Isoquinolin-3-yl carboxamides and preparation and use thereof

This application claims the benefit of U.S. Provisional Application No. 62/328,210, filed Apr. 27, 2016, which is incorporated herein by reference in its entirety.

This disclosure relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins, and compositions comprising the same. More particularly, it concerns the use of an isoquinoline compound or salts or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, inflammation, auto-immune diseases fibrotic disorders, cartilage (chondral) defects, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states, as well as neurological conditions/disorders/diseases linked to overexpression of DYRK1A.

The Wnt growth factor family includes more than 10 genes identified in the mouse and at least 19 genes identified in the human. Members of the Wnt family of signaling molecules mediate many short- and long-range patterning processes during invertebrate and vertebrate development. The Wnt signaling pathway is known for its role in the inductive interactions that regulate growth and differentiation, and it also plays roles in the homeostatic maintenance of post-embryonic 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 defects and is implicated in the genesis of several human cancers. The Wnt pathway has also been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues including skin, blood, gut, prostate, muscle, and the nervous system.

Dual specificity tyrosine-phosphorylation-regulated kinase 1A is an enzyme that in humans is encoded by the DYRK1A gene. DYRK1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. DYRK1A contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. It catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. DYRK1A is localized in the Down syndrome critical region of chromosome 21, and is considered to be a candidate gene for learning defects associated with Down syndrome. DYRK1A is also expressed in adult brain neurons, indicating that DYRK1A may play a role in the mature central nervous system. Thus, several lines of evidence point to some synaptic functions of DYRK1A. For instance, it has been found that DYRK1A phosphorylates and modulates the interaction of several components of the endocytic protein complex machinery (Dynamin 1, Amphiphysin, and Synaptojanin), suggesting a role in synaptic vesicle recycling. In addition, a polymorphism (SNP) in DYRK1A was found to be associated with HIV-1 replication in monocyte-derived macrophages, as well as with progression to AIDS in two independent cohorts of HIV-1-infected individuals.

The present disclosure provides methods and reagents, involving contacting a cell with an agent, such as an isoquinoline compound, in a sufficient amount to antagonize a Wnt activity, e.g., to reverse or control an aberrant growth state or correct a genetic disorder due to mutations in Wnt signaling components.

The present disclosure also provides methods and reagents, involving contacting a cell with an agent, such as an isoquinoline compound, in a sufficient amount to antagonize DYRK1A activity, e.g., i) to normalize prenatal and early postnatal brain development; ii) to improve cognitive function in youth and adulthood; and/or iii) to attenuate Alzheimer's-type neurodegeneration.

Some embodiments disclosed herein include Wnt and/or DYRK1A inhibitors containing an isoquinoline core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.

One embodiment disclosed herein includes a compound having the structure of Formula I:

as well as prodrugs and pharmaceutically acceptable salts thereof.

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 —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , —(C 1-4 alkylene)N(R 46 )(R 47 ), and —CF(C 1-9 alkyl) 2 ; wherein each alkyl of —CF(C 1-9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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), —(C 1-4 alkylene) p OR 42 , —(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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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), —(C 1-4 alkylene) p OR 42 , —(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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 39 independently 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 R 44 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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), and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 44 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, two adjacent R 45 taken together 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 46 is attached to the nitrogen and is 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 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 47 is attached to the nitrogen and is 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 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

each p is independently 0 or 1.

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:

wherein each of R 7 -R 35 is, independently, a substituent as defined anywhere herein or a single bond connecting R 3 to the isoquinoline ring; wherein only one of R 7 -R 10 (when present) is a bond, only one of R 11 -R 14 (when present) is a bond, only one of R 15 -R 17 (when present) is a bond, only one of R 18 -R 20 (when present) is a bond, only one of R 21 -R 23 (when present) is a bond, only one of R 24 -R 26 (when present) is a bond, only one of R 27 -R 29 (when present) is a bond, only one of R 30 -R 31 (when present) is a bond, only one of R 32 -R 33 (when present) is a bond, and only one of R 34 -R 35 (when present) is a bond; for purposes of clarification, any one 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; likewise, any one 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 can serve as the point of attachment of R 3 to the isoquinoline ring; so that:

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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting R 3 to the isoquinoline ring;

R 6 is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , —(C 1-4 alkylene)N(R 46 )(R 47 ), and —CF(C 1-9 alkyl) 2 ; wherein each alkyl of —CF(C 1-9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 8 , R 9 , and R 10 are independently selected from the group consisting of a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 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 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 12 , R 13 , and R 14 are independently selected from the group consisting of a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 -heterocyclyl optionally substituted with 1-10 R 40 and -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) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 16 and R 17 are independently selected from the group consisting of a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;

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 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 19 and R 20 are independently selected from the group consisting of a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 22 and R 23 are independently selected from the group consisting of a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;

R 27 , R 28 , and R 29 are independently selected from the group consisting of a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, R 27 and R 28 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 30 and R 31 are independently selected from the group consisting of a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, R 30 and R 31 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 32 and R 33 are independently selected from the group consisting of a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 34 and R 35 are independently selected from the group consisting of a 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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), —(C 1-4 alkylene) p OR 42 , —(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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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), —(C 1-4 alkylene) p OR 42 , —(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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 38 independently 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 R 44 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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), and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 44 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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;

R 46 is attached to the nitrogen and is 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 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 47 is attached to the nitrogen and is 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 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

each X is O or S; and

each p is independently 0 or 1.

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

with the proviso that R 3 is not

R 6 is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , —(C 1-4 alkylene)N(R 46 )(R 47 ), —N(R 48 )(R 49 ), —CF(C 1-9 alkyl) 2 , —(C 1-4 alkylene) p O(C 3-9 alkyl), and —(C 2-9 alkynyl) optionally substituted with one or more halides; wherein each alkyl of —CF(C 1-9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

with the proviso that R 6 is not unsubstituted —(CH 2 )tetrahydropyranyl;

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), —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 43 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 44 , —C(═O)(R 50 ), —(C 1-4 alkylene)C(═O)OR 51 , —(C 1-4 alkylene)aryl optionally substituted with one or more halides, —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides, and —SO 2 (R 52 ); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, two R 36 attached to the same carbon atom can together represent ═O to form a carbonyl group;

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), —(C 1-4 alkylene) p OR 42 , —N(R 53 ) 2 , —C(═O)(R 50 ), —C(═O)OR 51 , —(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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 38 independently 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 R 44 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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), and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 44 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 H, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, two adjacent R 45 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 46 is attached to the nitrogen and is 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 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 47 is attached to the nitrogen and is 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 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 48 is attached to the nitrogen and 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);

R 49 is attached to the nitrogen and is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 50 is selected from the group consisting of H, unsubstituted —(C 3-5 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 one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 51 is 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) p aryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 52 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 one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

each R 53 is independently selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), and unsubstituted —(C 2-5 alkynyl);

each p is independently 0 or 1; and

with the proviso that Formula I is not a structure selected from the group consisting of:

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:

wherein each of R 7 -R 35 is, independently, a substituent as defined anywhere herein or a single bond connecting R 3 to the isoquinoline ring; wherein only one of R 7 -R 10 (when present) is a bond, only one of R 11 -R 14 (when present) is a bond, only one of R 15 -R 17 (when present) is a bond, only one of R 18 -R 20 (when present) is a bond, only one of R 21 -R 23 (when present) is a bond, only one of R 24 -R 26 (when present) is a bond, only one of R 27 -R 29 (when present) is a bond, only one of R 30 -R 31 (when present) is a bond, only one of R 32 -R 33 (when present) is a bond, and only one of R 34 -R 35 (when present) is a bond; for purposes of clarification, any one 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; likewise, any one 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 can serve as the point of attachment of R 3 to the isoquinoline ring; so that:

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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting 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 connecting R 3 to the isoquinoline ring;

R 6 is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , —(C 1-4 alkylene)N(R 46 )(R 47 ), —N(R 48 )(R 49 ), —CF(C 1-9 alkyl) 2 , —(C 1-4 alkylene) p O(C 3-9 alkyl), and —(C 2-9 alkynyl) optionally substituted with one or more halides; wherein each alkyl of —CF(C 1-9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

with the proviso that R 6 is not unsubstituted —(CH 2 )tetrahydropyranyl;

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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 8 , R 9 , and R 10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 12 , R 13 , and R 14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 -heterocyclyl optionally substituted with 1-10 R 40 and -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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 16 and R 17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;

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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 19 and R 20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 22 and R 23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

with the proviso that when R 25 is a single bond connecting R 3 to the isoquinoline ring, R 24 and R 26 are not methyls;

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 -heterocyclyl optionally substituted with 1-10 R 40 and -carbocyclyl optionally substituted with 1-12 R 41 ;

R 27 , R 28 , and R 29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, R 27 and R 28 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 30 and R 31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, R 30 and R 31 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 32 and R 33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 34 and R 35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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), —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 43 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 44 , —C(═O)(R 50 ), —(C 1-4 alkylene)C(═O)OR 51 , —(C 1-4 alkylene)aryl optionally substituted with one or more halides, —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides, and —SO 2 (R 52 ); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

alternatively, two R 36 attached to the same carbon atom can together represent ═O to form a carbonyl group;

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), —(C 1-4 alkylene) p OR 42 , —N(R 53 ) 2 , —C(═O)(R 50 ), —C(═O)OR 51 , —(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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

each R 38 independently 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 R 44 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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), and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 44 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere 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;

R 46 is attached to the nitrogen and is 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 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 47 is attached to the nitrogen and is 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 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

R 48 is attached to the nitrogen and 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);

R 49 is attached to the nitrogen and is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 50 is selected from the group consisting of H, unsubstituted —(C 3-5 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 one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 51 is 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) p aryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein;

R 52 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 one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein;

each R 53 is independently selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), and unsubstituted —(C 2-5 alkynyl);

each X is O or S; and

each p is independently 0 or 1; and

with the proviso that Formula I is not a structure selected from the group consisting of:

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).

Some embodiments include pro-drugs of a compound of Formula (I).

Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient.

Other embodiments disclosed herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins by administering to a patient affected by a disorder or disease in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, cell cycling and mutations in Wnt signaling components, a compound according to Formula (I). Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation and correct a genetic disorder due to mutations in Wnt signaling components.

Other embodiments disclosed herein include methods of inhibiting DYRK1A by administering to a patient affected by a disorder or disease in which DYRK1A overexpression is implicated, such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington's Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor and Stroke.

Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

Some embodiments of the present disclosure include methods to prepare compounds of Formula (I).

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed.

Provided herein are compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins. Other Wnt inhibitors and methods for using the same are disclosed in U.S. application Ser. Nos. 13/614,296; 14/019,229; and Ser. No. 14/664,517, all of which are incorporated by reference in their entirety herein.

Provided herein are compositions and methods for inhibiting DYRK1A. Other DYRK1A inhibitors and methods for using the same are disclosed in U.S. application Ser. No. 14/664,517, which is incorporated by reference in its entirety herein.

Some embodiments provided herein relate to a method for treating a disease including, but not limited to, neurological diseases or disorders, cancers, chronic inflammation, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis, psoriasis, scleroderma, mycotic and viral infections, bone and cartilage diseases, lung disease, osteoarthritis, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

In some embodiments, non-limiting examples of bone and cartilage diseases which can be treated with the compounds and compositions provided herein include bone spur (osteophytes), craniosynostosis, fibrodysplasia ossificans progressive, fibrous dysplasia, giant cell tumor of bone, hip labral tear, meniscal tears, osteoarthritis, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), osteochondritis dissecans, osteochondroma (bone tumor), osteopetrosis, relapsing polychondritis, and Salter-Harris fractures.

In some embodiments, non-limiting examples of a neurological disease or disorder associated with tau protein, amyloid or alpha-synuclein pathology which can be treated with the compounds and compositions provided herein include, but are not limited to, Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington's Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.

In some embodiments, non-limiting examples of diseases in which chronic inflammation is involved which can be treated with the compounds and compositions provided herein include eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders such as multiple sclerosis, Parkinson's and dementia including Alzheimer's disease.

In some embodiments, non-limiting examples of cancers which can be treated with the compounds and compositions provided herein include colon, ovarian, pancreatic, breast, liver, prostate, and hematologic cancers.

In some embodiments, pharmaceutical compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by either the pathological activation or mutations of the Wnt pathway or DYRK1A overexpression. The composition includes a pharmaceutically acceptable carrier and a compound as described herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

As used herein, “alkyl” means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkenyl” means 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, alkenyl groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkynyl” means a straight or branched chain 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 can either be unsubstituted or substituted with one or more substituents. Typically, alkynyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene and neo-pentylene. Alkylene groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkenylene” means a bivalent branched, or straight chain 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, alkenylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkynylene” means a bivalent branched, or straight 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, alkynylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkynylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkoxy” means an alkyl-O— group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also the linear or branched positional isomers thereof.

As used herein, “haloalkoxy” means a haloalkyl-O— group in which the haloalkyl group is as described herein. Exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and also the linear or branched positional isomers thereof.

As used herein, “carbocyclyl” means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that none of the rings in the ring system are aromatic. Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups include 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

As used herein, “aryl” means a mono-, bi-, tri- or polycyclic group with only carbon atoms present in the ring backbone having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic. Aryl groups can either be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, and others. In some embodiments, the aryl is phenyl.

As used herein, “arylalkylene” means an aryl-alkylene-group in which the aryl and alkylene moieties are as previously described. In some embodiments, arylalkylene groups contain a C 1-4 alkylene moiety. Exemplary arylalkylene groups include benzyl and 2-phenethyl.

As used herein, the term “heteroaryl” means a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein 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 can either be unsubstituted or substituted with one or more substituents. 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, benzotriazolyl, cinnolinyl, 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, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

As used herein, “halo”, “halide” or “halogen” is a chloro, bromo, fluoro, or iodo atom radical. In some embodiments, a halo is a chloro, bromo or fluoro. For example, a halide can be fluoro.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is a linear or branched, alkyl, alkenyl or alkynyl substituted with one or more chloro, bromo, fluoro, and/or iodo atom(s). In some embodiments, a haloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. In some embodiments, haloalkyls are of 1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or 1 carbon in length). The term “haloalkylene” means a diradical variant of haloalkyl, and such diradicals may act as spacers between radicals, other atoms, or between a ring and another functional group.

As used herein, “heterocyclyl” means a nonaromatic cyclic ring system comprising at least one heteroatom in the ring system backbone. Heterocyclyls may include multiple fused rings. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 3-11 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, or S. Examples of 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, the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

As used herein, “monocyclic heterocyclyl” means a single nonaromatic cyclic ring comprising at least one heteroatom in the ring system backbone. Heterocyclyls 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) are selected from one to three of O, N or S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, or S. Examples of 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.

As used herein, “bicyclic heterocyclyl” means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone. Bicyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, bicyclic heterocycles have 4-11 members with the heteroatom(s) being selected from one to five of 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, and the like.

As used herein, “spirocyclic heterocyclyl” means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone and with the rings connected through just one atom. Spirocyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, spirocyclic heterocycles have 5-11 members with the heteroatom(s) being selected from one to five of 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.

The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more non-hydrogen atoms of the molecule. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Substituents can include, for example, —(C 1-9 alkyl) optionally substituted with one or more of hydroxyl, —NH 2 , —NH(C 1-3 alkyl), and —N(C 1-3 alkyl) 2 ; —(C 1-9 haloalkyl); a halide; a hydroxyl; a carbonyl [such as —C(O)OR, and —C(O)R]; a thiocarbonyl [such as —C(S)OR, —C(O)SR, and —C(S)R]; —(C 1-9 alkoxy) optionally substituted with one or more of halide, hydroxyl, —NH 2 , —NH(C 1-3 alkyl), and —N(C 1-3 alkyl) 2 ; —OPO(OH) 2 ; a phosphonate [such as —PO(OH) 2 and —PO(OR′) 2 ]; —OPO(OR′)R″; —NRR′; —C(O)NRR′; —C(NR)NR′R″; —C(NR′)R″; a cyano; a nitro; an azido; —SH; —S—R; —OSO 2 (OR); a sulfonate [such as —SO 2 (OH) and —SO 2 (OR)]; —SO 2 NR′R″; and —SO 2 R; in which each occurrence of R, R′ and R″ are independently selected from H; —(C 1-9 alkyl); C 6-10 aryl optionally substituted with from 1-3R′″; 5-10 membered heteroaryl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with from 1-3 R′″; C 3-7 carbocyclyl optionally substituted with from 1-3 R′″; and 3-8 membered heterocyclyl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with from 1-3 R′″; wherein each R′″ is independently selected from —(C 1-6 alkyl), —(C 1-6 haloalkyl), a halide (e.g., F), a hydroxyl, —C(O)OR, —C(O)R, —(C 1-6 alkoxyl), —NRR′, —C(O)NRR′, and a cyano, in which each occurrence of R and R′ is 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), a halide (e.g., F), a hydroxyl, —C(O)OR, —C(O)R, —(C 1-6 alkoxyl), —NRR′, —C(O)NRR′, and a cyano, in which each occurrence of R and R′ is independently selected from H and —(C 1-6 alkyl).

As used herein, when two groups are indicated to be “linked” or “bonded” to form a “ring”, it is to be understood that a bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with the bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions. In some embodiments, such rings have from 3-7 members, for example, 5 or 6 members.

The skilled artisan will recognize that some chemical structures described herein may be represented on paper by one or more other resonance forms; or may exist in one or more other tautomeric forms, even when kinetically, the artisan recognizes that such tautomeric forms represent only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this disclosure, though such resonance forms or tautomers are not explicitly represented herein.

The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

The present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of Formula I wherein 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 which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include, 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.

The term “administration” or “administering” refers to a method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., orally, subcutaneously, intravenously, intralymphatic, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic device. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease.

A “diagnostic” as used herein is a compound, method, system, or device that assists in the identification or characterization of a health or disease state. The diagnostic can be used in standard assays as is known in the art.

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

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 absorption delaying 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. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, N.J. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12 th Ed ., The McGraw-Hill Companies.

The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. 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 can 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, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

“Patient” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate, or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the patient is a human.

A “therapeutically effective amount” of a compound as provided herein is one which is sufficient to achieve the desired physiological effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. “Therapeutically effective amount” is also intended to include one or more of the compounds of Formula I in combination with one or more other agents that are effective to treat the diseases and/or conditions described herein. The combination of compounds can be a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. This amount can further depend upon the patient's height, weight, sex, age and medical history.

A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease.

“Treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder, and/or reducing the severity of symptoms that will or are expected to develop.

“Drug-eluting” and/or controlled release as used herein refers to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the drug(s) incorporated in the drug-eluting material pass therefrom over time into the surrounding body tissue.

“Drug-eluting material” and/or controlled release material as used herein refers to any natural, synthetic or semi-synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time.

“Elutable drug” as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body.

Compounds

The compounds and compositions described herein can be used as anti-proliferative agents, e.g., anti-cancer and anti-angiogenesis agents, and/or as inhibitors of the Wnt signaling pathway, e.g., for treating 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 for controlling cellular proliferation, differentiation, and/or apoptosis.

The compounds and compositions described herein can be used to inhibit DYRK1A for treating a disorder or disease in which DYRK1A overexpression is implicated, such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington's Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.

Some embodiments of the present disclosure include compounds of Formula I:

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

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);

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

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

In some embodiments, R 1 , R 2 , R 4 , and R 5 are all H.

In some embodiments, R 1 is F, and R 2 , R 4 , and R 5 are all H.

In some embodiments, R 2 is F, and R 1 , R 4 , and R 5 are all H.

In some embodiments, R 4 is F, and R 1 , R 2 , and R 5 are all H.

In some embodiments, R 5 is F, and R 1 , R 2 , and R 4 are all H.

In some embodiments, R 3 is a 5-membered heteroaryl ring optionally substituted as defined anywhere herein.

In some embodiments, R 3 is 5-membered heteroaryl ring optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R 45 ;

In some embodiments, there is the proviso that R 3 is not

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 (e.g., 1-3, 1-2, 1) R 45 ,

wherein each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).

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

wherein each of R 7 -R 35 is, independently, a substituent as defined anywhere herein or a single bond connecting R 3 to the isoquinoline ring; wherein only one of R 7 -R 10 (when present) is a bond, only one of R 11 -R 14 (when present) is a bond, only one of R 15 -R 17 (when present) is a bond, only one of R 18 -R 20 (when present) is a bond, only one of R 21 -R 23 (when present) is a bond, only one of R 24 -R 26 (when present) is a bond, only one of R 27 -R 29 (when present) is a bond, only one of R 30 -R 31 (when present) is a bond, only one of R 32 -R 33 (when present) is a bond, and only one of R 34 -R 35 (when present) is a bond; for purposes of clarification, any one 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; likewise, any one 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 can serve as the point of attachment of R 3 to the isoquinoline ring.

In some embodiments, R 6 is selected from the group consisting of —(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 36 , —(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 37 , —(C 1-4 alkylene)N(R 46 )(R 47 ), and —CF(C 1-9 alkyl) 2 ; wherein each alkyl of —CF(C 1-9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 6 is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 , —(C 1-4 alkylene)N(R 46 )(R 47 ), —N(R 48 )(R 49 ), —CF(C 1-9 alkyl) 2 , —(C 1-4 alkylene) p O(C 3-9 alkyl), and —(C 2-9 alkynyl) optionally substituted with one or more halides; wherein each alkyl of —CF(C 1-9 alkyl) 2 is, independently, optionally substituted with one or more halides; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, there is the proviso that R 6 is not unsubstituted —(CH 2 )tetrahydropyranyl.

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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 8 , R 9 , and R 10 are independently selected from the group consisting of a 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 8 , R 9 , and R 10 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

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 which is selected from the group consisting of -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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .

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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 12 , R 13 , and R 14 are independently selected from the group consisting of a 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 12 , R 13 , and R 14 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

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 which is selected from the group consisting of -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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .

In some embodiments, R 15 is 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 16 and R 17 are independently selected from the group consisting of 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 16 and R 17 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, 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 -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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .

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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 19 and R 20 are independently selected from the group consisting of a 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 19 and R 20 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein

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 .

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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

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)OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 22 and R 23 are independently selected from the group consisting of a 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 22 and R 23 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, 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 (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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .

In some embodiments, R 24 , R 25 , and R 26 are independently selected from the group consisting of a 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 24 , R 25 , and R 26 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, there is the proviso that when R 25 is a single bond connecting R 3 to the isoquinoline ring, R 24 and R 26 are not methyls.

In some embodiments, there is the proviso that when R 25 is a single bond connecting R 3 to the isoquinoline ring, R 24 and R 26 are not both methyls.

In some embodiments, there is the proviso that when R 25 is a single bond connecting R 3 to the isoquinoline ring, R 24 and R 26 are not selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-2 alkyl), unsubstituted —(C 2 alkenyl), unsubstituted —(C 2 alkynyl), unsubstituted —(C 1-2 haloalkyl).

In some embodiments, 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 -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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .

In some embodiments, R 27 , R 28 , and R 29 are independently selected from the group consisting of a 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 27 , R 28 , and R 29 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 27 and R 28 are taken together to form a ring which is selected from the group consisting of -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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .

In some embodiments, R 30 and R 31 are independently selected from the group consisting of a 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 30 and R 31 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 30 and R 31 are taken together to form a ring which is selected from the group consisting of -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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .

In some embodiments, R 32 and R 33 are independently selected from the group consisting of a 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 32 and R 33 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 34 and R 35 are independently selected from the group consisting of a 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 34 and R 35 are independently selected from the group consisting of a single bond, H, halide, unsubstituted —(C 1-9 alkyl), unsubstituted —(C 2-9 alkenyl), unsubstituted —(C 2-9 alkynyl), unsubstituted —(C 1-9 haloalkyl), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, 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 (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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .

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), —(C 1-4 alkylene) p OR 42 , —(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 (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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

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), —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 43 , —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 44 , —C(═O)(R 50 ), —(C 1-4 alkylene)C(═O)OR 1 , —(C 1-4 alkylene)aryl optionally substituted with one or more halides, —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides (e.g. F, Cl, Br, I), and —SO 2 (R 52 ); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, two R 36 that are attached to the same carbon atom can together represent ═O to form a carbonyl group.

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), —(C 1-4 alkylene) p OR 42 , —(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 (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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

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), —(C 1-4 alkylene) p OR 42 , —N(R 53 ) 2 , —C(═O)(R 50 ), —C(═O)OR 51 , —(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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, 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 (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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, 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 (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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, 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 (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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, 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.

In some embodiments, 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), 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

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, 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 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, 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.

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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

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), —N(R 53 ) 2 , —(C 1-4 alkylene) p OR 42 , —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and -carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, two adjacent R 45 groups are taken together to form a ring which is selected from the group consisting of -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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 41 .

In some embodiments, R 46 is attached to the nitrogen and is 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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 47 is attached to the nitrogen and is 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 (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 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 39 ; wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 48 is attached to the nitrogen and 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).

In some embodiments, R 49 is attached to the nitrogen and is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 38 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 39 ; wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 50 is selected from the group consisting of H, unsubstituted —(C 3-5 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 one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 51 is 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) p aryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein each —(C 1-4 alkylene) is, independently, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, R 52 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 one or more halides or unsubstituted —(C 1-5 alkyl), —(C 1-4 alkylene) p heteroaryl optionally substituted with one or more halides or unsubstituted —(C 1-5 alkyl), and —(C 1-4 alkylene) p heterocyclyl optionally substituted with one or more halides or one or more unsubstituted —(C 1-5 alkyl); wherein —(C 1-4 alkylene) is, optionally substituted with one or more substituents as defined anywhere herein.

In some embodiments, each R 53 is independently selected from the group consisting of H, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 2-5 alkenyl), and unsubstituted —(C 2-5 alkynyl).

In some embodiments, there is the proviso that Formula I is not a structure selected from the group consisting of:

In some embodiments, the carbocyclyl of —(C 1-4 alkylene) p carbocyclyl is optionally substituted with 1-12 R 37 .

In some embodiments, the —(C 1-4 alkylene) of —(C 1-4 alkylene) p carbocyclyl is optionally substituted with 1-12 R 37 .

In some embodiments, the heterocyclyl of —(C 1-4 alkylene) p heterocyclyl is optionally substituted with 1-10 R 38 .

In some embodiments, the —(C 1-4 alkylene) of —(C 1-4 alkylene) p heterocyclyl is optionally substituted with 1-10 R 38 .

In some embodiments, the carbocyclyl of —(C 1-4 alkylene) p carbocyclyl is optionally substituted with 1-12 R 44 .

In some embodiments, the —(C 1-4 alkylene) of —(C 1-4 alkylene) p carbocyclyl is optionally substituted with 1-12 R 44 .

In some embodiments, the heterocyclyl of —(C 1-4 alkylene) p heterocyclyl is optionally substituted with 1-10 R 43 .

In some embodiments, the —(C 1-4 alkylene) of —(C 1-4 alkylene) p heterocyclyl is optionally substituted with 1-10 R 43 .

In some embodiments, —(C 1-4 alkylene) is optionally substituted with 1-5 halide or 1-5 unsubstituted —(C 1-3 alkyl).

In some embodiments, —(C 1-4 alkylene) is substituted with 1-2 fluorines.

In some embodiments, —(C 1-4 alkylene) is substituted with 1-2 methyls.

In some embodiments, each X is O or S.

In some embodiments, each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).

In some embodiments, each n is independently 0 to 3 (e.g., 0-2, 0-1, 0).

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

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).

In some embodiments, R 3 is

In certain embodiments, R 9 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:

In some embodiments, R 3 is

and n is 1 to 3.

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 .

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 .

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

In some embodiments, R 7 is methyl.

In some embodiments, R 7 is —CD 3 .

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 .

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

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

In some embodiments, R 8 is H.

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

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

In some embodiments, R 10 is H.

In some embodiments, R 3 is

In certain embodiments, R 12 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:

In some embodiments, R 3 is

and n is 1 to 3.

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 .

In some embodiments, R 11 is selected from the group consisting of H, methyl, —CF 3 , and cyclopropyl optionally substituted with 1-2 R 39 .

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

In some embodiments, R 11 is methyl.

In some embodiments, R 11 is —CD 3 .

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

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

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).

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

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

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

In some embodiments, R 3 is

In some embodiments, R 3 is

and X is S.

In some embodiments, R 3 is

and X is O.

In certain embodiments, R 27 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:

In some embodiments, R 3 is

In some embodiments, R 3 is

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

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

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).

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

In some embodiments, R 3 is

In some embodiments, R 3 is

and X is S.

In some embodiments, R 3 is

and X is O.

In certain embodiments, R 33 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:

In some embodiments, R 3 is

In some embodiments, R 3 is

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 .

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

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

In some embodiments, R 32 is methyl.

In some embodiments, R 3 is

In certain embodiments, R 20 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:

In some embodiments, R 3 is

In certain embodiments, R 16 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:

In certain embodiments, R 17 is a single bond connecting R 3 to the isoquinoline ring, i.e., R 3 has the following formula:

In some embodiments, R 15 is selected from the group consisting of H and unsubstituted —(C 1-2 alkyl).

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

In some embodiments, R 15 is methyl.

In some embodiments, R 15 is —CD 3 .

In some embodiments, R 3 is

and n is 1 to 3.

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 .

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 .

In some embodiments, R 18 is selected from the group consisting of H and methyl.

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).

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

In some embodiments, R 39 is selected from the group consisting of halide, unsubstituted —(C 1-3 alkyl), and unsubstituted —(C 1-2 haloalkyl).

In some embodiments, R 39 is selected from the group consisting of F, methyl, and —CF 3 .

In some embodiments, R 40 is selected from the group consisting of H and unsubstituted —(C 1-2 alkyl).

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

In some embodiments, R 6 is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 , and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 .

In some embodiments, R 6 is a -heterocyclyl optionally substituted with 1-2 R 36 .

In some embodiments, R 6 is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R 6 is selected from the group consisting of:

and q is 0 to 2.

In some embodiments, R 6 is a -carbocyclyl optionally substituted with 1-2 R 37 .

In some embodiments, R 6 is a —(CH 2 )carbocyclyl optionally substituted with 1-2 R 37 .

In some embodiments, R 6 is a —(C 1-4 alkylene)N(R 46 )(R 47 ).

In some embodiments, R 6 is a (CH 2 )N(R 46 )(R 47 ).

In some embodiments, R 6 is a —(CH 2 )NH(C 1-5 alkyl).

In some embodiments, R 6 is a —(CH 2 )NH(C 1-4 alkyl).

In some embodiments, R 6 is a —(CH 2 )NH(C 1-3 alkyl).

In some embodiments, R 6 is a —(CH 2 )NHEt.

In some embodiments, R 6 is a —(CH 2 )NHMe.

In some embodiments, R 6 is a —(CH 2 )NHcarbocyclyl.

In some embodiments, R 6 is a —(CH 2 )NH(CH 2 )carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )N(C 1-5 alkyl) 2 .

In some embodiments, R 6 is a —(CH 2 )N(C 1-4 alkyl) 2 .

In some embodiments, R 6 is a —(CH 2 )N(C 1-3 alkyl) 2 .

In some embodiments, R 6 is a —(CH 2 )N(C 1-2 alkyl) 2 .

In some embodiments, R 6 is a —(CH 2 )NMe 2 .

In some embodiments, R 6 is a —(CH 2 )N(C 1-5 alkyl)carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )N(C 1-5 alkyl)(CH 2 )carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )N(C 1-4 alkyl)carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )N(C 1-4 alkyl)(CH 2 )carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )N(C 1-3 alkyl)carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )N(C 1-3 alkyl)(CH 2 )carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )N(C 1-2 alkyl)carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )N(C 1-2 alkyl)(CH 2 )carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )N(Me)carbocyclyl.

In some embodiments, R 6 is a —(CH 2 )NMe(CH 2 )carbocyclyl.

In some embodiments, R 6 is —CF(C 1-9 alkyl) 2 ; wherein each alkyl of —CF(C 1-9 alkyl) 2 is, independently, optionally substituted with one or more halides.

In some embodiments, R 6 is —CF(C 1-9 alkyl) 2 ; wherein each alkyl of —CF(C 1-9 alkyl) 2 is, independently, optionally substituted with one or more fluorines.

In some embodiments, R 6 is —CF(C 1-7 alkyl) 2 .

In some embodiments, R 6 is —CF(C 1-5 alkyl) 2 .

In some embodiments, R 6 is —CF(C 1-4 alkyl) 2 .

In some embodiments, R 6 is —CF(C 1-3 alkyl) 2 .

In some embodiments, R 6 is —CF(C 1-2 alkyl) 2 .

In some embodiments, R 6 is —CFMe 2 .

In some embodiments, R 6 is —CF(Me)(Et).

In some embodiments, R 6 is —CFEt 2 .

In some embodiments, R 6 is —CF(Et)( n Pr).

In some embodiments, R 6 is —CF n Pr 2 .

In some embodiments, R 6 is —CF(Me)( n Pr).

In some embodiments, R 6 is —CF i Pr 2 .

In some embodiments, R 6 is —CF(Et)( i Pr).

In some embodiments, R 6 is —CF(Me)( i Pr).

In some embodiments, R 36 is selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 1-5 haloalkyl), —(CH 2 CH 2 )OR 42 , -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 .

In some embodiments, R 37 is selected from the group consisting of halide, unsubstituted —(C 1-5 alkyl), unsubstituted —(C 1-5 haloalkyl), —OR 42 , -heterocyclyl optionally substituted with 1-2 R 43 , and —(CH 2 )heterocyclyl optionally substituted with 1-2 R 43 .

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

In some embodiments, R 42 is selected from the group consisting of unsubstituted —(C 1-3 alkyl), and unsubstituted —(C 1-3 haloalkyl).

In some embodiments, R 42 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, —CF 3 .

In some embodiments, R 43 is selected from the group consisting of halide, unsubstituted —(C 1-2 alkyl), and unsubstituted —(C 1-2 haloalkyl).

In some embodiments, R 43 is selected from the group consisting of F, methyl, ethyl, —CF 3 .

In some embodiments, R 44 is selected from the group consisting of halide, unsubstituted —(C 1-2 alkyl), and unsubstituted —(C 1-2 haloalkyl).

In some embodiments, R 44 is selected from the group consisting of F, methyl, ethyl, —CF 3 .

In some embodiments, R 36 is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, neopentyl, —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 C(CH 3 ) 2 F, —CH 2 CH 2 CF 3 , —(CH 2 CH 2 )O(C 1-3 alkyl),

In some embodiments, R 37 is selected from the group consisting of F, methyl, ethyl, —CF 3 , —OCF 3 , —OMe,

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

where in X is S or O and R 6 is selected from the group consisting of:

and q is 0 to 2.

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

where in X is S or O and R 6 is selected from the group consisting of -carbocyclyl optionally substituted with 1-2 R 37 and —(CH 2 )carbocyclyl optionally substituted with 1-2 R 37 .

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

where in X is S or O and R 6 is —CF(C 1-9 alkyl) 2 ; wherein the alkyl of —CF(C 1-9 alkyl) 2 is optionally substituted with one or more halides.

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

where in X is S or O and R 6 is selected from the group consisting of:

and q is 0 to 2.

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

and R is selected from the group consisting of:

and q is 0 to 2.

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

and R 6 is selected from the group consisting of:

and q is 0 to 2.

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

and R 6 is —CF(C 1-7 alkyl) 2 ; wherein the alkyl of —CF(C 1-7 alkyl) 2 is optionally substituted with one or more fluorines.

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

and R 6 is selected from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl each independently optionally substituted with 1-2 R 37 and —(CH 2 )cyclopropyl, —(CH 2 )cyclobutyl, —(CH 2 )cyclopentyl, and —(CH 2 )cyclohexyl, each independently optionally substituted with 1-2 R 37 .

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

and R 6 is selected from the group consisting of:

and q is 0 to 2.

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

and R 6 is selected from the group consisting of:

and q is 0 to 2.

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

and R 6 is selected from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with 1-2 R 37 and —(CH 2 )cyclopropyl, —(CH 2 )cyclobutyl, —(CH 2 )cyclopentyl, and —(CH 2 )cyclohexyl, each optionally substituted with 1-2 R 37 .

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

and R 6 is —CF(C 1-5 alkyl) 2 ; wherein the alkyl of —CF(C 1-5 alkyl) 2 is optionally substituted with 1-4 fluorines.

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

R 6 is selected from the group consisting of:

q is 1; and R 36 is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, neopentyl, —CHF 2 , —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 C(CH 3 ) 2 F, —CH 2 CH 2 CF 3 , —(CH 2 CH 2 )O(C 1-3 alkyl),

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

R 6 is selected from the group consisting of:

q is 0 to 2, and each R 36 is independently selected from the group consisting of F, methyl, and —CF 3 .

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

and R 6 is selected from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with 1-2 R 37 and —(CH 2 )cyclopropyl, —(CH 2 )cyclobutyl, —(CH 2 )cyclopentyl, and —(CH 2 )cyclohexyl, each optionally substituted with 1-2 R 37 , and each R 37 is independently selected from the group consisting of F, methyl, —CF 3 , —OCF 3 , and —OMe.

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

R 6 is selected from the group consisting of:

q is 1; and R 36 is selected from the group consisting of F, methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, neopentyl, —CHF 2 , —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 C(CH 3 ) 2 F, —CH 2 CH 2 CF 3 , —(CH 2 CH 2 )O(C 1-3 alkyl),

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

R 6 is selected from the group consisting of:

and, and R 36 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 C(CH 3 ) 2 F, —CH 2 CH 2 CF 3 , —(CH 2 CH 2 )OMe, —(CH 2 CH 2 )OiPr,

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

R 6 is selected from the group consisting of —(C 1-4 alkylene) p heterocyclyl optionally substituted with 1-10 R 36 and —(C 1-4 alkylene) p carbocyclyl optionally substituted with 1-12 R 37 .

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

R 6 is selected from the group consisting of —(CH 2 )heterocyclyl optionally substituted with 1-2 R 36 -heterocyclyl optionally substituted with 1-2 R 36 , and -carbocyclyl optionally substituted with 1-2 R 37 , and R 36 is selected from the group consisting of halide and unsubstituted —(C 1-9 alkyl), and R 37 is selected from the group consisting of halide and unsubstituted —(C 1-9 alkyl), —N(R 53 ) 2 , and -heterocyclyl optionally substituted with 1-2 R 43 .

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

R 6 is selected from the group consisting of —(CH 2 )heterocyclyl optionally substituted with 1 R 36 -heterocyclyl optionally substituted with 1 R 36 , and -carbocyclyl substituted with 1 R 37 , and R 36 is unsubstituted —(C 1-5 alkyl), and R 37 is selected from the group consisting of —N(C 1-3 alkyl) 2 , and an unsubstituted -heterocyclyl.

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

R 6 is selected from the group consisting of:

and R 36 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, —NMe 2 , and

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

R 6 is selected from the group consisting of:

and R 36 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 C(CH 3 ) 2 F, —CH 2 CH 2 CH 2 F 3 , —(CH 2 CH 2 )OMe, —(CH 2 CH 2 )OiPr,

In some embodiments, R 6 is selected from the group consisting of

and R 36 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 C(CH 3 ) 2 F, —CH 2 CH 2 CF 3 , —(CH 2 CH 2 )OMe, —(CH 2 CH 2 )OiPr,

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

R 6 is selected from the group consisting of:

q is 0 to 2, and each R 36 is independently selected from the group consisting of F, methyl, and —CF 3 .

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

and R 6 is selected from the group consisting of -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl each optionally substituted with 1-2 R 37 and —(CH 2 )cyclopropyl, —(CH 2 )cyclobutyl, —(CH 2 )cyclopentyl, and —(CH 2 )cyclohexyl, each optionally substituted with 1-2 R 37 , and each R 37 is independently selected from the group consisting of F, methyl, —CF 3 , —OCF 3 , and —OMe.

