RU2795572C2 - Compounds and compositions for ire1 inhibition - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: compound of formula (Ia), formula (Ib) or formula (Ic), or a pharmaceutically acceptable salt or enantiomer thereof, having inhibitory activity against IRE1α kinase, pharmaceutical composition based on it, method of treatment associated with IRE1α disease and a method for inhibiting the activity of the IRE1 protein.

EFFECT: development of compounds that effectively inhibit IRE1α kinase. In general formulas (Ia), (Ib) and (Ic), R¹ is selected from the group consisting of

,

,

and

; R² is selected from the group consisting of H, methyl, ethyl, propyl, CF₃, CHF₂, 1-methyl-cyclopropyl, isopropyl, t-butyl and C₃-C₈ cycloalkyl; L is selected from the group consisting of a bond, -CH₂- and -C(=O)-; R³ is selected from the group consisting of

,

,

, C₃-C₈ cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl and oxadiazolyl; or -LR³ is

, where R''' is selected from the group consisting of -OH, C₁-C₆ alkoxy group, -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)(C₁-C₆ alkyl) and -NH(oxetanyl); R⁴ is selected from the group consisting of halogen, -NH₂ and -NHR⁸; in each occurrence, R⁵ is independently selected from the group consisting of halogenid, C₁-C₆ alkyl and C₁-C₆ alkoxy group; R⁶ is H; in each occurrence R⁹ is independently selected from the group consisting of H, C₁-C₈ alkyl, oxetanyl, C₁-C₆ haloalkyl, C₁-C₆ carboxamidoalkyl, C₁-C₆ carboxyalkyl and C₁-C₆ cyanoalkyl ; R⁸ is C₁-C₃ alkyl; Cy is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidinyl, thienyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl,

,

and

; where Cy is substituted with 0 to 'n' X, in each occurrence X is independently selected from the group consisting of H, OH, halogenid, nitrile, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy groups, phenyl and

in each occurrence, Z, if present, is independently selected from the group consisting of CH and N; m is an integer selected from the group consisting of 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3, 4 and 5; q means an integer selected from 0, 1, 2, 3, 4 and 5; p means an integer selected from 0, 1, 2, 3, 4 and 5.

22 cl, 7 tbl, 235 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

According to the present application in accordance with 35 U.S.C. §119(e) claims priority on provisional application U.S. No. 62/553320, filed September 1, 2017, which is incorporated herein by reference in its entirety.

INDICATION OF FEDERAL SUPPORT FOR RESEARCH OR DEVELOPMENT

The present invention is supported by the government through grants No. R41 DK108377 and R41 EY026370 issued by the National Institutes of Health (national institutes of health). The government has certain rights to the present invention.

BACKGROUND OF THE INVENTION

Cells are often under conditions where the load on the endoplasmic reticulum ("ER") protein folding machinery exceeds its capacity, causing ER stress. ER stress may be due to overload of the secretory system, expression of secretory proteins with defective folding, loss of nutrients or oxygen, changes in luminal calcium concentration, and deviation from the resting redox state. Under ER stress, secretory proteins accumulate in the organelle in unfolded forms and initiate a sequence of intracellular signaling pathways called the unfolded protein response (UPR). UPR signaling enhances the transcription of genes encoding chaperones, oxidoreductases, lipid biosynthetic enzymes, and ER-associated degradation (ERAD) components.

In some cases, ER stress remains too great and cannot be cured by UPR homeostasis products. In these cases, the UPR changes strategies and actively initiates apoptosis. Apoptosis of incurable stressed cells is a quality control strategy that protects micellar organisms from exposure to immature and damaged secretory proteins. Many fatal human diseases occur when too many cells die in this process. On the other hand, many human diseases, such as diabetes mellitus and retinopathy, are due to unhindered cell degeneration under ER stress.

IRE1α and IRE1β are transmembrane ER proteins that are activated when unfolded proteins accumulate in the organelle. IRE1α is the more widely expressed member of the family. The bifunctional kinase/endoribonuclease IRE1α regulates terminal UPR. IRE1α senses unfolded proteins via the luminal domain of the ER, which becomes oligomerized during stress.

Under incurable ER stress, the UPR generates positive feedback signals and becomes integrated and amplified at key positions to initiate apoptosis. IRE1α is a key initiator of these pro-apoptotic signals. IRE1α uses autophosphorylation as a timer. Treatable ER stress induces weak transient autophosphorylation that limits RNase activity to XBP1 mRNA splicing. However, sustained kinase autophosphorylation causes IRE1α's RNase to become less specific, causing it to endonucleolytically degrade thousands of ER-located mRNAs in close proximity to IRE1α. These mRNAs encode secretory proteins that are cotranslationally translocated (eg, insulin in β cells). As mRNA degradation continues, the content of transcripts encoding enzymes located in the ER also decreases, which destabilizes the entire ER protein folding machinery. When IRE1α's RNase becomes overactive, the adaptive signal through XBPl splicing is suppressed by ER mRNA destruction, leading to cell apoptosis.

The terminal UPR signature, tightly regulated by overactive RNase activity in IRE1α, results in (1) widespread mRNA disruption at the ER membrane, which induces mitochondrial apoptosis, (2) induction of a pro-oxidative thioredoxin-interacting protein (TXNIP), which activates the NLRP3 inflammosome with maturation, and secretion of interleukin-1β and subsequent sterile inflammation of the pancreatic islets leading to diabetes and (3) destruction of pre-miRNA 17 leading to translational upregulation and cleavage of premitochondrial caspase 2 and stabilization of the mRNA encoding TXNIP.

Retinitis pigmentosa (RP) forms a clinically and genetically heterogeneous group of retinal disorders characterized by diffuse progressive dysfunction and loss of rod and cone receptors and the retinal pigment epithelium. There are no approved treatments for RP in patients who suffer from irreversible vision loss. The accumulation of unfolded proteins in the ER seems to be the main mechanism for the occurrence of many forms of RP. Mutations in rhodopsin result in a defective rhodopsin protein that unfolds and accumulates in the ER, causing ER stress.

There is a need in the art for novel small molecule compounds that are capable of treating ER stress without UPR-based apoptosis, thus treating a wide range of diseases and disorders associated with ER stress. Such diseases include, for example, neurodegenerative diseases, demyelinating diseases, cancers, eye diseases, fibrotic diseases, and/or diabetes. The present invention solves this problem.

Accordingly, the technical result of the present invention: compounds of formula (Ia), (Ib) or (Ic) or their salt, solvate, enantiomer, diastereoisomer, isotopologue or tautomer, or a pharmaceutical composition containing them, which are applicable for the treatment of IRE1α associated disease in a subject wherein IRE1α related diseases may include neurodegenerative diseases, demyelinating diseases, cancers, eye diseases, fibrotic diseases and/or diabetes.

SUMMARY OF THE INVENTION

The present invention provides certain compounds as well as a pharmaceutical composition containing at least one compound of the present invention and at least one pharmaceutically acceptable carrier. The present invention also provides a method for treating an IRE1α associated disease in a subject. The present invention also provides a method for inhibiting the activity of an IRE1 protein.

где: R¹ выбран из группы, включающей

и

; R² выбран из группы, включающей H, метил, этил, пропил, CF₃, CHF₂, 1-метилциклопропил, изопропил, трет-бутил и C₃-C₈ циклоалкил, где каждый заместитель, не представляющий собой H, независимо необязательно замещен одним R⁷, при условии, что, если R⁷ содержится, R³ означает H; L выбран из группы, включающей связь, -CH₂- и -C(=O)-; R³ выбран из группы, включающей H, необязательно замещенный C₁-C₈ алкил, необязательно замещенный C₃-C₈ циклоалкил, необязательно замещенный C₂-C₈ алкенил, необязательно замещенный C₂-C₈ алкинил, необязательно замещенный C₁-C₈ гетероалкил, необязательно замещенный C₃-C₈ гетероциклоалкил, необязательно замещенный C₂-C₈ гетероалкенил, необязательно замещенный бензил, необязательно замещенный C₂-C₈ циклогетероалкенил, необязательно замещенный гетероциклил, необязательно замещенный арил и необязательно замещенный гетероарил (такие как, но не ограничиваясь только ими, имидазолил или пиразолил); R⁴ выбран из группы, включающей -H, -OH, C₁-C₆ алкоксигруппу, галоген, -NH₂ и -NHR⁸; в каждом случае R⁵ независимо выбран из группы, включающей галогенид, -OH, C₁-C₆ алкоксигруппу, необязательно замещенный фенил, необязательно замещенный C₁-C₆ алкил, необязательно замещенную C₁-C₆ алкоксигруппу и необязательно замещенный гетероциклоалкил; R⁶ выбран из группы, включающей H и необязательно замещенный C₁-C₆ алкил; R⁷ выбран из группы, включающей необязательно замещенный C₁-C₈ алкил, необязательно замещенный C₃-C₈ циклоалкил, необязательно замещенный C₂-C₈ алкенил, необязательно замещенный C₂-C₈ алкинил, необязательно замещенный C₁-C₈ гетероалкил, необязательно замещенный C₃-C₈ гетероциклоалкил, необязательно замещенный C₂-C₈ гетероалкенил, необязательно замещенный арил, необязательно замещенный гетероарил (такие как, но не ограничиваясь только ими, имидазолил или пиразолил) и необязательно замещенный бензил; R⁸ означает необязательно замещенный C₁-C₃ алкил; Cy выбран из группы, включающей арил, гетероарил, C₃-C₁₀ циклоалкил, C₃-C₁₀ циклоалкенил, C₃-C₁₀ гетероциклоалкил, C₃-C₁₀ гетероциклоалкенил, полициклический арил, полициклический гетероарил, полициклический C₃-C₁₀ циклоалкил, полициклический C₃-C₁₀ циклоалкенил, полициклический C₃-C₁₀ гетероциклоалкил и полициклический C₃-C₁₀ гетероциклоалкенил; где Cy замещен с помощью от 0 до ‘n’ X, в каждом случае X независимо выбран из группы, включающей H, OH, галогенид, нитрил, необязательно замещенный C₁-C₆ алкил, C₁-C₆ галогеналкил, необязательно замещенную C₁-C₆ алкоксигруппу, необязательно замещенный арил, необязательно замещенный гетероарил и

; в каждом случае Z, если содержится, независимо выбран из группы, включающей CH и N; m означает целое число, выбранное из группы, включающей 0, 1, 2, 3 и 4; n означает целое число, выбранное из группы, включающей 0, 1, 2, 3, 4 и 5; и q означает целое число, выбранное из группы, включающей 0, 1, 2, 3, 4 и 5.In some embodiments, the compound is a compound of formula (Ia), formula (Ib), or formula (Ic), or a salt, solvate, enantiomer, diastereomer, isotopologue, or tautomer thereof:

where: R ¹ is selected from the group consisting of

And

; R ² is selected from the group consisting of H, methyl, ethyl, propyl, CF ₃ , CHF ₂ , 1-methylcyclopropyl, isopropyl, tert-butyl, and C ₃ -C ₈ cycloalkyl, wherein each non-H substituent is independently optionally substituted one R ⁷ , provided that if R ⁷ is present, R ³ is H; L is selected from the group consisting of a bond, -CH ₂ - and -C(=O)-; R ³ is selected from the group consisting of H, optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₈ alkenyl, optionally substituted C ₂ -C ₈ alkynyl, optionally substituted C ₁ - C ₈ heteroalkyl, optionally substituted C ₃ -C ₈ heterocycloalkyl, optionally substituted C ₂ -C ₈ heteroalkenyl, optionally substituted benzyl, optionally substituted C ₂ -C ₈ cycloheteroalkenyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl (such as, but not limited to imidazolyl or pyrazolyl); R ⁴ is selected from the group consisting of -H, -OH, C ₁ -C ₆ alkoxy, halogen, -NH ₂ and -NHR ⁸ ; in each occurrence, R ⁵ is independently selected from the group consisting of halide, -OH, C ₁ -C ₆ alkoxy, optionally substituted phenyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, and optionally substituted heterocycloalkyl; R ⁶ is selected from the group consisting of H and optionally substituted C ₁ -C ₆ alkyl; R ⁷ is selected from the group consisting of optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₈ alkenyl, optionally substituted C ₂ -C ₈ alkynyl, optionally substituted C ₁ -C ₈ heteroalkyl, optionally substituted C ₃ -C ₈ heterocycloalkyl, optionally substituted C ₂ -C ₈ heteroalkenyl, optionally substituted aryl, optionally substituted heteroaryl (such as, but not limited to, imidazolyl or pyrazolyl), and optionally substituted benzyl; R ⁸ means optionally substituted C ₁ -C ₃ alkyl; Cy is selected from the group consisting of aryl, heteroaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, C ₃ -C ₁₀ heterocycloalkyl, C ₃ -C ₁₀ heterocycloalkenyl, polycyclic aryl, polycyclic heteroaryl, polycyclic C ₃ -C ₁₀ cycloalkyl, polycyclic C ₃ -C ₁₀ cycloalkenyl, polycyclic C ₃ -C ₁₀ heterocycloalkyl and polycyclic C ₃ -C ₁₀ heterocycloalkenyl; where Cy is substituted with 0 to 'n' X, in each occurrence X is independently selected from the group consisting of H, OH, halide, nitrile, optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and

; in each case, Z, if present, is independently selected from the group consisting of CH and N; m is an integer selected from the group consisting of 0, 1, 2, 3 and 4; n is an integer selected from the group consisting of 0, 1, 2, 3, 4 and 5; and q is an integer selected from the group consisting of 0, 1, 2, 3, 4 and 5.

In some embodiments, in each occurrence, an optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, heterocycloalkyl, heteroalkenyl, benzyl, heterocyclyl, or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of C ₁ -C ₆ alkyl, halogen, - OR ^a , optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ^a )C(=O)R ^a , -C(=O)NR ^a R ^a and -N(R ^a )(R ^a ) , where in each case R ^a is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, or two R ^a groups are combined with the N atom with which they linked to form a heterocycle.

In some embodiments, in each occurrence, the optionally substituted aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, halogen, - CN, -OR ^b , -N(R ^b )(R ^b ), -NO ₂ , -S(=O) ₂ N(R ^b )(R ^b ), acyl and C ₁ -C ₆ alkoxycarbonyl, where in each in the case of R ^b independently means H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl.

In some embodiments, in each occurrence, the optionally substituted aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, halogen, - CN, -OR ^c , -N(R ^c )(R ^c ) and C ₁ -C ₆ alkoxycarbonyl, where in each case R ^c independently means H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl.

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

и

.

And

.

In some embodiments, R ¹ is selected from the group consisting of:

и

.

And

.

In some embodiments, R ¹ is selected from the group consisting of:

и

.

And

.

In some embodiments, R ² is selected from the group consisting of methyl, ethyl, and isopropyl.

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

H, C ₁ -C ₈ alkyl,

и

; где p является целым числом, равным 0-5; и где в каждом случае R⁹ независимо выбран из группы, включающей H, оксетанил, C₁-C₆ гидроксиалкил, C₁-C₆ галогеналкил, C₁-C₆ карбоксамидоалкил, C₁-C₆ карбоксиалкил, C₁-C₆ карбокси(C₁-C₆)алкилалкил и C₁-C₆ цианоалкил.

And

; where p is an integer equal to 0-5; and where in each occurrence R ⁹ is independently selected from the group consisting of H, oxetanyl, C ₁ -C ₆ hydroxyalkyl, C 1 -C ₆ haloalkyl, C ₁ -C ₆ carboxamidoalkyl, C _{1 -C 6} carboxyalkyl, C ₁ -C ₆ carboxy(C ₁ -C ₆ )alkylalkyl and C ₁ -C ₆ cyanoalkyl.

,

и

. В некоторых вариантах осуществления R⁴ означает H или -NH₂. В некоторых вариантах осуществления R⁵, если содержится, означает -F.In some embodiments, R ³ is selected from the group consisting of:

,

And

. In some embodiments, R ⁴ is H or -NH ₂ . In some embodiments, R ⁵ , if present, is -F.

In some embodiments, R ⁷ , if present, is selected from the group consisting of:

и

; где p является целым числом, равным 0-5; и где в каждом случае R⁹ независимо выбран из группы, включающей H, оксетанил, C₁-C₆ гидроксиалкил, C₁-C₆ галогеналкил, C₁-C₆ карбоксамидоалкил, C₁-C₆ карбоксиалкил, C₁-C₆ карбокси(C₁-C₆)алкилалкил и C₁-C₆ цианоалкил.

And

; where p is an integer equal to 0-5; and where in each occurrence R ⁹ is independently selected from the group consisting of H, oxetanyl, C ₁ -C ₆ hydroxyalkyl, C 1 -C ₆ haloalkyl, C ₁ -C ₆ carboxamidoalkyl, C _{1 -C 6} carboxyalkyl, C ₁ -C ₆ carboxy(C ₁ -C ₆ )alkylalkyl and C ₁ -C ₆ cyanoalkyl.

In some embodiments, at each occurrence, R ⁹ is independently selected from the group consisting of: H, oxetanyl, C ₁ -C ₈ alkyl,

и

.

And

.

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

и

, где R' означает R³.

And

where R' means R ³ .

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

и

.

And

.

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

и

, где в каждом случае R'' независимо означает H или C₁-C₆ алкил.

And

, where in each case R'' independently means H or C ₁ -C ₆ alkyl.

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

и

, где в каждом случае R''' независимо выбран из группы, включающей -OH, C₁-C₆ алкоксигруппу, -NH₂, -NH(C₁-C₆ алкил), -N(C₁-C₆ алкил)(C₁-C₆ алкил) и -NH(оксетанил), где каждый C₁-C₆ алкил необязательно замещен по меньшей мере одним заместителем, независимо выбранным из группы, включающей галоген, -C(=O)NH₂, -C(=O)N(C₁-C₆ алкил), -C(=O)N(C₁-C₆ алкил)(C₁-C₆ алкил), -OH и - C₁-C₆ алкоксигруппу.

And

where in each occurrence R''' is independently selected from the group consisting of -OH, C ₁ -C ₆ alkoxy, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) and -NH(oxetanyl) wherein each C ₁ -C ₆ alkyl is optionally substituted with at least one substituent independently selected from the group consisting of halogen, -C(=O)NH ₂ , -C (=O)N(C ₁ -C ₆ alkyl), -C(=O)N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -OH and -C ₁ -C ₆ alkoxy.

.In some embodiments, R''' is selected from the group consisting of -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₂ F, -N(Me)CH ₂ CH ₂ F, -NHCH ₂ CHF ₂ , -N(Me)CH ₂ CHF ₂ , -NHCH ₂ CF ₃ , -N(Me)CH ₂ CF ₃ , -NHCH ₂ CH ₂ CF ₃ , -N(Me)CH ₂ CH ₂ CF ₃ , -NHCH ₂ CH ₂ C(=O)NMe ₂ , -N(Me)CH ₂ CH ₂ C(=O)NMe ₂ , -NHCH ₂ CH ₂ C(=O)NH ₂ , -N(Me) CH ₂ CH ₂ C(=O)NH ₂ , -NHCH ₂ CH ₂ C(=O)NHMe, -N(Me)CH ₂ CH ₂ C(=O)NHMe ₂ and

.

In some embodiments, the compound is selected from the group consisting of the compound of Example 1-Example 232; or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof.

In some embodiments, the method includes administering to a subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, solvate, enantiomer, diastereoisomer, or tautomer thereof, and/or a composition of the present invention.

In some embodiments, the method includes contacting the IRE1 protein with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, and/or a composition of the present invention.

In some embodiments, the disease is selected from the group consisting of neurodegenerative disease, demyelinating disease, cancer, eye disease, fibrotic disease, and diabetes.

In some embodiments, the neurodegenerative disease is selected from the group consisting of retinitis pigmentosa, amyotrophic lateral sclerosis, retinal degeneration, macular degeneration, Parkinson's disease, Alzheimer's disease, Huntington's disease, prion disease, Creutzfeldt-Jakob disease, and kuru.

In some embodiments, the demyelinating disease is selected from the group consisting of Wolfram syndrome, Pelizeus-Merzbacher disease, transverse myelitis, Charcot-Marie-Tooth disease, and multiple sclerosis.

In some embodiments, the cancer is multiple myeloma.

In some embodiments, diabetes is selected from the group consisting of type I diabetes and type II diabetes.

In some embodiments, the eye disease is selected from the group consisting of retinitis pigmentosa, retinal degeneration, macular degeneration, and Wolfram's syndrome.

In some embodiments, the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), myocardial infarction, cardiac hypertrophy, heart failure, cirrhosis, acetaminophen (Tylenol®) liver toxicity, hepatitis C liver disease, hepatosteatosis (fatty liver) or fibrosis of the liver.

In some embodiments, the activity is selected from the group consisting of kinase activity, oligomerization activity, and RNase activity.

In some embodiments, the implementation of the IRE1 protein is in the cell.

In some embodiments, cell apoptosis is prevented or minimized.

In some embodiments, the cell is in an organism that has an IRE1α associated disease or disorder.

In some embodiments, the subject is a subject in need of treatment.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates in part to the unexpected discovery that novel IRE1α inhibitors prevent oligomerization and/or allosterically inhibit its RNase activity. In some embodiments, the implementation of the compounds proposed in the present invention are compounds of formula (Ia), (Ib) or (Ic):

or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof. These compounds can be used to treat diseases or disorders associated with ER stress, such as those selected from the group consisting of neurodegenerative disease, demyelinating disease, cancer, eye disease, fibrotic disease, and diabetes. In some embodiments, the disease or disorder is a neurodegenerative disease. In other embodiments, the disease or disorder is a demyelinating disease. In other embodiments, the disease or disorder is cancer. In other embodiments, the disease or disorder is an eye disease. In other embodiments, the disease or disorder is a fibrotic disease. In other embodiments, the disease or disorder is diabetes.

Definitions

When used in the present invention, each of the following terms has the meaning associated with it in this section.

Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as generally understood by a person with a general background in the technical field to which the present invention pertains. While any techniques and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, typical techniques and materials are described.

Generally, the nomenclature used in the present invention and laboratory procedures in pharmaceuticals and organic chemistry are well known and commonly used in the art.

When used in the present invention, objects in the singular means one or more than one object (ie, at least one). For example, element means one element or more than one element.

When used in the present invention, the term "about" is understood by those of ordinary skill in the art and varies to some extent depending on the context in which it is used. When used in the present invention when referring to a measurable value such as amount, duration, etc., the term "about" means the inclusion of deviations equal to ± 20% or ± 10%, in some other embodiments equal to ± 5%, in others in embodiments of ±1% and in other embodiments of ±0.1% of the set value, all such deviations are suitable for carrying out the disclosed methods.

As used in the present invention, the term "cancer" is defined as a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of cancer include, but are not limited to, bone cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, etc.

As used herein, a "disease" is a state of health of a subject in which the subject cannot maintain homeostasis and in which, if the disease is not alleviated, the subject's health continues to deteriorate.

As used herein, "impairment" in a subject means a state of health in which the subject is able to maintain homeostasis, but in which the subject's health is less favorable than it would be in the absence of the impairment. If left untreated, the disorder does not necessarily lead to further deterioration in the subject's health.

When used in the present invention, the term "ED ₅₀ " or "ED50" means the effective dose of the drug, which produces approximately 50% of the maximum effect in subjects administered with this drug.

As used herein, an "effective amount", "therapeutically effective amount", or "pharmaceutically effective amount" of a compound is that amount of a compound that is sufficient to provide a beneficial effect to the subject to whom the compound is administered.

"Information material" as a term used in the present invention includes a publication, record, diagram, or any other means of expression that can be used to indicate the applicability of the composition and/or compound of the present invention in a kit. The kit information material can, for example, be attached to a container that contains the compound and/or composition of the present invention, or transported along with the container that contains the compound and/or composition. Alternatively, the information material may be transported separately from the container so that the recipient shares the information material and the connection. The delivery of information material can be done, for example, by mechanical delivery of a publication or other expressive means that communicates the applicability of the set, or alternatively can be delivered by electronic message, for example, using a computer, for example, by means of an email or by downloading from a website. .

As used herein, a "patient" or "subject" can be a human or non-human mammal or bird. Non-human mammals include, for example, livestock and domestic animals such as sheep, ruminant, pig, dog, cat, and mouse. In some other embodiments, the subject is a human.

When used in the present invention, the term "pharmaceutical composition" or "composition" means a mixture of at least one compound useful in the present invention, with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

As used in the present invention, the term "pharmaceutically acceptable" means a material, such as a carrier or diluent, which does not interfere with the biological activity or characteristics of the compound useful in the present invention and is relatively non-toxic, i. the material can be administered to a subject without exhibiting undesirable biological effects or adverse interactions with any of the components of the composition in which it is contained.

As used in the present invention, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier such as a liquid or solid excipient, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material involved in transferring or transporting a compound useful in the present invention in or to a subject so that it can perform its intended effect. Typically, such structures are transferred or transported from one organ or body part to another organ or body part. Each carrier must be "acceptable" in the sense that it must be compatible with the other ingredients of the formulation, including the compound useful in the present invention, and not harmful to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic solution; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic substances used in pharmaceutical preparations. As used herein, a "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and fungicidal agents, and absorption delaying agents, and the like, which are compatible with the activity of the compound useful in the present invention and are physiologically acceptable to the subject. Additional active compounds may also be included in the compositions. A "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of a compound useful in the present invention. Other additional ingredients that may be included in pharmaceutical compositions useful in the practice of the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA) , which is incorporated into the present invention by reference.

When used in the present invention, the term "pharmaceutically acceptable salt" means a salt of an administered compound derived from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates and clathrates thereof.

When used in the present invention, the term "pharmaceutical composition" means a mixture of at least one compound useful in the present invention with other chemical components such as carriers, stabilizers, diluents, dispersing agents, suspendida agents, thickening agents and/or excipients. The pharmaceutical composition facilitates the administration of the compound to the body. Various methods for administering a compound include, but are not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

The term "prevent", "prevention" as used herein means to prevent or delay the onset of symptoms associated with a disease or disorder in a subject who has not developed such symptoms at the time the agent or compound is administered. Disease, pathological condition and disorder are used interchangeably in the present invention.

The term "solvate" as used in the present invention means a compound formed by solvation, which is the process of addition and association of solvent molecules with solute molecules or ions. When molecules or ions of a solute are dissolved in a solvent, they spread out and are surrounded by solvent molecules.

The term "treat", "treatment" as used in the present invention means reducing the frequency or severity with which the symptoms of a disease or pathological condition are perceived by the subject due to the introduction of an agent or compound to the subject.

When used in the present invention, the term "alkyl" alone or as part of another substituent means, unless otherwise specified, a linear or branched hydrocarbon containing the specified number of carbon atoms (i.e. C ₁ -C ₁₀ means from 1 to 10 atoms carbon) and includes linear, branched or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Most preferred is (C ₁ -C ₆ )alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.

When used in the present invention, the term "alkylene" alone or as part of another substituent means, unless otherwise indicated, a linear or branched hydrocarbon group containing the specified number of carbon atoms (i.e. C ₁ -C ₁₀ means from 1 to 10 carbon atoms) and includes linear, branched or cyclic substituent groups, where the group contains two free valencies. Examples include methylene, 1,2-ethylene, 1,1-ethylene, 1,1-propylene, 1,2-propylene and 1,3-propylene.

When used in the present invention, the term "cycloalkyl" alone or as part of another substituent means, unless otherwise indicated, a cyclic chain hydrocarbon containing the specified number of carbon atoms (i.e. C3-C6 means a cyclic group including a ring group containing from 3 to 6 carbon atoms), and includes linear, branched or cyclic substituent groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Most preferred is (C ₃ -C ₆ )cycloalkyl such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

When used in the present invention, the term "alkenyl", when used alone or in combination with other terms, means, unless otherwise indicated, a stable monounsaturated or diunsaturated linear or branched hydrocarbon group containing the specified number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologues and isomers. An example of an alkene functional group is -CH ₂ -CH=CH ₂ .

When used in the present invention, the term "alkynyl", when used alone or in combination with other terms, means, unless otherwise indicated, a stable linear or branched hydrocarbon group containing a carbon-carbon triple bond containing the specified number of carbon atoms. Non-limiting examples include ethynyl and propynyl and higher homologues and isomers. The term "propargyl" means a group exemplified by -CH ₂ -C≡CH. The term "homopropargyl" means a group exemplified by -CH ₂ CH ₂ -C≡CH. The term "substituted propargyl" means a group exemplified by -CR ₂ -C≡CR, where in each occurrence R is independently H, alkyl, substituted alkyl, alkenyl, or substituted alkenyl, provided that at least one R group is not hydrogen. The term "substituted homopropargyl" means a group exemplified by -CR ₂ CR ₂ -C≡CR, where in each occurrence R is independently H, alkyl, substituted alkyl, alkenyl, or substituted alkenyl, provided that at least one R group does not mean hydrogen.

When used in the present invention, the term "alkenylene" when used alone or in combination with other terms means, unless otherwise indicated, a stable monounsaturated or diunsaturated linear or branched hydrocarbon group containing the indicated number of carbon atoms, where the group contains two free valencies.

When used in the present invention, the term "alkynylene", when used alone or in combination with other terms, means, unless otherwise indicated, a stable linear or branched hydrocarbon group containing a carbon-carbon triple bond containing the indicated number of carbon atoms, where the group contains two free valencies.

When used in the present invention, the term "substituted alkyl", "substituted cycloalkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkylene", "substituted alkenylene", "substituted alkynylene", "substituted heteroalkyl", "substituted heteroalkenyl" , "substituted heteroalkynyl", "substituted aryl", "substituted heteroaryl" or "substituted heterocycloalkyl" means alkyl, cycloalkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl or heterocycloalkyl as defined above, substituted with one, two or three substituents selected from the group consisting of C ₁ -C ₁₀ alkyl, halogen, perhaloalkyl, =O, -OH, alkoxy, -NH ₂ , -N(CH ₃ ) ₂ , -NH(CH ₃ ) ₂ , phenyl, benzyl, (1-methylimidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, -OC(=O) (C ₁ -C ₄ )alkyl, -C(=O)(C ₁ -C ₄ )alkyl, -C≡N, -C(=O)O(C ₁ -C ₄ )alkyl, -C(=O)NH ₂ , -C(=O)NH(C ₁ -C ₄ )alkyl, -C(=O)N((C ₁ -C ₄ )alkyl) _2, -SO ₂ NH ