from the group consisting of:

, R ⁶ is selected from the group consisting of -phenyl substituted with 1-2 R ³⁶ and -pyridinyl substituted with 1-2 R ³⁷ , and R ³⁶ is selected from the group consisting of -XR ⁴² , -(C _1-4 alkylene ) _p heterocyclyl optionally substituted with 1-2 R ⁴³ , and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-2 R ⁴⁴ , and R ³⁷ is selected from the group consisting of -XR ⁴² , -(C _{1- 4} alkylene) _p heterocyclyl optionally substituted with 1-2 R ⁴³ ; and -(C _1-4 alkylene) _p carbocyclyl optionally substituted with 1-2 R ⁴⁴ .

, R⁶ выбран из группы, состоящей из -фенила, замещенного 1 R³⁶, и -пиридинила, замещенного 1 R³⁷, и R³⁶ выбран из группы, состоящей из -Xгетероциклила, необязательно замещенного 1-2 R⁴³, -гетероциклила, необязательно замещенного 1-2 R⁴³, и R³⁷ выбран из группы, состоящей из -Xгетероциклила, необязательно замещенного 1-2 R⁴³, -гетероциклила, необязательно замещенного 1-2 R⁴³. [0268] In some embodiments, R ³ is selected from the group consisting of:

, R ⁶ is selected from the group consisting of -phenyl substituted with 1 R ³⁶ , and -pyridinyl substituted with 1 R ³⁷ , and R ³⁶ is selected from the group consisting of -Xheterocyclyl optionally substituted with 1-2 R ⁴³ , -heterocyclyl, optionally substituted with 1-2 R ⁴³ , and R ³⁷ is selected from the group consisting of -Xheterocyclyl optionally substituted with 1-2 R ⁴³ , -heterocyclyl optionally substituted with 1-2 R ⁴³ .

, R⁶ представляет собой -пиридинил, замещенный 1 R³⁷, и R³⁷ выбран из группы, состоящей из -Xгетероциклила, необязательно замещенного 1-2 R⁴³, -гетероциклила, необязательно замещенного 1-2 R⁴³, и X выбран из группы, состоящей из O, S, -NH. [0269] In some embodiments, R ³ is selected from the group consisting of:

, R ⁶ is -pyridinyl substituted with 1 R ³⁷ , and R ³⁷ is selected from the group consisting of -Xheterocyclyl optionally substituted with 1-2 R ⁴³ , -heterocyclyl optionally substituted with 1-2 R ⁴³ , and X is selected from the group, consisting of O, S, -NH.

[0270] Exemplary compounds of formula ( I ) are shown in Table 1.

Table 1 one

2

3

four

5

6

7

eight

9

ten

eleven

12

13

fourteen

fifteen

16

17

eighteen

19

twenty

21

22

23

24

25

26

27

28

29

thirty

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

fifty

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

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Introduction and pharmaceutical compositions

[0271] Some embodiments include pharmaceutical compositions comprising: (a) a therapeutically effective amount of a compound provided herein, or its corresponding enantiomer, diastereoisomer, or tautomer, or a pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.

[0272] The compounds provided herein may also be used in combination (given together or sequentially) with other known agents.

[0273] Non-limiting examples of diseases that can be treated by combining a compound of formula ( I ) with other known agents are colon and rectal cancer, ovarian cancer, retinitis pigmentosa, macular degeneration, diabetic retinopathy, idiopathic pulmonary fibrosis/pulmonary fibrosis, and osteoarthritis.

[0274] In some embodiments, colon and rectal cancer can be treated with a combination of a compound of formula ( I ) and one or more of the following drugs: 5-fluorouracil (5-FU), which is often administered with the vitamin-like drug leucovorin (also referred to as folinic acid ); capecitabine (Xeloda®), irinotecan (Camptosar®), oxaliplatin (Eloxatin®). Examples of combinations of such drugs that can also be combined with a compound of any formula ( I ) are FOLFOX (5-FU, leucovorin and oxaliplatin), FOLFIRI (5-FU, leucovorin and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin and irinotecan) and CareOx (capecitabine and oxaliplatin). In the case of rectal cancer, chemotherapy with 5-FU or capecitabine combined with radiation (neoadjuvant treatment) may be given before surgery.

[0275] In some embodiments, ovarian cancer can be treated with a combination of a compound of formula ( I ) and one or more of the following drugs: topotecan, liposomal doxorubicin (doxil®), gemcitabine (Gemzar®), cyclophosphamide (Cytoxan®), vinorelbine (navelbin® ), ifosfamide (ifex®), etoposide (VP-16), altertamine (hexalen®), capecitabine (Xeloda®), irinotecan (CPT-11, camptosar®), melphalan, pemetrexed (Alimta®), and albumin-bound paclitaxel (nabpaclitaxel, abraxane®). Examples of combinations of such drugs that can also be combined with a compound of formula ( I ) are TIP (paclitaxel [taxol], ifosfamide and cisplatin), VeIP (vinblastine, ifosfamide and cisplatin) and VIP (etoposide [VP-16], ifosfamide and cisplatin).

[0276] In some embodiments, a compound of formula ( I ) can be used to treat cancer in combination with any of the following: ( a ) hormone replacement therapy, such as aromatase inhibitors, LHRH [luteinizing hormone releasing hormone] analogs and inhibitors, and others; ( b ) ablation or embolization procedures such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy, and cryosurgery (cryotherapy); ( c ) chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide; ( d ) chemotherapy using antimetabolites such as azathioprine and mercaptopurine; ( f ) chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (ie vincristine, vinblastine, vinorelbine and vindesine) and taxanes; ( f ) chemotherapy using podophyllotoxin, etoposide, teniposide, and docetaxel; ( g ) chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; ( h ) chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and mitomycin; ( i ) chemotherapy using tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC®, also known as STI-571), gefitinib (Iressa, also known as ZD1839), erlotinib (marketed as TARCEVA®), bortezomib (VELCADE®), tamoxifen , tofacitinib, crizotinib, Bcl-2 inhibitors (eg, obatoclax in clinical trials, ABT-263, and gossypol), PARP inhibitors (eg, iniparib, olaparib in clinical trials), P13K inhibitors (eg, perifosine in phase III trials), inhibitors VEGF receptor 2 (eg, apatinib), AN-152 (AEZS-108), Braf inhibitors (eg, vemurafenib, dabrafenib, and LGX818), MEK inhibitors (eg, trametinib and MEK162), CDK inhibitors (eg, PD-0332991), salinomycin and sorafenib; ( j ) chemotherapy using monoclonal antibodies such as rituximab (marketed as MABTHERA® or RITUXAN®), trastuzumab (Herceptin, also known as ErbB2), cetuximab (marketed as ERBITUX®), and bevacizumab (marketed as Avastin®); and ( k ) radiation therapy.

[0277] In some embodiments, diabetic retinopathy can be treated with a combination of a compound of formula ( I ) and one or more of the following natural supplements: bilberry, pontic butcher's broom, ginkgo, grape seed extract, and pycnogenol (pine bark).

[0278] In some embodiments, idiopathic pulmonary fibrosis/pulmonary fibrosis can be treated with a combination of a compound of formula ( I ) and one or more of the following drugs: pirfenidone (pirfenidone approved for use in 2011 in Europe under the brand name Esbriet®), prednisone, azathioprene, N-acetylcysteine, interferon-γ 1b, bosentan (bosentan is currently being tested in patients with [ The American Journal of Respiratory and Critical Care Medicine (2011), 184(1), 92-9]), Nintedanib (BIBF 1120 and Vargatef ), QAX576 [ British Journal of Pharmacology (2011), 163(1), 141-172], and anti-inflammatory agents such as corticosteroids.

[0279] In some embodiments, a compound of formula ( I ) can be used to treat idiopathic pulmonary fibrosis in combination with any of the following: oxygen therapy, pulmonary rehabilitation, and surgery.

[0280] In some embodiments, a compound of formula ( I ) can be used to treat osteoarthritis in combination with any of the following: ( a ) non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin, and acetaminophen; ( b ) physical therapy; ( c ) injections of corticosteroid drugs; ( d ) injections of hyaluronic acid derivatives (eg hyalgan, synvisc); ( e ) narcotic drugs like codeine; ( f ) in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help relieve pressure on it (such as splints, orthotics, shoe inserts, or other medical devices); ( g ) re-correction of the bone deformity (osteotomy); ( h ) joint replacement (arthroplasty); and ( i ) in combination with the chronic pain class.

[0281] In some embodiments, macular degeneration can be treated with a combination of a compound of formula ( I ) and one or more of the following drugs: bevacizumab (Avastin®), ranibizumab (Lucentis®), pegaptanib (Macugen), aflibercept (Eylea®), verteporfin ( Visudyne®) in combination with photodynamic therapy (PDT) or any of the following: ( a ) in combination with a laser to destroy abnormal blood vessels (photocoagulation) and ( b ) in combination with increased intake of vitamins such as antioxidants and zinc.

[0282] In some embodiments, retinitis pigmentosa can be treated with a combination of a compound of formula ( I ) and one or more of the following drugs: UF-021 (Ocuseva™), vitamin A palmitate, and pikachurin, or with any of the following: (a) with an Argus® II retinal implant; and (b) stem cell therapy and/or gene therapy.

[0283] Administration of the compounds described herein, or their pharmaceutically acceptable salts, may be by any of the accepted routes of administration, including, but not limited to: orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonaryly, vaginally, rectally, ontologically, otoneurologically, intraocularly, subconjunctivally, by injection into the anterior chamber of the eyeball, by injection into the vitreous body, intraperitoneally, intrathecally, intracystically, intrapleurally, by wound lavage, intrabuccal, intraperitoneally, intraarticularly, intraauricularly, intrabronchially, intracapsularly, intrameningeally, by inhalation, endotracheal or endobronchial instillation, direct instillation into the lung cavity, intraspinal, intrasynovial, intrathoracic injection, lavage during thoracostomy, epidural, introduction into the tympanic cavity, intracisternally, intravascularly, intraventricularly, intrakos Obviously, by rinsing the infected bone, or by applying as part of any mixture with a prosthesis. In some embodiments, the implementation of the method of administration includes oral or parenteral administration.

[0284] Compounds of the invention for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions may include solid, semi-solid, liquid, solutions, colloids, liposomes, emulsions, suspensions, complexes, coacervates, and aerosols. Dosage forms may be, for example, tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release forms, or the like. They can be obtained, for example, in the form of solid disks, powders or films by methods such as precipitation, crystallization, grinding, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying or drying. evaporation. Microwave or RF drying can be used for this purpose. The compounds may also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and capsules), transdermal (including electrotransfer) patches, implants, and the like. for prolonged and/or intermittent pulse administration at a pre-set rate.

[0285] The compounds may be administered either alone or in combination with a conventional pharmaceutical carrier, excipient, or the like. Pharmaceutically acceptable excipients include, but are not limited to, ion exchange resins, alumina, aluminum stearate, lecithin, self-emulsifiable drug delivery systems (SEDDS) such as polyethylene glycol 1000-d-α-tocopherol succinate, surfactants used in pharmaceutical dosage forms such as tweens, poloxamers, or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffering agents such as phosphates, tris, glycine, sorbic acid, potassium sorbate, mixtures of partial saturated vegetable fatty glycerides acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene block copolymers and polyoxyprop ilena, and lanolin. Also, to improve the delivery of the compounds described herein, cyclodextrins such as α-, β- and γ-cyclodextrin, or chemically modified derivatives thereof, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, can be advantageously used, or other soluble derivatives. You can get dosage forms or compositions containing the compound described herein, in the range of 0.005%-100% with the rest of the non-toxic carrier. Contemplated compositions may contain 0.001%-100% active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%, in another embodiment 20-80%. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy , 22nd ^Edition (Pharmaceutical Press, London, UK. 2012).

[0286] In one embodiment, the compositions will take the form of a unit dosage form, such as a pill or tablet, and then such a composition may contain, along with the active ingredient, a diluent, such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution, or suspension (eg, in propylene carbonate, vegetable oils, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Also contemplated are unit dosage forms in which the two active ingredients are physically separated, such as granule capsules (or tablets within a capsule) of each drug; bilayer tablets; gelatin capsules with two compartments, etc. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[0287] Liquid pharmaceutically acceptable compositions can be obtained, for example, by dissolving, dispersing, and the like. a compound provided herein and optional pharmaceutical excipients in a carrier (eg, water, saline, aqueous dextrose, glycerol, glycols, ethanol, or the like) to form a solution, colloid, liposomes, emulsion, complexes, coacervate, or suspension. If desired, the pharmaceutical composition may also contain minor amounts of non-toxic excipients such as wetting agents, emulsifiers, cosolvents, solubilizers, pH adjusting buffers and the like (e.g. sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, oleate triethanolamine and the like).

[0288] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 0.25 mg/kg to about 50 mg/kg in humans.

[0289] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 0.25 mg/kg to about 20 mg/kg in humans.

[0290] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 0.50 mg/kg to about 19 mg/kg in humans.

[0291] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is about 0.75 mg/kg to about 18 mg/kg in humans.

[0292] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 1.0 mg/kg to about 17 mg/kg in humans.

[0293] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 1.25 mg/kg to about 16 mg/kg in humans.

[0294] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is about 1.50 mg/kg to about 15 mg/kg in humans.

[0295] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 1.75 mg/kg to about 14 mg/kg in humans.

[0296] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 2.0 mg/kg to about 13 mg/kg in humans.

[0297] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 3.0 mg/kg to about 12 mg/kg in humans.

[0298] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 4.0 mg/kg to about 11 mg/kg in humans.

[0299] In some embodiments, the implementation of the standard dose of the compounds of formula ( I ) is from about 5.0 mg/kg to about 10 mg/kg in humans.

[0300] In some embodiments, the compositions are presented in unit dosage forms suitable for single administration.

[0301] In some embodiments, the compositions are presented in unit dosage forms suitable for twice daily administration.

[0302] In some embodiments, the compositions are presented in unit dosage forms suitable for administration three times a day.

[0303] Injections can be obtained in conventional forms or in the form of liquid solutions, colloids, liposomes, complexes, coacervates or suspensions, in the form of emulsions, or in solid forms suitable for reconstitution in liquid prior to injection. The percentage of the compound contained herein contained in such parenteral compositions is highly dependent on its specific nature, as well as the potency of the compound and the needs of the patient. However, a percentage of the active ingredient ranging from 0.01% to 10% in solution can be used and may be higher if the composition is a solid or suspension, which can then be diluted to the above percentage.

[0304] In some embodiments, the implementation of the composition will include about 0.1-10% of the active substance in solution.

[0305] In some embodiments, the implementation of the composition will include about 0.1-5% of the active substance in solution.

[0306] In some embodiments, the implementation of the composition will include about 0.1-4% of the active substance in solution.

[0307] In some embodiments, the implementation of the composition will include about 0.15-3% of the active substance in solution.

[0308] In some embodiments, the implementation of the composition will include about 0.2-2% of the active substance in solution.

[0309] In some embodiments, compositions are provided in dosage forms suitable for continuous dosing by intravenous infusion over a period of about 1-96 hours.

[0310] In some embodiments, compositions are provided in dosage forms suitable for continuous dosing by intravenous infusion over a period of about 1-72 hours.

[0311] In some embodiments, compositions are provided in dosage forms suitable for continuous dosing by intravenous infusion over a period of about 1-48 hours.

[0312] In some embodiments, compositions are provided in dosage forms suitable for continuous dosing by intravenous infusion over a period of about 1-24 hours.

[0313] In some embodiments, compositions are provided in dosage forms suitable for continuous dosing by intravenous infusion over a period of about 1-12 hours.

[0314] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosing by intravenous infusion over a period of about 1-6 hours.

[0315] In some embodiments, these compositions may be administered by intravenous infusion to a human at doses from about 5 mg/m ² to about 300 mg/m ² .

[0316] In some embodiments, these compositions may be administered by intravenous infusion to a human at doses from about 5 mg/m ² to about 200 mg/m ² .

[0317] In some embodiments, these compositions may be administered by intravenous infusion to a human at doses from about 5 mg/m ² to about 100 mg/m ² .

[0318] In some embodiments, these compositions may be administered by intravenous infusion to a human at doses from about 10 mg/m ² to about 50 mg/m ² .

[0319] In some embodiments, these compositions may be administered by intravenous infusion to a human at doses from about 50 mg/m ² to about 200 mg/m ² .

[0320] In some embodiments, these compositions may be administered by intravenous infusion to a human at doses from about 75 mg/m ² to about 175 mg/m ² .

[0321] In some embodiments, these compositions may be administered by intravenous infusion to a human at doses from about 100 mg/m ² to about 150 mg/m ² .

[0322] It should be noted that, depending on the particular compound and the severity of the condition to be alleviated, concentrations and doses may also vary. It should also be understood that for any particular patient, specific dosing regimens will be adjusted over time to the needs of the patient and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges given herein are by way of example and not intended to limit the scope or practical application of the claimed compositions.

[0323] In one embodiment, the compositions can be administered into the respiratory tract (including nasally and into the lungs), for example, through a nebulizer, metered dose inhalers, nebulizer, aerosol generator, aerosol inhaler, dry powder inhaler, insufflator, instillator, or other suitable device or other suitable method.

[0324] In some embodiments, for nasal inhalation, an aerosol is provided for delivery to the nasal mucosa. For optimal delivery to the nasal cavity, respirable particles of about 5 to about 100 microns are used, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, larger particles are desirable to maximize retention on the nasal mucosa and to minimize or prevent deposition of the administered composition in the lungs. In some embodiments, aerosols are provided for delivery to the lungs by inhalation through the nose or mouth. For delivery to the lungs, inhalable aerodynamic particles smaller than 10 µm (eg, about 1 to about 10 µm) are useful. Respirable particles can be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspension medium), dry pure drug particles, drug included in excipients, liposomes, emulsions, colloid systems, coacervates, drug nanoparticle aggregates, or dry diluent particles that contain drug nanoparticles surrounded by it.

[0325] In some embodiments, compounds of formula ( I ) described herein for respiratory delivery (either systemic or topical) may be administered as aqueous compositions, non-aqueous solutions or suspensions, suspensions or emulsions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates or as dry powders. Aqueous formulations may be aerosolized with liquid nebulizers using either hydraulic or ultrasonic nebulization or modified micropump systems (eg, Aerodose® or AERx® systems fine aerosol inhalers). Propellant-based systems may use suitable pressurized metered dose inhalers (pMDIs). Dry powders can be used in powder inhalation (DPI) devices that are capable of dispersing the drug substance efficiently. The desired particle size and distribution can be obtained by selecting the appropriate device.

[0326] In some embodiments, the compositions of formula ( I ) described herein may be administered to the ear in a variety of ways. For example, you can use a catheter for the round window of the cochlea (see, for example, US patent No. 6440102 and 6648873).

[0327] Alternatively, the compositions can be incorporated into a turunda for use between the outer and middle ear (eg, US Pat. No. 6,120,484) or absorbed onto a collagen sponge or other solid carrier (eg, US Pat. No. 4,164,559).

[0328] If necessary, the compositions of the invention can be included in gel compositions (see, for example, US patent No. 4474752 and 6911211).

[0329] In some embodiments, compounds of formula ( I ) described herein for delivery to the ear may be administered via an implanted pump and needle delivery system directly into the middle or inner ear (cochlea) or through the fine electrode channel of the implant into the cochlea, or alternatively a derived drug delivery channel, such as, but not limited to, a needle, through the temporal bone into the cochlea.

[0330] Other possibilities include pump delivery through a thin film deposited on a multichannel electrode or an electrode with a specially embedded drug delivery channel (pathway) punched into the thin film for this purpose. In other embodiments, the implementation of the acidic or basic compound of formula ( I ) can be delivered through the tank external or internal implanted pumping system.

[0331] Compositions of the invention can also be administered to the ear by tympanic injection into the middle ear, inner ear, or cochlea (see, for example, US Pat. No. 6,377,849 and Serial No. 11/337,815).

[0332] Tympanic injection of therapeutic agents is a method of injecting a therapeutic agent into the region behind the tympanic membrane in the middle ear and/or inner ear. In one embodiment, the compositions described herein are injected directly into the membrane of the round window of the cochlea by injection through the tympanic cavity. In another embodiment, the ear-acceptable ion channel modulator compositions described herein are administered through the membrane of the cochlear window into the inner ear in a manner other than the tympanic cavity. In other embodiments, the composition described herein is administered through the membrane of the round window of the cochlea by operation on the membrane of the window of the cochlea, including the modification of the ridge of the window of the cochlea.

[0333] In some embodiments, compounds of formula ( I ) are included in rectal compositions such as enemas, rectal gels, rectal foams, rectal sprays, suppositories, gelatinous suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides. , as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments) and the like.

[0334] Suppositories for rectal drug administration (either as a solution, colloid, suspension or complex) can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperature but liquid at rectal temperature and will therefore melt or erode/dissolve in the rectum and release the drug. Such materials include cocoa butter, glycinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In suppository form compositions, a low melting wax is first melted, such as, but limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter.

[0335] Solid compositions can be provided in various types of dosage forms, depending on the physico-chemical properties of the drug, the desired dissolution rate, cost factor and other criteria. In one embodiment, the implementation of the solid composition is a separate unit. This means that one unit dose of the drug is enclosed in a separate, physically packaged solid form or article. In other words, the solid composition is coherent in contrast to the dosage form formed by multiple structurally separate designed units, in which the units are incoherent.

[0336] Examples of single units that can be used as dosage forms for a solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In one embodiment, the solid composition is in a highly porous lyophilized form. Such lyophilisates, sometimes also referred to as cachets or lyophilized tablets, are useful in particular because of their rapid disintegration, which also promotes rapid dissolution of the active compound.

[0337] On the other hand, for some applications, the solid composition can also be obtained in the form of a dosage form formed by multiple structurally separate designed units, as defined above. Examples of multiple structurally distinct shaped units are powders, granules, microparticles, beads, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system contains a plurality of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular porous microstructure through which the powder is able to absorb water very quickly, resulting in rapid dissolution. Effervescent compositions are also considered to facilitate rapid dispersion and absorption of the compound.

[0338] Another type of multiparticulate system that is also capable of rapidly dissolving a drug is a system of powders, granules, or beads of water-soluble excipients onto which the drug is applied so that the drug is localized to the outer surface of the individual particles. In this type of system, a water soluble low molecular weight excipient is used to form the core of such coated particles, which are subsequently coated with a coating composition containing a drug, preferably one or more additional excipients such as a binder, blowing agent, saccharide, sugar alcohol, film former, plasticizer or other excipients used in pharmaceutical coating compositions.

[0339] Kits are also provided herein. Typically, the kit includes one or more of the compounds or compositions described herein. In some embodiments, the kit may include one or more delivery systems, eg, for delivering or administering a compound of the invention, and directions for using the kit (eg, instructions for treating the patient). In another embodiment, a kit may include a compound or composition as described herein and a label indicating the content to be administered to a patient with cancer. In another embodiment, a kit may include a compound or composition described herein and a label indicating the content to be administered to a patient with one or more of the following diseases: hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer , diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer's disease, lung disease, bone fracture / osteoporotic fracture (wrist, spine, shoulder and hip) , articular cartilage defects (chondral), degenerative disc disease (or intervertebral disc degeneration), coli-polyposis, defects in bone density and blood vessels in the eye (osteoporosis-pseudoglioma syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early ischemic disease, tetra-amelia syndrome, virilis Müllerian duct regression, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel syndrome, odonto-onychodermal dysplasia, obesity, cleft hand/foot malformation, caudal duplication syndrome, dental agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha thalassemia syndrome (ARTX), fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Norrie's disease , Rett syndrome.

Methods of treatment

[0340] The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more components of the Wnt pathway, which can include one or more Wnt proteins, and thus can be used to treat various disorders and diseases, in which aberrant Wnt signaling is involved, such as cancer and other diseases associated with abnormal angiogenesis, cell proliferation, and cell cycle. Accordingly, the compounds and compositions of the present invention may be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cell proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease resulting from mutations or dysregulation of the Wnt pathway. and/or one or more Wnt signaling components. Non-limiting examples of diseases that may be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, neurological conditions/diseases such such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), motor neuron disease, multiple sclerosis or autism, lung disease, bone fracture/osteoporotic fracture (wrist, spine, shoulder and hip), coli polyposis, defects in bone density and blood vessels in eye (osteoporosis-pseudoglioma syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, Tetra-Amelia syndrome, Mullerian duct virilization and regression, SERKAL syndrome, type II diabetes, Furman syndrome, Al-Awadi/Raas phocomelia syndrome -Rothschild/Schinzel, odonto-onychodermal dysplasia ju, obesity, cleft hand/foot malformation, duplication tail syndrome, dental agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha thalassemia syndrome (ARTX), fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Norrie's disease, Rett's syndrome.

[0341] In relation to cancer, the Wnt pathway is known to be constitutively activated in various cancers, including, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, and leukemias such as CML, CLL and T-ALL. Accordingly, the compounds and compositions described herein can be used to treat those cancers in which the Wnt pathway is constitutively activated. In some embodiments, the cancer is selected from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, and ovarian cancer.

[0342] Other cancers may also be treated with the compounds and compositions described herein.

[0343] More specifically, cancers that can be treated with the compounds, compositions, and methods described herein include, but are not limited to, the following tumors:

[0344] 1) Breast cancer, including, for example, ER ⁺ breast cancer, ER ^- breast cancer, her2 ^- breast cancer, her2 ⁺ breast cancer, stromal tumors such as fibroadenomas, leaf-shaped tumors, and sarcomas, and epithelial tumors such as large duct papillomas; breast carcinomas, including carcinoma in situ (non-invasive), which includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ , and invasive (infiltrating) carcinoma, including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma , medullary carcinoma, colloid (mucus-forming) carcinoma, tubular carcinoma and invasive papillary carcinoma; and mixed malignant neoplasms. Other examples of breast cancers may include luminal type A, luminal type B, basal type A, basal type B, and triple negative breast cancer that ^is estrogen receptor (ER-) negative, progesterone receptor negative, and her2 negative ( ^her2- ). In some embodiments, the breast cancer may have a high oncotype score.

[0345] 2) Malignant tumors of the heart, including, for example, sarcoma, such as angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma.

[0346] 3) Malignant tumors of the lung, including, for example, bronchogenic carcinoma, such as squamous cell, undifferentiated small cell, undifferentiated large cell carcinoma, and adenocarcinoma; alveolar and bronchial carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

[0347] 4) Gastrointestinal cancer, including, for example, cancers of the esophagus, such as small cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; malignant tumors of the stomach, for example, carcinoma, lymphoma and leiomyosarcoma; malignant tumors of the pancreas, for example, adenocarcinoma of the ducts, insulinoma, glucagonoma, gastrinoma, carcinoid tumors and vipoma; malignant tumors of the small intestine, for example, adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma and fibroma; malignant tumors of the colon, for example, adenocarcinoma, tubular adenoma, villous adenoma, hamartoma and leiomyoma.

[0348] 5) Malignant tumors of the urogenital tract, including, for example, malignant tumors of the kidneys, for example, adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, and leukemia; malignant tumors of the bladder and urethra, for example, small cell carcinoma, transitional cell carcinoma and adenocarcinoma; malignant tumors of the prostate, for example, adenocarcinoma and sarcoma; testicular cancer such as seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors and lipoma.

[0349] 6) Malignant tumors of the liver, including, for example, hepatoma, for example, hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.

[0350] 7) Malignant bone tumors, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, giant cell tumor chordoma, osteochondroma (bone cartilage exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.

[0351] 8) Malignant tumors of the nervous system, including, for example, malignant tumors of the skull, for example, osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; malignant tumors of the meninges, for example, meningioma, meningiosarcoma and gliomatosis; malignant brain tumors, for example, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma and congenital tumors; and malignant tumors of the spinal cord, for example, neurofibroma, meningioma, glioma and sarcoma.

[0352] 9) Gynecological malignancies, including, for example, malignant tumors of the uterus, for example, endometrial carcinoma; malignant tumors of the cervix, for example, cervical carcinoma and precancerous cervical dysplasia; ovarian cancers, for example, ovarian carcinoma, including serous cystodenocarcinoma, mucinous adenocarcinoma, unclassified carcinoma, granulosa cell tumors, Sertoli-Leylig cell tumors, dysgerminoma, and malignant teratoma; malignant tumors of the vulva, for example, small cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; malignant tumors of the vagina, for example, clear cell carcinoma, small cell carcinoma, botryoid sarcoma, and fetal rhabdomyosarcoma; and malignant tumors of the fallopian tubes, such as carcinoma.

[0353] 10) Hematologic malignancies, including, for example, malignant blood tumors, for example, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma and myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma ( malignant lymphoma) and Waldenström's macroglobulinemia.

[0354] 11) Skin cancers and skin disorders including, for example, malignant melanoma and metastatic melanoma, basal cell carcinoma, small cell carcinoma, Kaposi's sarcoma, pigmented dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and scleroderma.

[0355] 12) Adrenal cancers, including, for example, neuroblastoma.

[0356] Malignant tumors may be solid tumors, which may or may not be metastatic. Malignant tumors can also occur in diffuse tissue, as in leukemia. Thus, the term "tumor cell" as used herein includes a cell affected by any of the above disorders.

[0357] A method of treating cancer using a compound or composition described herein may be combined with existing cancer treatments, such as chemotherapy, radiation, or surgery (eg, oophorectomy). In some embodiments, a compound or composition may be administered before, during, or after another anticancer agent or treatment.

[0358] The compounds and compositions described herein can be used as anti-angiogenic agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatment for cancer and other diseases associated with protein kinase-mediated cell proliferation. For example, the compounds described herein can inhibit the activity of one or more kinases. Accordingly, provided herein is a method for treating cancer or preventing or reducing angiogenesis by inhibiting kinases.

[0359] In addition, and including the treatment of cancer, the compounds and compositions described herein can function as cell cycle regulating agents for the treatment of proliferative disorders in a patient. Disorders associated with increased proliferation include, for example, malignancies, scleroderma, immunological disorders including unwanted proliferation of leukocytes and restenosis, and other smooth muscle disorders. In addition, such compounds can be used to prevent dedifferentiation of postmyotic tissue and/or cells.

[0360] Diseases or disorders associated with uncontrolled or abnormal cell proliferation include, but are not limited to, the following:

various types of malignant tumor, including, but not limited to, carcinoma, hematopoietic tumors of lymphoid origin, hematopoietic tumors of myeloid origin, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, and other tumors, including melanoma, seminoma, and Kaposi's sarcoma.

a pathological process characterized by abnormal cell proliferation, such as benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis after angioplasty or angioplasty, inflammatory bowel disease, transplant rejection, endotoxic shock, and fungal infections. Fibrotic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; pulmonary fibrosis; muscular fibrosis; fibrosis of the kidneys; glomerulosclerosis; glomerulonephritis; hypertrophic scarring; fibrosis of the uterus; renal fibrosis; cirrhosis of the liver, fibrosis of the liver; fatty liver disease (FLD); adhesions, such as those present in the abdomen, pelvis, spine, or tendons; chronic obstructive pulmonary disease; fibrosis after myocardial infarction; pulmonary fibrosis; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; fibrosis of the central nervous system, such as post-stroke fibrosis; fibrosis associated with neurodegenerative disorders such as Alzheimer's disease or multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis.

defective apoptosis-associated conditions such as malignant tumors (including but not limited to the types identified herein), viral infections (including but not limited to herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), developmental prevention AIDS in HIV-infected individuals, autoimmune diseases (including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, autoimmune-mediated glomerulonephritis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscle atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarction yes, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin-induced or alcohol-related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to, osteoporosis and arthritis), tendinopathies such as tendonitis and tendinosis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.

genetic diseases due to mutations in Wnt signaling components, such as coli-polyposis, defects in bone density and blood vessels in the eye (osteoporosis-pseudoglioma syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early ischemic disease, Tetra-Amelia syndrome, virilization and regression of Muller ducts, SERKAL syndrome, type II diabetes, Furman syndrome, Al-Awadi/Raas-Rothschild/Schinzel syndrome, odonto-onychodermal dysplasia, obesity, cleft hand/foot malformation, caudal duplication syndrome, dental agenesis, tumor Wilms, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha thalassemia syndrome (ARTX), fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Norrie's disease, Rett syndrome.

[0361] The compounds and compositions described herein can be used in the treatment of neurological conditions, disorders and/or diseases caused by dysfunction in the Wnt signaling pathway. Non-limiting examples of neurological conditions/disorders/diseases that may be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia-telangiectasia, attention deficit hyperactivity disorder, tympanic temporal bone process disorder , autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism paralysis, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, co depression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative traumatic disorder, Cushing's syndrome, cytomegalic inclusion disease (CIBD), Dandy-Walker syndrome, Dawson's disease, de Morsier syndrome, Dejerine-Klumpke palsy , Dejerine-Sott's disease, delayed phase sleep syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet's syndrome, autonomic dystonia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential trembling, Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrile attack, Fischer's syndrome, Friedreich's ataxia, fibromyalgia, Fauville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant inclusion disease, globoid cell disease leucode hystrophy, gray matter heterotopia, Guillain-Barré syndrome, HTLV-1-associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary paraplegia, Refsum syndrome, Ramsay Hunt syndrome, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus , hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, skin pigmentation defect, phytanic acid storage disease in children, Refsum disease in children, convulsions in children, convulsions in children, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert's syndrome, syndrome Karak, Kearns-Sayre syndrome, Kennedy syndrome, Kinsbourne syndrome, Klippel-Feil syndrome, Krabbe disease, Kugelberg-Welander disease, Kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Klefner syndrome, lateral medullary syndrome (Wallenberg), disease Leich, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, dementia Lewy body disease, lissencephaly, surround syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar stenosis, Lyme disease, Machado-Joseph disease (spinal ataxia type 3), macroencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Meniere, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, Miller-Fischer syndrome, mysophobia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neuron disease, impaired motor skills, moyamoya disease, mucopolysaccharidoses, polyinfarction dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, severe pseudoparalytic myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic encephalopathy in children, myoclonus, myopathy, myotubular myopathy, myotonia congenita, narcolepsy, neurofibromatosis, neurofibromatosis ku, neuromyotonia, neural waxy lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital neuralgia, latent spinal cord dysraphia, Otahara's syndrome, olivopontocerebellar atrophy, dancing eye syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesia, Parkinson's disease , congenital paramyotonia, paraneoplastic diseases, paroxysmal seizures, Parry-Romberg syndrome, Pelizeus-Merzbacher disease, periodic paralysis, peripheral neuropathy, light sneeze reflex, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, postpolio syndrome , postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifecal atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudocerebellar tumor, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsey Hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum's disease, restless legs syndrome, retrovirus-associated myelopathy, Rett's syndrome, Reye's syndrome, rhythmic movement disorder, Romberg's syndrome, St. Vitus' dance, Sandhoff's disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjögren's syndrome, a medical condition characterized by an uncontrolled burst of sneezing caused by full stomach (snatiation), Sotos syndrome, spasticity, spina bifida, spinal cord tumors, spinal muscle atrophy, spinocerebellar ataxia, progressive supranuclear gaze palsy, stiff man syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syrinomyelia, tarsal tunnel syndrome, late juvenile dyskinesia, tardive dysphrenia, Tarlov's cyst, Tay-Sachs disease, temporal arteritis, tetanus, spinal cord fixation syndrome, Thomsen's disease, chest outlet syndrome, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, ubiciosis, von Hippel-Landau disease (VHL), Vilyui encephalomyelitis (VE), Wallenberg syndrome, (Werdnig's disease), Hoffmann's disease, western syndrome, Williams syndrome, Wilson's disease and Zellweger's syndrome.

[0362] The compounds and compositions can also be used in inhibiting the development of invasive cancer, tumor angiogenesis, and metastasis.

[0363] In some embodiments, the invention relates to a method of treating a disease or disorder associated with aberrant cell proliferation by administering to a patient in need of such treatment, an effective amount of one or more compounds of formula ( I ) in combination (simultaneously or sequentially) with, by at least one other means.

[0364] In some embodiments, the invention relates to a method of treating or reducing the intensity in a patient of a disease selected from the group including: malignant tumor, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative intervertebral disc disease, bone fracture / osteoporotic fracture, disease bone or cartilage tissue; and osteoarthritis, wherein the method comprises administering to a patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

[0365] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula ( I ), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0366] In some embodiments, the method relates to the treatment of a disorder or disease in a patient in which aberrant Wnt signaling is involved, the method comprising administering to the patient a therapeutically effective amount of a compound of formula ( I ) or a pharmaceutically acceptable salt thereof.

[0367] In some embodiments, the disorder or disease is a cancer.

[0368] In some embodiments, the disorder or disease is systemic inflammation.

[0369] In some embodiments, the disorder or disease is metastatic melanoma.

[0370] In some embodiments, the disorder or disease is fatty liver disease.

[0371] In some embodiments, the disorder or disease is liver fibrosis.

[0372] In some embodiments, the disorder or disease is tendon regeneration.

[0373] In some embodiments, the disorder or disease is diabetes.

[0374] In some embodiments, the disorder or disease is a degenerative disease of the intervertebral discs.

[0375] In some embodiments, the disorder or disease is osteoarthritis.

[0376] In some embodiments, the disorder or disease is diabetic retinopathy.

[0377] In some embodiments, the disorder or disease is pulmonary fibrosis.

[0378] In some embodiments, the disorder or disease is idiopathic pulmonary fibrosis (IPF).

[0379] In some embodiments, the disorder or disease is a degenerative disease of the intervertebral discs.

[0380] In some embodiments, the disorder or disease is rheumatoid arthritis.

[0381] In some embodiments, the disorder or disease is scleroderma.

[0382] In some embodiments, the disorder or disease is a fungal or viral infection.

[0383] In some embodiments, the disorder or disease is a bone or cartilage disease.

[0384] In some embodiments, the disorder or disease is Alzheimer's disease.

[0385] In some embodiments, the disorder or disease is osteoarthritis.

[0386] In some embodiments, the disorder or disease is a lung disease.

[0387] In some embodiments, the disorder or disease is a genetic disease caused by mutations in components of Wnt signaling, where the genetic disease is selected from: coli-polyposis, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, syndrome tetra-amelia, virilization and regression of Muller's ducts, SERKAL syndrome, type 2 diabetes mellitus, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel syndrome, odonto-onychodermal dysplasia, obesity, cleft hand/foot malformation, tail duplication syndrome, agenesia teeth, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha thalassemia syndrome (ARTX), fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Norria's disease, Rett's syndrome.

[0388] In some embodiments, the patient is a human.

[0389] In some embodiments, the cancer is selected from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin's lymphoma, lymphoma, sarcoma, and ovarian cancer.

[0390] In some embodiments, the cancer is selected from: non-small cell lung cancer, small cell lung cancer, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, basal cell and squamous cell skin cancer, malignant skin tumor - melanoma, small intestine cancer, malignant tumors of the stomach, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi's sarcoma, gestational trophoblastic tumor, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, malignant tumor of the eye (melanoma and lymphoma), Ewing's tumor, esophageal cancer, endometrial cancer, colon and rectal cancer, cervical cancer, brain tumor or spinal cord, bone metastasis, bone cancer, m bladder, bile duct cancer, anal cancer and adrenal cortex cancer.

[0391] In some embodiments, the cancer is a hepatocellular carcinoma.

[0392] In some embodiments, the cancer is colon cancer.

[0393] In some embodiments, the cancer is colon and rectal cancer.

[0394] In some embodiments, the cancer is breast cancer.

[0395] In some embodiments, the cancer is pancreatic cancer.

[0396] In some embodiments, the cancer is chronic myeloid leukemia (CML).

[0397] In some embodiments, the cancer is chronic myelomonocytic leukemia.

[0398] In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).

[0399] In some embodiments, the cancer is acute myelocytic leukemia.

[0400] In some embodiments, the cancer is acute lymphocytic leukemia.

[0401] In some embodiments, the cancer is Hodgkin's lymphoma.

[0402] In some embodiments, the cancer is a lymphoma.

[0403] In some embodiments, the cancer is a sarcoma.

[0404] In some embodiments, the cancer is ovarian cancer.

[0405] In some embodiments, the cancer is a non-small cell lung cancer.

[0406] In some embodiments, the cancer is small cell lung cancer.

[0407] In some embodiments, the cancer is multiple myeloma.

[0408] In some embodiments, the cancer is nasopharyngeal cancer.

[0409] In some embodiments, the cancer is a neuroblastoma.

[0410] In some embodiments, the cancer is an osteosarcoma.

[0411] In some embodiments, the cancer is penile cancer.

[0412] In some embodiments, the cancer is pituitary tumors.

[0413] In some embodiments, the cancer is prostate cancer.

[0414] In some embodiments, the cancer is a retinoblastoma.

[0415] In some embodiments, the cancer is rhabdomyosarcoma.

[0416] In some embodiments, the cancer is salivary gland cancer.

[0417] In some embodiments, the cancer is a basal cell and squamous cell skin cancer.

[0418] In some embodiments, the cancer is a skin cancer, melanoma.

[0419] In some embodiments, the cancer is small bowel cancer.

[0420] In some embodiments, the cancer is gastric cancer.

[0421] In some embodiments, the cancer is testicular cancer.

[0422] In some embodiments, the cancer is thymus cancer.

[0423] In some embodiments, the cancer is thyroid cancer.

[0424] In some embodiments, the cancer is a uterine sarcoma.

[0425] In some embodiments, the cancer is vaginal cancer.

[0426] In some embodiments, the cancer is vulvar cancer.

[0427] In some embodiments, the cancer is a Wilms tumor.

[0428] In some embodiments, the cancer is laryngeal cancer or hypopharyngeal cancer.

[0429] In some embodiments, the cancer is a kidney cancer.

[0430] In some embodiments, the cancer is Kaposi's sarcoma.

[0431] In some embodiments, the cancer is a gestational trophoblastic tumor.

[0432] In some embodiments, the cancer is a gastrointestinal stromal tumor.

[0433] In some embodiments, the cancer is a gastrointestinal carcinoid tumor.

[0434] In some embodiments, the cancer is gallbladder cancer.

[0435] In some embodiments, the cancer is an eye cancer (melanoma and lymphoma).

[0436] In some embodiments, the cancer is an Ewing tumor.

[0437] In some embodiments, the cancer is esophageal cancer.

[0438] In some embodiments, the cancer is endometrial cancer.

[0439] In some embodiments, the cancer is colon and rectal cancer.

[0440] In some embodiments, the cancer is cervical cancer.

[0441] In some embodiments, the implementation of the malignant tumor is a tumor of the brain or spinal cord.

[0442] In some embodiments, the cancer is a bone metastasis.

[0443] In some embodiments, the cancer is bone cancer.

[0444] In some embodiments, the cancer is bladder cancer.

[0445] In some embodiments, the cancer is bile duct cancer.

[0446] In some embodiments, the cancer is anal cancer.

[0447] In some embodiments, the implementation of the malignant tumor is cancer of the adrenal cortex.

[0448] In some embodiments, the disorder or disease is a neurological condition, disorder or disease, wherein the neurological condition/disorder/disease is selected from Alzheimer's disease, frontotemporal dementia, Lewy body dementia, prion diseases, Parkinson's disease, Huntington's disease , progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis, and Charcot-Marie disease Tuta.

[0449] In some embodiments, a compound of formula ( I ) inhibits one or more proteins in the Wnt pathway.

[0450] In some embodiments, a compound of formula ( I ) inhibits signaling induced by one or more Wnt proteins.

[0451] In some embodiments, Wnt proteins are selected from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11 and WNT16.

[0452] In some embodiments, a compound of formula ( I ) inhibits kinase activity.

[0453] In some embodiments, the method is a method of treating a disease or disorder in a patient mediated by the Wnt pathway, the method comprising administering to the patient a therapeutically effective amount of a compound (or compounds) of formula ( I ), or a pharmaceutically acceptable salt(s) thereof ).

[0454] In some embodiments, the compound of formula ( I ) inhibits one or more Wnt proteins.

[0455] In some embodiments, the method is a method of treating a disease or disorder in a patient mediated by kinase activity, and includes administering to the patient a therapeutically effective amount of a compound (or compounds) of formula ( I ), or its (their) pharmaceutically acceptable salt (salts).

[0456] In some embodiments, the disease or disorder includes tumor growth, cell proliferation, or angiogenesis.

[0457] In some embodiments, the method inhibits the activity of a protein kinase receptor, the method comprising contacting the receptor with an effective amount of a compound (or compounds) of formula ( I ) or a pharmaceutically acceptable salt(s) thereof.

[0458] In some embodiments, the method is a method of treating a disease or disorder associated with aberrant cell proliferation in a patient; the method comprises administering to a patient a therapeutically effective amount of a compound (or compounds) of formula ( I ) or a pharmaceutically acceptable salt(s) thereof(s).

[0459] In some embodiments, the method is a method of preventing or reducing angiogenesis in a patient; the method comprises administering to a patient a therapeutically effective amount of a compound (or compounds) of formula ( I ) or a pharmaceutically acceptable salt(s) thereof(s).

[0460] In some embodiments, the method is a method of preventing or reducing abnormal cell proliferation in a patient; the method comprises administering to a patient a therapeutically effective amount of a compound (or compounds) of formula ( I ) or a pharmaceutically acceptable salt(s) thereof(s).

[0461] In some embodiments, the method is a method of treating a disease or disorder associated with aberrant cell proliferation in a patient, the method includes administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more by other means.

[0462] In addition, compounds and compositions, for example, as inhibitors of cyclin-dependent kinases (CDKs), can modulate the level of cellular RNA and DNA synthesis, and thus are expected to be useful in the treatment of viral infections such as HIV, human papillomavirus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, poxvirus and the like.

[0463] The compounds and compositions described herein can inhibit kinase activity, for example, CDK/cyclin complexes, such as complexes active at the G _0. or G _.1 stage of the cell cycle, for example, CDK2, CDK4 and/or CDK6.

Assessment of biological activity

[0464] The biological activity of the compounds described herein can be determined using any suitable assay known to those skilled in the art, see, for example, WO 2001/053268 or WO 2005/009997. For example, the activity of a compound can be determined using one or more of the assays described below.

[0465] In one example, tumor cells can be examined for Wnt-independent growth. In such a method, tumor cells of interest are contacted with a compound (ie, inhibitor) of interest and cell proliferation is controlled, for example, by uptake of tritiated thymidine. In some embodiments, tumor cells may be isolated from a candidate patient who is being tested for a cancer that is associated with a mutation in the Wnt signaling component. Suspected cancers include, without limitation, the cancers listed above.

[0466] In another example, in vitro assays for Wnt biological activity, such as β-catenin stabilization and stem cell growth promotion, can be used. Wnt biological activity assays include stabilization of β-catenin, which can be measured, for example, by serial dilutions of the composition of the inhibitor of interest. A typical assay for Wnt biological activity involves contacting an inhibitor of interest with cells containing constitutively active Wnt/β-catenin signaling. The cells are cultured for a period of time sufficient to stabilize the β-catenin, typically at least about 1 hour, and lysed. The cell lysate is dissolved in SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for β-catenin.

[0467] In another example, the activity of a compound of interest can be measured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell ( 1997), 88(6), 747-756).

[0468] To further illustrate the present invention, the following examples are included. Of course, the examples are not to be construed as specifically limiting the present invention. Variants of such examples within the scope of the claims are within the purview of those skilled in the art, and are intended to be included within the scope of the present invention as described and claimed herein. It will be understood by the reader that a person skilled in the art armed with the present invention will be able to make and use the present invention without exhaustive examples.

EXAMPLES

Getting connections

[0469] The starting materials used in the preparation of the compounds of the invention are known, prepared by known methods, or commercially available. A person skilled in the art will be obvious that methods for obtaining precursors and functional groups related to the compounds claimed herein, as a rule, are described in the literature. Those skilled in the art will be provided with the literature and this specification for any compounds.

[0470] Obviously, those skilled in the art of organic chemistry will be able to easily perform the manipulations without further guidance, that is, performing such manipulations is within the scope of knowledge and practice of those skilled in the art. Such manipulations include reduction of carbonyl compounds to their respective alcohols, operations of oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic, ester and ester preparation and saponification, and similar manipulations. Such manipulations are described in manuals such as March 's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7 ^th Ed., John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5 ^th Ed., Springer (2007) , Comprehensive Organic Transformations: A Guide to Functional Group Transformations , 2nd ^Ed ., John Wiley & Sons (1999) (incorporated here in full by reference) and the like.

[0471] One skilled in the art will readily appreciate that some reactions are best performed when other functional groups are hidden or protected in the molecule, thus avoiding unwanted side reactions and/or increasing the yield of the reaction product. Typically, the skilled artisan uses protecting groups to achieve such improved yields or to prevent unwanted reactions. These reactions are described in the literature and are also within the skill of the skilled artisan. Examples of many of these manipulations can be found, for example, in T. Greene and P. Wuts Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated herein by reference in its entirety.

[0472] Trademarks used in the present description are only examples and reflect illustrative substances used at the time of the creation of the invention. Those skilled in the art will appreciate that changes in batch, production method, and the like are contemplated. Therefore, the examples and the trademarks used therein are not intended to be limiting, and are intended to be non-limiting, but merely illustrative of what a person skilled in the art may choose to carry out one or more embodiments of the invention.

[0473] ( ¹ H) nuclear magnetic resonance (NMR) spectra were measured in the indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for ¹ H or Avance TM DRX500, 500 MHz for ¹ H) or a Varian NMR spectrometer ( Mercury ^400BB , 400MHz for 1H). Peak positions are expressed in parts per million (ppm) shift relative to tetramethylsilane. Peak multiplicity was designated as follows: s - singlet; d - doublet; t - triplet; kv - quartet; ABq -ABquartet; quin - quintet; sextet; sep-septet; non-none; dd-doublet of doublets; ddd - doublet of doublets of doublets; d/ABq - doublet of AB quartet; dt - doublet of triplets; td - triplet of doublets; dkv - doublet of quartets; m - multiplet.

[0474] The abbreviations used have the following meanings:

Boc= tert -butyloxycarbonyl

Saturated saline = saturated aqueous sodium chloride solution

CDCl ₃ = deuterated chloroform

CuI=copper(I) iodide or copper iodide

DCE=dichloroethane

DCM=dichloromethane

DIPEA=N,N-diisopropylethylamine

DMAP=4-dimethylaminopyridine

DMF=N,N-dimethylformamide

DMSO=dimethyl sulfoxide

DMSO- d ₆ = deuterated dimethyl sulfoxide

ESIMS=electron sputtering mass spectrometry

EtOAc=ethyl acetate

HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluorophosphate

HCl=hydrochloric acid

HOAc=acetic acid

LC/MS=liquid chromatography mass spectrometry

MeCN=acetonitrile

MeOH=methanol

MgSO ₄ = magnesium sulfate

NaBH(OAc) ₃ = sodium triacetoxyborohydride

NMR = nuclear magnetic resonance

ON=during the night

Pd(dppf)Cl ₂ = 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride

Pd (PPh ₃ ) ₄ \u003d tetrakis (triphenylphosphine) palladium (0)

RT=room temperature

THF=tetrahydrofuran

TLC=thin layer chromatography

pTsO-=p-toluenesulfonate ester

[0475] The following scheme examples are provided as a guide to the reader and collectively represent examples of the methods for preparing the compounds described herein. In addition, other methods for preparing the compounds of the invention will be apparent to those skilled in the art in light of the following reaction schemes and examples. The specialist is well trained to obtain such compounds by methods described in the literature and in the present description. The numbering of the compounds used in the synthetic schemes below refers only to these specific schemes and should not be construed as or identified with similar numbers elsewhere in this application. Unless otherwise noted, all variables have the values specified above.

General procedures

[0476] The compounds of formula I according to the present invention can be obtained as shown in scheme 1 .

[0477] Scheme 1 shows a process for preparing isoquinoline-3-carboxamide derivatives ( IX ) by first coupling an amine with various acids ( III ) to give an amide IV . The bromine compound IV is then reacted with bis(pinacolato)diborone to give the pinacol ester ( V ). Suzuki coupling with various 5-membered heteroaryl bromides ( VIII ) gives the desired substituted R ³ isoquinoline IX . Alternatively, the bromo derivative IV is Suzuki coupled with various 5-membered heteroaryl pinacol esters ( VI ) or coupled with various 5-membered heteroaryl tin compounds ( VII ) to give the final substituted R ³ isoquinoline IX .

[0478] In some embodiments, the compounds of formula I of the present invention can be obtained by the method presented in scheme 2 .

[0479] Scheme 2 shows a process for preparing isoquinoline-3-carboxamide derivatives ( IXa ) starting from bromo intermediate IV and nitrogen bonding of the R ³ NH series of heteroaryryls to give the final R ³ substituted isoquinoline IXa .

Illustrative connection examples

[0480] The preparation of intermediate 2-((1-( tert -butoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid ( XII ) is shown in Scheme 4 below.

Stage one

[0481] To a solution of 2-fluoropyridine-4-carboxylic acid ( X ) (6.65 g, 47.13 mmol) in DMSO (180 mL) was added tert -butyl 4-hydroxypiperidine-1-carboxylate ( XI ) (14, 23 g, 70.69 mmol) and 2-fluoropyridine-4-carboxylic acid (6.65 g, 47.13 mmol). To this mixture was added NaH (8.48 g, 212.08 mmol) in 3 portions. This mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into 1N NaOH, the aqueous layer was washed with EtOAc, then the aqueous layer was acidified with concentrated HCl (20 ml), extracted with EtOAc and dried over Na ₂ SO ₄ . The solvent was removed and the residue was purified by C18 silica gel column chromatography (0-40% MeCN/0.1% formic acid in water) to give 2-((1-( tert -butoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid ( XII ) (12.85 g, 39.9 mmol, 84.6% yield) as white solid. ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.41 (s, 9H), 1.52-1.62 (m, 2H), 1.90-1.98 (m, 2H), 3.12-3.23 (m, 2H), 3 .64-3.72 (m, 2H), 5.21 (tt, J =8.13, 3.95 Hz, 1H), 7.15 (s, 1H), 7.36 (dd, J =5 .21, 1.37 Hz, 1H), 8.31 (d, J = 5.21 Hz, 1H), 13.62 (broad s, 1H); ESIMS found for C ₁₆ H ₂₂ N ₂ O ₅ m/z 323.1 (M+H).

[0482] The preparation of intermediate 4-((1-( tert -butoxycarbonyl)piperidin-4-yl)oxy)benzoic acid ( XV ) is shown in Scheme 5 below.

Stage one

[0483] To a solution of DEAD (12.3 ml, 27.08 mmol) (40% in toluene) was added a mixture of ethyl 4-hydroxybenzoate ( XIII ) (3.0 g, 18.05 mmol), tert -butyl 4-hydroxypiperidine -1-carboxylate ( XI ) (4.72 g, 23.47 mmol) and triphenylphosphane (6.16 g, 23.47 mmol) in THF (40 ml) at 0°C. The mixture was stirred at 0° C. to room temperature for 1 day before concentrating in vacuo. The residue was diluted with EtOAc, washed with 1N NaOH and brine, and then evaporated in vacuo. The crude product was purified by chromatography (0→30% EtOAc/hexanes) to give tert -butyl 4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylate ( XIV ) (5.4 g, 15.45 mmol, 85.6% yield) as a colorless oil. ESIMS found for C ₁₉ H ₂₇ NO ₅ m/z 372.1 (M+Na).

Stage 2

[0484] LiOH ( 15 .5 ml, 61.82 mmol) and the mixture was stirred at 60° C. for 2 hours. The mixture was concentrated and the residue was triturated with water. The resulting solution was acidified with 2N HCl until a solid precipitated. The solid was filtered and washed with water to give 4-[(1- tert -butoxycarbonyl-4-piperidyl)oxy]benzoic acid ( XV ) (4.7 g, 14.63 mmol, 94.6% yield) as a solid white. ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.40(9H, s), 1.47-1.57(2H, m), 1.89-1.97(2H, m), 3.12-3.23(2H, m), 3, 63-3.70 (2H, m), 4.63-4.71 (1H, m), 7.04 (2H, d, J = 9.06 Hz), 7.87 (2H, d, J = 9.06 Hz); ESIMS found for C ₁₇ H ₂₃ NO ₅ m/z 344.1 (M+Na).

[0485] The preparation of intermediate 1-(methyl- d ₃ )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole ( XVII ) is shown below in scheme 6 .

Stage one

[0486] To a stirred suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole ( XVI ) (1.435 g, 7.4 mmol) and Cs ₂ CO ₃ (2.89 g, 8.87 mmol) in DMF (15 ml) was added trideuterio(iodine)methane (0.51 ml, 8.13 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrates were concentrated and dried under high vacuum to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)pyrazole ( XVII ) (3 .9 g, 18.48 mmol, 249.8% yield) as a white solid, which was used in the next step without purification. ESIMS found for C ₁₀ H ₁₄ [ ² H ₃ ]BN ₂ O ₂ m/z 212. (M+1).

[0487] The preparation of intermediate 6-bromoisoquinoline-1- d -3-amine( XIX ) is shown in Scheme 8 below.

Stage 1

[0488] A mixture of 1,6-dibromoisoquinoline-3-amine ( XVIII ) (0.5 g, 1.66 mmol), ammonium formate- d ₅ (0.56 g, 8.28 mmol) and Pd(PPh ₃ ) ₄ (191.3 mg, 0.170 mmol) in DMF (5 ml) was heated to 50°C for 48 hours. The solvents were concentrated and the residue was suspended in chloroform. The solid was collected by filtration and washed with water and EtOAc. The solid was dried in vacuo to give 6-bromo-1-deuterio-isoquinoline-3-amine ( XIX ) (115 mg, 0.513 mmol, 31.0% yield) as a light yellow solid. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 6.11(2H, s), 6.55(1H, s), 7.22(1H, dd, J =8.78, 1.92 Hz), 7.73(1H, d, J =8, 51 Hz), 7.79 (1H, d, J =1.92 Hz); ESIMS found for C ₉ H ₆ DBrN ₂ m/z 224.0 ( ⁷⁹ BrM+H).

[0489] The preparation of intermediate 6-bromo-4-chloroisoquinoline-3-amine ( XXI ) is shown in Scheme 9 below.

Stage 1

[0490] To a stirred suspension of 6-bromoisoquinoline-3-amine ( XX ) (1.0 g, 4.48 mmol) in DMF (15 mL) was added 1-chloropyrrolidine-2,5-dione ( XXI ) at 0°C (598.6 mg, 4.48 mmol) in servings. The mixture was stirred at 0°C for 6 hours. The reaction mixture was added to water (150 ml), stirred for 1 h and the resulting solids were collected by filtration and air dried overnight to give 6-bromo-4-chloro-isoquinoline-3-amine ( XXII ) (922 mg, 3 .58 mmol, 79.9% yield) as a beige solid, which was used in the next step without purification. ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 6.55 (2H, s), 7.40 (1H, dd, J = 8.64, 1.78 Hz), 7.88 (1H, d, J = 8.51 Hz), 7.90 (1H , d, J = 1.10 Hz), 8.86 (1H, s); ESIMS found for C ₉ H ₆ BrClN ₂ m/z 256.9 ( ⁷⁹ BrM+H).

[0491] The preparation of intermediate 6-bromo-4-methylisoquinoline-3-amine ( XXV ) is shown in Scheme 10 below.

Stage 1

[0492] To a stirred suspension of 6-bromoisoquinoline-3-amine ( XX ) (2 g, 8.97 mmol) in DMF (25.1 mL) was added 1-iodopyrrolidine-2,5-dione ( XXIII ) at 0°C (2.02 g, 8.97 mmol) in portions. The mixture was stirred at 0°C for 1 hour. Analysis of the mixture by LC-MS showed completion of the reaction and the desired product. Solvent was removed in vacuo, residue was purified with C18 silica gel (240 g) [0→100% H ₂ O/MeCN (0.1% formic acid)] to give 6-bromo-4-iodo-isoquinoline-3-amine ( XXIV ) (1.95 g, 5.58 mmol, 62.2% yield) as a brown solid. ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 6.41(2H, brs), 7.40(1H, dd, J =8.64, 1.78 Hz), 7.76-7.81(1H, m), 7.82(1H, e, J = 8.51 Hz), 8.81 (1H, s); ESIMS found for C ₉ H ₆ BrIN ₂ m/z 348.9 ( ⁷⁹ BrM+H).

Stage 2

[0493] Stirring solution of 6-bromo-4-iodo-isoquinoline-3-amine ( XXIV ) (1.0 g, 2.87 mmol), 2,4,6-trimethyl-1,3,5,2,4 ,6-trioxatriborinane (0.72 g, 2.87 mmol), Pd(dppf)Cl ₂ (0.23 g, 0.29 mmol) and K ₃ PO ₄ (5.73 ml, 5.73 mmol) in 1,4-dioxane (10 ml) was heated to 90°C for 3 days. The solvent was removed under high vacuum and the residue was purified with silica gel C18 (240 g) [0→20% H ₂ O/MeCN (0.1% Formic acid)] to give 6-bromo-4-methyl-isoquinoline-3-amine ( XXV ) (74 mg, 0.312 mmol, 10.9% yield) as off-white solid. ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, brs), 5.91(2H, brs), 7.27(1H, brd, J =2.20Hz), 7.71-7.82(1H, m), 7.92 (1H, brs), 8.72 (1H, brs); ESIMS found for C ₁₀ H ₉ BrN ₂ m/z 239.0 ( ⁸¹ BrM+H).

[0494] The preparation of intermediate 6-bromo-7-fluoroisoquinoline-3-amine ( XXVIII ) is shown in Scheme 11 below.

Stage 1

[0495] 2,2-diethoxyacetonitrile ( XXVI ) (1.0 g, 7.74 mmol) dissolved MeOH (7.74 ml) was added to the vessel, followed by MeONa/MeOH (0.18 ml, 0 .77 mmol). The reaction mixture was stirred at room temperature for 20 hours. HOAc (44.3 μl, 0.77 mmol) was added until pH=7-8 was reached (using litmus strips). (4-Bromo-3-fluoro-phenyl)methanamine hydrochloride ( XXVII ) (1.86 g, 7.74 mmol) was added and stirred at 40° C. for 4 h. The solvent was removed in vacuo. Sulfuric acid (12.6 ml, 232.3 mmol) was added and stirred at 40°C for 16 hours. NH ₄ OH (30.8 ml, 240.0 mmol) was added dropwise at 0°C. The solvent was removed in vacuo and the residue was purified with C18 silica gel (240 g) [0→50% H ₂ O/MeCN (0.1% formic acid)] to give 6-bromo-7-fluoro-isoquinoline-3-amine ( XXVIII ) (1.33 g, 5.50 mmol, 71.1% yield) as off-white solid, 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm. 6.07 (2H, s), 6.61 (1H, s), 7.76 (1H, d, J = 9.33 Hz), 8.01 (1H, d, J = 6.86 Hz), 8.80 (1H, s); ESIMS found for C ₉ H ₆ BrFN ₂ m/z 242.9 ( ⁸¹ BrM+H).

[0496] The preparation of intermediates 6-bromo-7-chloroisoquinoline-3-amine ( XXX ) and 6-bromo-5-chloroisoquinoline-3-amine ( XXXI ) is shown in Scheme 12 below.

Stage 1

[0497] MeONa (0.1 ml, 0.46 mmol). The reaction mixture was stirred at 35° C. for 20 hours. HOAc (26.1 μl, 0.46 mmol) was added (pH was checked to be 7-8 using litmus strips), then (4-bromo-3-chloro- phenyl)methanamine ( XXIX ) (1.01 g, 4.57 mmol). The mixture was stirred at 35° C. for 40 hours. The solvent was removed in vacuo. Then sulfuric acid (7.43 ml, 137.0 mmol) was added and stirred at 35°C for 16 hours. NH ₄ OH (60.6 ml, 141.6 mmol) was added at 0°C. The reaction mixture was filtered through Celite and purified with C18 silica gel (240 g) [0→30% H ₂ O/MeCN (0.1% formic acid)] to give a 1:1 mixture (by NMR) of 6-bromo-7 -chloro-isoquinoline-3-amine ( XXX ) and 6-bromo-5-chloroisoquinoline-3-amine ( XXXI ) (633.7 mg, 2.46 mmol, 53.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 6.23(2H, s), 6.46(2H, s), 6.57(1H, s), 6.83(1H, s), 7.40(1H, d, J =8.51 Hz ), 7.74 (1H, d, J = 8.51 Hz), 8.05 (1H, s), 8.09 (1H, s), 8.81 (1H, s), 8.88 (1H , With); ESIMS found for C ₉ H ₆ BrClN ₂ m/z 256.9 ( ⁷⁹ BrM+H).

[0498] The preparation of intermediates 6-bromo-7-methylisoquinoline-3-amine ( XXXIII ) and 6-bromo-5-methylisoquinoline-3-amine ( XXXIV ) is shown in Scheme 13 below.

Stage 1

[0499] To a stirred solution of 2,2-diethoxyacetonitrile ( XXVI ) (0.33 g, 2.52 mmol) in a vessel containing MeOH (2.52 ml), mmol). The reaction mixture was stirred at 22° C. for 20 h. HOAc (14.4 μl, 0.25 mmol) was added (pH 7-8 was checked using litmus strips), then (4-bromo-3-methyl- phenyl)methanamine ( XXXII ) (0.5 g, 2.52 mmol). The mixture was stirred at 40° C. for 40 hours. The solvent was removed in vacuo. Then sulfuric acid (4.09 ml, 75.49 mmol) was added and stirred at 40°C for 16 hours. NH ₄ OH (33.4 ml, 78 mmol) was added at 0°C. The reaction mixture was filtered through Celite and purified with C18 silica gel (240 g) [0→30% H ₂ O/MeCN (0.1% formic acid)] to give a 1:1 mixture (by NMR) of 6-bromo-7 -methylisoquinoline-3-amine ( XXXIII ) and 6-bromo-5-methylisoquinoline-3-amine ( XXXIV ) (378 mg, 1.59 mmol, 63.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.40(3H, s), 2.52(3H, s), 5.96(2H, s), 6.12(1H, s), 6.54(1H, s), 6.71(1H , s), 7.27 (1H, d, J = 8.78 Hz), 7.58 (1H, d, J = 8.78 Hz), 7.73 (1H, s), 7.86 (1H , s), 8.74 (1H, s), 8.79 (1H, s); ESIMS found for C ₁₀ H ₉ BrN ₂ m/z 237.0 ( ⁷⁹ BrM+H).

Example 1

[0500] The preparation of 4-(difluoromethoxy)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide ( 29 ) is shown in Scheme 14 below.

Stage one

[0501] A mixture of 4-(difluoromethoxy)benzoic acid ( XXXV ) (337 mg, 1.79 mmol), HATU (682 mg, 1.79 mmol) and DIPEA (0.47 ml, 2.69 mmol) in DCE (8 ml) was stirred at room temperature for 10 min. To the above mixture were added 6-bromoisoquinoline-3-amine ( XX ) (200 mg, 0.900 mmol) and DMAP (110 mg, 0.900 mmol) and the resulting mixture was stirred at 80°C for 17 h. The reaction mixture was poured into 1 N HCl and extracted with DCM (2×). The combined organic layers were dried, filtered and concentrated. The crude product was purified by silica gel chromatography with EtOAc/hexanes (0-25%) as eluent to give N-(6-bromoisoquinolin-3-yl)-4-(difluoromethoxy)benzamide ( XXXVI ) as a white solid (300 mg, 0.763 mmol, 85.1% yield. ESIMS found for C ₁₇ H ₁₁ BrF ₂ N ₂ O ₂ m/z 395.0 (M ^Br81 +H).

Stage 2

[0502] A mixture of N-(6-bromoisoquinolin-3-yl)-4-(difluoromethoxy)benzamide ( XXXVI ) (100 mg, 0.250 mmol), tributyl-(3-methylimidazol-4-yl)tin ( XXXVII ) (104 mg, 0.280 mmol), Pd(PPh ₃ ) ₄ (23 mg, 0.030 mmol) and CuI (5 mg, 0.030 mmol) were dissolved in DMF (2 ml). N ₂ gas was bubbled into the mixture for 10 min and then heated at 90° C. for 21 h. The reaction mixture was cooled to room temperature, concentrated, absorbed onto silica gel and purified by flash column chromatography using 7N NH ₃ -MeOH/CHCl ₃ (0-10%) as eluents. Pure fractions were concentrated, the residue suspended in diethyl ether was sonicated and the resulting solids were collected by filtration and dried to give 4-(difluoromethoxy)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3 -yl)benzamide ( 29 ) as white solid (16 mg, 0.040 mmol, 15.6% yield), 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm. 3.85 (s, 3H), 7.40 (t, J = 73.65 Hz, 1H), 7.32 (d, J = 8.78 Hz, 2H), 7.33 (br s, 1H ), 7.73 (dd, J = 8.37, 1.51 Hz, 1H), 7.81 (s, 1H), 8.09 (s, 1H), 8.15 (d, J = 8, 51 Hz, 1H), 8.17 (d, J =8.78 Hz, 2H), 8.69 (s, 1H), 9.22 (s, 1H), 10.96 (s, 1H); ESIMS found for C ₂₁ H ₁₆ F ₂ N ₄ O ₂ m/z 395.1 (M+1).

Example 2

[0503] Preparation of 2-(4-aminopiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide ( 53 ) and 2-(4- (dimethylamino)piperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide a( 55 ) is shown in Scheme 15 below.

Stage one

[0504] 2-Fluoropyridine-4-carboxylic acid ( XXXVIII ) (1.27 g, 8.97 mmol), HATU (1.7 g, 4.48 mmol), DMAP (0.55 g, 4 .48 mmol) and 6-bromoisoquinoline-3-amine ( XX ) (1.0 g, 4.48 mmol) in MeCN (22.4 ml) then DIPEA (3.12 ml, 17.93 mmol) at room temperature, then stirred at 60°C for 90 min. Added another eq. HATU (1.7 g, 4.48 mmol) and the reaction mixture was stirred overnight. Added another 0.05 equiv. HATU and stirred for another 1 hour. The reaction mixture was poured into 300 ml of water, the solid was filtered and washed with MeOH to give N-(6-bromoisoquinolin-3-yl)-2-fluoroisonicotinamide ( XXXIX ) as an off-white solid (1.38 g, 3. 99 mmol, 89.0% yield). ESIMS found for C ₁₅ H ₉ BrFN ₃ O m/z 346.2 (M+H).

Stage 2

[0505] To a suspension of N-(6-bromoisoquinolin-3-yl)-2-fluoroisonicotinamide ( XXXIX ) (300 mg, 0.870 mmol) in MeCN (4.3 mL) was added tert -butyl N-(4-piperidyl)carbamate ( XL ) (868 mg, 4.33 mmol). The mixture was heated under reflux for 1 day and then cooled to room temperature. The reaction mixture was concentrated in vacuo and purified with silica gel (24 g) 0-100% EtOAc/hexanes to give t- butyl (1-(4-((6-bromoisoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperidin- 4-yl)carbamate ( XLI ) as off-white solid (0.319 g, 0.606 mmol, 69.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.31-1.45 (m, 2H), 1.39 (s, 9 H), 1.80 (brd, J = 10.43 Hz, 2H), 2.97 (brd, J =11.53 Hz, 2H), 3.49-3.60 (m, 1H), 4.35 (brd, J = 13.17 Hz, 2H), 6.85 (brd, J = 7.41 Hz, 1H), 7.10 (dd, J = 5.08, 1.23 Hz, 1H), 7.46 (s, 1H), 7.70 (dd, J = 8.78, 1 .92 Hz, 1H), 8.07 (d, J =8.78 Hz, 1H), 8.24 (d, J =4.94 Hz, 1H), 8.29 (d, J =1.37 Hz, 1H), 8.61 (s, 1H), 9.25 (s, 1H), 11.16 (s, 1H); ESIMS found for C ₂₅ H ₂₈ BrN ₅ O ₃ m/z 528.1 (M ^Br81 +H).

Stage 3

[0506] To a solution of tert -butyl (1-(4-((6-bromoisoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperidin-4-yl)carbamate ( XLI ) (95.0 mg, 0.220 mmol ) in 1,4-dioxane (6.0 ml) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole ( XLII ) (55.6 mg, 0.270 mmol), K ₃ PO ₄ (210 mg, 0.990 mmol) and Pd(dppf)Cl ₂ (0.05 g, 0.060 mmol). The mixture was degassed with argon and heated to 90° C. for 16 hours. The solvent was removed in vacuo and the residue was purified on silica gel (220 g) using 0-10% 1.7N NH ₃ in CHCl ₃ . The solid was titrated with diethyl ether and placed under vacuum overnight, then titrated with hot ethanol and dried in a vacuum oven at 50° C. to give t- butyl (1-(4-((6-(1-methyl-1H-pyrazole- 4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperidin-4-yl)carbamate ( XLIII ) as off-white solid (294.4 mg, 0.558 mmol, 93.0% exit). ESIMS found for C ₂₉ H ₃₃ N ₇ O ₃ m/z 528.3 (M+H).

Stage four

[0507] To a solution of tert -butyl(1-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperidin-4-yl )carbamate ( XLIII ) (294.0 mg, 0.560 mmol) in MeOH (5.6 mL) HCl (1.39 mL, 5.57 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h. The solvent was removed in vacuo and the residue was purified on silica gel (24 g) using 0-10% 1.7N NH ₃ in MeOH to give 2-(4-aminopiperidin-1-yl )-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide ( 53 ) as off-white solid (195 mg, 0.456 mmol, 81.9% yield ), 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.20-1.29 (m, 2H), 1.76-1.83 (m, 2H), 2.82-2.90 (m, 1H), 2.93-3.02 (m, 2H ), 3.91 (s, 3H), 4.32 (bd, J = 13.17 Hz, 2H), 7.10 (dd, J = 5.21, 1.10 Hz, 1H), 7 .45 (s, 1H), 7.81 (dd, J = 8.51, 1.65 Hz, 1H), 8.07 (d, J = 8.78 Hz, 1H), 8.11 (s, 1H), 8.13 (s, 1H), 8.23 (d, J =4.94 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.12 ( s, 1H), 11.03 (br s, 1H); ESIMS found for C ₂₄ H ₂₅ N ₇ O m/z 428.2 (M+1).

Stage 5

[0508] To a solution of 2-(4-aminopiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide ( 53 ) (90.0 mg , 0.210 mmol) in DCM (2.1 ml) were added formaldehyde (170.9 mg, 2.11 mmol), HOAc (2.5 mg, 0.042 mmol) and NaBH(OAc) ₃ (178.5 mg, 0.840 mmol ). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified on silica gel (12 g) using 0-30% 1.7N NH ₃ in MeOH/CHCl ₃ to give 2-[4-(dimethylamino) -1-piperidyl]-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide ( 55 ) as off-white solid (30.0 mg, 0.066 mmol, 31.3% yield), 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.37 (qvd, J = 11.94, 3.70 Hz, 2H), 1.83 (bd, J = 11.25 Hz, 2H), 2.19 (s, 6 H), 2, 30-2.40 (m, 1H), 2.84-2.93 (m, 2H), 3.91 (s, 3H), 4.44 (bd, J =13.17 Hz, 2H) , 7.11 (dd, J =5.21, 1.10 Hz, 1H), 7.45 (s, 1H), 7.81 (dd, J =8.51, 1.65 Hz, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.13 (s, 1H), 8.24 (d, J = 5.21 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.12 (s, 1H), 11.03 (s, 1H); ESIMS found for C ₂₆ H ₂₉ N ₇ O m/z 456.2 (M+1).

Example 3

[0509] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-yloxy)isonicotinamide ( 16 ) and N-(6-(1 -methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)oxy)isonicotinamide ( 17 ) is shown in Scheme 16 below.

Stage one

[0510] To a solution of 6-bromoisoquinoline-3-amine ( XX ) (3.0 g, 13.45 mmol) and 2-((1-( tert -butoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid ( XII ) (10.62 g, 32.94 mmol) in DCE was added DMAP (1.64 g, 13.45 mmol), DIPEA (7.03 ml, 40.35 mmol), HATU (12.32 g, 32. 4 mmol) in DCE (67.2 ml), stirred at 75°C for 16 h. The solvent was removed in vacuo and purified with silica gel (40 g) using 0-50% EtOAc/hexanes to give t -butyl 4-( (4-((6-Bromoisoquinolin-3-yl)carbamoyl)pyridin-2-yl)oxy)piperidin-1-crboxylate ( XLIV ) as off-white solid (4.37 g, 8.29 mmol, 61.6% yield). ESIMS found for C ₂₅ H ₂₇ BrN ₄ O ₄ m/z 426.1 (M-Boc).

Stage 2

[0511] To a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole ( XLII ) (2.59 g, 12.43 mmol) in 1,4-dioxane (82.8 ml) was added tert -butyl 4-((4-((6-bromoisoquinolin-3-yl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate ( XLIV ) (4.37 g, 8.29 mmol), K ₃ PO ₄ (4.4 g, 20.7 mmol) and Pd(dppf)Cl ₂ (338.3 mg, 0.410 mmol). The mixture was degassed with Ar and heated to 90° C. for 16 h. The solvent was removed in vacuo and the residue was purified on silica gel (120 g) using 0-100% EtOAc/hexanes to give tert -butyl 4-((4-((6 -(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate ( XLV ) as white solid (3.56 g, 6.73 mmol, 81.3% yield). ESIMS found for C ₂₉ H ₃₂ N ₆ O ₄ m/z 529.3 (M+H).

Stage 3

[0512] To a solution of tert -butyl 4-((4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)oxy)piperidin-1 -carboxylate ( XLV ) (5.56 g, 6.73 mmol) in MeOH (67.4 ml) HCl in dioxane (16.8 ml, 67.35 mmol) was added. The reaction mixture was stirred at 60°C for 4 h. The solvent was neutralized with 7N NH ₃ in MeOH and then removed in vacuo and the residue was purified with silica gel (120 g) using 0-10% 1.0N NH ₃ in MeOH/CHCl ₃ , with obtaining N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-yloxy)isonicotinamide ( 16 ) as a white solid (2.51 g , 5.56 mmol, 82.6% yield), 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.48-1.58(m, 2H), 1.92-2.00(m, 2H), 2.56-2.65(m, 2H), 2.98(dt, J =12.49 , 3.91 Hz, 2H), 3.91 (s, 3H), 5.06-5.15 (m, 1H), 7.34 (s, 1H), 7.50 (dd, J =5, 21, 1.37 Hz, 1H), 7.82 (dd, J = 8.51, 1.37 Hz, 1H), 8.06 (d, J = 8.51 Hz, 1H), 8.11 ( s, 1H), 8.15 (s, 1H), 8.31 (d, J = 5.21 Hz, 1H), 8.38 (s, 1H), 8.58 (s, 1H), 9, 12 (s, 1H), 11.06 (br s, 1H); ESIMS found for C ₂₄ H ₂₄ N ₆ O ₂ m/z 429.2 (M+1).

Stage four

[0513] To a solution of N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-yloxy)isonicotinamide ( 16 ) (1.1 g, 2 .57 mmol) in MeOH (25.7 ml) were added formaldehyde (275.2 mg, 3.35 mmol), HOAc (464 mg, 7.72 mmol) and NaBH(OAc) ₃ (818 mg, 3.86 mmol ). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified on silica gel (40 g) using 0-30% 1.0 N NH ₃ in MeOH/CHCl ₃ to give N-(6-(1-methyl -1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)oxy)isonicotinamide ( 17 ) as off-white solid (1.02 g, 2. 20 mmol, 85.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.66-1.76 (m, 2H), 1.99 (br.dd, J =9.47, 3.70 Hz, 2H), 2.17 (br.s, 2H), 2.19 ( s, 3H), 2.61-2.70 (m, 2H), 3.91 (s, 3H), 5.01-5.09 (m, 1H), 7.35 (s, 1H), 7 .51 (dd, J =5.21, 1.37 Hz, 1H), 7.82 (dd, J =8.64, 1.51 Hz, 1H), 8.06 (d, J =8.78 Hz, 1H), 8.11 (s, 1H), 8.15 (s, 1H), 8.31 (d, J = 5.21 Hz, 1H), 8.38 (s, 1H), 8, 57 (s, 1H), 9.12 (s, 1H), 11.06 (s, 1H); ESIMS found for C ₂₅ H ₂₆ N ₆ O ₂ m/z 443.2 (M+1).

Example 4

[0514] Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(1-methylpiperidin-4-yl)isonicotinamide ( 84 ) and 1'-methyl- N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-4- carboxamide ( 85 ) is shown below in Scheme 17 .

Stage one

[0515] Into a hermetically sealed vessel containing 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine ( XLVII ) (0.29 g, 1.32 mmol), K ₃ PO ₄ (2.2 ml, 2.2 mmol), Pd (dppf) Cl ₂ -CH ₂ Cl ₂ adduct (180 mg, 0.220 mmol) in 1 ,4-dioxane (8 ml), 2-iodo-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide ( XLVI ) (0.4 g, 0.880 mmol) was added . This mixture was degassed with Ar, sealed and heated to 70° C. for 16 h. The solvent was removed and the residue was purified with silica gel (0→10% 1.5N NH ₃ in MeOH/CHCl ₃ ) to give 2-(1-methyl-3 ,6-dihydro-2H-pyridin-4-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide ( 85 ) (247 mg, 0.582 mmol, 66, 2% yield) as an off-white solid. ESIMS found for C ₂₅ H ₂₇ BrN ₄ O ₄ m/z 426.1 (M+H), 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.31(3H, s), 2.57-2.63(2H, m), 2.63-2.70(2H, m), 3.11(2H, brd, J =3.02 Hz), 3.91 (3H, s), 6.89 (1H, t, J = 3.43 Hz), 7.78 (1H, dd, J = 4.94, 1.37 Hz), 7, 82 (1H, dd, J = 8.51, 1.65 Hz), 8.08 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.16 (2H, d , J = 6.04 Hz), 8.38 (1H, s), 8.61 (1H, s), 8.71 (1H, d, J = 4.94 Hz), 9.14 (1H, s ), 11.23 (1H, s); ESIMS found for C ₂₅ H ₂₄ N ₆ O m/z 425.0 (M+1).

Stage 2

[0516] To a solution of 2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridin-4- carboxamide ( 85 ) (200 mg, 0.470 mmol) in EtOH (15 ml), degassed solvent N ₂ , palladium on carbon (100.3 mg, 0.050 mmol) was added and the reaction mixture was stirred under H ₂ atmosphere for 16 h. the mixture was filtered through celite, the solvent was removed in vacuo and the residue was purified with silica gel (24 g) (0→10% 1.5N NH ₃ in CHCl ₃ ) to give 2-(1-methyl-4-piperidyl)-N-[6- (1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide ( 84 ) (100 mg, 0.235 mmol, 49.8% yield) as off-white solid, 1H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.77-1.92(4H, m), 2.00(2H, td, J =11.60, 2.61 Hz), 2.21(3H, s), 2.72(1H, tt, J = 11.49, 4.15 Hz), 2.85-2.93 (2H, m), 3.91 (3H, s), 7.76 (1H, dd, J = 5.21, 1, 65 Hz), 7.82 (1H, dd, J = 8.51, 1.65 Hz), 7.91 (1H, s), 8.07 (1H, d, J = 8.51 Hz), 8 .12 (1H, d, J = 0.82 Hz), 8.15 (1H, d, J = 0.82 Hz), 8.39 (1H, s), 8.60 (1H, s), 8 .66-8.71(1H, m), 9.13(1H, s), 11.17(1H, s); ESIMS found for C ₂₅ H ₂₆ N ₆ O m/z 427.0 (M+1).

Example 5

[0517] Preparation of N-(6-(1-methyl-5-(morpholinomethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide ( 204 ) and N-(6-(1- methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide ( 429 ) is shown in Scheme 18 below.

stages 1-2

[0518] A mixture of 6-bromoisoquinoline-3-amine ( XX ) (4.0 g, 17.93 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ adduct (1.03 g, 1.26 mmol), KOAc (4.39 g, 44.83 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 ,3,2-dioxaborolane (5.01 g, 19.72 mmol) in 1,4-dioxane (50 mL) was sparged with N ₂ for 2 min. The reaction mixture was sealed and heated at 90° C. for 1.5 hours. The reaction mixture was cooled to room temperature, filtered and washed with EtOAc. The filtrate was concentrated and the residue was treated with dioxane (50 ml). 4-Bromo-2-methyl-pyrazole-3-carbaldehyde ( XLVIII ) (3.39 g, 17.93 mmol) was added to the suspension, then K ₃ PO ₄ (9.52 g, 44.83 mmol), Pd( dppf)Cl ₂ -CH ₂ Cl ₂ adduct (1.03 g, 1.26 mmol) and water (15 ml). The mixture was purged with N ₂ for minutes, sealed again and heated at 90° C. for 19 hours. The mixture was cooled to room temperature and concentrated to about 20 ml. The concentrate was diluted with EtOAc and filtered through a Celite pad. The filtrate was diluted with water and the organic layer was separated. The organic layer was washed with brine, dried, filtered and concentrated. The residue was triturated in ether and the resulting solid was filtered to give 4-(3-amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde ( XLIX ) (4.1 g, 16.2 mmol, 90.6% yield) as a brown solid. ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 0.01(6H, s), 0.86(9H, s), 0.88-1.00(2H, m), 1.23-1.35(2H, m), 1.35-1, 46(1H, m), 1.69-1.79(2H, m), 1.85-1.95(2H, m), 2.21(1H, tt, J =12.21, 3.57 Hz), 3.38 (2H, d, J =6.31 Hz), 3.57 (3H, s) ESIMS found for C ₁₄ H ₁₂ N ₄ O m/z 252.95 (M+1).

Stage 3

[0519] A mixture of 4-(3-amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde ( XLIX ) (1.07 g, 4.25 mmol), piperidine (0.84 ml, 8.51 mmol) and catalytic HOAc in DCE (10 ml) were stirred for 30 min. Na(OAc) ₃ BH (1.8 g, 8.51 mmol) was added and stirring was continued for 12 h at room temperature. The reaction mixture was quenched with a minimal amount of saturated aqueous ammonium chloride and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by chromatography (0→20% 7N NH ₃ -MeOH/CHCl ₃ ) to give 6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]isoquinoline-3-amine ( L ) (800 mg, 2.49 mmol, 58.5% yield) as a white solid. ESIMS found for C ₁₉ H ₂₃ N ₅ m/z 322.2 (M+1).

Stage four

[0520] To a suspension of 6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]isoquinolin-3-amine ( L ) (0.14 g, 0.440 mmol), 2-fluoropyridine-4-carboxylic acids ( LI ) (0.07 g, 0.520 mmol), DMAP (0.03 g, 0.220 mmol) and HATU (0.2 g, 0.520 mmol) in DMF (4 ml) was added DIPEA (0.23 ml, 1 .31 mmol). The resulting mixture was stirred at 80° C. for 1.5 hours. An additional 1.2 eq. HATU and stirred at 80°C for another 16 hours, the Reaction mixture was diluted with water and the resulting solid was filtered. The crude product was purified by silica gel chromatography (0→10% 7N NH ₃ -MeOH/CHCl ₃ ) to give 2-fluoro-N-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]- 3-isoquinolyl]pyridine-4-carboxamide ( LII ) (85.0 mg, 0.191 mmol, 43.9% yield) as a brown solid. ESIMS found for C ₂₅ H ₂₅ FN ₆ O m/z 444.9 (M+H).

Stage 5

[0521] To a solution of 2-fluoro-N-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]pyridine-4-carboxamide ( LII ) (80 mg, 0.180 mmol) in DMSO (1 ml) was added morpholine (0.05 ml, 0.540 mmol). The mixture was sealed in the vessel and irradiated with MW at The mixture was sealed in the vessel and subjected to microwave irradiation at 120° C. for 30 minutes. The reaction mixture was heated at 90°C for another 16 h and the mixture was cooled to room temperature, poured into water and the resulting solid was filtered. The crude product was purified by silica gel chromatography (0→5% MeOH/CHCl ₃ ) as eluent, then purified by HPLC (0→65% MeCN/water). Both purified products were separated. Fractions for each product were pooled and concentrated. The residue for each product was redissolved in the minimum amount of CHCl ₃ /MeOH and filtered through carbonate resin (load: 0.23 mmol/500 mg). The filtrate was concentrated and the residue was triturated in ether. The resulting solid was filtered to give N-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]-2-morpholino-pyridine-4-carboxamide ( 429 ) (23 mg , 0.045 mmol, 25.0% yield as a white solid; ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.32-1.44(2H, m), 1.45-1.55(4H, m), 2.38(4H, brs), 3.53-3.62(4H, m), 3.67 (2H, s), 3.71-3.77 (4H, m), 3.92 (3H, s), 7.21 (1H, dd, J =5.21, 1.10 Hz) , 7.47(1H, s), 7.76(1H, dd, J =8.51, 1.65 Hz), 7.82(1H, s), 8.09(1H, d, J =8 .51 Hz), 8.14 (1H, s), 8.29 (1H, d, J = 5.21 Hz), 8.61 (1H, s), 9.17 (1H, s), 11, 01 (1H, s); ESIMS found for C ₂₉ H ₃₃ N ₇ O ₂ m/z 512.0 (M+1) and N-[6-[1-methyl-5-(morpholinomethyl)pyrazol-4-yl]-3-isoquinolyl]- 2-morpholino-pyridine-4-carboxamide ( 204 ) (10 mg, 0.020 mmol, 10.8% yield) as off-white solid, 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.42 (4H, brd, J = 3.84 Hz), 3.53-3.61 (8 H, m), 3.70-3.78 (6H, m), 3.94 (3H , s), 7.21 (1H, dd, J = 5.21, 1.37 Hz), 7.47 (1H, s), 7.76 (1H, dd, J = 8.51, 1.65 Hz), 7.83(1H, s), 8.11(2H, d, J =11.25 Hz), 8.29(1H, d, J =4.94 Hz), 8.62(1H, s), 9.18 (1H, s), 11.02 (1H, s); ESIMS found for C ₂₈ H ₃₁ N ₇ O ₃ m/z 514.0 (M+1).

Example 6

[0522] Preparation of N-(6-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide ( 428 ) and N-(6-(5-amino-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide ( 430 ) is shown below in Scheme 19 .

Stage one

[0523] To a solution of N-(6-bromo-3-isoquinolyl)-2-(4-methylpiperazin-1-yl)pyridine-4-carboxamide ( LIII ) (328 mg, 0.770 mmol) in MeOH (4 mL) was added molybdenum hexacarbonyl (557 mg, 2.02 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ adduct (125.7 mg, 0.150 mmol), sonicated for some time and stirred at 75° C. for night. The reaction mixture was diluted with water, extracted into EtOAc and purified on a silica gel column (0→100% (20% NH ₃ in MeOH-CHCl ₃ /CHCl ₃ )) to give methyl 3-[[2-(4-methylpiperazine-1- yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylate ( LIV ) (232 mg, 0.572 mmol, 74.4% yield). ESIMS found for C ₂₂ H ₂₃ N ₅ O ₃ m/z 406.2 (M+H).

Stage 2

[0524] To a solution of methyl 3-[[2-(4-methylpiperazin-1-yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylate ( LIV ) (232 mg, 0.570 mmol) in THF (4 mL) MeOH (4 ml) and LiOH (137 mg, 5.72 mmol) in water (3 ml) were added. The reaction mixture was stirred for 3 hours at room temperature. The solvent was removed and the residue was suspended in water. Aqueous HCl was added to pH=6 and the solid was collected by filtration to give 3-[[2-(4-methylpiperazin-1-yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylic acid ( LV ) (162 mg, 0.414 mmol, 72.3% yield as a yellow solid. ESIMS found for C ₂₁ H ₂₁ N ₅ O ₃ m/z 392.0 (M+H).

Stage 3

[0525] 3-[[2-(4-Methylpiperazin-1-yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylic acid solution ( LV ) (45 mg, 0.110 mmol), 3-amino-1, 1-dimethylthiourea ( LVI ) (20.6 mg, 0.170 mmol) in POCl ₃ (2.25 ml, 24.14 mmol) was heated at 80°C for 60 hours. The reaction mixture was concentrated and quenched with ice and the pH was adjusted to >12 with 1N NaOH. The solid was collected by filtration to give N-[6-[5-(dimethylamino)-1,3,4-thiadiazol-2-yl]-3-isoquinolyl]-2-(4-methylpiperazin-1-yl)pyridin-4 -carboxamide ( 428 ) (14.6 mg, 0.031 mmol, 26.8% yield) as yellow solid, 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm. 2.32 (3H, brs), 2.52-2.67 (4H, m), 3.19 (6H, s), 3.64 (4H, brs), 7.14-7, 21(1H, m), 7.48(1H, s), 8.07(1H, dd, J =8.51, 1.65Hz), 8.17(1H, s), 8.24-8 .29 (2H, m), 8.70 (1H, s), 9.24 (1H, s), 11.14 (1H, s); ESIMS found for C ₂₄ H ₂₆ N ₈ OS m/z 475.2 (M+1).

Stage four

[0526] 3-[[2-(4-Methylpiperazin-1-yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylic acid ( LV ) solution (60 mg, 0.150 mmol), aminothiourea ( LVII ) (21 0 mg, 0.230 mmol) in POCl ₃ (3 ml, 32.19 mmol) was heated at 80° C. for 60 hours. The reaction mixture was concentrated and quenched with ice and the pH was adjusted to >12 with 1N NaOH. The solid was collected by filtration and purified by column chromatography (0→100% (10% NH ₃ MeOH in EtOAc/hexanes)) to give N-[6-(5-amino-1,3,4-thiadiazol-2-yl)- 3-isoquinolyl]-2-(4-methylpiperazin-1-yl)pyridine-4-carboxamide ( 430 ) (3.7 mg, 0.008 mmol, 5.4% yield) as yellow solid, 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.27(3H, brs), 3.62(4H, brs), 7.12-7.20(1H, m), 7.48(1H, s), 7.60(2H, s), 8.07 (1H, dd, J = 8.51, 1.65 Hz), 8.16 (1H, d, J = 8.78 Hz), 8.25 (1H, s), 8, 27 (1H, d, J = 4.94 Hz), 8.71 (1H, s), 9.24 (1H, s), 11.13 (1H, s); ESIMS found for C ₂₂ H ₂₂ N ₈ OS m/z 447.2 (M+1).

Example 7

[0527] Preparation of 1-methyl-4-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperazine 1-oxide ( 87 ) is shown below in diagram 20 .

Stage one

[0528] To a suspension of 2-(4-methylpiperazin-1-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide ( 10 ) (109 mg, 0.250 mmol ) in DCM (5 ml) was added 3-chlorobenzenecarboperoxoic acid (66 mg, 0.380 mmol). The mixture was stirred at room temperature for 2 hours and concentrated. The crude product was purified by silica gel chromatography (0→10%7n NH ₃ -MeOH/CHCl ₃ ). Fractions containing product were concentrated and the residue was triturated in ether. The resulting solid was filtered and dried to give 2-(4-methyl-4-oxido-piperazin-4-ium-1-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine -4-carboxamide ( 87 ) (65 mg, 0.147 mmol, 57.5% yield) as white solid, 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm. 2.99 (2H, brd, J = 10.70 Hz), 3.11 (3H, s), 3.41 (2H, td, J = 11.53, 3.29 Hz), 3.61 -3.72(2H, m), 3.91(3H, s), 4.25(2H, brd, J =13.17 Hz), 7.20(1H, dd, J =5.08 , 1.23 Hz), 7.55 (1H, s), 7.82 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz ), 8.11 (1H, s), 8.14 (1H, s), 8.29 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.60 (1H , s), 9.13 (1H, s), 11.10 (1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ O ₂ m/z 444.2 (M+1).

[0529] The following compounds were obtained in accordance with the procedure described in the above examples 1-7 .

one

[0530] N-(6-(1H-Pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 1 .

[0531] Off-white solid (38.0 mg, 0.091 mmol, 39.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24 (s, 3H), 2.43 (bt, J = 4.80 Hz, 4H), 3.57-3.65 (m, 4H), 7.16 (dd, J = 5, 21, 0.82 Hz, 1H), 7.46 (s, 1H), 7.88 (dd, J =8.64, 1.51 Hz, 1H), 8.07 (d, J =8.51 Hz, 1H), 8.14-8.31 (m, 1H), 8.19 (s, 1H), 8.26 (d, J =5.21 Hz, 1H), 8.38-8.51 (m, 1H), 8.60 (s, 1H), 9.13 (s, 1H), 11.04 (s, 1H), 13.12 (br s, 1H); ESIMS found for C ₂₃ H ₂₃ N ₇ O m/z 414.2 (M+1).

2

[0532] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(piperazin-1-yl)benzamide 2 .

[0533] Off -white solid (58.3 mg, 0.141 mmol, 49.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.94 (bd, J =3.29 Hz, 4H), 3.22 (bd, J =3.84 Hz, 4H), 3.91 (s, 3H), 7.15 (dd , J = 8.23, 1.92 Hz, 1H), 7.35 (t, J = 7.96 Hz, 1H), 7.48 (d, J = 7.41 Hz, 1H), 7.63 (s, 1H), 7.79 (dd, J =8.51, 1.65 Hz, 1H), 8.06 (d, J =8.78 Hz, 1H), 8.10-8.14 ( m, 2H), 8.38 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.80 (s, 1H); ESIMS found for C ₂₄ H ₂₄ N ₆ O m/z 413.2 (M+1).

3

[0534] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(4-methylpiperazin-1-yl)benzamide 3 .

[0535] White solid (860 mg, 1.92 mmol, 69.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24 (s, 3H), 2.48 (bd, J = 4.94 Hz, 4H), 3.22-3.28 (m, 4H), 3.91 (s, 3H), 7 .15 (dd, J =8.23, 2.20 Hz, 1H), 7.35 (t, J =7.82 Hz, 1H), 7.46 (d, J =7.68 Hz, 1H) , 7.64 (s, 1H), 7.79 (dd, J =8.51, 1.65 Hz, 1H), 8.05 (d, J =8.51 Hz, 1H), 8.09- 8.14 (m, 2H), 8.38 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.80 (s, 1H); ESIMS found for C ₂₅ H ₂₆ N ₆ O m/z 427. (M+1).

four

[0536] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(pyrrolidin-1-ylmethyl)benzamide 4 .

[0537] Light yellow solid (75.5 mg, 0.183 mmol, 41.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.70-1.76 (m, 4H), 2.49 (br s, 4H), 3.68 (s, 2H), 3.91 (s, 3H), 7.43-7.50 ( m, 1H), 7.52-7.57 (m, 1H), 7.80 (dd, J = 8.51, 1.65 Hz, 1H), 7.95 (d, J = 7.68 Hz , 1H), 8.00 (s, 1H), 8.06 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.13 (s, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.80 (s, 1H); ESIMS found for C ₂₅ H ₂₅ N ₅ O m/z 412.2 (M+1).

5

[0538] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(piperidin-4-yloxy)benzamide 5 .

[0539] Off -white solid (540.6 mg, 1.20 mmol, 81.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.42-1.54 (m, 2H), 1.92-1.99 (m, 2H), 2.56-2.64 (m, 2H), 2.97 (dt, J =12.62 , 4.25 Hz, 2H), 3.91 (s, 3H), 4.49-4.61 (m, 1H), 7.16 (dd, J =8.10, 1.51 Hz, 1H) , 7.41 (t, J = 8.23 Hz, 1H), 7.59-7.68 (m, 2H), 7.80 (dd, J = 8.51, 1.65 Hz, 1H), 8.06 (d, J = 8.78 Hz, 1H), 8.10-8.16 (m, 2H), 8.38 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.82 (s, 1H); ESIMS found for C ₂₅ H ₂₅ N ₅ O ₂ m/z 428.2 (M+1).

6

[0540] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide 6 .

[0541] Off-white solid (115.9 mg, 0.249 mmol, 71.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.61-1.74 (m, 2H), 1.92-2.02 (m, 2H), 2.15-2.26 (m, 2H), 2.19 (s, 3H), 2, 58-2.68 (m, 2H), 3.91 (s, 3H), 4.48-4.58 (m, 1H), 7.16 (dd, J =7.96, 1.65 Hz, 1H), 7.42 (t, J = 8.23 Hz, 1H), 7.60-7.68 (m, 2H), 7.80 (dd, J = 8.51, 1.37 Hz, 1H ), 8.06 (d, J = 8.51 Hz, 1H), 8.08-8.16 (m, 2H), 8.38 (s, 1H), 8.59 (s, 1H), 9 .11 (s, 1H), 10.83 (s, 1H); ESIMS found for C ₂₆ H ₂₇ N ₅ O ₂ m/z 442.2 (M+1).

7

[0542] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(piperidin-4-yloxy)benzamide 7 .

[0543] White solid (554 mg, 1.23 mmol, 91.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.42-1.51(m, 2H), 1.90-1.98(m, 2H), 2.55-2.63(m, 2H), 2.95(dt, J =12.69 , 3.95 Hz, 2H), 3.91 (s, 3H), 4.51-4.58 (m, 1H), 7.05 (d, J =8.78 Hz, 2H), 7.78 (dd, J =8.51, 1.37 Hz, 1H), 8.02-8.08 (m, 3H), 8.11 (s, 1H), 8.11 (brs, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 9.10 (s, 1H), 10.63 (s, 1H); ESIMS found for C ₂₅ H ₂₅ N ₅ O ₂ m/z 428.2 (M+1).

eight

[0544] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((1-methylpiperidin-4-yl)oxy)benzamide 8 .

[0545] White solid (82.0 mg, 0.186 mmol, 89.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.61-1.72 (m, 2H), 1.91-2.02 (m, 2H), 2.14-2.26 (m, 2H), 2.18 (s, 3H), 2, 58-2.68 (m, 2H), 3.91 (s, 3H), 4.51 (tt, J =8.16, 3.91 Hz, 1H), 7.06 (d, J =8, 78 Hz, 2H), 7.78 (dd, J = 8.64, 1.51 Hz, 1H), 8.01-8.07 (m, 3H), 8.09-8.13 (m, 2H ), 8.37 (s, 1H), 8.58 (s, 1H), 9.10 (s, 1H), 10.64 (s, 1H); ESIMS found for C ₂₆ H ₂₇ N ₅ O ₂ m/z 442.2 (M+1).

9

[0546] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperazin-1-yl)isonicotinamide 9 .

[0547] Off-white solid (57.3 mg, 0.139 mmol, 91.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.78-2.85 (m, 4H), 3.50-3.56 (m, 4H), 3.91 (s, 3H), 7.14 (dd, J =5.08, 1.24 Hz, 1H), 7.42 (s, 1H), 7.81 (dd, J =8.51, 1.65 Hz, 1H), 8.07 (d, J =8.51 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.25 (d, J = 4.94 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H ), 9.12 (s, 1H), 11.03 (s, 1H); ESIMS found for C ₂₃ H ₂₃ N ₇ O m/z 414.2 (M+1).

ten

[0548] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 10 .

[0549] Brown solid (71.6 mg, 0.168 mmol, 66.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24 (s, 3H), 2.43 (bt, J = 4.80 Hz, 4H), 3.56-3.65 (m, 4H), 3.91 (s, 3H), 7 .16 (dd, J =5.08, 0.96 Hz, 1H), 7.46 (s, 1H), 7.81 (dd, J =8.37, 1.51 Hz, 1H), 8, 07 (d, J = 8.51 Hz, 1H), 8.10-8.16 (m, 2H), 8.26 (d, J = 5.21 Hz, 1H), 8.38 (s, 1H ), 8.59 (s, 1H), 9.12 (s, 1H), 11.05 (s, 1H); ESIMS found for C ₂₄ H ₂₅ N ₇ O m/z 428.2 (M+1).

eleven

[0550] 2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 11 .

[0551] White solid (58.7 mg, 0.129 mmol, 88.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.01 (d, J = 6.59 Hz, 6 H), 2.53-2.59 (m, 4H), 2.65-2.76 (m, 1H), 3.56-3.62 (m, 4H), 3.91 (s, 3H), 7.15 (d, J = 5.21 Hz, 1H), 7.44 (s, 1H), 7.81 (dd, J = 8, 51, 1.65 Hz, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.25 (d, J = 5.21 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.12 (s, 1H), 11.04 (s, 1H); ESIMS found for C ₂₆ H ₂₉ N ₇ O m/z 456.2 (M+1).

12

[0552] 2-(4-Cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 12 .

[0553] Off -white solid (124.0 mg, 0.273 mmol, 68.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 0.38 (broad, J = 2.74 Hz, 2H), 0.46 (broad, J = 4.67 Hz, 2H), 1.66 (dt, J = 6.24, 3, 05 Hz, 1H), 2.61-2.67 (m, 4H), 3.57 (brs, 4H), 3.91 (s, 3H), 7.15 (d, J =4.94 Hz, 1H), 7.46 (s, 1H), 7.81 (d, J = 8.23 Hz, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.11 ( s, 1H), 8.14 (s, 1H), 8.25 (d, J =4.94 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9, 12 (s, 1H), 11.04 (s, 1H); ESIMS found for C ₂₆ H ₂₇ N ₇ O m/z 454.2 (M+1).

13

[0554] 2-(4-(2-Fluoroethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 13 .

[0555] White solid (13.2 mg, 0.029 mmol, 17.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.55-2.61 (m, 4H), 2.69 (dt, J = 28.85, 4.95 Hz, 2H), 3.59-3.64 (m, 4H), 4.59 ( dt, J = 47.85, 4.95 Hz, 2H), 7.16 (dd, J = 5.08, 0.96 Hz, 1H), 7.47 (s, 1H), 7.81 (dd , J = 8.51, 1.37 Hz, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8 .26 (d, J = 4.94 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.13 (s, 1H), 11.04 (s, 1H) ; ESIMS found for C ₂₅ H ₂₆ FN ₇ O m/z 460.2 (M+1).

fourteen

[0556] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)nicotinamide 14 .

[0557] Beige solid (28.0 mg, 0.062 mmol, 66.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.22 (s, 3H), 2.40 (t, J =5.08 Hz, 4H), 3.60-3.67 (m, 4H), 3.91 (s, 3H), 6.90 (d, J =9.06 Hz, 1H), 7.78 (dd, J =8.51, 1.65 Hz, 1H), 8.04 (d, J =8.78 Hz, 1H), 8 .08-8.12 (m, 2H), 8.19 (dd, J = 9.06, 2.47 Hz, 1H), 8.37 (s, 1H), 8.57 (s, 1H), 8.84 (d, J =2.20 Hz, 1H), 9.09 (s, 1H), 10.63 (s, 1H); ESIMS found for C ₂₄ H ₂₅ N ₇ O m/z 428.2 (M+1).

fifteen

[0558] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-5-(piperidin-4-yloxy)nicotinamide 15 .

[0559] White solid (29.0 mg, 0.064 mmol, 75.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.45-1.55(m, 2H), 1.95-2.01(m, 2H), 2.57-2.65(m, 2H), 2.98(dt, J =12.83 , 4.15 Hz, 2H), 3.91 (s, 3H), 4.60-4.69 (m, 1H), 7.82 (dd, J =8.51, 1.37 Hz, 1H) , 7.98-8.02 (m, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8, 38 (s, 1H), 8.45 (d, J =2.74 Hz, 1H), 8.60 (s, 1H), 8.75 (d, J =1.65 Hz, 1H), 9, 13 (s, 1H), 11.11 (br s, 1H); ESIMS found for C ₂₄ H ₂₄ N ₆ O ₂ m/z 429.2 (M+1).

16

[0560] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-yloxy)isonicotinamide 16 .

[0561] Off-white solid (113.3 mg, 0.264 mmol, 58.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.47-1.61(2H, m), 1.92-2.01(2H, m), 2.57-2.67(2H, m), 2.98(2H, dt, J =12 .49, 3.91 Hz), 3.91(3H, s), 5.06-5.15(1H, m), 7.34(1H, s), 7.50(1H, dd, J = 5.21, 1.37 Hz), 7.82 (1H, dd, J = 8.51, 1.37 Hz), 8.06 (1H, d, J = 8.51 Hz), 8.11 ( 1H, s), 8.15 (1H, s), 8.31 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.58 (1H, s), 9, 12(1H, s), 11.06(1H, brs); ESIMS found for C ₂₄ H ₂₄ N ₆ O ₂ m/z 429.2 (M+1).

17

[0562] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)oxy)isonicotinamide 17 .

[0563] Off-white solid (1.02 g, 2.20 mmol, 85.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.64-1.77 (2H, m), 1.99 (2H, br.dd, J = 8.92, 3.98 Hz), 2.17 (2H, br.s), 2.19 ( 3H, s), 2.60-2.70 (2H, m), 3.91 (3H, s), 5.04 (1H, tt, J =8.40, 3.95 Hz), 7.35 (1H, s), 7.51 (1H, dd, J = 5.21, 1.37 Hz), 7.82 (1H, dd, J = 8.51, 1.65 Hz), 8.06 ( 1H, d, J = 8.78 Hz), 8.11 (1H, s), 8.15 (1H, s), 8.31 (1H, d, J = 5.21 Hz), 8.38 ( 1H, s), 8.57 (1H, s), 9.12 (1H, s), 11.06 (1H, s); ESIMS found for C ₂₅ H ₂₆ N ₆ O ₂ m/z 443.2 (M+1).

eighteen

[0564] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-5-(piperidin-4-ylamino)nicotinamide 18 .

[0565] Off-white solid (274.3 mg, 0.610 mmol, 65.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.22-1.36 (m, 3H), 1.86 (brd, J =9.88 Hz, 2H), 2.52-2.60 (m, 2H), 2.92-3, 01 (m, 2H), 3.73-3.84 (m, 1H), 3.91 (s, 3H), 6.70 (d, J = 7.68 Hz, 1H), 6.98 (s , 1H), 6.99-7.04 (m, 1H), 7.81 (dd, J = 8.51, 1.37 Hz, 1H), 8.06 (d, J = 8.51 Hz, 1H), 8.09 (d, J =5.21 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H), 8.55 ( s, 1H), 9.11 (s, 1H), 10.78 (br s, 1H); ESIMS found for C ₂₄ H ₂₅ N ₇ O m/z 428.2 (M+1).

19

[0566] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-5-((1-methylpiperidin-4-yl)amino)nicotinamide 19 .

[0567] Off -white solid (42.3 mg, 0.091 mmol, 51.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.41-1.53 (m, 2H), 1.84-1.93 (m, 2H), 2.00 (bt, J = 10.84 Hz, 2H), 2.17 (s, 3H), 2.73 (brd, J = 11.80 Hz, 2H), 3.65-3.76 (m, 1H), 3.91 (s, 3H), 6.69 (d, J = 7.41 Hz, 1H), 6.99 (s, 1H), 7.01 (dd, J = 5.35, 1.51 Hz, 1H), 7.81 (dd, J = 8.51, 1.65 Hz, 1H), 8.06 (d, J = 8.51 Hz, 1H), 8.09 (d, J = 5.21 Hz, 1H), 8.11 (s, 1H), 8 .14 (s, 1H), 8.38 (s, 1H), 8.55 (s, 1H), 9.11 (s, 1H), 10.79 (s, 1H); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

twenty

[0568] N-(6-(1-Isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(piperidin-4-yloxy)benzamide 20 .

[0569] White solid (77.3 mg, 0.170 mmol, 77.3% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.44-1.54 (m, 2H), 1.49 (d, J = 6.59 Hz, 6 H), 1.92-2.01 (m, 2H), 2.61 (ddd, J = 12.49, 10.02, 2.74 Hz, 2H), 2.98 (dt, J = 12.69, 4.22 Hz, 2H), 4.50-4.60 (m, 2H), 7.13-7.19 (m, 1H), 7.41 (t, J = 8.10 Hz, 1H), 7.61-7.65 (m, 2H), 7.83 (dd, J = 8.51, 1.65 Hz, 1H), 8.05 (d, J =8.51 Hz, 1H), 8.11 (s, 1H), 8.15 (s, 1H), 8.48 ( s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.80 (s, 1H); ESIMS found for C ₂₇ H ₂₉ N ₅ O ₂ m/z 456.2 (M+1).

21

[0570] N-(6-(1-Isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide 21 .

[0571] Off-white solid (54.6 mg, 0.116 mmol, 92.8% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.49 (d, J = 6.59 Hz, 6 H), 1.63-1.74 (m, 2H), 1.93-2.02 (m, 2H), 2.16-2.26 (m, 2H), 2.19 (s, 3H), 2.58-2.68 (m, 2H), 4.50-4.59 (m, 2H), 7.13-7.21 (m , 1H), 7.42 (t, J = 8.23 Hz, 1H), 7.61-7.67 (m, 2H), 7.83 (dd, J = 8.51, 1.65 Hz, 1H), 8.06 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.16 (s, 1H), 8.49 (s, 1H), 8.59 ( s, 1H), 9.11 (s, 1H), 10.81 (s, 1H); ESIMS found for C ₂₈ H ₃₁ N ₅ O ₂ m/z 470.3 (M+1).

22

[0572] N-(6-(1-Isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(piperidin-4-yloxy)benzamide 22 .

[0573] White solid (52.0 mg, 0.108 mmol, 75.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.42-1.54 (m, 2H), 1.48 (d, J = 6.59 Hz, 6 H), 1.91-1.99 (m, 2H), 2.55-2.64 (m, 2H), 2.95 (dt, J =12.83, 4.15 Hz, 2H), 4.50-4.59 (m, 2H), 7.05 (d, J =8.78 Hz, 2H), 7.82 (dd, J = 8.51, 1.37 Hz, 1H), 8.02-8.08 (m, 3H), 8.11 (s, 1H), 8.14 (s, 1H), 8.48 (s, 1H), 8.58 (s, 1H), 9.09 (s, 1H), 10.62 (s, 1H); ESIMS found for C ₂₇ H ₂₉ N ₅ O ₂ m/z 456.2 (M+1).

23

[0574] N-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 23 .

[0575] Off-white solid (83.0 mg, 0.183 mmol, 78.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 0.99-1.04 (m, 2H), 1.09-1.14 (m, 2H), 2.24 (s, 3H), 2.43 (bt, J = 4.94 Hz, 4H), 3.58-3.65 (m, 4H), 3.79 (tt, J =7.38, 3.88 Hz, 1H), 7.12-7.19 (m, 1H), 7 .46 (s, 1H), 7.84 (dd, J = 8.64, 1.51 Hz, 1H), 8.06 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.16 (s, 1H), 8.26 (d, J =4.94 Hz, 1H), 8.49 (s, 1H), 8.59 (s, 1H), 9.12 ( s, 1H), 11.04 (s, 1H); ESIMS found for C ₂₆ H ₂₇ N ₇ O m/z 454.2 (M+1).

24

[0576] 4-Fluoro-N-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 24 .

[0577] Beige solid (49.0 mg, 0.108 mmol, 53.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.94-2.13 (m, 6H), 2.22 (s, 3H), 2.88 (bd, J = 11.25 Hz, 2H), 4.11-4.21 (m , 1H), 7.36 (t, J = 8.92 Hz, 2H), 7.83 (dd, J = 8.51, 1.37 Hz, 1H), 8.06 (d, J = 8, 51 Hz, 1H), 8.12-8.20 (m, 4H), 8.51 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.89 ( s, 1H); ESIMS found for C ₂₅ H ₂₄ FN ₅ O m/z 430.2 (M+1).

25

[0578] 4-(Difluoromethoxy)-N-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 25 .

[0579] Beige solid (67.0 mg, 0.133 mmol, 52.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.95-2.11 (m, 6H), 2.22 (s, 3H), 2.88 (bd, J =10.98 Hz, 2H), 4.11-4.20 (m , 1H), 7.40 (t, J = 73.95 Hz, 1H), 7.31 (d, J = 8.78 Hz, 2H), 7.83 (dd, J = 8.51, 1, 37 Hz, 1H), 8.06 (d, J = 8.51 Hz, 1H), 8.13 (s, 1H), 8.15-8.18 (m, 3H), 8.51 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.88 (s, 1H); ESIMS found for C ₂₆ H ₂₅ F ₂ N ₅ O ₂ m/z 478.2 (M+1).

26

[0580] 5-Fluoro-N-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)nicotinamide 26 .

[0581] White solid (38.0 mg, 0.088 mmol, 75.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.95-2.11 (m, 6H), 2.22 (s, 3H), 2.88 (bd, J =11.25 Hz, 2H), 4.11-4.20 (m , 1H), 7.86 (dd, J = 8.78, 1.37 Hz, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.14 (s, 1H), 8 .19 (s, 1H), 8.33 (dt, J = 9.47, 2.26 Hz, 1H), 8.52 (s, 1H), 8.60 (s, 1H), 8.80 ( e, J = 2.74 Hz, 1H), 9.07 (s, 1H), 9.13 (s, 1H), 11.24 (s, 1H); ESIMS found for C ₂₄ H ₂₃ FN ₆ O m/z 431.2 (M+1).

27

[0582] N ² -Methyl-N ⁵ -(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)pyridine-2,5-dicarboxamide 27 .

[0583] Beige solid (23.0 mg, 0.049 mmol, 31.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.96-2.12 (m, 6H), 2.22 (s, 3H), 2.89 (broad s, 2H), 2.85 (d, J = 4.67 Hz, 3H), 4.12-4.20 (m, 1H), 7.86 (dd, J =8.51, 1.65 Hz, 1H), 8.07 (d, J =8.51 Hz, 1H), 8 .13-8.17 (m, 2H), 8.19 (s, 1H), 8.52 (s, 1H), 8.55 (dd, J =7.96, 2.20 Hz, 1H), 8.62 (s, 1H), 8.94 (q, J =4.85 Hz, 1H), 9.13 (s, 1H), 9.21 (d, J =1.92 Hz, 1H), 11.30 (s, 1H); ESIMS found for C ₂₆ H ₂₇ N ₇ O ₂ m/z 470.2 (M+1).

28

[0584] 4-Fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide 28 .

[0585] Beige solid (43.0 mg, 0.122 mmol, 46.7% yield). ¹ H NMR (499 MHz, METHANOL- d ₄ ) δ ppm 3.86 (s, 3H), 7.28 (t, J = 8.78 Hz, 2H), 7.45 (broad s, 1H), 7.68 (d, J = 8.51 Hz, 1H ), 7.94 (br. s, 1H), 8.00 (s, 1H), 8.06-8.15 (m, 3H), 8.66 (s, 1H), 9.13 (br. s, 1H); ESIMS found for C ₂₀ H ₁₅ FN ₄ O m/z 347.1 (M+1).

29

[0586] 4-(Difluoromethoxy)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide 29 .

[0587] White solid (16.0 mg, 0.040 mmol, 15.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.85 (3H, s), 7.41 (1H, t, J = 73.70 Hz), 7.31 (1H, s), 7.32 (1H, s), 7.33 (1H, broad .s), 7.73 (1H, dd, J = 8.37, 1.51 Hz), 7.81 (1H, s), 8.09 (1H, s), 8.15 (1H, d, J = 8.51 Hz), 8.16-8.17 (1H, m), 8.17-8.21 (1H, m), 8.69 (1H, s), 9.22 (1H, s ), 10.96 (1H, s); ESIMS found for C ₂₁ H ₁₆ F ₂ N ₄ O ₂ m/z 395.1 (M+1).

37

[0588] N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 37 .

[0589] White solid (102.0 mg, 0.239 mmol, 82.9% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.38-2.46(4H, m), 3.55-3.64(4H, m), 3.85(3H, s), 7.16(1H, dd, J =5.08, 1.23 Hz), 7.33(1H, d, J =1.10 Hz), 7.48(1H, s), 7.74(1H, dd, J =8 .51, 1.65 Hz), 7.81 (1H, s), 8.10 (1H, d, J = 0.82 Hz), 8.15 (1H, d, J = 8.51 Hz), 8.24-8.28(1H, m), 8.70(1H, s), 9.23(1H, s), 11.11(1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ O m/z 428.2 (M+1).

40

[0590] N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-isopropoxybenzamide 40 .

[0591] Light green solid (33.0 mg, 0.082 mmol, 31.7% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.31 (d, J = 6.04 Hz, 6 H), 2.47 (broad s, 3H), 3.71 (broad s, 3H), 4.75 (dquin, J = 12.06 , 5.97, 5.97, 5.97, 5.97 Hz, 1H), 7.03 (d, J = 9.06 Hz, 2H), 7.32 (broad s, 1H), 7, 65 (brd, J = 8.23 Hz, 1H), 8.02 (brd s, 1H), 8.05-8.09 (m, 2H), 8.15 (brd, J = 8.51 Hz, 1H), 8.68 (brs, 1H), 9.22 (brs, 1H), 10.71 (brs, 1H); ESIMS found for C ₂₄ H ₂₄ N ₄ O ₂ m/z 401.2 (M+1).

45

[0592] N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(piperidin-4-yloxy)benzamide 45 .

[0593] White solid (30.0 mg, 0.065 mmol, 41.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.42-1.53 (m, 2H), 1.91-1.98 (m, 2H), 2.40 (s, 3H), 2.55-2.63 (m, 2H), 2, 95 (dt, J = 12.62, 4.12 Hz, 2H), 3.68 (s, 3H), 4.49-4.58 (m, 1H), 7.06 (d, J = 8, 78 Hz, 2H), 7.13 (s, 1H), 7.64 (dd, J =8.51, 1.65 Hz, 1H), 7.97 (s, 1H), 8.06 (d, J = 8.78 Hz, 2H), 8.12 (d, J = 8.51 Hz, 1H), 8.66 (s, 1H), 9.19 (s, 1H), 10.69 (s, 1H); ESIMS found for C ₂₆ H ₂₇ N ₅ O ₂ m/z 442.1 (M+1).

47

[0594] 4-(Benzyloxy)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide 47 .

[0595] Beige solid (114.0 mg, 0.254 mmol, 64.8% yield). ¹¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.41 (s, 3H), 3.69 (s, 3H), 5.22 (s, 2H), 7.12-7.19 (m, 3H), 7.31-7.38 (m, 1H), 7.42 (t, J = 7.41 Hz, 2H), 7.48 (d, J = 7.14 Hz, 2H), 7.64 (dd, J = 8.64, 1.51 Hz, 1H), 7.99 (s, 1H), 8.10 (d, J = 8.78 Hz, 2H), 8.13 (d, J = 8.51 Hz, 1H), 8.67 ( s, 1H), 9.20 (s, 1H), 10.73 (s, 1H); ESIMS found for C ₂₈ H ₂₄ N ₄ O ₂ m/z 449.2 (M+1).

49

[0596] N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 49 .

[0597] Beige solid (12.0 mg, 0.027 mmol, 11.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.40(3H, s), 2.41-2.44(4H, m), 3.53-3.64(4H, m), 3.68(3H, s), 7.14(1H, s), 7.16(1H, dd, J =5.21, 1.10 Hz), 7.47(1H, s), 7.67(1H, dd, J =8.51, 1.65Hz), 8.00(1H, s), 8.14(1H, d, J =8.51Hz), 8.26(1H, d, J =4.94Hz) ), 8.67 (1H, s), 9.22 (1H, s), 11.09 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.0 (M+1).

52

[0598] 4-Isopropoxy-N-(6-(5,6,7,8-tetrahydroimidazo[1,2- a ]pyrazin-3-yl)isoquinolin-3-yl)benzamide 52 .

[0599] Beige solid (20.0 mg, 0.044 mmol, 27.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.31 (d, J = 6.04 Hz, 6 H), 2.79 (br.s, 1H), 3.08 (b. t, J = 5.21 Hz, 2H), 3.96 ( s, 2H), 4.13 (t, J = 5.21 Hz, 2H), 4.75 (sep, J = 6.04 Hz, 1H), 7.03 (d, J = 8.78 Hz, 2H), 7.31 (s, 1H), 7.69 (dd, J =8.64, 1.51 Hz, 1H), 8.01 (s, 1H), 8.07 (d, J =8 .78 Hz, 2H), 8.10 (d, J =8.78 Hz, 1H), 8.66 (s, 1H), 9.17 (s, 1H), 10.67 (s, 1H); ESIMS found for C ₂₅ H ₂₅ N ₅ O ₂ m/z 428.2 (M+1).

53

[0600] 2-(4-Aminopiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 53 .

[0601] Off-white solid (195.0 mg, 0.456 mmol, 81.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.19-1.29(2H, m), 1.76-1.85(2H, m), 2.80-2.90(1H, m), 2.93-3.04(2H, m ), 3.91 (3H, s), 4.32 (2H, brd, J = 13.17 Hz), 7.10 (1H, dd, J = 5.21, 1.10 Hz), 7 .45 (1H, s), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.78 Hz), 8.11 (1H, s), 8.13(1H, s), 8.23(1H, d, J =4.94 Hz), 8.38(1H, s), 8.59(1H, s), 9.12( 1H, s), 11.03 (1H, brs); ESIMS found for C ₂₄ H ₂₅ N ₇ O m/z 428.2 (M+1).

54

[0602] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methylamino)piperidin-1-yl)isonicotinamide 54 .

[0603] White solid (69.0 mg, 0.156 mmol, 41.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.17-1.31 (m, 2H), 1.88 (brd, J = 10.43 Hz, 2H), 2.31 (s, 3H), 2.52-2.60 (m, 1H), 3.01 (bt, J = 11.11 Hz, 2H), 3.91 (s, 3H), 4.29 (bd, J = 13.17 Hz, 2H), 7, 10 (d, J =5.21 Hz, 1H), 7.44 (s, 1H), 7.81 (d, J =8.51 Hz, 1H), 8.07 (d, J =8.51 Hz, 1H), 8.11 (s, 1H), 8.13 (s, 1H), 8.23 (d, J =4.94 Hz, 1H), 8.38 (s, 1H), 8, 59 (s, 1H), 9.12 (s, 1H), 11.03 (br s, 1H); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

55

[0604] 2-(4-(Dimethylamino)piperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 55 .

[0605] Off-white solid (30.0 mg, 0.066 mmol, 31.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.37 (2H, qvd, J = 11.94, 3.70 Hz), 1.83 (2H, brd, J = 11.25 Hz), 2.19 (6H, s), 2.30 -2.40 (1H, m), 2.83-2.94 (2H, m), 3.91 (3H, s), 4.44 (2H, brd, J = 13.17 Hz), 7.11(1H, dd, J =5.21, 1.10 Hz), 7.45(1H, s), 7.81(1H, dd, J =8.51, 1.65 Hz), 8 .07 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.24 (1H, d, J = 5.21 Hz), 8 .38 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.03 (1H, s); ESIMS found for C ₂₆ H ₂₉ N ₇ O m/z 456.2 (M+1).

56

[0606] 2-((1-Isopropylpiperidin-4-yl)oxy)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 56 .

[0607] White solid (20.0 mg, 0.043 mmol, 12.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 0.99 (d, J = 6.31 Hz, 6 H), 1.61-1.71 (m, 2H), 1.96-2.05 (m, 2H), 2.28-2.39 (m, 2H), 2.68-2.79 (m, 3H), 3.91 (s, 3H), 4.98-5.07 (m, 1H), 7.35 (s, 1H), 7.50 (dd, J =5.35, 1.51 Hz, 1H), 7.82 (dd, J =8.64, 1.51 Hz, 1H), 8.06 (d, J =8, 51 Hz, 1H), 8.11 (d, J =0.82 Hz, 1H), 8.15 (s, 1H), 8.31 (d, J =5.76 Hz, 1H), 8.38 (s, 1H), 8.57 (s, 1H), 9.12 (s, 1H), 11.06 (s, 1H); ESIMS found for C ₂₇ H ₃₀ N ₆ O ₂ m/z 471.2 (M+1).

57

[0608] 2-(3-aminoazetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 57 .

[0609] Off-white solid (200.4 mg, 0.502 mmol, 65.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.17 (brs, 2H), 3.62 (dd, J =8.10, 5.90 Hz, 2H), 3.80-3.89 (m, 1H), 4.19 (t, J = 7.68 Hz, 2H), 7.01 (s, 1H), 7.14 (dd, J = 5.21, 1.37 Hz, 1H), 7.81 (dd, J = 8.64 , 1.51 Hz, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.13 (s, 1H), 8.19 (d, J =5.21 Hz, 1H), 8.38 (s, 1H), 8.58 (s, 1H), 9.12 (s, 1H), 10.97 (s, 1H); ESIMS found for C ₂₂ H ₂₁ N ₇ O m/z 400.2 (M+1).

59

[0610] 2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 59 .

[0611] Off-white solid (286.7 mg, 0.671 mmol, 77.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.14 (6H, s), 3.19-3.26 (1H, m), 3.81 (2H, dd, J =8.51, 5.21 Hz), 3.91 (3H, s) , 4.04-4.12 (2H, m), 7.03 (1H, s), 7.15 (1H, dd, J = 5.21, 1.65 Hz), 7.81 (1H, dd , J = 8.51, 1.65 Hz), 8.06 (1H, d, J = 8.78 Hz), 8.10 (1H, d, J = 0.82 Hz), 8.13 (1H , s), 8.21 (1H, d, J = 5.21 Hz), 8.37 (1H, s), 8.57 (1H, s), 9.12 (1H, s), 10.92 (1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ O m/z 428.0 (M+1).

60

[0612] 2-Fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)benzamide 60 .

[0613] Off -white solid (18.0 mg, 0.052 mmol, 13.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 4.15 (s, 3H), 7.32-7.39 (m, 2H), 7.55-7.65 (m, 1H), 7.76 (td, J =7.55, 1.65 Hz, 1H), 8.08 (dd, J = 8.51, 1.65 Hz, 1H), 8.16 (d, J = 8.78 Hz, 1H), 8.39 (s, 1H), 8.64 (s, 1H), 8.75 (s, 1H), 9.17 (s, 1H), 10.88 (s, 1H); ESIMS found for C ₁₉ H ₁₄ FN ₅ O m/z 348.2 (M+1).

61

[0614] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide 61 .

[0615] Brown solid (72.9 mg, 0.176 mmol, 60.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.54-3.61 (m, 4H), 3.71-3.77 (m, 4H), 3.91 (s, 3H), 7.21 (dd, J =5.08, 1.23 Hz, 1H), 7.47 (s, 1H), 7.81 (dd, J =8.51, 1.65 Hz, 1H), 8.07 (d, J =8.78 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.29 (d, J = 5.21 Hz, 1H), 8.38 (s, 1H), 8.60 (s, 1H ), 9.13 (s, 1H), 11.05 (s, 1H); ESIMS found for C ₂₃ H ₂₂ N ₆ O ₂ m/z 415.2 (M+1).

62

[0616] 2-((2-(Dimethylamino)ethyl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 62 .

[0617] Brown solid (79.2 mg, 0.191 mmol, 66.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.19 (s, 6H), 2.43 (t, J = 6.72 Hz, 2H), 3.35-3.43 (m, 2H), 3.91 (s, 3H), 6, 61 (t, J = 5.49 Hz, 1H), 7.02 (dd, J = 5.21, 1.37 Hz, 1H), 7.04 (s, 1H), 7.81 (dd, J = 8.51, 1.65 Hz, 1H), 8.06 (d, J = 8.78 Hz, 1H), 8.08-8.12 (m, 2H), 8.14 (s, 1H) , 8.38 (s, 1H), 8.56 (s, 1H), 9.11 (s, 1H), 10.80 (s, 1H); ESIMS found for C ₂₃ H ₂₅ N ₇ O m/z 416.2 (M+1).

63

[0618] 2-(2-(Dimethylamino)ethoxy)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 63 .

[0619] Brown solid (84.1 mg, 0.202 mmol, 70.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23 (s, 6H), 2.65 (t, J =5.76 Hz, 2H), 3.91 (s, 3H), 4.41 (t, J =5.90 Hz, 2H) , 7.39 (d, J =0.82 Hz, 1H), 7.53 (dd, J =5.21, 1.37 Hz, 1H), 7.82 (dd, J =8.51, 1 .65 Hz, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.15 (s, 1H), 8.33 (d, J = 5 .21 Hz, 1H), 8.38 (s, 1H), 8.58 (s, 1H), 9.12 (s, 1H), 11.08 (s, 1H); ESIMS found for C ₂₃ H ₂₄ N ₆ O ₂ m/z 417.2 (M+1).

64

[0620] 2-(4-Isobutylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 64 .

[0621] Off-white solid (61.3 mg, 0.131 mmol, 45.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 0.90 (d, J = 6.59 Hz, 6 H), 1.83 (dquin, J = 13.48, 6.85, 6.85, 6.85, 6.85 Hz, 1H), 2 .09 (d, J = 7.41 Hz, 2H), 2.45 (bt, J = 4.94 Hz, 4H), 3.57-3.64 (m, 4H), 3.91 ( s, 3H), 7.12-7.18 (m, 1H), 7.45 (s, 1H), 7.81 (dd, J =8.51, 1.37 Hz, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.25 (d, J = 5.21 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.12 (s, 1H), 11.04 (s, 1H); ESIMS found for C ₂₇ H ₃₁ N ₇ O m/z 470.2 (M+1).

65

[0622] 2-(Azetidin-3-yloxy)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 65 .

[0623] Off -white solid (64.9 mg, 0.162 mmol, 23.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.51-3.58 (m, 2H), 3.77 (brt, J = 7.68 Hz, 2H), 3.91 (s, 3H), 5.39 (quin, J = 6, 24 Hz, 1H), 7.40 (s, 1H), 7.54 (dd, J =5.21, 1.37 Hz, 1H), 7.82 (dd, J =8.51, 1.37 Hz, 1H), 8.07 (d, J = 8.51 Hz, 1H), 8.11 (s, 1H), 8.15 (s, 1H), 8.30 (d, J = 5.21 Hz, 1H), 8.38 (s, 1H), 8.58 (s, 1H), 9.13 (s, 1H), 11.09 (br s, 1H); ESIMS found for C ₂₂ H ₂₀ N ₆ O ₂ m/z 401.2 (M+1).

66

[0624] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylazetidin-3-yl)oxy)isonicotinamide 66 .

[0625] Off-white solid (144.0 mg, 0.347 mmol, 48.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.30(3H, s), 2.99-3.05(2H, m), 3.69-3.77(2H, m), 3.91(3H, s), 5.16(1H, quin, J = 5.76 Hz), 7.40 (1H, d, J = 1.37 Hz), 7.55 (1H, dd, J = 5.21, 1.37 Hz), 7.82 ( 1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.78 Hz), 8.11 (1H, s), 8.15 (1H, s), 8.30 (1H, d, J = 5.49 Hz), 8.38 (1H, s), 8.58 (1H, s), 9.12 (1H, s), 11.09 (1H, s ); ESIMS found for C ₂₃ H ₂₂ N ₆ O ₂ m/z 415.0 (M+1).

67

[0626] 2-(4-ethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 67 .

[0627] Brown solid (98.3 mg, 0.223 mmol, 77.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.05 (3H, t, J = 7.27 Hz), 2.38 (2H, q, J = 7.14 Hz), 2.46-2.49 (4H, m), 3.57-3 .64 (4H, m), 3.91 (3H, s), 7.16 (1H, dd, J = 4.94, 1.10 Hz), 7.46 (1H, s), 7.81 ( 1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.14 (1H, s), 8.26(1H, d, J =5.21Hz), 8.38(1H, s), 8.59(1H, s), 9.12(1H, s), 11.04(1H, s ) ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

71

[0628] 4-((Dimethylamino)methyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 71 .

[0629] Off-white solid (15.2 mg, 0.039 mmol, 14.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.19 (6H, s), 3.49 (2H, s), 3.91 (3H, s), 7.44 (2H, d, J =8.23 Hz), 7.79 (1H, dd , J = 8.51, 1.65 Hz), 8.05 (3H, d, J = 8.23 Hz), 8.10 (1H, s), 8.12 (1H, s), 8.36 (1H, s), 8.59 (1H, s), 9.11 (1H, s), 10.70 (1H, s); ESIMS found for C ₂₃ H ₂₃ N ₅ O m/z 386.0 (M+1).

72

[0630] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(1-methylpiperidin-4-yl)benzamide 72 .

[0631] Off-white solid (78.0 mg, 0.174 mmol, 75.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.72-1.84(4H, m), 2.00(2H, td, J =10.91, 3.16Hz), 2.22(3H, s), 2.52-2.60( 1H, m), 2.90(2H, brd, J =11.25 Hz), 3.91(3H, s), 7.40-7.51(2H, m), 7.79(1H , dd, J = 8.51, 1.37 Hz), 7.89 (1H, brd, J = 7.41 Hz), 8.01 (1H, s), 8.05 (1H, d, J = 8.51 Hz), 8.10 (1H, s), 8.12 (1H, s), 8.37 (1H, s), 8.59 (1H, s), 9.11 (1H, s), 10.80 (1H, s); ESIMS found for C ₂₆ H ₂₇ N ₅ O m/z 426.05 (M+1).

74

[0632] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)benzamide 74 .

[0633] Off -white solid (65.0 mg, 0.196 mmol, 33.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.16(3H, s), 2.27-2.38(4H, m), 2.38-2.45(4H, m), 3.54(2H, s), 3.92(3H, s), 7.44-7.50 (1H, m), 7.50-7.55 (1H, m), 7.79 (1H, dd, J =8.64, 1.51 Hz), 7 .96 (1H, brd, J = 7.68 Hz), 7.98 (1H, s), 8.06 (1H, d, J = 8.51 Hz), 8.10 (1H, s) , 8.12(1H, s), 8.37(1H, s), 8.58(1H, s), 9.11(1H, s), 10.74(1H, s); ESIMS found for C ₂₆ H ₂₈ N ₆ O m/z 441.0 (M+1).

76

[0634] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 76 .

[0635] Brown solid (80 mg, 0.243 mmol, 41.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.91 (3H, s), 7.84 (1H, dd, J = 8.51, 1.65 Hz), 8.09 (1H, d, J = 8.51 Hz), 8.12 (1H , s), 8.16-8.21 (3H, m), 8.39 (1H, s), 8.60 (1H, s), 8.92 (2H, d, J = 6.31 Hz) , 9.16 (1H, s), 11.38 (1H, s); ESIMS found for C ₁₉ H ₁₅ N ₅ O m/z 330.1 (M+1).

78

[0636] 2-Hydroxy-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 78 .

[0637] Off -white solid (89.0 mg, 0.258 mmol, 21.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.91 (3H, s), 6.62 (1H, dd, J = 6.72, 1.51 Hz), 6.92 (1H, d, J = 1.10 Hz), 7.50 (1H , d, J = 6.59 Hz), 7.81 (1H, dd, J = 8.51, 1.37 Hz), 8.06 (1H, d, J = 8.51 Hz), 8.10 (1H, s), 8.14 (1H, s), 8.37 (1H, s), 8.53 (1H, s), 9.11 (1H, s), 10.97 (1H, s) , 11.81 (1H, brs); ESIMS found for C ₁₉ H ₁₅ N ₅ O ₂ m/z 345.9 (M+1).

80

[0638] 2-Isopropoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 80 .

[0639] Off-white solid (49.2 mg, 0.127 mmol, 38.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.33 (6H, d, J = 6.31 Hz), 3.91 (3H, s), 5.30 (1H, sep, J = 6.17 Hz), 7.30 (1H, s), 7.50 (1H, dd, J =5.35, 1.51 Hz), 7.82 (1H, dd, J =8.51, 1.65 Hz), 8.06 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.15 (1H, s), 8.32 (1H, d, J =5.21 Hz), 8.38 (1H, s), 8 .58 (1H, s), 9.12 (1H, s), 11.05 (1H, s); ESIMS found for C ₂₂ H ₂₁ N ₅ O ₂ m/z 388.2 (M+1).

84

[0640] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(1-methylpiperidin-4-yl)isonicotinamide 84 .

[0641] Off -white solid (100.0 mg, 0.235 mmol, 49.8% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.77-1.92(4H, m), 2.00(2H, td, J =11.60, 2.61 Hz), 2.21(3H, s), 2.72(1H, tt, J = 11.49, 4.15 Hz), 2.85-2.93 (2H, m), 3.91 (3H, s), 7.76 (1H, dd, J = 5.21, 1, 65 Hz), 7.82 (1H, dd, J = 8.51, 1.65 Hz), 7.91 (1H, s), 8.07 (1H, d, J = 8.51 Hz), 8 .12 (1H, d, J = 0.82 Hz), 8.15 (1H, d, J = 0.82 Hz), 8.39 (1H, s), 8.60 (1H, s), 8 .66-8.71(1H, m), 9.13(1H, s), 11.17(1H, s); ESIMS found for C ₂₅ H ₂₆ N ₆ O m/z 427.0 (M+1).

85

[0642] 1'-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1',2',3',6'-tetrahydro-[2, 4'-bipyridine]-4-carboxamide 85 .

[0643] Off -white solid (89.0 mg, 0.210 mmol, 17.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.31(3H, s), 2.57-2.63(2H, m), 2.63-2.70(2H, m), 3.11(2H, brd, J =3.02 Hz), 3.91 (3H, s), 6.89 (1H, t, J = 3.43 Hz), 7.78 (1H, dd, J = 4.94, 1.37 Hz), 7, 82 (1H, dd, J = 8.51, 1.65 Hz), 8.08 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.16 (2H, d , J = 6.04 Hz), 8.38 (1H, s), 8.61 (1H, s), 8.71 (1H, d, J = 4.94 Hz), 9.14 (1H, s ), 11.23 (1H, s); ESIMS found for C ₂₅ H ₂₄ N ₆ O m/z 425.0 (M+1).

86

[0644] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(6-(4-methylpiperazin-1-yl)nicotinoyl)piperazin-1 -yl)isonicotinamide 86 .

[0645] Off -white solid (30.0 mg, 0.049 mmol, 89.4% yield). ¹ H NMR (499 MHz, solvent) δ ppm 2.21(3H, s), 2.36-2.41(4H, m), 3.42(2H, brs), 3.49-3.56(4H, m), 3.64( 2H, brs), 3.75 (4H, brs), 3.91 (3H, s), 6.64 (1H, dd, J =5.08, 0.96 Hz), 6.82 (1H, s), 7.20 (1H, dd, J = 5.21, 1.10 Hz), 7.49 (1H, s), 7.81 (1H, dd, J = 8.64, 1 .51 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.11 (1H, d, J = 0.82 Hz), 8.14 (1H, s), 8.18 ( 1H, d, J =4.94 Hz), 8.29(1H, d, J =5.21 Hz), 8.38(1H, s), 8.60(1H, s), 9.13( 1H, s), 11.06 (1H, s); ESIMS found for C ₃₄ H ₃₆ N ₁₀ O ₂ m/z 617.3 (M+1).

87

[0646] 1-Methyl-4-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperazine 1-oxide 87 .

[0647] White solid (65.0 mg, 0.147 mmol, 57.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.99 (2H, brd, J = 10.70 Hz), 3.11 (3H, s), 3.41 (2H, td, J = 11.53, 3.29 Hz), 3.61 -3.72(2H, m), 3.91(3H, s), 4.25(2H, brd, J =13.17 Hz), 7.20(1H, dd, J =5.08 , 1.23 Hz), 7.55 (1H, s), 7.82 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz ), 8.11 (1H, s), 8.14 (1H, s), 8.29 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.60 (1H , s), 9.13 (1H, s), 11.10 (1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ O ₂ m/z 444.2 (M+1).

88

[0648] 2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)isonicotinamide 88 .

[0649] Brown solid (33.2 mg, 0.075 mmol, 26.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.39(3H, s), 2.40-2.44(4H, m), 3.54-3.62(4H, m), 3.91(3H, s), 7.04 (1H, s), 7.26 (1H, s), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.06 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.14 (1H, d, J = 0.82 Hz), 8.38 (1H, s), 8.58 (1H, s), 9.12 (1H, s), 10.94 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

89

[0650] 3-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 89 .

[0651] Brown solid (18.8 mg, 0.043 mmol, 11.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.29(3H, s), 2.45-2.54(4H, m), 3.09(4H, brs), 3.91(3H, s) , 7.08 (1H, d, J =4.94 Hz), 7.80 (1H, dd, J =8.51, 1.65 Hz), 8.04 (1H, d, J =8.78 Hz), 8.11 (1H, s), 8.16 (1H, s), 8.21 (1H, d, J = 4.94 Hz), 8.38 (1H, s), 8.58 ( 1H, s), 9.07 (1H, s), 11.00 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

90

[0652] 2-(4-Methyl-1,4-diazepan-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 90 .

[0653] Off -white solid (82.0 mg, 0.186 mmol, 32.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.93 (2H, quin, J = 5.76 Hz), 2.27 (3H, s), 2.48 (2H, br s), 2.59-2.67 (2H, m), 3 .69 (2H, t, J = 6.17 Hz), 3.78-3.85 (2H, m), 3.91 (3H, s), 7.05 (1H, dd, J = 5.08 , 0.96 Hz), 7.21 (1H, s), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.78 Hz ), 8.11 (1H, s), 8.13 (1H, s), 8.20 (1H, d, J = 4.94 Hz), 8.38 (1H, s), 8.59 (1H , s), 9.12 (1H, s), 11.02 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

91

[0654] 2-((2S,6R)-2,6-Dimethylmorpholino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 91 .

[0655] Brown solid (32.0 mg, 0.072 mmol, 31.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.20 (6H, d, J = 6.04 Hz), 2.44-2.49 (2H, m), 3.60-3.70 (2H, m), 3.91 (3H, s) , 4.28 (2H, broad dd, J = 12.76, 1.51 Hz), 7.18 (1H, dd, J = 5.21, 1.37 Hz), 7.44 (1H, s ), 7.81 (1H, dd, J =8.51, 1.65 Hz), 8.07 (1H, d, J =8.78 Hz), 8.10 (1H, d, J =0, 82 Hz), 8.13 (1H, s), 8.27 (1H, d, J =5.49 Hz), 8.37 (1H, s), 8.58 (1H, s), 9.12 (1H, s), 10.94 (1H, s); ESIMS found for C ₂₅ H ₂₆ N ₆ O ₂ m/z 443.0 (M+1).

92

[0656] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide 92 .

[0657] Off -white solid (120.0 mg, 0.265 mmol, 47.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.66 (4H, br.t, J = 4.94 Hz), 2.66 (4H, br.s), 3.73 (4H, s), 3.91 (3H, s), 7.02 (1H, s), 7.12 (1H, dd, J = 5.21, 1.37 Hz), 7.81 (1H, dd, J = 8.64, 1.51 Hz), 8.07 ( 1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.19 (1H, d, J = 4.94 Hz), 8.38 ( 1H, s), 8.58 (1H, s), 9.12 (1H, s), 10.96 (1H, br s); ESIMS found for C ₂₆ H ₂₇ N ₇ O m/z 454.2 (M+1).

93

[0658] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide 93 .

[0659] White solid (63.9 mg, 0.137 mmol, 77.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.76 (4H, br.t, J =5.21 Hz), 2.15 (3H, s), 2.27 (4H, br.s), 3.74 (4H, s), 3.91 (3H, s), 7.03 (1H, s), 7.13 (1H, dd, J = 5.21, 1.37 Hz), 7.81 (1H, dd, J = 8.51, 1 .65 Hz), 8.07(1H, d, J =8.51 Hz), 8.11(1H, s), 8.13(1H, s), 8.20(1H, d, J =5 .76 Hz), 8.38(1H, s), 8.58(1H, s), 9.12(1H, s), 10.96(1H, s); ESIMS found for C ₂₇ H ₂₉ N ₇ O m/z 468.1 (M+1).

94

[0660] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,7-diazaspiro[3.5]nonan-7-yl)isonicotinamide 94 .

[0661] Off-white solid (190.0 mg, 0.419 mmol, 76.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.72-1.79(4H, m), 3.32-3.43(4H, m), 3.54-3.60(4H, m), 3.91(3H, s), 7, 11 (1H, dd, J =5.21, 1.10 Hz), 7.46 (1H, s), 7.81 (1H, dd, J =8.64, 1.51 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.23 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.02 (1H, brs); ESIMS found for C ₂₆ H ₂₇ N ₇ O m/z 454.1 (M+1).

95

[0662] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)isonicotinamide 95 .

[0663] White solid (136.0 mg, 0.291 mmol, 79.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.66-1.76(4H, m), 2.24(3H, s), 2.97(4H, s), 3.53-3.62(4H, m), 3.91(3H, s), 7.10 (1H, dd, J = 5.08, 1.23 Hz), 7.45 (1H, s), 7.81 (1H, dd, J = 8.51, 1.65 Hz ), 8.07 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.23 (1H, d, J = 4.94 Hz ), 8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.02 (1H, s); ESIMS found for C ₂₇ H ₂₉ N ₇ O m/z 468.0 (M+1).

97

[0664] 2-(Methyl(1-methylpiperidin-4-yl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 97 .

[0665] Brown solid (72.9 mg, 0.160 mmol, 55.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.50-1.62(2H, m), 1.80(2H, qvd, J =12.08, 3.84 Hz), 1.97-2.08(2H, m), 2.19( 3H, s), 2.86 (2H, brd, J = 11.25 Hz), 2.93 (3H, s), 3.91 (3H, s), 4.49 (1H, ddt, J = 11.63, 7.79, 4.01, 4.01 Hz), 7.07 (1H, dd, J = 5.08, 1.23 Hz), 7.18 (1H, s), 7, 81 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.13 (1H, s ), 8.22 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.58 (1H, s), 9.12 (1H, s), 10.99 (1H , With); ESIMS found for C ₂₆ H ₂₉ N ₇ O m/z 456.2 (M+1).

99

[0666] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)thio)isonicotinamide 99 .

[0667] Off-white solid (50.0 mg, 0.109 mmol, 15.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.60-1.72 (2H, m), 1.99-2.08 (2H, m), 2.12 (2H, brt, J = 10.84 Hz), 2.17 (3H, s), 2.65-2.73(2H, m), 3.78-3.88(1H, m), 3.91(3H, s), 7.64(1H, dd, J =5, 08, 1.51 Hz), 7.79-7.85 (2H, m), 8.07 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.15 ( 1H, s), 8.38(1H, s), 8.57(1H, s), 8.59-8.64(1H, m), 9.12(1H, s), 11.14(1H , With); ESIMS found for C ₂₅ H ₂₆ N ₆ OS m/z 458.9 (M+1).

100

[0668] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide 100 .

[0669] Brown solid (78.0 mg, 0.182 mmol, 63.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.25 (3H, s), 2.44 (4H, brt, J = 4.94 Hz), 3.82-3.89 (4H, m), 3.91 (3H, s), 7 .30 (1H, d, J =4.67 Hz), 7.83 (1H, dd, J =8.64, 1.51 Hz), 8.08 (1H, d, J =8.78 Hz) , 8.12(1H, s), 8.17(1H, s), 8.39(1H, s), 8.58(1H, s), 8.69(1H, d, J =4.67 Hz), 9.12 (1H, s), 10.36 (1H, s); ESIMS found for C ₂₃ H ₂₄ N ₈ O m/z 429.2 (M+1).

101

[0670] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)pyridazin-4-carboxamide 101 .

[0671] Off -white solid (6.2 mg, 0.015 mmol, 3.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.16 (3H, brs), 2.40 (4H, brs), 3.43 (4H, brd, J = 3.57 Hz), 3.91 (3H, s), 7 .72 (1H, s), 7.80 (1H, dd, J = 8.51, 1.65 Hz), 8.04 (1H, d, J = 8.78 Hz), 8.10 (1H, d, J = 0.82 Hz), 8.14 (1H, s), 8.36 (1H, s), 8.54 (1H, br s), 9.08 (1H, s), 11, 04 (1H, s), 12.68 (1H, s); ESIMS found for C ₂₃ H ₂₄ N ₈ O m/z 429.0 (M+1).

102

[0672] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide 102 .

[0673] White solid (72.1 mg, 0.168 mmol, 39.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.25 (3H, s), 2.44 (3H, br s), 3.76 (4H, br s), 3.91 (3H, s), 7.48 (1H, d, J = 0.82 Hz), 7.82 (1H, dd, J =8.51, 1.65 Hz), 8.07 (1H, d, J =8.51 Hz), 8.11 (1H, s) , 8.16 (1H, s), 8.38 (1H, s), 8.58 (1H, s), 8.67 (1H, d, J =1.10 Hz), 9.11 (1H, s), 10.41 (1H, s); ESIMS found for C ₂₃ H ₂₄ N ₈ O m/z 429.0 (M+1).

103

[0674] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-phenylacetamide 103 .

[0675] Beige solid (57.0 mg, 0.167 mmol, 37.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.77(2H, s), 3.89(3H, s), 7.20-7.27(1H, m), 7.33(2H, t, J =7.68 Hz), 7.37 -7.44 (2H, m), 7.75 (1H, dd, J = 8.51, 1.65 Hz), 8.00 (1H, d, J = 8.51 Hz), 8.03 ( 1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.40 (1H, s), 9.04 (1H, s), 10.75 (1H, s); ESIMS found for C ₂₁ H ₁₈ N ₄ O m/z 343.1 (M+1).

104

[0676] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-phenylpropanamide 104 .

[0677] Beige solid (67.0 mg, 0.188 mmol, 42.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.72-2.80(2H, m), 2.92-2.96(2H, m), 3.90(3H, s), 7.15-7.22(1H, m), 7, 26-7.32(4H, m), 7.74(1H, dd, J =8.51, 1.37Hz), 7.99(1H, d, J =8.51Hz), 8.06 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.54 (1H, s) ; ESIMS found for C ₂₂ H ₂₀ N ₄ O m/z 357.2 (M+1).

105

[0678] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyridin-3-yl)acetamide 105 .

[0679] Orange-brown solid (21.0 mg, 0.061 mmol, 13.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.83(2H, s), 3.89(3H, s), 7.37(1H, dd, J =7.82, 4.80 Hz), 7.76(1H, dd, J =8, 51, 1.65 Hz), 7.79 (1H, dt, J = 7.82, 1.85 Hz), 8.01 (1H, d, J = 8.51 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.39 (1H, s), 8.47 (1H, dd, J =4.67, 1.65 Hz), 8.57 (1H, d, J =1.65 Hz), 9.05 (1H, s), 10.86 (1H, s); ESIMS found for C ₂₀ H ₁₇ N ₅ O m/z 344.1 (M+1).

106

[0680] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(pyridin-3-yl)propanamide 106 .

[0681] Brown solid (65.0 mg, 0.182 mmol, 40.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.76-2.83(2H, m), 2.93-3.00(2H, m), 3.90(3H, s), 7.31(1H, dd, J =7.82, 4 .80 Hz), 7.69 (1H, dt, J = 7.82, 1.85 Hz), 7.75 (1H, dd, J = 8.51, 1.65 Hz), 7.99 (1H , d, J = 8.51 Hz), 8.06 (1H, s), 8.09 (1H, d, J = 0.82 Hz), 8.36 (1H, s), 8.40 (1H , dd, J =4.80, 1.51 Hz), 8.43(1H, s), 8.51(1H, d, J =1.92 Hz), 9.01(1H, s), 10 .56 (1H, s); ESIMS found for C ₂₁ H ₁₉ N ₅ O m/z 358.1 (M+1).

107

[0682] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyridin-4-yl)acetamide 107 .

[0683] Beige solid (30.0 mg, 0.087 mmol, 19.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.84(2H, s), 3.89(3H, s), 7.39(2H, d, J =6.04 Hz), 7.76(1H, dd, J =8.64, 1, 51 Hz), 8.01 (1H, d, J = 8.51 Hz), 8.04 (1H, s), 8.07 (1H, s), 8.35 (1H, s), 8.40 (1H, s), 8.49-8.55 (2H, m), 9.05 (1H, s), 10.88 (1H, s); ESIMS found for C ₂₀ H ₁₇ N ₅ O m/z 344.1 (M+1).

108

[0684] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(pyridin-4-yl)propanamide 108 .

[0685] Beige solid (45.0 mg, 0.126 mmol, 28.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.77-2.85(2H, m), 2.92-3.00(2H, m), 3.90(3H, s), 7.27-7.33(2H, m), 7, 75 (1H, dd, J = 8.51, 1.37 Hz), 8.00 (1H, d, J = 8.78 Hz), 8.06 (1H, s), 8.09 (1H, d , J = 0.82 Hz), 8.35 (1H, s), 8.43 (1H, s), 8.44-8.50 (2H, m), 9.02 (1H, s), 10 .58 (1H, s); ESIMS found for C ₂₁ H ₁₉ N ₅ O m/z 358.2 (M+1).

109

[0686] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isoindoline-5-carboxamide 109 .

[0687] Off-white solid (120.0 mg, 0.325 mmol, 33.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.91 (3H, s), 4.14 (4H, s), 7.39 (1H, d, J = 7.68 Hz), 7.79 (1H, dd, J = 8.51, 1, 65 Hz), 7.92 (1H, dd, J = 7.96, 1.37 Hz), 7.97 (1H, s), 8.05 (1H, d, J = 8.51 Hz), 8 .11 (1H, s), 8.13 (1H, s), 8.37 (1H, s), 8.59 (1H, s), 9.10 (1H, s), 10.70 (1H, With); ESIMS found for C ₂₂ H ₁₉ N ₅ O m/z 369.95 (M+1).

110

[0688] 2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isoindoline-5-carboxamide 110 .

[0689] Off-white solid. ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.52 (3H, s), 3.88 (4H, s), 3.91 (3H, s), 7.37 (1H, d, J = 7.68 Hz), 7.79 (1H, dd , J = 8.51, 1.65 Hz), 7.90-7.97 (2H, m), 8.05 (1H, d, J = 8.78 Hz), 8.10 (1H, d, J = 0.82 Hz), 8.12 (1H, s), 8.37 (1H, s), 8.58 (1H, s), 9.10 (1H, s), 10.70 (1H, With); ESIMS found for C ₂₃ H ₂₁ N ₅ O m/z 383.95 (M+1).

111

[0690] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide 111 .

[0691] Off -white solid (120.0 mg, 0.313 mmol, 32.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.73-2.78(2H, m), 2.97(2H, t, J =5.90 Hz), 3.90-3.93(2H, m), 3.91(3H, s) , 7.20 (1H, d, J = 7.96 Hz), 7.75-7.85 (3H, m), 8.05 (1H, d, J = 8.51 Hz), 8.11 ( 1H, s), 8.12 (1H, s), 8.37 (1H, s), 8.58 (1H, s), 9.10 (1H, s), 10.63 (1H, s); ESIMS found for C ₂₃ H ₂₁ N ₅ O m/z 384.0 (M+1).

112

[0692] 2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-carboxamide 112 .

[0693] Off -white solid (115.9 mg, 0.277 mmol, 93.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.37(3H, s), 2.63(2H, brt, J =5.90Hz), 2.89(2H, brt, J =5.76Hz), 3.52-3 .59 (2H, m), 3.91 (3H, s), 7.25 (1H, d, J = 7.96 Hz), 7.76-7.89 (3H, m), 8.05 ( 1H, d, J = 8.51 Hz), 8.10 (1H, s), 8.12 (1H, s), 8.37 (1H, s), 8.58 (1H, s), 9, 10(1H, s), 10.65(1H, s); ESIMS found for C ₂₄ H ₂₃ N ₅ O m/z 398.0 (M+1).

113

[0694] 2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-carboxamide 113 .

[0695] Off -white solid (115.9 mg, 0.277 mmol, 65.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.36(3H, s), 2.64(2H, t, J =5.90 Hz), 2.91(2H, brt, J =5.63 Hz), 3.55(2H, s ), 3.91 (3H, s), 7.19 (1H, d, J = 7.96 Hz), 7.81 (2H, ddd, J = 17.36, 8.30, 1.51 Hz) , 7.86 (1H, s), 8.05 (1H, d, J = 8.51 Hz), 8.10 (1H, s), 8.12 (1H, s), 8.37 (1H, s), 8.58 (1H, s), 9.10 (1H, s), 10.66 (1H, s); ESIMS found for C ₂₄ H ₂₃ N ₅ O m/z 398.0 (M+1).

114

[0696] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide 114 .

[0697] Off -white solid (170.0 mg, 0.443 mmol, 31.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.78 (2H, brt, J = 5.76 Hz), 2.98 (2H, t, J = 5.90 Hz), 3.86-3.97 (5 H, m), 7, 15 (1H, d, J = 7.68 Hz), 7.76-7.82 (2H, m), 7.83 (1H, s), 8.05 (1H, d, J = 8.78 Hz ), 8.11(1H, s), 8.12(1H, s), 8.37(1H, s), 8.58(1H, s), 9.10(1H, s), 10.64 (1H, s); ESIMS found for C ₂₃ H ₂₁ N ₅ O m/z 384.0 (M+1).

116

[0698] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1H-indole-5-carboxamide 116 .

[0699] White solid (18.0 mg, 0.049 mmol, 10.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.91(3H, s), 6.59(1H, ddd, J =2.95, 1.99, 0.82Hz), 7.44-7.48(1H, m), 7.49( 1H, d, J = 8.51 Hz), 7.78 (1H, dd, J = 8.51, 1.65 Hz), 7.86 (1H, dd, J = 8.64, 1.78 Hz ), 8.05 (1H, d, J = 8.78 Hz), 8.11 (1H, s), 8.12 (1H, d, J = 0.82 Hz), 8.38 (1H, s ), 8.42 (1H, d, J = 1.65 Hz), 8.62 (1H, s), 9.11 (1H, s), 10.53 (1H, s), 11.39 (1H , broad.s); ESIMS found for C ₂₂ H ₁₇ N ₅ O m/z 368.1 (M+1).

117

[0700] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzofuran-5-carboxamide 117 .

[0701] Light yellow solid (8.7 mg, 0.024 mmol, 7.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.91 (3H, s), 7.11 (1H, d, J = 1.37 Hz), 7.73 (1H, d, J = 8.51 Hz), 7.80 (1H, dd, J = 8.51, 1.65 Hz), 8.06 (2H, d, J = 8.51 Hz), 8.11 (1H, s), 8.12 (1H, d, J = 2.20 Hz ), 8.14 (1H, s), 8.38 (1H, s), 8.45 (1H, d, J = 1.92 Hz), 8.62 (1H, s), 9.12 (1H , s), 10.83 (1H, s); ESIMS found for C ₂₂ H ₁₆ N ₄ O ₂ m/z 369.1 (M+1).

118

[0702] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)furo[2,3-c]pyridine-5-carboxamide 118 .

[0703] Light yellow solid (10.8 mg, 0.029 mmol, 9.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 7.30 (1H, d, J = 1.92 Hz), 7.82 (1H, dd, J = 8.51, 1.37 Hz), 8.07 (1H , d, J = 8.51 Hz), 8.13 (1H, s), 8.18 (1H, s), 8.39 (1H, s), 8.43 (1H, d, J = 1, 92 Hz), 8.64 (1H, s), 8.65 (1H, s), 9.12 (1H, s), 9.15 (1H, s), 10.59 (1H, s); ESIMS found for C ₂₁ H ₁₅ N ₅ O ₂ m/z 370.1 (M+1).

119

[0704] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[b]thiophene-5-carboxamide 119 .

[0705] Yellow solid (20.0 mg, 0.052 mmol, 14.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 7.61 (1H, d, J = 5.49 Hz), 7.80 (1H, dd, J = 8.51, 1.65 Hz), 7.90 (1H , d, J = 5.49 Hz), 8.02-8.09 (2H, m), 8.12 (1H, s), 8.13-8.19 (2H, m), 8.39 ( 1H, s), 8.63 (1H, s), 8.66 (1H, d, J = 1.10 Hz), 9.13 (1H, s), 10.89 (1H, s); ESIMS found for C ₂₂ H ₁₆ N ₄ OS m/z 385.1 (M+1).

120

[0706] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzofuran-6-carboxamide 120 .

[0707] Light yellow solid (6.9 mg, 0.019 mmol, 6.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92(3H, s), 7.08(1H, dd, J =2.20, 0.82Hz), 7.80(1H, d, J =8.23Hz), 7.80(1H , dd, J =8.51, 1.65 Hz), 8.01 (1H, dd, J =8.10, 1.51 Hz), 8.06 (1H, d, J =8.78 Hz) , 8.12 (1H, s), 8.14 (1H, s), 8.19 (1H, d, J = 2.20 Hz), 8.39 (1H, s), 8.39 (1H, s), 8.62 (1H, s), 9.13 (1H, s), 10.88 (1H, s); ESIMS found for C ₂₂ H ₁₆ N ₄ O ₂ m/z 369.1 (M+1).

122

[0708] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[d]oxazole-6-carboxamide 122 .

[0709] Yellow solid (33.4 mg, 0.090 mmol, 20.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.91(3H, s), 7.81(1H, dd, J =8.51, 1.65Hz), 7.94(1H, d, J =8.51Hz), 8.07(1H , d, J = 8.51 Hz), 8.12 (1H, s), 8.13-8.17 (2H, m), 8.38 (1H, s), 8.54 (1H, d, J = 1.10 Hz), 8.63 (1H, s), 8.93 (1H, s), 9.13 (1H, s), 11.00 (1H, s); ESIMS found for C ₂₁ H ₁₅ N ₅ O ₂ m/z 370.1 (M+1).

123

[0710] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[d]thiazole-6-carboxamide 123 .

[0711] Yellow solid (35.0 mg, 0.091 mmol, 20.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.12 (1H , s), 8.16 (1H, s), 8.18-8.25 (2H, m), 8.38 (1H, s), 8.64 (1H, s), 8.91-8, 96 (1H, m), 9.13 (1H, s), 9.58 (1H, s), 10.98 (1H, s); ESIMS found for C ₂₁ H ₁₅ N ₅ OS m/z 386.1 (M+1).

126

[0712] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[d]oxazole-5-carboxamide 126 .

[0713] Yellow solid (52.7 mg, 0.143 mmol, 32.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 7.81 (1H, dd, J = 8.51, 1.37 Hz), 7.92 (1H, d, J = 8.51 Hz), 8.07 (1H , d, J = 8.78 Hz), 8.12 (1H, s), 8.15 (1H, s), 8.18 (1H, dd, J = 8.51, 1.65 Hz), 8 .38 (1H, s), 8.57 (1H, d, J = 1.65 Hz), 8.62 (1H, s), 8.88 (1H, s), 9.13 (1H, s) , 10.99 (1H, s); ESIMS found for C ₂₁ H ₁₅ N ₅ O ₂ m/z 370.1 (M+1).

127

[0714] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[d]thiazole-5-carboxamide 127 .

[0715] Yellow solid (41.7 mg, 0.108 mmol, 24.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.12 (1H , d, J = 0.82 Hz), 8.14-8.16 (1H, m), 8.18 (1H, dd, J = 8.51, 1.65 Hz), 8.33 (1H, d, J = 8.51 Hz), 8.39 (1H, s), 8.64 (1H, s), 8.82 (1H, d, J = 1.37 Hz), 9.14 (1H, s), 9.52 (1H, s), 11.06 (1H, s); ESIMS found for C ₂₁ H ₁₅ N ₅ OS m/z 386.1 (M+1).

130

[0716] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)quinoline-3-carboxamide 130 .

[0717] Beige solid (55.0 mg, 0.145 mmol, 32.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 7.70-7.78 (1H, m), 7.82 (1H, dd, J = 8.51, 1.65 Hz), 7.91 (1H, dd, J = 8.30, 6.93, 1.23 Hz), 8.08 (1H, d, J = 8.51 Hz), 8.10-8.14 (2H, m), 8.15 (1H , d, J =7.96 Hz), 8.17(1H, s), 8.40(1H, s), 8.66(1H, s), 9.11(1H, d, J =2, 20 Hz), 9.15 (1H, s), 9.43 (1H, d, J =2.20 Hz), 11.26 (1H, s); ESIMS found for C ₂₃ H ₁₇ N ₅ O m/z 380.2 (M+1).

131

[0718] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)quinoline-6-carboxamide 131 .

[0719] Beige solid (57.0 mg, 0.150 mmol, 33.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 7.65 (1H, dd, J = 8.23, 4.12 Hz), 7.82 (1H, dd, J = 8.51, 1.65 Hz), 8 .08 (1H, d, J = 8.51 Hz), 8.10-8.16 (2H, m), 8.17 (1H, s), 8.35 (1H, dd, J = 8.78 , 2.20 Hz), 8.39(1H, s), 8.52-8.57(1H, m), 8.66(1H, s), 8.81(1H, d, J =2, 20 Hz), 9.03 (1H, dd, J =4.25, 1.78 Hz), 9.15 (1H, s), 11.08 (1H, s); ESIMS found for C ₂₃ H ₁₇ N ₅ O m/z 380.1 (M+1).

132

[0720] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isoquinolin-6-carboxamide 132 .

[0721] Beige solid (10.0 mg, 0.026 mmol, 5.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 7.82 (1H, dd, J = 8.51, 1.65 Hz), 7.99 (1H, d, J = 5.76 Hz), 8.08 (1H , d, J = 8.51 Hz), 8.13 (1H, s), 8.17 (1H, s), 8.21-8.30 (2H, m), 8.39 (1H, s) , 8.62 (1H, d, J = 5.76 Hz), 8.65 (1H, s), 8.74 (1H, s), 9.15 (1H, s), 9.44 (1H, s), 11.15 (1H, s); ESIMS found for C ₂₃ H ₁₇ N ₅ O m/z 380.1 (M+1).

133

[0722] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)quinoxalin-6-carboxamide 133 .

[0723] Beige solid (29.0 mg, 0.076 mmol, 17.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 7.83 (1H, dd, J = 8.51, 1.65 Hz), 8.08 (1H, d, J = 8.51 Hz), 8.13 (1H , s), 8.17 (1H, s), 8.23 (1H, d, J = 8.78 Hz), 8.39 (1H, s), 8.44 (1H, dd, J = 8, 78, 1.92 Hz), 8.66 (1H, s), 8.84 (1H, d, J =1.92 Hz), 9.06 (1H, d, J =1.65 Hz), 9 .08 (1H, d, J = 1.65 Hz), 9.15 (1H, s), 11.31 (1H, s); ESIMS found for C ₂₂ H ₁₆ N ₆ O m/z 381.1 (M+1).

134

[0724] N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 134 .

[0725] Off -white solid (36.0 mg, 0.081 mmol, 26.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.42(4H, t, J =4.94Hz), 3.55-3.65(4H, m), 3.94(3H, s), 7.15 (1H, dd, J =5.08, 1.23Hz), 7.46(1H, s), 7.97(1H, d, J =11.80Hz), 8.14(1H, s) , 8.26 (1H, d, J =4.94 Hz), 8.33 (1H, d, J =2.74 Hz), 8.37 (1H, d, J =7.41 Hz), 8 .65 (1H, s), 9.14 (1H, s), 11.08 (1H, s); ESIMS found for C ₂₄ H ₂₄ FN ₇ O m/z 446.2 (M+1).

135

[0726] N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 135 .

[0727] Off -white solid (65.0 mg, 0.146 mmol, 64.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.42(4H, brt, J =4.80 Hz), 3.56-3.64(4H, m), 3.91(3H, s), 7 .09-7.20 (1H, m), 7.46 (1H, s), 7.66 (1H, d, J = 12.08 Hz), 8.02 (1H, s), 8.15 ( 1H, s), 8.26 (1H, d, J = 5.21 Hz), 8.42 (1H, s), 8.65 (1H, s), 9.24 (1H, s), 11, 19 (1H, s); ESIMS found for C ₂₄ H ₂₄ FN ₇ O m/z 446.2 (M+1).

136

[0728] N-(5-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 136 .

[0729] White solid (20.0 mg, 0.043 mmol, 41.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.26 (3H, s), 2.47 (4H, br s), 3.62 (4H, br s), 3.96 (3H, s), 7.19 (1H, dd, J = 5.08, 0.96 Hz), 7.49 (1H, s), 7.84 (1H, d, J = 8.51 Hz), 8.08-8.12 (2H, m), 8, 27 (1H, d, J = 5.21 Hz), 8.48 (1H, s), 9.05 (1H, s), 9.24 (1H, s), 11.24 (1H, s); ESIMS found for C ₂₄ H ₂₄ ClN ₇ O m/z 462.2 (M+1).

137

[0730] N-(7-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 137 .

[0731] White solid (18.0 mg, 0.039 mmol, 37.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.27 (3H, s), 2.47 (4H, br s), 3.61 (4H, br s), 3.94 (3H, s), 7.15 (1H, dd, J = 5.21, 1.10 Hz), 7.46 (1H, s), 8.01 (1H, d, J =0.82 Hz), 8.20 (1H, s), 8.26 (1H, d, J = 5.49 Hz), 8.32 (1H, s), 8.34 (1H, s), 8.64 (1H, s), 9.18 (1H, s), 11.13 ( 1H, s); ESIMS found for C ₂₄ H ₂₄ ClN ₇ O m/z 462.2 (M+1).

138

[0732] N-(1-Amino-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 138 .

[0733] Brown solid (4.8 mg, 0.011 mmol, 7.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.39-2.46(4H, m), 3.53-3.62(4H, m), 3.89(3H, s), 6.89(1H, s), 7.07 (1H, dd, J = 5.08, 1.24 Hz), 7.26 (1H, s), 7.60 (1H, dd, J = 8.23, 1.65 Hz ), 7.81 (1H, d, J = 1.65 Hz), 8.03 (1H, s), 8.08 (1H, d, J = 8.51 Hz), 8.28-8.33 (2H, m), 10.39 (1H, brs), 11.08 (1H, brs); ESIMS found for C ₂₄ H ₂₆ N ₈ O m/z 444.2 (M+2).

139

[0734] N-(7-Methyl-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 139 .

[0735] Beige solid (28.0 mg, 0.063 mmol, 63.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24 (3H, s), 2.43 (4H, brt, J = 4.94 Hz), 2.67 (3H, s), 3.57-3.64 (4H, m), 3 .94 (3H, s), 7.18 (1H, dd, J = 5.08, 1.23 Hz), 7.48 (1H, s), 7.58 (1H, d, J = 8.51 Hz), 7.79 (1H, d, J = 0.82 Hz), 7.95 (1H, d, J = 8.78 Hz), 8.10 (1H, s), 8.26 (1H, e, J = 5.76 Hz), 8.85 (1H, s), 9.16 (1H, s), 11.10 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

140

[0736] N-(5-Methyl-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 140 .

[0737] White solid (20.0 mg, 0.045 mmol, 54.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24 (3H, s), 2.43 (4H, br.t, J = 4.94 Hz), 2.67 (3H, s), 3.58-3.63 (4H, m), 3 .94 (3H, s), 7.18 (1H, dd, J = 5.21, 1.10 Hz), 7.48 (1H, s), 7.58 (1H, d, J = 8.51 Hz), 7.79(1H, s), 7.95(1H, d, J =8.51 Hz), 8.10(1H, s), 8.26(1H, d, J =5.21 Hz), 8.85(1H, s), 9.16(1H, s), 11.10(1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

141

[0738] N-(4-Methyl-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 141 .

[0739] Off -white solid (16.5 mg, 0.037 mmol, 12.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.40-2.45(4H, m), 2.51(3H, brs), 3.55-3.63(4H, m), 3.92( 3H, s), 7.16 (1H, dd, J = 5.08, 0.96 Hz), 7.40 (1H, s), 7.92 (1H, dd, J = 8.51, 1, 65 Hz), 8.12(1H, d, J =8.23 Hz), 8.16(1H, s), 8.23(1H, s), 8.28(1H, d, J =4, 94 Hz), 8.46 (1H, s), 9.04 (1H, s), 10.73 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

142

[0740] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin- ₃ -yl)-2-(4-(methyl- d3 )piperazin-1-yl)isonicotinamide 142 .

[0741] Beige solid (38.0 mg, 0.088 mmol, 94.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.45 (4H, brs), 3.61 (4H, brs), 3.91 (3H, s), 7.16 (1H, dd, J =5.21, 1.10 Hz) , 7.46 (1H, s), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.11 ( 1H, s), 8.14 (1H, s), 8.26 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.59 (1H, s), 9, 12 (1H, s), 11.04 (1H, s); ESIMS found for C ₂₄ H ₂₂ [ ² H ₃ ]N ₇ O m/z 431.2 (M+1).

143

[0742] N-(6-(1-(Methyl- d ₃ )-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 143 .

[0743] Beige solid (27.0 mg, 0.063 mmol, 38.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.43(4H, t, J =4.94Hz), 3.58-3.63(4H, m), 7.16(1H, dd, J =5, 21, 1.10 Hz), 7.46(1H, s), 7.81(1H, dd, J =8.51, 1.65 Hz), 8.07(1H, d, J =8.51 Hz), 8.11 (1H, s), 8.14 (1H, s), 8.26 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.59 ( 1H, s), 9.12 (1H, s), 11.04 (1H, s); ESIMS found for C ₂₄ H ₂₂ [ ² H ₃ ]N ₇ O m/z 431.2 (M+1).

144

[0744] N-(6-(1-(Methyl- d3 )-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl- d3 )piperazin-1-yl)isonicotinamide 144 .

[0745] Beige solid (30.0 mg, 0.069 mmol, 70.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.42 (4H, brt, J = 4.80 Hz), 3.56-3.64 (4H, m), 7.15 (1H, dd, J = 5.21, 0.82 Hz) , 7.46 (1H, s), 7.81 (1H, dd, J = 8.51, 1.37 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.11 ( 1H, s), 8.14 (1H, s), 8.26 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.59 (1H, s), 9, 12 (1H, s), 11.04 (1H, s); ESIMS found for C ₂₄ H ₁₉ [ ² H ₆ ]N ₇ O m/z 434.2 (M+1).

145

[0746] N-(6-(1H-Pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl- d ₃ )piperazin-1-yl)isonicotinamide 145 .

[0747] White solid (80.0 mg, 0.173 mmol, 37.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.39-2.46 (4H, m), 3.57-3.65 (4H, m), 7.16 (1H, dd, J =5.08, 1.24 Hz), 7.46 ( 1H, s), 7.88 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.19 (2H, br s ), 8.26 (1H, d, J =4.94 Hz), 8.46 (1H, br s), 8.60 (1H, s), 9.13 (1H, s), 11.04 (1H, s), 13.12 (1H, brs); ESIMS found for C ₂₃ H ₂₀ [ ² H ₃ ]N ₇ O m/z 417.2 (M+1).

146

[0748] N-(6-(1-(Difluoromethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 146 .

[0749] Beige solid (60.0 mg, 0.130 mmol, 78.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.43(4H, t, J =4.94Hz), 3.58-3.64(4H, m), 7.16(1H, dd, J =5, 21, 1.10 Hz), 7.47 (1H, s), 7.89 (1H, t, J =59.40 Hz), 7.94 (1H, dd, J =8.51, 1.65 Hz), 8.14 (1H, d, J = 8.51 Hz), 8.26 (1H, d, J = 5.21 Hz), 8.34 (1H, s), 8.52 (1H, s), 8.65 (1H, s), 8.97 (1H, s), 9.18 (1H, s), 11.09 (1H, s); ESIMS found for C ₂₄ H ₂₃ F ₂ N ₇ O m/z 464.2 (M+1).

147

[0750] N-(6-(1-ethyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 147 .

[0751] Off -white solid (25.0 mg, 0.057 mmol, 34.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.44 (3H, t, J = 7.27 Hz), 2.23 (3H, s), 2.43 (4H, t, J = 5.08 Hz), 3.57-3.64 (4H , m), 4.20 (2H, q, J = 7.41 Hz), 7.16 (1H, dd, J = 5.21, 1.37 Hz), 7.46 (1H, s), 7 .83 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.78 Hz), 8.12 (1H, s), 8.15 (1H, s), 8.26 (1H, d, J = 5.21 Hz), 8.45 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.04 ( 1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

148

[0752] N-(6-(1-Methyl-1H-pyrazol-3-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 148 .

[0753] Beige solid (53.0 mg, 0.124 mmol, 75.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.43(4H, t, J =4.94Hz), 3.58-3.64(4H, m), 3.94(3H, s), 6.97 (1H, d, J = 2.47 Hz), 7.16 (1H, dd, J = 4.94, 1.10 Hz), 7.47 (1H, s), 7.82 (1H, d, J = 2.20 Hz), 8.02-8.08 (1H, m), 8.08-8.13 (1H, m), 8.26 (1H, d, J = 4.94 Hz), 8.31 (1H, s), 8.64 (1H, s), 9.17 (1H, s), 11.06 (1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ O m/z 428.2 (M+1).

149

[0754] N-(6-(5-amino-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 149 .

[0755] Off -white solid (15.0 mg, 0.034 mmol, 12.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.40-2.46(4H, m), 3.57-3.62(4H, m), 3.64(3H, s), 5.72(2H, s), 7.15(1H, d, J =4.12 Hz), 7.46(1H, s), 7.67(1H, s), 7.72(1H, dd, J =8.64 , 1.51 Hz), 7.93 (1H, s), 7.99 (1H, d, J = 8.51 Hz), 8.26 (1H, d, J = 5.21 Hz), 8, 59 (1H, s), 9.06 (1H, s), 10.92 (1H, s); ESIMS found for C ₂₄ H ₂₆ N ₈ O m/z 443.0 (M+1).

151

[0756] 4-(Difluoromethoxy)-N-(6-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 151 .

[0757] White solid (11.2 mg, 0.026 mmol, 5.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.94 (3H, s), 4.66 (2H, d, J = 5.49 Hz), 5.58 (1H, t, J = 5.49 Hz), 7.40 (1H, t, J = 74.00 Hz), 7.31 (2H, d, J = 8.78 Hz), 7.73 (1H, dd, J = 8.37, 1.51 Hz), 7.84 (1H, s ), 8.03 (1H, s), 8.11 (1H, d, J = 8.51 Hz), 8.14-8.20 (2H, m), 8.63 (1H, s), 9 .18 (1H, s), 10.92 (1H, s); ESIMS found for C ₂₂ H ₁₈ F ₂ N ₄ O ₃ m/z 424.9 (M+1).

168

[0758] N-(6-(5-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 168 .

[0759] White solid (73.0 mg, 0.160 mmol, 45.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.43(4H, t, J =4.94Hz), 3.56-3.64(4H, m), 3.94(3H, s), 4.66 (2H, d, J =5.21 Hz), 5.58 (1H, t, J =5.35 Hz), 7.16 (1H, dd, J =5.21, 1.10 Hz), 7 .47 (1H, s), 7.75 (1H, dd, J = 8.51, 1.65 Hz), 7.84 (1H, s), 8.03 (1H, s), 8.12 ( 1H, d, J = 8.51 Hz), 8.26 (1H, d, J = 5.21 Hz), 8.64 (1H, s), 9.19 (1H, s), 11.08 ( 1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O ₂ m/z 458.2 (M+1).

172

[0760] N-(6-(5-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(7-methyl-2,7-diazaspiro[3.5]nonane -2-yl)isonicotinamide 172 .

[0761] Off-white solid (6.0 mg, 0.012 mmol, 24.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.76 (4H, br.t, J =5.08 Hz), 2.15 (3H, s), 2.28 (4H, br.s), 3.74 (4H, s), 3.94 (3H, s), 4.66 (2H, brd, J = 3.84 Hz), 5.54-5.62 (1H, m), 7.03 (1H, s), 7.13 ( 1H, dd, J =5.21, 1.37 Hz), 7.74(1H, dd, J =8.51, 1.65 Hz), 7.84(1H, s), 8.03(1H , s), 8.12 (1H, d, J = 8.51 Hz), 8.20 (1H, d, J = 5.21 Hz), 8.62 (1H, s), 9.18 (1H , s), 11.00 (1H, s); ESIMS found for C ₂₈ H ₃₁ N ₇ O ₂ m/z 498.3 (M+1).

182

[0762] 4-Fluoro-N-(6-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 182 .

[0763] White solid (15.0 mg, 0.033 mmol, 22.6% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.68 (4H, brt, J = 3.02 Hz), 2.43-2.48 (4H, m), 3.85 (2H, s), 3.93 (3H, s), 7 .36 (2H, t, J = 8.78 Hz), 7.74 (1H, dd, J = 8.51, 1.65 Hz), 7.81 (1H, s), 8.05 (1H, s), 8.09 (1H, d, J = 8.51 Hz), 8.13-8.21 (2H, m), 8.59 (1H, s), 9.16 (1H, s), 10.90 (1H, s); ESIMS found for C ₂₅ H ₂₄ FN ₅ O m/z 430.0 (M+1).

183

[0764] 4-Fluoro-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 183 .

[0765] Beige foam (43.0 mg, 0.092 mmol, 34.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.33-1.42(2H, m), 1.46-1.55(4H, m), 2.37(4H, brs), 3.67(2H, s), 3.92( 3H, s), 7.35 (2H, t, J = 8.92 Hz), 7.74 (1H, dd, J = 8.51, 1.37 Hz), 7.82 (1H, s), 8.08 (1H, d, J = 8.51 Hz), 8.13 (1H, s), 8.14-8.21 (2H, m), 8.60 (1H, s), 9.16 (1H, s), 10.85 (1H, s); ESIMS found for C ₂₆ H ₂₆ FN ₅ O m/z 444.0 (M+1).

184

[0766] 4-(Difluoromethoxy)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 184 .

[0767] White solid (13.4 mg, 0.026 mmol, 5.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.34-1.43(2H, m), 1.46-1.55(4H, m), 2.38(4H, brs), 3.67(2H, s), 3.92( 3H, s), 7.40(2H, t, J =73.70 Hz), 7.31(2H, d, J =8.51 Hz), 7.75(1H, dd, J =8.51 , 1.37 Hz), 7.83 (1H, s), 8.09 (1H, d, J = 8.51 Hz), 8.14 (1H, s), 8.15-8.20 (2H , m), 8.61 (1H, s), 9.16 (1H, s), 10.90 (1H, s); ESIMS found for C ₂₇ H ₂₇ F ₂ N ₅ O ₂ m/z 491.9 (M+1).

185

[0768] N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(pyrrolidin-1-ylmethyl)benzamide 185 .

[0769] White solid (35.0 mg, 0.065 mmol, 9.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.34-1.44(2H, m), 1.47-1.55(4H, m), 1.71(4H, dt, J =6.66, 3.12 Hz), 2.38( 4H, brs), 2.44-2.49(4H, m), 3.66(2H, s), 3.67(2H, s), 3.92(3H, s), 7.41 -7.50(1H, m), 7.50-7.58(1H, m), 7.75(1H, dd, J =8.51, 1.65Hz), 7.83(1H, s ), 7.95 (1H, d, J = 7.68 Hz), 8.00 (1H, s), 8.08 (1H, d, J = 8.78 Hz), 8.14 (1H, s ), 8.60 (1H, s), 9.16 (1H, s), 10.82 (1H, s); ESIMS found for C ₃₁ H ₃₆ N ₆ O m/z 509.3 (M+1).

186

[0770] N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(7-methyl-2,7-diazaspiro [3.5]nonan-2-yl)isonicotinamide 186 .

[0771] Off-white solid (8.0 mg, 0.014 mmol, 23.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.39 (2H, brd, J = 4.39 Hz), 1.46-1.53 (4H, m), 1.76 (4H, brd, J = 5.08 Hz), 2 .15(3H, s), 2.19-2.33(4H, m), 2.38(4H, brs), 3.67(2H, s), 3.74(4H, s), 3.92(3H, s), 7.03(1H, s), 7.13(1H, dd, J =5.21, 1.37 Hz), 7.77(1H, dd, J =8, 51, 1.37 Hz), 7.83 (1H, s), 8.09 (1H, d, J =8.51 Hz), 8.15 (1H, s), 8.20 (1H, d, J = 5.21 Hz), 8.60 (1H, s), 9.17 (1H, s), 10.98 (1H, s); ESIMS found for C ₃₃ H ₄₀ N ₈ O m/z 565.4 (M+1).

204

[0772] N-(6-(1-Methyl-5-(morpholinomethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide 204 .

[0773] Off-white solid (10.0 mg, 0.020 mmol, 10.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.42 (4H, brd, J = 3.84 Hz), 3.53-3.61 (8 H, m), 3.70-3.78 (6H, m), 3.94 (3H , s), 7.21 (1H, dd, J = 5.21, 1.37 Hz), 7.47 (1H, s), 7.76 (1H, dd, J = 8.51, 1.65 Hz), 7.83(1H, s), 8.11(2H, d, J =11.25 Hz), 8.29(1H, d, J =4.94 Hz), 8.62(1H, s), 9.18 (1H, s), 11.02 (1H, s); ESIMS found for C ₂₈ H ₃₁ N ₇ O ₃ m/z 514.0 (M+1).

219

[0774] 4-Fluoro-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)benzamide 219 .

[0775] Off-white solid (20.0 mg, 0.052 mmol, 22.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.18 (2H, brt, J =5.21 Hz), 4.07 (2H, brt, J =5.21 Hz), 4.25 (2H, s), 7.33-7 .41 (2H, m), 7.68 (1H, dd, J = 8.51, 1.37 Hz), 7.86 (1H, s), 8.00 (1H, s), 8.07 ( 1H, d, J = 8.51 Hz), 8.12-8.21 (2H, m), 8.61 (1H, s), 9.13 (1H, s), 10.86 (1H, s ); ESIMS found for C ₂₂ H ₁₈ FN ₅ O m/z 387.9 (M+1).

220

[0776] N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-3-(4 -methylpiperazin-1-yl)benzamide 220 .

[0777] Yellow solid (2.0 mg, 0.004 mmol, 2.1% yield). ¹ H NMR (499 MHz, methanol- d ₄ ) δ ppm 2.37(3H, s), 2.65-2.69(4H, m), 3.00-3.05(1H, m), 3.14(4H, dt, J =57.10.5 .50 Hz), 3.33-3.36(4H, m), 3.70-3.77(1H, m), 4.15(2H, s), 4.28(2H, t, J = 5.49 Hz), 4.62-4.76 (2H, m), 6.70 (1H, brd, J = 6.31 Hz), 7.23 (1H, dd, J = 7.96 , 2.20 Hz), 7.39-7.46 (1H, m), 7.46-7.52 (1H, m), 7.60 (1H, d, J =1.65 Hz), 7 .67 (1H, dd, J = 8.51, 1.65 Hz), 7.81 (1H, s), 7.95 (1H, s), 8.59 (1H, s), 9.05 ( 1H, s); ESIMS found for C ₂₉ H ₃₂ FN ₇ O m/z 514.3 (M+1).

221

[0778] N ⁵ -(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-N ² - methylpyridine-2,5-dicarboxamide 221 .

[0779] White solid (66.0 mg, 0.139 mmol, 62.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.85 (3H, brd, J = 4.39 Hz), 2.94-3.04 (2H, m), 3.08 (2H, brs), 4.10 (2H, s) , 4.19 (2H, brs), 4.59-4.75 (2H, m), 7.71 (1H, brd, J = 8.51 Hz), 7.87 (1H, s ), 8.04 (1H, s), 8.10 (1H, brd, J = 8.51 Hz), 8.16 (1H, brd, J = 7.96 Hz), 8.56 (1H, brd, J =7.68 Hz), 8.66 (1H, s), 8.94 (1H, brd, J =4.67 Hz), 9.16 (1H, s) , 9.22 (1H, s), 11.31 (1H, s); ESIMS found for C ₂₅ H ₂₄ FN ₇ O ₂ m/z 474.2 (M+1).

222

[0780] N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-6-(4 -methylpiperazin-1-yl)nicotinamide 222 .

[0781] Yellow solid (21.0 mg, 0.041 mmol, 11.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23 (3H, s), 2.38-2.43 (4H, m), 3.00 (3H, dt, J =28.60, 4.70 Hz), 3.09 (2H, br. t, J = 5.35 Hz), 3.61-3.70 (4H, m), 4.10 (2H, s), 4.19 (2H, br.t, J = 5.35 Hz), 4.67 (2H, dt, J = 47.80, 5.00 Hz), 6.90 (1H, d, J = 9.06 Hz), 7.66 (1H, dd, J = 8.64, 1.51 Hz), 7.81 (1H, s), 8.01 (1H, s), 8.07 (1H, d, J = 8.51 Hz), 8.20 (1H, dd, J = 9.06, 2.47 Hz), 8.60 (1H, s), 8.85 (1H, d, J =2.47 Hz), 9.12 (1H, s), 10.58 (1H, With); ESIMS found for C ₂₈ H ₃₁ FN ₈ O m/z 515.0 (M+1).

223

[0782] 2-(Azetidin-3-yloxy)-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinoline -3-yl)isonicotinamide 223 .

[0783] Beige solid (5.0 mg, 0.010 mmol, 10.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.99 (2H, dt, J = 28.60, 5.00 Hz), 3.08 (2H, brd, J = 5.35 Hz), 3.71 (2H, brd, J = 4.67 Hz), 3.96 (2H, brs), 4.10 (2H, s), 4.19 (2H, brs, J =5.35 Hz), 4.67 (2H, s). dt, J = 47.80, 4.70 Hz), 5.41 (1H, quint, J = 5.90 Hz), 7.43 (1H, s), 7.59 (1H, brd, J =4.67 Hz), 7.71(1H, dd, J =8.51, 1.65 Hz), 7.87(1H, s), 8.03(1H, s), 8.10(1H , d, J = 8.51 Hz), 8.31 (1H, d, J = 5.21 Hz), 8.63 (1H, s), 9.16 (1H, s), 11.12 (1H , br.s); ESIMS found for C ₂₆ H ₂₆ FN ₇ O ₂ m/z 488.2 (M+1).

230

[0784] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide 230 .

[0785] Dirty yellow solid (34.5 mg, 0.074 mmol, 40.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.62-1.75(2H, m), 1.93-2.02(2H, m), 2.15-2.27(2H, m), 2.20(3H, s), 2, 58-2.67(2H, m), 4.15(3H, s), 4.47-4.59(1H, m), 7.17(1H, ddd, J =8.30, 2.40 , 1.10 Hz), 7.42 (1H, t, J = 8.10 Hz), 7.59-7.69 (2H, m), 8.06 (1H, dd, J = 8.51, 1.65 Hz), 8.17 (1H, d, J =8.51 Hz), 8.37 (1H, s), 8.65 (1H, s), 8.74 (1H, s), 9 .20 (1H, s), 10.83 (1H, s); ESIMS found for C ₂₅ H ₂₆ N ₆ O ₂ m/z 443.0 (M+1).

232

[0786] N ² -methyl-N ⁵ -(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)pyridine-2,5-dicarboxamide 232 .

[0787] Yellow solid (12.7 mg, 0.033 mmol, 7.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.86 (3H, d, J = 4.67 Hz), 4.15 (3H, s), 8.09 (1H, dd, J = 8.51, 1.65 Hz), 8.17 (2H , dd, J = 12.21, 8.37 Hz), 8.40 (1H, s), 8.57 (1H, dd, J = 8.10, 2.33 Hz), 8.67 (1H, s), 8.75(1H, s), 8.89(1H, q, J =4.48 Hz), 9.22(2H, s), 11.31(1H, s); ESIMS found for C ₂₀ H ₁₇ N ₇ O ₂ m/z 387.9. (M+1).

233

[0788] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)nicotinamide 233 .

[0789] Yellow solid (42.7 mg, 0.100 mmol, 28.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.38-2.43(4H, m), 3.61-3.68(4H, m), 4.15(3H, s), 6.89(1H, d, J = 9.06 Hz), 8.04 (1H, dd, J = 8.51, 1.65 Hz), 8.14 (1H, d, J = 8.51 Hz), 8.20 ( 1H, dd, J =9.06, 2.47 Hz), 8.34(1H, s), 8.63(1H, s), 8.73(1H, s), 8.85(1H, d , J = 2.47 Hz), 9.17 (1H, s), 10.64 (1H, s); ESIMS found for C ₂₃ H ₂₄ N ₈ O m/z 429.0 (M+1).

236

[0790] 2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide 236 .

[0791] Beige solid (30.0 mg, 0.070 mmol, 24.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.14 (6H, s), 3.19-3.25 (1H, m), 3.81 (2H, dd, J = 8.37, 5.35 Hz), 4.07 (2H, t, J = 7.68 Hz), 4.15 (3H, s), 7.04 (1H, s), 7.16 (1H, dd, J = 5.21, 1.37 Hz), 8.08 ( 1H, dd, J =8.51, 1.37 Hz), 8.17(1H, d, J =8.51 Hz), 8.20-8.26(1H, m), 8.38(1H , s), 8.64 (1H, s), 8.74 (1H, s), 9.20 (1H, s), 10.99 (1H, s); ESIMS found for C ₂₃ H ₂₄ N ₈ O m/z 429.0 (M+1).

238

[0792] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(1-methylpiperidin-4-yl)isonicotinamide 238 .

[0793] Off -white solid (36.0 mg, 0.084 mmol, 68.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.77-1.93(4H, m), 2.00(2H, td, J =11.53, 2.47Hz), 2.21(3H, s), 2.73(1H, tt, J = 11.46, 4.05 Hz), 2.90 (2H, brd, J = 11.25 Hz), 4.15 (3H, s), 7.77 (1H, dd, J = 4 .94, 1.65 Hz), 7.92 (1H, s), 8.09 (1H, dd, J = 8.51, 1.65 Hz), 8.18 (1H, d, J = 8, 78 Hz), 8.40 (1H, s), 8.67 (1H, s), 8.69 (1H, d, J =5.21 Hz), 8.76 (1H, s), 9.22 (1H, s), 11.23 (1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ O m/z 428.2 (M+1).

240

[0794] 2-(4-(Dimethylamino)piperidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide 240 .

[0795] White solid (18.0 mg, 0.039 mmol, 28.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.40 (2H, qd, J = 11.98, 3.84 Hz), 1.85 (2H, brd, J = 11.80 Hz), 2.24 (6H, s), 2.37 -2.46 (1H, m), 2.81-2.92 (2H, m), 4.15 (3H, s), 4.44 (2H, brd, J = 13.17 Hz), 7.13 (1H, dd, J =5.08, 0.96 Hz), 7.46 (1H, s), 8.07 (1H, dd, J =8.51, 1.37 Hz), 8 .17 (1H, d, J = 8.51 Hz), 8.25 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.65 (1H, s), 8 .74 (1H, s), 9.21 (1H, s), 11.04 (1H, s); ESIMS found for C ₂₅ H ₂₈ N ₈ O m/z 457.0 (M+1).

241

[0796] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide 241 .

[0797] Off-white solid (70.0 mg, 0.169 mmol, 53.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.52-3.63(4H, m), 3.70-3.78(4H, m), 4.15(3H, s), 7.22(1H, dd, J =5.08, 1 .23 Hz), 7.47 (1H, s), 8.08 (1H, dd, J = 8.51, 1.65 Hz), 8.17 (1H, d, J = 8.78 Hz), 8.29(1H, d, J =4.94Hz), 8.38(1H, s), 8.66(1H, s), 8.74(1H, s), 9.21(1H, s ), 11.06 (1H, s); ESIMS found for C ₂₂ H ₂₁ N ₇ O ₂ m/z 415.9 (M+1).

242

[0798] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 242 .

[0799] White solid (38.0 mg, 0.089 mmol, 37.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23 (3H, s), 2.43 (4H, brt, J = 4.67 Hz), 3.56-3.66 (4H, m), 4.15 (3H, s), 7 .17 (1H, d, J = 4.94 Hz), 7.47 (1H, s), 8.04-8.10 (1H, m), 8.18 (1H, d, J = 8.51 Hz), 8.26 (1H, d, J =4.94 Hz), 8.38 (1H, s), 8.66 (1H, s), 8.75 (1H, s), 9.21 ( 1H, s), 11.10 (1H, s); ESIMS found for C ₂₃ H ₂₄ N ₈ O m/z 429.0 (M+1).

243

[0800] 2-(4-Methyl-1,4-diazepan-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl ) isonicotinamide 243 .

[0801] Beige solid (47.0 mg, 0.106 mmol, 37.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.93 (2H, dt, J = 11.39, 5.83 Hz), 2.27 (3H, s), 2.48 (2H, br s), 2.63 (2H, dd, J = 5.63, 4.25 Hz), 3.69 (2H, t, J = 6.17 Hz), 3.78-3.85 (2H, m), 4.15 (3H, s), 7, 06 (1H, dd, J =5.21, 1.10 Hz), 7.21 (1H, s), 8.08 (1H, dd, J =8.51, 1.65 Hz), 8.18 (1H, d, J = 8.51 Hz), 8.21 (1H, d, J = 4.94 Hz), 8.38 (1H, s), 8.65 (1H, s), 8.76 (1H, s), 9.21 (1H, s), 11.08 (1H, s); ESIMS found for C ₂₄ H ₂₆ N ₈ O m/z 443.2 (M+1).

245

[0802] 2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide 245 .

[0803] Beige solid (198.0 mg, 0.434 mmol, 36.8% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.01 (6H, d, J = 6.59 Hz), 2.53-2.59 (4H, m), 2.65-2.75 (1H, m), 3.53-3.63 ( 4H, m), 4.15(3H, s), 7.16(1H, dd, J =5.21, 1.37 Hz), 7.45(1H, s), 8.08(1H, dd , J = 8.51, 1.37 Hz), 8.18 (1H, d, J = 8.78 Hz), 8.26 (1H, d, J = 5.21 Hz), 8.38 (1H , s), 8.66 (1H, s), 8.76 (1H, s), 9.21 (1H, s), 11.11 (1H, s); ESIMS found for C ₂₅ H ₂₈ N ₈ O m/z 457.2 (M+1).

249

[0804] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-ylamino)isonicotinamide 249 .

[0805] White solid (7.0 mg, 0.016 mmol, 57.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.33-1.46(2H, m), 1.93(2H, brd, J =10.15 Hz), 2.69(2H, brd, J =10.98 Hz), 3 .06 (2H, brd, J = 12.62 Hz), 3.81-3.93 (1H, m), 4.15 (3H, s), 6.78 (1H, d, J = 7 .68 Hz), 7.00 (1H, s), 7.03 (1H, dd, J = 5.21, 1.37 Hz), 8.07 (1H, dd, J = 8.51, 1, 37 Hz), 8.10 (1H, d, J = 5.49 Hz), 8.17 (1H, d, J = 8.51 Hz), 8.39 (1H, s), 8.62 (1H , s), 8.75 (1H, s), 9.20 (1H, s), 10.88 (1H, br s); ESIMS found for C ₂₃ H ₂₄ N ₈ O m/z 429.0 (M+1).

250

[0806] 2-(Methyl(1-methylpiperidin-4-yl)amino)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide 250 .

[0807] Brown solid (19.0 mg, 0.042 mmol, 14.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.49-1.64(2H, m), 1.75-1.87(2H, m), 2.05(2H, brt, J =10.84 Hz), 2.20(3H, s), 2.82-2.90(2H, m), 2.94(3H, s), 4.15(3H, s), 4.45-4.56(1H, m), 7.08 (1H, dd, J =5.08, 1.23 Hz), 7.19 (1H, s), 8.07 (1H, dd, J =8.37, 1.51 Hz), 8.17 ( 1H, d, J = 8.51 Hz), 8.23 (1H, d, J = 5.21 Hz), 8.37 (1H, s), 8.65 (1H, s), 8.74 ( 1H, s), 9.21 (1H, s), 11.01 (1H, s); ESIMS found for C ₂₅ H ₂₈ N ₈ O m/z 457.0 (M+1).

253

[0808] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)thio)isonicotinamide 253 .

[0809] Off-white solid (28.0 mg, 0.061 mmol, 19.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.58-1.72(2H, m), 1.99-2.07(2H, m), 2.12(2H, brt, J =10.29 Hz), 2.17(3H, s), 2.69 (2H, brd, J =10.70 Hz), 3.84 (1H, brd, J =9.74 Hz), 4.15 (3H, s), 7, 64 (1H, dd, J =5.21, 1.65 Hz), 7.82 (1H, s), 8.09 (1H, dd, J =8.51, 1.65 Hz), 8.18 (1H, d, J =8.51 Hz), 8.39 (1H, s), 8.62 (1H, d, J =5.21 Hz), 8.64 (1H, s), 8.75 (1H, s), 9.21 (1H, s), 11.22 (1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ OS m/z 460.2 (M+1).

256

[0810] 2-Methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6- carboxamide 256 .

[0811] Off-white solid (39.0 mg, 0.093 mmol, 85.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.37(3H, s), 2.64(2H, t, J =5.90 Hz), 2.92(2H, brt, J =5.76 Hz), 3.56(2H, s ), 4.15 (3H, s), 7.19 (1H, d, J = 7.96 Hz), 7.83 (1H, dd, J = 7.96, 1.92 Hz), 7.88 (1H, s), 8.06 (1H, dd, J = 8.51, 1.65 Hz), 8.16 (1H, d, J = 8.78 Hz), 8.36 (1H, d, J = 0.82 Hz), 8.64 (1H, s), 8.74 (1H, s), 9.18 (1H, s), 10.69 (1H, s); ESIMS found for C ₂₃ H ₂₂ N ₆ O m/z 399.0 (M+1).

257

[0812] N-(7-Fluoro-6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 257 .

[0813] Light brown solid (14.0 mg, 0.031 mmol, 17.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24 (3H, s), 2.43 (4H, brt, J = 4.94 Hz), 3.57-3.66 (4H, m), 4.17 (3H, s), 7 .17 (1H, dd, J = 5.21, 1.10 Hz), 7.47 (1H, s), 8.07 (1H, d, J = 11.25 Hz), 8.26 (1H, d, J = 5.49 Hz), 8.60 (1H, d, J = 4.39 Hz), 8.67 (1H, d, J = 6.86 Hz), 8.71 (1H, s) , 9.22 (1H, s), 11.11 (1H, s); ESIMS found for C ₂₃ H ₂₃ FN ₈ O m/z 447.2 (M+1).

258

[0814] N-(6-(1H-1,2,4-Triazol-1-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 258 .

[0815] Beige solid (40.0 mg, 0.097 mmol, 41.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.43(4H, t, J =4.94Hz), 3.56-3.66(4H, m), 7.16(1H, dd, J =5, 21, 1.10 Hz), 7.47(1H, s), 8.11(1H, dd, J =8.78, 1.92 Hz), 8.26(1H, d, J =5.21 Hz), 8.32 (1H, d, J = 9.06 Hz), 8.35 (1H, s), 8.48 (1H, d, J = 1.92 Hz), 8.73 (1H, s), 9.29 (1H, s), 9.53 (1H, s), 11.18 (1H, s); ESIMS found for C ₂₂ H ₂₂ N ₈ O m/z 415.2 (M+1).

261

[0816] N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-(pyrrolidin-1-ylmethyl)benzamide 261 .

[0817] White solid (25.0 mg, 0.061 mmol, 27.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.72 (4H, dt, J =6.66, 3.12 Hz), 2.48 (4H, brs), 3.67 (2H, s), 3.85 (3H, s), 7 .32 (1H, d, J = 0.82 Hz), 7.41-7.51 (1H, m), 7.54 (1H, brd, J = 7.68 Hz), 7.72 ( 1H, dd, J = 8.51, 1.65 Hz), 7.80 (1H, s), 7.96 (1H, brd, J = 7.96 Hz), 8.01 (1H, s ), 8.08 (1H, s), 8.14 (1H, d, J = 8.51 Hz), 8.68 (1H, s), 9.21 (1H, s), 10.81 (1H , With); ESIMS found for C ₂₅ H ₂₅ N ₅ O m/z 412.0 (M+1).

265

[0818] 2-(Dimethylamino)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 265 .

[0819] White solid (16.0 mg, 0.043 mmol, 14.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.11 (6H, s), 3.85 (3H, s), 7.09 (1H, dd, J =5.08, 1.23 Hz), 7.25 (1H, s), 7.33 (1H, d, J = 1.10 Hz), 7.29-7.29 (1H, m), 7.74 (1H, dd, J = 8.51, 1.65 Hz), 7.81 ( 1H, s), 8.10 (1H, d, J = 0.82 Hz), 8.15 (1H, d, J = 8.51 Hz), 8.23 (1H, d, J = 5.21 Hz), 8.69 (1H, s), 9.22 (1H, s), 11.07 (1H, s); ESIMS found for C ₂₁ H ₂₀ N ₆ O m/z 373.2 (M+1).

266

[0820] 2-(3-aminoazetidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 266 .

[0821] Yellow solid (25.3 mg, 0.063 mmol, 51.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.15 (2H, brs), 3.62 (2H, dd, J = 8.23, 5.76 Hz), 3.79-3.89 (4H, m), 4.19 (2H, t, J =7.68 Hz), 7.02(1H, s), 7.14(1H, dd, J =5.21, 1.37 Hz), 7.33(1H, d, J =1 .10 Hz), 7.74 (1H, dd, J = 8.51, 1.65 Hz), 7.81 (1H, s), 8.09 (1H, s), 8.15 (1H, d , J = 8.51 Hz), 8.20 (1H, d, J = 5.21 Hz), 8.68 (1H, s), 9.22 (1H, s), 11.04 (1H, broad .With); ESIMS found for C ₂₂ H ₂₁ N ₇ O m/z 400.2 (M+1).

268

[0822] N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)isonicotinamide 268 .

[0823] White solid (69.0 mg, 0.173 mmol, 62.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.94-2.03 (4H, m), 3.47 (4H, brt, J = 6.59 Hz), 3.85 (3H, s), 7.06 (1H, dd, J = 5.21, 1.37 Hz), 7.08 (1H, s), 7.33 (1H, s), 7.74 (1H, dd, J =8.51, 1.65 Hz), 7, 81 (1H, s), 8.09 (1H, s), 8.15 (1H, d, J = 8.78 Hz), 8.21 (1H, d, J = 5.21 Hz), 8, 69 (1H, s), 9.22 (1H, s), 11.04 (1H, s); ESIMS found for C ₂₃ H ₂₂ N ₆ O m/z 399.2 (M+1).

271

[0824] N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)isonicotinamide 271 .

[0825] White solid (85.0 mg, 0.206 mmol, 74.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.53-1.62(4H, m), 1.62-1.69(2H, m), 3.61-3.66(4H, m), 3.85(3H, s), 7, 09 (1H, dd, J = 5.21, 1.37 Hz), 7.33 (1H, s), 7.44 (1H, s), 7.74 (1H, dd, J = 8.51, 1.65 Hz), 7.81 (1H, s), 8.09 (1H, s), 8.15 (1H, d, J = 8.51 Hz), 8.23 (1H, d, J = 5.21 Hz), 8.69(1H, s), 9.22(1H, s), 11.09(1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ O m/z 413.2 (M+1).

273

[0826] N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide 273 .

[0827] White solid (70.0 mg, 0.169 mmol, 61.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.54-3.59(4H, m), 3.71-3.77(4H, m), 3.85(3H, s), 7.21(1H, dd, J =5.08, 1 .23 Hz), 7.33 (1H, s), 7.48 (1H, s), 7.74 (1H, dd, J = 8.51, 1.65 Hz), 7.81 (1H, s ), 8.10 (1H, s), 8.16 (1H, d, J = 8.51 Hz), 8.29 (1H, d, J = 4.94 Hz), 8.70 (1H, s ), 9.23 (1H, s), 11.11 (1H, s); ESIMS found for C ₂₃ H ₂₂ N ₆ O ₂ m/z 415.2 (M+1).

275

[0828] 2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 275 .

[0829] Beige solid (85.0 mg, 0.187 mmol, 64.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.02 (6H, d, J = 6.59 Hz), 2.53-2.59 (4H, m), 2.66-2.75 (1H, m), 3.52-3.63 ( 4H, m), 3.85(3H, s), 7.15(1H, dd, J =5.08, 1.23Hz), 7.32(1H, d, J =1.10Hz), 7.44(1H, s), 7.73(1H, dd, J =8.51, 1.65Hz), 7.80(1H, s), 7.77-7.78(1H, m) , 8.09 (1H, s), 8.15 (1H, d, J = 8.51 Hz), 8.26 (1H, d, J = 5.21 Hz), 8.69 (1H, s) , 9.22 (1H, s), 11.04 (1H, s); ESIMS found for C ₂₆ H ₂₉ N ₇ O m/z 456.0 (M+1).

276

[0830] 2-(4-Cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 276 .

[0831] White solid (46.0 mg, 0.101 mmol, 73.6% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 0.34-0.41 (2H, m), 0.41-0.49 (2H, m), 1.66 (1H, tt, J =6.62, 3.53 Hz), 2.62- 2.68 (4H, m), 3.52-3.61 (4H, m), 3.85 (3H, s), 7.15 (1H, dd, J =5.08, 1.23 Hz) , 7.33 (1H, d, J = 1.10 Hz), 7.47 (1H, s), 7.74 (1H, dd, J = 8.51, 1.65 Hz), 7.81 ( 1H, s), 8.10 (1H, s), 8.15 (1H, d, J = 8.78 Hz), 8.26 (1H, d, J = 5.21 Hz), 8.69 ( 1H, s), 9.23 (1H, s), 11.12 (1H, s); ESIMS found for C ₂₆ H ₂₇ N ₇ O m/z 454.0 (M+1).

277

[0832] N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide 277 .

[0833] Off-white solid (131.6 mg, 0.290 mmol, 31.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.62-1.71(4H, m), 2.66(4H, brs), 3.73(4H, s), 3.85(3H, s), 7.03(1H, s) , 7.12 (1H, dd, J = 5.21, 1.37 Hz), 7.33 (1H, s), 7.74 (1H, dd, J = 8.51, 1.65 Hz), 7.81 (1H, s), 8.10 (1H, s), 8.15 (1H, d, J = 8.51 Hz), 8.20 (1H, d, J = 5.21 Hz), 8.68 (1H, s), 9.22 (1H, s), 11.04 (1H, br s); ESIMS found for C ₂₆ H ₂₇ N ₇ O m/z 454.2 (M+1).

278

[0834] N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide 278 .

[0835] Off-white solid (39.0 mg, 0.079 mmol, 35.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.76 (4H, br.t, J =5.08 Hz), 2.14 (3H, s), 2.27 (4H, br.s), 3.73 (4H, s), 3.85 (3H, s), 7.03 (1H, s), 7.13 (1H, dd, J = 5.08, 1.51 Hz), 7.33 (1H, s), 7.74 (1H, dd, J =8.51, 1.65 Hz), 7.81(1H, s), 8.10(1H, s), 8.15(1H, d, J =8.51 Hz), 8, 20(1H, d, J =5.21Hz), 8.68(1H, s), 9.22(1H, s), 11.04(1H, s); ESIMS found for C ₂₇ H ₂₉ N ₇ O m/z 468.2 (M+1).

285

[0836] N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isoindoline-5-carboxamide 285 .

[0837] Off-white solid (233.7 mg, 0.633 mmol, 68.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.85(4H, s), 4.07(1H, s), 4.27(3H, s), 7.33(1H, s), 7.44(1H, d, J =7.96 Hz ), 7.72 (1H, dd, J = 8.51, 1.65 Hz), 7.81 (1H, s), 7.97 (1H, dd, J = 7.82, 1.24 Hz) , 8.01 (1H, s), 8.09 (1H, s), 8.14 (1H, d, J = 8.51 Hz), 8.69 (1H, s), 9.21 (1H, s), 10.84 (1H, s); ESIMS found for C ₂₂ H ₁₉ N ₅ O m/z 370.2 (M+1).

286

[0838] 2-Methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isoindoline-5-carboxamide 286 .

[0839] Off -white solid (39.0 mg, 0.097 mmol, 17.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.51 (3H, brs), 3.85 (3H, s), 3.87 (4H, s), 7.33 (1H, s), 7.37 (1H, d, J =7, 96 Hz), 7.72 (1H, dd, J = 8.64, 1.51 Hz), 7.81 (1H, s), 7.89-7.98 (2H, m), 8.09 ( 1H, s), 8.14 (1H, d, J = 8.51 Hz), 8.68 (1H, s), 9.20 (1H, s), 10.80 (1H, s); ESIMS found for C ₂₃ H ₂₁ N ₅ O m/z 384.2 (M+1).

289

[0840] N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide 289 .

[0841] Beige solid (37.0 mg, 0.085 mmol, 35.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.40(3H, s), 3.54-3.61(4H, m), 3.68(3H, s), 3.70-3.77(4H, m), 7.14(1H, s), 7.21 (1H, dd, J = 5.08, 1.23 Hz), 7.47 (1H, s), 7.67 (1H, dd, J = 8.51, 1.65 Hz ), 8.00 (1H, s), 8.14 (1H, d, J = 8.78 Hz), 8.29 (1H, d, J = 4.94 Hz), 8.67 (1H, s ), 9.21 (1H, s), 11.05 (1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ O ₂ m/z 429.0 (M+1).

290

[0842] N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)-7-fluoroisoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 290 .

[0843] Off -white solid (54.0 mg, 0.118 mmol, 42.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.41(3H, s), 2.41-2.45(4H, m), 3.54(3H, d, J =0.82 Hz), 3.58 -3.63(4H, m), 7.07(1H, d, J =0.82Hz), 7.15(1H, dd, J =5.21, 1.10Hz), 7.47( 1H, s), 8.05 (1H, d, J = 10.43 Hz), 8.08 (1H, d, J = 7.14 Hz), 8.26 (1H, d, J = 5.21 Hz), 8.71(1H, s), 9.23(1H, s), 11.14(1H, s); ESIMS found for C ₂₅ H ₂₆ FN ₇ O m/z 460.2 (M+1).

291

[0844] 4-Fluoro-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)benzamide 291 .

[0845] Beige solid (55.0 mg, 0.142 mmol, 83.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.79 (1H, br s), 3.09 (2H, t, J = 5.21 Hz), 3.96 (2H, s), 4.14 (2H, t, J = 5.21 Hz ), 7.31 (1H, s), 7.36 (2H, t, J = 8.78 Hz), 7.71 (1H, dd, J = 8.64, 1.51 Hz), 8.03 (1H, s), 8.11 (1H, d, J = 8.51 Hz), 8.14-8.21 (2H, m), 8.67 (1H, s), 9.18 (1H, s), 10.92 (1H, s); ESIMS found for C ₂₂ H ₁₈ FN ₅ O m/z 387.9 (M+1).

292

[0846] 4-(Difluoromethoxy)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)benzamide 292 .

[0847] Yellow solid (12.7 mg, 0.029 mmol, 12.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.78 (1H, br s), 3.09 (2H, br t, J = 5.21 Hz), 3.96 (2H, s), 4.14 (2H, t, J = 5, 35 Hz), 7.40(1H, t, J =73.70 Hz), 7.31(3H, t, J =4.25 Hz), 7.71(1H, dd, J =8.51, 1.65 Hz), 8.03 (1H, s), 8.12 (1H, d, J = 8.51 Hz), 8.14-8.20 (2H, m), 8.68 (1H, s), 9.19 (1H, s), 10.93 (1H, s); ESIMS found for C ₂₃ H ₁₉ F ₂ N ₅ O ₂ m/z 435.9 (M+1).

293

[0848] 2-((2-(Dimethylamino)ethyl)amino)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl )isonicotinamide 293 .

[0849] Beige solid (8.0 mg, 0.018 mmol, 11.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.20(6H, s), 2.44(2H, brt, J =6.59Hz), 3.09(2H, brt, J =5.35Hz), 3.39(2H , q, J =6.31 Hz), 3.96(2H, s), 4.13(2H, brt, J =5.35 Hz), 6.57(1H, brt, J = 5.63 Hz), 7.03 (1H, dd, J = 5.21, 1.37 Hz), 7.05 (1H, s), 7.31 (1H, s), 7.72 (1H, dd, J = 8.64, 1.51 Hz), 8.03 (1H, s), 8.11 (2H, d, J = 6.04 Hz), 8.64 (1H, s), 9, 17(1H, s), 10.79(1H, brs); ESIMS found for C ₂₅ H ₂₈ N ₈ O m/z 457.0 (M+1).

294

[0850] 2-((1-Isopropylpiperidin-4-yl)oxy)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3- yl) isonicotinamide 294 .

[0851] Beige solid (22.0 mg, 0.043 mmol, 21.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 0.99 (6H, d, J = 6.59 Hz), 1.60-1.72 (2H, m), 1.95-2.04 (2H, m), 2.30-2.39 ( 2H, m), 2.68-2.84 (4H, m), 3.08 (2H, br.t, J = 5.21 Hz), 3.96 (2H, s), 4.14 (2H , t, J = 5.35 Hz), 5.02 (1H, tt, J = 8.54, 4.08 Hz), 7.32 (1H, s), 7.35 (1H, s), 7 .50 (1H, dd, J = 5.49, 1.37 Hz), 7.73 (1H, dd, J = 8.64, 1.51 Hz), 8.05 (1H, s), 8, 12 (1H, d, J = 8.51 Hz), 8.31 (1H, d, J = 5.21 Hz), 8.66 (1H, s), 9.19 (1H, s), 11, 10 (1H, s); ESIMS found for C ₂₉ H ₃₃ N ₇ O ₂ m/z 512.3 (M+1).

296

[0852] 4-(Difluoromethoxy)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)benzamide 296 .

[0853] Brown solid (16.1 mg, 0.042 mmol, 7.4% yield), 1H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 7.41(1H, t, J =73.60Hz), 7.29-7.34(2H, m), 7.92(1H, dd, J =8.51, 1.65Hz), 7 .98(1H, s), 8.14-8.22(3H, m), 8.29(1H, s), 8.59(1H, s), 8.69(1H, s), 9, 22 (1H, s), 10.99 (1H, s); ESIMS found for C ₂₀ H ₁₃ F ₂ N ₃ O ₃ m/z 381.9 (M+1).

301

[0854] 3-((1-Methylpiperidin-4-yl)oxy)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)benzamide 301 .

[0855] Yellow solid (35.1 mg, 0.078 mmol, 58.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.61-1.75(2H, m), 1.92-2.02(2H, m), 2.14-2.25(2H, m), 2.19(3H, s), 2, 58-2.67(2H, m), 4.48-4.59(1H, m), 7.14-7.21(1H, m), 7.42(1H, t, J =8.10 Hz), 7.61-7.68(2H, m), 7.92(1H, dd, J =8.51, 1.65 Hz), 7.98(1H, s), 8.19(1H , d, J = 8.51 Hz), 8.29 (1H, s), 8.24-8.25 (1H, m), 8.60 (1H, s), 8.69 (1H, s) , 9.22 (1H, s), 10.93 (1H, s); ESIMS found for C ₂₅ H ₂₄ N ₄ O ₃ m/z 429.1 (M+1).

306

[0856] 2-(3-aminoazetidin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isonicotinamide 306 .

[0857] Yellow solid (5.1 mg, 0.013 mmol, 3.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.62 (2H, dd, J = 8.23, 5.76 Hz), 3.85 (1H, quint, J = 6.38 Hz), 4.19 (2H, t, J = 7.68 Hz ), 7.01 (1H, s), 7.14 (1H, dd, J =5.21, 1.37 Hz), 7.94 (1H, dd, J =8.51, 1.65 Hz) , 7.98(1H, s), 8.19(1H, d, J =2.47 Hz), 8.21(1H, s), 8.29(1H, s), 8.59(1H, s), 8.68 (1H, s), 9.23 (1H, s), 11.07 (1H, br s); ESIMS found for C ₂₁ H ₁₈ N ₆ O ₂ m/z 387.2 (M+1).

309

[0858] 2-(1-Methylpiperidin-4-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isonicotinamide 309 .

[0859] Off-white solid (15.0 mg, 0.036 mmol, 51.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.78-1.92(4H, m), 2.00(2H, td, J =11.53, 2.47 Hz), 2.21(3H, s), 2.73(1H, tt, J = 11.49, 4.15 Hz), 2.90 (2H, brd, J = 11.25 Hz), 7.77 (1H, dd, J = 5.21, 1.65 Hz), 7.92(1H, s), 7.94(1H, dd, J =8.51, 1.65Hz), 7.98(1H, s), 8.20(1H, d, J =8, 51 Hz), 8.31 (1H, s), 8.60 (1H, s), 8.69 (1H, d, J =4.94 Hz), 8.70 (1H, s), 9.24 (1H, s), 11.26 (1H, s); ESIMS found for C ₂₄ H ₂₃ N ₅ O ₂ m/z 414.2 (M+1).

310

[0860] 1'-Methyl-N-(6-(oxazol-5-yl)isoquinolin-3-yl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]- 4-carboxamide 310 .

[0861] Brown solid (51.0 mg, 0.124 mmol, 54.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.31 (3H, s), 2.56-2.63 (2H, m), 2.65 (2H, brd, J = 2.74 Hz), 3.11 (2H, brd, J =3.02Hz), 6.89(1H, brs), 7.78(1H, dd, J =4.94, 1.37Hz), 7.94(1H, dd, J =8 .51, 1.65 Hz), 7.98 (1H, s), 8.17 (1H, s), 8.21 (1H, d, J = 8.51 Hz), 8.31 (1H, s ), 8.59 (1H, s), 8.65-8.75 (2H, m), 9.24 (1H, s), 11.33 (1H, s); ESIMS found for C ₂₄ H ₂₁ N ₅ O ₂ m/z 412.2 (M+1).

313

[0862] 2-(4-Methylpiperazin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isonicotinamide 313 .

[0863] Brown solid (13.0 mg, 0.031 mmol, 19.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.43(4H, t, J =4.94Hz), 3.55-3.64(4H, m), 7.16(1H, dd, J =5, 21, 1.10 Hz), 7.47 (1H, s), 7.93 (1H, dd, J = 8.51, 1.65 Hz), 7.98 (1H, s), 8.20 ( 1H, d, J =8.51 Hz), 8.26(1H, d, J =4.94 Hz), 8.30(1H, s), 8.59(1H, s), 8.69( 1H, s), 9.23 (1H, s), 11.13 (1H, s); ESIMS found for C ₂₃ H ₂₂ N ₆ O ₂ m/z 415.2 (M+1).

317

[0864] 2-(7-Methyl-2,7-diazaspiro[3.5]nonan-2-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isonicotinamide 317 .

[0865] Off-white solid (24.0 mg, 0.050 mmol, 57.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.76 (4H, br.t, J =5.08 Hz), 2.15 (3H, s), 2.27 (4H, br.s), 3.74 (4H, s), 7.03 (1H, s), 7.13 (1H, dd, J = 5.35, 1.51 Hz), 7.94 (1H, dd, J = 8.51, 1.65 Hz), 7.98 ( 1H, s), 8.19 (1H, d, J = 2.74 Hz), 8.21 (1H, s), 8.30 (1H, s), 8.59 (1H, s), 8, 68 (1H, s), 9.23 (1H, s), 11.06 (1H, s); ESIMS found for C ₂₆ H ₂₆ N ₆ O ₂ m/z 455.2 (M+1).

318

[0866] N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-2-(2,7-diazaspiro[3.5]nonan-7-yl)isonicotinamide 318 .

[0867] Beige solid (9.0 mg, 0.020 mmol, 50.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.74 (4H, brs), 3.27 (4H, brs), 3.58 (4H, brd, J = 4.67 Hz), 7.11 (1H, brd, J = 4.67 Hz), 7.46 (1H, s), 7.94 (1H, dd, J = 8.51, 1.37 Hz), 7.98 (1H, s), 8.20 ( 1H, d, J =8.51 Hz), 8.24(1H, d, J =4.94 Hz), 8.30(1H, s), 8.60(1H, s), 8.69( 1H, s), 9.24 (1H, s), 11.13 (1H, br s); ESIMS found for C ₂₅ H ₂₄ N ₆ O ₂ m/z 441.2 (M+1).

319

[0868] N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-2-(piperidin-4-ylamino)isonicotinamide 319 .

[0869] White solid (18.0 mg, 0.043 mmol, 8.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.65-1.76(2H, m), 2.04-2.13(2H, m), 2.97-3.07(2H, m), 3.25-3.30(2H, m ), 4.05 (1H, brs), 7.09 (1H, brd, J = 4.12 Hz), 7.93 (1H, dd, J = 8.51, 1.65 Hz) , 7.98 (1H, s), 8.12 (1H, d, J = 5.49 Hz), 8.19 (1H, d, J = 8.78 Hz), 8.31 (1H, s) , 8.59(1H, s), 8.65(1H, s), 8.99(2H, brs), 9.22(1H, s), 10.94(1H, brs); ESIMS found for C ₂₃ H ₂₂ N ₆ O ₂ m/z 415.2 (M+1).

325

[0870] 2-Methyl-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isoindoline-5-carboxamide 325 .

[0871] Off-white solid (39.0 mg, 0.100 mmol, 57.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.51 (3H, br s), 3.88 (4H, s), 7.37 (1H, d, J = 7.96 Hz), 7.88-7.96 (3H, m), 7 .98 (1H, s), 8.18 (1H, d, J = 8.78 Hz), 8.29 (1H, s), 8.59 (1H, s), 8.68 (1H, s) , 9.21 (1H, s), 10.83 (1H, s); ESIMS found for C ₂₂ H ₁₈ N ₄ O ₂ m/z 371.1 (M+1).

326

[0872] N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide 326 .

[0873] Off-white solid (17.0 mg, 0.046 mmol, 26.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.74-2.81 (2H, m), 2.99 (2H, br.t, J = 5.76 Hz), 3.90-3.96 (2H, m), 7.22 (1H, d, J = 7.96 Hz), 7.80 (1H, s), 7.81-7.85 (1H, m), 7.91 (1H, dd, J = 8.51, 1.65 Hz ), 7.98(1H, s), 8.18(1H, d, J =8.78 Hz), 8.28(1H, s), 8.59(1H, s), 8.68(1H , s), 9.21 (1H, s), 10.76 (1H, s); ESIMS found for C ₂₂ H ₁₈ N ₄ O ₂ m/z 371.2 (M+1).

328

[0874] N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 328 .

[0875] Beige solid (149.0 mg, 0.348 mmol, 74.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.43(4H, t, J =4.94Hz), 2.55(3H, s), 3.56-3.66(4H, m), 7.16 (1H, dd, J =5.21, 1.10 Hz), 7.46(1H, s), 7.82(1H, s), 7.88(1H, dd, J =8.51, 1 .65 Hz), 8.16 (1H, d, J = 8.78 Hz), 8.20 (1H, s), 8.26 (1H, d, J = 5.21 Hz), 8.66 ( 1H, s), 9.20 (1H, s), 11.11 (1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ O ₂ m/z 429.2 (M+1).

329

[0876] N-(6-(5-Methyl-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 329 .

[0877] Beige solid (20.0 mg, 0.047 mmol, 19.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24 (3H, s), 2.43 (4H, brt, J = 4.80 Hz), 2.65 (3H, s), 3.56-3.67 (4H, m), 7 .17 (1H, dd, J = 5.08, 1.23 Hz), 7.47 (1H, s), 8.11 (1H, dd, J = 8.51, 1.65 Hz), 8, 27 (1H, d, J =4.94 Hz), 8.30 (1H, d, J =8.51 Hz), 8.58 (1H, s), 8.78 (1H, s), 9, 34 (1H, s), 11.20 (1H, s); ESIMS found for C ₂₃ H ₂₃ N ₇ O ₂ m/z 430.0 (M+1).

330

[0878] N-(6-(5-chlorothiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 330 .

[0879] Yellow solid (1.3 mg, 0.003 mmol, 1.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.40-2.46(4H, m), 3.58-3.64(4H, m), 7.10-7.20(1H, m), 7, 46 (1H, s), 7.89 (1H, dd, J = 8.64, 1.78 Hz), 8.18 (1H, d, J = 8.23 Hz), 8.26 (1H, d , J = 5.21 Hz), 8.28 (1H, s), 8.38 (1H, s), 8.69 (1H, s), 9.24 (1H, s), 11.09 (1H , With); ESIMS found for C ₂₃ H ₂₁ ClN ₆ OS m/z 464.9 (M+1).

331

[0880] 2-(4-Methylpiperazin-1-yl)-N-(6-(5-methylthiazol-2-yl)isoquinolin-3-yl)isonicotinamide 331 .

[0881] Dirty yellow solid (11.5 mg, 0.026 mmol, 9.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.38-2.47(4H, m), 2.56(3H, d, J =1.10 Hz), 3.56-3.66(4H, m) , 7.17 (1H, dd, J = 5.21, 1.10 Hz), 7.47 (1H, s), 7.73 (1H, d, J = 1.37 Hz), 8.09 ( 1H, dd, J = 8.51, 1.65 Hz), 8.19 (1H, d, J = 8.51 Hz), 8.26 (1H, d, J = 5.21 Hz), 8, 43 (1H, s), 8.71 (1H, s), 9.25 (1H, s), 11.09 (1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ OS m/z 444.9 (M+1).

332

[0882] 2-(4-Methylpiperazin-1-yl)-N-(6-(4-methylthiazol-2-yl)isoquinolin-3-yl)isonicotinamide 332 .

[0883] Black solid (23.6 mg, 0.053 mmol, 18.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.40-2.46(4H, m), 2.49(3H, brs), 3.55-3.65(4H, m), 7.17( 1H, dd, J = 5.08, 1.24 Hz), 7.46 (1H, br s), 7.47 (1H, d, J = 0.82 Hz), 8.11 (1H, dd , J = 8.51, 1.65 Hz), 8.20 (1H, d, J = 8.51 Hz), 8.26 (1H, d, J = 4.94 Hz), 8.49 (1H , s), 8.72 (1H, s), 9.26 (1H, s), 11.09 (1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ OS m/z 444.9 (M+1).

333

[0884] 2-(3-(2-(4-Methylpiperazin-1-yl)isonicotinamido)isoquinolin-6-yl)thiazole-5-carboxamide 333 .

[0885] Yellow solid (7.6 mg, 0.016 mmol, 5.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.41-2.45(4H, m), 3.58-3.64(4H, m), 7.17(1H, dd, J =5.08, 1 .23 Hz), 7.47 (1H, s), 7.69 (1H, br s), 8.15 (1H, dd, J = 8.64, 1.78 Hz), 8.24 (2H , broadd, J = 8.78 Hz), 8.27 (1H, d, J = 4.94 Hz), 8.54 (1H, s), 8.60 (1H, s), 8.75 (1H, s), 9.29 (1H, s), 11.13 (1H, s); ESIMS found for C ₂₄ H ₂₃ N ₇ O ₂ S m/z 473.9 (M+1).

334

[0886] 6-(4-Methylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)nicotinamide 334 .

[0887] White solid (64.1 mg, 0.149 mmol, 42.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.37-2.45(4H, m), 3.60-3.68(4H, m), 6.90(1H, d, J =9.06 Hz) , 7.89 (1H, dd, J =8.51, 1.92 Hz), 8.14 (1H, d, J =8.51 Hz), 8.20 (1H, dd, J =9.06 , 2.47 Hz), 8.25 (1H, d, J = 0.82 Hz), 8.57 (1H, s), 8.66 (1H, s), 8.85 (1H, d, J = 2.47 Hz), 9.19 (2H, d, J = 2.47 Hz), 10.66 (1H, s); ESIMS found for C ₂₃ H ₂₂ N ₆ OS m/z 430.9 (M+1).

335

[0888] 1'-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]- 4-carboxamide 335 .

[0889] Off -white solid (7.6 mg, 0.018 mmol, 33.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.31(3H, s), 2.56-2.63(2H, m), 2.63-2.69(2H, m), 3.11(2H, brd, J =3.02 Hz), 6.85-6.93(1H, m), 7.78(1H, dd, J =4.94, 1.37 Hz), 7.94(1H, dd, J =8.51, 1.65 Hz), 8.13-8.22(2H, m), 8.32(1H, d, J =0.82 Hz), 8.60(1H, s), 8.71(2H, dd, J =3.43, 1.51 Hz), 9.21(1H, s), 9.24(1H, s), 11.33(1H, s); ESIMS found for C ₂₄ H ₂₁ N ₅ OS m/z 428.2 (M+1).

336

[0890] 2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 336 .

[0891] Beige solid (15.0 mg, 0.035 mmol, 12.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.14 (6H, s), 3.19-3.25 (1H, m), 3.81 (2H, dd, J = 8.23, 5.21 Hz), 4.07 (2H, t, J = 7.68 Hz), 7.04 (1H, s), 7.15 (1H, dd, J = 5.21, 1.37 Hz), 7.93 (1H, dd, J = 8.51 , 1.65 Hz), 8.17 (1H, d, J = 8.78 Hz), 8.21 (1H, d, J = 5.21 Hz), 8.30 (1H, s), 8, 58 (1H, s), 8.67 (1H, s), 9.20 (1H, s), 9.22 (1H, s), 11.01 (1H, s); ESIMS found for C ₂₃ H ₂₂ N ₆ OS m/z 430.9 (M+1).

337

[0892] 2-(4-(Dimethylamino)piperidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 337 .

[0893] Off -white solid (390.0 mg, 0.851 mmol, 80.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.31-1.46 (2H, m), 1.84 (2H, brd, J = 10.70 Hz), 2.19 (6H, s), 2.34 (1H, ddd, J = 10.98, 7.41, 3.29 Hz), 2.88 (2H, brd, J =11.80 Hz), 4.44 (2H, brd, J =12.62 Hz), 7.05-7.15 (1H, m), 7.46 (1H, s), 7.93 (1H, dd, J = 8.51, 1.65 Hz), 8.17 (1H, d, J = 8.51 Hz), 8.24 (1H, d, J = 5.21 Hz), 8.31 (1H, s), 8.59 (1H, s), 8.69 (1H, s) , 9.21 (1H, s), 9.23 (1H, s), 11.12 (1H, s); ESIMS found for C ₂₅ H ₂₆ N ₆ OS m/z 459.2 (M+1).

338

[0894] 2-(4-Methylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 338 .

[0895] Dirty yellow solid (42.9 mg, 0.100 mmol, 42.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.37-2.46(4H, m), 3.55-3.66(4H, m), 7.16(1H, d, J =4.12 Hz) , 7.46 (1H, s), 7.92 (1H, dd, J = 8.51, 1.65 Hz), 8.17 (1H, d, J = 8.51 Hz), 8.26 ( 1H, d, J =5.21 Hz), 8.30(1H, s), 8.58(1H, s), 8.68(1H, s), 9.20(1H, s), 9, 22 (1H, s), 11.07 (1H, s); ESIMS found for C ₂₃ H ₂₂ N ₆ OS m/z 430.9 (M+1).

339

[0896] 2-((1-Methylpiperidin-4-yl)thio)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 339 .

[0897] Off -white solid (54.7 mg, 0.119 mmol, 41.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.58-1.74(2H, m), 1.98-2.07(2H, m), 2.12(2H, brt, J =10.15 Hz), 2.17(3H, s), 2.65-2.75(2H, m), 3.79-3.90(1H, m), 7.64(1H, dd, J =5.08, 1.51 Hz), 7 .82 (1H, s), 7.94 (1H, dd, J = 8.51, 1.65 Hz), 8.17 (1H, d, J = 8.51 Hz), 8.32 (1H, s), 8.59 (1H, s), 8.62 (1H, d, J = 5.21 Hz), 8.68 (1H, s), 9.21 (1H, s), 9.23 ( 1H, s), 11.24 (1H, s); ESIMS found for C ₂₄ H ₂₃ N ₅ OS ₂ m/z 462.1 (M+1).

340

[0898] N-(6-(Thiazol-5-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide 340 .

[0899] Off-white solid (57.3 mg, 0.148 mmol, 39.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.73-2.80(2H, m), 2.98(2H, brt, J =5.76 Hz), 3.93(2H, s), 7.22(1H, d, J = 8.23 Hz), 7.71 (1H, brd, J = 5.76 Hz), 7.79 (1H, s), 7.89-7.96 (1H, m), 8.16 ( 1H, d, J = 8.78 Hz), 8.29 (1H, s), 8.59 (1H, s), 8.67 (1H, s), 9.20 (2H, s), 10, 75 (1H, s); ESIMS found for C ₂₂ H ₁₈ N ₄ OS m/z 387.1 (M+1).

359

[0900] N-(6-(2-aminothiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 359 .

[0901] Dirty yellow solid (3.8 mg, 0.009 mmol, 3.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.40-2.44(4H, m), 3.57-3.64(4H, m), 7.15(1H, dd, J =5.08, 1 .24 Hz), 7.33-7.38(2H, m), 7.45(1H, s), 7.71(1H, s), 7.73-7.80(2H, m), 8 .01 (1H, d, J = 8.23 Hz), 8.26 (1H, d, J = 4.94 Hz), 8.55 (1H, s), 9.09 (1H, s), 10 .98 (1H, s); ESIMS found for C ₂₃ H ₂₃ N ₇ OS m/z 445.9 (M+1).

373

[0902] 2-(3-aminoazetidin-1-yl)-N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 373 .

[0903] Yellow solid (21.5 mg, 0.048 mmol, 39.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.13 (6H, s), 3.63 (2H, dd, J = 8.23, 5.76 Hz), 3.85 (1H, quint, J = 6.45 Hz), 4.19 (2H , t, J = 7.82 Hz), 7.00 (1H, s), 7.13 (1H, dd, J = 5.21, 1.37 Hz), 7.80 (1H, dd, J = 8.64, 1.78 Hz), 7.85 (1H, s), 7.91 (1H, s), 8.03 (1H, d, J =8.51 Hz), 8.19 (1H, e, J = 5.21 Hz), 8.54 (1H, s), 9.10 (1H, s), 10.97 (1H, s); ESIMS found for C ₂₃ H ₂₃ N ₇ OS m/z 446.1 (M+1).

374

[0904] 2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(2-(methylamino)thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 374 .

[0905] Yellow solid (10.3 mg, 0.022 mmol, 5.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.13(6H, s), 2.90(3H, d, J =4.67Hz), 3.19-3.26(1H, m), 3.80(2H, dd, J =8, 37, 5.35 Hz), 4.06 (2H, t, J = 7.68 Hz), 7.03 (1H, s), 7.14 (1H, dd, J = 5.21, 1.37 Hz), 7.77-7.80(2H, m), 7.81(1H, s), 7.95(1H, q, J =4.67 Hz), 8.02(1H, d, J = 8.23 Hz), 8.21 (1H, d, J = 5.21 Hz), 8.54 (1H, s), 9.09 (1H, s), 10.97 (1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ OS m/z 460.2 (M+1).

375

[0906] 2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 375 .

[0907] Yellow solid (34.6 mg, 0.073 mmol, 27.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.13(6H, s), 3.13(6H, s), 3.18-3.26(1H, m), 3.80(2H, dd, J =8.51, 5.21 Hz) , 4.06 (2H, t, J = 7.68 Hz), 7.03 (1H, s), 7.15 (1H, dd, J = 5.21, 1.37 Hz), 7.79 ( 1H, dd, J =8.51, 1.65 Hz), 7.84(1H, s), 7.90(1H, s), 8.02(1H, d, J =8.51 Hz), 8.20 (1H, d, J = 5.49 Hz), 8.54 (1H, s), 9.09 (1H, s), 10.98 (1H, br s); ESIMS found for C ₂₅ H ₂₇ N ₇ OS m/z 474.2 (M+1).

376

[0908] N-(6-(2-(Methylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 376 .

[0909] Yellow solid (59.0 mg, 0.128 mmol, 29.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23 (3H, s), 2.42 (4H, brt, J = 4.94 Hz), 2.90 (3H, d, J = 4.67 Hz), 3.56-3.63 (4H, m), 7.15 (1H, dd, J =5.08, 1.23 Hz), 7.46 (1H, s), 7.76-7.80 (2H, m), 7, 81 (1H, s), 7.95 (1H, q, J =4.57 Hz), 8.02 (1H, d, J =8.51 Hz), 8.25 (1H, d, J =5 .21 Hz), 8.55(1H, s), 9.10(1H, s), 11.03(1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ OS m/z 460.2 (M+1).

377

[0910] N-(6-(2-(Dimethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 377 .

[0911] Yellow solid (25.6 mg, 0.054 mmol, 11.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.20-2.27(3H, m), 2.39-2.47(4H, m), 3.09-3.20(6H, m), 3.55-3.66(4H, m ), 7.15 (1H, dd, J = 4.94, 1.10 Hz), 7.46 (1H, s), 7.80 (1H, dd, J = 8.64, 1.78 Hz) , 7.85 (1H, s), 7.91 (1H, s), 8.03 (1H, d, J = 8.51 Hz), 8.25 (1H, d, J = 5.21 Hz) , 8.56 (1H, s), 9.10 (1H, s), 11.03 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ OS m/z 474.2 (M+1).

378

[0912] 2-(4-Isopropylpiperazin-1-yl)-N-(6-(2-(methylamino)thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 378 .

[0913] Yellow solid (53.8 mg, 0.110 mmol, 35.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.02 (6H, brd, J = 6.04 Hz), 2.56 (4H, brs), 2.70 (1H, brs), 2.90 (3H, d, J = 4.67 Hz), 3.58 (4H, br s), 7.14 (1H, d, J = 4.67 Hz), 7.44 (1H, s), 7.75-7.81 ( 2H, m), 7.81(1H, s), 7.95(1H, q, J =4.85Hz), 8.02(1H, d, J =8.51Hz), 8.25( 1H, d, J =4.94 Hz), 8.55(1H, s), 9.10(1H, s), 11.03(1H, s); ESIMS found for C ₂₆ H ₂₉ N ₇ OS m/z 488.2 (M+1).

379

[0914] 2-(4-Methylpiperazin-1-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)isonicotinamide 379 .

[0915] Dirty yellow solid (44.4 mg, 0.100 mmol, 42.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.38-2.46(4H, m), 2.73(3H, s), 3.55-3.66(4H, m), 7.16(1H, dd, J =5.08, 0.96 Hz), 7.46(1H, s), 7.85(1H, dd, J =8.51, 1.65 Hz), 8.13(1H, d , J = 8.51 Hz), 8.17 (1H, s), 8.26 (1H, d, J = 5.21 Hz), 8.29 (1H, s), 8.65 (1H, s ), 9.19 (1H, s), 11.05 (1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ OS m/z 444.9 (M+1).

380

[0916] 6-(4-Methylpiperazin-1-yl)-N-(6-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)nicotinamide 380 .

[0917] White solid (5.2 mg, 0.010 mmol, 6.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23 (3H, s), 2.40 (4H, brt, J = 4.80 Hz), 3.60-3.71 (4H, m), 6.91 (1H, d, J = 9.06 Hz), 8.21 (2H, dd, J = 8.64, 1.78 Hz), 8.30 (1H, d, J = 8.51 Hz), 8.76 (1H, s) , 8.80(1H, s), 8.86(1H, d, J =2.20 Hz), 9.34(1H, s), 10.84(1H, s); ESIMS found for C ₂₃ H ₂₀ F ₃ N ₇ OS m/z 500.1 (M+1).

381

[0918] 2-(4-Methylpiperazin-1-yl)-N-(6-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)isonicotinamide 381 .

[0919] White solid (4.0 mg, 0.008 mmol, 3.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24 (3H, s), 2.43 (4H, brt, J = 4.80 Hz), 3.55-3.65 (4H, m), 7.17 (1H, dd, J = 5.21, 1.10 Hz), 7.48 (1H, s), 8.21-8.26 (1H, m), 8.27 (1H, d, J =5.21 Hz), 8, 30-8.37(1H, m), 8.82(2H, d, J =8.51 Hz), 9.37(1H, s), 11.25(1H, s); ESIMS found for C ₂₃ H ₂₀ F ₃ N ₇ OS m/z 500.1 (M+1).

382

[0920] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-4-(difluoromethoxy)benzamide 382 .

[0921] White solid (5.0 mg, 0.013 mmol, 6.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 7.41 (2H, t, J = 73.70 Hz), 7.32 (2H, d, J = 8.78 Hz), 8.16-8.19 (2H, m), 8.20-8 .23(1H, m), 8.26-8.32(1H, m), 8.66(1H, s), 8.79(1H, s), 9.32(1H, s), 9, 75 (1H, s), 11.07 (1H, s); ESIMS found for C ₁₉ H ₁₂ F ₂ N ₄ O ₂ S m/z 398.8 (M+1).

383

[0922] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-3-(4-methylpiperazin-1-yl)benzamide 383 .

[0923] Yellow solid (9.4 mg, 0.022 mmol, 4.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(2H, s), 2.46-2.49(4H, m), 3.23-3.29(4H, m), 7.10-7.21(1H, m), 7, 36 (1H, t, J = 7.96 Hz), 7.46-7.53 (1H, m), 7.62-7.70 (1H, m), 8.16-8.24 (1H, m), 8.24-8.32(1H, m), 8.64(1H, d, J =0.82 Hz), 8.79(1H, s), 9.31(1H, s), 9.74 (1H, s), 10.96 (1H, s); ESIMS found for C ₂₃ H ₂₂ N ₆ OS m/z 431.9 (M+1).

384

[0924] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-4-(piperidin-4-yloxy)benzamide 384 .

[0925] White solid (15.7 mg, 0.036 mmol, 69.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.41-1.54(2H, m), 1.95(2H, brdd, J =8.64, 3.16 Hz), 2.56-2.66(2H, m), 2, 96 (2H, dt, J = 12.49, 3.91 Hz), 4.49-4.60 (1H, m), 7.01-7.10 (2H, m), 8.01-8, 14(2H, m), 8.14-8.23(1H, m), 8.23-8.32(1H, m), 8.63(1H, s), 8.78(1H, s) , 9.30 (1H, s), 9.74 (1H, s), 10.80 (1H, s); ESIMS found for C ₂₃ H ₂₁ N ₅ O ₂ S m/z 432.1 (M+1).

385

[0926] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-4-((1-methylpiperidin-4-yl)oxy)benzamide 385 .

[0927] Dirty yellow solid (17.7 mg, 0.038 mmol, 40.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.60-1.73(2H, m), 1.97(2H, brdd, J =9.47, 3.98 Hz), 2.16-2.24(2H, m), 2, 18(3H, s), 2.57-2.69(2H, m), 4.52(1H, tt, J =8.13, 3.95 Hz), 7.07(2H, d, J = 9.06 Hz), 8.03-8.14(2H, m), 8.14-8.23(1H, m), 8.23-8.30(1H, m), 8.64(1H , s), 8.78 (1H, s), 9.30 (1H, s), 9.74 (1H, s), 10.82 (1H, s); ESIMS found for C ₂₄ H ₂₃ N ₅ O ₂ S m/z 445.9 (M+1).

386

[0928] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide 386 .

[0929] Yellow solid (162.0 mg, 0.345 mmol, 24.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.63-1.76(2H, m), 1.93-2.03(2H, m), 2.18-2.25(2H, m), 2.19(3H, s), 2, 57-2.68(2H, m), 4.53(1H, tt, J =7.99, 3.95 Hz), 7.18(1H, ddd, J =8.23, 2.47, 1 .10 Hz), 7.43 (1H, t, J = 8.10 Hz), 7.62-7.70 (2H, m), 8.16-8.24 (1H, m), 8.24 -8.32(1H, m), 8.65(1H, d, J =0.82Hz), 8.79(1H, s), 9.32(1H, s), 9.75(1H, s), 10.99 (1H, s); ESIMS found for C ₂₄ H ₂₃ N ₅ O ₂ S m/z 446.2 (M+1).

387

[0930] N ⁵ -(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-N ² -methylpyridine-2,5-dicarboxamide 387 .

[0931] White solid (5.2 mg, 0.013 mmol, 6.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.86 (3H, d, J = 4.94 Hz), 8.16 (1H, d, J = 7.96 Hz), 8.20-8.27 (1H, m), 8.27-8 .32 (1H, m), 8.57 (1H, dd, J = 8.23, 2.20 Hz), 8.69 (1H, s), 8.82 (1H, s), 8.95 ( 1H, q, J =4.57 Hz), 9.23(1H, d, J =1.37 Hz), 9.34(1H, s), 9.75(1H, s), 11.47( 1H, s); ESIMS found for C ₁₉ H ₁₄ N ₆ O ₂ S m/z 391.1 (M+1).

388

[0932] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)nicotinamide 388 .

[0933] Brown solid (14.1 mg, 0.033 mmol, 10.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.22(3H, s), 2.40(4H, t, J =5.08Hz), 3.60-3.71(4H, m), 6.91(1H, d, J =9, 06 Hz), 8.14-8.23(2H, m), 8.23-8.30(1H, m), 8.62(1H, s), 8.76(1H, s), 8, 86 (1H, d, J = 2.47 Hz), 9.30 (1H, s), 9.74 (1H, s), 10.80 (1H, s); ESIMS found for C ₂₂ H ₂₁ N ₇ OS m/z 431.9 (M+1).

389

[0934] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-1'-methyl-1',2',3',6'-tetrahydro-[2, 4'-bipyridine]-4-carboxamide 389 .

[0935] White solid (2.5 mg, 0.006 mmol, 5.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.31(3H, s), 2.58-2.63(2H, m), 2.64-2.69(2H, m), 3.08-3.15(2H, m), 6, 90(1H, t, J =3.43Hz), 7.79(1H, dd, J =4.94, 1.37Hz), 8.18(1H, s), 8.21-8.26 (1H, m), 8.26-8.35 (1H, m), 8.64-8.74 (2H, m), 8.82 (1H, s), 9.35 (1H, s), 9.75 (1H, s), 11.41 (1H, brs); ESIMS found for C ₂₃ H ₂₀ N ₆ OS m/z 429.1 (M+1).

390

[0936] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-2-(3-(dimethylamino)azetidin-1-yl)isonicotinamide 390 .

[0937] White solid (15.0 mg, 0.035 mmol, 10.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.14 (6H, s), 3.17-3.26 (1H, m), 3.81 (2H, dd, J = 8.37, 5.35 Hz), 4.07 (2H, t, J = 7.55 Hz), 7.05 (1H, s), 7.16 (1H, dd, J = 5.21, 1.10 Hz), 8.18-8.25 (2H, m), 8.25-8.33(1H, m), 8.66(1H, s), 8.78(1H, s), 9.33(1H, s), 9.75(1H, s), 11 .15 (1H, s); ESIMS found for C ₂₂ H ₂₁ N ₇ OS m/z 432.1 (M+1).

391

[0938] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 391 .

[0939] White solid (15.2 mg, 0.035 mmol, 9.6% yield), 1H NMR (499 MHz, DMSO- d ₆ ) δ ppm. 2.24 (3H, s), 2.44 (4H, brd, J = 4.12 Hz), 3.61 (4H, brd s), 7.17 (1H, brd, J = 4.94 Hz), 7.47(1H, s), 8.18-8.25(1H, m), 8.25-8.33(2H, m), 8.65(1H, s), 8.78(1H, s), 9.32(1H, s), 9.69-9.78(1H, m), 11.15(1H, brs); ESIMS found for C ₂₂ H ₂₁ N ₇ OS m/z 431.9 (M+1).

392

[0940] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-isopropylpiperazin-1-yl)isonicotinamide 392 .

[0941] Yellow solid (10.1 mg, 0.022 mmol, 16.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.02 (6H, d, J = 6.59 Hz), 2.52-2.60 (4H, m), 2.66-2.76 (1H, m), 3.53-3.64 ( 4H, m), 7.16(1H, dd, J =5.21, 1.37Hz), 7.46(1H, s), 8.18-8.25(1H, m), 8.26 (1H, d, J =5.21Hz), 8.27-8.32(1H, m), 8.67(1H, d, J =0.82Hz), 8.80(1H, s) , 9.33(1H, s), 9.75(1H, s), 11.20(1H, s); ESIMS found for C ₂₄ H ₂₅ N ₇ OS m/z 460.2 (M+1).

393

[0942] N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide 393 .

[0943] Beige solid (10.0 mg, 0.024 mmol, 8.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.54-3.60 (4H, m), 3.69-3.76 (4H, m), 7.22 (1H, dd, J =5.21, 1.10 Hz), 7.48 ( 1H, s), 8.18-8.25(1H, m), 8.25-8.33(2H, m), 8.67(1H, s), 8.80(1H, s), 9 .33 (1H, s), 9.75 (1H, s), 11.21 (1H, s); ESIMS found for C ₂₁ H ₁₈ N ₆ O ₂ S m/z 419.1 (M+1).

406

[0944] 2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)isonicotinamide 406 .

[0945] Beige solid (20.0 mg, 0.045 mmol, 25.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.13(6H, s), 2.84(3H, s), 3.17-3.26(1H, m), 3.81(2H, dd, J =8.51, 5.49 Hz) , 4.07 (2H, t, J = 7.55 Hz), 7.05 (1H, s), 7.16 (1H, dd, J = 5.21, 1.37 Hz), 8.16 ( 1H, dd, J = 8.51, 1.65 Hz), 8.22 (1H, d, J = 4.94 Hz), 8.26 (1H, d, J = 8.78 Hz), 8, 55 (1H, s), 8.76 (1H, s), 9.31 (1H, s), 11.14 (1H, s); ESIMS found for C ₂₃ H ₂₃ N ₇ OS m/z 446.2 (M+1).

409

[0946] 1'-Methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1',2',3',6'-tetrahydro -[2,4'-bipyridine]-4-carboxamide 409 .

[0947] Off -white solid (2.6 g, 5.87 mmol, 56.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.31(3H, s), 2.56-2.63(2H, m), 2.63-2.69(2H, m), 2.84(3H, s), 3.08-3, 16(2H, m), 6.89(1H, dt, J =3.29, 1.92Hz), 7.79(1H, dd, J =4.94, 1.65Hz), 8.12 -8.22(2H, m), 8.26(1H, d, J =8.78 Hz), 8.57(1H, d, J =0.82 Hz), 8.72(1H, d, J = 4.94 Hz), 8.80 (1H, s), 9.33 (1H, s), 11.39 (1H, s); ESIMS found for C ₂₄ H ₂₂ N ₆ OS m/z 443.2 (M+1).

412

[0948] N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 412 .

[0949] Beige solid (35.0 mg, 0.079 mmol, 38.3% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.41-2.46(4H, m), 2.84(3H, s), 3.55-3.66(4H, m), 7.16(1H, dd, J = 5.21, 1.10 Hz), 7.48 (1H, s), 8.16 (1H, dd, J = 8.51, 1.65 Hz), 8.20-8.30 (2H, m), 8.55 (1H, s), 8.78 (1H, s), 9.31 (1H, s), 11.20 (1H, s); ESIMS found for C ₂₃ H ₂₃ N ₇ OS m/z 446.2 (M+1).

419

[0950] 2-(Methyl(1-methylpiperidin-4-yl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)isonicotinamide 419 .

[0951] Beige solid (35.0 mg, 0.074 mmol, 36.0% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 1.49-1.61(2H, m), 1.80(2H, qvd, J =12.12, 3.70 Hz), 1.98-2.08(2H, m), 2.19( 3H, s), 2.86 (2H, brd, J = 11.53 Hz), 2.93 (3H, s), 4.50 (1H, ddt, J = 11.66, 7.89, 3.95, 3.95 Hz), 7.08(1H, dd, J =5.21, 1.37 Hz), 7.19(1H, s), 8.16(1H, dd, J =8 .51, 1.65 Hz), 8.23 (1H, d, J = 5.21 Hz), 8.25 (1H, d, J = 8.78 Hz), 8.55 (1H, s), 8.77 (1H, s), 9.31 (1H, s), 11.16 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ OS m/z 474.2 (M+1).

420

[0952] 2-(Azetidin-3-yloxy)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)isonicotinamide 420 .

[0953] Beige solid (4.0 mg, 0.010 mmol, 10.1% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 2.84(3H, s), 3.50-3.59(2H, m), 3.72-3.81(2H, m), 5.35-5.45(1H, m), 7, 41 (1H, s), 7.55 (1H, dd, J =5.49, 1.37 Hz), 8.17 (1H, dd, J =8.51, 1.65 Hz), 8.26 (1H, d, J = 8.51 Hz), 8.31 (1H, d, J = 5.49 Hz), 8.57 (1H, s), 8.77 (1H, s), 9.32 (1H, s), 11.26 (1H, brs); ESIMS found for C ₂₁ H ₁₈ N ₆ O ₂ S m/z 419.1 (M+1).

422

[0954] N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide 422 .

[0955] Yellow solid (22.8 mg, 0.047 mmol, 10.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.63-1.74(2H, m), 1.93-2.00(2H, m), 2.16-2.24(2H, m), 2.19(3H, s), 2, 56-2.69(2H, m), 2.84(3H, s), 4.53(1H, tt, J =8.03, 3.91 Hz), 7.18(1H, ddd, J = 8.16, 2.40, 0.96Hz), 7.43(1H, t, J =8.10Hz), 7.59-7.69(2H, m), 8.15(1H, dd , J = 8.51, 1.65 Hz), 8.25 (1H, d, J = 8.78 Hz), 8.54 (1H, d, J = 0.82 Hz), 8.77 (1H , s), 9.30 (1H, s), 10.98 (1H, s); ESIMS found for C ₂₅ H ₂₅ N ₅ O ₂ S m/z 460.2 (M+1).

423

[0956] N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)thio)isonicotinamide 423 .

[0957] Light yellow solid (44.0 mg, 0.092 mmol, 33.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.60-1.72 (2H, m), 1.98-2.07 (2H, m), 2.12 (2H, brt, J = 10.43 Hz), 2.17 (3H, s), 2.69 (2H, brd, J = 10.98 Hz), 2.84 (3H, s), 3.84 (1H, brd, J = 10.15 Hz), 7, 64 (1H, dd, J =5.21, 1.37 Hz), 7.82 (1H, s), 8.17 (1H, dd, J =8.51, 1.65 Hz), 8.26 (1H, d, J =8.51 Hz), 8.56 (1H, s), 8.62 (1H, d, J =5.21 Hz), 8.76 (1H, s), 9.31 (1H, s), 11.30 (1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ OS ₂ m/z 477.1 (M+1).

427

[0958] N-(7-Fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 427 .

[0959] Off -white solid (15.0 mg, 0.032 mmol, 17.9% yield). ¹¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.39-2.45(4H, m), 2.86(3H, s), 3.58-3.64(4H, m), 7.16(1H, dd, J =5.21, 1.37 Hz), 7.47(1H, s), 8.20(1H, d, J =11.25 Hz), 8.26(1H, d, J =4 .94 Hz), 8.23-8.24 (1H, m), 8.79 (1H, s), 8.84 (1H, d, J = 7.14 Hz), 9.30 (1H, s ), 11.20 (1H, s); ESIMS found for C ₂₃ H ₂₂ FN ₇ OS m/z 464.2 (M+1).

428

[0960] N-(6-(5-(Dimethylamino)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 428 .

[0961] Yellow solid (14.6 mg, 0.031 mmol, 26.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.32 (3H, brs), 2.52-2.67 (4H, m), 3.19 (6H, s), 3.64 (4H, brs), 7.14-7, 21(1H, m), 7.48(1H, s), 8.07(1H, dd, J =8.51, 1.65Hz), 8.17(1H, s), 8.24-8 .29 (2H, m), 8.70 (1H, s), 9.24 (1H, s), 11.14 (1H, s); ESIMS found for C ₂₄ H ₂₆ N ₈ OS m/z 475.2 (M+1).

429

[0962] N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide 429 .

[0963] White solid (23.0 mg, 0.045 mmol, 25.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.32-1.44(2H, m), 1.45-1.55(4H, m), 2.38(4H, brs), 3.53-3.62(4H, m), 3.67 (2H, s), 3.71-3.77 (4H, m), 3.92 (3H, s), 7.21 (1H, dd, J =5.21, 1.10 Hz) , 7.47(1H, s), 7.76(1H, dd, J =8.51, 1.65 Hz), 7.82(1H, s), 8.09(1H, d, J =8 .51 Hz), 8.14 (1H, s), 8.29 (1H, d, J = 5.21 Hz), 8.61 (1H, s), 9.17 (1H, s), 11, 01 (1H, s); ESIMS found for C ₂₉ H ₃₃ N ₇ O ₂ m/z 512.0 (M+1).

430

[0964] N-(6-(5-amino-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 430 .

[0965] Yellow solid (3.7 mg, 0.008 mmol, 5.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.27(3H, brs), 3.62(4H, brs), 7.12-7.20(1H, m), 7.48(1H, s), 7.60(2H, s), 8.07 (1H, dd, J = 8.51, 1.65 Hz), 8.16 (1H, d, J = 8.78 Hz), 8.25 (1H, s), 8, 27 (1H, d, J = 4.94 Hz), 8.71 (1H, s), 9.24 (1H, s), 11.13 (1H, s); ESIMS found for C ₂₂ H ₂₂ N ₈ OS m/z 447.2 (M+1).

431

[0966] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperazin-1-yl)isonicotinamide 431 .

[0967] Beige solid (76.0 mg, 0.183 mmol, 42.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.77-2.85(4H, m), 3.50-3.58(4H, m), 4.15(3H, s), 7.14(1H, dd, J =5.21, 1 .10 Hz), 7.43 (1H, s), 8.08 (1H, dd, J = 8.51, 1.37 Hz), 8.18 (1H, d, J = 8.51 Hz), 8.25(1H, d, J =5.21Hz), 8.38(1H, s), 8.66(1H, s), 8.76(1H, s), 9.21(1H, s ), 11.09 (1H, s); ESIMS found for C ₂₂ H ₂₂ N ₈ O m/z 415.2 (M+1).

432

[0968] 2-(Azetidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 432 .

[0969] Off -white solid (73.7 mg, 0.192 mmol, 66.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.31-2.41(2H, m), 3.85(3H, s), 4.03(4H, t, J =7.41 Hz), 7.01(1H, d, J =0, 82 Hz), 7.15 (1H, dd, J = 5.21, 1.65 Hz), 7.33 (1H, d, J = 1.10 Hz), 7.74 (1H, dd, J = 8.37, 1.78 Hz), 7.81 (1H, s), 8.09 (1H, s), 8.15 (1H, d, J =8.51 Hz), 8.21 (1H, e, J = 5.21 Hz), 8.68 (1H, s), 9.22 (1H, s), 11.04 (1H, s); ESIMS found for C ₂₂ H ₂₀ N ₆ O m/z 385.2 (M+1).

433

[0970] 2-Methoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 433 .

[0971] Off-white solid (28.0 mg, 0.078 mmol, 34.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.85 (3H, s), 3.93 (3H, s), 7.33 (1H, s), 7.42 (1H, d, J =1.37 Hz), 7.55 (1H, dd , J = 5.21, 1.37 Hz), 7.75 (1H, dd, J = 8.51, 1.65 Hz), 7.81 (1H, s), 8.11 (1H, d, J = 0.82 Hz), 8.16 (1H, d, J = 8.51 Hz), 8.35 (1H, d, J = 5.21 Hz), 8.69 (1H, s), 9 .23 (1H, s), 11.16 (1H, s); ESIMS found for C ₂₀ H ₁₇ N ₅ O ₂ m/z 360.1 (M+1).

434

[0972] 2-Methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 434 .

[0973] Off-white solid (32.1 mg, 0.094 mmol, 41.9% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.58(3H, s), 3.85(3H, s), 7.33(1H, d, J =0.82 Hz), 7.71-7.78(2H, m), 7.81 (1H, s), 7.86 (1H, s), 8.12 (1H, s), 8.16 (1H, d, J = 8.51 Hz), 8.64 (1H, d, J = 4.94 Hz), 8.69(1H, s), 9.23(1H, s), 11.14(1H, s); ESIMS found for C ₂₀ H ₁₇ N ₅ O m/z 344.1 (M+1).

435

[0974] 2-Cyano-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 435 .

[0975] Off-white solid (36.0 mg, 0.102 mmol, 45.6% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.86 (3H, s), 7.34 (1H, d, J = 0.82 Hz), 7.77 (1H, dd, J = 8.51, 1.65 Hz), 7.81 (1H , s), 8.14 (1H, s), 8.17 (1H, d, J = 8.51 Hz), 8.26 (1H, dd, J = 4.94, 1.65 Hz), 8 .60 (1H, d, J = 0.82 Hz), 8.70 (1H, s), 8.93-8.99 (1H, m), 9.24 (1H, s), 11.44 ( 1H, s); ESIMS found for C ₂₀ H ₁₄ N ₆ O m/z 355.1 (M+1).

436

[0976] 5-Chloro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 436 .

[0977] Off-white solid (18.7 mg, 0.041 mmol, 67.2% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.21(3H, s), 2.39(4H, brt, J =4.94 Hz), 3.49-3.58(4H, m), 3.91(3H, s), 7 .08 (1H, s), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.05 (1H, d, J = 8.78 Hz), 8.11 (1H, s), 8.16 (1H, s), 8.19 (1H, s), 8.38 (1H, s), 8.55 (1H, s), 9.08 (1H, s), 11, 15 (1H, s); ESIMS found for C ₂₄ H ₂₄ ClN ₇ O m/z 462.2 (M+1).

437

[0978] 2-(3,3-Difluoroazetidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 437 .

[0979] White solid (11.5 mg, 0.027 mmol, 9.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.85(3H, s), 4.49(4H, t, J =12.49 Hz), 7.24(1H, s), 7.31(1H, dd, J =5.21, 1, 37 Hz), 7.33 (1H, s), 7.75 (1H, dd, J = 8.64, 1.51 Hz), 7.81 (1H, s), 8.10 (1H, s) , 8.16 (1H, d, J = 8.51 Hz), 8.31 (1H, d, J = 5.21 Hz), 8.69 (1H, s), 9.23 (1H, s) , 11.11 (1H, s); ESIMS found for C ₂₂ H ₁₈ F ₂ N ₆ O m/z 421.1 (M+1).

438

[0980] 2-(4,4-Bis(methyl- d3 )-4λ4-piperazin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl) isoquinolin-3-yl)isonicotinamide 438 .

[0981] Beige solid (62.0 mg, 0.108 mmol, 74.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.53(4H, t, J =5.21Hz), 3.94-4.04(4H, m), 4.15(3H, s), 7.32(1H, dd, J =5, 21, 1.10 Hz), 7.61(1H, s), 8.08(1H, dd, J =8.64, 1.51 Hz), 8.19(1H, d, J =8.78 Hz), 8.35 (1H, d, J = 5.21 Hz), 8.40 (1H, s), 8.68 (1H, s), 8.76 (1H, s), 9.23 ( 1H, s), 11.13 (1H, s); ESIMS found for C ₂₄ H ₂₁ [ ² H ₆ ]N ₈ O m/z 449.3 (M+).

439

[0982] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl- d3 )piperazin-1-yl) isonicotinamide 439 .

[0983] Beige solid (44.0 mg, 0.102 mmol, 35.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.43(4H, t, J =4.94Hz), 3.56-3.63(4H, m), 4.15(3H, s), 7.17(1H, dd, J =5, 08, 0.96 Hz), 7.47(1H, s), 8.08(1H, dd, J =8.37, 1.51 Hz), 8.18(1H, d, J =8.51 Hz), 8.26 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.66 (1H, s), 8.76 (1H, s), 9.21 ( 1H, s), 11.11 (1H, s); ESIMS found for C ₂₃ H ₂₁ [ ² H ₃ ]N ₈ O m/z 432. (M+1).

440

[0984] 3-Chloro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 440 .

[0985] Off-white solid (90.7 mg, 0.196 mmol, 29.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.24(3H, s), 2.49(4H, brs), 3.26-3.31(4H, m), 3.91(3H, s), 7.17(1H, d, J = 4.67 Hz), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.05 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.17(1H, s), 8.29(1H, d, J =4.67 Hz), 8.38(1H, s), 8.55(1H, s), 9.07( 1H, s), 11.21 (1H, s); ESIMS found for C ₂₄ H ₂₄ ClN ₇ O m/z 462.2 (M+1).

441

[0986] 2-(4,4-Difluoropiperidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 441 .

[0987] White solid (18.9 mg, 0.042 mmol, 24.4% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.99-2.09 (4H, m), 3.81 (4H, brd, J = 5.76 Hz), 3.85 (3H, s), 7.19 (1H, dd, J = 5.21, 1.10 Hz), 7.33(1H, d, J =0.82 Hz), 7.58(1H, s), 7.74(1H, dd, J =8.51, 1 .65 Hz), 7.81(1H, s), 8.10(1H, s), 8.16(1H, d, J =8.51 Hz), 8.29(1H, d, J =5 .21 Hz), 8.70(1H, s), 9.23(1H, s), 11.14(1H, s); ESIMS found for C ₂₄ H ₂₂ F ₂ N ₆ O m/z 449.2 (M+1).

442

[0988] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl ) isonicotinamide 442 .

[0989] Off -white solid (74.4 mg, 0.161 mmol, 59.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.77 (1H, brd, J =9.06 Hz), 1.90 (1H, brd, J =8.78 Hz), 2.30 (3H, s), 2.48 (1H , br s), 2.86 (1H, dd, J = 9.47, 1.78 Hz), 3.34 (1H, dd, J = 9.88, 2.20 Hz), 3.49 ( 1H, brs), 3.57(1H, brd, J =9.88Hz), 3.91(3H, s), 4.70(1H, brs), 7.05(1H , dd, J = 5.21, 1.37 Hz), 7.11 (1H, s), 7.81 (1H, dd, J = 8.64, 1.51 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.09-8.16 (2H, m), 8.19 (1H, d, J = 4.94 Hz), 8.38 (1H, s), 8, 59 (1H, s), 9.12 (1H, s), 10.98 (1H, s); ESIMS found for C ₂₅ H ₂₅ N ₇ O m/z 440.2 (M+1).

443

[0990] 2-Isopropoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 443 .

[0991] Off -white solid (94.6 mg, 0.244 mmol, 54.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.33 (6H, d, J = 6.31 Hz), 3.85 (3H, s), 5.30 (1H, sep, J = 6.17 Hz), 7.30 (1H, s), 7.33(1H, d, J =0.82Hz), 7.50(1H, dd, J =5.21, 1.37Hz), 7.75(1H, dd, J =8.37, 1.78 Hz), 7.81 (1H, s), 8.11 (1H, s), 8.15 (1H, d, J = 8.51 Hz), 8.32 (1H, d, J = 5.21 Hz), 8.68(1H, s), 9.22(1H, s), 11.11(1H, s); ESIMS found for C ₂₂ H ₂₁ N ₅ O ₂ m/z 388.2 (M+1).

444

[0992] 2-(2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 444 .

[0993] Off-white solid (145.0 mg, 0.324 mmol, 88.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.71(1H, brd, J =9.06Hz), 1.82(1H, brd, J =9.33Hz), 2.86(1H, brd, J =9, 61 Hz), 2.96 (1H, brd, J = 8.78 Hz), 3.29 (1H, br s), 3.52 (1H, dd, J = 9.33, 1.37 Hz), 3.75 (1H, brs), 3.91 (3H, s), 4.76 (1H, brs), 7.07 (1H, d, J = 4.94 Hz), 7.12 (1H, br s), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.19 (1H, d, J =4.94 Hz), 8.38 (1H, s), 8.59 (1H, s), 9 .12 (1H, s), 10.97 (1H, s); ESIMS found for C ₂₄ H ₂₃ N ₇ O m/z 426.2 (M+1).

445

[0994] N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2-(4-methylpiperazin-1-yl)pyridine- 4-yl)acetamide 445 .

[0995] Beige solid (2.0 mg, 0.005 mmol, 3.1% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.22(3H, s), 2.40(4H, brt, J =4.94 Hz), 3.45-3.51(4H, m), 3.71(2H, s), 4 .13 (3H, s), 6.66 (1H, d, J = 4.67 Hz), 6.83 (1H, s), 8.01-8.06 (2H, m), 8.12 ( 1H, d, J = 8.78 Hz), 8.28 (1H, s), 8.46 (1H, s), 8.72 (1H, s), 9.13 (1H, s), 10, 85 (1H, s); ESIMS found for C ₂₄ H ₂₆ N ₈ O m/z 443.2 (M+1).

454

[0996] 3-Fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 454 .

[0997] Off-white solid (85.9 mg, 0.193 mmol, 24.0% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.42-2.47(4H, m), 3.41-3.49(4H, m), 3.91(3H, s), 7.05(1H, t, J = 4.39 Hz), 7.82 (1H, dd, J = 8.51, 1.65 Hz), 8.06 (1H, d, J = 8.51 Hz), 8.08 ( 1H, d, J =4.94 Hz), 8.11(1H, s), 8.16(1H, s), 8.38(1H, s), 8.55(1H, s), 9, 09 (1H, s), 11.17 (1H, s); ESIMS found for C ₂₄ H ₂₄ FN ₇ O m/z 446.2 (M+1).

455

[0998] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((4-methylpiperazin-1-yl)methyl)isonicotinamide 455 .

[0999] Off -white solid (12.5 mg, 0.028 mmol, 15.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.17 (3H, s), 2.36 (4H, dt, J = 3.77, 2.09 Hz), 2.42-2.49 (4H, m), 3.68 (2H, s) , 3.91 (3H, s), 7.83 (1H, dd, J = 13.45, 1.65 Hz), 7.83 (1H, d, J = 1.65 Hz), 7.95 ( 1H, s), 8.07 (1H, d, J = 8.51 Hz), 8.12 (1H, s), 8.15 (1H, s), 8.39 (1H, s), 8, 59 (1H, s), 8.68 (1H, d, J =4.94 Hz), 9.13 (1H, s), 11.18 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

456

[01000] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(morpholinomethyl)isonicotinamide 456 .

[01001] Off-white solid (13.6 mg, 0.032 mmol, 80.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.47(4H, brs), 3.59-3.65(4H, m), 3.69(2H, s), 3.91(3H, s), 7.83(1H, brs). dd, J = 16.47, 1.65 Hz), 7.83-7.84 (1H, m), 7.98 (1H, s), 8.08 (1H, d, J = 8.51 Hz ), 8.12(1H, s), 8.15(1H, s), 8.39(1H, s), 8.59(1H, s), 8.69(1H, d, J =4, 94 Hz), 9.13 (1H, s), 11.19 (1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ O ₂ m/z 429.2 (M+1).

457

[01002] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-ylmethyl)isonicotinamide 457 .

[01003] Off -white solid (12.0 mg, 0.029 mmol, 80.7% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.74 (4H, dt, J =6.52, 3.19 Hz), 2.56 (4H, br s), 3.82 (2H, s), 3.91 (3H, s), 7 .81-7.84 (2H, m), 7.96 (1H, s), 8.07 (1H, d, J = 8.51 Hz), 8.12 (1H, s), 8.15 ( 1H, s), 8.39 (1H, s), 8.59 (1H, s), 8.67 (1H, d, J =4.94 Hz), 9.13 (1H, s), 11, 19 (1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ O m/z 413.2 (M+1).

458

[01004] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetamide 458 .

[01005] Beige solid (10.0 mg, 0.023 mmol, 5.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.21(3H, s), 2.37-2.42(4H, m), 3.43-3.49(4H, m), 3.70(2H, s), 3.89(3H, s), 6.66 (1H, d, J = 4.94 Hz), 6.83 (1H, s), 7.76 (1H, dd, J = 8.51, 1.65 Hz), 8, 01 (1H, d, J = 8.51 Hz), 8.03-8.05 (2H, m), 8.08 (1H, s), 8.35 (1H, s), 8.39 (1H , s), 9.04 (1H, s), 10.77 (1H, s); ESIMS found for C ₂₅ H ₂₇ N ₇ O m/z 442.2 (M+1).

459

[01006] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1- d )-2-(4-methylpiperazin-1-yl)isonicotinamide 459 .

[01007] Off -white solid (69.0 mg, 0.179 mmol, 64.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.23(3H, s), 2.43(4H, t, J =4.94Hz), 3.56-3.64(4H, m), 3.91(3H, s), 7.16 (1H, dd, J =5.08, 1.24 Hz), 7.46 (1H, s), 7.81 (1H, dd, J =8.64, 1.51 Hz), 8.07 ( 1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.14 (1H, s), 8.26 (1H, d, J = 4.94 Hz), 8.38 ( 1H, s), 8.59 (1H, s), 11.04 (1H, s); ESIMS found for C ₂₄ H ₂₄ [ ² H]N ₇ O m/z 429. (M+1).

461

[01008] N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1- d )-2-(piperazin-1-yl)isonicotinamide 461 .

[01009] Off -white solid (69.0 mg, 0.179 mmol, 64.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.77-2.84(4H, m), 3.48-3.57(4H, m), 3.91(3H, s), 7.13(1H, dd, J =5.08, 1 .24 Hz), 7.42 (1H, s), 7.81 (1H, dd, J = 8.51, 1.65 Hz), 8.07 (1H, d, J = 8.51 Hz), 8.11 (1H, s), 8.14 (1H, s), 8.25 (1H, d, J = 5.21 Hz), 8.38 (1H, s), 8.59 (1H, s ), 11.03 (1H, s); ESIMS found for C ₂₃ H ₂₂ [ ² H]N ₇ O m/z 415. (M+1).

462

[01010] 1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1H-indazol-5-carboxamide 462 .

[01011] Light yellow solid (32.0 mg, 0.084 mmol, 18.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.92 (3H, s), 4.11 (3H, s), 7.75 (1H, d, J = 9.06 Hz), 7.80 (1H, dd, J = 8.51, 1, 65 Hz), 8.06 (1H, d, J = 8.51 Hz), 8.12 (1H, dd, J = 8.92, 1.51 Hz), 8.12 (1H, s), 8 .14 (1H, s), 8.24 (1H, s), 8.38 (1H, s), 8.62 (2H, s), 9.12 (1H, s), 10.82 (1H, With); ESIMS found for C ₂₂ H ₁₈ N ₆ O m/z 383.15 (M+1).

463

[01012] 1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1H-benzo[d]imidazole-5-carboxamide 463 .

[01013] Light yellow solid (35.6 mg, 0.093 mmol, 20.8% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 3.90 (3H, s), 3.92 (3H, s), 7.70 (1H, d, J = 8.51 Hz), 7.79 (1H, dd, J = 8.51, 1, 65 Hz), 8.06 (2H, d, J = 8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.33 (1H, s), 8.38 (1H, s), 8.47 (1H, d, J = 1.65 Hz), 8.62 (1H, s), 9.12 (1H, s), 10.78 (1H, s); ESIMS found for C ₂₂ H ₁₈ N ₆ O m/z 383.2 (M+1).

464

[01014] N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)isonicotinamide 464 .

[01015] Off -white solid (51.7 mg, 0.125 mmol, 45.3% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 1.95-2.01(4H, m), 2.40(3H, s), 3.45-3.51(4H, m), 3.68(3H, s), 7.06(1H, dd, J =5.21, 1.37 Hz), 7.08(1H, s), 7.14(1H, s), 7.67(1H, dd, J =8.51, 1.65 Hz ), 8.00 (1H, s), 8.14 (1H, d, J = 8.78 Hz), 8.17-8.23 (1H, m), 8.67 (1H, s), 9 .22 (1H, s), 11.03 (1H, s); ESIMS found for C ₂₄ H ₂₄ N ₆ O m/z 413.2 (M+1).

465

[01016] N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(dimethylamino)isonicotinamide 465 .

[01017] Off -white solid (69.0 mg, 0.179 mmol, 64.5% yield). ¹ H NMR (499 MHz, DMSO- d ₆ ) δ ppm 2.40 (3H, s), 3.11 (6H, s), 3.68 (3H, s), 7.09 (1H, dd, J =5.21, 1.10 Hz), 7.14 (1H, s), 7.25 (1H, s), 7.67 (1H, dd, J = 8.51, 1.65 Hz), 8.00 (1H, s), 8.14 (1H, d, J = 8.51 Hz), 8.23 (1H, d, J = 4.94 Hz), 8.68 (1H, s), 9.22 (1H, s), 11.07 (1H, With); ESIMS found for C ₂₂ H ₂₂ N ₆ O m/z 387.2 (M+1).

Example 4

[01018] Screening study of Wnt activity is described as follows. Reporter cell lines can be generated by stable transduction of tumor cell lines (eg, colon cancer) or primary cells (eg, IEC-6 intestinal cells) with a lentiviral construct that includes a Wnt-responsive promoter driving firefly luciferase gene expression.

[01019] SW480 colon carcinoma cells were transduced with a lentiviral vector expressing luciferase with a human Sp5 promoter consisting of a sequence of eight TCF/LEF binding sites. SW480 cells stably expressing the Sp5-Luc reporter gene and hygromycin resistance gene were selected by treatment with 150 μg/ml hygromycin for 7 days. These stably transduced SW480 cells were expanded in cell culture and used for all further screening studies. Each compound was dissolved in DMSO as a 10 mM stock solution and used to prepare stock plates. Serial dilution (1:3, 10-point dose-response curves starting at 10 μM) and compound transfer were performed using an ECHO 550 (Labcyte, Sunnyvale, CA) in 384-well white hard bottom assay plates (Greiner Bio-One ) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. For Sp5-Luc reporter gene assays, cells were seeded at 4,000 cells/well in 384-well DMEM plates containing 1% fetal bovine serum and 1% penicillin-streptomycin and incubated for 36-48 hours at 37°C and ₅ % CO2. After incubation, 15 µl of BriteLite Plus Fluorescent Assay Reagent (Perkin Elmer) was added to each well of 384-well assay plates. The plates were shaken on an orbital shaker for 2 minutes and then luminescence was quantified using an Envision plate reader (Perkin Elmer). Data was normalized to DMSO-treated cells only and the normalized activities were used to calculate EC ₅₀ using dose-effect logarithm (inhibitor) vs. response - variable slope equation (four parameters) non-linear regression function available in GraphPad Prism 5.0 (or Dotmatics) . In the case of an EC ₅₀ >10 μM, percent inhibition is provided at 10 μM.

[01020] Table 2 shows measured activity for representative compounds of Formula I provided herein.

table 2 Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) one 0.067 90 0.132 219 0.890 339 0.699 2 0.091 91 0.107 220 0.463 340 0.346 3 0.116 92 0.103 221 0.608 359 0.013 four 0.370 93 0.036 222 0.189 373 6.427 5 0.089 94 0.110 223 0.489 374 0.211 6 0.070 95 >10 (3.5%) 230 0.037 375 >10 (44.7%) 7 0.113 97 0.041 232 0.256 376 0.113 eight 0.170 99 0.041 233 0.120 377 5.568 9 0.039 100 8.409 236 0.070 378 0.268 ten 0.046 101 1.041 238 0.036 379 0.100 eleven 0.116 102 0.979 240 0.035 380 >10 (11.2%) 12 0.487 103 2.272 241 0.183 381 3.515 13 0.171 104 0.177 242 0.042 382 0.509 fourteen 0.153 105 0.764 243 0.094 383 0.116 fifteen >10 (8.0%) 106 0.307 245 0.038 384 0.162 16 0.062 107 0.912 249 1.223 385 0.211 17 0.058 108 0.193 250 0.055 386 0.106 eighteen 0.200 109 0.312 253 0.054 387 >10 (46.4%) 19 0.066 110 0.320 256 0.117 388 0.139 twenty 0.705 111 0.184 257 3.911 389 0.561 21 0.745 112 0.128 258 1.749 390 0.117 22 2.109 113 0.120 261 0.101 391 0.043 23 0.425 114 0.131 265 0.106 392 0.111 24 >10 (0%) 116 0.136 266 0.057 393 0.080 25 >10 (48.8%) 117 0.375 268 0.104 406 0.116 26 3.785 118 >10 (0%) 271 0.114 409 0.041 27 4.362 119 0.554 273 0.083 412 0.059 28 0.472 120 0.328 275 0.012 419 0.069 29 0.307 122 0.238 276 0.093 420 0.449 37 0.033 123 0.264 277 0.156 422 0.107 40 0.684 126 0.185 278 0.088 423 0.040 45 0.449 127 0.214 285 0.090 427 3.676 47 3.357 130 0.250 286 0.107 428 0.138 49 0.098 131 0.285 289 0.174 429 0.073 52 1.003 132 0.365 290 0.104 430 0.036 53 0.039 133 0.223 291 0.710 431 0.047 54 0.035 134 0.058 292 0.375 432 0.109 55 0.032 135 0.236 293 2.268 433 0.559 56 0.031 136 2.124 294 0.161 434 0.104 57 0.109 137 0.949 296 >10 (14.6%) 435 0.136 59 0.062 138 3.188 301 0.101 436 3.134 60 0.680 139 2.962 306 1.019 437 0.500 61 0.182 140 0.152 309 0.103 438 2.511 62 0.127 141 >10 (8.8%) 310 1.692 439 0.048 63 0.108 142 0.055 313 2.139 440 >10 (48.0%) 64 0.298 143 0.045 317 0.279 441 0.228 65 0.422 144 0.051 318 0.396 442 0.116 66 0.047 145 0.039 319 0.844 443 0.501 67 0.057 146 0.749 325 3.564 444 0.133 71 0.044 147 0.179 326 1.722 445 0.144 72 0.062 148 3.766 328 0.113 454 0.324 74 0.052 149 0.047 329 0.162 455 0.113 76 0.295 151 0.265 330 >10 (15.0%) 456 0.497 78 0.776 168 0.106 331 >10 (28.7%) 457 0.475 80 0.597 172 0.270 332 3.841 458 0.214 84 0.021 182 0.230 333 1.042 459 0.055 85 0.034 183 0.414 334 0.126 461 0.043 86 0.162 184 0.182 335 0.107 462 0.193 87 3.639 185 0.189 336 0.060 463 0.159 88 0.131 186 0.074 337 0.091 464 0.480 89 3.376 204 0.023 338 0.057 465 0.231

Example 5

[01021] Representative compounds were assayed using the DYRK1A kinase activity assay procedure as described below.

[01022] Each compound was dissolved in DMSO as a 10 mM stock solution and used to prepare stock plates. Serial dilution (1:3, 11-point dose-response curves, 10 μM to 0.00016 μM) and compound transfer were performed using an ECHO 550 (Labcyte, Sunnyvale, CA) in 1536-well black guarded round bottom plates. (Corning).

[01023] The DYRK1A kinase assay was performed using the Ser/Thr 18 Z-lyte peptide assay kit according to the manufacturer's instructions (Life Technologies - a division of Thermo-Fisher). This assay is a non-radioactive assay using fluorescence resonance energy transfer (FRET) between coumarin and fluorescein to detect kinase activity, which is represented as the ratio of coumarin emission to fluorescein emission.

[01024] Briefly, recombinant DYRK1A kinase, ATP, and Ser/Thr peptide 18 were prepared in 1x kinase buffer to final concentrations of 0.19 μg/ml, 30 μM, and 4 μM, respectively. The mixture was left to incubate with representative compounds for one hour at room temperature. All interactions were duplicated. The non-phosphorylated ('0% control') and phosphorylated ('100% control') forms of Ser/Thr 18 served as controls. In addition, an 11-point 'dose-response' curve of staurosporine (upper value 1 μM) was plotted for use as a positive compound control.

[01025] After incubation, Development Reagent A was diluted in Development Buffer, then added to the reaction mixture and left for further incubation for one hour at room temperature. The plate was read at Ex 400 Em 455 for coumarin signal detection and Ex 400 Em 520 for signal measurement (EnVision Multilabel Plate Reader, PerkinElmer).

[01026] The emission factor (Em) was calculated as the ratio of the coumarin (C) emission signal (at 445 nm) and the fluorescein (F) emission signal (at 520 nm). Then, percent phosphorylation was calculated by the following formula: [1 - ((Em x F100%)-C100%)/((C0%-C100%)+(Em x (F100%-F0%)))]. Dose-response curves were built and inhibitory concentration (IC ₅₀ ) values were calculated using a non-linear regression curve corresponding to Dotmatics' Studies software (Bishops Stortford, UK).

[01027] Table 3 shows measured activity for representative compounds of Formula I presented herein.

Table 3 Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) one 0.0012 90 0.0023 219 0.0027 339 0.0395 2 0.0013 91 0.0067 220 0.0063 340 0.0012 3 0.0009 92 0.0010 221 0.0026 359 0.0037 four 0.0025 93 0.0007 222 0.0014 373 0.0177 5 0.0012 94 0.0013 223 0.0045 374 0.0038 6 0.0011 95 0.0034 230 0.0019 375 0.0126 7 0.0012 97 0.0013 232 0.0017 376 0.0067 eight 0.0009 99 0.0025 233 0.0015 377 0.0093 9 0.0004 100 0.0444 236 0.0012 378 0.0028 ten 0.0010 101 0.0257 238 0.0027 379 0.0025 eleven 0.0013 102 0.0093 240 0.0018 380 0.8647 12 0.0029 103 0.0055 241 0.0025 381 >10 (48.9%) 13 0.0020 104 0.0077 242 0.0017 382 0.0023 fourteen 0.0009 105 0.0435 243 0.0024 383 0.0021 fifteen 0.3124 106 0.0034 245 0.0016 384 0.0012 16 0.0011 107 0.0021 249 0.0018 385 0.0009 17 0.0018 108 0.0024 250 0.0022 386 0.0015 eighteen 0.0017 109 0.0022 253 0.0014 387 0.0030 19 0.0015 110 0.0024 256 0.0017 388 0.0008 twenty 0.0552 111 0.0017 257 0.0184 389 0.0053 21 0.0632 112 0.0023 258 0.0189 390 0.0014 22 0.0551 113 0.0019 261 0.0016 391 0.0007 23 0.0100 114 0.0022 265 0.0019 392 0.0011 24 0.0673 116 0.0047 266 0.0013 393 0.0012 25 0.1583 117 0.0056 268 0.0019 406 0.0027 26 0.0412 118 0.0320 271 0.0021 409 0.0025 27 0.0333 119 0.0103 273 0.0011 412 0.0022 28 0.0011 120 0.0127 275 0.0006 419 0.0019 29 0.0012 122 0.0041 276 0.0011 420 0.0071 37 0.0009 123 0.0035 277 0.0008 422 0.0026 40 0.0035 126 0.0038 278 0.0028 423 0.0025 45 0.0018 127 0.0053 285 0.0012 427 0.0137 47 0.0397 130 0.0032 286 0.0008 428 0.0073 49 0.0042 131 4.9972 289 0.0033 429 0.0064 52 0.0031 132 0.0032 290 0.0029 430 0.0023 53 0.0020 133 0.0044 291 0.0116 431 0.0019 54 0.0020 134 0.0016 292 0.0057 432 0.0016 55 0.0011 135 0.0039 293 0.0145 433 0.0068 56 0.0014 136 0.0038 294 0.0105 434 0.0013 57 0.0026 137 0.0062 296 0.0053 435 0.0010 59 0.0013 138 0.0553 301 0.0009 436 0.0212 60 0.0037 139 0.0185 306 0.0023 437 0.0013 61 0.0026 140 0.0042 309 0.0015 438 0.0024 62 0.0023 141 0.3745 310 0.0017 439 0.0024 63 0.0027 142 0.0016 313 0.0021 440 0.0191 64 0.0033 143 0.0015 317 0.0011 441 0.0011 65 0.0030 144 0.0012 318 0.0017 442 0.0017 66 0.0055 145 0.0008 319 0.0014 443 0.0019 67 0.0017 146 0.0374 325 0.0018 444 0.0021 71 0.0019 147 0.0057 326 0.0026 445 0.0023 72 0.0019 148 0.2215 328 0.0036 454 0.0059 74 0.0070 149 0.0020 329 0.0046 455 0.0024 76 0.0028 151 0.0043 330 0.0115 456 0.0030 78 0.0021 168 0.0034 331 0.1220 457 0.0037 80 0.0136 172 0.0015 332 0.3297 458 0.0015 84 0.0029 182 0.0063 333 0.0435 459 0.0014 85 0.0016 183 0.0203 334 0.0010 461 0.0015 86 0.0019 184 0.0311 335 0.0015 462 0.0017 87 0.0039 185 0.0023 336 0.0011 463 0.0014 88 0.0028 186 0.0024 337 0.0017 464 0.0058 89 0.0223 204 0.0021 338 0.0010 465 0.0087

Example 6

[01028] Representative compounds were analyzed using the GSK3β kinase activity assay procedure as described below.

[01029] Each compound was dissolved in DMSO as a 10 mM stock solution and used to prepare compound source plates. Serial dilution (1:3, 11-point dose-response curves, 10 μM to 0.0003 μM) and compound transfer was performed using an ECHO 550 (Labcyte, Sunnyvale, CA) in 1536-well, black, round-bottomed fenced plates. (Corning).

[01030] The GSK3β kinase assay was performed using the Ser/Thr 18 Z-lyte peptide assay kit according to the manufacturer's instructions (Life Technologies - a division of Thermo-Fisher). This assay is a non-radioactive assay using fluorescence resonance energy transfer (FRET) between coumarin and fluorescein to detect kinase activity represented as a ratio of coumarin emission to fluorescein emission.

[01031] Briefly, recombinant GSK3β kinase, ATP, and Ser/Thr 09 peptide were prepared in 1x kinase buffer to final concentrations of 0.04 μg/ml, 46 μM, and 4 μM, respectively. The mixture was left to incubate with representative compounds for one hour at room temperature. All interactions were duplicated. Non-phosphorylated ('0% control') and phosphorylated ('100% control') forms of Ser/Thr 18 served as control reactions.

[01032] After incubation, the diluted Development Reagent A was added to the reaction mixture and left for further incubation for one hour at room temperature. The plate was read at Ex 400 Em 455 for coumarin signal detection and Ex 400 Em 520 for signal measurement (EnVision Multilabel Plate Reader, PerkinElmer).

[01033] The emission factor (Em) was calculated as the ratio of the coumarin (C) emission signal (at 445 nm) and the fluorescein (F) emission signal (at 520 nm). Then, percent phosphorylation was calculated by the following formula: [1 - ((Em x F100%)-C100%)/((C0%-C100%)+(Em x (F100%-F0%)))].

[01034] Dose-response curves were built and inhibitory concentration (IC ₅₀ ) values were calculated using a non-linear regression curve fitted with software (Bishops Stortford, UK).

[01035] Table 4 shows the activity of representative compounds of Formula I provided herein.

Table 4 Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) one 3.346 90 3.862 219 0.986 339 8.182 2 3.689 91 9.164 220 4.438 340 2.603 3 3.726 92 5.321 221 0.343 359 1.833 four 2.066 93 6.272 222 0.780 373 >10 5 3,250 94 4.553 223 1.914 374 5.461 6 2.931 95 >10 230 0.886 375 >10 7 0.330 97 6.640 232 0.112 376 >10 eight 0.668 99 1.566 233 0.100 377 >10 9 3.403 100 >10 236 0.299 378 3.696 ten 1.842 101 >10 238 0.750 379 3.192 eleven 3.895 102 9.067 240 0.212 380 >10 12 4.032 103 0.040 241 0.514 381 >10 (6.1%) 13 4.265 104 0.012 242 0.361 382 0.367 fourteen 0.479 105 0.009 243 0.809 383 0.829 fifteen 9.838 106 0.002 245 0.740 384 0.212 16 1.258 107 0.010 249 1.090 385 0.256 17 1.532 108 0.001 250 0.568 386 0.608 eighteen 3.756 109 0.469 253 0.295 387 0.101 19 6.027 110 1.795 256 0.378 388 0.085 twenty 9.838 111 2.150 257 >10 389 0.827 21 9.838 112 3.832 258 >10 390 0.955 22 9.838 113 1.713 261 1.884 391 0.595 23 >10 114 2.137 265 3.429 392 1.957 24 >10 116 1.138 266 2.498 393 0.460 25 >10 117 >10 268 3.128 406 0.142 26 >10 118 >10 271 4,550 409 0.242 27 >10 119 >10 273 2.901 412 0.368 28 0.537 120 >10 275 4.177 419 1.164 29 0.818 122 4.616 276 1.853 420 0.333 37 3.519 123 0.492 277 1.520 422 1.201 40 >10 126 2.097 278 >10 423 0.351 45 1.884 127 2.891 285 0.256 427 >10 47 >10 130 4,464 286 0.938 428 1.412 49 >10 131 >10 (5.2%) 289 6,000 429 1.658 52 4.322 132 >10 290 >10 430 0.610 53 0.859 133 3.207 291 2.176 431 0.563 54 2.421 134 >10 292 1.876 432 4.216 55 1.435 135 7.398 293 3.571 433 7.370 56 3.967 136 >10 294 6.573 434 1,860 57 2.037 137 >10 296 >10 435 2.368 59 3.856 138 0.666 301 8.288 436 >10 60 0.439 139 >10 306 >10 437 3.472 61 2.225 140 >10 309 2.693 438 1.646 62 2.825 141 >10 310 0.584 439 0.453 63 2.701 142 6.388 313 7.538 440 4,544 64 5,842 143 3.270 317 >10 441 4.314 65 1.085 144 1.359 318 2.822 442 7.115 66 2.712 145 3.694 319 7.099 443 5.029 67 3.649 146 >10 325 5.953 444 4.103 71 0.728 147 7.824 326 6,980 445 0.003 72 5.046 148 >10 328 1.410 454 1,350 74 4.124 149 2.941 329 0.811 455 2.892 76 0.937 151 >10 330 >10 456 2.226 78 1.291 168 >10 331 >10 457 >10 80 >10 172 >10 332 5.472 458 0.010 84 1.523 182 1.882 333 >10 459 3.845 85 0.506 183 0.704 334 0.593 461 3.198 86 3.051 184 1.959 335 0.685 462 >10 (41.3%) 87 3.566 185 1.445 336 1.477 463 0.261 88 8.925 186 1.859 337 3.832 464 9.708 89 7.389 204 0.763 338 2.073 465 >10 (51.0%)

Example 7

[01036] Representative compounds were tested using the Cell Viability Impact Assay procedure as described below.

[01037] SW480 colon carcinoma cells were transduced with a lentiviral luciferase-expressing vector with a human Sp5 promoter consisting of a sequence of eight TCF/LEF binding sites. SW480 cells stably expressing the Sp5-Luc reporter gene and hygromycin resistance gene were selected by treatment with 150 μg/ml hygromycin for 7 days. These stably transduced SW480 cells were expanded in cell culture and used for all further screening studies. Each compound was dissolved in DMSO as a 10 mM stock solution and used to prepare compound source plates. Serial dilution (1:3, 10-point dose-response curves, 10 μM - 0.0045 μM) and compound transfer were performed using an ECHO 550 (Labcyte, Sunnyvale, CA) in 384-well white hard bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill to give a final DMSO concentration of 0.1%.

[01038] For cell viability assays, cells were seeded at a concentration of 2000 cells/well in 384-well plates with DMEM containing 1% fetal bovine serum and 1% penicillin-streptomycin and incubated for four days at 37°C and 5% CO2 _. Eight copies of DMSO-treated cells served as controls and compound-treated cells were obtained in duplicate.

[01039] After incubation, 10 μl of CellTiter-Glo (Promega) was added to each well and allowed to incubate for about 12 minutes. This reagent "ensures cell lysis and the formation of a luminescent signal proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in the culture, according to previous data. The CellTiter-Glo® assay generates a luminescent “glow” signal produced by the luciferase reaction (Promega.com)”.

[01040] After incubation, plates were read at Ex 560 nm Em 590 nm (Cytation 3, BioTek). Dose-response curves were built and EC ₅₀ was calculated using a non-linear regression curve corresponding to GraphPad Prism software (San Diego, CA) or Dotmatics' Studies Software (Bishops Stortford, UK). In the case of an EC ₅₀ >10 μM, percent inhibition is provided at 10 μM.

[01041] Table 5 shows the activity of representative compounds of Formula I provided herein.

Table 5 Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) one 0.165 90 0.165 219 2.255 339 4,763 2 0.091 91 0.415 220 0.645 340 1.050 3 0.105 92 0.323 221 1.413 359 0.045 four 0.390 93 0.126 222 0.371 373 6.837 5 0.038 94 0.470 223 4,893 374 0.383 6 0.049 95 7.608 230 0.084 375 >10 (23.5%) 7 0.089 97 0.182 232 0.418 376 0.387 eight 0.087 99 0.089 233 0.310 377 8.204 9 0.037 100 >10 (34.8%) 236 0.193 378 0.852 ten 0.101 101 3.251 238 0.065 379 0.464 eleven 0.222 102 4.969 240 0.066 380 >10 (19.9%) 12 0.632 103 4.344 241 0.446 381 9.050 13 0.159 104 0.037 242 2.437 382 7.854 fourteen 0.269 105 0.694 243 0.214 383 0.276 fifteen >10 106 0.367 245 0.123 384 0.426 16 0.048 107 0.890 249 2.519 385 4.465 17 0.075 108 0.567 250 0.159 386 0.222 eighteen 0.137 109 0.834 253 0.238 387 >10 (32.4%) 19 0.080 110 0.675 256 0.277 388 0.334 twenty 0.478 111 0.447 257 3.581 389 0.595 21 0.677 112 0.318 258 2.221 390 0.388 22 0.745 113 0.369 261 0.286 391 0.132 23 0.733 114 0.410 265 0.174 392 0.260 24 9.391 116 0.210 266 0.174 393 0.475 25 >10 117 0.544 268 0.168 406 0.336 26 1,700 118 >10 (10.6%) 271 0.460 409 0.124 27 >10 119 0.649 273 0.106 412 0.218 28 0.547 120 0.058 275 0.012 419 0.273 29 0.368 122 0.301 276 0.503 420 0.542 37 0.060 123 0.400 277 0.569 422 3.151 40 0.826 126 0.105 278 1.583 423 0.113 45 0.187 127 0.149 285 0.690 427 8.055 47 2,900 130 0.360 286 0.297 428 0.403 49 0.430 131 0.406 289 0.405 429 0.464 52 1.454 132 0.359 290 0.234 430 0.058 53 0.072 133 0.258 291 2.771 431 0.089 54 0.060 134 0.242 292 0.491 432 0.273 55 0.076 135 2.292 293 3.024 433 1.091 56 0.094 136 2.127 294 0.469 434 0.245 57 0.476 137 1.542 296 >10 (17.3%) 435 0.429 59 0.213 138 4.142 301 0.682 436 3.641 60 0.886 139 4.949 306 2.492 437 0.782 61 0.406 140 0.308 309 0.310 438 3.528 62 0.455 141 >10 (12.2%) 310 4.996 439 0.108 63 0.225 142 0.099 313 2.796 440 4.307 64 0.413 143 0.114 317 1,730 441 0.535 65 0.427 144 0.100 318 0.799 442 0.283 66 0.111 145 0.080 319 5.486 443 1.052 67 0.139 146 3.190 325 9.738 444 0.272 71 0.044 147 0.318 326 2.651 445 0.470 72 0.107 148 2.174 328 0.334 454 0.578 74 0.266 149 0.073 329 0.512 455 0.112 76 0.564 151 0.343 330 >10 (13.3%) 456 0.765 78 3.556 168 0.121 331 6.588 457 0.449 80 0.869 172 0.486 332 5.109 458 0.208 84 0.059 182 0.464 333 >10 (45.9%) 462 0.443 85 0.234 183 0.586 334 0.275 463 0.381 86 0.402 184 0.325 335 0.266 464 0.481 87 5.293 185 0.236 336 0.246 465 0.413 88 0.228 186 0.115 337 0.400 89 >10 (41.5%) 204 0.058 338 0.328

Example 6

[01042] Representative compounds were assayed using the Tau phosphorylation activity assay procedure described below.

[01043] SH-SY5Y (human neuroblastoma) cells were cultured in DMEM/F-12 supplemented with 15% FBS, an essential amino acid, and penicillin/streptomycin. Two days prior to treatment, cells were seeded in 96-well plates at a concentration of 5 x 10 ⁴ cells/well.

[01044] The above synthesized compounds were examined using a cellular assay procedure to assess the reduction in Tau phosphorylation at Ser396 (pSer396) described below.

[01045] DMSO-resuspended compounds were dispensed into 8 wells as a serial titration of 10 μM - 4.6 nM in medium and the cells were kept overnight (16-18 h) in a humidified 36.6 sec incubator before harvesting the cells. Wells were visually inspected for cell death or morphology changes and, if necessary, supernatants were examined for cytotoxicity by measuring lactate dehydrogenase (LDH, CytoToxOne kit, Promega) release. As controls, the commercially available DYRK1A inhibitors, Harmine and Indy were present, which showed good inhibition of DYRK1A in the kinase assay with no CDK1 activity (EC ₅₀ 18 and 53 nM, respectively, 6 μM for CDK1), but low EC ₅₀ in the Tau assay > 10 μM.

[01046] Cells were lysed with RIPA buffer supplemented with phosphatase and protease inhibitors, then the lysates were centrifuged at 12,000 g for 10 minutes to remove any cellular debris. Lysates were then either directly analyzed for pSer396 by ELISA (Life Technology, Kit KHB7031) or loaded onto NuPage Bis-Tris gels for Western blot analysis. Colorimetric analysis of the ELISA signal was performed using a Cytation3 reader (Biotek) and the chemiluminescence signal for HRP-bound antibodies used in Western blotting was detected using a Carestream Image Station. The same pSer396 antibody was used to detect pTau in both assays.

[01047] pSer396 and β-actin were analyzed by blot densitometry using ImageJ (NIH), and the pSer396 Tau ELISA signal was used to plot, curve, and determine the EC ₅₀ of each compound using the Prism program (GraphPad).

[01048] Table 6 shows the activity of representative compounds provided herein.

Table 6 Comm. pSer396 Tau EC _fifty (µM) Comm. pSer396 Tau EC _fifty (µM) Comm. pSer396 Tau EC _fifty (µM) Comm. pSer396 Tau EC _fifty (µM) 5 1,390 232 0.095 285 7,600 406 >10 6 >10 233 0.174 382 >10 409 >10 7 1,100 236 >10 384 0.583 412 >10 fourteen 3,900 240 >10 385 0.337 420 >10 60 3,500 242 >10 387 >10 423 5,600 109 >10 253 1,800 388 1,100 221 >10 256 1,200 393 >10

Example 7

[01049] Representative compounds were tested using primary human fibroblasts (obtained from idiopathic pulmonary fibrosis (IPF) patients) treated with TGF-β1 to determine their ability to inhibit the fibrotic process.

[01050] Human Fibroblast Cell Culture: Primary Human Fibroblasts Derived from Idiopathic Lung Fibrosis (IPF) Patients (LL29 Cells) [ ¹ Xiaoqiu Liu, et.al., ʺFibrotic Lung Fibroblasts Show Blunted Inhibition by cAMP Due to Deficient cAMP Response Element -Binding Protein Phosphorylation', Journal of Pharmacology and Experimental Therapeutics (2005), 315(2), 678-687; ² Watts , KL, et.al., ʺRhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis', Respiratory Research (2006), 7(1), 88], were obtained from the American Type Culture Collection (ATCC) and propagated in F12 medium supplemented with 15% fetal bovine serum and 1% penicillin/streptomycin.

[01051] Compound Assay: Each compound was dissolved in DMSO as a 10 mM stock solution and used to prepare compound source plates. Serial dilution (1:2, 11-point dose-response curves, 10 μM - 0.94 nM) and compound transfer were performed using ECHO 550 (Labcyte, Sunnyvale, CA) in 384-well clear bottom assay plates (Greiner Bio -One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. LL29 cells were seeded at a concentration of 1500 cells/well in F12 medium 70 μl/well supplemented with 1% fetal bovine serum. TGF-β1 (Peprotech; 20 ng/ml) was added to the plates to induce fibrosis (refs 1 and 2 above). Wells treated with TGF-β1 and containing DMSO were used as a positive control, while DMSO-only cells were the negative control. Cells were incubated at 37°C and 5% CO ₂ for 4 days. After incubation for 4 days, SYTOX nucleic acid green stain (Life Technologies [Thermo Fisher Scientific]) was added to the wells at a final concentration of 1 μM and incubated at room temperature for 30 min. Cells were then fixed with 4% formaldehyde (Electron Microscopy Sciences), washed 3 times with PBS followed by blocking and permeabilization with 3% bovine serum albumin (BSA, Sigma) and 0.3% Triton X-100 (Sigma) in PBS. Next, the cells were stained with antibodies specific for α-smooth muscle actin (αSMA, Abcam) (ref. 1 and 2 above) in 3% bovine serum albumin (BSA, Sigma) and 0.3% Triton X-100 (Sigma) in PBS, and incubated overnight at 4°C. Cells were then washed 3 times with PBS followed by incubation with conjugated secondary antibodies Alexa Flor-647 (Life Technologies [Thermo Fisher Scientific]) and DAPI in 3% bovine serum albumin (BSA, Sigma) and 0.3% Triton X-100 (Sigma ) in PBS at room temperature for 1 hour. The cells were then washed 3 times with PBS and the plates were sealed for visualization. Image αSMA staining was obtained with excitation at 630 nm and emission at 665 nm, and quantified using the Compartmental Analysis program on CellInsight CX5 (Thermo Scientific). Dead or apoptotic cells were excluded from the analysis based on positive SYTOX green staining. The percentage of all cells positive for αSMA was counted in each well and normalized to the average of 11 wells treated with TGF-β1 on the same plate using Dotmatics' Studies Software. Normalized means (treatment fold change) of 3 replicate wells for each compound concentration were used to generate dose-response curves and EC ₅₀ values were calculated using a non-linear regression curve corresponding to Dotmatics' Studies Software. In the case of an EC ₅₀ >10 μM, percent inhibition is provided at 10 μM.

[01052] Table 7 shows the activity of representative compounds of formula I as indicated in this document.

Table 7 Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) one 0.079 72 0.135 185 0.300 325 0.863 2 1.162 74 6.836 186 0.585 326 0.611 3 0.158 78 >10 (0.5%) 204 0.143 328 0.159 four 0.239 84 0.094 219 >10 (25.1%) 329 0.339 5 0.179 85 1.244 220 0.276 330 >10 (6.0%) 6 0.195 86 0.433 221 0.978 331 2.196 7 2.563 87 >10 (48.7%) 222 0.190 332 2.230 eight 0.196 91 0.204 223 >10 (13.5%) 333 >10 (15.8%) 9 0.083 92 0.708 230 0.181 334 0.090 ten 0.085 93 0.270 232 0.612 335 0.196 eleven 0.071 94 0.678 233 0.144 336 0.254 12 1.058 95 >10 (3.0%) 236 >10 (39.7%) 337 1.589 13 0.194 97 0.117 238 0.145 338 0.335 fourteen 0.061 99 0.079 240 0.120 339 3.846 fifteen >10 (36.3%) 100 0.829 241 0.499 340 0.299 16 1,000 101 5.193 242 0.197 359 0.087 17 0.937 102 0.820 245 2.152 373 1.270 eighteen 0.152 109 0.601 249 3.022 374 1.382 19 0.083 110 0.187 250 0.127 375 2.654 twenty 3.881 111 0.167 253 0.360 376 1.043 21 2.370 112 0.181 256 0.752 377 2.701 22 3.826 113 0.217 257 1.202 378 1.292 23 0.769 114 0.186 258 0.329 379 0.379 24 >10 (24.3%) 116 0.298 261 1.246 380 4,899 25 1.656 122 1.296 265 0.293 381 >10 (38.4%) 26 1,200 123 0.262 266 0.353 382 0.624 27 1.677 127 0.207 268 0.324 383 0.438 28 0.207 130 0.273 271 0.133 384 0.406 29 0.302 131 0.154 273 0.253 385 1.948 37 0.142 132 >10 (37.6%) 275 0.292 386 0.437 40 2.006 133 0.151 276 0.147 387 >10 (37.7%) 45 0.992 134 0.244 277 0.869 388 0.807 47 1.099 135 0.653 278 5.494 389 4,200 49 1.249 136 0.312 285 1.391 390 0.538 52 3,894 137 0.333 286 0.665 391 2.764 53 0.553 138 1.525 289 0.329 392 0.297 54 0.120 139 2.120 290 0.562 393 0.350 55 0.081 140 0.317 291 6.396 406 1.280 56 >10 (30.2%) 143 0.094 292 1.264 409 0.281 57 0.133 145 0.092 293 5.338 412 0.245 59 0.013 146 1.847 294 0.544 419 1.005 60 >10 (24.6%) 147 0.128 296 0.198 420 2.467 61 0.694 148 1.251 301 0.501 422 0.202 62 0.167 149 0.149 306 0.820 423 0.307 63 0.263 151 0.859 309 0.392 427 4.578 64 >10 (40.9%) 168 0.466 310 0.920 428 >10 (12.5%) 65 1.991 172 0.463 313 0.306 429 0.411 66 0.603 182 0.509 317 1.139 430 0.139 67 0.030 183 0.644 318 1.480 71 1.915 184 0.194 319 4.728

Example 8

[01053] Representative compounds were tested using the following assay procedure to determine their ability to inhibit IL-6 and hence to demonstrate their anti-inflammatory properties.

[01054] Human Peripheral Blood Mononuclear Cells: Fresh Normal PB MNC (Catalog # PB001, AllCells, Alameda, CA) delivered overnight at 4°C and resuspended in Roswell Park Memorial Institute (RPMI) 1640 media supplemented with GlutaMAX Supplement (Catalogue # 61870127, ThermoFisherScientific, Waltham, MA) supplemented with 1% penicillin-streptomycin (Catalogue # 15140163, ThermoFisher Scientific, Waltham, MA) and 1% fetal bovine serum (FBS) (Catalog # 16140089, ThermoFisher Scientific, Waltham, MA).

[01055] Compound Assay: Fresh normal human peripheral blood mononuclear cells (huPBMC) were resuspended in 1% FBS-RPMI assay medium with 1% penicillin-streptomycin 1% to a cell concentration of 1 x 10 ⁶ cells/mL. Each compound was dissolved in DMSO (Catalog #D8418-100 ml, Sigma-Aldrich, St. Louis, MO O) as a 10 mM stock solution and used to prepare compound source plates. Serial dilution (1:3, 10-point dose-response curves starting at 10 μM) and compound transfer was performed using an ECHO 550 (Labcyte, Sunnyvale, CA) in Proxiplate-Plus 384-well white assay plates (Catalog #6008289, PerkinElmer, Shelton, CT) with appropriate DMSO backfill to give a final DMSO concentration of 0.25%. Normal human peripheral blood mononuclear cells were seeded at a concentration of 5000 cells/well in 384-well Proxiplate-Plus plates and incubated at 37 ^o C-5% CO ₂ for 2 hours. After 2 hours, 50 ng/ml lipopolysaccharides from Escherichia coli 0111 were added :B4 (Catalogue L5293-2 ml, Sigma-Aldrich, St. Louis, MO) and cells were incubated for another 22 hours at 37°C-5% CO ₂ . After a 22 hour incubation, a mixture of anti-IL6 XL665 and anti-IL-6 cryptate diluted in recovery buffer (Catalog # 62IL6PEC, Cisbio Inc., Bedford, MA) was added to each well. After incubation for 3 hours at room temperature, time resolved homogeneous fluorescence (HTRF) was measured using Envision (Perkin Elmer, Shelton, CT) at 665 nm and 620 nm. The ratio of fluorescence at 665 nm and 620 nm was used as an index for quantifying IL-6. All samples were processed in duplicate. The data was normalized to DMSO-treated cells and the normalized activities were used to calculate EC ₅₀ . The EC ₅₀ value was determined using software developed by Dotmatics Limited (Windhill Bishops Stortford Herts, UK) using a 4-parameter Levenberg-Marquardt approximation procedure with finite different gradients. In the case of an EC ₅₀ >10 μM, percent inhibition is provided at 10 μM.

[01056] Table 8 shows the activity of representative compounds of Formula I provided herein.

Table 8 Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) Comm. EU _fifty (µM) one 0.389 89 >10 (4.0%) 186 0.216 336 1.579 2 0.270 90 1.081 204 2.637 337 >10 (4.0%) 3 0.287 91 1.858 219 7.679 338 3.821 four 1.714 92 0.671 220 3.292 339 >10 (6.3%) 5 0.143 93 1.811 221 3.773 340 2.114 6 0.173 94 2.007 222 1.486 359 3.396 7 0.307 95 1.653 223 >10 (12.7%) 373 >10 (8.0%) eight 1.541 97 0.823 230 0.216 374 >10 (12.1%) 9 0.166 99 0.791 232 7.768 375 >10 (4.3%) ten 0.428 100 >10 (1.3%) 233 0.566 376 >10 (11.9%) eleven 0.215 101 >10 (18.2%) 236 2.136 377 >10 (4.8%) 12 2.621 102 >10 (12.2%) 238 0.325 378 >10 (27.0%) 13 0.489 103 1.081 240 0.237 379 1.594 fourteen 0.584 104 1.125 241 1.118 380 >10 (3.1%) fifteen >10 (2.8%) 105 0.362 242 0.349 381 >10 (26.4%) 16 0.805 106 0.369 243 2.657 382 >10 (11.8%) 17 1.028 107 0.426 245 1.211 383 1.048 eighteen 0.376 108 0.361 249 3.976 384 1.060 19 0.194 109 1.699 250 1.503 385 >10 (23.4%) twenty 1.178 110 0.942 253 1.274 386 5.074 21 1.323 111 1.048 256 0.744 387 >10 (6.1%) 22 1.209 112 4.463 257 >10 (3.9%) 388 1.140 23 2.474 113 0.791 258 >10 (12.9%) 389 >10 (27.6%) 24 >10 (5.5%) 114 1.386 261 2.599 390 7.186 25 >10 (41.8%) 116 2.346 265 0.936 391 0.867 26 4.477 117 3.252 266 0.371 392 8.722 27 4.510 118 >10 (14.3%) 268 2.838 393 1.119 28 0.834 119 >10 (17.4%) 271 1.610 406 >10 (15.1%) 29 0.669 120 1.383 273 0.829 409 >10 (32.5%) 37 0.379 122 >10 (41.7%) 275 0.292 412 1.180 40 3.648 123 1.187 276 3.078 419 >10 (43.6%) 45 1.499 126 >10 (6.0%) 277 0.819 420 >10 (11.7%) 47 1.301 127 >10 (26.1%) 278 3.352 422 0.452 49 0.614 130 >10 (18.3%) 285 3.009 423 4.204 52 >10 (31.2%) 131 >10 (16.4%) 286 1.123 427 >10 (15.6%) 53 1.156 132 >10 (8.3%) 289 0.828 428 >10 (36.4%) 54 0.208 133 >10 (35.2%) 290 1.410 429 1.806 55 0.308 134 >10 (46.7%) 291 >10 (47.1%) 430 0.388 56 0.172 135 7.724 292 9.705 431 0.499 57 0.364 136 2.355 293 >10 (32.2%) 432 1.157 59 0.339 137 3.928 294 >10 (48.9%) 433 >10 (12.5%) 60 >10 (9.6%) 138 >10 (4.5%) 296 >10 (4.4%) 434 3.259 61 2.625 139 >10 (1.2%) 301 >10 (33.0%) 435 >10 (7.2%) 62 0.725 140 3.093 306 3.107 436 >10 (11.3%) 63 0.455 141 >10 (4.6%) 309 5.244 437 2.718 64 1.329 142 0.666 310 >10 (17.3%) 438 >10 (30.9%) 65 2.815 143 0.232 313 8.611 439 0.747 66 0.259 144 0.375 317 >10 (11.4%) 440 >10 (4.7%) 67 0.293 145 0.293 318 5.272 441 0.819 71 0.477 146 >10 (22.4%) 319 >10 (3.7%) 442 1.286 72 0.196 147 0.650 325 >10 (9.7%) 443 >10 (47.2%) 74 0.485 148 >10 (5.2%) 326 8.423 444 0.921 76 3.190 149 0.307 328 9.285 445 0.992 78 >10 (6.0%) 151 1.042 329 3.206 454 1.217 80 >10 (31.3%) 168 1.161 330 >10 (6.8%) 455 0.749 84 0.187 172 0.890 331 5.799 456 2.203 85 1.049 182 0.613 332 7.290 457 1.852 86 >10 (36.2%) 183 0.733 333 >10 (18.2%) 458 0.170 87 >10 (13.4%) 184 4.005 334 3.891 88 1.562 185 0.865 335 3.535

Claims (10)

1. Compound formula

or a pharmaceutically acceptable salt thereof. 2. Compound formula

or a pharmaceutically acceptable salt thereof. 3. Pharmaceutical composition for the treatment of a disease caused by pathological activation or mutations of the Wnt pathway, containing a therapeutically effective amount of a compound according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 4. A method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, wherein the patient is a human. 5. The method of claim 4, wherein the cancer is selected from the group consisting of: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL) , acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin's lymphoma, lymphoma, sarcoma, and ovarian cancer. 6. The method of claim 4, wherein the cancer is selected from the group consisting of: non-small cell lung cancer, small cell lung cancer, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma , salivary gland cancer, basal cell and squamous cell skin cancer, skin cancer - melanoma, small intestine cancer, malignant tumors of the stomach, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, cancer of the larynx or hypopharyngeal cancer, kidney cancer, Kaposi's sarcoma, gestational trophoblastic tumor, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, malignant tumor of the eye (melanoma and lymphoma), Ewing's tumor, esophageal cancer, endometrial cancer, colon and rectal cancer, cervical cancer, tumors of the brain or spinal cord, bone metastasis, bone cancer, urinary tract cancer bladder, bile duct cancer, anal cancer and adrenal cortex cancer.