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

and R 6 is —CF(C 1-3 alkyl) 2 ; wherein the alkyl of —CF(C 1-3 alkyl) 2 is optionally substituted with 1-2 fluorines.

Illustrative compounds of Formula (I) are shown in Table 1.

Administration and Pharmaceutical Compositions

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

The compounds provided herein may also be useful in combination (administered together or sequentially) with other known agents.

Non-limiting examples of diseases which can be treated with a combination of a compound of Formula (I) and other another active agent are colorectal cancer, ovarian cancer, chronic inflammation, diabetic retinopathy, pulmonary fibrosis, and osteoarthritis. For example, a compound of Formula (I) can be combined with one or more chemotherapeutic compounds.

In some embodiments, colorectal 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 can be administered with the vitamin-like drug leucovorin (also called folinic acid); capecitabine (XELODA®), irinotecan (CAMPOSTAR®), oxaliplatin (ELOXATIN®). Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin). For rectal cancer, chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment).

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 (NAVELBINE®), Ifosfamide (IFEX®), Etoposide (VP-16), Altretamine (HEXALEN®), Capecitabine (XELODA®), Irinotecan (CPT-11, CAMPTOSAR®), Melphalan, Pemetrexed (ALIMTA®) and Albumin bound paclitaxel (nab-paclitaxel, ABRAXANE®). Examples of combinations of these drugs which could be further 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).

In some embodiments, a compound of Formula (I) can be used to treat cancer in combination with any of the following methods: (a) Hormone 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 anti-metabolites such as azathioprine and mercaptopurine; (e) Chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (i.e. 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 (e.g. obatoclax in clinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib, Olaparib in clinical trials), PI3K inhibitors (e.g. perifosine in a phase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818), MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g. 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.

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, Butcher's broom, Ginkgo, Grape seed extract, and Pycnogenol (Pine bark).

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 was approved for use in 2011 in Europe under the brand name Esbriet®), prednisone, azathioprine, N-acetylcysteine, interferon-γ 1b, bosentan (bosentan is currently being studied in patients with IPF, [ 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.

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

In some embodiments, a compound of Formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (a) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine; (f) in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices); (g) realigning bones (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with a chronic pain class.

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 with any of the following methods: (a) in combination with laser to destroy abnormal blood vessels (photocoagulation); and (b) in combination with increased vitamin intake of antioxidant vitamins and zinc.

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 methods: (a) with the Argus® II retinal implant; and (b) with stem cell and/or gene therapy.

Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration, including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic devices. In some embodiments, the administration method includes oral or parenteral administration.

Compounds provided herein intended for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.

The compounds can 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 exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. The contemplated compositions may contain 0.001%-100% of a compound provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound provided herein, 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 acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more compounds provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. a compound provided herein and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome, emulsion, complexes, coacervate or suspension. If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).

In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 50 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 20 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 0.50 mg/Kg to about 19 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 0.75 mg/Kg to about 18 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 1.0 mg/Kg to about 17 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 1.25 mg/Kg to about 16 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 1.50 mg/Kg to about 15 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 1.75 mg/Kg to about 14 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 2.0 mg/Kg to about 13 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 3.0 mg/Kg to about 12 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 4.0 mg/Kg to about 11 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is about 5.0 mg/Kg to about 10 mg/Kg in humans.

In some embodiments, the compositions are provided in unit dosage forms suitable for single administration.

In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration.

In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration.

Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection. The percentage of a compound provided herein contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the patient. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages.

In some embodiments, the composition will comprise about 0.1-10% of the active agent in solution.

In some embodiments, the composition will comprise about 0.1-5% of the active agent in solution.

In some embodiments, the composition will comprise about 0.1-4% of the active agent in solution.

In some embodiments, the composition will comprise about 0.15-3% of the active agent in solution.

In some embodiments, the composition will comprise about 0.2-2% of the active agent in solution.

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

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

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

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

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

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

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2 to about 300 mg/m 2 .

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2 to about 200 mg/m 2 .

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2 to about 100 mg/m 2 .

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 10 mg/m 2 to about 50 mg/m 2 .

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 50 mg/m 2 to about 200 mg/m 2 .

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 75 mg/m 2 to about 175 mg/m 2 .

In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 100 mg/m 2 to about 150 mg/m 2 .

It is to be noted that concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

In one embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique.

In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size may be desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth. For delivery to the lung, inhaled aerodynamic particle sizes of about less than 10 μm are useful (e.g., about 1 to about 10 microns). Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.

In some embodiments, compounds of Formula (I) disclosed herein intended for respiratory delivery (either systemic or local) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates, or as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose® or the AERx® systems). Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.

In some embodiments, the compositions of Formula (I) disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can be used.

Alternatively, formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No. 4,164,559).

If desired, formulations of the disclosure can be incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea.

Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose. In other embodiments the acidic or basic solid compound of Formula (I) can be delivered from the reservoir of an external or internal implanted pumping system.

Formulations of the disclosure also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).

Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. In one embodiment, the formulations described herein are administered directly onto the round window membrane via transtympanic injection. In another embodiment, the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In additional embodiments, the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.

In some embodiments, the compounds of Formula (I) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly 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.

Suppositories for rectal administration of the drug (either as a solution, colloid, suspension or a complex) can be prepared by mixing a compound provided herein with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the compound. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the compound provided herein, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the compound is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the 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 a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the compound.

On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multitude 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 capable of absorbing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound.

Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with a compound provided herein so that the compound is located at the outer surface of the individual particles. In this type of system, the water-soluble low molecular weight excipient may be useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the compound and, for example, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or more compounds or compositions as described herein. In certain embodiments, a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided herein, and directions for use of the kit (e.g., instructions for treating a patient). In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with cancer. In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of 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/osteoporotic (wrist, spine, shoulder and hip) fractures, articular cartilage (chondral) defects, degenerative disc disease (or intervertebral disc degeneration), polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

Methods of Treatment

The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more components of the Wnt pathway, which may include one or more Wnt proteins, and thus can be used to treat a variety of disorders and diseases in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Non-limiting examples of diseases which can 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 as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), motor neuron disease, multiple sclerosis or autism, lung disease, bone/osteoporotic (wrist, spine, shoulder and hip) fractures, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

With respect to cancer, the Wnt pathway is known to be constitutively activated in a variety of 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 may be used to treat these cancers in which the Wnt pathway is constitutively activated. In certain embodiments, the cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.

Other cancers can also be treated with the compounds and compositions described herein.

More particularly, cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following:

1) Breast cancers, including, for example ER breast cancer, ER-breast cancer, her2 − breast cancer, her2 + breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that 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 (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; and miscellaneous malignant neoplasms. Further examples of breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER − ), progesterone receptor negative, and her2 negative (her2 − ). In some embodiments, the breast cancer may have a high risk Oncotype score.

2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma.

3) Lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

4) Gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.

5) Genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma.

6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.

7) Bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.

8) Nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma.

9) Gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma.

10) Hematologic cancers, including, for example, cancers of the blood, e.g., 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.

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

12) Adrenal gland cancers, including, for example, neuroblastoma.

More particularly, tumors of the central nervous system that may be treated by the compounds, compositions and methods described herein include:

1) Astrocytic tumors, e.g., diffuse astrocytoma (fibrillary, protoplasmic, gemistocytic, mixed), anaplastic (malignant) astrocytoma, glioblastoma multiforme (giant cell glioblastoma and gliosarcoma), pilocytic astrocytoma (pilomyxoid astrocytoma), pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and gliomatosis cerebri.

2) Oligodendroglial tumors, e.g., oligodendroglioma and anaplastic oligodendroglioma.

3) Oligoastrocytic tumors, e.g., oligoastrocytoma and anaplastic oligoastrocytoma.

4) Ependymal tumors, e.g., subependymoma, myxopapillary ependymoma, ependymoma, (cellular, papillary, clear cell, tanycytic), and anaplastic (malignant) ependymoma.

5) Choroid plexus tumors, e.g., choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma.

6) Neuronal and mixed neuronal-glial tumors, e.g., gangliocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos), desmoplastic infantile astrocytoma/ganglioglioma, central neurocytoma, anaplastic ganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma, Papillary glioneuronal tumor, Rosette-forming glioneuronal tumor of the fourth ventricle, and paraganglioma of the filum terminale.

7) Pineal tumors, e.g., pineocytoma, pineoblastoma, papillary tumors of the pineal region, and pineal parenchymal tumor of intermediate differentiation.

8) Embryonal tumors, e.g., medulloblastoma (medulloblastoma with extensive nodularity, anaplastic medulloblastoma, desmoplastic, large cell, melanotic, medullomyoblastoma), medulloepithelioma, supratentorial primitive neuroectodermal tumors, and primitive neuroectodermal tumors (PNETs) such as neuroblastoma, ganglioneuroblastoma, ependymoblastoma, and atypical teratoid/rhabdoid tumor.

9) Neuroblastic tumors, e.g., olfactory (esthesioneuroblastoma), olfactory neuroepithelioma, and neuroblastomas of the adrenal gland and sympathetic nervous system.

10) Glial tumors, e.g., astroblastoma, chordoid glioma of the third ventricle, and angiocentric glioma.

11) Tumors of cranial and paraspinal nerves, e.g., schwannoma, neurofibroma Perineurioma, and malignant peripheral nerve sheath tumor.

12) Tumors of the meninges such as tumors of meningothelial cells, e.g., meningioma (atypical meningioma and anaplastic meningioma); mesenchymal tumors, e.g., lipoma, angiolipoma, hibernoma, liposarcoma, solitary fibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid hemangioendothelioma, haemangiopericytoma, anaplastic haemangiopericytoma, angiosarcoma, Kaposi Sarcoma, and Ewing Sarcoma; primary melanocytic lesions, e.g., diffuse melanocytosis, melanocytoma, malignant melanoma, meningeal melanomatosis; and hemangioblastomas.

13) Tumors of the hematopoietic system, e.g., malignant Lymphomas, plasmocytoma, and granulocytic sarcoma.

14) Germ cell tumors, e.g., germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumors.

15) Tumors of the sellar region, e.g., craniopharyngioma, granular cell tumor, pituicytoma, and spindle cell oncocytoma of the adenohypophysis.

Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term “tumor cell,” as provided herein, includes a cell afflicted by any one of the above identified disorders.

A method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some embodiments, a compound or composition can be administered before, during, or after another anticancer agent or treatment.

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

In addition, and including treatment of cancer, the compounds and compositions described herein can function as cell-cycle control agents for treating proliferative disorders in a patient. Disorders associated with excessive proliferation include, for example, cancers, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth muscle disorders. Furthermore, such compounds may be used to prevent de-differentiation of post-mitotic tissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellular proliferation include, but are not limited to, the following:

a variety of cancers, including, but not limited to, carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kaposi's sarcoma. a disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Fibrotic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; fatty liver disease (FLD); adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis, such as fibrosis following stroke; fibrosis associated with neuro-degenerative 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 cancers (including but not limited to those types mentioned herein), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development 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), neuro-degenerative disorders (including but not limited to Alzheimer's disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, 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 tendinitis and tendinosis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain. genetic diseases due to mutations in Wnt signaling components, such as polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

The compounds and compositions provided herein have been found to possess immunomodulatory activities and are expected to control the innate and adaptive immune system (e.g. macrophages, microglia, dendritic cells, B and T cells) and suppress pro-inflammatory cytokine release (e.g. TNF, IL-6, IL-1, IFNγ) which is well known to be involved in chronic inflammation in a wide variety of disease areas. Therefore compounds and compositions provided herein can used to treat chronic inflammation associated with disorders and diseases including but not limited to eye disorders, joint pain, arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast, lung, pancreas, and others), gastrointestinal disorders (ulcerative colitis and inflammatory bowel diseases), pulmonary disorders (chronic obstructive pulmonary disorder and asthma), allergies, skin disorders (atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heart disease, myocarditis, stroke, lupus, and neurological disorders such as multiple sclerosis, Parkinson's and dementia including Alzheimer's disease.

The compounds and compositions provided herein can be used as inhibitors and/or modulators of the enzyme DYRK1A, and thus can be used to treat a variety of disorders and diseases associated with tau protein, amyloid, alpha-synuclein, TDP-43 or FUS pathology including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), down syndrome, frontotemporal dementia (FTD) including FTD with Parkinsonism-17 (FTDP-17), behavioural variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis, also called FTD-ALS), corticobasal degeneration (CBD) (also called corticobasal ganglionic degeneration), progressive supranuclear palsy, primary progressive aphasia (PPA), globular glial tauopathy (GGT), myotonic dystrophy type 1 (DM1) (also called Steinert disease), myotonic dystrophy type 2 (DM2) (also called proximal myotonic myopathy), Guam complex, argyrophilic grain disease, dementia pugilistica, post-encephalitic parkinsonism, Lewy body dementia, Parkinson's disease, Pick's disease, and additional diseases with pronounced neurodegeneration such as autism, dementia, epilepsy, Huntington's disease, multiple sclerosis; diseases and disorders associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumor, and stroke.

Non-limiting examples of neurological disorders (e.g., neurological conditions and neurological diseases) which can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing 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, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrile seizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barré syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, herpes zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Meniere's disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, Miller Fisher syndrome, misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neuron disease, motor skills disorder, Moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenital, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital Neuralgia, occult Spinal Dysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, photic sneeze reflex, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson's disease, and Zellweger syndrome.

The compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.

In some embodiments, the disclosure provides a method for treating a disease or disorder associated with aberrant cellular proliferation by administering to a patient in need of such treatment an effective amount of one or more of the compounds of Formula (I), in combination (simultaneously or sequentially) with at least one other agent.

In some embodiments, the disclosure provides a method of treating or ameliorating in a patient a disorder or disease selected from the group consisting of: cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), degenerative disc disease, bone/osteoporotic fractures, bone or cartilage disease, and osteoarthritis, the method comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

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.

In some embodiments, the method of treats a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder or disease is the pain and inflammation associated with cancer.

In some embodiments, the disorder or disease is the pain and inflammation associated with a joint.

In some embodiments, the disorder or disease is the pain and inflammation associated with the knee.

In some embodiments, the disorder or disease is the pain and inflammation associated with the hip.

In some embodiments, the disorder or disease is the pain and inflammation associated with the shoulder.

In some embodiments, the disorder or disease is the pain and inflammation associated with arthritis.

In some embodiments, the disorder or disease is the pain and inflammation associated with gastrointestinal disorders.

In some embodiments, the disorder or disease is the pain and inflammation associated with pulmonary disorders.

In some embodiments, the disorder or disease is the pain and inflammation associated with allergies.

In some embodiments, the disorder or disease is the pain and inflammation associated with skin disorders.

In some embodiments, the disorder or disease is the pain and inflammation associated with diabetes.

In some embodiments, the disorder or disease is the pain and inflammation associated with pancreatitis.

In some embodiments, the disorder or disease is the pain and inflammation associated with tendonitis.

In some embodiments, the disorder or disease is the pain and inflammation associated with heart disease.

In some embodiments, the disorder or disease is the pain and inflammation associated with lupus.

In some embodiments, the disorder or disease is the pain and inflammation associated with a neurological disorder.

In some embodiments, the disorder or disease is the pain and inflammation associated with multiple sclerosis.

In some embodiments, the disorder or disease is the pain and inflammation associated with Parkinson's.

In some embodiments, the disorder or disease is cancer.

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

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

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

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

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

In some embodiments, the disorder or disease is diabetes.

In some embodiments, the disorder or disease is degenerative disc disease.

In some embodiments, the disorder or disease is osteoarthritis.

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

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

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

In some embodiments, the disorder or disease is degenerative disc disease.

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

In some embodiments, the disorder or disease is scleroderma.

In some embodiments, the disorder or disease is a mycotic or viral infection.

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

In some embodiments, the disorder or disease is a neurological disorder.

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

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is lung disease.

In some embodiments, the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

In some embodiments, the patient is a human.

In some embodiments, the cancer is chosen 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 lymphoma, lymphoma, sarcoma and ovarian cancer.

In some embodiments, the cancer is chosen from: lung cancer—non-small cell, lung cancer—small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer—basal and squamous cell, skin cancer—melanoma, small intestine cancer, stomach (gastric) cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer and adrenal cortical cancer.

In some embodiments, the cancer is hepatocellular carcinoma.

In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is pancreatic cancer.

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

In some embodiments, the cancer is chronic myelomonocytic leukemia.

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

In some embodiments, the cancer is acute myeloid leukemia.

In some embodiments, the cancer is acute lymphocytic leukemia.

In some embodiments, the cancer is Hodgkin lymphoma.

In some embodiments, the cancer is lymphoma.

In some embodiments, the cancer is sarcoma.

In some embodiments, the cancer is ovarian cancer.

In some embodiments, the cancer is lung cancer—non-small cell.

In some embodiments, the cancer is lung cancer—small cell.

In some embodiments, the cancer is multiple myeloma.

In some embodiments, the cancer is nasopharyngeal cancer.

In some embodiments, the cancer is neuroblastoma.

In some embodiments, the cancer is osteosarcoma.

In some embodiments, the cancer is penile cancer.

In some embodiments, the cancer is pituitary tumors.

In some embodiments, the cancer is prostate cancer.

In some embodiments, the cancer is retinoblastoma.

In some embodiments, the cancer is rhabdomyosarcoma.

In some embodiments, the cancer is salivary gland cancer.

In some embodiments, the cancer is skin cancer—basal and squamous cell.

In some embodiments, the cancer is skin cancer—melanoma.

In some embodiments, the cancer is small intestine cancer.

In some embodiments, the cancer is stomach (gastric) cancers.

In some embodiments, the cancer is testicular cancer.

In some embodiments, the cancer is thymus cancer.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is uterine sarcoma.

In some embodiments, the cancer is vaginal cancer.

In some embodiments, the cancer is vulvar cancer.

In some embodiments, the cancer is Wilms tumor.

In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.

In some embodiments, the cancer is kidney cancer.

In some embodiments, the cancer is Kaposi sarcoma.

In some embodiments, the cancer is gestational trophoblastic disease.

In some embodiments, the cancer is gastrointestinal stromal tumor.

In some embodiments, the cancer is gastrointestinal carcinoid tumor.

In some embodiments, the cancer is gallbladder cancer.

In some embodiments, the cancer is eye cancer (melanoma and lymphoma).

In some embodiments, the cancer is Ewing tumor.

In some embodiments, the cancer is esophagus cancer.

In some embodiments, the cancer is endometrial cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is cervical cancer.

In some embodiments, the cancer is brain or spinal cord tumor.

In some embodiments, the cancer is bone metastasis.

In some embodiments, the cancer is bone cancer.

In some embodiments, the cancer is bladder cancer.

In some embodiments, the cancer is bile duct cancer.

In some embodiments, the cancer is anal cancer.

In some embodiments, the cancer is adrenal cortical cancer.

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 dementias, dementia with Lewy bodies, 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-Tooth disease.

In some embodiments, the disorder or disease is a neurological disease or disorder associated with tau protein, amyloid,alpha-synuclein pathology, Tar DNA-binding Protein of 43 KDa (TDP-43), Prion protein PrP or fused in sarcoma (FUS).

In some embodiments, the disorder or disease is selected from the group consisting of: Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington's Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.

In some embodiments, a compound of Formula (I) inhibits DYRK1A.

In some embodiments, a compound of Formula (I) inhibits GSK3.

In some embodiments, a compound of Formula (I) inhibits GSK3β.

In some embodiments, a compound of Formula (I) inhibits DYRK1A and GSK313.

In some embodiments, the compound of Formula (I) inhibits one or more proteins in the Wnt pathway.

In some embodiments, the compound of Formula (I) inhibits signaling induced by one or more Wnt proteins.

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

In some embodiments, the compound of Formula (I) inhibits a kinase activity.

In some embodiments, the method treats a disease or disorder mediated by the Wnt pathway in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) inhibits one or more Wnt proteins.

In some embodiments, the method treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.

In some embodiments, the method inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces angiogenesis in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprises 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 other agents.

Moreover, the compounds and compositions, for example, as inhibitors of the cyclin-dependent kinases (CDKs), can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like.

Compounds and compositions described herein can inhibit the kinase activity of, for example, CDK/cyclin complexes, such as those active in the G 0 or G 1 stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes.

Evaluation of Biological Activity

The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, see, e.g., WO 2001/053268 and WO 2005/009997. For example, the activity of a compound may be tested using one or more of the test methods outlined below.

In one example, tumor cells may be screened for Wnt independent growth. In such a method, tumor cells of interest are contacted with a compound (i.e. inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored. In some embodiments, tumor cells may be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway. Candidate cancers include, without limitation, those listed above.

In another example, one may utilize in vitro assays for Wnt biological activity, e.g. stabilization of β-catenin and promoting growth of stem cells. Assays for biological activity of Wnt include stabilization of β-catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition. An exemplary assay for Wnt biological activity contacts a candidate inhibitor with cells containing constitutively active Wnt/β-catenin signaling. The cells are cultured for a period of time sufficient to stabilize β-catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for β-catenin.

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

In another example, in vitro assays for DYRK1A biological activity may be used, e.g. regulation of microtubule-associated protein tau (MAPT/Tau) phosphorylation in neuronal cell line such as the human SH-SY5Y neuroblastoma cell line. Assays for DYRK1A-regulated level of phosphorylation can include monitoring levels of basal pSer396 Tau, which can be measured, for example, by serial dilutions of a candidate inhibitor composition using a ten micromolar top concentration and detected by ELISA or Western Blotting. An exemplary assay for DYRK-1A-regulated phosphorylation uses the SH-SY5Y cells cultured in a 96 well plate format for a period of time sufficient to stabilize microtubules and Tau phosphorylation, usually at least 2 days, then treated with a ⅓ serial dilution of compounds overnight and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with an antibody specific for pSer396 Tau. The chemiluminescence signal for HRP-linked antibodies used in western blotting is detected using a Carestream Image Station and blot densitometry for pSer396 and beta-actin are analyzed using ImageJ (NIH).

In a further example, the activity of a candidate compound can be measured by ELISA by adding the lysate mentioned above onto total Tau-coated plates and detected with a specific pSer396 antibody. Colorimetric detection of ELISA signal is performed by Cytation3 plate reader (Biotek).

To further illustrate this disclosure, the following examples are included. The examples should not, of course, be construed as specifically limiting the disclosure. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the disclosure as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the disclosure without exhaustive examples.

Compound Preparation

The starting materials used in preparing the compounds of the disclosure are known, made by known methods, or are commercially available. It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts 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, 2 nd Ed., John Wiley & Sons (1999) (incorporated herein by reference in its entirety) and the like.

The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in P. Wuts Greene's Protective Groups in Organic Synthesis, 5th Ed., John Wiley & Sons (2014), incorporated herein by reference in its entirety.

Trademarks used herein are examples only and reflect illustrative materials used at the time of the disclosure. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the disclosure.

( 1 H) nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHz for 1 H or Avance™ DRX500, 500 MHz for 1 H) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for 1 H). Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets of doublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; dq, doublet of quartets; m, multiplet.

The following abbreviations have the indicated meanings:

brine=saturated aqueous sodium chloride CDCl 3 =deuterated chloroform DCE=dichloroethane DCM=dichloromethane DIPEA=N,N-diisopropylethylamine DMAP=4-dimethylaminopyridine DMF=N,N-dimethylformamide DMSO-d 6 =deuterated dimethylsulfoxide ESIMS=electron spray mass spectrometry EtOAc=ethyl acetate HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HCl=hydrochloric acid HOAc=acetic acid ISCO=Teledyne ISCO, Inc brand CombiFlash® Rf200 KOAc=potassium acetate LAH=Lithium aluminium hydride LC/MS=Liquid chromatography-mass spectrometry MeCN=acetonitrile MeOH=methanol MgSO 4 =magnesium sulfate MsCl=mesyl chloride or methanesulfonyl chloride MTBE=methyl tert-butyl ether MW=microwave irradiation NaBH 3 CN=sodium cyanoborohydride NaHCO 3 =sodium bicarbonate Na(OAc) 3 BH=Sodium triacetoxyborohydride NMR=nuclear magnetic resonance ON=overnight Pd(dppf)Cl 2 =1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride Pd(PPh 3 ) 4 =tetrakis(triphenylphosphine)palladium(0) r.t.=room temperature SPhos Pd G3=[(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate methanesulfonate SPhos Pd G4=Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) TBAF=Tetra-n-butylammonium fluoride, TEA=triethylamine TFA=trifluoroacetic acid THF=tetrahydrofuran TLC=thin layer chromatography

The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds of the disclosure will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application. Unless otherwise indicated, all variables are as defined above.

General Procedures

Compounds of Formula I of the present disclosure can be prepared as depicted in Scheme 1.

Scheme 1 describes a method for preparation of isoquinoline-3-carboxamide derivatives (IX) by first coupling the amine with a variety of acids (III) to produce amide IV. The bromo derivative IV is then reacted with bis(pinacolato)diboron to give the pinacol ester (V). Suzuki coupling with a variety of 5-membered heteroaryl bromides (VIII) yields the desired R 3 substituted isoquinoline IX. Alternatively, the bromo derivative IV is Suzuki coupled with a variety of 5-membered heteroaryl pinacol esters (VI) or coupled to a variety of 5-membered heteroaryl stannanes (VII) to produce the final R 3 substituted isoquinoline IX.

In some embodiments, compounds of Formula I of the present disclosure can be prepared as depicted in Scheme 2.

Scheme 2 describes a method for preparation of isoquinoline-3-carboxamide intermediate (IVa) by first coupling the amine 4-nitrophenyl carbonochloridate followed by coupling with a variety of R 6 NH heterocyclyls. Intermediate IVa could then be used in place of IV in Scheme 1 or 3.

In other embodiments, compounds of Formula I of the present disclosure can be prepared as depicted in Scheme 3.

Scheme 3 describes a method for preparation of isoquinoline-3-carboxamide derivatives (IXa) starting with bromo intermediate IV or IVa and couple with the nitrogen of a variety of R 3 NH heteroaryls to produce the final R 3 substituted isoquinoline IXa.

Illustrative Compound Examples

Preparation of intermediate 6-bromoisoquinolin-1-d-3-amine (XI) is depicted below in Scheme 4.

To a mixture of 1,6-dibromoisoquinolin-3-amine (X) (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 h. 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 were dried under high vacuo to obtain 6-bromo-1-deuterio-isoquinolin-3-amine (XI) (115 mg, 0.513 mmol, 31.0% yield) as a pale 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).

Preparation of intermediate 6-bromo-4-chloroisoquinolin-3-amine (XIII) is depicted below in Scheme 5.

To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (1.0 g, 4.48 mmol) in DMF (15 mL) at 0° C. was added 1-chloropyrrolidine-2,5-dione (598.6 mg, 4.48 mmol) portionwise. The mixture was stirred at 0° C. for 6 h. 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 obtain 6-bromo-4-chloro-isoquinolin-3-amine (XIII) (922 mg, 3.58 mmol, 79.9% yield) as a beige solid which was used for 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).

Preparation of intermediate 6-bromo-4-methylisoquinolin-3-amine (XV) is depicted below in Scheme 6.

To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (2 .g, 8.97 mmol) in DMF (25.1 mL) at 0° C. was added 1-iodopyrrolidine-2,5-dione (2.02 g, 8.97 mmol) portionwise, The mixture was stirred at 0° C. for 1 hr. LC-MS of the mixture showed completion of the reaction and the desired product. The solvent was removed under vacuum, the residue was purified by C18 Silica gel (240 g) [0→100% H 2 O/MeCN (0.1% Formic acid)] to produce 6-bromo-4-iodo-isoquinolin-3-amine (XIV) (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, br s), 7.40 (1H, dd, J=8.64, 1.78 Hz), 7.76-7.81 (1H, m), 7.82 (1H, d, J=8.51 Hz), 8.81 (1H, s); ESIMS found for C 9 H 6 BrlN 2 m/z 348.9 ( 79 BrM+H).

A stirred solution of 6-bromo-4-iodo-isoquinolin-3-amine (XIV) (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 by C18 silica gel (240 g) [0→20% H 2 O/MeCN (0.1% Formic acid)] to produce 6-bromo-4-methyl-isoquinolin-3-amine (XV) (74 mg, 0.312 mmol, 10.9% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.23 (3H, br s), 5.91 (2H, br s), 7.27 (1H, br d, J=2.20 Hz), 7.71-7.82 (1H, m), 7.92 (1H, br s), 8.72 (1H, br s); ESIMS found for C 10 H 9 BrN 2 m/z 239.0 ( 81 BrM+H).

Preparation of intermediate 6-bromo-7-fluoroisoquinolin-3-amine (XVIII) is depicted below in Scheme 7.

To a vial was added 2,2-diethoxyacetonitrile (XVI) (1.0 g, 7.74 mmol) dissolved MeOH (7.74 mL) followed by addition of MeONa/MeOH (0.18 mL, 0.77 mmol) dropwise. The reaction was stirred at room temperature for 20 h. HOAc (44.3 μL, 0.77 mmol) was added until pH=7-8 (using pH strips). (4-Bromo-3-fluoro-phenyl)methanamine hydrochloride (XVII) (1.86 g, 7.74 mmol) was added and stirred at 40° C. for 4 h. The solvent was removed under vacuum. Sulfuric acid (12.6 mL, 232.3 mmol) was added and stirred at 40° C. for 16 h. NH 4 OH (30.8 mL, 240.0 mmol) was added dropwise at 0° C. The solvent was removed under vacuum and the residue was purified by C18 silica gel (240 g) [0→50% H 2 O/MeCN (0.1% Formic acid)] to produce 6-bromo-7-fluoro-isoquinolin-3-amine (XVIII) (1.33 g, 5.50 mmol, 71.1% yield) as an off-white solid. 1 H 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).

Preparation of intermediates 6-bromo-7-chloroisoquinolin-3-amine (XX) and 6-bromo-5-chloroisoquinolin-3-amine (XXI) is depicted below in Scheme 8.

To a stirred solution of 2,2-diethoxyacetonitrile (XVI) (0.59 g, 4.57 mmol) in a vial containing MeOH (4.57 mL) was added MeONa (0.1 mL, 0.46 mmol) dropwise. The reaction was stirred at 35° C. for 20 h. HOAc was added (26.1 μL, 0.46 mmol) (checked that the pH is 7-8 using pH strips) followed by (4-bromo-3-chloro-phenyl)methanamine (XIX) (1.01 g, 4.57 mmol). The mixture was stirred at 35° C. for 40 h. The solvent was removed under vacuum. Sulfuric Acid (7.43 mL, 137.0 mmol) was then added and stirred at 35° C. for 16 h. NH 4 OH (60.6 mL, 141.6 mmol) was added at 0° C. The reaction was filtered through Celite and purified by C18 silica gel (240 g) [0→30% H 2 O/MeCN (0.1% Formic acid)] to produce a 1:1 mixture (by nmr) of 6-bromo-7-chloro-isoquinolin-3-amine (XX) and 6-bromo-5-chloroisoquinolin-3-amine (XXI) (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, s); ESIMS found for C 9 H 6 BrClN 2 m/z 256.9 ( 79 BrM+H).

Preparation of intermediates 6-bromo-7-methylisoquinolin-3-amine (XXIII) and 6-bromo-5-methylisoquinolin-3-amine (XXIV) is depicted below in Scheme 9.

To a stirred solution of 2,2-diethoxyacetonitrile (XVI) (0.33 g, 2.52 mmol) in a vial containing MeOH (2.52 mL) was added MeONa (0.23 mL, 0.25 mmol) dropwise. The reaction was stirred at 22° C. for 20 h. HOAc was added (14.4 μL, 0.25 mmol) (checked that the pH is 7-8 using pH strips) followed by (4-bromo-3-methyl-phenyl)methanamine (XXII) (0.5 g, 2.52 mmol). The mixture was stirred at 40° C. for 40 h. The solvent was removed under vacuum. Sulfuric Acid (4.09 mL, 75.49 mmol) was then added and stirred at 40° C. for 16 h. NH 4 OH (33.4 mL, 78 mmol) was added at 0° C. The reaction was filtered through Celite and purified by C18 silica gel (240 g) [0→30% H 2 O/MeCN (0.1% Formic acid)] to produce a 1:1 mixture (by nmr) of 6-bromo-7-methylisoquinolin-3-amine (XXIII) and 6-bromo-5-methylisoquinolin-3-amine (XXIV) (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).

Preparation of intermediate 1-(bromomethyl)-1-(trifluoromethyl) cyclopropane (XXVII) is depicted below in Scheme 10.

1-(Trifluoromethyl)cyclopropane-1-carboxylic acid (XXV) (3.7334 g, 24.23 mmol) was dissolved in THF (162 mL) and cooled to 0° C. LAH (1.1614 g, 29.07 mmol) was then added and the reaction heated to 40° C. overnight. The reaction was cooled to 0° C. Water (2 mL) was added to quench the reaction followed by 2 N NaOH (0.3 mL). The reaction was stirred forming a precipitate which was filtered off and washed with ether. The aqueous phase was removed and the organic phase was washed with brine, dried, and carefully concentrated to give (1-(trifluoromethyl)cyclopropyl)methanol (XXVI) (1.5376 g, 10.98 mmol, 45.3% yield) as a clear, volatile liquid.

To a solution of (1-(Trifluoromethyl)cyclopropyl)methanol (XXVI) (1.6 g, 11.42 mmol) in DCM (23 mL) was added Et 3 N (1.9 mL, 13.7 mmol). The reaction was cooled to 0° C. and MsCl was added dropwise. The reaction was stirred at 0° C. for 1 h. The reaction was poured into water, and extracted with DCM. The organic phase was separated, washed with brine, dried, and concentrated. The crude mesylate was then dissolved in acetone (22 mL). LiBr (4.96 g, 57.1 mmol) was added, and the reaction stirred at room temperature overnight. The acetone was carefully removed, and the residue was partitioned between water and ether. The aqueous phase was separated and reextracted with ether. The organic phases were combined, washed with brine, dried, and carefully concentrated to give 1-(bromomethyl)-1-(trifluoromethyl)cyclopropane (XXVII) (1.2867 g, 6.34 mmol, 55.5% yield) as a gold liquid with residual amounts of acetone. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.04 (2H, tquin, J=5.17, 5.17, 1.74, 1.74, 1.74, 1.74 Hz), 1.23-1.27 (2H, m), 3.77 (2H, s).

Preparation of N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide (271) is depicted below in Scheme 11.

To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (XXVIII) (1.542 g, 6.72 mmol) and HATU (2.56 g, 6.72 mmol) was added DIPEA (2.349 mL, 13.45 mmol). After 10 min, 6-bromoisoquinolin-3-amine (XII) (1 g, 4.48 mmol) was added followed by the addition of DMAP (0.110 g, 0.897 mmol) and the mixture was heated to 70° C. overnight. The LC/MS of mixture showed complete conversion of the amine to the product. The solvents were concentrated in vacuo, the residue taken into EtOAc, washed with water, sat. aq. NaHCO 3 and brine solution. The organic layer was dried over anhydrous Na 2 SO 4 , solvents removed in vacuo and the residue was dried under high vacuo to obtain crude tert-butyl 4-((6-bromoisoquinolin-3-yl)carbamoyl)piperidine-1-carboxylate (XXIX) as a brown gummy solid (2.29 g, 5.27 mmol, 11.8% yield). Used for next step without purification.

To a stirred solution of tert-butyl 4-((6-bromoisoquinolin-3-yl)carbamoyl)piperidine-1-carboxylate (XXIX) (1.0 g, 2.302 mmol) in DCM (4.0 mL) was added TFA (4.0 mL, 51.9 mmol) dropwise and the mixture was stirred at room temperature for 2 h. The solvent were evaporated in vacuo, the residue was neutralized with 7 N NH 3 /MeOH, concentrated and dried under high vacuo to obtain N-(6-bromoisoquinolin-3-yl)piperidine-4-carboxamide as a dark brown solid (0.769 g, 2.302 mmol, 100% yield). Used for next step without purification. ESIMS found for C 15 H 16 BrN 3 O m/z 336.1 ( 81 BrM+H).

To a stirred suspension of N-(6-bromoisoquinolin-3-yl)piperidine-4-carboxamide (0.769 g, 2.30 mmol) and potassium carbonate (1.271 g, 9.20 mmol) in MeCN (10 ml) was added 1,1,1-trifluoro-3-iodopropane (0.270 mL, 2.300 mmol). The mixture was then heated to 90° C. overnight. Another equivalents of 1,1,1-trifluoro-3-iodopropane (0.270 mL, 2.300 mmol) was added and heating continued at 90° C. over a 2 nd night. The reaction mixture was absorbed on silica and was purified by ISCO using EtOAc/hexanes (0→100%) and then with CHCl 3 /MeOH (0→100% to recover unreacted starting material). The pure fractions were combined, concentrated, the residue suspended in diethylether, sonicated and the solid were collected by filtration and dried under high vacuo to obtain N-(6-bromoisoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide (XXX) as an off-white solid (0.31 g, 0.720 mmol, 31.3% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.57-1.71 (m, 2H), 1.79 (br d, J=11.80 Hz, 2H), 1.89-2.01 (m, 2H), 2.41-2.60 (m, 5H), 2.88-2.98 (m, 2H), 7.63 (dd, J=8.78, 1.92 Hz, 1H), 8.00 (d, J=8.78 Hz, 1H), 8.18 (d, J=1.37 Hz, 1H), 8.45 (s, 1H), 9.14 (s, 1H), 10.61 (s, 1H); ESIMS found for C 18 H 19 BrF 3 N 3 O m/z 432.3 ( 81 BrM+H).

To a solution of N-(6-bromoisoquinolin-3-yl)-1-(3,3,3-trifluoropropyl) piperidine-4-carboxamide (XXX) (0.170 g, 0.395 mmol), bis(pinacolato)diboron (0.150 g, 0.593 mmol), potassium acetate (0.116 g, 1.185 mmol) and Pd(dppf)Cl 2 —CH 2 Cl 2 adduct (0.032 g, 0.040 mmol) was taken in dioxane (2.5 mL). N 2 gas was bubbled into the mixture for 10 min and then the mixture was heated to 95° C. for 5 h to produce N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl) piperidine-4-carboxamide (XXXI). ESIMS found for C 24 H 31 BF 3 N 3 O 3 m/z 478.1 (M+1). Use for next step without work up or further purification.

To the above solution was added 4-bromo-1-methyl-1H-1,2,3-triazole (XXXII) (0.064 g, 0.395 mmol), Pd(dppf)Cl 2 —CH 2 Cl 2 adduct (0.032 g, 0.040 mmol) and 2 M aqueous solution of potassium carbonate (0.395 mL, 0.790 mmol). The reaction mixture was heated overnight at 95° C. The reaction mixture was absorbed on silica and purified by ISCO using CHCl 3 /7N NH 3 in MeOH (0→5%) followed by preparative TLC to obtain N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl) piperidine-4-carboxamide (271) as a beige solid (0.011 g, 0.025 mmol, 6.44% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.60-1.73 (m, 2H), 1.76-1.84 (m, 2H), 1.92-2.01 (m, 2H), 2.41-2.60 (m, 5H), 2.94 (br d, J=11.25 Hz, 2 H), 4.14 (s, 3H), 8.01 (dd, J=8.51, 1.37 Hz, 1H), 8.11 (d, J=8.51 Hz, 1H), 8.28 (s, 1H), 8.50 (s, 1H), 8.73 (s, 1H), 9.11 (s, 1H), 10.55 (s, 1H); ESIMS found for C 21 H 23 F 3 N 6 O m/z 433.2 (M+1).

Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl) piperidine-4-carboxamide (86) is depicted below in Scheme 12.

To a solution of N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide (72) (0.095 g, 0.283 mmol) in MeOH (1.5 mL) was added oxetan-3-one (0.027 mL, 0.425 mmol) followed by the addition of HOAc (0.081 mL, 1.416 mmol). The mixture was stirred for 20 min, then, sodium cyanoborohydride (0.027 g, 0.425 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, the residue partitioned between EtOAc/sat. aq. NaHCO 3 , the organic layer separated, washed with water and brine. The organic layer was dried over anhydrous Na 2 SO 4 , solvents removed in vacuo and the crude product was purified by ISCO (0→5% CHCl 3 /7 N NH 3 in MeOH). The pure fractions were combined, concentrated, the residue suspended in DCM, sonicated and the solids were collected by filtration to obtain N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide (86) off-white solid (62.0 mg, 0.158 mmol, 56.0% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.62-1.73 (m, 2H), 1.74-1.86 (m, 4H), 2.52-2.60 (m, 1H), 2.71-2.80 (m, 2H), 3.38 (quin, J=6.45 Hz, 1H), 3.90 (s, 3H), 4.43 (t, J=6.17 Hz, 2H), 4.53 (t, J=6.59 Hz, 2H), 7.74 (dd, J=8.51, 1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.45 (s, 1H), 9.02 (s, 1H), 10.48 (s, 1H); ESIMS found for C 22 H 25 N 5 O 2 m/z 392.2 (M+1).

Preparation of N-(6-(5-(Dimethylamino)-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide (1075) and N-(6-(5-(dimethylamino)-1,3,4-oxadiazol-2-yl) isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide (1076) is depicted below in Scheme 13.

To a mixture of tert-butyl 4-[(6-bromo-3-isoquinolyl)carbamoyl]piperidine-1-carboxylate (XXXIII) (1 g, 2.3 mmol), NaOAc (566.6 mg, 6.91 mmol), molybednumhexacarbonyl (953 mg, 3.45 mmol) and Pd(dppf)Cl 2 (376 mg, 0.46 mmol) in MeOH (20 mL) was heated to 75° C. overnight. The reaction mixture was absorbed on silica gel and was purified by column chromatography using (25%→100% EtOAc/hexanes) to obtain methyl 3-[(1-tert-butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylate (XXXIV) (950 mg, 2.30 mmol, 99.8% yield) as a grey solid. ESIMS found for C 22 H 27 N 3 O 5 m/z 414.2 (M+1).

To a stirred solution of methyl 3-[(1-tert-butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylate (XXXIV) (950 .mg, 2.3 mmol) in MeOH (15 mL) was added 2N aqueous solution of NaOH (2.3 mL, 4.6 mmol) and the mixture was heated to 50° C. The reaction mixture was concentrated, the residue taken up in water and acidified with 1N HCl and the resulting solid was collected by filtration, washed with water and dried under high vacuo to obtain 3-[(1-tert-butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylic acid (XXXV) (900 mg, 2.25 mmol, 98.1% yield) as a brown solid. ESIMS found for C 21 H 25 N 3 O 5 m/z 400.2 (M+1).

To a mixture of 3-[(1-tert-butoxycarbonylpiperidine-4-carbonyl)amino]isoquinoline-6-carboxylic acid (XXXV) (0.5 g, 1.26 mmol), HATU (0.48 g, 1.26 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.66 mL, 3.77 mmol) in DMF (10 mL) was stirred for 10 min. Then 3-amino-1, 1-dimethylthiourea (0.18 g, 1.51 mmol) was added and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated, the residue taken in CHCl 3 , washed with sat. NaHCO 3 , H 2 O and brine. The organic layer was separated and dried (MgSO 4 ) before concentration to dryness to obtain tert-butyl 4-[[6-[(dimethylcarbamothioylamino)carbamoyl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate (XXXVI) (600 mg, 1.20 mmol, 95.4% yield) as a brown solid which was used for next step without purification. ESIMS found for C 24 H 32 N 6 O 4 S m/z 501.2 (M+1).

To a mixture of tert-butyl 4-[[6-[(dimethylcarbamothioylamino)carbamoyl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate (XXXVI) (600 mg, 1.2 mmol), 2-chloro-1,3-dimethyl-4,5-dihydroimidazol-1-ium chloride (405.2 mg, 2.4 mmol) and N,N-diethylethanamine (0.5 mL, 3.6 mmol) in DCM (10 mL) was stirred overnight at room temperature. Reaction mixture was concentrated and the residue was purified by column chromatography (0-+10% 7N—NH 3 -MeOH/CHCl 3 ) to obtain tert-butyl 4-[[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate (XXXVII) (60 mg, 0.129 mmol, 10.7% yield) as a brown solid. ESIMS found for C 24 H 30 N 6 O 4 m/z 467.2 (M+1).

To a stirred solution of tert-butyl 4-[[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate (XXXVII) (60 mg, 0.130 mmol) in DCM (2 mL) was added TFA (0.2 mL, 2.57 mmol) and the mixture was stirred at room temperature for 5 h. Reaction mixture was concentrated and the residue was absorbed on silica gel, purified by flash column chromatography (0-10% 7N—NH 3 -MeOH/CHCl 3 ) to obtain N-[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]piperidine-4-carboxamide (1075) (32 mg, 0.087 mmol, 67.9% yield) as a white solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.54 (2H, qd, J=12.17, 4.12 Hz), 1.71 (2H, br d, J=10.43 Hz), 2.44-2.49 (2H, m), 2.65 (1H, tt, J=11.49, 3.60 Hz), 2.98 (2H, br d, J=12.08 Hz), 3.13 (6H, s), 7.96 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.51 Hz), 8.35 (1H, s), 8.59 (1H, s), 9.17 (1H, s), 10.55 (1H, s); ESIMS found for C 19 H 22 N 6 O 2 m/z 367.2 (M+1).

To a mixture of N-[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]piperidine-4-carboxamide (1075) (27 mg, 0.070 mmol), NaBH 3 CN (14.03 mg, 0.070 mmol) and catalytic HOAc in MeOH (2 mL) was stirred for 30 min, formaldehyde (2.21 mg, 0.070 mmol) was added and the stirring was continued 2 h. The reaction mixture was quenched with minimum amount of aq. saturated NH 4 Cl, concentrated on under vacuum and the residue was adsorbed on silica gel, purified by chromatography (0→20% 7N.NH 3 -MeOH/CHCl 3 ) to obtain N-[6-[5-(dimethylamino)-1,3,4-oxadiazol-2-yl]-3-isoquinolyl]-1-methyl-piperidine-4-carboxamide (1076) (25 mg, 0.066 mmol, 89.2% yield) as a white solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.62-1.74 (2H, m), 1.74-1.81 (2H, m), 1.87 (2H, td, J=11.66, 2.20 Hz), 2.16 (3H, s), 2.51-2.56 (1H, m), 2.77-2.85 (2H, m), 3.13 (6H, s), 7.96 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.51 Hz), 8.35 (1H, s), 8.59 (1H, s), 9.18 (1H, s), 10.61 (1H, s); ESIMS found for C 20 H 24 N 6 O 2 m/z 381.2 (M+1).

Preparation of N-(6-(1H-1,2,3-triazol-1-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide (1074) and N-(6-(2H-1,2,3-triazol-2-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide (1075) is depicted below in Scheme 14.

To a mixture of 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid (XXXVIII) (1.07 mL, 13.99 mmol), HATU (7.09 g, 18.65 mmol) and DIPEA (4.87 mL, 27.97 mmol) in DMF (40 mL) was stirred for 10 min. Then, 6-bromoisoquinolin-3-amine (XII) (2.08 g, 9.32 mmol) and DMAP (0.23 g, 1.86 mmol) was added then the mixture was heated to 80° C. overnight. The reaction mixture was concentrated, the residue partitioned between EtOAc/sat.NaHCO 3 , organic layer separated, washed with water and brine. The organics were then separated and dried (MgSO 4 ) before concentration to dryness. The crude was then purified by flash column chromatography (0→40% EtOAc/hexanes). The desired fractions were concentrated to dryness en vacuo and recrystallized with hexanes to obtain tert-butyl 4-[(6-bromo-3-isoquinolyl)carbamoyl]-4-fluoro-piperidine-1-carboxylate (XXXIX) (2.94 g, 6.50 mmol, 69.7% yield) as a white solid. ESIMS found for C 20 H 23 BrFN 3 O 3 m/z 452.1 ( 79 BrM+1).

To a suspension of tert-butyl 4-[(6-bromo-3-isoquinolyl)carbamoyl]-4-fluoro-piperidine-1-carboxylate (XXXIX) (1.92 g, 4.24 mmol) in DCM (8 mL) was added TFA (8 .mL, 103.84 mmol) at 0° C. and the mixture was stirred for 1 h. The solvents were concentrated, triturated with CHCl 3 (3×) and the resulting solids were dried under high vacuo to obtain N-(6-bromo-3-isoquinolyl)-4-fluoro-piperidine-4-carboxamide (XL) (1.979 g, 4.24 mmol, 100% yield) as an off-white solid which was used for next step without further purification. ESIMS found for C 15 H 15 BrFN 3 O m/z 352.0 ( 79 BrM+1).

To a suspension of N-(6-bromo-3-isoquinolyl)-4-fluoro-piperidine-4-carboxamide (XL) (1.98 g, 4.24 mmol) in MeCN (20 mL) was added 1-iodo-2-methyl-propane (0.98 mL, 8.48 mmol) and the mixture was stirred for 30 min. The solvents were concentrated, treated with 7N NH 3 /MeOH, absorbed on silica gel and purified by column chromatography (0→30% CHCl 3 /10% 7N NH 3 MeOH) to obtain N-(6-bromo-3-isoquinolyl)-4-fluoro-1-isobutyl-piperidine-4-carboxamide (XLI) (1.4 g, 3.43 mmol, 80.9% yield) as a beige solid. ESIMS found for C 19 H 23 BrFN 3 O m/z 408.1 ( 79 BrM+1).

To a mixture of N-(6-bromo-3-isoquinolyl)-4-fluoro-1-isobutyl-piperidine-4-carboxamide (XLI) (150 mg, 0.370 mmol), 1H-triazole (0.04 mL, 0.730 mmol), Cs 2 CO 3 (239 mg, 0.730 mmol), N,N-dimethylethylenediamine (6.48 mg, 0.070 mmol) and CuI (0 .mL, 0.040 mmol) in DMF (2 mL) was purged with N 2 gas for 10 min. The mixture was then heated to 120° C. overnight. The reaction mixture was filtered through Celite and to the filtrates, water was added and extracted with EtOAc. The organics were separated, washed with brine, dried over anhydrous Na 2 SO 4 , and evaporated under vacuo. The crude products were purified by RP-HPLC. The pure fractions were combined and dried under vacuum to obtain N-(6-(2H-1,2,3-triazol-2-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide (1073) (3.5 mg, 0.008 mmol, 2.2% yield) as an off-white solid; 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.88 (6H, d, J=6.59 Hz), 1.79 (1H, dquin, J=13.55, 6.84, 6.84, 6.84, 6.84 Hz), 1.92-2.02 (2H, m), 2.05-2.21 (6H, m), 2.75-2.82 (2H, m), 8.25 (2H, s), 8.26-8.29 (1H, m), 8.29-8.33 (1H, m), 8.52 (1H, d, J=1.37 Hz), 8.56 (1H, s), 9.25 (1H, s), 10.02 (1H, br d, J=3.29 Hz); ESIMS found for C 21 H 25 FN 6 O m/z 397.0 (M+1) and N-(6-(1H-1,2,3-triazol-1-yl)isoquinolin-3-yl)-4-fluoro-1-isobutylpiperidine-4-carboxamide (1074) (2 mg, 0.005 mmol, 1.2% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.88 (6H, d, J=6.59 Hz), 1.79 (1H, dquin, J=13.46, 6.79, 6.79, 6.79, 6.79 Hz), 1.92-2.02 (2H, m), 2.06-2.12 (2H, m), 2.12-2.21 (4H, m), 2.73-2.83 (2H, m), 8.06 (1H, d, J=1.10 Hz), 8.19 (1H, dd, J=8.92, 2.06 Hz), 8.34 (1H, d, J=9.06 Hz), 8.53 (1H, d, J=1.92 Hz), 8.58 (1H, s), 9.03 (1H, d, J=1.10 Hz), 9.28 (1H, s), 10.07 (1H, br d, J=3.84 Hz); ESIMS found for C 21 H 25 FN 6 O m/z 397.0 (M+1).

Preparation of trans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide (1064) is depicted below in Scheme 15.

To a mixture of trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (XLII) (1.15 mL, 56.04 mmol), HATU (21.31 g, 56.04 mmol), 6-bromoisoquinolin-3-amine (XII) (10.g, 44.83 mmol), and DMAP (1.1 g, 8.97 mmol) in DMF (100 mL) was added DIPEA (23.4 mL, 134.49 mmol). The mixture was stirred at 70° C. overnight. The reaction mixture was cooled before water (800 mL) was added and stirred for ˜2 h. The solid was collected by filtration and sequentially washed with aq. sat.NH 4 Cl, water and aq. sat.NaHCO 3 . The solid was dried under high vacuo to obtain tert-butyl trans-N-[4-[(6-bromo-3-isoquinolyl)carbamoyl]cyclohexyl]carbamate (XLIII) (17.87 g, 39.86 mmol, 88.9% yield) as a grey solid which was used for next step without further purification. ESIMS found for C 21 H 26 BrN 3 O 3 m/z 448.1 ( 79 BrM+1).

To a stirred solution of tert-butyl trans-N-[4-[(6-bromo-3-isoquinolyl) carbamoyl]cyclohexyl]carbamate (XLIII) (5.g, 11.15 mmol) in DCM (20 mL) was added TFA (10 mL, 129.8 mmol). The mixture was stirred for 1 h at 25° C. The solvent was concentrated and the residue was treated with 7N NH 3 /MeOH. The crude product was purified by column chromatography (25→100% CHCl 3 /10% 7N NH 3 MeOH in CHCl 3 ). The pure fractions were combined, concentrated, the residue suspended in EtOAc, sonicated and the solid was collected by filtration, washed with diethyl ether and dried under high vacuo to obtain trans-4-amino-N-(6-bromo-3-isoquinolyl)cyclohexanecarboxamide (XLIV) (3 g, 8.61 mmol, 77.2% yield) as a beige solid. ESIMS found for C 16 H 18 BrN 3 O m/z 348.1 ( 79 BrM+1).

To a mixture of trans-4-amino-N-(6-bromo-3-isoquinolyl) cyclohexanecarboxamide (XLIV) (550 mg, 1.58 mmol), 1-bromo-2-(2-bromoethoxy)ethane (XLV) (439.53 mg, 1.9 mmol) and K 2 CO 3 (654.8 mg, 4.74 mmol) in MeCN (8 mL) was heated to reflux for 24 h. The reaction mixture was concentrated and the residue was taken into DCM, washed with water and brine. The organic layer was then separated and dried (MgSO 4 ) before concentration to dryness. The crude was dissolved in EtOAc, sonicated and the solid was collected by filtration and dried under high vacuo to obtain the desired product trans-N-(6-bromo-3-isoquinolyl)-4-morpholino-cyclohexanecarboxamide (XLVI) (320 mg, 0.765 mmol, 48.4% yield) as an off-white solid. ESIMS found for C 20 H 24 BrN 3 O 2 m/z 418.1 ( 79 BrM+1).

To a mixture of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (XLVII) (62.5 mg, 0.300 mmol), Pd(dppf)Cl 2 —CH 2 Cl 2 adduct (9.76 mg, 0.010 mmol) and trans-N-(6-bromo-3-isoquinolyl)-4-morpholino-cyclohexanecarboxamide (XLVI) (100 mg, 0.240 mmol) in MeCN (1 mL) was added a 2 M aqueous solution of K 2 CO 3 (0.3 mL, 0.600 mmol). N 2 gas was bubbled into the mixture for 10 min and then the solution was heated to 90° C. for 0.5 h. The organic layer was carefully separated, absorbed on silica gel and purified by flash column chromatography (0→40% CHCl 3 /10% 7N NH 3 in MeOH) followed by preparative TLC. The purified product was suspended in EtOAc, sonicated and the solid was collected by filtration and dried under high vacuo to obtain trans-N-[6-(2-methyloxazol-5-yl)-3-isoquinolyl]-4-morpholino-cyclohexanecarboxamide (1064) (18 mg, 0.043 mmol, 17.9% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.16-1.27 (2H, m), 1.42-1.56 (2H, m), 1.91 (4H, br t, J=11.80 Hz), 2.17-2.27 (1H, m), 2.44-2.49 (4H, m), 2.53 (3H, s), 3.26-3.30 (1H, m), 3.54-3.58 (4H, m), 7.78 (1H, s), 7.79-7.83 (1H, m), 8.09 (2H, dd, J=4.80, 3.98 Hz), 8.50 (1H, s), 9.10 (1H, s), 10.51 (1H, s); ESIMS found for C 24 H 28 N 4 O 3 m/z 421.2 (M+1).

Preparation of trans-4-(dimethylamino)-N-(6-(2-methyloxazol-5-yl) isoquinolin-3-yl)cyclohexane-1-carboxamide (1017) is depicted below in Scheme 16.

To a stirred solution of trans-4-amino-N-(6-bromo-3-isoquinolyl) cyclohexanecarboxamide (XLVIII) (3 g, 8.61 mmol) in MeOH (50 mL) was added formaldehyde (8.64 mL, 42.93 mmol). After 15 min, Na(OAc) 3 BH (9.1 g, 42.93 mmol) was added and the mixture was stirred at room temperature for 2 h. The solvents were removed in vacuo, the residue taken in water, basified with 1N NaOH solution and extracted with CHCl 3 . The organic layer was separated, washed with water and brine, and dried over anhydrous Na 2 SO 4 . The solvent was concentrated and the crude was suspended in diethyl ether, sonicated and the solid was collected by filtration and dried under high vacuo to obtain the desired product trans-N-(6-bromo-3-isoquinolyl)-4-(dimethylamino)cyclohexanecarboxamide (XLIX) (2.28 g, 6.06 mmol, 70.3% yield) as a beige solid. ESIMS found for C 18 H 22 BrN 3 O m/z 376.1 ( 79 BrM+1).

To a mixture of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (L) (138.9 mg, 0.660 mmol), Pd(dppf)Cl 2 —CH 2 Cl 2 adduct (43.4 mg, 0.050 mmol), a 2 M aqueous solution of K 2 CO 3 (0.66 mL, 1.33 mmol) and trans-N-(6-bromo-3-isoquinolyl)-4-(dimethylamino)cyclohexanecarboxamide (XLIX) (200 mg, 0.530 mmol) in MeCN (2.5 mL). N 2 gas was bubbled into the mixture for 10 min and then the solution was heated to 110° C. for 30 min in a microwave. The organic layer was carefully separated, absorbed on silica gel and purified by column chromatography (0→50% CHCl 3 /10% 7N NH 3 MeOH in CHCl 3 ). The pure fractions were combined, concentrated and the product was suspended in EtOAc, sonicated and the solid was collected by filtration, washed with diethyl ether and dried under high vacuo to obtain trans-4-(dimethylamino)-N-[6-(2-methyloxazol-5-yl)-3-isoquinolyl]cyclohexanecarboxamide (1017) (92 mg, 0.243 mmol, 45.7% yield) as a beige solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.14-1.23 (2H, m), 1.43-1.54 (2H, m), 1.83-1.95 (4H, m), 2.10-2.16 (1H, m), 2.18 (6H, s), 2.44-2.49 (1H, m), 2.53 (3H, s), 7.78 (1H, s), 7.79-7.84 (1H, m), 8.06-8.13 (2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.49 (1H, s); ESIMS found for C 22 H 26 N 4 O 2 m/z 379.2 (M+1).

Preparation of trans-4-((4-methylpiperazin-1-yl)methyl)-N-(6-(oxazol-5-yl) isoquinolin-3-yl)cyclohexane-1-carboxamide (1007) is depicted below in Scheme 17.

To a mixture of methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate (LI) (5.0 g, 29.03 mmol) imidazole (3.95 g, 58.07 mmol) and tert-butyl-chloro-dimethyl-silane (4.81 g, 31.94 mmol) in DMF (50 mL) was stirred at room temperature for 48 h. The solvents were concentrated to ½ volume, water (200 mL) was added and extracted with MTBE. The organic layer was separated and washed with 1 N HCl, H 2 O and brine. The organics were dried over anhydrous Na 2 SO 4 and the solvent was concentrated to dryness to obtain methyl trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylate (LII) (8.09 g, 28.24 mmol, 97.3% yield) as a colorless oil. ESIMS found for C 15 H 30 O 3 Si m/z 287.1 (M+1).

To a stirred solution of methyl trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylate (LII) (8.05 g, 28.1 mmol) in a mixture of THF (20 mL) and MeOH (20 mL) was added 2 M solution of NaOH (28.1 mL, 56.2 mmol). The mixture was stirred at room temperature for 5 h. The solvent was reduced to ⅓ volume, acidified with 1 N HCl and the resulting solid was filtered, washed with water and dried under high vacuo to obtain 5 grams of the desired product. The filtrates were extracted with EtOAc (2×), washed with water, brine, dried over anhydrous Na 2 SO 4 , concentrated, and dried in vacuo to obtain another 1.1 g of trans-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxylic acid (LIII) (Total 6.1 g, 22.39 mmol, 79.7% yield) as a white solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.01 (6H, s), 0.83-0.87 (8H, m), 0.88-0.96 (2H, m), 1.19-1.32 (2H, m), 1.32-1.43 (1H, m), 1.74 (2H, br dd, J=13.31, 3.16 Hz), 1.84-1.94 (2H, m), 2.09 (1H, tt, J=12.18, 3.46 Hz), 3.38 (2H, d, J=6.31 Hz), 11.98 (1H, br s); ESIMS found for C 14 H 28 O 3 Si m/z 273.1 (M+1).

A mixture of DIPEA (5.86 mL, 33.62 mmol), DMAP (0.27 g, 2.24 mmol) and HATU (5.11 g, 13.45 mmol) in DMF (30 mL) was stirred for 10 min. 6-Bromoisoquinolin-3-amine (XII) (2.5 g, 11.21 mmol) was then added followed by the addition of trans-4-[[tert-butyl (dimethyl)silyl]oxymethyl]cyclohexanecarboxylic acid (LIII) (3.66 g, 13.45 mmol). The mixture was heated to 70° C. overnight. An additional 0.5 equiv. of HATU were added and the mixture was continued for additional 6 h. The solvent was concentrated, the residue taken up in EtOAc, washed with sat. NaHCO 3 and brine. The organic layer was then concentrated and the crude product was purified by column chromatography (0→30% EtOAc/hexanes). The pure fractions were combine and concentrated to obtain trans-N-(6-bromo-3-isoquinolyl)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanecarboxamide (LIV) (2.25 g, 4.71 mmol, 42.0% yield) as a crystalline off-white solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.03 (6H, s), 0.87 (9H, s), 0.98 (2H, qd, J=12.72, 3.29 Hz), 1.38-1.51 (3H, m), 1.73-1.82 (2H, m), 1.85-1.92 (2H, m), 2.46-2.55 (1H, m), 3.41 (2H, d, J=6.04 Hz), 7.62 (1H, dd, J=8.64, 1.78 Hz), 7.99 (1H, d, J=8.78 Hz), 8.16 (1H, d, J=1.65 Hz), 8.44 (1H, s), 9.13 (1H, s), 10.53 (1H, s); ESIMS found for C 23 H 33 BrN 2 O 2 Si m/z 477.2 ( 79 BrM+1).

To a stirred solution of trans-N-(6-bromo-3-isoquinolyl)-4-[[tert-butyl (dimethyl)silyl]oxymethyl]cyclohexanecarboxamide (LIV) (2.24 g, 4.69 mmol) in THF (10 mL) was added 1 M solution of TBAF (7.04 mL, 7.04 mmol) in THF. The mixture was stirred at room temperature overnight (monitored by LCMS). Water was added to the reaction mixture and extracted with EtOAc (2×). The organic layer was separated, washed with brine, and dried over anhydrous Na 2 SO 4 . The solvent was concentrated and the crude product was suspended in EtOAc, sonicated and the solid was collected by filtration and dried under high vacuo to obtain trans-N-(6-bromo-3-isoquinolyl)-4-(hydroxymethyl)cyclohexanecarboxamide (LV) (1.437 g, 3.96 mmol, 84.3% yield) as a light beige solid. ESIMS found for C 17 H 19 BrN 2 O 2 m/z 363.1 ( 79 BrM+1).

To a stirred solution of DMSO (0.59 mL, 8.26 mmol) in DCM (3 mL) at −78° C. was added dropwise under Ar, oxalyl dichloride (0.36 mL, 4.13 mmol) in DCM (1 mL). After 15 min, trans-N-(6-bromo-3-isoquinolyl)-4-(hydroxymethyl)cyclohexanecarboxamide (LV) (1.0 g, 2.75 mmol) in a mixture of THF (12 mL) and DMSO (0.5 mL) was added and the mixture was stirred at −78° C. for 1 h. Then, TEA (1.15 mL, 8.26 mmol) was added and the mixture was continued to stir for 1 h and warmed to room temperature for 1 h. The reaction mixture was diluted with H 2 O and DCM and the organic layer separated, washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to obtain trans-4-formyl-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]cyclohexanecarboxamide (LVI) (215 mg, 0.593 mmol, 108.1% yield) as a white solid which was used for next step without further purification. ESIMS found for C 17 H 17 BrN 2 O 2 m/z 361.05 ( 79 BrM+1).

To a mixture of 1-methylpiperazine (0.23 mL, 2.03 mmol), trans-N-(6-bromo-3-isoquinolyl)-4-formyl-cyclohexanecarboxamide (LVI) (490 mg, 1.36 mmol) and in DCE (6 mL) was stirred for 20 min. Then, Na(OAc) 3 BH (431.2 mg, 2.03 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with sat. NaHCO 3 , H 2 O and brine. The organic layer was then separated and dried (MgSO 4 ) before concentration to dryness to obtain trans-N-(6-bromo-3-isoquinolyl)-4-[(4-methylpiperazin-1-yl)methyl]cyclohexanecarboxamide (LVII) (610 mg, 1.37 mmol, 100% yield) as a beige solid. ESIMS found for C 22 H 29 BrN 4 O m/z 445.1 ( 79 BrM+1).

To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (LVIII) (54.7 mg, 0.280 mmol), Pd(dppf)Cl 2 —CH 2 Cl 2 adduct (18.3 mg, 0.020 mmol), and trans-N-(6-bromo-3-isoquinolyl)-4-[(4-methylpiperazin-1-yl)methyl]cyclohexanecarboxamide (LVII) (100 mg, 0.220 mmol) was taken in MeCN (1 mL) and was added a 2 M aqueous solution of K 2 CO 3 (0.28 mL, 0.560 mmol). N 2 gas was bubbled into the mixture for 10 min and then was heated to 110° C. for 0.5 h. The organic layer was separated, absorbed on silica gel and was purified by column chromatography (10→80% CHCL 3 /10% 7N NH 3 MeOH in CHCl 3 ). The pure fractions were combined, concentrated, the residue suspended in a mixture EtOAc/diethyl ether, sonicated and the resulting solid was collected by filtration and dried under vacuo to obtain trans-4-[(4-methylpiperazin-1-yl)methyl]-N-(6-oxazol-5-yl-3-isoquinolyl)cyclohexanecarboxamide (1007) (25 mg, 0.058 mmol, 25.7% yield) as a light brown solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.83-0.96 (2H, m), 1.41-1.54 (3H, m), 1.79-1.92 (4H, m), 2.08 (2H, d, J=7.41 Hz), 2.14 (3H, s), 2.31 (8H, br s), 2.52-2.56 (1H, m), 7.86 (1H, dd, J=8.51, 1.65 Hz), 7.94 (1H, s), 8.12 (1H, d, J=8.51 Hz), 8.18 (1H, s), 8.53 (1H, s), 8.57 (1H, s), 9.12 (1H, s), 10.50 (1H, s); ESIMS found for C 25 H 31 N 5 O 2 m/z 434.2 (M+1).

Preparation of 1-isobutyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide (822) is depicted below in Scheme 18.

Steps 1-2

To a mixture of 6-bromoisoquinolin-3-amine (XII) (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 bubbled with N 2 for 2 min. The reaction mixture was sealed and heated at 90° C. for 1.5 h. The reaction was cooled to room temperature, filtered and washed with EtOAc. The filtrate was concentrated and the residue taken in dioxane (50 mL). To the suspension was added 4-bromo-2-methyl-pyrazole-3-carbaldehyde (LX) (3.39 g, 17.93 mmol) followed by 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 a min, sealed and heated again at 90° C. for 19 h. The mixture was cooled to room temperature and concentrated to about 20 mL. The concentrate was diluted with EtOAc and filtered through a pad of Celite. The filtrate was diluted with water and the organic layer separated. The organic layer was washed with brine; dried, filtered and concentrated. The residue was triturated in ether and the resulting solid filtered to afford 4-(3-amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde (LXI) (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).

To a mixture of 4-(3-amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde (LXI) (1.07 g, 4.25 mmol), piperidine (0.84 mL, 8.51 mmol) and catalytic HOAc in DCE (10 mL) was 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 minimum amount of aq. saturated ammonium chloride solution, and concentrated under vacuum. The residue was adsorbed on silica gel and purified by chromatography (0→20% 7N NH 3 -MeOH/CHCl 3 ) to obtain 6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]isoquinolin-3-amine (LXII) (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).

To a mixture of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (XXVIII) (1.15 mL, 1.63 mmol), HATU (703.87 mg, 1.85 mmol) and DIPEA (0.57 mL, 3.27 mmol) in DMF (5 mL) was stirred for 10 min. To this mixture was added 6-[1-methyl-5-(1-piperidylmethyl) pyrazol-4-yl]isoquinolin-3-amine (LXII) (350 mg, 1.09 mmol) and DMAP (26.61 mg, 0.220 mmol) and the mixture was stirred at 50° C. overnight. The solvent was concentrated and the residue was taken up in EtOAc, washed with sat. NaHCO 3 , water and brine. The organic layer was then separated and dried (MgSO 4 ) before concentrating to dryness. The crude product was purified by column chromatography (25%→100% EtOAc/hexanes). The pure fractions were combined, concentrated, the residue triturated with diethyl ether, sonicated and the solid were collected by filtration and dried under high vacuo to obtain tert-butyl 4-[[6-[1-methyl-5-(1-piperidylmethyl) pyrazol-4-yl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate (LXIII) (550 mg, 1.03 mmol, 94.8% yield) as a dark beige solid. ESIMS found for C 30 H 40 N 6 O 3 m/z 533.3 (M+1).

To a stirred solution of tert-butyl 4-[[6-[1-methyl-5-(1-piperidylmethyl) pyrazol-4-yl]-3-isoquinolyl]carbamoyl]piperidine-1-carboxylate (LXIII) (300 mg, 0.560 mmol) in DCM (5 mL) was added TFA (1.23 mL, 15.91 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was adsorbed on silica gel, purified by column chromatography (0-10% 7N.NH 4 -MeOH/CHCl 3 ), pure fractions were concentrated and the solid were triturated with MeOH, filtered and dried to obtain N-[6-[1-methyl-5-(1-piperidylmethyl) pyrazol-4-yl]-3-isoquinolyl]piperidine-4-carboxamide (LXIV) (191 mg, 0.441 mmol, 78.4% yield) as a white solid. ESIMS found for C 25 H 32 N 6 O m/z 433.3 (M+1).

To stirred mixture of N-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]piperidine-4-carboxamide (LXIV) (95 mg, 0.220 mmol) and 2-methylpropanal (0.06 mL, 0.660 mmol) in MeOH (2 mL) was added NaCNBH 3 (27.6 mg, 0.440 mmol) at 0° C. The mixture was stirred for 30 min-1 h at room temperature. Reaction mixture was quenched with minimum amount of aq. saturated ammonium chloride solution, concentrated under vacuum and the residue was adsorbed on silica gel, purified by chromatography (0→10% 7N.NH3-MeOH/CHCl 3 ) to obtain 1-isobutyl-N-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]piperidine-4-carboxamide (822) (30 mg, 0.061 mmol, 28.0% yield) as a beige solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.33-1.42 (2H, m), 1.45-1.53 (4H, m), 1.61-1.72 (2H, m), 1.72-1.81 (3H, m), 1.86 (2H, td, J=11.60, 1.78 Hz), 2.02 (2H, d, J=7.41 Hz), 2.36 (4H, br s), 2.52-2.59 (1H, m), 2.86 (2H, br d, J=11.53 Hz), 3.65 (2H, s), 3.91 (3H, s), 7.68 (1H, dd, J=8.37, 1.51 Hz), 7.79 (1H, s), 8.02 (1H, d, J=9.33 Hz), 8.03 (1H, s), 8.46 (1H, s), 9.07 (1H, s), 10.46 (1H, s); ESIMS found for C 29 H 40 N 6 O m/z 489.3 (M+1).

Preparation of 2-[(3R)-3-fluoropyrrolidin-1-yl]-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]acetamide (274) is depicted below in Scheme 19.

To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (1.0 g, 4.48 mmol) and DMAP (109.5 mg, 0.90 mmol) in DCE (35 mL) was added DIPEA (3.12 mL, 17.93 mmol) followed by the addition of 2-chloroacetyl chloride (1.07 mL, 13.45 mmol). The mixture was heated to 75° C. overnight. The reaction mixture was then cooled to room temperature, diluted with DCM, washed with H 2 O and brine, the organic layer were then separated and dried over MgSO 4 before concentrating to dryness. The crude product was then purified by flash column chromatography using EtOAc/hexanes (0→100%) to obtain N-(6-bromo-3-isoquinolyl)-2-chloro-acetamide (LXV) as a light yellow solid (350 mg, 1.16 mmol, 26.1% yield). ESIMS found for C 11 H 8 BrClN 2 O m/z 298.9 ( 79 BrM+H).

To a solution of N-(6-bromo-3-isoquinolyl)-2-chloro-acetamide (LXV) (100 mg, 0.33 mmol), (3R)-3-fluoropyrrolidine hydrochloride (LXVI) (209.6 mg, 1.67 mmol), KI (0.02 mL, 0.33 mmol) and K 2 CO 3 (461.4 mg, 3.34 mmol) in DMF (2 mL) was heated to 90° C. overnight. The reaction was then concentrated to dryness and the residue was taken up in EtOAc and the organic layer was washed with water then brine. The organic layer was then separated and dried over MgSO 4 before concentration to dryness to obtain N-(6-bromo-3-isoquinolyl)-2-[(3R)-3-fluoropyrrolidin-1-yl]acetamide (LXVII) as a dark brown thick gum (110 mg, 0.312 mmol, 94.6% yield). Used for next step without purification. ESIMS found for C 15 H 15 BrFN 3 O m/z 352.2 ( 79 BrM+H).

To a solution of N-(6-bromo-3-isoquinolyl)-2-[(3R)-3-fluoropyrrolidin-1-yl]acetamide (LXVII) (116.2 mg, 0.33 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo (LXVIII) (103 mg, 0.50 mmol), Pd(dppf)Cl 2 (27 mg, 0.03 mmol) in MeCN (1.5 mL) was added a 2 M aqueous solution of K 2 CO 3 (0.5 mL, 0.99 mmol). N 2 gas was bubbled into the mixture for 10 min and then heated to 80° C. for 3 h. The organic layer was carefully separated, absorbed on silica gel and purified by flash column chromatography (0→30% CHCl 3 /10% 7 N NH 3 in MeOH). The pure fractions were concentrated, the residue suspended in minimum EtOAc, sonicated and the resulting solid was collected by filtration, washed with diethyl ether and dried to obtain 2-[(3R)-3-fluoropyrrolidin-1-yl]-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]acetamide (274) as a white solid (58.0 mg, 0.164 mmol, 49.7% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.88-2.03 (m, 1H), 2.12-2.28 (m, 1H), 2.53-2.61 (m, 1H), 2.86 (ddd, J=32.40, 11.80, 4.95 Hz, 1H), 2.95-3.04 (m, 2H), 3.41 (s, 2H), 3.90 (s, 3H), 5.26 (ddd, J=55.80, 6.05, 4.95 Hz, 1H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.02 (d, J=8.78 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.44 (s, 1H), 9.03 (s, 1H), 10.02 (s, 1H); ESIMS found for C 19 H 20 FN 5 O m/z 354.1 (M+1).

Preparation of (S)—N-(6-(1-(methyl-d 3 )-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)propanamide (971) is depicted below in Scheme 20.

To a stirred suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (LXIX) (1.435 g, 7.4 mmol) and Cs 2 CO 3 (2.89 g, 8.87 mmol) in DMF (15 mL) was added trideuterio(iodo)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 vacuo to obtain 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)pyrazole (LXX) (3.9 g, 18.48 mmol, 249.8% yield) as a white solid which was used for next step without purification. ESIMS found for C 10 H 14 [ 2 H 3 ]BN 2 O 2 m/z 212. (M+1).

To a mixture of 6-bromo-3-chloro-isoquinoline (XII) (0.5 g, 2.06 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)pyrazole (LXX) (1.305 g, 6.19 mmol) and SPhos Pd G4 (81.9 mg, 0.100 mmol) in 1,4-dioxane (10 mL) and was added a 2 M aqueous solution of K 2 CO 3 (3.88 mL, 7.77 mmol). N 2 gas was bubbled into the mixture for 10 min and then the mixture was heated to 110° C. for 0.5 h in a microwave. The organic layer was carefully separated, absorbed on silica gel and purified by column chromatography (0→100% hexanes/EtOAc) to obtain 3-chloro-6-[1-(trideuteriomethyl)pyrazol-4-yl]isoquinoline (LXXI) (400 mg, 1.62 mmol, 78.6% yield) as an off-white solid. ESIMS found for C 13 H 7 [ 2 H 3 ]ClN 3 m/z 246.9 (M+1).

To a mixture of (S)-2-aminopropanamide HCl (LXXII) (100 mg, 0.330 mmol), 1,4-dibromobutane (LXXIII) (1.9 mL, 16.06 mmol), K 2 CO 3 (4.437 g, 32.11 mmol) and KI (266.5 mg, 1.61 mmol) in MeCN (80 mL) was heated to reflux for 40 h. 1 N hydrochloric acid (100 mL) and DCM (100 mL) were added to the reaction mixture. The organic phase is separated off and discarded. The aqueous phase is made basic with a NaOH solution and extracted with CHCl 3 (3×80 ml). The organic layers were combined and dried under high vacuo to obtain (2S)-2-pyrrolidin-1-ylpropanamide (LXXIV) (1.10 g, 7.45 mmol, 46.4% yield) as a white solid which was used for next step without purification. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.15 (3H, d, J=6.86 Hz), 1.63-1.72 (4H, m), 2.44-2.49 (4H, m), 2.72 (1H, q, J=6.68 Hz), 6.88 (1H, br s), 7.07 (1H, br s) ESIMS found for C 7 H 14 N 2 O m/z 143.1 (M+1).

To a mixture of (2S)-2-pyrrolidin-1-ylpropanamide (LXXIV) (420.1 mg, 2.95 mmol) BrettPhos Pd G3 (223.2 mg, 0.250 mmol), 3-chloro-6-[1-(trideuteriomethyl)pyrazol-4-yl]isoquinoline (LXXI) (200 mg, 0.810 mmol) and K 3 PO 4 (1.045 g, 4.92 mmol) was taken in 1,4-dioxane (5 mL). N 2 gas was bubbled into the mixture for 10 min and then the mixture was heated to 100° C. for 16 h. The reaction mixture was filtered through Celite, washed with EtOAc, the filtrates concentrated and the crude product was purified by flash chromatography followed by preparative TLC (50% CHCl 3 /10% 7N NH 3 in MeOH) to obtain (2S)-2-pyrrolidin-1-yl-N-[6-[1-(trideuteriomethyl)pyrazol-4-yl]-3-isoquinolyl]propanamide (971) (150.0 mg, 0.426 mmol, 50.6% yield) as a beige solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.75 (4H, br s), 2.59-2.69 (4H, m), 3.29-3.32 (1H, m), 7.76 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.08 (2H, s), 8.35 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 9.91 (1H, s); ESIMS found for C 20 H 20 [ 2 H 3 ]N 5 O m/z 353.0 (M+1).

Preparation of N-[6-(3-methylimidazol-4-yl)-3-isoquinolyl]-2-(1-piperidyl) acetamide (275) is depicted below in Scheme 21.

To a stirred mixture of N-(6-bromo-3-isoquinolyl)-2-(1-piperidyl)acetamide (LXXV) (100 mg, 0.29 mmol) tributyl-(3-methylimidazol-4-yl)stannane (LXXVI) (117.24 mg, 0.32 mmol) Pd(PPh 3 ) 4 (33.2 mg, 0.03 mmol) and cuprous iodide (5.47 mg, 0.03 mmol) in DMF (2 mL) was bubbled N 2 gas for 10 min and then heated to 90° C. overnight. The reaction mixture was concentrated, absorbed on silica gel and purified by flash column chromatography using CHCl 3 /10% 7 N NH 3 in MeOH (0→40%). The pure fractions were concentrated, the residue suspended in diethyl ether, sonicated and the resulting solids were collected by filtration, and dried to obtain N-[6-(3-methylimidazol-4-yl)-3-isoquinolyl]-2-(1-piperidyl)acetamide (275) as a white solid (53.0 mg, 0.152 mmol, 52.3% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.43 (br d, J=4.94 Hz, 2H), 1.59 (quin, J=5.63 Hz, 4H), 2.52 (br d, J=5.21 Hz, 4H), 3.18 (s, 2H), 3.84 (s, 3H), 7.33 (br s, 1H), 7.70 (dd, J=8.51, 1.65 Hz, 1H), 7.81 (br s, 1H), 8.06 (s, 1H), 8.11 (d, J=8.51 Hz, 1H), 8.53 (s, 1H), 9.14 (s, 1H), 9.98 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

Preparation of 1-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(1-methylpiperidin-4-yl)urea (1037) is depicted below in Scheme 22.

To a stirred suspension of 6-bromoisoquinolin-3-amine (XII) (200 mg, 0.900 mmol), DMAP (11 mg, 0.090 mmol) and TEA (0.5 mL, 3.59 mmol) in THF (40 ml) was added trichloromethyl carbonochloridate (0.11 mL, 0.900 mmol) and the mixture was stirred for 1 h at room temperature. N,1-dimethylpiperidin-4-amine (LXXVII) (115 mg, 0.900 mmol) was then added and the mixture was stirred for 2 h at room temperature. The reaction was concentrated and the residue taken in DCM, washed with water, sat.NaHCO 3 and brine. The organic layer was dried over anhydrous Na 2 SO 4 , solvents removed in vacuo and the crude was purified by column chromatography (0→10% CHCl 3 /7N NH 3 in MeOH) to obtain 3-(6-bromo-3-isoquinolyl)-1-methyl-1-(1-methyl-4-piperidyl)urea (LXXVIII) (98 mg, 0.260 mmol, 29.0% yield) as a beige solid. ESIMS found for C 17 H 21 BrN 4 O m/z 377.1 ( 79 BrM+H).

To a mixture of Pd(dppf)Cl 2 —CH 2 Cl 2 adduct (19.6 mg, 0.020 mmol), 1-(6-bromo-3-isoquinolyl)-3-(1-methyl-4-piperidyl)urea (LXXVIII) (87 mg, 0.240 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (LXVIII) (59.8 mg, 0.290 mmol) in MeCN (5 mL) was added a 2 M aqueous solution of K 2 CO 3 (0.24 mL, 0.480 mmol). N 2 gas was bubbled into the mixture for 10 min and then heated at 110° C. for 30 min in a microwave. The organic layer was carefully separated, absorbed on silica gel and purified by flash column chromatography (0→10% 7N NH 3 in MeOH/CHCl 3 ). The pure fractions were combined, concentrated and the residue was triturated from DCM/hexanes. The solid was collected by filtration and dried under high vacuum to obtain 1-(1-methyl-4-piperidyl)-3-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]urea (1037) (35 mg, 0.096 mmol, 40.1% yield) as a beige solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.52 (2H, br d, J=10.15 Hz), 1.74 (2H, qd, J=12.12, 3.70 Hz), 1.93-2.02 (2H, m), 2.17 (3H, s), 2.82 (2H, br d, J=11.25 Hz), 2.88 (3H, s), 3.90 (3H, s), 4.09 (1H, tt, J=12.01, 3.91 Hz), 7.65-7.72 (1H, m), 7.93-7.99 (2H, m), 8.06 (1H, s), 8.15 (1H, s), 8.33 (1H, s), 8.76 (1H, s), 8.97 (1H, s); ESIMS found for C 21 H 26 N 6 O m/z 379.2 (M+1).

The following compounds were prepared in accordance with the procedures described in the above Examples 1-12.

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclopropanecarboxamide 1

Beige solid (32.0 mg, 0.109 mmol, 31.9% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.77-0.90 (m, 4H), 2.03-2.12 (m, 1H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1 H), 7.96-8.03 (m, 2H), 8.08 (s, 1H), 8.35 (s, 1H), 8.40 (s, 1H), 9.03 (s, 1H), 10.83 (s, 1H); ESIMS found for C 17 H 16 N 4 O m/z 293.1 (M+1).

4,4-Difluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) cyclohexanecarboxamide 3

Beige solid (41.6 mg, 0.112 mmol, 56.2% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.66-1.90 (m, 4H), 1.91-2.00 (m, 2H), 2.06-2.18 (m, 2H), 2.66-2.76 (m, 1H), 3.90 (s, 3H), 7.75 (dd, J=8.64, 1.51 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.43 (s, 1H), 9.03 (s, 1H), 10.57 (s, 1H); ESIMS found for C 20 H 20 F 2 N 4 O m/z 371.2 (M+1).

trans-4-Methoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) cyclohexane-1-carboxamide 4

White solid (101 mg, 0.277 mmol, 62.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.07-1.17 (2H, m), 1.43-1.56 (2H, m), 1.84-1.95 (2H, m), 2.03-2.11 (2H, m), 2.51-2.57 (1H, m), 3.12 (1H, tt, J=10.67, 4.15 Hz), 3.25 (3H, s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.42 (1H, s); ESIMS found for C 21 H 24 N 4 O 2 m/z 365.2 (M+1).

trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide 6

White solid (36 mg, 0.086 mmol, 30.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.15-1.30 (2H, m), 1.41-1.56 (2H, m), 1.91 (4H, brt, J=11.11 Hz), 2.17-2.28 (1H, m), 3.28 (4H, br s), 3.50-3.60 (4H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.41 (1H, s); ESIMS found for C 24 H 29 N 5 O 2 m/z 420.2 (M+1).

trans-4-((3-Fluoroazetidin-1-yl)methyl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)cyclohexane-1-carboxamide 10

White solid (42.0 mg, 0.100 mmol, 36.1% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.91 (2H, qd, J=12.67, 3.16 Hz), 1.20-1.33 (1H, m), 1.37-1.51 (2H, m), 1.51-1.61 (1H, m), 1.75-1.90 (4H, m), 2.29 (2H, d, J=6.86 Hz), 2.96-3.08 (2H, m), 3.48-3.60 (2H, m), 3.90 (3H, s), 5.02-5.22 (1H, m), 7.73 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.42 (1H, s), 9.01 (1H, s), 10.38 (1H, s); ESIMS found for C 24 H 28 FN 5 O m/z 422.0 (M+1).

trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide 14

White solid (35.0 mg, 0.078 mmol, 28.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.82-0.95 (2H, m), 1.40-1.54 (4H, m), 1.79-1.91 (4H, m), 2.08 (2H, d, J=7.14 Hz), 2.14 (3H, s), 2.23-2.41 (8H, m), 3.90 (3H, s), 7.73 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.43 (1H, s), 9.01 (1H, s), 10.37 (1H, s); ESIMS found for C 26 H 34 N 6 O m/z 447.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azetidine-3-carboxamide 16

Yellow solid (10.8 mg, 0.035 mmol, 62.4% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 3.50 (br s, 2H), 3.76 (br s, 3H), 3.90 (s, 3H), 7.75 (dd, J=8.51, 1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.06 (s, 1H), 8.09 (s, 1H), 8.36 (s, 1H), 8.47 (s, 1H), 9.02 (s, 1H), 10.45 (s, 1H); ESIMS found for C 17 H 17 N 5 O m/z 308.1 (M+1).

(S)-2-(3-Fluoropyrrolidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 69

Off-white solid (70.0 mg, 0.198 mmol, 41.0% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.87-2.04 (m, 1H), 2.12-2.29 (m, 1H), 2.55-2.62 (m, 1H), 2.81-2.94 (m, 1H), 2.96-3.06 (m, 2H), 3.42 (s, 2H), 5.17-5.35 (m, 1H), 7.77 (dd, J=8.64, 1.51 Hz, 1H), 8.02 (d, J=8.78 Hz, 1H), 8.10 (d, J=0.82 Hz, 2H), 8.36 (s, 1H), 8.44 (s, 1H), 9.03 (s, 1H), 10.02 (s, 1H); ESIMS found for C 19 H 20 FN 5 O m/z 354.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide 71

Off-white solid (30.0 mg, 0.093 mmol, 59.8% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.83-1.96 (m, 2H), 1.97-2.07 (m, 1H), 2.19-2.30 (m, 1H), 3.83-3.88 (m, 1H), 3.90 (s, 3H), 3.99-4.07 (m, 1H), 4.53 (dd, J=8.23, 5.76 Hz, 1H), 7.78 (dd, J=8.51, 1.65 Hz, 1H), 8.03 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.42 (s, 1H), 9.05 (s, 1H), 9.75 (s, 1H); ESIMS found for C 18 H 18 N 4 O 2 m/z 323.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 72

White solid (75.0 mg, 0.224 mmol, 92.2% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.65 (qd, J=12.30, 3.70 Hz, 2H), 1.81 (br d, J=10.70 Hz, 2H), 2.64 (td, J=12.28, 2.33 Hz, 2H), 2.71 (ddt, J=11.32, 7.62, 3.84, 3.84 Hz, 1H), 3.12 (br d, J=12.35 Hz, 2H), 3.90 (s, 3H), 7.75 (dd, J=8.51, 1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.43 (s, 1H), 9.03 (s, 1H), 10.50 (s, 1H); ESIMS found for C 19 H 21 N 5 O m/z 336.1 (M+1).

1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 73

White solid (114.0 mg, 0.326 mmol, 42.1% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.60-1.73 (m, 2H), 1.73-1.80 (m, 2H), 1.86 (td, J=11.66, 2.20 Hz, 2H), 2.16 (s, 3H), 2.45-2.55 (m, 1H), 2.81 (br d, J=11.53 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.02 (s, 1H), 8.07 (s, 1H), 8.35 (s, 1H), 8.43 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

1-Isopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 75

Off-white solid (43.0 mg, 0.114 mmol, 40.22% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.97 (d, J=6.31 Hz, 6H), 1.63 (qd, J=11.98, 3.57 Hz, 2H), 1.78 (br d, J=10.15 Hz, 2H), 2.11 (br t, J=11.11 Hz, 2H), 2.45-2.55 (m, 1H), 2.62-2.73 (m, 1H), 2.83 (br d, J=10.98 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (d, J=0.82 Hz, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.44 (s, 1H); ESIMS found for C 22 H 27 N 5 O m/z 378.3 (M+1).

1-Cyclopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 76

White solid (42.0 mg, 0.112 mmol, 24.6% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.25-0.33 (m, 2H), 0.38-0.46 (m, 2H), 1.53-1.65 (m, 3H), 1.76 (br d, J=10.98 Hz, 2H), 2.11-2.22 (m, 2H), 2.51-2.60 (m, 1H), 2.98 (br d, J=11.25 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07 (s, 1H), 8.34 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.47 (s, 1H); ESIMS found for C 22 H 25 N 5 O m/z 376.2 (M+1).

1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 77

White solid (128.0 mg, 0.327 mmol, 60.3% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.85 (d, J=6.59 Hz, 6H), 1.60-1.73 (m, 2H), 1.73-1.80 (m, 3H), 1.82-1.90 (m, 2H), 2.01 (d, J=7.41 Hz, 2H), 2.51-2.57 (m, 1H), 2.86 (br d, J=11.53 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.37 Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found for C 23 H 29 N 5 O m/z 392.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-neopentylpiperidine-4-carboxamide 78

White solid (16.5 mg, 0.041 mmol, 13.7% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.85 (s, 9H), 1.67-1.76 (m, 4H), 2.04 (s, 2H), 2.16-2.26 (m, 2H), 2.81 (br d, J=11.25 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.45 (s, 1H); ESIMS found for C 24 H 31 N 5 O m/z 406.3 (M+1).

1-(2-Fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 81

White solid (257.0 mg, 0.674 mmol, 62.1% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.68 (qd, J=12.12, 3.70 Hz, 2H), 1.75-1.83 (m, 2H), 2.03 (td, J=11.66, 2.20 Hz, 2H), 2.51-2.56 (m, 1H), 2.61 (dt, J=28.30, 4.90 Hz, 2H), 2.91-2.99 (m, 2H), 3.90 (s, 3H), 4.53 (dt, J=47.75, 4.95 Hz, 2H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07 (s, 1H), 8.34 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found for C 21 H 24 FN 5 O m/z 382.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl) piperidine-4-carboxamide 82

White solid (137.0 mg, 0.318 mmol, 54.9% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.58-1.74 (m, 2H), 1.79 (br d, J=10.70 Hz, 2H), 1.92-2.02 (m, 2H), 2.40-2.60 (m, 5H), 2.93 (br d, J=11.25 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.48 (s, 1H); ESIMS found for C 22 H 24 F 3 N 5 O m/z 432.2 (M+1).

1-(2,2-Difluoropropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 83

Off-white solid (29.0 mg, 0.070 mmol, 23.5% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.62 (t, J=19.21 Hz, 3H), 1.66-1.73 (m, 2H), 1.73-1.81 (m, 2H), 2.21 (td, J=11.66, 2.47 Hz, 2H), 2.50-2.57 (m, 1H), 2.70 (t, J=14.00 Hz, 2H), 2.94 (br d, J=11.53 Hz, 2H), 3.89 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07 (d, J=0.82 Hz, 1H), 8.34 (s, 1H), 8.43 (s, 1H), 9.01 (s, 1H), 10.48 (s, 1H); ESIMS found for C 22 H 25 F 2 N 5 O m/z 414.2 (M+1).

1-(2,2-Difluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 84

White solid (147.0 mg, 0.368 mmol, 7.71% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.68 (qd, J=12.12, 3.70 Hz, 2H), 1.74-1.83 (m, 2H), 2.14-2.23 (m, 2H), 2.52-2.59 (m, 1H), 2.72 (td, J=15.57, 4.25 Hz, 2H), 2.96 (br d, J=11.53 Hz, 2H), 3.90 (s, 3H), 6.13 (tt, J=55.75, 4.15 Hz, 1H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07 (s, 1H), 8.34 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.47 (s, 1H); ESIMS found for C 21 H 23 F 2 N 5 O m/z 400.2 (M+1).

1-(2-Fluoro-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 85

Off-white solid (110.0 mg, 0.269 mmol, 47.4% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.31 (d, J=21.45 Hz, 6H), 1.64-1.81 (m, 4H), 2.10 (td, J=11.53, 2.74 Hz, 2H), 2.45 (t, J=22.85 Hz, 2H), 2.51-2.57 (m, 1H), 2.95 (br d, J=11.53 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found for C 23 H 28 FN 5 O m/z 410.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl) methyl)piperidine-4-carboxamide 87

White solid (58.0 mg, 0.138 mmol, 57.8% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.31 (s, 3H), 1.59-1.70 (m, 2H), 1.71-1.79 (m, 2H), 1.97 (td, J=11.53, 2.47 Hz, 2H), 2.48 (s, 2H), 2.51-2.57 (m, 1H), 2.62 (br d, J=11.25 Hz, 2H), 3.90 (s, 3H), 4.19 (d, J=5.49 Hz, 2H), 4.36 (d, J=5.76 Hz, 2H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.47 (s, 1H); ESIMS found for C 24 H 29 N 5 O 2 m/z 420.3 (M+1).

1-(2-Methoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 89

White solid (32.0 mg, 0.081 mmol, 28.7% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.59-1.71 (m, 2H), 1.73-1.81 (m, 2H), 1.92-2.04 (m, 2H), 2.46 (t, J=5.90 Hz, 2H), 2.51-2.58 (m, 1H), 2.92 (br d, J=11.25 Hz, 2H), 3.24 (s, 3H), 3.43 (t, J=6.04 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (d, J=0.82 Hz, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found for C 22 H 27 N 5 O 2 m/z 394.2 (M+1).

1-(2-Isopropoxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 90

Off-white solid (71.0 mg, 0.168 mmol, 56.5% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.08 (d, J=6.04 Hz, 7H), 1.59-1.71 (m, 2H), 1.73-1.82 (m, 2H), 1.98 (td, J=11.60, 2.06 Hz, 2H), 2.44 (t, J=6.17 Hz, 2H), 2.51-2.58 (m, 1H), 2.92 (br d, J=11.53 Hz, 2H), 3.46 (t, J=6.31 Hz, 2H), 3.53 (dt, J=12.14, 6.14 Hz, 1H), 3.90 (s, 3H), 7.74 (dd, J=8.64, 1.51 Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.45 (s, 1H); ESIMS found for C 24 H 31 N 5 O 2 m/z 422.2 (M+1).

4-Fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 91

White solid (54.0 mg, 0.153 mmol). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.79-1.90 (m, 2H), 1.93-2.12 (m, 2H), 2.74 (td, J=12.28, 2.33 Hz, 2H), 2.86-2.94 (m, 2H), 3.90 (s, 3H), 7.81 (dd, J=8.64, 1.51 Hz, 1H), 8.05 (d, J=8.51 Hz, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.36 (s, 1H), 8.40 (s, 1H), 9.08 (s, 1H), 9.78 (d, J=4.39 Hz, 1H); ESIMS found for C 19 H 20 FN 5 O m/z 354.2 (M+1).

4-Fluoro-1-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 92

White solid (57.0 mg, 0.155 mmol, 68.5% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.89-2.01 (m, 2H), 2.05-2.20 (m, 4H), 2.22 (s, 3H), 2.69-2.77 (m, 2H), 3.91 (s, 3H), 7.81 (dd, J=8.51, 1.37 Hz, 1H), 8.05 (d, J=8.78 Hz, 1H), 8.09 (s, 1H), 8.11 (s, 1H), 8.36 (s, 1H), 8.40 (s, 1H), 9.08 (s, 1H), 9.87 (d, J=4.12 Hz, 1H); ESIMS found for C 20 H 22 FN 5 O m/z 368.2 (M+1).

4-Fluoro-1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 96

White solid (37.0 mg, 0.090 mmol, 39.9% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.88 (d, J=6.59 Hz, 6H), 1.74-1.85 (m, 1H), 1.91-2.01 (m, 2H), 2.09 (d, J=7.41 Hz, 2H), 2.11-2.21 (m, 4H), 2.78 (br d, J=8.23 Hz, 2H), 3.90 (s, 3H), 7.81 (dd, J=8.51, 1.65 Hz, 1H), 8.05 (d, J=8.51 Hz, 1H), 8.10 (s, 1H), 8.12 (s, 1H), 8.37 (s, 1H), 8.40 (s, 1H), 9.08 (s, 1H), 9.86 (d, J=4.39 Hz, 1H); ESIMS found for C 23 H 28 FN 5 O m/z 410.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide 110

White solid (37.7 mg, 0.112 mmol, 47.0% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.34-1.48 (m, 1H), 1.55-1.64 (m, 1H), 1.64-1.73 (m, 1H), 1.81-1.92 (m, 1H), 2.52-2.67 (m, 2H), 2.71-2.85 (m, 2H), 2.98 (dd, J=11.94, 3.16 Hz, 1H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.42 (s, 1H), 9.01 (s, 1H), 10.75 (s, 1H); ESIMS found for C 19 H 21 N 5 O m/z 336.1 (M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide 111

White solid (6.5 mg, 0.019 mmol, 44.8% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.33-1.49 (m, 1H), 1.55-1.64 (m, 1H), 1.64-1.74 (m, 1H), 1.81-1.93 (m, 1H), 2.52-2.66 (m, 2H), 2.71-2.86 (m, 2H), 2.98 (dd, J=11.80, 2.74 Hz, 1H), 3.90 (s, 3H), 7.74 (dd, J=8.64, 1.51 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.42 (s, 1H), 9.01 (s, 1H), 10.75 (s, 1H); ESIMS found for C 19 H 21 N 5 O m/z 336.2 (M+1).

(S)-1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide 112

Beige solid (17.8 mg, 0.045 mmol, 4.7% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.88 (d, J=6.59 Hz, 3H), 0.90 (d, J=6.59 Hz, 3H), 1.48-1.60 (m, 2H), 1.64-1.73 (m, 1H), 1.77-1.86 (m, 2H), 2.07 (d, J=7.41 Hz, 2H), 2.10 (br dd, J=4.25, 3.16 Hz, 1H), 2.30 (br d, J=7.14 Hz, 1H), 2.55-2.63 (m, 1H), 2.76 (br d, J=7.68 Hz, 2H), 3.90 (s, 3H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.78 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.42 (s, 1H), 9.01 (s, 1H), 10.68 (s, 1H); ESIMS found for C 23 H 29 N 5 O m/z 392.2 (M+1).

(R)-1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide 113

Beige solid (110 mg, 0.281 mmol, 26.8% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.88 (3H, d, J=6.59 Hz), 0.90 (3H, d, J=6.59 Hz), 1.49-1.59 (2H, m), 1.68 (1H, br dd, J=8.23, 3.29 Hz), 1.76-1.88 (2H, m), 2.07 (2H, d, J=7.41 Hz), 2.10 (1H, br s), 2.30 (1H, br d, J=6.59 Hz), 2.55-2.62 (1H, m), 2.76 (2H, br d, J=7.68 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.37 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.01 (1H, s), 10.68 (1H, s); ESIMS found for C 23 H 29 N 5 O m/z 392.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide 114

White solid (95.0 mg, 0.282 mmol, 63.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.62-1.80 (m, 4H), 2.76-2.87 (m, 1H), 3.32-3.38 (m, 2H), 3.90 (s, 3H), 3.91-3.95 (m, 2H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.03 (s, 1H), 10.49 (s, 1H); ESIMS found for C 19 H 20 N 4 O 2 m/z 337.15 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl) acetamide 115

Off-white solid (23.0 mg, 0.066 mmol, 16.5% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.43 (2H, br d, J=4.39 Hz), 1.59 (4H, quin, J=5.56 Hz), 2.52 (4H, br s), 3.17 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.37 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.91 (1H, s); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

2-(4-Fluoropiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 116

Off-white solid (80.0 mg, 0.218 mmol, 44.3% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.73-1.86 (2H, m), 1.87-2.01 (2H, m), 2.54 (2H, ddd, J=11.39, 7.41, 3.70 Hz), 2.67-2.76 (2H, m), 3.24 (2H, s), 4.66-4.83 (1H, m), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.36 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 9.98 (1H, s); ESIMS found for C 20 H 22 FN 5 O m/z 368.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 118

Beige solid (18.0 mg, 0.049 mmol, 59.8% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.19 (3H, s), 2.33-2.46 (4H, m), 2.58 (4H, br s), 3.22 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.93 (1H, s); ESIMS found for C 20 H 24 N 6 O m/z 365.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl) cyclopropanecarboxamide 119

Beige solid (70.0 mg, 0.228 mmol, 28.9% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.78-0.91 (4H, m), 2.02-2.13 (1H, m), 2.39 (3H, s), 3.65 (3H, s), 7.11 (1H, s), 7.59 (1H, dd, J=8.51, 1.37 Hz), 7.88 (1H, s), 8.07 (1H, d, J=8.51 Hz), 8.49 (1H, s), 9.12 (1H, s), 10.89 (1H, s); ESIMS found for C 18 H 18 N 4 O m/z 307.1 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl) cyclohexanecarboxamide 120

Beige solid (20.0 mg, 0.056 mmol, 18.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.17-1.34 (3H, m), 1.44 (2H, qd, J=12.21, 2.61 Hz), 1.66 (1H, br d, J=11.53 Hz), 1.71-1.79 (2H, m), 1.83 (2H, br d, J=13.17 Hz), 2.39 (3H, br s), 2.52-2.62 (1H, m), 3.66 (3H, s), 7.13 (1H, br s), 7.58 (1H, dd, J=8.51, 1.37 Hz), 7.89 (1H, s), 8.07 (1H, d, J=8.51 Hz), 8.51 (1H, s), 9.11 (1H, s), 10.43 (1H, s); ESIMS found for C 21 H 24 N 4 O m/z 349.0 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4,4-difluorocyclohexanecarboxamide 121

Off-white solid (40.0 mg, 0.104 mmol, 38.4% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.66-1.76 (2H, m), 1.77-1.91 (2H, m), 1.92-2.01 (2H, m), 2.08-2.21 (2H, m), 2.39 (3H, s), 2.71 (1H, br t, J=10.43 Hz), 3.66 (3H, s), 7.12 (1H, br s), 7.61 (1H, dd, J=8.51, 1.37 Hz), 7.91 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.51 (1H, s), 9.12 (1H, s), 10.63 (1H, s); ESIMS found for C 21 H 22 F 2 N 4 O m/z 385.2 (M+1).

(S)—N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide 188

Light yellow solid (60.0 mg, 0.178 mmol, 57.3% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.83-1.95 (2H, m), 1.97-2.07 (1H, m), 2.19-2.30 (1H, m), 2.39 (3H, s), 3.67 (3H, s), 3.82-3.91 (1H, m), 3.98-4.07 (1H, m), 4.54 (1H, dd, J=8.23, 5.49 Hz), 7.13 (1H, s), 7.64 (1H, dd, J=8.51, 1.65 Hz), 7.96 (1H, s), 8.11 (1H, d, J=8.51 Hz), 8.50 (1H, s), 9.14 (1H, s), 9.85 (1H, s); ESIMS found for C 19 H 20 N 4 O 2 m/z 337.1 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 248

Off-white solid (99.0 mg, 0.229 mmol, 50.3% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.61-1.74 (m, 2H), 1.80 (br d, J=10.70 Hz, 2H), 1.97 (br t, J=11.11 Hz, 2H), 2.40-2.61 (m, 5H), 2.89-3.00 (m, 2H), 4.20 (s, 3H), 7.68-7.77 (m, 1H), 8.10 (s, 1H), 8.17-8.21 (m, 2H), 8.60 (s, 1H), 9.21 (s, 1H), 10.62 (br s, 1H); ESIMS found for C 21 H 23 F 3 N 6 O m/z 433.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl) piperidine-4-carboxamide 262

White solid (82.5 mg, 0.191 mmol, 82.4% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.68 (qd, J=12.17, 3.57 Hz, 2H), 1.81 (br d, J=11.25 Hz, 2H), 1.97-2.11 (m, 2H), 2.50 (dt, J=3.64, 1.89 Hz, 2H), 2.52-2.62 (m, 3H), 2.97 (br d, J=10.43 Hz, 2H), 3.83 (s, 3H), 7.30 (d, J=0.82 Hz, 1H), 7.67 (dd, J=8.51, 1.65 Hz, 1H), 7.80 (s, 1H), 8.00 (s, 1H), 8.08 (d, J=8.51 Hz, 1H), 8.54 (s, 1H), 9.12 (s, 1H), 10.55 (s, 1H); ESIMS found for C 22 H 24 F 3 N 5 O m/z 432.2 (M+1).

4,4-Difluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl) cyclohexanecarboxamide 263

White solid (60.0 mg, 0.162 mmol, 46.0% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.63-1.76 (m, 2H), 1.76-1.91 (m, 2H), 1.95 (br d, J=12.90 Hz, 2H), 2.06-2.20 (m, 2H), 2.71 (br t, J=10.84 Hz, 1H), 3.83 (s, 3H), 7.30 (d, J=0.82 Hz, 1H), 7.67 (dd, J=8.37, 1.78 Hz, 1H), 7.79 (s, 1H), 8.01 (d, J=0.82 Hz, 1H), 8.09 (d, J=8.78 Hz, 1H), 8.53 (s, 1H), 9.13 (s, 1H), 10.64 (s, 1H); ESIMS found for C 20 H 20 F 2 N 4 O m/z 371.2 (M+1).

1-Methyl-N-(6-(1-methyl-1H-pyrazol-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide 264

White solid (36.5 mg, 0.104 mmol, 48.5% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.60-1.72 (m, 2H), 1.74-1.80 (m, 2H), 1.86 (td, J=11.60, 2.06 Hz, 2H), 2.16 (s, 3H), 2.45-2.56 (m, 1H), 2.81 (br d, J=11.25 Hz, 2H), 3.93 (s, 3H), 6.93 (d, J=2.20 Hz, 1H), 7.81 (d, J=2.20 Hz, 1H), 7.95-8.01 (m, 1H), 8.01-8.08 (m, 1H), 8.20 (s, 1H), 8.49 (s, 1H), 9.07 (s, 1H), 10.49 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

N-(6-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl) cyclopropanecarboxamide 265

Off-white solid (168.0 mg, 0.504 mmol, 87.3% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.78-0.90 (m, 4H), 2.03-2.13 (m, 1H), 2.77 (br s, 1H), 3.07 (t, J=5.35 Hz, 2H), 3.95 (s, 2H), 4.10 (t, J=5.35 Hz, 2H), 7.28 (s, 1H), 7.65 (dd, J=8.51, 1.65 Hz, 1H), 7.91 (s, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.49 (s, 1H), 9.10 (s, 1H), 10.87 (s, 1H); ESIMS found for C 19 H 19 N 5 O m/z 334.1 (M+1).

N-(6-(7-Methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide 266

White solid (75.0 mg, 0.216 mmol, 69.9% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.77-0.90 (m, 4H), 2.01-2.13 (m, 1H), 2.42 (s, 3H), 2.80 (t, J=5.35 Hz, 2H), 3.63 (s, 2H), 4.21 (t, J=5.35 Hz, 2H), 7.29 (s, 1H), 7.66 (dd, J=8.51, 1.65 Hz, 1H), 7.95 (s, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.49 (s, 1H), 9.10 (s, 1H), 10.87 (s, 1H); ESIMS found for C 20 H 21 N 5 O m/z 348.2 (M+1).

3,3-Difluoro-N-(6-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl) isoquinolin-3-yl)cyclobutanecarboxamide 267

Beige solid (65.0 mg, 0.164 mmol, 28.5% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.55 (br s, 2H), 2.75-2.88 (m, 4H), 2.93-3.10 (m, 1H), 3.94-4.10 (m, 1H), 4.21 (br s, 2H), 7.66 (dd, J=8.51, 1.65 Hz, 1H), 7.79 (s, 1H), 8.02 (s, 1H), 8.05 (d, J=8.51 Hz, 1H), 8.52 (s, 1H), 9.08 (s, 1H), 10.76 (s, 1H); ESIMS found for C 21 H 21 F 2 N 5 O m/z 398.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3,3-difluorocyclobutanecarboxamide 268

White solid (67.0 mg, 0.188 mmol, 49.3% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 2.39 (s, 3H), 2.76-2.92 (m, 4H), 3.27-3.36 (m, 1H), 3.67 (s, 3H), 7.12 (s, 1H), 7.62 (dd, J=8.51, 1.65 Hz, 1H), 7.93 (s, 1H), 8.09 (d, J=8.51 Hz, 1H), 8.55 (s, 1H), 9.13 (s, 1H), 10.80 (s, 1H); ESIMS found for C 19 H 18 F 2 N 4 O m/z 357.1 (M+1).

2,2,3,3-Tetramethyl-N-[6-(3-methylimidazol-4-yl)-3-isoquinolyl]cyclopropanecarboxamide 269

Light yellow solid (132.0 mg, 0.379 mmol, 65.3% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.19 (s, 6H), 1.28 (s, 6H), 1.63 (s, 1H), 3.83 (s, 3H), 7.26-7.40 (m, 1H), 7.64 (dd, J=8.51, 1.37 Hz, 1H), 7.75-7.87 (m, 1H), 8.00 (s, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.52 (s, 1H), 9.09 (s, 1H), 10.51 (s, 1H); ESIMS found for C 21 H 24 N 4 O m/z 349.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl) piperidine-4-carboxamide 270

Off-white solid (45.0 mg, 0.104 mmol, 44.9% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.61-1.75 (m, 2H), 1.75-1.86 (m, 2H), 1.98 (br d, J=1.92 Hz, 2H), 2.42-2.63 (m, 5H), 2.95 (br d, J=1.10 Hz, 2H), 3.97 (s, 3H), 6.60 (d, J=1.92 Hz, 1H), 7.54 (d, J=1.92 Hz, 1H), 7.66 (dd, J=8.37, 1.51 Hz, 1H), 8.07 (s, 1H), 8.14 (d, J=8.51 Hz, 1H), 8.58 (s, 1H), 9.18 (s, 1H), 10.60 (s, 1H); ESIMS found for C 22 H 24 F 3 N 5 O m/z 432.2 (M+1).

2-(4-Isobutylpiperazin-1-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]acetamide 272

Off-white solid (39.0 mg, 0.096 mmol, 29.1% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 0.85 (d, J=6.59 Hz, 6H), 1.76 (dquin, J=13.64, 6.81, 6.81, 6.81, 6.81 Hz, 1H), 2.06 (d, J=7.41 Hz, 2H), 2.41 (br s, 4H), 2.58 (br s, 4H), 3.22 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.43 (s, 1H), 9.04 (s, 1H), 9.92 (s, 1H); ESIMS found for C 23 H 30 N 6 O m/z 407.2 (M+1).

2-(3,3-Dimethylazetidin-1-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]acetamide 273

Off-white solid (51.0 mg, 0.146 mmol, 44.2% yield). 1 H NMR (DMSO-d 6 , 500 MHz) δ ppm 1.23 (s, 6H), 3.10 (s, 4H), 3.31 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.36 (s, 1H), 8.41 (s, 1H), 9.04 (s, 1H), 9.88 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl) acetamide 276

White solid (61.0 mg, 0.174 mmol, 51.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.44 (br d, J=5.21 Hz, 2H), 1.59 (quin, J=5.56 Hz, 4H), 2.53 (br s, 4H), 3.18 (s, 2H), 4.14 (s, 3H), 8.04 (dd, J=8.51, 1.65 Hz, 1H), 8.13 (d, J=8.51 Hz, 1H), 8.34 (s, 1H), 8.50 (s, 1H), 8.74 (s, 1H), 9.13 (s, 1H), 9.97 (s, 1H); ESIMS found for C 19 H 22 N 6 O m/z 351.2 (M+1).

2,2,3,3-Tetramethyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl) cyclopropane-1-carboxamide 277

White solid (6.0 mg, 0.017 mmol, 6.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.19 (s, 6H), 1.29 (s, 6H), 1.63 (s, 1H), 4.14 (s, 3H), 7.99 (dd, J=8.51, 1.37 Hz, 1H), 8.09 (d, J=8.51 Hz, 1H), 8.28 (s, 1H), 8.47 (s, 1H), 8.69 (s, 1H), 9.09 (s, 1H), 10.50 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

N-(6-(4-Methyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 278

Off-white solid (30.0 mg, 0.069 mmol, 30.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.60-1.74 (m, 2H), 1.80 (br d, J=10.70 Hz, 2H), 1.92-2.03 (m, 2H), 2.40-2.49 (m, 2H), 2.51-2.62 (m, 3H), 2.94 (br d, J=11.25 Hz, 2H), 3.88 (s, 3H), 7.90 (dd, J=8.51, 1.65 Hz, 1H), 8.19 (d, J=8.51 Hz, 1H), 8.27 (s, 1H), 8.63 (s, 1H), 8.65 (s, 1H), 9.22 (s, 1H), 10.63 (s, 1H); ESIMS found for C 21 H 23 F 3 N 6 O m/z 433.2 (M+1).

N-(6-(4,5-Dimethyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 279

Light pink solid (53.0 mg, 0.119 mmol, 51.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.62-1.73 (m, 2H), 1.80 (br d, J=11.53 Hz, 2H), 1.92-2.04 (m, 2H), 2.40-2.49 (m, 5H), 2.51-2.61 (m, 3H), 2.94 (br d, J=10.98 Hz, 2H), 3.70 (s, 3H), 7.82 (dd, J=8.51, 1.65 Hz, 1H), 8.14-8.22 (m, 2H), 8.62 (s, 1H), 9.21 (s, 1H), 10.63 (s, 1H); ESIMS found for C 22 H 25 F 3 N 6 O m/z 447.2 (M+1).

4-Fluoro-1-isobutyl-N-(6-(4-methyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl) piperidine-4-carboxamide 280

White solid (38.0 mg, 0.093 mmol, 25.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.88 (d, J=6.59 Hz, 6H), 1.79 (dquin, J=13.46, 6.79, 6.79, 6.79, 6.79 Hz, 1H), 1.92-2.02 (m, 2H), 2.09 (d, J=7.41 Hz, 3H), 2.12-2.21 (m, 3H), 2.74-2.83 (m, 2H), 3.89 (s, 3H), 7.97 (dd, J=8.51, 1.65 Hz, 1H), 8.24 (d, J=8.51 Hz, 1H), 8.36 (s, 1H), 8.60 (s, 1H), 8.66 (s, 1H), 9.28 (s, 1H), 10.06 (d, J=3.84 Hz, 1H); ESIMS found for C 22 H 27 FN 6 O m/z 411.2 (M+1).

4-Fluoro-1-isobutyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 281

Off-white solid (31.0 mg, 0.076 mmol, 20.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.88 (d, J=6.59 Hz, 6H), 1.79 (dquin, J=13.52, 6.71, 6.71, 6.71, 6.71 Hz, 1H), 1.91-2.01 (m, 2H), 2.06-2.22 (m, 6H), 2.78 (br d, J=7.96 Hz, 2H), 4.15 (s, 3H), 8.07 (dd, J=8.51, 1.65 Hz, 1H), 8.16 (d, J=8.78 Hz, 1H), 8.37 (s, 1H), 8.47 (s, 1H), 8.74 (s, 1H), 9.17 (s, 1H), 9.95 (d, J=4.12 Hz, 1H); ESIMS found for C 22 H 27 FN 6 O m/z 411.2 (M+1).

1-Ethyl-4-fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 282

Beige solid (6.0 mg, 0.016 mmol, 5.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.03 (t, J=7.14 Hz, 3H), 1.93-2.02 (m, 2H), 2.05-2.13 (m, 1H), 2.13-2.20 (m, 3H), 2.39 (q, J=7.14 Hz, 2H), 2.80-2.88 (m, 2H), 4.15 (s, 3H), 8.03-8.10 (m, 1H), 8.16 (d, J=8.51 Hz, 1H), 8.36 (s, 1H), 8.47 (s, 1H), 8.73 (s, 1H), 9.17 (s, 1H), 9.94 (d, J=4.12 Hz, 1H); ESIMS found for C 20 H 23 FN 6 O m/z 383.2 (M+1).

4,4-Difluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 283

Beige solid (7.7 mg, 0.017 mmol, 12.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.66-1.77 (m, 2H), 1.77-1.91 (m, 2H), 1.92-2.01 (m, 2H), 2.08-2.19 (m, 2H), 2.67-2.76 (m, 1H), 2.96 (t, J=4.80 Hz, 1H), 3.01 (t, J=4.80 Hz, 1H), 3.07 (t, J=5.35 Hz, 2H), 4.08 (s, 2H), 4.18 (t, J=5.35 Hz, 2H), 4.66 (dt, J=47.85, 4.95 Hz, 2H), 7.64 (dd, J=8.51, 1.37 Hz, 1H), 7.76 (s, 1H), 8.00 (s, 1H), 8.03 (d, J=8.78 Hz, 1H), 8.47 (s, 1H), 9.06 (s, 1H), 10.58 (s, 1H); ESIMS found for C 24 H 26 F 3 N 5 O m/z 458.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) acetamide 284

White gummy paste (53.0 mg, 0.150 mmol, 45.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (dt, J=6.52, 3.19 Hz, 4H), 2.66 (br t, J=5.90 Hz, 4H), 3.35 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.43 (s, 1H), 9.03 (s, 1H), 9.92 (s, 1H); ESIMS found for C 19 H 21 N 5 O m/z 336.2 (M+1).

N-(6-(1-Ethyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) acetamide 285

Dark pink paste (42.0 mg, 0.114 mmol, 63.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.44 (t, J=7.27 Hz, 3H), 1.78 (dt, J=6.66, 3.12 Hz, 4H), 2.62-2.69 (m, 4H), 3.35 (s, 2H), 4.18 (q, J=7.41 Hz, 2H), 7.78 (dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.09-8.14 (m, 2H), 8.43 (s, 2H), 9.03 (s, 1H), 9.92 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

N-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) acetamide 286

White paste (68.0 mg, 0.179 mmol, 59.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.98-1.05 (m, 2H), 1.08-1.13 (m, 2H), 1.78 (dt, J=6.86, 3.16 Hz, 4H), 2.62-2.69 (m, 4H), 3.35 (s, 2H), 3.78 (tt, J=7.34, 3.77 Hz, 1H), 7.79 (dd, J=8.51, 1.65 Hz, 1H), 8.01 (d, J=8.78 Hz, 1H), 8.08-8.15 (m, 2H), 8.43 (s, 1H), 8.48 (s, 1H), 9.03 (s, 1H), 9.92 (s, 1H); ESIMS found for C 21 H 23 N 5 O m/z 362.2 (M+1).

2-(Pyrrolidin-1-yl)-N-(6-(5-(trifluoromethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 287

White solid (83.0 mg, 0.203 mmol, 45.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (dt, J=6.72, 3.22 Hz, 4H), 2.61-2.70 (m, 4H), 3.36 (s, 2H), 7.60 (dd, J=8.37, 1.24 Hz, 1H), 7.93 (s, 1H), 8.12 (d, J=8.51 Hz, 1H), 8.40 (s, 1H), 8.46 (s, 1H), 9.14 (s, 1H), 10.01 (s, 1H); ESIMS found for C 19 H 8 F 3 N 5 O m/z 390.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) propanamide 288

White solid (58.8 mg, 0.158 mmol, 50.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.30 (d, J=6.86 Hz, 3H), 1.74 (br s, 4H), 2.57-2.69 (m, 4H), 3.28 (q, J=6.95 Hz, 1H), 3.90 (s, 3H), 7.76 (dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.06-8.12 (m, 2H), 8.36 (s, 1H), 8.43 (s, 1H), 9.03 (s, 1H), 9.95 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.1 (M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide 289

White paste (79.5 mg, 0.216 mmol, 65.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.09 (d, J=6.04 Hz, 3H), 1.42 (dddd, J=12.25, 10.33, 8.30, 6.45 Hz, 1H), 1.66-1.83 (m, 2H), 1.91-2.02 (m, 1H), 2.40 (q, J=8.78 Hz, 1H), 2.56-2.66 (m, 1H), 3.12 (d, J=16.19 Hz, 1H), 3.14-3.19 (m, 1H), 3.54 (d, J=16.47 Hz, 1H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.65 Hz, 1 H), 8.02 (d, J=8.51 Hz, 1H), 8.07-8.14 (m, 2H), 8.37 (s, 1H), 8.44 (s, 1H), 9.03 (s, 1H), 9.89 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylpyrrolidin-1-yl)acetamide 290

White solid (77.0 mg, 0.209 mmol, 66.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.09 (d, J=6.04 Hz, 3H), 1.42 (dddd, J=12.32, 10.39, 8.30, 6.31 Hz, 1H), 1.66-1.84 (m, 2H), 1.91-2.01 (m, 1H), 2.40 (q, J=8.78 Hz, 1H), 2.57-2.66 (m, 1H), 3.12 (d, J=16.47 Hz, 1H), 3.14-3.19 (m, 1H), 3.54 (d, J=16.19 Hz, 1H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.08-8.13 (m, 2H), 8.37 (s, 1H), 8.44 (s, 1H), 9.03 (s, 1H), 9.88 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

2-(3-Azabicyclo[3.1.0]hexan-3-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 291

White solid (72.0 mg, 0.207 mmol, 62.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.44 (td, J=7.55, 4.12 Hz, 1H), 0.70 (q, J=3.84 Hz, 1H), 1.40-1.48 (m, 2H), 2.57 (br d, J=8.23 Hz, 2H), 3.04 (d, J=8.78 Hz, 2H), 3.33 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.09 (s, 2H), 8.36 (s, 1H), 8.41 (s, 1H), 9.03 (s, 1H), 9.77 (s, 1H); ESIMS found for C 20 H 21 N 5 O m/z 348.2 (M+1).

2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 292

Beige solid (64.0 mg, 0.177 mmol, 53.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.34 (br d, J=6.86 Hz, 4H), 1.74 (br d, J=6.59 Hz, 4H), 3.19 (s, 2H), 3.34-3.39 (m, 2 H), 3.90 (s, 3H), 7.74-7.83 (m, 1H), 8.02 (d, J=8.78 Hz, 1H), 8.08-8.14 (m, 2H), 8.37 (s, 1H), 8.46 (s, 1H), 9.04 (s, 1H), 10.08 (s, 1H); ESIMS found for C 21 H 23 N 5 O m/z 362.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide 293

White solid (56.0 mg, 0.146 mmol, 44.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.93 (d, J=6.59 Hz, 3H), 1.18-1.29 (m, 2H), 1.32-1.43 (m, 1H), 1.64 (br d, J=11.25 Hz, 2H), 2.20 (td, J=11.53, 1.92 Hz, 2H), 2.87 (br d, J=11.53 Hz, 2H), 3.18 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.43 (s, 1H), 9.04 (s, 1H), 9.90 (s, 1H); ESIMS found for C 21 H 25 N 5 O m/z 364.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(trifluoromethyl) piperidin-1-yl)acetamide 294

Off-white solid (92.0 mg, 0.209 mmol, 63.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.56 (qd, J=12.44, 3.84 Hz, 2H), 1.83 (br d, J=12.62 Hz, 2H), 2.28 (td, J=11.94, 1.92 Hz, 2H), 2.30-2.39 (m, 1H), 3.00 (br d, J=11.53 Hz, 2H), 3.25 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.64, 1.51 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.44 (s, 1H), 9.04 (s, 1H), 9.98 (s, 1H); ESIMS found for C 21 H 22 F 3 N 5 O m/z 418.2 (M+1).

2-(4-(Difluoromethyl)piperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 295

Beige solid (70.0 mg, 0.167 mmol, 62.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.47 (qd, J=12.44, 3.84 Hz, 2H), 1.71 (br d, J=12.35 Hz, 2H), 1.75-1.90 (m, 1H), 2.23 (td, J=11.80, 1.92 Hz, 2H), 2.97 (br d, J=11.53 Hz, 2H), 3.23 (s, 2H), 3.90 (s, 3H), 5.95 (td, J=56.90, 4.40 Hz, 1H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.44 (s, 1H), 9.04 (s, 1H), 9.93 (s, 1H); ESIMS found for C 21 H 23 F 2 N 5 O m/z 400.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)acetamide 296

Off-white solid (60.0 mg, 0.152 mmol, 56.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.29 (s, 4H), 1.42 (br s, 4H), 2.56-2.64 (m, 4H), 3.24 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.64, 1.51 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.08-8.14 (m, 2H), 8.37 (s, 1H), 8.44 (s, 1H), 9.04 (s, 1H), 9.96 (s, 1H); ESIMS found for C 22 H 25 N 5 O m/z 376.2 (M+1).

N-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 297

Off-white solid (21.0 mg, 0.046 mmol, 24.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.97-1.06 (m, 2H), 1.08-1.14 (m, 2H), 1.60-1.73 (m, 2H), 1.79 (br d, J=10.43 Hz, 2H), 1.92-2.02 (m, 2H), 2.40-2.60 (m, 5H), 2.93 (br d, J=11.25 Hz, 2H), 3.78 (tt, J=7.44, 3.81 Hz, 1H), 7.76 (dd, J=8.51, 1.37 Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.04-8.11 (m, 2H), 8.45 (d, J=9.06 Hz, 2H), 9.02 (s, 1H), 10.47 (s, 1H); ESIMS found for C 24 H 26 F 3 N 5 O m/z 458.2 (M+1).

N-(6-(5-(Azetidin-1-ylmethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4,4-difluorocyclohexane-1-carboxamide 298

Beige solid (4.4 mg, 0.010 mmol, 3.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.67-2.02 (m, 8H), 2.07-2.19 (m, 2H), 2.67-2.77 (m, 1H), 3.11 (t, J=6.86 Hz, 4H), 3.77 (s, 2H), 3.92 (s, 3H), 7.67 (dd, J=8.51, 1.37 Hz, 1H), 7.75 (s, 1H), 7.93 (s, 1H), 8.05 (d, J=8.51 Hz, 1H), 8.46 (s, 1H), 9.09 (s, 1H), 10.60 (s, 1H); ESIMS found for C 24 H 27 F 2 N 5 O m/z 440.2 (M+1).

4,4-Difluoro-N-(6-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl) isoquinolin-3-yl)cyclohexane-1-carboxamide 299

Beige solid (26.4 mg, 0.058 mmol, 23.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.67 (br s, 4H), 1.69-1.91 (m, 4H), 1.95 (br d, J=12.90 Hz, 2H), 2.06-2.18 (m, 2H), 2.44 (br s, 4H), 2.71 (br t, J=10.84 Hz, 1H), 3.83 (s, 2H), 3.92 (s, 3H), 7.68 (dd, J=8.51, 1.65 Hz, 1H), 7.78 (s, 1H), 7.96 (s, 1H), 8.03 (d, J=8.51 Hz, 1H), 8.44 (s, 1H), 9.08 (s, 1H), 10.59 (s, 1H); ESIMS found for C 25 H 29 F 2 N 5 O m/z 454.2 (M+1).

4,4-Difluoro-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl) isoquinolin-3-yl)cyclohexane-1-carboxamide 300

White solid (10.6 mg, 0.023 mmol, 18.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.38 (br d, J=4.12 Hz, 2H), 1.44-1.53 (m, 4H), 1.66-1.90 (m, 4H), 1.92-2.01 (m, 2H), 2.06-2.18 (m, 2H), 2.36 (br d, J=1.65 Hz, 4H), 2.65-2.76 (m, 1H), 3.65 (s, 2H), 3.91 (s, 3H), 7.70 (dd, J=8.51, 1.65 Hz, 1H), 7.80 (s, 1H), 7.98-8.07 (m, 2H), 8.45 (s, 1H), 9.08 (s, 1H), 10.58 (s, 1H); ESIMS found for C 26 H 31 F 2 N 5 O m/z 468.2 (M+1).

7-(2-Fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-7-azaspiro[3.5]nonane-2-carboxamide 301

Beige solid (50.0 mg, 0.119 mmol, 18.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.53 (br t, J=5.35 Hz, 2H), 1.59 (br t, J=5.35 Hz, 2H), 1.97 (d, J=8.51 Hz, 4H), 2.30 (br s, 2H), 2.33-2.44 (m, 2H), 2.55 (dt, J=28.30, 5.20 Hz, 2H), 3.33-3.42 (m, 1H), 3.90 (s, 3H), 4.50 (dt, J=48.10, 5.25 Hz, 2H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 7.99 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.46 (s, 1H), 9.01 (s, 1H), 10.34 (s, 1H); ESIMS found for C 24 H 28 FN 5 O m/z 422.2 (M+1).

2-(Cyclobutyl(methyl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 302

Off-white solid (69.0 mg, 0.198 mmol, 59.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.53-1.69 (m, 2H), 1.81-1.92 (m, 2H), 1.97-2.07 (m, 2H), 2.23 (s, 3H), 3.03-3.10 (m, 1H), 3.11 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.03 (d, J=8.51 Hz, 1H), 8.08-8.14 (m, 2H), 8.37 (s, 1H), 8.43 (s, 1H), 9.04 (s, 1H), 9.91 (s, 1H); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

2-(Diethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) acetamide 303

White paste (74.0 mg, 0.219 mmol, 66.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.05 (t, J=7.14 Hz, 6H), 2.65 (q, J=7.14 Hz, 4H), 3.24 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.51, 1.37 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.08-8.14 (m, 2H), 8.37 (s, 1H), 8.43 (s, 1H), 9.03 (s, 1H), 9.93 (s, 1H); ESIMS found for C 19 H 23 N 5 O m/z 338.2 (M+1).

N-(6-(1-(Methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 304

Off-white solid (54.0 mg, 0.124 mmol, 44.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.60-1.72 (m, 2H), 1.79 (br d, J=10.15 Hz, 2H), 1.91-2.02 (m, 2H), 2.39-2.60 (m, 5H), 2.93 (br d, J=11.25 Hz, 2H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07 (s, 1H), 8.34 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.47 (s, 1H); ESIMS found for C 22 H 21 D 3 F 3 N 5 O m/z 435.2 (M+1).

N-(6-(1-(Methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) acetamide 305

White paste (80.0 mg, 0.236 mmol, 71.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (dt, J=6.59, 3.29 Hz, 4H), 2.62-2.70 (m, 4H), 3.35 (s, 2H), 7.77 (dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.36 (s, 1H), 8.43 (s, 1H), 9.03 (s, 1H), 9.92 (s, 1H); ESIMS found for C 19 H 18 D 3 N 5 O m/z 339.2 (M+1).

N-(6-(1-(Methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl) acetamide 306

Beige solid (82.0 mg, 0.233 mmol, 70.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.43 (br d, J=4.94 Hz, 2H), 1.59 (quin, J=5.56 Hz, 4H), 2.52 (br d, J=1.92 Hz, 4H), 3.17 (s, 2H), 7.77 (dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.78 Hz, 1H), 8.10 (s, 2H), 8.36 (s, 1H), 8.43 (s, 1H), 9.04 (s, 1H), 9.91 (s, 1H); ESIMS found for C 20 H 20 D 3 N 5 O m/z 353.2 (M+1).

N-(6-(3-Methylisoxazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl) piperidine-4-carboxamide 307

White solid (3.0 mg, 0.007 mmol, 2.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.61-1.73 (m, 2H), 1.80 (br d, J=10.43 Hz, 2H), 1.92-2.02 (m, 2H), 2.41-2.61 (m, 5H), 2.51 (s, 3H), 2.93 (br d, J=11.25 Hz, 2H), 7.68 (dd, J=8.37, 1.51 Hz, 1H), 8.04 (s, 1H), 8.11 (d, J=8.51 Hz, 1H), 8.54 (s, 1H), 9.13 (s, 1H), 9.34 (s, 1H), 10.56 (s, 1H); ESIMS found for C 22 H 23 F 3 N 4 O 2 m/z 433.2 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide 308

Off-white solid (16.0 mg, 0.038 mmol, 16.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.58-1.72 (m, 2H), 1.80 (br d, J=10.70 Hz, 2H), 1.91-2.03 (m, 2H), 2.40-2.61 (m, 5H), 2.94 (br d, J=11.25 Hz, 2H), 7.87 (dd, J=8.64, 1.51 Hz, 1H), 7.95 (s, 1H), 8.13 (d, J=8.51 Hz, 1H), 8.20 (s, 1H), 8.54 (s, 1H), 8.58 (s, 1H), 9.13 (s, 1H), 10.58 (s, 1H); ESIMS found for C 21 H 21 F 3 N 4 O 2 m/z 419.1 (M+1).

4-Fluoro-1-isobutyl-N-(6-(5-methyl-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl) piperidine-4-carboxamide 309

Off-white solid (20.0 mg, 0.049 mmol, 13.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.88 (d, J=6.59 Hz, 6H), 1.80 (dquin, J=13.55, 6.84, 6.84, 6.84, 6.84 Hz, 1H), 1.92-2.02 (m, 2H), 2.09 (d, J=7.41 Hz, 2H), 2.06-2.21 (m, 4H), 2.64 (s, 3H), 2.75-2.82 (m, 2H), 8.11 (dd, J=8.51, 1.65 Hz, 1H), 8.29 (d, J=8.51 Hz, 1H), 8.57 (s, 1H), 8.60 (s, 1H), 9.30 (s, 1H), 10.11 (d, J=3.57 Hz, 1H); ESIMS found for C 22 H 26 FN 5 O 2 m/z 412.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl) cyclopropyl)methyl)piperidine-4-carboxamide 310

Off-white solid (70.0 mg, 0.153 mmol, 76.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.73 (s, 2H), 0.93-0.99 (m, 2H), 1.60-1.72 (m, 2H), 1.73-1.82 (m, 2H), 1.89-2.00 (m, 2H), 2.49 (br s, 2H), 2.52-2.58 (m, 1H), 2.96 (br d, J=11.25 Hz, 2H), 3.90 (s, 3 H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found for C 24 H 26 F 3 N 5 O m/z 458.2 (M+1).

(S)-1-(2-Fluoropropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 311

White solid (71.0 mg, 0.180 mmol, 60.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.26 (dd, J=23.95, 6.35 Hz, 3H), 1.62-1.72 (m, 2H), 1.74-1.82 (m, 2H), 2.00-2.12 (m, 2H), 2.34-2.49 (m, 2H), 2.52-2.59 (m, 1H), 2.93 (brt, J=11.80 Hz, 2H), 3.90 (s, 3H), 4.75-4.94 (m, 1H), 7.74 (dd, J=8.51, 1.65 Hz, 1H), 8.00 (d, J=8.78 Hz, 1H), 8.04 (s, 1H), 8.07 (s, 1H), 8.34 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.45 (s, 1H); ESIMS found for C 22 H 26 FN 5 O m/z 396.2 (M+1).

2-Fluoro-2-methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl) propanamide 312

Off-white solid (21.0 mg, 0.067 mmol, 10.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.64 (d, J=22.00 Hz, 6H), 4.15 (s, 3H), 8.07 (dd, J=8.51, 1.65 Hz, 1H), 8.16 (d, J=8.51 Hz, 1H), 8.36 (s, 1H), 8.46 (s, 1H), 8.74 (s, 1H), 9.17 (s, 1H), 9.91 (d, J=3.57 Hz, 1H); ESIMS found for C 16 H 16 FN 5 O m/z 314.1 (M+1).

(R)-1-(2-Fluoropropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 313

White solid (30.0 mg, 0.076 mmol, 25.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.26 (dd, J=23.90, 6.30 Hz, 3H), 1.68 (q, J=11.53 Hz, 2H), 1.74-1.81 (m, 2H), 1.99-2.09 (m, 2H), 2.35-2.47 (m, 1H), 2.52-2.57 (m, 1H), 2.93 (br t, J=11.80 Hz, 2H), 3.90 (s, 3H), 4.74-4.94 (m, 1H), 7.74 (dd, J=8.51, 1.37 Hz, 1H), 8.00 (d, J=8.51 Hz, 1H), 8.03 (s, 1H), 8.07 (s, 1H), 8.35 (s, 1H), 8.44 (s, 1H), 9.02 (s, 1H), 10.46 (s, 1H); ESIMS found for C 22 H 26 FN 5 O m/z 396.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl) propanamide 314

Off-white solid (57.0 mg, 0.157 mmol, 51.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.20 (d, J=7.14 Hz, 3H), 1.39-1.46 (m, 2H), 1.53-1.64 (m, 4H), 2.52-2.58 (m, 2H), 3.44 (q, J=6.86 Hz, 1H), 3.90 (s, 3H), 7.76 (dd, J=8.51, 1.65 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.06-8.11 (m, 2H), 8.36 (s, 1H), 8.44 (s, 1H), 9.04 (s, 1H), 10.09 (s, 1H); ESIMS found for C 21 H 25 N 5 O m/z 364.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl-2,2,5,5-d 4 )acetamide 315

Beige solid (43.0 mg, 0.127 mmol, 42.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.76 (s, 4H), 3.36 (s, 2H), 3.90 (s, 3H), 7.77 (dd, J=8.64, 1.51 Hz, 1H), 8.02 (d, J=8.51 Hz, 1H), 8.10 (s, 2H), 8.37 (s, 1H), 8.43 (s, 1H), 9.03 (s, 1H), 9.93 (s, 1H); ESIMS found for C 19 H 17 D 4 N 5 O m/z 340.2 (M+1).

4-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperazine-1-carboxamide 316

Off-white solid (14.0 mg, 0.040 mmol, 46.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.20 (s, 3H), 2.29-2.35 (m, 4H), 3.48-3.54 (m, 4H), 3.90 (s, 3H), 7.68 (dd, J=8.51, 1.65 Hz, 1H), 7.94-8.00 (m, 2H), 8.06 (s, 1H), 8.14 (s, 1H), 8.33 (s, 1H), 8.97 (s, 1H), 9.13 (s, 1H); ESIMS found for C 19 H 22 N 6 O m/z 351.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) propanamide 317

White solid (75.0 mg, 0.215 mmol, 65.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.74 (4H, br s), 2.57-2.68 (4H, m), 3.25-3.30 (1H, m), 3.90 (3H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.08 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 9.94 (1H, s); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) propanamide 318

Light beige solid (89.0 mg, 0.255 mmol, 62.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.74 (4H, br s), 2.56-2.70 (4H, m), 3.25-3.30 (1H, m), 3.90 (3H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.08 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 9.94 (1H, s); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide 320

Brown solid (830.0 mg, 2.58 mmol, 78.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.67 (2H, quin, J=6.86 Hz), 1.79-1.90 (1H, m), 2.04-2.16 (1H, m), 2.87 (1H, dt, J=10.15, 6.31 Hz), 2.97 (1H, dt, J=10.15, 6.72 Hz), 3.35 (1H, br s), 3.80 (1H, dd, J=9.19, 5.35 Hz), 3.90 (3H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.09 (1H, br s), 8.09 (1H, s), 8.36 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.34 (1H, s); ESIMS found for C 18 H 19 N 5 O m/z 322.15 (M+1).

2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide 324

Off-white solid (32.0 mg, 0.089 mmol, 38.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.15 (3H, s), 2.21-2.35 (4H, m), 3.04 (2H, s), 3.14 (2H, s), 3.21-3.28 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.44 (1H, s), 9.01 (1H, s), 10.35 (1H, s); ESIMS found for C 21 H 23 N 5 O m/z 362.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,2,2-trifluoroacetyl)-2-azaspiro[3.3]heptane-6-carboxamide 325

White solid (26.0 mg, 0.059 mmol, 18.0% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.40-2.49 (4H, m), 3.22-3.31 (1H, m), 4.06-4.15 (2H, m), 4.44 (2H, br d, J=17.56 Hz), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.06 (1H, s), 8.09 (1H, d, J=1.10 Hz), 8.35 (1H, d, J=1.65 Hz), 8.46 (1H, s), 9.02 (1H, s), 10.47 (1H, s); ESIMS found for C 22 H 20 F 3 N 5 O 2 m/z 444.15 (M+1).

2-(2-Fluoroethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide 326

Beige solid (10.0 mg, 0.025 mmol, 24.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.23-2.36 (4H, m), 2.60 (2H, dt, J=29.00, 5.00 Hz), 3.13 (2H, s), 3.22 (2H, s), 3.24-3.29 (1H, m), 4.36 (2H, dt, J=48.00, 5.00 Hz), 7.74 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.44 (1H, s), 9.01 (1H, s), 10.36 (1H, s); ESIMS found for C 22 H 24 FN 5 O m/z 394.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 327

Beige solid (650.0 mg, 1.72 mmol, 46.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.11-1.27 (3H, m), 1.41-1.54 (2H, m), 1.83-1.96 (4H, m), 2.10-2.16 (1H, m), 2.18 (6H, s), 2.42-2.49 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, s), 8.35 (1H, s), 8.43 (1H, s), 9.02 (1H, s), 10.41 (1H, s); ESIMS found for C 22 H 27 N 5 O m/z 378.2 (M+1).

1-Benzoyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 328

White solid (65.0 mg, 0.148 mmol, 55.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.57-1.72 (2H, m), 1.75-2.00 (2H, m), 2.86 (2H, tt, J=11.18, 3.77 Hz), 3.04-3.19 (1H, m), 3.57-3.75 (1H, m), 3.90 (3H, s), 4.43-4.63 (1H, m), 7.38-7.43 (2H, m), 7.43-7.49 (3H, m), 7.75 (1H, dd, J=8.51, 1.37 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 10.54 (1H, s); ESIMS found for C 26 H 25 N 5 O 2 m/z 440.0 (M+1).

1-Acetyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 329

White solid (60.0 mg, 0.159 mmol, 59.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.47 (1H, qd, J=12.26, 4.39 Hz), 1.56-1.69 (1H, m), 1.77-1.91 (2H, m), 2.02 (3H, s), 2.58 (1H, td, J=12.62, 2.47 Hz), 2.75-2.84 (1H, m), 3.03-3.11 (1H, m), 3.88 (1H, br d, J=13.15 Hz), 3.90 (3H, s), 4.41 (1H, br d, J=13.17 Hz), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 10.53 (1H, s); ESIMS found for C 21 H 23 N 5 O 2 m/z 378.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(methylsulfonyl) piperidine-4-carboxamide 330

White solid (60.0 mg, 0.145 mmol, 54.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.65-1.77 (2H, m), 1.95 (2H, br dd, J=13.31, 2.61 Hz), 2.69 (1H, tt, J=11.25, 3.84 Hz), 2.76 (2H, td, J=11.94, 2.20 Hz), 2.89 (3H, s), 3.59-3.67 (2H, m), 3.90 (3H, s), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.01 (1H, d, J=8.51 Hz), 8.05 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.44 (1H, s), 9.03 (1H, s), 10.59 (1H, s); ESIMS found for C 20 H 23 N 5 O 3 S m/z 413.9 (M+1).

1′-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide 331

White solid (4.0 mg, 0.009 mmol, 3.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.44 (2H, qd, J=11.89, 3.57 Hz), 1.58-1.71 (4H, m), 1.73-1.87 (4H, m), 2.06-2.20 (4H, m), 2.12 (3H, s), 2.78 (2H, br d, J=11.53 Hz), 2.91 (2H, br d, J=11.25 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.78 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.42 (1H, s); ESIMS found for C 25 H 32 N 6 O m/z 433.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)piperidine-4-carboxamide 332

White solid (11.0 mg, 0.026 mmol, 8.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.43 (2H, qd, J=12.08, 4.39 Hz), 1.59-1.69 (4H, m), 1.79 (2H, br d, J=11.80 Hz), 2.08-2.17 (2H, m), 2.42 (1H, tt, J=11.35, 3.60 Hz), 2.51-2.58 (1H, m), 2.94 (2H, br d, J=11.53 Hz), 3.22-3.29 (2H, m), 3.87 (2H, br d, J=3.57 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.78 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.43 (1H, s); ESIMS found for C 24 H 29 N 5 O 2 m/z 420.0 (M+1).

trans-4-(Hydroxymethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 333

Light beige solid (215.0 mg, 0.59 mmol, 51.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.95 (2H, qd, J=12.72, 3.29 Hz), 1.31-1.39 (1H, m), 1.45 (2H, qd, J=12.72, 3.02 Hz), 1.80 (2H, br dd, J=13.17, 2.74 Hz), 1.84-1.93 (2H, m), 3.24 (2H, t, J=5.76 Hz), 3.90 (3H, s), 4.37 (1H, t, J=5.35 Hz), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.43 (1H, s), 9.02 (1H, s), 10.38 (1H, s); ESIMS found for C 21 H 24 N 4 O 2 m/z 365.0 (M+1).

Methyl 2-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl) piperidin-1-yl)acetate 334

White solid (20.0 mg, 0.049 mmol, 16.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.62-1.73 (2H, m), 1.74-1.82 (2H, m), 2.22 (2H, td, J=11.53, 2.20 Hz), 2.51-2.58 (1H, m), 2.84-2.92 (2H, m), 3.24 (2H, s), 3.62 (3H, s), 3.90 (3H, s), 7.74 (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), 8.44 (1H, s), 9.02 (1H, s), 10.45 (1H, s); ESIMS found for C 22 H 25 N 5 O 3 m/z 408.0 (M+1).

1-Benzyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 335

White solid (22.0 mg, 0.052 mmol, 17.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.60-1.72 (2H, m), 1.73-1.81 (2H, m), 1.98 (2H, td, J=11.60, 2.06 Hz), 2.51-2.57 (1H, m), 2.88-2.96 (2H, m), 3.24 (2H, s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.78 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.43 (1H, s); ESIMS found for C 26 H 27 N 5 O m/z 426.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl) acetyl)piperidine-4-carboxamide 336

White solid (21.0 mg, 0.047 mmol, 15.8% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.43-1.54 (1H, m), 1.55-1.66 (1H, m), 1.67-1.73 (4H, m), 1.84 (2H, br d, J=10.98 Hz), 2.48 (4H, br s), 2.56-2.66 (1H, m), 2.76-2.87 (1H, m), 2.97-3.07 (1H, m), 3.32 (2H, br s), 3.90 (3H, s), 4.11 (1H, br d, J=13.17 Hz), 4.40 (1H, br d, J=12.90 Hz), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 10.52 (1H, s); ESIMS found for C 25 H 30 N 6 O 2 m/z 447.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoacetamide 338

Beige solid (13.0 mg, 0.037 mmol, 33.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.55-2.60 (3H, m), 3.24 (2H, s), 3.62-3.70 (4H, m), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.09 (2H, s), 8.35 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.97 (1H, s); ESIMS found for C 19 H 21 N 5 O 2 m/z 352.0 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-2-carboxamide 340

Light beige solid (35.0 mg, 0.104 mmol, 56.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.31-1.41 (1H, m), 1.41-1.47 (2H, m), 1.47-1.56 (1H, m), 1.72-1.79 (1H, m), 1.84-1.91 (1H, m), 2.58-2.64 (1H, m), 2.93-3.00 (1H, m), 3.34 (1H, br dd, J=9.19, 3.16 Hz), 3.90 (3H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz), 8.01 (1H, d, J=8.51 Hz), 8.07 (1H, br s), 8.08 (1H, s), 8.35 (1H, s), 8.43 (1H, s), 9.03 (1H, s), 9.85 (1H, br s); ESIMS found for C 19 H 21 N 5 O m/z 336.0 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide 341

Beige solid (32.5 mg, 0.089 mmol, 34.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.95 (3H, d, J=6.59 Hz), 2.52-2.58 (1H, m), 2.58-2.65 (1H, m), 2.81 (1H, dt, J=11.80, 2.47 Hz), 3.15-3.23 (2H, m), 3.47 (1H, d, J=16.47 Hz), 3.58 (1H, td, J=10.70, 2.20 Hz), 3.68 (1H, dd, J=11.25, 2.74 Hz), 3.71-3.79 (1H, m), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.37 Hz), 8.03 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.11 (1H, br s), 8.37 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 9.97 (1H, s); ESIMS found for C 20 H 23 N 5 O 2 m/z 366.2 (M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide 342

Beige solid (37.0 mg, 0.101 mmol, 38.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.96 (3H, d, J=6.59 Hz), 2.55 (1H, ddd, J=11.80, 10.15, 3.02 Hz), 2.61 (1H, ddd, J=9.13, 6.24, 3.02 Hz), 2.81 (1H, dt, J=11.73, 2.50 Hz), 3.13-3.23 (2H, m), 3.47 (1H, d, J=16.47 Hz), 3.58 (1H, td, J=10.70, 2.20 Hz), 3.68 (1H, dd, J=11.25, 3.02 Hz), 3.74 (1H, dt, J=11.32, 2.71 Hz), 3.90 (3H, s), 7.77 (1H, dd, J=8.64, 1.51 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.10 (1H, br s), 8.36 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.97 (1H, s); ESIMS found for C 20 H 23 N 5 O 2 m/z 366.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methylmorpholino)acetamide 343

Beige solid (19.0 mg, 0.052 mmol, 15.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.07 (3H, d, J=6.31 Hz), 2.00 (1H, dd, J=10.98, 10.15 Hz), 2.30 (1H, td, J=11.39, 3.02 Hz), 2.73-2.79 (1H, m), 2.83 (1H, br d, J=11.25 Hz), 3.23 (2H, d, J=1.92 Hz), 3.53-3.66 (2H, m), 3.75-3.81 (1H, m), 3.90 (3H, s), 7.77 (1H, dd, J=8.64, 1.51 Hz), 8.02 (1H, d, J=8.78 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 10.00 (1H, s); ESIMS found for C 20 H 23 N 5 O 2 m/z 366.2 (M+1).

2-((2R,6S)-2,6-Dimethylmorpholino)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 344

Off-white solid (53.0 mg, 0.140 mmol, 46.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.07 (6H, d, J=6.31 Hz), 1.92 (2H, t, J=10.84 Hz), 2.82 (2H, br d, J=10.15 Hz), 3.22 (2H, s), 3.62-3.71 (2H, m), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.36 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 9.98 (1H, s); ESIMS found for C 21 H 25 N 5 O 2 m/z 380.2 (M+1).

2-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 345

Ash colored solid (22.0 mg, 0.061 mmol, 18.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.67 (1H, dt, J=9.61, 1.10 Hz), 1.87 (1H, dd, J=9.74, 1.78 Hz), 2.62 (1H, d, J=10.43 Hz), 2.95 (1H, dd, J=10.02, 1.51 Hz), 3.45 (2H, d, J=5.21 Hz), 3.59 (1H, dd, J=7.82, 1.78 Hz), 3.63 (1H, s), 3.88 (1H, d, J=7.68 Hz), 3.90 (3H, s), 4.41 (1H, s), 7.77 (1H, dd, J=8.64, 1.51 Hz), 8.03 (1H, d, J=8.78 Hz), 8.10 (1H, s), 8.11 (1H, br s), 8.37 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 9.92 (1H, s); ESIMS found for C 20 H 21 N 5 O 2 m/z 364.2 (M+1).

2-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 346

Ash colored solid (25.0 mg, 0.069 mmol, 18.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.63-1.70 (1H, m), 1.87 (1H, dd, J=9.74, 1.78 Hz), 2.62 (1H, d, J=10.15 Hz), 2.95 (1H, dd, J=10.02, 1.51 Hz), 3.45 (2H, d, J=4.94 Hz), 3.59 (1H, dd, J=7.68, 1.92 Hz), 3.63 (1H, s), 3.88 (1H, d, J=7.68 Hz), 3.90 (3H, s), 4.41 (1H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.03 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.11 (1H, br s), 8.37 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 9.92 (1H, s); ESIMS found for C 20 H 21 N 5 O 2 m/z 364.2 (M+1).

2-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 347

Off-white solid (8.0 mg, 0.021 mmol, 8.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.75-1.82 (2H, m), 1.86-1.94 (2H, m), 3.14 (2H, s), 3.17 (2H, br d, J=0.82 Hz), 3.48-3.55 (2H, m), 3.68 (2H, d, J=10.43 Hz), 3.90 (3H, s), 7.78 (1H, dd, J=8.51, 1.37 Hz), 8.03 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.11 (1H, s), 8.37 (1H, s), 8.46 (1H, s), 9.06 (1H, s), 10.15 (1H, s); ESIMS found for C 21 H 23 N 5 O 2 m/z 378.2 (M+1).

(S)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinopropanamide 348

Light yellow solid (68.0 mg, 0.186 mmol, 45.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.23 (3H, d, J=6.86 Hz), 2.51-2.57 (2H, m), 2.57-2.65 (2H, m), 3.45 (1H, q, J=6.77 Hz), 3.64 (4H, t, J=4.67 Hz), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.37 Hz), 8.02 (1H, d, J=8.51 Hz), 8.08 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.45 (1H, s), 9.04 (1H, s), 10.17 (1H, s); ESIMS found for C 20 H 23 N 5 O 2 m/z 366.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(morpholin-2-yl) acetamide 349

Off-white solid (275.0 mg, 0.783 mmol, 91.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.41-2.48 (2H, m), 2.57-2.69 (3H, m), 2.83 (1H, br dd, J=12.21, 2.06 Hz), 3.43 (1H, td, J=10.63, 3.43 Hz), 3.70 (1H, br d, J=10.70 Hz), 3.78-3.85 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.64, 1.51 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.43 (1H, s), 9.02 (1H, s), 10.41 (1H, s); ESIMS found for C 19 H 21 N 5 O 2 m/z 352.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylmorpholin-2-yl)acetamide 350

White solid (71.0 mg, 0.194 mmol, 68.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (1H, t, J=11.00 Hz), 1.97 (1H, td, J=11.32, 3.16 Hz), 2.18 (3H, s), 2.53 (1H, br d, J=5.49 Hz), 2.58 (1H, br dd, J=11.25, 1.37 Hz), 2.66 (1H, dd, J=14.68, 7.82 Hz), 2.74 (1H, br d, J=11.25 Hz), 3.50 (1H, td, J=11.11, 2.47 Hz), 3.72-3.80 (1H, m), 3.86-3.96 (1H, m), 3.90 (3H, s), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.45 (1H, s); ESIMS found for C 20 H 23 N 5 O 2 m/z 366.0 (M+1).

2-(4-Ethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) acetamide 351

Beige solid (52.0 mg, 0.137 mmol, 52.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.03 (3H, br s), 2.30-2.47 (4H, m), 2.53-2.74 (6H, m), 3.24 (2H, br s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.37 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.96 (1H, br s); ESIMS found for C 21 H 26 N 6 O m/z 379.2 (M+1).

2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 352

Beige solid (66.0 mg, 0.162 mmol, 66.7% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.99 (6H, d, J=6.59 Hz), 2.51-2.54 (2H, m), 2.57 (4H, br s), 2.61-2.69 (1H, m), 3.20 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.64, 1.51 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.36 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.89 (1H, s); ESIMS found for C 22 H 28 N 6 O m/z 393.0 (M+1).

2-(4-Cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 353

Beige solid (44.0 mg, 0.109 mmol, 44.7% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.26-0.32 (2H, m), 0.39-0.45 (2H, m), 1.66 (1H, tt, J=6.59, 3.43 Hz), 2.51-2.57 (4H, m), 2.62 (4H, br s), 3.20 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.78 Hz), 8.09 (2H, s), 8.36 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.92 (1H, s); ESIMS found for C 22 H 26 N 6 O m/z 391.0 (M+1).

2-(4-(2-Fluoroethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 354

Off-white solid (33.0 mg, 0.083 mmol, 25.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.54 (4H, br s), 2.57-2.60 (3H, m), 2.64 (4H, dt, J=28.60, 4.95 Hz), 3.22 (2H, s), 3.90 (3H, s), 4.54 (2H, dt, J=47.80, 4.70 Hz), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.93 (1H, s); ESIMS found for C 21 H 25 FN 6 O m/z 397.2 (M+1).

(S)-2-(2,4-Dimethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 355

Beige solid (20.0 mg, 0.053 mmol, 20.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.01 (3H, d, J=6.31 Hz), 1.87 (1H, br t, J=8.51 Hz), 2.11-2.19 (1H, m), 2.17 (3H, s), 2.51-2.57 (1H, m), 2.57-2.67 (3H, m), 2.83 (1H, dt, J=11.25, 3.02 Hz), 3.13 (1H, d, J=16.47 Hz), 3.43 (1H, d, J=16.74 Hz), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.11 (1H, br s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.92 (1H, s); ESIMS found for C 21 H 26 N 6 O m/z 379.2 (M+1).

1-(2-Hydroxyethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 358

White solid (41.0 mg, 0.108 mmol, 36.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.62-1.73 (2H, m), 1.73-1.81 (2H, m), 1.98 (2H, td, J=11.46, 2.06 Hz), 2.39 (2H, t, J=6.31 Hz), 2.52-2.57 (1H, m), 2.92 (2H, br d, J=11.53 Hz), 3.50 (2H, q, J=6.04 Hz), 3.90 (3H, s), 4.30 (1H, br t, J=5.35 Hz), 7.73 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.06 (1H, s), 8.33 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.39 (1H, s); ESIMS found for C 21 H 25 N 5 O 2 m/z 380.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyridin-2-ylmethyl) piperidine-4-carboxamide 359

Beige solid (11.0 mg, 0.026 mmol, 8.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.66-1.77 (2H, m), 1.77-1.84 (2H, m), 2.01-2.12 (2H, m), 2.53-2.62 (1H, m), 2.85-2.94 (2H, m), 3.60 (2H, s), 3.90 (3H, s), 7.25 (1H, dd, J=6.86, 5.49 Hz), 7.46 (1H, d, J=7.96 Hz), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.77 (1H, td, J=7.62, 1.78 Hz), 7.99 (1H, d, J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.33 (1H, s), 8.44 (1H, s), 8.49 (1H, br d, J=4.12 Hz), 9.02 (1H, s), 10.41 (1H, s); ESIMS found for C 25 H 26 N 6 O m/z 427.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxazol-2-ylmethyl) piperidine-4-carboxamide 360

White solid (65.0 mg, 0.156 mmol, 52.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.68 (2H, qd, J=12.21, 3.43 Hz), 1.79 (2H, br d, J=10.43 Hz), 2.07-2.18 (2H, m), 2.51-2.57 (1H, m), 2.85-2.94 (2H, m), 3.67 (2H, s), 3.90 (3H, s), 7.17 (1H, d, J=0.82 Hz), 7.73 (1H, dd, J=8.64, 1.51 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.06 (1H, s), 8.06 (1H, d, J=0.82 Hz), 8.33 (1H, s), 8.43 (1H, s), 9.01 (1H, s), 10.40 (1H, s); ESIMS found for C 23 H 24 N 6 O 2 m/z 416.95 (M+1).

(R)—N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-oxotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-carboxamide 362

White solid (120.0 mg, 0.360 mmol, 57.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.70-1.83 (2H, m), 2.02 (1H, dtd, J=12.49, 8.16, 8.16, 3.84 Hz), 2.08-2.18 (1H, m), 2.64 (1H, td, J=9.33, 6.86 Hz), 3.17 (1H, ddd, J=9.74, 6.17, 4.12 Hz), 3.90 (3H, s), 3.96 (1H, dd, J=9.06, 4.12 Hz), 4.99-5.10 (2H, m), 7.80 (1H, dd, J=8.51, 1.65 Hz), 8.04 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.38 (1H, s), 8.60 (1H, s), 9.09 (1H, s); ESIMS found for C 19 H 19 N 5 O m/z 334.1 (M+1).

(R)-1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide 363

Off-white solid (65.0 mg, 0.194 mmol, 62.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.74-1.82 (2H, m), 1.82-1.90 (1H, m), 2.17-2.28 (1H, m), 2.37-2.44 (1H, m), 2.42 (3H, s), 3.07 (1H, dd, J=9.88, 5.49 Hz), 3.17 (1H, ddd, J=8.92, 6.04, 3.16 Hz), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.03 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.44 (1H, s), 9.03 (1H, s), 9.92 (1H, s); ESIMS found for C 19 H 21 N 5 O m/z 336.2 (M+1).

N-(4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) cyclopropanecarboxamide 364

Beige solid (240.0 mg, 0.734 mmol, 95.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.80-0.86 (4H, m), 1.91 (1H, quin, J=6.24 Hz), 3.92 (3H, s), 7.99 (1H, dd, J=8.51, 1.37 Hz), 8.14 (1H, s), 8.19 (1H, d, J=8.78 Hz), 8.22 (1H, d, J=0.82 Hz), 8.49 (1H, s), 9.10 (1H, s), 10.48 (1H, s); ESIMS found for C 17 H 15 ClN 4 O m/z 327.1 (M+1).

trans-4-Amino-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) cyclohexane-1-carboxamide 365

Beige solid (350.0 mg, 1.00 mmol, 90.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.99-1.11 (2H, m), 1.42-1.64 (4H, m), 1.82 (4H, br d, J=11.80 Hz), 2.42-2.49 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.40 (1H, s); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 366

White solid (260.0 mg, 0.736 mmol, 73.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.53 (2H, qd, J=12.21, 3.98 Hz), 1.70 (2H, br d, J=10.98 Hz), 2.42-2.49 (2H, m), 2.60-2.70 (1H, m), 2.97 (2H, br d, J=14.00 Hz), 3.90 (3H, s), 7.58 (1H, dd, J=12.08, 1.10 Hz), 7.92 (1H, s), 8.11 (1H, s), 8.39 (1H, s), 8.49 (1H, s), 9.14 (1H, s), 10.56 (1H, s); ESIMS found for C 19 H 20 FN 5 O m/z 354.15 (M+1).

N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide 367

Beige solid (15.0 mg, 0.037 mmol, 16.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.61-1.72 (2H, m), 1.73-1.81 (3H, m), 1.83-1.92 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.59 (1H, m), 2.82-2.91 (2H, m), 3.90 (3H, s), 7.58 (1H, dd, J=12.08, 1.10 Hz), 7.92 (1H, s), 8.11 (1H, s), 8.39 (1H, s), 8.49 (1H, s), 9.15 (1H, s), 10.61 (1H, s); ESIMS found for C 23 H 28 FN 5 O m/z 410.2 (M+1).

N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoroethyl) piperidine-4-carboxamide 368

Off-white solid (26.0 mg, 0.065 mmol, 28.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.68 (2H, qd, J=12.21, 3.70 Hz), 1.75-1.83 (2H, m), 2.00-2.07 (2H, m), 2.52-2.57 (1H, m), 2.61 (2H, dt, J=28.30, 4.95 Hz), 2.94 (2H, br d, J=11.53 Hz), 3.90 (3H, s), 4.53 (2H, dt, J=48.10, 5.25 Hz), 7.59 (1H, dd, J=12.08, 1.37 Hz), 7.92 (1H, s), 8.11 (1H, d, J=0.82 Hz), 8.39 (1H, s), 8.50 (1H, s), 9.15 (1H, s), 10.62 (1H, s); ESIMS found for C 21 H 23 F 2 N 5 O m/z 400.2 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 369

Off-white solid (135.0 mg, 0.382 mmol, 74.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.53 (2H, qd, J=12.17, 3.84 Hz), 1.70 (2H, br dd, J=12.08, 1.65 Hz), 2.43-2.49 (2H, m), 2.63 (1H, tt, J=11.63, 3.74 Hz), 2.97 (2H, br d, J=12.08 Hz), 3.93 (3H, s), 7.89 (1H, d, J=11.80 Hz), 8.10 (1H, s), 8.26 (1H, d, J=7.41 Hz), 8.30 (1H, d, J=2.74 Hz), 8.49 (1H, s), 9.03 (1H, s), 10.44 (1H, s); ESIMS found for C 19 H 20 FN 5 O m/z 354.15 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide 370

Off-white solid (45.0 mg, 0.106 mmol, 53.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.61-1.72 (2H, m), 1.73-1.81 (3H, m), 1.83-1.92 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.58 (1H, m), 2.86 (2H, br d, J=11.25 Hz), 3.93 (3H, s), 7.89 (1H, d, J=11.53 Hz), 8.10 (1H, d, J=0.82 Hz), 8.27 (1H, d, J=7.41 Hz), 8.30 (1H, d, J=2.74 Hz), 8.50 (1H, s), 9.03 (1H, s), 10.49 (1H, s); ESIMS found for C 23 H 28 FN 5 O m/z 410.2 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-fluoroethyl) piperidine-4-carboxamide 371

White solid (30.0 mg, 0.072 mmol, 51.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.68 (2H, qd, J=12.21, 3.70 Hz), 1.76-1.83 (2H, m), 2.04 (2H, td, J=11.80, 2.20 Hz), 2.54 (1H, td, J=7.62, 3.98 Hz), 2.61 (2H, dt, J=28.35, 4.95 Hz), 2.94 (2H, br d, J=11.53 Hz), 3.93 (3H, s), 4.53 (2H, dt, J=47.80, 4.95 Hz), 7.89 (1H, d, J=11.53 Hz), 8.10 (1H, s), 8.27 (1H, d, J=7.68 Hz), 8.30 (1H, d, J=2.74 Hz), 8.50 (1H, s), 9.04 (1H, s), 10.49 (1H, s); ESIMS found for C 21 H 23 F 2 N 5 O m/z 400.2 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 372

Off-white solid (16.0 mg, 0.042 mmol, 13.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.58 (4H, br s), 3.22 (2H, s), 3.93 (3H, s), 7.92 (1H, d, J=11.53 Hz), 8.13 (1H, s), 8.32 (1H, d, J=3.02 Hz), 8.34 (1H, d, J=7.41 Hz), 8.49 (1H, s), 9.05 (1H, s), 9.95 (1H, s); ESIMS found for C 20 H 23 FN 6 O m/z 383.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-fluorocyclopropane-1-carboxamide 376

Beige solid (32.0 mg, 0.094 mmol, 19.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.33-1.42 (2H, m), 1.43-1.53 (2H, m), 2.39 (3H, s), 3.67 (3H, s), 7.13 (1H, s), 7.67 (1H, dd, J=8.51, 1.65 Hz), 7.97 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.46 (1H, s), 9.18 (1H, s), 10.28 (1H, s); ESIMS found for C 18 H 17 FN 4 O m/z 325.1 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl) cyclopropanecarboxamide 433

Beige solid (14.0 mg, 0.048 mmol, 10.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.79-0.91 (4H, m), 2.03-2.12 (1H, m), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.65 Hz), 8.11 (1H, d, J=8.78 Hz), 8.26 (1H, s), 8.47 (1H, s), 8.72 (1H, s), 9.12 (1H, s), 10.90 (1H, s); ESIMS found for C 16 H 15 N 5 O m/z 294.1 (M+1).

4,4-Difluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl) cyclohexane-1-carboxamide 441

White solid (57.8 mg, 0.156 mmol, 43.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.67-1.91 (4H, m), 1.96 (2H, br d, J=12.90 Hz), 2.08-2.18 (2H, m), 2.69-2.75 (1H, m), 4.14 (3H, s), 8.02 (1H, dd, J=8.51, 1.37 Hz), 8.11 (1H, d, J=8.51 Hz), 8.29 (1H, s), 8.50 (1H, s), 8.73 (1H, s), 9.12 (1H, s), 10.63 (1H, s); ESIMS found for C 9 H 19 F 2 N 5 O m/z 372.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 443

White solid (8.0 mg, 0.021 mmol, 10.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.13-1.23 (2H, m), 1.43-1.55 (2H, m), 1.83-1.96 (4H, m), 2.11-2.16 (1H, m), 2.18 (6H, s), 2.44-2.48 (1H, m), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.27 (1H, s), 8.49 (1H, s), 8.72 (1H, s), 9.11 (1H, s), 10.47 (1H, s); ESIMS found for C 21 H 26 N 6 O m/z 379.2 (M+1).

trans-N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide 448

Off-white solid (22.0 mg, 0.049 mmol, 14.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.82-0.95 (2H, m), 1.41-1.52 (3H, m), 1.79-1.91 (4H, m), 2.08 (2H, d, J=7.14 Hz), 2.14 (3H, s), 2.31 (8H, br s), 2.51-2.55 (1H, m), 4.14 (3H, s), 8.00 (1H, dd, J=8.51, 1.37 Hz), 8.10 (1H, d, J=8.51 Hz), 8.27 (1H, s), 8.50 (1H, s), 8.72 (1H, s), 9.10 (1H, s), 10.47 (1H, s); ESIMS found for C 25 H 33 N 7 O m/z 448.3 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 452

White solid (119.4 mg, 0.355 mmol, 77.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.54 (2H, qd, J=12.17, 3.84 Hz), 1.71 (2H, br d, J=11.25 Hz), 2.45-2.49 (2H, m), 2.65 (1H, tt, J=11.70, 3.67 Hz), 2.98 (2H, br d, J=12.08 Hz), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.37 Hz), 8.11 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.50 (1H, s), 8.73 (1H, s), 9.11 (1H, s), 10.48 (1H, s); ESIMS found for C 18 H 20 N 6 O m/z 337.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide 470

White solid (75.9 mg, 0.166 mmol, 79.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.73 (2H, br s), 0.93-1.00 (2H, m), 1.63-1.74 (2H, m), 1.78 (2H, br d, J=10.70 Hz), 1.95 (2H, brt, J=10.57 Hz), 2.52-2.60 (1H, m), 2.97 (2H, br d, J=10.98 Hz), 3.28 (2H, s), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.37 Hz), 8.11 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.50 (1H, s), 8.72 (1H, s), 9.11 (1H, s), 10.52 (1H, s); ESIMS found for C 23 H 25 F 3 N 6 O m/z 459.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-((3-methyloxetan-3-yl)methyl)piperidine-4-carboxamide 472

Beige solid (32.0 mg, 0.076 mmol, 21.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.31 (3H, s), 1.60-1.71 (2H, m), 1.72-1.80 (2H, m), 1.93-2.02 (2H, m), 2.48 (2H, br s), 2.52-2.59 (1H, m), 2.59-2.67 (2H, m), 4.14 (3H, s), 4.19 (2H, d, J=5.49 Hz), 4.36 (2H, d, J=5.76 Hz), 8.01 (1H, dd, J=8.51, 1.37 Hz), 8.11 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.50 (1H, s), 8.73 (1H, s), 9.11 (1H, s), 10.54 (1H, s); ESIMS found for C 23 H 28 N 6 O 2 m/z 421.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl) acetyl)piperidine-4-carboxamide 475

White solid (7.8 mg, 0.017 mmol, 20.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.44-1.55 (2H, m), 1.57-1.66 (2H, m), 1.67-1.73 (4H, m), 1.85 (2H, br d, J=10.43 Hz), 2.58-2.65 (1H, m), 2.82 (1H, ddd, J=11.32, 7.34, 4.39 Hz), 2.99-3.06 (1H, m), 3.16-3.21 (2H, m), 3.30-3.38 (2H, m), 4.10 (1H, br d, J=1.10 Hz), 4.14 (3H, s), 4.36-4.44 (1H, m), 8.01 (1H, dd, J=8.51, 1.37 Hz), 8.11 (1H, d, J=8.78 Hz), 8.28 (1H, s), 8.49 (1H, s), 8.71 (1H, s), 9.11 (1H, s), 10.56 (1H, s); ESIMS found for C 24 H 29 N 7 O 2 m/z 448.0 (M+1).

1′-Methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide 477

Off-white solid (65.0 mg, 0.150 mmol, 37.6% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.43 (2H, qd, J=11.94, 3.70 Hz), 1.57-1.70 (4H, m), 1.75-1.86 (4H, m), 2.08-2.19 (1H, m), 2.12 (3H, s), 2.51-2.57 (1H, m), 2.77 (2H, br d, J=11.53 Hz), 2.90 (2H, br d, J=11.25 Hz), 3.17 (2H, d, J=2.20 Hz), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.51 (1H, s), 8.72 (1H, s), 9.10 (1H, s), 10.51 (1H, s); ESIMS found for C 24 H 31 N 7 O m/z 434.25 (M+1).

(R)—N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)piperidine-3-carboxamide 481

White solid (80.4 mg, 0.239 mmol, 87.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.36-1.46 (1H, m), 1.56-1.64 (1H, m), 1.64-1.72 (1H, m), 1.84-1.92 (1H, m), 2.53-2.60 (1H, m), 2.63 (1H, dq, J=8.71, 4.41 Hz), 2.75 (1H, dd, J=11.94, 8.92 Hz), 2.81 (1H, dt, J=12.14, 3.95 Hz), 3.00 (1H, dd, J=11.94, 3.16 Hz), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.65 Hz), 8.11 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.49 (1H, s), 8.73 (1H, s), 9.10 (1H, s), 10.81 (1H, s); ESIMS found for C 18 H 20 N 6 O m/z 337.2 (M+1).

(R)-1-Isobutyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl) piperidine-3-carboxamide 483

White solid (45.9 mg, 0.117 mmol, 82.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.88 (3H, d, J=6.59 Hz), 0.91 (3H, d, J=6.59 Hz), 1.50-1.61 (2H, m), 1.65-1.73 (1H, m), 1.78-1.86 (2H, m), 2.08 (2H, br d, J=7.41 Hz), 2.10-2.16 (1H, m), 2.25-2.33 (1H, m), 2.55-2.62 (1H, m), 2.77 (2H, br d, J=7.68 Hz), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.65 Hz), 8.11 (1H, d, J=8.78 Hz), 8.28 (1H, s), 8.49 (1H, s), 8.73 (1H, s), 9.10 (1H, s), 10.73 (1H, s); ESIMS found for C 22 H 28 N 6 O m/z 393.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) acetamide 487

Off-white solid (18.2 mg, 0.054 mmol, 16.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (4H, dt, J=6.52, 3.19 Hz), 2.62-2.70 (4H, m), 3.36 (2H, s), 4.14 (3H, s), 8.04 (1H, dd, J=8.51, 1.37 Hz), 8.13 (1H, d, J=8.51 Hz), 8.34 (1H, s), 8.50 (1H, s), 8.74 (1H, s), 9.12 (1H, s), 9.98 (1H, s); ESIMS found for C 18 H 20 N 6 O m/z 337.15 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 500

Beige solid (5.0 mg, 0.014 mmol, 4.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.19 (3H, s), 2.34-2.46 (4H, m), 2.58 (4H, br s), 3.23 (2H, s), 4.14 (3H, s), 8.04 (1H, dd, J=8.51, 1.65 Hz), 8.14 (1H, d, J=8.51 Hz), 8.34 (1H, s), 8.50 (1H, s), 8.74 (1H, s), 9.13 (1H, s), 10.00 (1H, s); ESIMS found for C 19 H 23 N 7 O m/z 366.2 (M+1).

2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl) isoquinolin-3-yl)acetamide 513

White solid (12.2 mg, 0.034 mmol, 17.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.34 (4H, br d, J=7.14 Hz), 1.75 (4H, br d, J=6.86 Hz), 3.20 (2H, s), 3.37 (2H, br s), 4.14 (3H, s), 8.05 (1H, dd, J=8.51, 1.37 Hz), 8.14 (1H, d, J=8.51 Hz), 8.35 (1H, s), 8.52 (1H, s), 8.74 (1H, s), 9.12 (1H, s), 10.14 (1H, s); ESIMS found for C 20 H 22 N 6 O m/z 363.2 (M+1).

2-Fluoro-2-methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl) propanamide 517

Off-white solid (70.0 mg, 0.224 mmol, 50.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.64 (6H, d, J=21.70 Hz), 3.83 (3H, s), 7.32 (1H, d, J=1.10 Hz), 7.73 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 8.07 (1H, s), 8.14 (1H, d, J=8.51 Hz), 8.49 (1H, s), 9.18 (1H, s), 9.85 (1H, br d, J=3.57 Hz); ESIMS found for C 17 H 17 FN 4 O m/z 313.0 (M+1).

1-Fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclopropane-1-carboxamide 521

White solid (100.0 mg, 0.306 mmol, 63.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.34-1.42 (2H, m), 1.42-1.52 (2H, m), 3.83 (3H, s), 7.38 (1H, br s), 7.73 (1H, br d, J=8.51 Hz), 7.86 (1H, br s), 8.06 (1H, s), 8.14 (1H, d, J=8.51 Hz), 8.47 (1H, s), 9.19 (1H, s), 10.29 (1H, s); ESIMS found for C 17 H 15 FN 4 O m/z 311.1 (M+1).

2-Methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide 523

White solid (5.0 mg, 0.014 mmol, 7.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.15 (3H, s), 2.22-2.36 (4H, m), 3.04 (2H, s), 3.14 (2H, s), 3.22-3.29 (1H, m), 3.83 (3H, s), 7.30 (1H, d, J=1.10 Hz), 7.66 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 8.00 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.54 (1H, s), 9.11 (1H, s), 10.42 (1H, s); ESIMS found for C 21 H 23 N 5 O m/z 362.2 (M+1).

1-Fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 527

White solid (16.0 mg, 0.043 mmol, 10.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.30-1.42 (1H, m), 1.50-1.63 (2H, m), 1.68 (3H, br d, J=9.61 Hz), 1.85-2.02 (4H, m), 3.84 (3H, s), 7.32 (1H, d, J=1.10 Hz), 7.73 (1H, dd, J=8.51, 1.92 Hz), 7.80 (1H, s), 8.07 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.50 (1H, s), 9.17 (1H, s), 9.83 (1H, d, J=4.12 Hz); ESIMS found for C 20 H 21 FN 4 O m/z 353.15 (M+1).

trans-4-Methoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl) cyclohexane-1-carboxamide 528

White solid (96.6 mg, 0.265 mmol, 39.6% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.06-1.18 (2H, m), 1.44-1.56 (2H, m), 1.86-1.95 (2H, m), 2.04-2.12 (2H, m), 2.52-2.58 (1H, m), 3.07-3.16 (1H, m), 3.25 (3H, s), 3.82 (3H, s), 7.30 (1H, s), 7.66 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 7.99 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.52 (1H, s), 9.12 (1H, s), 10.50 (1H, s); ESIMS found for C 21 H 24 N 4 O 2 m/z 365.2 (M+1).

trans-4-(Hydroxymethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 531

Off-white solid (17.0 mg, 0.047 mmol, 7.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.95 (2H, qd, J=12.81, 3.29 Hz), 1.36 (1H, dtt, J=14.75, 5.90, 5.90, 3.05, 3.05 Hz), 1.45 (2H, qd, J=12.76, 3.16 Hz), 1.80 (2H, br dd, J=13.04, 2.61 Hz), 1.84-1.93 (2H, m), 2.51-2.54 (1H, m), 3.24 (2H, t, J=5.76 Hz), 3.82 (3H, s), 4.38 (1H, t, J=5.35 Hz), 7.30 (1H, d, J=1.10 Hz), 7.66 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 7.98 (1H, d, J=0.82 Hz), 8.08 (1H, d, J=8.51 Hz), 8.53 (1H, s), 9.12 (1H, s), 10.47 (1H, s); ESIMS found for C 21 H 24 N 4 O 2 m/z 365.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide 535

Orange solid (4.0 mg, 0.013 mmol, 3.5% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 3.23-3.32 (1H, m), 3.70-3.78 (2H, m), 3.83 (3H, s), 3.90-3.98 (2H, m), 7.31 (1H, d, J=1.10 Hz), 7.69 (1H, dd, J=8.51, 1.65 Hz), 7.80 (1H, s), 8.03 (1H, s), 8.10 (1H, d, J=8.51 Hz), 8.57 (1H, s), 9.13 (1H, s), 10.65 (1H, br s) ESIMS found for C 17 H 17 N 5 O m/z 308.15 (M+1).

(R)—N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide 537

Off-white solid (100.0 mg, 0.310 mmol, 69.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.84-1.97 (2H, m), 1.98-2.08 (1H, m), 2.20-2.31 (1H, m), 3.83 (3H, s), 3.84-3.90 (1H, m), 4.00-4.07 (1H, m), 4.54 (1H, dd, J=8.23, 5.76 Hz), 7.31 (1H, d, J=0.82 Hz), 7.70 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 8.05 (1H, s), 8.11 (1H, d, J=8.51 Hz), 8.52 (1H, s), 9.14 (1H, s), 9.79 (1H, s); ESIMS found for C 18 H 18 N 4 O 2 m/z 323.0 (M+1).

1-(2-Methoxyethyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl) piperidine-4-carboxamide 547

Yellow-white solid (5.0 mg, 0.013 mmol, 8.5% yield). 1 H NMR (499 MHz, METHANOL-d 4 ) δ ppm 1.88-1.98 (4H, m), 2.25 (2H, dt, J=11.05, 7.51 Hz), 2.56 (1H, dt, J=15.51, 7.62 Hz), 2.66 (2H, t, J=5.63 Hz), 3.12 (2H, br d, J=11.80 Hz), 3.36 (3H, s), 3.57 (2H, t, J=5.63 Hz), 3.85 (3H, s), 7.28 (1H, s), 7.64 (1H, dd, J=8.51, 1.65 Hz), 7.85 (1H, s), 7.94 (1H, s), 8.07 (1H, d, J=8.51 Hz), 8.51 (1H, s), 9.06 (1H, s); ESIMS found for C 22 H 27 N 5 O 2 m/z 394.2 (M+1).

1-Isobutyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 554

White solid (50.0 mg, 0.121 mmol, 31.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.85 (6H, d, J=6.59 Hz), 1.60-1.73 (2H, m), 1.74-1.81 (3H, m), 1.83-1.91 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.60 (1H, m), 2.86 (2H, br d, J=11.25 Hz), 3.83 (3H, s), 7.30 (1H, d, J=1.10 Hz), 7.66 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 8.00 (1H, s), 8.08 (1H, d, J=8.78 Hz), 8.54 (1H, s), 9.12 (1H, s), 10.52 (1H, s); ESIMS found for C 23 H 29 N 5 O m/z 392.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-1-(methylsulfonyl) piperidine-4-carboxamide 561

Beige solid (15.0 mg, 0.036 mmol, 21.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.64-1.77 (2H, m), 1.91-1.98 (2H, m), 2.65-2.73 (1H, m), 2.77 (2H, td, J=11.94, 2.20 Hz), 2.89 (3H, s), 3.59-3.67 (2H, m), 3.83 (3H, s), 7.30 (1H, d, J=1.10 Hz), 7.67 (1H, dd, J=8.64, 1.51 Hz), 7.78 (1H, s), 8.01 (1H, s), 8.09 (1H, d, J=8.51 Hz), 8.54 (1H, s), 9.13 (1H, s), 10.62 (1H, s); ESIMS found for C 20 H 23 N 5 O 3 S m/z 413.9 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) propanamide 579

White solid (15.0 mg, 0.043 mmol, 10.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.74 (4H, br s), 2.56-2.69 (4H, m), 3.28-3.31 (1H, m), 3.83 (3H, s), 7.31 (1H, s), 7.69 (1H, dd, J=8.51, 1.65 Hz), 7.80 (1H, s), 8.04 (1H, s), 8.10 (1H, d, J=8.51 Hz), 8.53 (1H, s), 9.13 (1H, s), 10.02 (1H, s); ESIMS found for C 20 H 23 N 5 O m/z 350.2 (M+1).

N-(6-(1H-Pyrazol-4-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide 643

Brown solid (31.0 mg, 0.082 mmol, 32.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.73 (2H, m), 1.73-1.80 (3H, m), 1.82-1.91 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.59 (1H, m), 2.86 (2H, br d, J=11.25 Hz), 7.80 (1H, dd, J=8.64, 1.51 Hz), 7.99 (1H, d, J=8.51 Hz), 8.09 (1H, s), 8.14 (1H, br s), 8.42 (1H, br s), 8.45 (1H, s), 9.02 (1H, s), 10.44 (1H, s), 13.09 (1H, br s); ESIMS found for C 22 H 27 N 5 O m/z 378.2 (M+1).

3,3-Difluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclobutane-1-carboxamide 699

Beige solid (8.0 mg, 0.023 mmol, 8.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.75-2.90 (5H, m), 7.89 (1H, dd, J=8.64, 1.78 Hz), 8.12 (1H, d, J=8.51 Hz), 8.24 (1H, s), 8.56 (1H, s), 8.57 (1H, s), 9.14 (1H, s), 9.20 (1H, s), 10.82 (1H, s); ESIMS found for C 17 H 13 F 2 N 3 OS m/z 346.05 (M+1).

2-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide 700

Beige solid (4.0 mg, 0.011 mmol, 12.8% yield). 1 H NMR (499 MHz, METHANOL-d 4 ) δ ppm 2.39 (3H, s), 2.42-2.55 (4H, m), 3.22-3.29 (1H, m), 3.41 (2H, s), 3.48 (2H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.05 (1H, d, J=8.51 Hz), 8.11 (1H, d, J=0.82 Hz), 8.40 (1H, s), 8.50 (1H, s), 9.02 (1H, s), 9.06 (1H, s); ESIMS found for C 20 H 20 N 4 OS m/z 365.1 (M+1).

1-Fluoro-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 704

Light pink solid (14.0 mg, 0.039 mmol, 17.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.28-1.42 (1H, m), 1.49-1.62 (2H, m), 1.68 (3H, br d, J=9.61 Hz), 1.85-2.02 (4H, m), 7.93 (1H, dd, J=8.64, 1.78 Hz), 8.15 (1H, d, J=8.78 Hz), 8.28 (1H, s), 8.49 (1H, s), 8.58 (1H, s), 9.18 (1H, s), 9.20 (1H, s), 9.87 (1H, d, J=4.12 Hz); ESIMS found for C 19 H 18 FN 3 OS m/z 355.9 (M+1).

trans-4-(Dimethylamino)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 707

White solid (48.0 mg, 0.126 mmol, 25.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.12-1.22 (2H, m), 1.42-1.54 (2H, m), 1.83-1.97 (4H, m), 2.11-2.16 (1H, m), 2.18 (6H, s), 2.43-2.49 (1H, m), 7.85 (1H, dd, J=8.64, 1.51 Hz), 8.10 (1H, d, J=8.51 Hz), 8.19 (1H, s), 8.52 (1H, s), 8.55 (1H, s), 9.12 (1H, s), 9.19 (1H, s), 10.49 (1H, s); ESIMS found for C 21 H 24 N 4 OS m/z 381.2 (M+1).

trans-4-((3-Fluoroazetidin-1-yl)methyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 711

Beige solid (22.0 mg, 0.052 mmol, 21.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.84-0.97 (2H, m), 1.21-1.33 (1H, m), 1.44 (2H, qd, J=12.76, 2.88 Hz), 1.80 (2H, br dd, J=12.76, 2.33 Hz), 1.86 (2H, br d, J=10.70 Hz), 2.29 (2H, d, J=6.86 Hz), 2.45-2.49 (1H, m), 2.97-3.08 (2H, m), 3.48-3.60 (2H, m), 5.12 (1H, dq, J=58.00, 5.20 Hz), 7.86 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.19 (1H, s), 8.52 (1H, s), 8.56 (1H, s), 9.12 (1H, s), 9.19 (1H, s), 10.49 (1H, s); ESIMS found for C 23 H 25 FN 4 OS m/z 425.2 (M+1).

N-(6-(Thiazol-5-yl)isoquinolin-3-yl)azetidine-3-carboxamide 713

Orange solid (6.0 mg, 0.019 mmol, 8.4% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 3.70 (2H, br t, J=7.96 Hz), 3.82 (1H, dt, J=15.09, 7.55 Hz), 3.87-3.93 (2H, m), 7.88 (1H, dd, J=8.51, 1.92 Hz), 8.11 (1H, d, J=8.51 Hz), 8.24 (1H, s), 8.57 (1H, br s), 8.57 (1H, s), 9.13 (1H, s), 9.20 (1H, s), 10.65 (1H, br s); ESIMS found for C 16 H 14 N 4 OS m/z 311.1 (M+1).

1-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 718

Beige solid (16.0 mg, 0.045 mmol, 21.1% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.62-1.73 (2H, m), 1.74-1.81 (2H, m), 1.87 (2H, td, J=11.53, 1.92 Hz), 2.16 (3H, s), 2.51-2.56 (1H, m), 2.81 (2H, br d, J=11.25 Hz), 7.86 (1H, dd, J=8.64, 1.51 Hz), 8.10 (1H, d, J=8.51 Hz), 8.20 (1H, s), 8.53 (1H, s), 8.55 (1H, s), 9.12 (1H, s), 9.19 (1H, s), 10.54 (1H, s); ESIMS found for C 19 H 20 N 4 OS m/z 352.9 (M+1).

1-(2,2-Difluoropropyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 731

White solid (54.3 mg, 0.131 mmol, 52.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.63 (3H, t, J=19.07 Hz), 1.68-1.75 (2H, m), 1.75-1.81 (2H, m), 2.22 (2H, td, J=11.66, 2.47 Hz), 2.51-2.60 (1H, m), 2.71 (2H, t, J=14.00 Hz), 2.95 (2H, br d, J=11.53 Hz), 7.86 (1H, dd, J=8.64, 1.78 Hz), 8.10 (1H, d, J=8.78 Hz), 8.21 (1H, d, J=0.82 Hz), 8.53 (1H, s), 8.56 (1H, s), 9.13 (1H, s), 9.19 (1H, s), 10.56 (1H, s); ESIMS found for C 21 H 22 F 2 N 4 OS m/z 417.2 (M+1).

1-(Oxetan-3-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 737

White solid (39.0 mg, 0.099 mmol, 42.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.64-1.73 (2H, m), 1.75-1.85 (4H, m), 2.53-2.61 (1H, m), 2.71-2.78 (2H, m), 3.35-3.41 (1H, m), 4.43 (2H, t, J=6.17 Hz), 4.53 (2H, t, J=6.45 Hz), 7.86 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.21 (1H, d, J=1.10 Hz), 8.55 (1H, s), 8.56 (1H, s), 9.12 (1H, s), 9.19 (1H, s), 10.56 (1H, s) ESIMS found for C 21 H 22 N 4 O 2 S m/z 395.1 (M+1).

1-(2-(Pyrrolidin-1-yl)acetyl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 741

White solid (124.6 mg, 0.277 mmol, 69.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.42-1.55 (1H, m), 1.57-1.68 (1H, m), 1.72 (4H, br s), 1.85 (2H, br d, J=10.98 Hz), 2.55 (4H, br s), 2.58-2.67 (1H, m), 2.78-2.88 (1H, m), 3.03 (1H, br t, J=11.94 Hz), 3.25-3.30 (1H, m), 3.44 (1H, br d, J=13.17 Hz), 4.07 (1H, br d, J=14.00 Hz), 4.40 (1H, br d, J=12.62 Hz), 7.87 (1H, dd, J=8.51, 1.65 Hz), 8.11 (1H, d, J=8.78 Hz), 8.21 (1H, s), 8.53 (1H, s), 8.56 (1H, s), 9.13 (1H, s), 9.19 (1H, s), 10.64 (1H, s); ESIMS found for C 24 H 27 N 5 O 2 S m/z 449.9 (M+1).

1′-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide 743

Beige solid (55.0 mg, 0.126 mmol, 36.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.43 (2H, qd, J=11.94, 3.70 Hz), 1.58-1.71 (4H, m), 1.75-1.87 (4H, m), 2.09-2.20 (3H, m), 2.12 (3H, s), 2.51-2.57 (1H, m), 2.77 (2H, br d, J=11.53 Hz), 2.90 (2H, br d, J=11.25 Hz), 7.86 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.20 (1H, s), 8.54 (1H, s), 8.55 (1H, s), 9.12 (1H, s), 9.19 (1H, s), 10.52 (1H, s); ESIMS found for C 24 H 29 N 5 OS m/z 436.2 (M+1).

2-(Pyrrolidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)propanamide 758

Beige solid (40.0 mg, 0.114 mmol, 26.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.30 (3H, d, J=6.86 Hz), 1.74 (4H, br s), 2.56-2.68 (4H, m), 3.27-3.34 (1H, m), 7.88 (1H, dd, J=8.64, 1.78 Hz), 8.12 (1H, d, J=8.78 Hz), 8.25 (1H, d, J=0.82 Hz), 8.53 (1H, s), 8.57 (1H, s), 9.13 (1H, s), 9.20 (1H, s), 10.04 (1H, s); ESIMS found for C 19 H 20 N 4 OS m/z 353.2 (M+1).

2-(Piperidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide 760

Yellow-white solid (8.0 mg, 0.023 mmol, 16.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.40-1.48 (2H, m), 1.59 (4H, dt, J=11.05, 5.59 Hz), 2.51-2.57 (4H, m), 3.18 (2H, s), 7.89 (1H, dd, J=8.51, 1.92 Hz), 8.13 (1H, d, J=8.51 Hz), 8.27 (1H, d, J=1.10 Hz), 8.53 (1H, s), 8.58 (1H, d, J=0.82 Hz), 9.14 (1H, s), 9.20 (1H, s), 9.99 (1H, s); ESIMS found for C 19 H 20 N 4 OS m/z 353.1 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide 767

Beige solid (10.0 mg, 0.027 mmol, 8.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.59 (4H, br s), 3.23 (2H, s), 7.89 (1H, dd, J=8.51, 1.65 Hz), 8.13 (1H, d, J=8.78 Hz), 8.28 (1H, s), 8.53 (1H, s), 8.58 (1H, s), 9.14 (1H, s), 9.20 (1H, s), 10.02 (1H, s); ESIMS found for C 19 H 21 N 5 OS m/z 368.0 (M+1).

2-Morpholino-N-(6-(thiazol-5-yl)isoquinolin-3-yl)acetamide 773

Pale green solid (43.0 mg, 0.121 mmol, 42.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.54-2.62 (4H, m), 3.26 (2H, s), 3.62-3.69 (4H, m), 7.89 (1H, dd, J=8.64, 1.78 Hz), 8.13 (1H, d, J=8.51 Hz), 8.27 (1H, s), 8.53 (1H, s), 8.58 (1H, s), 9.15 (1H, s), 9.20 (1H, s), 10.10 (1H, s); ESIMS found for C 18 H 18 N 4 O 2 S m/z 355.1 (M+1).

2-Fluoro-2-methyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)propanamide 784

Beige solid (40.0 mg, 0.098 mmol, 36.9% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.38 (2H, br d, J=3.29 Hz), 1.49 (4H, quin, J=5.21 Hz), 1.64 (6H, d, J=22.00 Hz), 2.37 (4H, br s), 3.65 (2H, s), 3.92 (3H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz), 7.82 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.13 (1H, s), 8.42 (1H, s), 9.13 (1H, s), 9.85 (1H, d, J=3.84 Hz); ESIMS found for C 23 H 28 FN 5 O m/z 410.2 (M+1).

2-(Diethylamino)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 785

Orange gum (200.0 mg, 0.460 mmol, 60.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.05 (6H, t, J=7.14 Hz), 1.34-1.42 (2H, m), 1.44-1.54 (4H, m), 2.36 (4H, br s), 2.64 (4H, q, J=6.95 Hz), 3.24 (2H, s), 3.64 (2H, s), 3.91 (3H, s), 7.72 (1H, dd, J=8.37, 1.51 Hz), 7.81 (1H, s), 8.04 (1H, d, J=8.51 Hz), 8.12 (1H, s), 8.45 (1H, s), 9.08 (1H, s), 9.93 (1H, s); ESIMS found for C 25 H 34 N 6 O m/z 435.3 (M+1).

2-(2-Fluoroethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl) isoquinolin-3-yl)-2-azaspiro[3.3]heptane-6-carboxamide 791

White solid (20.0 mg, 0.041 mmol, 23.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.38 (2H, br d, J=3.57 Hz), 1.45-1.54 (4H, m), 2.24-2.33 (4H, m), 2.36 (4H, br s), 2.60 (2H, dt, J=28.60, 4.95 Hz), 3.12 (2H, s), 3.22 (2H, s), 3.27 (1H, t, J=8.37 Hz), 3.65 (2H, s), 3.91 (3H, s), 4.36 (2H, dt, J=47.80, 4.95 Hz), 7.69 (1H, dd, J=8.51, 1.37 Hz), 7.80 (1H, s), 8.02 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.46 (1H, s), 9.06 (1H, s), 10.39 (1H, s); ESIMS found for C 28 H 35 FN 6 O m/z 491.3 (M+1).

trans-4-Methoxy-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 795

White solid (33.7 mg, 0.073 mmol, 54.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.07-1.18 (2H, m), 1.38 (2H, br d, J=3.29 Hz), 1.43-1.52 (6H, m), 1.89 (2H, br d, J=11.53 Hz), 2.04-2.12 (2H, m), 2.36 (4H, br s), 2.51-2.57 (1H, m), 3.12 (1H, tt, J=10.67, 4.15 Hz), 3.25 (3H, s), 3.64 (2H, s), 3.91 (3H, s), 7.69 (1H, dd, J=8.37, 1.51 Hz), 7.80 (1H, s), 8.02 (1H, d, J=8.51 Hz), 8.04 (1H, br s), 8.45 (1H, s), 9.07 (1H, s), 10.46 (1H, s); ESIMS found for C 27 H 35 N 5 O 2 m/z 462.3 (M+1).

trans-4-(Hydroxymethyl)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 798

White solid (50.6 mg, 0.110 mmol, 103% yield). 11 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.90-1.01 (2H, m), 1.32-1.42 (4H, m), 1.42-1.53 (6H, m), 1.80 (2H, br dd, J=13.04, 2.61 Hz), 1.85-1.91 (2H, m), 2.36 (4H, br s), 3.24 (2H, t, J=5.63 Hz), 3.64 (2H, s), 3.91 (3H, s), 4.39 (1H, t, J=5.21 Hz), 7.68 (1H, dd, J=8.37, 1.51 Hz), 7.80 (1H, s), 8.00-8.06 (2H, m), 8.46 (1H, s), 9.07 (1H, s), 10.42 (1H, s); ESIMS found for C 27 H 35 N 5 O 2 m/z 462.3 (M+1).

(R)—N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)pyrrolidine-2-carboxamide 803

Off-white solid (40.0 mg, 0.096 mmol, 58.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.38 (2H, br s), 1.46-1.52 (4H, m), 1.67 (2H, quin, J=6.79 Hz), 1.80-1.89 (1H, m), 2.05-2.15 (1H, m), 2.36 (4H, br s), 2.87 (1H, dt, J=10.15, 6.31 Hz), 2.97 (1H, dt, J=10.15, 6.72 Hz), 3.64 (2H, s), 3.80 (1H, dd, J=9.06, 5.49 Hz), 3.91 (3H, s), 7.71 (1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 8.04 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.46 (1H, s), 9.07 (1H, s), 10.36 (1H, s); ESIMS found for C 24 H 30 N 6 O m/z 419.3 (M+1).

N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(oxetan-3-yl)piperidine-4-carboxamide 826

Off-white solid (40.0 mg, 0.082 mmol, 27.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.34-1.42 (2H, m), 1.44-1.53 (4H, m), 1.63-1.73 (2H, m), 1.74-1.86 (4H, m), 2.36 (4H, br s), 2.53-2.61 (1H, m), 2.71-2.82 (2H, m), 3.40 (1H, br s), 3.65 (2H, br s), 3.91 (3H, s), 4.44 (2H, br t, J=5.90 Hz), 4.50-4.57 (2H, m), 7.69 (1H, dd, J=8.64, 1.51 Hz), 7.79 (1H, s), 7.99-8.06 (2H, m), 8.47 (1H, s), 9.07 (1H, s), 10.48 (1H, s); ESIMS found for C 28 H 36 N 6 O 2 m/z 489.3 (M+1).

1-Benzoyl-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl) isoquinolin-3-yl)piperidine-4-carboxamide 831

White solid (53.0 mg, 0.099 mmol, 58.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.38 (2H, br d, J=3.02 Hz), 1.45-1.54 (4H, m), 1.57-1.71 (2H, m), 1.74-1.86 (1H, m), 1.89-1.98 (1H, m), 2.36 (4H, br s), 2.45-2.49 (1H, m), 2.86 (2H, ddt, J=11.25, 7.55, 3.77, 3.77 Hz), 3.02-3.16 (1H, m), 3.65 (2H, s), 3.91 (3H, s), 4.46-4.61 (1H, m), 7.37-7.43 (2H, m), 7.43-7.49 (3H, m), 7.70 (1H, dd, J=8.51, 1.37 Hz), 7.80 (1H, s), 8.03 (1H, d, J=8.51 Hz), 8.06 (1H, s), 8.46 (1H, s), 9.08 (1H, s), 10.58 (1H, s); ESIMS found for C 32 H 36 N 6 O 2 m/z 537.3 (M+1).

N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl) tetrahydro-2H-pyran-4-carboxamide 839

White amorphous solid (25.8 mg, 0.060 mmol, 69.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.35-1.41 (2H, m), 1.46-1.52 (4H, m), 1.66-1.77 (4H, m), 2.36 (4H, br d, J=1.65 Hz), 2.77-2.88 (1H, m), 3.33-3.39 (2H, m), 3.65 (2H, s), 3.89-3.94 (2H, m), 3.91 (3H, s), 7.66-7.73 (1H, m), 7.80 (1H, s), 8.00-8.06 (2H, m), 8.46 (1H, s), 9.08 (1H, s), 10.52 (1H, s); ESIMS found for C 25 H 31 N 5 O 2 m/z 434.2 (M+1).

N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperidin-1-yl)acetamide 851

Off-white solid (180.0 mg, 0.391 mmol, 54.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.93 (3H, d, J=6.31 Hz), 1.20-1.30 (2H, m), 1.33-1.42 (3H, m), 1.44-1.53 (4H, m), 1.63 (2H, br d, J=11.53 Hz), 2.16-2.24 (2H, m), 2.36 (4H, br s), 2.87 (2H, br d, J=11.53 Hz), 3.18 (2H, s), 3.65 (2H, s), 3.91 (3H, s), 7.72 (1H, dd, J=8.51, 1.37 Hz), 7.82 (1H, s), 8.05 (1H, d, J=8.78 Hz), 8.12 (1H, s), 8.45 (1H, s), 9.08 (1H, s), 9.91 (1H, s); ESIMS found for C 27 H 36 N 6 O m/z 461.3 (M+1).

1-Fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 883

Off-white solid (36.5 mg, 0.099 mmol, 63.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.31-1.40 (1H, m), 1.51-1.62 (2H, m), 1.69 (3H, br d, J=9.33 Hz), 1.87-2.02 (4H, m), 2.83 (3H, s), 8.15 (1H, dd, J=8.51, 1.65 Hz), 8.24 (1H, d, J=8.51 Hz), 8.53 (1H, s), 8.58 (1H, s), 9.27 (1H, s), 9.97 (1H, d, J=3.84 Hz); ESIMS found for C 19 H 19 FN 4 OS m/z 371.1 (M+1).

trans-4-Methoxy-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl) cyclohexane-1-carboxamide 885

White solid (33.4 mg, 0.087 mmol, 21.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.08-1.19 (2H, m), 1.44-1.56 (2H, m), 1.88-1.94 (2H, m), 2.05-2.13 (2H, m), 2.52-2.58 (1H, m), 2.83 (3H, s), 3.09-3.17 (1H, m), 3.25 (3H, s), 8.09 (1H, dd, J=8.65, 1.51 Hz), 8.19 (1H, d, J=8.51 Hz), 8.44 (1H, s), 8.60 (1H, s), 9.21 (1H, s), 10.60 (1H, s); ESIMS found for C 20 H 22 N 4 O 2 S m/z 383.15 (M+1).

trans-4-(Hydroxymethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 888

White solid (12.4 mg, 0.032 mmol, 39.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.90-1.02 (2H, m), 1.30-1.40 (1H, m), 1.46 (2H, qd, J=12.76, 3.43 Hz), 1.81 (2H, br dd, J=13.04, 2.61 Hz), 1.86-1.93 (2H, m), 2.52-2.56 (1H, m), 2.83 (3H, s), 3.24 (2H, t, J=5.76 Hz), 4.39 (1H, t, J=5.35 Hz), 8.08 (1H, dd, J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51 Hz), 8.43 (1H, s), 8.61 (1H, s), 9.21 (1H, s), 10.57 (1H, s); ESIMS found for C 20 H 22 N 4 O 2 S m/z 383.1 (M+1).

1-(2-Fluoroethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl) piperidine-4-carboxamide 900

Beige solid (41.0 mg, 0.103 mmol, 19.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.69 (2H, qd, J=12.12, 3.70 Hz), 1.76-1.85 (2H, m), 2.02-2.09 (2H, m), 2.52-2.57 (1H, m), 2.62 (2H, dt, J=28.35, 4.95 Hz), 2.83 (3H, s), 2.95 (2H, br d, J=11.53 Hz), 4.54 (2H, dt, J=47.80, 4.95 Hz), 8.09 (1H, dd, J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51 Hz), 8.44 (1H, s), 8.63 (1H, s), 9.21 (1H, s), 10.62 (1H, s); ESIMS found for C 20 H 22 FN 5 OS m/z 400.15 (M+1).

1-Benzoyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide 921

Off-white solid (78.5 mg, 0.172 mmol, 42.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.64 (2H, br s), 1.77-1.89 (1H, m), 1.90-2.04 (1H, m), 2.78-2.92 (2H, m), 2.83 (3H, s), 3.10 (1H, tdd, J=5.01, 5.01, 2.88, 1.37 Hz), 3.58-3.76 (1H, m), 4.42-4.61 (1H, m), 7.37-7.43 (2H, m), 7.43-7.49 (3H, m), 8.10 (1H, dd, J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51 Hz), 8.46 (1H, d, J=0.82 Hz), 8.62 (1H, s), 9.22 (1H, s), 10.72 (1H, s); ESIMS found for C 25 H 23 N 5 O 52 S m/z 458.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl) acetamide 932

Beige solid (46.0 mg, 0.130 mmol, 21.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (7H, dt, J=6.86, 3.16 Hz), 2.62-2.70 (4H, m), 2.83 (3H, s), 3.38 (2H, s), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.21 (1H, d, J=8.51 Hz), 8.50 (1H, s), 8.61 (1H, s), 9.22 (1H, s), 10.08 (1H, s); ESIMS found for C 18 H 19 N 5 OS m/z 354.1 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(piperidin-1-yl) acetamide 939

Beige solid (77.0 mg, 0.210 mmol, 21.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.39-1.47 (2H, m), 1.59 (4H, quin, J=5.56 Hz), 2.52-2.57 (4H, m), 2.83 (3H, s), 3.19 (2H, s), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.21 (1H, d, J=8.51 Hz), 8.51 (1H, s), 8.61 (1H, s), 9.22 (1H, s), 10.06 (1H, s); ESIMS found for C 19 H 21 N 5 OS m/z 368.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 946

Beige solid (11.0 mg, 0.029 mmol, 8.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.59 (4H, br s), 2.83 (3H, s), 3.24 (2H, s), 8.12 (1H, dd, J=8.78, 1.65 Hz), 8.21 (1H, d, J=8.51 Hz), 8.51 (1H, s), 8.61 (1H, s), 9.23 (1H, s), 10.09 (1H, s); ESIMS found for C 19 H 22 N 6 OS m/z 383.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide 952

Pale yellow solid (11.0 mg, 0.030 mmol, 9.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.55-2.61 (4H, m), 2.83 (3H, s), 3.27 (2H, s), 3.62-3.70 (4H, m), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.21 (1H, d, J=8.78 Hz), 8.51 (1H, s), 8.62 (1H, s), 9.23 (1H, s), 10.17 (1H, s); ESIMS found for C 18 H 19 N 5 O 2 S m/z 370.1 (M+1).

(R)—N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(3-methylmorpholino)acetamide 953

Beige solid (66.0 mg, 0.172 mmol, 23.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.96 (3H, d, J=6.31 Hz), 2.54-2.60 (1H, m), 2.63 (1H, ddd, J=9.06, 6.17, 2.88 Hz), 2.80-2.82 (1H, m), 2.83 (3H, s), 3.19 (1H, dd, J=11.11, 8.92 Hz), 3.21 (1H, d, J=16.47 Hz), 3.49 (1H, d, J=16.47 Hz), 3.54-3.62 (1H, m), 3.68 (1H, dd, J=11.25, 3.02 Hz), 3.71-3.79 (1H, m), 8.08-8.18 (1H, m), 8.22 (1H, d, J=8.51 Hz), 8.51 (1H, s), 8.62 (1H, s), 9.23 (1H, s), 10.13 (1H, s); ESIMS found for C 19 H 21 N 5 O 2 S m/z 384.2 (M+1).

2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl) isoquinolin-3-yl)acetamide 959

Beige solid (27.0 mg, 0.071 mmol, 18.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.34 (4H, d, J=7.14 Hz), 1.71-1.79 (4H, m), 2.83 (3H, s), 3.21 (2H, s), 3.35-3.40 (2H, m), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.22 (1H, d, J=8.51 Hz), 8.52 (1H, s), 8.63 (1H, s), 9.22 (1H, s), 10.21 (1H, s); ESIMS found for C 20 H 21 N 5 OS m/z 380.1 (M+1).

2-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide 960

Off-white solid (110.0 mg, 0.288 mmol, 47.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.67 (1H, dd, J=9.74, 0.96 Hz), 1.87 (1H, dd, J=9.74, 1.78 Hz), 2.63 (1H, d, J=9.88 Hz), 2.83 (3H, s), 2.96 (1H, dd, J=9.88, 1.65 Hz), 3.48 (2H, d, J=4.94 Hz), 3.59 (1H, dd, J=7.68, 1.65 Hz), 3.64 (1H, s), 3.88 (1H, d, J=7.41 Hz), 4.41 (1H, s), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.22 (1H, d, J=8.78 Hz), 8.51 (1H, s), 8.62 (1H, s), 9.23 (1H, s), 10.07 (1H, s); ESIMS found for C 19 H 19 N 5 O 2 S m/z 382.1 (M+1).

2-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide 962

Off-white solid (175.0 mg, 0.065 mmol, 17.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.76-1.82 (2H, m), 1.87-1.94 (2H, m), 2.83 (3H, s), 3.16 (2H, s), 3.18 (2H, br d, J=1.10 Hz), 3.52 (2H, dd, J=10.57, 1.51 Hz), 3.68 (2H, d, J=10.43 Hz), 8.13 (1H, dd, J=8.51, 1.65 Hz), 8.22 (1H, d, J=8.78 Hz), 8.52 (1H, s), 8.63 (1H, s), 9.25 (1H, s), 10.28 (1H, s); ESIMS found for C 20 H 21 N 5 O 2 S m/z 396.15 (M+1).

N-(8-Fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide 963

Beige solid (25.0 mg, 0.065 mmol, 17.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.55-2.63 (4H, m), 2.83 (3H, s), 3.28 (2H, s), 3.61-3.69 (4H, m), 7.89 (1H, dd, J=11.11, 1.24 Hz), 8.40 (1H, s), 8.68 (1H, s), 9.34 (1H, s), 10.32 (1H, s); ESIMS found for C 18 H 18 FN 5 O 2 S m/z 388.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(phenylsulfonyl) piperidine-4-carboxamide 964

White solid (81.0 mg, 0.170 mmol, 63.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.62-1.75 (2H, m), 1.90 (2H, br dd, J=13.58, 2.88 Hz), 2.27-2.36 (2H, m), 2.51-2.56 (1H, m), 3.69 (2H, br d, J=12.08 Hz), 3.90 (3H, s), 7.65-7.70 (2H, m), 7.72-7.80 (4H, m), 7.99 (1H, d, J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.39 (1H, s), 9.01 (1H, s), 10.45 (1H, s); ESIMS found for C 25 H 25 N 5 O 3 S m/z 475.9 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl-d3) piperazin-1-yl)acetamide 965

Beige solid (70.0 mg, 0.191 mmol, 28.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.40 (4H, br s), 2.58 (4H, br s), 3.22 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.92 (1H, s); ESIMS found for C 20 H 21 [ 2 H 3 ]N 6 O m/z 368.2 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide 966

White solid (65.0 mg, 0.177 mmol, 80.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.62-1.72 (2H, m), 1.73-1.80 (2H, m), 1.86 (2H, td, J=11.66, 2.20 Hz), 2.16 (3H, s), 2.45-2.55 (1H, m), 2.76-2.85 (2H, m), 3.93 (3H, s), 7.89 (1H, d, J=11.80 Hz), 8.10 (1H, s), 8.26 (1H, d, J=7.41 Hz), 8.30 (1H, d, J=2.74 Hz), 8.49 (1H, s), 9.03 (1H, s), 10.49 (1H, s); ESIMS found for C 20 H 22 FN 5 O m/z 368.2 (M+1).

1-Ethyl-N-(7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) piperidine-4-carboxamide 967

White solid (20.0 mg, 0.052 mmol, 26.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.00 (3H, t, J=7.14 Hz), 1.67 (2H, td, J=12.21, 3.57 Hz), 1.75-1.81 (2H, m), 1.86 (2H, td, J=11.73, 2.06 Hz), 2.31 (2H, q, J=7.14 Hz), 2.51-2.58 (1H, m), 2.87-2.95 (2H, m), 3.93 (3H, s), 7.89 (1H, d, J=11.53 Hz), 8.10 (1H, d, J=0.82 Hz), 8.26 (1H, d, J=7.41 Hz), 8.30 (1H, d, J=2.47 Hz), 8.50 (1H, s), 9.03 (1H, s), 10.49 (1H, s); ESIMS found for C 21 H 24 FN 5 O m/z 382.2 (M+1).

N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 968

Beige solid (25.0 mg, 0.065 mmol, 23.1% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.33 (3H, br s), 2.52-2.77 (8H, m), 3.27 (2H, s), 3.90 (3H, s), 7.62 (1H, dd, J=12.08, 1.37 Hz), 7.99 (1H, s), 8.14 (1H, d, J=0.82 Hz), 8.41 (1H, s), 8.48 (1H, s), 9.17 (1H, s), 10.12 (1H, br s); ESIMS found for C 20 H 23 FN 6 O m/z 383.2 (M+1).

N-(6-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl) cyclohexanecarboxamide 969

Beige solid (79.0 mg, 0.189 mmol, 63.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.13-1.34 (3H, m), 1.39-1.51 (2H, m), 1.66 (1H, br d, J=11.25 Hz), 1.72-1.79 (2H, m), 1.82 (2H, brd, J=12.90 Hz), 1.94-2.11 (6H, m), 2.22 (3H, s), 2.52-2.60 (1H, m), 2.87 (2H, br d, J=11.25 Hz), 4.10-4.20 (1H, m), 7.77 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51 Hz), 8.05 (1H, s), 8.10 (1H, s), 8.43 (1H, s), 8.47 (1H, s), 9.01 (1H, s), 10.37 (1H, s) ESIMS found for C 25 H 31 N 5 O m/z 418.25 (M+1).

N-(6-(Isothiazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide 970

Beige solid (28.0 mg, 0.079 mmol, 17.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.63-1.74 (2H, m), 1.75-1.84 (2H, m), 1.88 (2H, td, J=11.46, 2.06 Hz), 2.17 (3H, s), 2.51-2.57 (1H, m), 2.81 (2H, br d, J=11.53 Hz), 7.95 (1H, dd, J=8.51, 1.65 Hz), 8.11 (1H, d, J=8.51 Hz), 8.35 (1H, s), 8.54 (1H, s), 9.12 (1H, s), 9.25 (1H, s), 9.59 (1H, s), 10.49 (1H, s); ESIMS found for C 19 H 20 N 4 OS m/z 352.9 (M+1).

1-Isobutyl-N-(6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 972

White solid (165.0 mg, 0.418 mmol, 49.8% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.72 (2H, m), 1.73-1.81 (3H, m), 1.82-1.91 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.59 (1H, m), 2.81-2.90 (2H, m), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.45 (1H, s); ESIMS found for C 23 H 26 [ 2 H 3 ]N 5 O m/z 395.2 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide 974

Beige solid (34.0 mg, 0.122 mmol, 25.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.78-0.91 (4H, m), 2.04-2.12 (1H, m), 7.86 (1H, dd, J=8.51, 1.65 Hz), 7.95 (1H, s), 8.13 (1H, d, J=8.78 Hz), 8.17 (1H, s), 8.50 (1H, s), 8.57 (1H, s), 9.14 (1H, s), 10.93 (1H, s); ESIMS found for C 16 H 13 N 3 O 2 m/z 280.1 (M+1).

(R)—N-(6-(Oxazol-5-yl)isoquinolin-3-yl)tetrahydrofuran-2-carboxamide 974

Light yellow solid (120.0 mg, 0.388 mmol, 41.0% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.83-1.97 (2H, m), 1.98-2.08 (1H, m), 2.20-2.31 (1H, m), 3.82-3.91 (1H, m), 3.97-4.06 (1H, m), 4.54 (1H, dd, J=8.37, 5.63 Hz), 7.90 (1H, dd, J=8.64, 1.51 Hz), 7.96 (1H, s), 8.16 (1H, d, J=8.51 Hz), 8.25 (1H, s), 8.52 (1H, s), 8.58 (1H, s), 9.15 (1H, s), 9.88 (1H, s); ESIMS found for C 17 H 15 N 3 O 3 m/z 310.1 (M+1).

(R)—N-(6-(Oxazol-5-yl)isoquinolin-3-yl)piperidine-3-carboxamide 975

Beige solid (19.0 mg, 0.059 mmol, 24.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.36-1.47 (1H, m), 1.56-1.64 (1H, m), 1.64-1.72 (1H, m), 1.87 (1H, dt, J=8.58, 4.08 Hz), 2.52-2.59 (1H, m), 2.59-2.67 (1H, m), 2.75 (1H, br dd, J=11.94, 8.92 Hz), 2.78-2.85 (1H, m), 2.99 (1H, br dd, J=12.08, 3.02 Hz), 7.86 (1H, dd, J=8.51, 1.65 Hz), 7.95 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.19 (1H, s), 8.52 (1H, s), 8.58 (1H, s), 9.12 (1H, s), 10.85 (1H, s); ESIMS found for C 18 H 18 N 4 O 2 m/z 323.0 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)tetrahydro-2H-pyran-4-carboxamide 976

Beige solid (17.5 mg, 0.054 mmol, 24.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.63-1.78 (4H, m), 2.78-2.87 (1H, m), 3.33-3.40 (2H, m), 3.88-3.96 (2H, m), 7.87 (1H, dd, J=8.64, 1.51 Hz), 7.95 (1H, s), 8.13 (1H, d, J=8.78 Hz), 8.20 (1H, s), 8.54 (1H, s), 8.58 (1H, s), 9.13 (1H, s), 10.60 (1H, s); ESIMS found for C 18 H 17 N 3 O 3 m/z 323.9 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-1-(2-(pyrrolidin-1-yl)acetyl)piperidine-4-carboxamide 977

White solid (33.4 mg, 0.077 mmol, 43.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.41-1.53 (1H, m), 1.55-1.66 (1H, m), 1.69 (4H, br s), 1.84 (2H, br d, J=10.98 Hz), 2.48 (4H, br s), 2.56-2.66 (1H, m), 2.82 (1H, ddt, J=11.25, 7.55, 3.91, 3.91 Hz), 3.01 (1H, brt, J=12.21 Hz), 3.14-3.21 (1H, m), 3.33-3.37 (1H, m), 4.11 (1H, br d, J=13.45 Hz), 4.40 (1H, br d, J=13.17 Hz), 7.87 (1H, dd, J=8.51, 1.10 Hz), 7.95 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.20 (1H, s), 8.53 (1H, s), 8.57 (1H, s), 9.14 (1H, s), 10.64 (1H, s); ESIMS found for C 24 H 27 N 5 O 3 m/z 434.0 (M+1).

1′-Methyl-N-(6-(oxazol-5-yl)isoquinolin-3-yl)-[1,4′-bipiperidine]-4-carboxamide 978

Beige solid (90.0 mg, 0.215 mmol, 61.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.43 (2H, qd, J=11.85, 3.43 Hz), 1.58-1.71 (4H, m), 1.75-1.86 (4H, m), 2.07-2.20 (3H, m), 2.12 (3H, s), 2.51-2.57 (1H, m), 2.77 (2H, br d, J=11.53 Hz), 2.90 (2H, br d, J=11.25 Hz), 7.86 (1H, dd, J=8.51, 1.65 Hz), 7.94 (1H, s), 8.12 (1H, d, J=8.78 Hz), 8.19 (1H, s), 8.54 (1H, s), 8.57 (1H, s), 9.12 (1H, s), 10.53 (1H, s); ESIMS found for C 24 H 29 N 5 O 2 m/z 420.2 (M+1).

cis-4-Morpholino-N-(6-(oxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 979

Off-white solid (125.0 mg, 0.308 mmol, 51.7% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.15-1.27 (2H, m), 1.42-1.55 (2H, m), 1.91 (4H, br t, J=12.62 Hz), 2.17-2.26 (1H, m), 2.45-2.49 (4H, m), 2.51-2.53 (1H, m), 3.52-3.59 (4H, m), 7.86 (1H, dd, J=8.51, 1.37 Hz), 7.95 (1H, s), 8.12 (1H, d, J=8.51 Hz), 8.18 (1H, s), 8.52 (1H, s), 8.57 (1H, s), 9.12 (1H, s), 10.53 (1H, s); ESIMS found for C 23 H 26 N 4 O 3 m/z 407.2 (M+1).

2-(Cyclobutyl(methyl)amino)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide 980

Beige solid (31.5 mg, 0.094 mmol, 49.2% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.54-1.69 (2H, m), 1.80-1.92 (2H, m), 1.98-2.06 (2H, m), 2.23 (3H, s), 3.03-3.11 (1H, m), 3.13 (2H, s), 7.89 (1H, dd, J=8.51, 1.65 Hz), 7.97 (1H, s), 8.16 (1H, d, J=8.51 Hz), 8.27 (1H, s), 8.53 (1H, s), 8.58 (1H, s), 9.15 (1H, s), 10.01 (1H, s); ESIMS found for C 19 H 20 N 4 O 2 m/z 337.1 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 981

Off-white solid (45.0 mg, 0.140 mmol, 42.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (4H, dt, J=6.79, 3.33 Hz), 2.62-2.70 (4H, m), 3.37 (2H, s), 7.89 (1H, dd, J=8.78, 1.65 Hz), 7.96 (1H, s), 8.15 (1H, d, J=8.51 Hz), 8.26 (1H, s), 8.53 (1H, s), 8.58 (1H, s), 9.14 (1H, s), 10.01 (1H, s); ESIMS found for C 18 H 18 N 4 O 2 m/z 323.1 (M+1).

(R)-2-(2-Methylpyrrolidin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl) acetamide 982

Beige solid (8.0 mg, 0.024 mmol, 23.8% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.09 (3H, d, J=6.04 Hz), 1.41 (1H, dddd, J=12.32, 10.39, 8.30, 6.31 Hz), 1.67-1.84 (2H, m), 1.91-2.02 (1H, m), 2.40 (1H, q, J=8.78 Hz), 2.57-2.66 (1H, m), 3.13 (1H, d, J=16.19 Hz), 3.13-3.20 (1H, m), 3.55 (1H, d, J=16.19 Hz), 7.89 (1H, dd, J=8.51, 1.65 Hz), 7.97 (1H, s), 8.16 (1H, d, J=8.51 Hz), 8.27 (1H, s), 8.53 (1H, s), 8.58 (1H, s), 9.14 (1H, s), 9.98 (1H, s); ESIMS found for C 19 H 20 N 4 O 2 m/z 337.2 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)acetamide 983

Pale yellow solid (43.0 mg, 0.122 mmol, 37.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.58 (4H, br s), 3.23 (2H, s), 7.89 (1H, dd, J=8.51, 1.65 Hz), 7.96 (1H, s), 8.15 (1H, d, J=8.78 Hz), 8.26 (1H, s), 8.53 (1H, s), 8.58 (1H, s), 9.15 (1H, s), 10.01 (1H, s); ESIMS found for C 19 H 21 N 5 O 2 m/z 352.2 (M+1).

N-(6-(5-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) tetrahydro-2H-pyran-4-carboxamide 984

Beige solid (30.0 mg, 0.082 mmol, 25.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.63-1.79 (4H, m), 2.77-2.87 (1H, m), 3.33-3.40 (2H, m), 3.91 (2H, br d, J=2.47 Hz), 3.93 (3H, s), 4.64 (2H, d, J=5.21 Hz), 5.56 (1H, t, J=5.35 Hz), 7.68 (1H, dd, J=8.51, 1.37 Hz), 7.81 (1H, s), 7.94 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.48 (1H, s), 9.09 (1H, s), 10.54 (1H, s); ESIMS found for C 20 H 22 N 4 O 3 m/z 367.0 (M+1).

N-(6-(5-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide 985

Beige solid (26.0 mg, 0.069 mmol, 12.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.62-1.73 (2H, m), 1.74-1.81 (2H, m), 1.86 (2H, td, J=11.60, 2.06 Hz), 2.16 (3H, s), 2.46-2.55 (1H, m), 2.77-2.85 (2H, m), 3.93 (3H, s), 4.63 (2H, d, J=5.21 Hz), 5.56 (1H, t, J=5.35 Hz), 7.67 (1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 7.94 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.48 (1H, s), 9.08 (1H, s), 10.50 (1H, s); ESIMS found for C 21 H 25 N 5 O 2 m/z 380.0 (M+1).

3,3-Difluoro-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl) isoquinolin-3-yl)cyclobutane-1-carboxamide 986

White solid (33.0 mg, 0.086 mmol, 28.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.75-2.90 (5H, m), 3.07 (2H, br t, J=5.21 Hz), 3.95 (2H, s), 4.11 (2H, t, J=5.35 Hz), 7.30 (1H, s), 7.68 (1H, dd, J=8.51, 1.65 Hz), 7.97 (1H, s), 8.07 (1H, d, J=8.51 Hz), 8.55 (1H, s), 9.11 (1H, s), 10.78 (1H, s); ESIMS found for C 20 H 19 F 2 N 5 O m/z 384.15 (M+1).

(R)—N-(6-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl) pyrrolidine-2-carboxamide 987

Beige solid (20.0 mg, 0.055 mmol, 34.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.67 (2H, quin, J=6.72 Hz), 1.78-1.90 (1H, m), 2.05-2.16 (1H, m), 2.87 (1H, dt, J=10.15, 6.45 Hz), 2.97 (1H, dt, J=10.15, 6.72 Hz), 3.07 (2H, t, J=5.49 Hz), 3.81 (1H, dd, J=9.06, 5.49 Hz), 3.95 (2H, s), 4.12 (2H, t, J=5.35 Hz), 7.30 (1H, s), 7.67 (1H, dd, J=8.51, 1.65 Hz), 7.98 (1H, s), 8.07 (1H, d, J=8.78 Hz), 8.52 (1H, s), 9.09 (1H, s), 10.38 (1H, s); ESIMS found for C 20 H 22 N 6 O m/z 363.2 (M+1).

(R)—N-(6-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl) piperidine-3-carboxamide 988

Dark brown gum (36.0 mg, 0.096 mmol, 55.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.31-1.56 (2H, m), 1.57-1.74 (2H, m), 2.32-2.46 (1H, m), 2.52-2.66 (2H, m), 2.70-2.88 (2H, m), 3.07 (2H, t, J=5.35 Hz), 3.95 (2H, s), 4.11 (2H, t, J=5.21 Hz), 7.29 (1H, s), 7.65 (1H, dd, J=8.51, 1.65 Hz), 7.93 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.51 (1H, s), 9.08 (1H, s), 10.79 (1H, s); ESIMS found for C 21 H 24 N 6 O m/z 377.0 (M+1).

1-Methyl-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide 989

White solid (3.0 mg, 0.008 mmol, 6.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.61-1.72 (2H, m), 1.73-1.80 (2H, m), 1.87 (2H, td, J=11.60, 2.06 Hz), 2.16 (3H, s), 2.51-2.56 (1H, m), 2.76-2.86 (3H, m), 3.07 (2H, brt, J=5.21 Hz), 3.95 (2H, s), 4.10 (2H, t, J=5.49 Hz), 7.28 (1H, s), 7.65 (1H, dd, J=8.51, 1.65 Hz), 7.93 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.52 (1H, s), 9.09 (1H, s), 10.51 (1H, s); ESIMS found for C 22 H 26 N 6 O m/z 391.2 (M+1).

N-(6-(5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide 990

Tan solid (31.0 mg, 0.062 mmol, 49.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.73 (2H, br s), 0.93-0.98 (2H, m), 1.62-1.71 (2H, m), 1.77 (2H, br d, J=10.70 Hz), 1.91-1.99 (2H, m), 2.53-2.59 (1H, m), 2.96 (2H, br d, J=11.25 Hz), 3.08 (2H, brt, J=5.21 Hz), 3.95 (2H, s), 4.11 (2H, br t, J=5.21 Hz), 7.29 (1H, s), 7.65 (1H, dd, J=8.51, 1.65 Hz), 7.94 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.52 (1H, s), 9.09 (1H, s), 10.51 (1H, s); ESIMS found for C 26 H 29 F 3 N 6 O m/z 499.2 (M+1).

1-Benzoyl-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide 991

White solid (27.7 mg, 0.058 mmol, 70.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.63 (2H, br s), 1.75-1.98 (2H, m), 2.69-2.96 (1H, m), 2.86 (2H, ddt, J=11.22, 7.51, 3.81, 3.81 Hz), 3.02-3.17 (1H, m), 3.07 (2H, brt, J=5.08 Hz), 3.95 (2H, s), 4.11 (2H, t, J=5.21 Hz), 7.29 (1H, s), 7.36-7.43 (2H, m), 7.43-7.50 (3H, m), 7.66 (1H, dd, J=8.51, 1.65 Hz), 7.94 (1H, s), 8.06 (1H, d, J=8.78 Hz), 8.52 (1H, s), 9.10 (1H, s), 10.61 (1H, s); ESIMS found for C 28 H 28 N 6 O 2 m/z 481.2 (M+1).

tert-Butyl 6-((6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl) isoquinolin-3-yl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate 992

White solid (200.0 mg, 0.367 mmol, 78.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.37 (11H, s), 1.45-1.54 (4H, m), 2.37 (4H, s), 2.38 (4H, s), 3.21-3.30 (1H, m), 3.65 (2H, s), 3.81 (2H, br s), 3.88 (2H, br s), 3.91 (3H, s), 7.69 (1H, dd, J=8.51, 1.65 Hz), 7.80 (1H, s), 8.02 (1H, d, J=8.78 Hz), 8.05 (1H, s), 8.47 (1H, s), 9.06 (1H, s), 10.44 (1H, s); ESIMS found for C 31 H 40 N 6 O 3 m/z 545.3 (M+1).

N-(6-(2-Methylthiazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 993

Beige solid (25.0 mg, 0.071 mmol, 21.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (4H, dt, J=6.79, 3.33 Hz), 2.62-2.69 (4H, m), 2.72 (3H, s), 3.36 (2H, s), 7.82 (1H, dd, J=8.51, 1.92 Hz), 8.10 (1H, d, J=8.51 Hz), 8.15 (1H, d, J=0.82 Hz), 8.30 (1H, s), 8.50 (1H, s), 9.11 (1H, s), 9.99 (1H, s); ESIMS found for C 19 H 20 N 4 OS m/z 353.1 (M+1).

N-(6-(2-Methylthiazol-5-yl)isoquinolin-3-yl)-2-morpholinoacetamide 994

Beige solid (44.0 mg, 0.119 mmol, 41.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.55-2.61 (4H, m), 2.72 (3H, s), 3.25 (2H, s), 3.60-3.68 (4H, m), 7.82 (1H, dd, J=8.64, 1.78 Hz), 8.10 (1H, d, J=8.51 Hz), 8.15 (1H, d, J=0.82 Hz), 8.30 (1H, s), 8.50 (1H, s), 9.12 (1H, s), 10.08 (1H, s); ESIMS found for C 19 H 20 N 4 O 2 S m/z 369.1 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl) acetamide 995

Brown solid (31.0 mg, 0.081 mmol, 31.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.58 (4H, br s), 2.72 (3H, s), 3.23 (2H, s), 7.82 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.15 (1H, s), 8.30 (1H, s), 8.50 (1H, s), 9.12 (1H, s), 10.00 (1H, s); ESIMS found for C 20 H 23 N 5 OS m/z 382.2 (M+1).

2-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)acetamide 996

Beige solid (50.0 mg, 0.131 mmol, 43.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.64-1.71 (1H, m), 1.87 (1H, dd, J=9.47, 1.78 Hz), 2.63 (1H, d, J=9.88 Hz), 2.72 (3H, s), 2.95 (1H, dd, J=9.88, 1.65 Hz), 3.46 (2H, d, J=4.39 Hz), 3.59 (1H, dd, J=7.68, 1.92 Hz), 3.63 (1H, s), 3.88 (1H, d, J=7.68 Hz), 4.41 (1H, s), 7.82 (1H, dd, J=8.64, 1.78 Hz), 8.10 (1H, d, J=8.51 Hz), 8.15 (1H, d, J=0.82 Hz), 8.30 (1H, s), 8.50 (1H, s), 9.12 (1H, s), 9.98 (1H, s); ESIMS found for C 20 H 20 N 4 O 2 S m/z 381.1 (M+1).

N-(6-(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide 997

Tan solid (33.6 mg, 0.067 mmol, 47.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.73 (2H, br s), 0.94-0.99 (2H, m), 1.62-1.72 (2H, m), 1.74-1.81 (2H, m), 1.91-1.99 (2H, m), 2.53-2.58 (1H, m), 2.93-2.99 (2H, m), 3.16 (2H, brt, J=5.21 Hz), 4.06 (2H, br t, J=5.35 Hz), 4.22 (2H, s), 7.63 (1H, dd, J=8.51, 1.65 Hz), 7.76 (1H, s), 7.98 (1H, s), 8.01 (1H, d, J=8.51 Hz), 8.47 (1H, s), 9.04 (1H, s), 10.46 (1H, s); ESIMS found for C 26 H 29 F 3 N 6 O m/z 499.25 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl) isoquinolin-3-yl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)piperidine-4-carboxamide 998

Off-white solid (15.0 mg, 0.028 mmol, 41.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.73 (2H, br s), 0.94-0.99 (2H, m), 1.62-1.72 (2H, m), 1.74-1.82 (2H, m), 1.91-1.99 (2H, m), 2.52-2.59 (1H, m), 2.93-3.03 (4H, m), 3.07 (2H, t, J=5.35 Hz), 4.08 (2H, s), 4.18 (2H, t, J=5.49 Hz), 4.66 (2H, dt, J=47.85, 4.70 Hz), 7.64 (1H, dd, J=8.51, 1.37 Hz), 7.76 (1H, s), 8.00 (1H, s), 8.02 (1H, d, J=8.51 Hz), 8.48 (1H, s), 9.05 (1H, s), 10.48 (1H, s); ESIMS found for C 28 H 32 F 4 N 6 O m/z 545.3 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl) isoquinolin-3-yl)-2-(pyrrolidin-1-yl)acetamide 999

Yellow oil (5.6 mg, 0.013 mmol, 38.4% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.78 (4H, dt, J=6.72, 3.22 Hz), 2.66 (4H, br s), 2.98 (3H, dt, J=28.55, 4.95 Hz), 3.07 (2H, t, J=5.49 Hz), 3.36 (2H, s), 4.09 (2H, s), 4.18 (2H, t, J=5.49 Hz), 4.66 (3H, dt, J=47.75, 4.95 Hz), 7.65 (1H, dd, J=8.51, 1.65 Hz), 7.82 (1H, s), 8.01 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.47 (1H, s), 9.06 (1H, s), 9.96 (1H, s); ESIMS found for C 23 H 27 FN 6 O m/z 423.2 (M+1).

2-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)acetamide 1000

Yellow solid (26.5 mg, 0.059 mmol, 52.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.35 (4H, br d, J=6.86 Hz), 1.69-1.79 (4H, m), 2.99 (2H, dt, J=28.90, 4.95 Hz), 3.08 (2H, br t, J=5.49 Hz), 3.19 (2H, s), 3.36 (2H, br s), 4.09 (2H, s), 4.18 (2H, br t, J=5.49 Hz), 4.66 (2H, dt, J=47.85, 4.95 Hz), 7.65 (1H, dd, J=8.51, 1.65 Hz), 7.82 (1H, s), 8.00 (1H, s), 8.05 (1H, d, J=8.78 Hz), 8.48 (1H, s), 9.06 (1H, s), 10.08 (1H, s); ESIMS found for C 25 H 29 FN 6 O m/z 449.25 (M+1).

cis-4-Methoxy-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl) cyclohexane-1-carboxamide 1001

White solid (33.4 mg, 0.087 mmol, 21.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.08-1.18 (2H, m), 1.45-1.55 (2H, m), 1.88-1.94 (2H, m), 2.05-2.11 (2H, m), 2.52-2.58 (1H, m), 2.83 (3H, s), 3.09-3.16 (1H, m), 3.25 (3H, s), 8.09 (1H, dd, J=8.65, 1.51 Hz), 8.19 (1H, d, J=8.51 Hz), 8.44 (1H, s), 8.60 (1H, s), 9.21 (1H, s), 10.60 (1H, s); ESIMS found for C 20 H 22 N 4 O 2 S m/z 383.15 (M+1).

(R)—N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl) isoquinolin-3-yl)-1-isobutylpiperidine-3-carboxamide 1002

Light yellow gum (31.1 mg, 0.065 mmol, 40.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.89 (6H, dd, J=11.11, 6.45 Hz), 1.50-1.58 (2H, m), 1.69 (1H, br dd, J=8.37, 3.98 Hz), 1.78-1.86 (2H, m), 2.11 (1H, d, J=7.14 Hz), 2.09-2.17 (1H, m), 2.28-2.37 (1H, m), 2.60-2.66 (1H, m), 2.75-2.84 (2H, m), 2.98 (3H, dt, J=28.60, 4.95 Hz), 3.07 (2H, brt, J=5.49 Hz), 4.07 (2H, s), 4.18 (2H, t, J=5.35 Hz), 4.66 (2H, dt, J=47.80, 4.95 Hz), 7.64 (1H, dd, J=8.51, 1.65 Hz), 7.75 (1H, s), 8.00 (1H, s), 8.02 (1H, d, J=8.78 Hz), 8.46 (1H, s), 9.05 (1H, s), 10.69 (1H, s); ESIMS found for C 27 H 35 FN 6 O m/z 479.3 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyrimidin-2-ylmethyl)piperidine-4-carboxamide 1003

Beige solid (75.0 mg, 0.175 mmol, 29.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.63-1.74 (2H, m), 1.74-1.82 (2H, m), 2.18 (2H, brt, J=10.70 Hz), 2.52-2.59 (1H, m), 2.98 (2H, br d, J=10.98 Hz), 3.74 (2H, s), 3.90 (3H, s), 7.41 (1H, t, J=4.80 Hz), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, d, J=0.82 Hz), 8.34 (1H, s), 8.44 (1H, s), 8.79 (2H, d, J=4.94 Hz), 9.02 (1H, s), 10.44 (1H, s); ESIMS found for C 24 H 25 N 7 O m/z 428.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(pyrazin-2-ylmethyl)piperidine-4-carboxamide 1004

Orange solid (20.0 mg, 0.047 mmol, 7.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.66-1.76 (2H, m), 1.76-1.83 (2H, m), 2.09 (2H, td, J=11.60, 2.33 Hz), 2.52-2.61 (1H, m), 2.90 (2H, br d, J=11.53 Hz), 3.67 (2H, s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.35 (1H, s), 8.44 (1H, s), 8.54 (1H, d, J=2.74 Hz), 8.58 (1H, dd, J=2.61, 1.51 Hz), 8.70 (1H, d, J=1.37 Hz), 9.02 (1H, s), 10.46 (1H, s); ESIMS found for C 24 H 25 N 7 O m/z 428.2 (M+1).

1-((5-Methyl-1,2,4-oxadiazol-3-yl)methyl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1005

White solid (45.0 mg, 0.104 mmol, 17.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.63-1.74 (2H, m), 1.78-1.84 (2H, m), 2.18 (2H, td, J=11.53, 2.20 Hz), 2.35 (3H, s), 2.52-2.57 (1H, m), 2.89-2.96 (2H, m), 3.87 (2H, s), 3.90 (3H, s), 7.74 (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), 8.44 (1H, s), 9.02 (1H, s), 10.45 (1H, s); ESIMS found for C 23 H 25 N 7 O 2 m/z 432.2 (M+1).

1-(2-Hydroxy-2-methylpropyl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1006

White solid (45.0 mg, 0.110 mmol, 18.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.09 (6H, s), 1.72 (4H, br d, J=2.74 Hz), 2.13 (2H, br s), 2.20 (2H, br s), 2.46-2.55 (1H, m), 2.99 (2H, br d, J=9.88 Hz), 3.90 (3H, s), 4.04 (1H, br s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.44 (1H, s); ESIMS found for C 23 H 29 N 5 O 2 m/z 408.2 (M+1).

2-Isopropoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide 1008

White solid (35.0 mg, 0.108 mmol, 18.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.20 (6H, d, J=6.04 Hz), 3.75 (1H, spt, J=6.13 Hz), 3.91 (3H, s), 4.15 (2H, s), 7.69 (1H, s), 7.73 (1H, dd, J=8.37, 1.78 Hz), 8.17 (1H, br s), 8.18 (1H, d, J=8.78 Hz), 8.51 (1H, s), 8.57 (1H, s), 9.20 (1H, s), 9.80 (1H, s); ESIMS found for C 18 H 20 N 4 O 2 m/z 325.2 (M+1).

3-Isopropoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl) propanamide 1009

White solid (105.0 mg, 0.310 mmol, 43.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.08 (6H, d, J=6.04 Hz), 2.66 (2H, t, J=6.31 Hz), 3.58 (1H, spt, J=6.08 Hz), 3.69 (2H, t, J=6.17 Hz), 3.84 (3H, s), 7.34 (1H, s), 7.67 (1H, dd, J=8.51, 1.65 Hz), 7.87 (1H, s), 8.03 (1H, d, J=0.82 Hz), 8.09 (1H, d, J=8.51 Hz), 8.55 (1H, s), 9.13 (1H, s), 10.55 (1H, s); ESIMS found for C 19 H 22 N 4 O 2 m/z 339.2 (M+1).

tert-Butyl 2-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) carbamoyl) piperidin-1-yl)acetate 1010

White solid (75.0 mg, 0.167 mmol, 18.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.42 (9H, s), 1.62-1.73 (2H, m), 1.74-1.81 (2H, m), 2.22 (2H, td, J=11.53, 2.20 Hz), 2.51-2.57 (1H, m), 2.83-2.91 (2H, m), 3.10 (2H, s), 3.90 (3H, s), 7.74 (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), 8.44 (1H, s), 9.02 (1H, s), 10.46 (1H, s); ESIMS found for C 25 H 31 N 5 O 3 m/z 450.2 (M+1).

2-(4-((6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-yl)acetic acid 1011

White solid. 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.76-1.90 (4H, m), 2.41-2.48 (2H, m), 2.57-2.66 (1H, m), 3.10-3.19 (4H, m), 3.90 (3H, s), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.36 (1H, br s), 8.44 (1H, s), 9.03 (1H, s), 10.53 (1H, s); ESIMS found for C 21 H 23 N 5 O 3 m/z 394.2 (M+1).

2-(4-Methyl-1,4-diazepan-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl)acetamide 1012

Off-white solid (40.0 mg, 0.106 mmol, 48.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (2H, quin, J=5.97 Hz), 2.28 (3H, s), 2.56-2.64 (4H, m), 2.79-2.87 (4H, m), 3.36 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.08-8.13 (2H, m), 8.36 (1H, s), 8.44 (1H, s), 9.04 (1H, s), 9.96 (1H, s); ESIMS found for C 21 H 26 N 6 O m/z 379.2 (M+1).

N-(7-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1013

Off-white solid (200.0 mg, 0.541 mmol, 99.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.75-1.85 (2H, m), 1.93-1.99 (2H, m), 2.79-2.90 (3H, m), 3.28-3.34 (2H, m), 3.93 (3H, s), 7.98 (1H, s), 8.11 (1H, s), 8.26 (1H, s), 8.31 (1H, s), 8.47 (1H, s), 9.09 (1H, s), 10.71 (1H, s); ESIMS found for C 19 H 20 ClN 5 O m/z 370.1 (M+1).

N-(6-(1-(Methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 1014

Light brown solid (92.0 mg, 0.250 mmol, 50.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.24 (3H, s), 2.46 (4H, br s), 2.60 (4H, br s), 3.23 (2H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.36 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.94 (1H, s); ESIMS found for C 20 H 21 [ 2 H 3 ]N 6 O m/z 368.2 (M+1).

N-(7-Fluoro-6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide 1015

Brown solid (20.0 mg, 0.054 mmol, 33.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.43 (2H, br d, J=5.21 Hz), 1.58 (4H, quin, J=5.56 Hz), 2.52 (4H, br s), 3.17 (2H, s), 7.92 (1H, d, J=11.53 Hz), 8.13 (1H, s), 8.31 (1H, d, J=2.47 Hz), 8.33 (1H, d, J=7.68 Hz), 8.49 (1H, s), 9.05 (1H, s), 9.93 (1H, s); ESIMS found for C 20 H 19 [ 2 H 3 ]FN 5 O m/z 371.2 (M+1).

N-(8-Fluoro-6-(1-(methyl-d3)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide 1016

Pale yellow solid (46.0 mg, 0.124 mmol, 40.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.43 (2H, br d, J=4.94 Hz), 1.58 (4H, quin, J=5.56 Hz), 2.51-2.57 (4H, m), 3.19 (2H, s), 7.62 (1H, dd, J=12.08, 1.10 Hz), 7.99 (1H, s), 8.13 (1H, s), 8.40 (1H, d, J=0.82 Hz), 8.48 (1H, s), 9.16 (1H, s), 10.04 (1H, s); ESIMS found for C 20 H 19 [ 2 H 3 ]FN 5 O m/z 371.2 (M+1).

trans-4-((3-Fluoroazetidin-1-yl)methyl)-N-(6-(2-methyloxazol-5-yl) isoquinolin-3-yl)cyclohexane-1-carboxamide 1018

Off-white solid (52.0 mg, 0.123 mmol, 51.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.91 (2H, qd, J=12.72, 3.02 Hz), 1.22-1.32 (1H, m), 1.44 (2H, qd, J=12.72, 3.29 Hz), 1.79 (2H, br dd, J=13.17, 2.47 Hz), 1.82-1.89 (2H, m), 2.29 (2H, d, J=6.59 Hz), 2.44-2.49 (1H, m), 2.53 (3H, s), 2.96-3.08 (2H, m), 3.49-3.59 (2H, m), 5.12 (1H, dq, J=58.00, 5.20 Hz), 7.78 (1H, s), 7.79-7.83 (1H, m), 8.06-8.12 (2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.48 (1H, s); ESIMS found for C 24 H 27 FN 4 O 2 m/z 423.2 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl) acetamide 1019

Off-white solid (60.0 mg, 0.164 mmol, 49.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.53 (3H, s), 2.58 (4H, br s), 3.23 (2H, s), 7.80 (1H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.12 (1H, d, J=8.51 Hz), 8.16 (1H, s), 8.50 (1H, s), 9.12 (1H, s), 10.00 (1H, s); ESIMS found for C 20 H 23 N 5 O 2 m/z 366.2 (M+1).

1-Isobutyl-N-(6-(5-methyl-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1020

Off-white solid (40.0 mg, 0.102 mmol, 34.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.73 (2H, m), 1.73-1.82 (3H, m), 1.83-1.92 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.59 (1H, m), 2.64 (3H, s), 2.87 (2H, br d, J=11.25 Hz), 8.04 (1H, dd, J=8.51, 1.37 Hz), 8.23 (1H, d, J=8.78 Hz), 8.47 (1H, s), 8.62 (1H, s), 9.24 (1H, s), 10.64 (1H, s); ESIMS found for C 22 H 27 N 5 O 2 m/z 394.2 (M+1).

4-Fluoro-1-isobutyl-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1021

White solid (66.0 mg, 0.147 mmol, 47.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.88 (6H, d, J=6.59 Hz), 1.75-1.86 (1H, m), 1.91-2.01 (2H, m), 2.05-2.22 (4H, m), 2.09 (2H, d, J=7.41 Hz), 2.78 (2H, br d, J=7.68 Hz), 3.07 (2H, br t, J=5.21 Hz), 3.95 (2H, s), 4.12 (2H, t, J=5.21 Hz), 7.31 (1H, s), 7.72 (1H, dd, J=8.64, 1.51 Hz), 8.02 (1H, s), 8.11 (1H, d, J=8.51 Hz), 8.49 (1H, s), 9.15 (1H, s), 9.91 (1H, d, J=4.12 Hz); ESIMS found for C 25 H 31 FN 6 O m/z 451.25 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1022

White solid (14.0 mg, 0.033 mmol, 46.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.54 (2H, qd, J=12.12, 3.70 Hz), 1.70 (2H, br d, J=10.98 Hz), 2.47 (2H, br s), 2.64 (1H, tt, J=11.46, 3.50 Hz), 2.93-3.04 (4H, m), 3.07 (2H, br t, J=5.49 Hz), 4.08 (2H, s), 4.18 (2H, t, J=5.35 Hz), 4.66 (2H, dt, J=47.80, 4.70 Hz), 7.63 (1H, dd, J=8.51, 1.65 Hz), 7.75 (1H, s), 8.00 (1H, s), 8.02 (1H, d, J=8.78 Hz), 8.48 (1H, s), 9.05 (1H, s), 10.42 (1H, s); ESIMS found for C 23 H 27 FN 6 O m/z 423.2 (M+1).

4-Fluoro-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-1-isobutylpiperidine-4-carboxamide 1023

White amorphous solid (48.8 mg, 0.098 mmol, 88.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.88 (6H, d, J=6.59 Hz), 1.79 (1H, dt, J=13.52, 6.83 Hz), 1.95 (2H, brt, J=11.66 Hz), 2.06-2.22 (4H, m), 2.09 (2H, d, J=7.68 Hz), 2.78 (2H, br d, J=7.96 Hz), 2.99 (2H, dt, J=28.60, 4.95 Hz), 3.08 (2H, t, J=5.49 Hz), 4.09 (2H, s), 4.18 (2H, t, J=5.49 Hz), 4.66 (2H, dt, J=47.85, 4.95 Hz), 7.70 (1H, dd, J=8.51, 1.65 Hz), 7.84 (1H, s), 8.01 (1H, s), 8.08 (1H, d, J=8.78 Hz), 8.45 (1H, s), 9.11 (1H, s), 9.86 (1H, d, J=4.39 Hz); ESIMS found for C 27 H 34 F 2 N 6 O m/z 497.3 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl) isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 1024

Orange solid (3.0 mg, 0.007 mmol, 4.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.19 (3H, s), 2.40 (4H, br s), 2.58 (4H, br s), 2.99 (2H, dt, J=28.60, 4.95 Hz), 3.07 (2H, t, J=5.49 Hz), 3.22 (2H, s), 4.09 (2H, s), 4.18 (2H, t, J=5.35 Hz), 4.66 (2H, dt, J=47.80, 4.95 Hz), 7.66 (1H, dd, J=8.51, 1.65 Hz), 7.82 (1H, s), 8.01 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.47 (1H, s), 9.07 (1H, s), 9.94 (1H, s); ESIMS found for C 24 H 30 FN 7 O m/z 452.2 (M+1).

tert-Butyl (6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamate 1025

White solid (96.0 mg, 0.296 mmol, 28.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.51 (9H, s), 3.90 (3H, s), 7.71 (1H, dd, J=8.51, 1.65 Hz), 7.97 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07 (1H, s), 8.10 (1H, s), 8.33 (1H, s), 8.97 (1H, s), 9.78 (1H, s); ESIMS found for C 18 H 20 N 4 O 2 m/z 325.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)but-2-ynamide 1026

Yellow solid (3.7 mg, 0.013 mmol, 2.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.05 (3H, s), 3.90 (3H, s), 7.78 (1H, dd, J=8.78, 1.65 Hz), 8.01 (1H, d, J=8.78 Hz), 8.08 (1H, s), 8.09 (1H, s), 8.34 (2H, s), 9.03 (1H, s), 11.06 (1H, br s); ESIMS found for C 17 H 14 N 4 O m/z 290.9 (M+1).

N-(7-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methylpiperidine-4-carboxamide 1027

White solid (2.0 mg, 0.005 mmol, 1.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.61-1.72 (2H, m), 1.73-1.80 (2H, m), 1.83-1.90 (2H, m), 2.16 (3H, s), 2.45-2.49 (1H, m), 2.81 (2H, br d, J=11.25 Hz), 3.93 (3H, s), 7.97 (1H, s), 8.09 (1H, s), 8.25 (1H, s), 8.30 (1H, s), 8.48 (1H, s), 9.08 (1H, s), 10.56 (1H, s); ESIMS found for C 20 H 22 ClN 5 O m/z 384.2 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)acetamide 1028

Off-white solid (57.0 mg, 0.163 mmol, 32.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.43 (2H, br d, J=5.21 Hz), 1.58 (4H, quin, J=5.56 Hz), 2.52 (4H, br s), 2.53 (3H, s), 3.18 (2H, s), 7.80 (1H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.12 (1H, d, J=8.78 Hz), 8.16 (1H, s), 8.50 (1H, s), 9.12 (1H, s), 9.98 (1H, s); ESIMS found for C 20 H 22 N 4 O 2 m/z 351.15 (M+1).

2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide 1029

Beige solid (200.0 mg, 0.506 mmol, 56.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.80-1.88 (2H, m), 2.00-2.06 (2H, m), 2.48 (2H, br s), 2.67 (2H, br d, J=10.98 Hz), 2.83 (3H, s), 3.20 (2H, s), 4.27 (2H, br d, J=1.92 Hz), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.20 (1H, d, J=8.78 Hz), 8.51 (1H, s), 8.61 (1H, s), 9.24 (1H, s), 10.09 (1H, s); ESIMS found for C 20 H 21 N 5 O 2 S m/z 396.15 (M+1).

(R)-2-(2-Methylpyrrolidin-1-yl)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)acetamide 1030

White solid (25.2 mg, 0.065 mmol, 36.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.09 (3H, d, J=6.04 Hz), 1.42 (1H, dddd, J=12.18, 10.26, 8.30, 6.59 Hz), 1.67-1.85 (2H, m), 1.90-2.02 (1H, m), 2.41 (1H, q, J=8.51 Hz), 2.57-2.67 (1H, m), 3.08 (2H, br t, J=5.21 Hz), 3.13-3.20 (2H, m), 3.54 (1H, d, J=16.19 Hz), 3.95 (2H, s), 4.12 (2H, t, J=5.21 Hz), 7.30 (1H, s), 7.68 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.51 (1H, s), 9.10 (1H, s), 9.93 (1H, s); ESIMS found for C 22 H 26 N 6 O m/z 391.2 (M+1).

2-(Cyclobutyl(methyl)amino)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)acetamide 1031

Light olive-colored gum (43.2 mg, 0.111 mmol, 46.4% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.54-1.71 (2H, m), 1.80-1.93 (2H, m), 1.96-2.07 (2H, m), 2.23 (3H, s), 3.12 (1H, br d, J=14.27 Hz), 3.06-3.09 (2H, m), 3.12 (2H, s), 3.95 (2H, s), 4.12 (2H, t, J=5.21 Hz), 7.30 (1H, s), 7.68 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.51 (1H, s), 9.11 (1H, s), 9.96 (1H, s); ESIMS found for C 22 H 26 N 6 O m/z 391.2 (M+1).

trans-4-((6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl) cyclohexane-1-carboxylic acid 1032

Beige solid (135.0 mg, 0.357 mmol, 70.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.29-1.40 (2H, m), 1.49 (2H, qd, J=12.76, 3.16 Hz), 1.85-1.94 (2H, m), 1.97 (2H, br dd, J=13.45, 2.74 Hz), 2.22 (1H, tt, J=12.18, 3.60 Hz), 2.51-2.58 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.03 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.43 (1H, s), 12.07 (1H, br s); ESIMS found for C 21 H 22 N 4 O 3 m/z 379.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-morpholinopropanamide 1034

White solid (12.0 mg, 0.033 mmol, 12.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.44 (4H, br s), 2.57-2.63 (2H, m), 2.63-2.70 (2H, m), 3.59 (4H, t, J=4.67 Hz), 3.90 (3H, s), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.06 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.44 (1H, s), 9.03 (1H, s), 10.74 (1H, s); ESIMS found for C 20 H 23 N 5 O 2 m/z 366.2 (M+1).

trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-morpholinocyclobutane-1-carboxamide 1035

White solid (18.0 mg, 0.075 mmol, 23.92% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.07-2.16 (2H, m), 2.22-2.32 (6H, m), 2.85-2.95 (1H, m), 3.22-3.30 (1H, m), 3.59 (4H, t, J=4.39 Hz), 3.91 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.47 (1H, s), 9.01 (1H, s), 10.41 (1H, s); ESIMS found for C 22 H 25 N 5 O 2 m/z 392. (M+1).

N-(6-(2-(Methylamino)thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1040

Beige solid (80.0 mg, 0.218 mmol, 91.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.46-1.60 (2H, m), 1.66-1.74 (2H, m), 2.43-2.49 (2H, m), 2.59-2.68 (1H, m), 2.89 (3H, d, J=4.94 Hz), 2.93-3.01 (2H, m), 7.69 (1H, s), 7.70-7.74 (1H, m), 7.78 (1H, s), 7.90-7.98 (2H, m), 8.40 (1H, s), 8.99 (1H, s), 10.40 (1H, s); ESIMS found for C 19 H 21 N 5 OS m/z 368.15 (M+1).

1-Methyl-N-(6-(2-(methylamino)thiazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1041

Yellow solid (32.0 mg, 0.084 mmol, 77.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.60-1.72 (2H, m), 1.73-1.80 (2H, m), 1.86 (2H, td, J=11.60, 2.06 Hz), 2.16 (3H, s), 2.44-2.49 (1H, m), 2.77-2.85 (2H, m), 2.89 (3H, d, J=4.94 Hz), 7.69 (1H, s), 7.72 (1H, dd, J=8.64, 1.78 Hz), 7.77 (1H, s), 7.89-7.97 (2H, m), 8.40 (1H, s), 8.99 (1H, s), 10.45 (1H, s); ESIMS found for C 20 H 23 N 5 OS m/z 382.2 (M+1).

N-(6-(2-(Diethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-fluoropiperidin-1-yl)acetamide 1047

Yellow solid (22.0 mg, 0.050 mmol, 26.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.21 (6H, t, J=7.14 Hz), 1.73-1.85 (2H, m), 1.86-1.99 (2H, m), 2.52-2.58 (2H, m), 2.66-2.75 (2H, m), 3.24 (2H, s), 3.52 (4H, q, J=7.14 Hz), 4.66-4.83 (1H, m), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, s), 7.86 (1H, s), 7.98 (1H, d, J=8.51 Hz), 8.40 (1H, s), 9.01 (1H, s), 9.97 (1H, s); ESIMS found for C 23 H 28 FN 5 OS m/z 442.2 (M+1).

N-(6-(2-(Diethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)acetamide 1048

Beige solid (25.0 mg, 0.057 mmol, 30.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.21 (6H, t, J=7.00 Hz), 2.19 (3H, s), 2.40 (4H, br s), 2.58 (4H, br s), 3.21 (2H, s), 3.52 (4H, q, J=7.14 Hz), 7.74 (1H, dd, J=8.64, 1.78 Hz), 7.79 (1H, s), 7.86 (1H, s), 7.98 (1H, d, J=8.51 Hz), 8.39 (1H, s), 9.01 (1H, s), 9.92 (1H, s); ESIMS found for C 23 H 30 N 6 OS m/z 439.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(1,4-oxazepan-4-yl) acetamide 1049

Beige solid (74.0 mg, 0.193 mmol, 35.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.87 (2H, quin, J=5.83 Hz), 2.83 (3H, s), 2.83-2.86 (4H, m), 3.43 (2H, s), 3.66-3.70 (2H, m), 3.74 (2H, t, J=6.04 Hz), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.21 (1H, d, J=8.51 Hz), 8.51 (1H, d, J=0.82 Hz), 8.62 (1H, s), 9.23 (1H, s), 10.15 (1H, s); ESIMS found for C 19 H 21 N 5 O 2 S m/z 384.15 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoacetamide-2,2-d 2 1051

White solid (20.0 mg, 0.054 mmol, 32.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.55-2.61 (4H, m), 2.83 (3H, s), 3.62-3.69 (4H, m), 8.12 (1H, dd, J=8.64, 1.78 Hz), 8.21 (1H, d, J=8.51 Hz), 8.51 (1H, s), 8.62 (1H, s), 9.23 (1H, s), 10.18 (1H, d, J=3.02 Hz); ESIMS found for C 18 H 17 [ 2 H 2 ]N 5 O 52 S m/z 372.1 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(morpholino-d 8 ) acetamide 1052

Off-white solid (22.0 mg, 0.058 mmol, 7.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.83 (3H, s), 3.26 (2H, s), 8.12 (1H, dd, J=8.51, 1.65 Hz), 8.21 (1H, d, J=8.51 Hz), 8.51 (1H, s), 8.62 (1H, s), 9.23 (1H, s), 10.17 (1H, s); ESIMS found for C 18 H 11 [ 2 H 8 ]N 5 O 2 S m/z 378.2 (M+1).

1-(2,2-Difluoropropyl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1057

White solid (22.5 mg, 0.056 mmol, 22.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.63 (3H, t, J=19.07 Hz), 1.67-1.74 (2H, m), 1.75-1.81 (2H, m), 2.22 (2H, td, J=11.60, 2.06 Hz), 2.52-2.60 (1H, m), 2.71 (2H, t, J=14.13 Hz), 2.95 (2H, br d, J=11.53 Hz), 7.87 (1H, dd, J=8.51, 1.65 Hz), 7.95 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.20 (1H, s), 8.54 (1H, s), 8.58 (1H, s), 9.13 (1H, s), 10.58 (1H, s); ESIMS found for C 21 H 22 F 2 N 4 O 2 m/z 401.2 (M+1).

trans-N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-3-morpholinocyclobutane-1-carboxamide 1061

Grey solid (15.0 mg, 0.038 mmol, 19.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.07-2.16 (2H, m), 2.22-2.32 (6H, m), 2.54 (3H, s), 2.90 (1H, quin, J=7.14 Hz), 3.23-3.30 (1H, m), 3.59 (4H, t, J=4.39 Hz), 7.79 (1H, s), 7.80-7.83 (1H, m), 8.07-8.13 (2H, m), 8.54 (1H, s), 9.10 (1H, s), 10.50 (1H, s); ESIMS found for C 22 H 24 N 4 O 3 m/z 393.2 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-morpholinoacetamide 1067

Off-white solid (41.0 mg, 0.116 mmol, 40.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.53 (3H, s), 2.55-2.60 (4H, m), 3.25 (2H, s), 3.62-3.69 (4H, m), 7.80 (1H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.12 (1H, d, J=8.78 Hz), 8.16 (1H, s), 8.51 (1H, s), 9.12 (1H, s), 10.08 (1H, s); ESIMS found for C 19 H 20 N 4 O 3 m/z 353.15 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-3-morpholinopropanamide 1068

Beige solid (21.0 mg, 0.057 mmol, 20.9% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.44 (4H, br s), 2.53 (3H, s), 2.57-2.64 (2H, m), 2.64-2.71 (2H, m), 3.59 (4H, t, J=4.53 Hz), 7.79 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.10 (1H, d, J=8.51 Hz), 8.12 (1H, s), 8.50 (1H, s), 9.11 (1H, s), 10.82 (1H, s); ESIMS found for C 20 H 22 N 4 O 3 m/z 367.15 (M+1).

1-(2-Hydroxy-2-methylpropyl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl) isoquinolin-3-yl)piperidine-4-carboxamide 1070

White solid (26.0 mg, 0.064 mmol, 22.5% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.73 (2H, m), 1.74-1.81 (2H, m), 1.83-1.92 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.59 (1H, m), 2.87 (2H, br d, J=11.53 Hz), 4.09 (1H, s), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.37 Hz), 8.11 (1H, d, J=8.51 Hz), 8.28 (1H, s), 8.51 (1H, s), 8.73 (1H, s), 9.11 (1H, s), 10.52 (1H, s); ESIMS found for C 22 H 28 N 6 O 2 m/z 409.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)quinuclidine-4-carboxamide 1071

Beige solid (27.0 mg, 0.075 mmol, 53.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.72-1.81 (6H, m), 2.74-2.83 (6H, m), 3.90 (3H, s), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.01 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.41 (1H, s), 9.04 (1H, s), 9.59 (1H, s); ESIMS found for C 21 H 23 N 5 O m/z 362.2 (M+1).

2-(4-Methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 1077

Off-white solid (79.0 mg, 0.208 mmol, 41.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.48-1.57 (2H, m), 1.83-1.93 (2H, m), 2.32-2.41 (2H, m), 2.73-2.82 (2H, m), 3.18-3.27 (1H, m), 3.20 (2H, s), 3.24 (3H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.78 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.94 (1H, s); ESIMS found for C 21 H 25 N 5 O 2 m/z 380.2 (M+1).

2-(4-Hydroxypiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide 1078

Off-white solid (84.0 mg, 0.230 mmol, 46.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.49 (2H, dtd, J=12.66, 9.52, 9.52, 3.70 Hz), 1.73-1.82 (2H, m), 2.28-2.35 (2H, m), 2.76-2.83 (2H, m), 3.19 (2H, s), 3.47-3.56 (1H, m), 3.90 (3H, s), 4.60 (1H, d, J=4.12 Hz), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.04 (1H, s), 9.93 (1H, s); ESIMS found for C 20 H 23 N 5 O 2 m/z 366.2 (M+1).

1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azepane-4-carboxamide 1079

Beige solid (12.0 mg, 0.030 mmol, 14.8% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.86 (3H, d, J=2.20 Hz), 0.88 (3H, d, J=2.20 Hz), 1.53-1.62 (1H, m), 1.64-1.82 (4H, m), 1.82-1.93 (2H, m), 2.13-2.25 (2H, m), 2.54-2.62 (3H, m), 2.66-2.74 (1H, m), 2.80-2.89 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.37 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.42 (1H, s); ESIMS found for C 24 H 31 N 5 O m/z 406.25 (M+1).

1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)azepane-4-carboxamide 1080

White solid (11.0 mg, 0.030 mmol, 15.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.56-1.66 (1H, m), 1.71-1.82 (2H, m), 1.82-1.93 (3H, m), 2.27 (3H, s), 2.45-2.58 (3H, m), 2.62-2.72 (1H, m), 2.81-2.90 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.37, 1.51 Hz), 7.99 (1H, d, J=8.51 Hz), 8.03 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.43 (1H, s); ESIMS found for C 21 H 25 N 5 O m/z 364.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 1081

Beige solid (5.0 mg, 0.013 mmol, 7.7% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.13-1.22 (2H, m), 1.43-1.54 (2H, m), 1.84-1.96 (4H, m), 2.11-2.20 (1H, m), 2.18 (6H, s), 2.42-2.49 (1H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.41 (1H, s); ESIMS found for C 22 H 27 N 5 O m/z 378.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl) cyclohexane-1-carboxamide 1082

Brown solid (3.0 mg, 0.008 mmol, 4.6% yield). 1 H NMR (499 MHz, METHANOL-d 4 ) δ ppm 1.35-1.46 (2H, m), 1.60-1.72 (2H, m), 2.04-2.12 (4H, m), 2.37 (6H, s), 2.39-2.44 (1H, m), 2.44-2.53 (1H, m), 2.58 (3H, s), 7.61 (1H, s), 7.80 (1H, dd, J=8.51, 1.65 Hz), 8.03 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.48 (1H, s), 9.01 (1H, s); ESIMS found for C 22 H 26 N 4 O 2 m/z 379.2 (M+1).

3-(Hydroxymethyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl) bicyclo[1.1.1]pentane-1-carboxamide 1083

White solid (310.4 mg, 0.891 mmol, 96.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.97 (6H, s), 3.41 (2H, d, J=5.76 Hz), 3.90 (3H, s), 4.56 (1H, t, J=5.49 Hz), 7.76 (1H, dd, J=8.51, 1.65 Hz), 8.02 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.09 (1H, d, J=0.82 Hz), 8.37 (1H, s), 8.40 (1H, s), 9.05 (1H, s), 10.13 (1H, s); ESIMS found for C 20 H 20 N 4 O 2 m/z 349.2 (M+1).

Methyl trans-4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl) cyclohexane-1-carboxylate 1084

Light yellow solid (350.0 mg, 0.892 mmol, 40.0% yield). 1 H NMR (499 MHz, METHANOL-d 4 ) δ ppm 1.47-1.58 (2H, m), 1.64 (2H, qd, J=12.76, 2.88 Hz), 2.04 (2H, br dd, J=13.31, 2.88 Hz), 2.09 (2H, br dd, J=13.31, 3.16 Hz), 2.39 (1H, tt, J=12.08, 3.57 Hz), 2.51 (1H, tt, J=11.87, 3.36 Hz), 3.68 (3H, s), 3.96 (3H, s), 7.73 (1H, dd, J=8.51, 1.65 Hz), 7.93-7.99 (2H, m), 8.00 (1H, s), 8.16 (1H, s), 8.40 (1H, s), 8.94 (1H, s); ESIMS found for C 22 H 24 N 4 O 3 m/z 393.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)piperidine-4-carboxamide 1085

Off-white solid (105.0 mg, 0.312 mmol, 81.1% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.53 (2H, qd, J=12.12, 3.98 Hz), 1.70 (2H, br dd, J=12.21, 1.78 Hz), 2.44-2.49 (2H, m), 2.64 (1H, tt, J=11.60, 3.64 Hz), 2.94-3.01 (2H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.03 (1H, d, J=1.37 Hz), 8.08 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.44 (1H, s), 10.40 (1H, s); ESIMS found for C 19 H 20 [ 2 H]N 5 O m/z 337.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-(2-(methyl-d 3 )propyl-1,1,2,3,3,3-d 6 )piperidine-4-carboxamide 1086

Beige solid (160.0 mg, 0.399 mmol, 67.0% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.61-1.73 (2H, m), 1.74-1.80 (2H, m), 1.86 (2H, td, J=11.66, 2.20 Hz), 2.51-2.58 (1H, m), 2.86 (2H, br d, J=11.25 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.45 (1H, s); ESIMS found for C 23 H 20 [ 2 H 9 ]N 5 O m/z 401.3 (M+1).

1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)piperidine-4-carboxamide 1087

White solid (75.0 mg, 0.191 mmol, 64.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.63-1.73 (2H, m), 1.74-1.80 (3H, m), 1.83-1.90 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.51-2.57 (1H, m), 2.86 (2H, br d, J=11.25 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, d, J=1.37 Hz), 8.08 (1H, s), 8.35 (1H, s), 8.44 (1H, s), 10.45 (1H, s); ESIMS found for C 23 H 28 [ 2 H]N 5 O m/z 393.25 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide 1088

Light brown amorphous solid (13.9 mg, 0.032 mmol, 30.2% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 2.04 (6H, s), 2.14 (3H, s), 2.31 (4H, br d, J=1.92 Hz), 2.36-2.46 (4H, m), 2.38 (2H, s), 3.90 (3H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz), 8.01 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.39 (1H, s), 9.04 (1H, s), 10.13 (1H, s); ESIMS found for C 25 H 30 N 6 O m/z 431.25 (M+1).

1-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(1-methylpiperidin-4-yl)urea 1090

Beige solid (35.0 mg, 0.096 mmol, 87.3% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.35-1.49 (2H, m), 1.77-1.88 (2H, m), 1.98-2.09 (2H, m), 2.17 (3H, s), 2.63 (2H, ddd, J=5.35, 3.43, 1.65 Hz), 3.54 (1H, br dd, J=4.12, 1.65 Hz), 3.90 (3H, s), 7.15-7.24 (1H, m), 7.65 (1H, dd, J=8.51, 1.65 Hz), 7.93 (3H, d, J=8.51 Hz), 8.07 (1H, s), 8.34 (1H, s), 8.88-8.96 (2H, m); ESIMS found for C 20 H 24 N 6 O m/z 365.2 (M+1).

trans-N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazine-1-carbonyl)cyclohexane-1-carboxamide 1091

Beige solid (80.0 mg, 0.174 mmol, 50.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.35-1.47 (2H, m), 1.57 (2H, qd, J=12.76, 2.88 Hz), 1.69-1.75 (2H, m), 1.84-1.93 (2H, m), 2.18 (3H, s), 2.23 (2H, br s), 2.30 (2H, br s), 2.51-2.60 (1H, m), 2.64 (1H, tt, J=11.73, 3.22 Hz), 3.44 (2H, br s), 3.50 (2H, br s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 8.43 (1H, s), 9.02 (1H, s), 10.43 (1H, s); ESIMS found for C 26 H 32 N 6 O 2 m/z 461.3 (M+1).

1-Isobutyl-N-(6-(1-methyl-1H-tetrazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 1092. N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)-2-(pyrrolidin-1-yl)acetamide

Off-white solid (18.0 mg, 0.046 mmol, 7.1% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.61-1.72 (2H, m), 1.74-1.82 (3H, m), 1.82-1.94 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.61 (1H, m), 2.87 (2H, br d, J=11.53 Hz), 4.29 (3H, s), 7.92 (1H, dd, J=8.51, 1.65 Hz), 8.26 (1H, d, J=8.51 Hz), 8.44 (1H, s), 8.67 (1H, s), 9.27 (1H, s), 10.67 (1H, s); ESIMS found for C 21 H 27 N 7 O m/z 394.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)-2-(pyrrolidin-1-yl) acetamide 1093

Beige solid (45.0 mg, 0.134 mmol, 44.6% yield). 1 H NMR (499 MHz, DMSO-d 6 ) δ ppm 1.78 (4H, dt, J=6.59, 3.29 Hz), 2.63-2.69 (4H, m), 3.35 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.64, 1.51 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.43 (1H, s), 9.92 (1H, s); ESIMS found for C 19 H 20 [ 2 H]N 5 O m/z 337.2 (M+1).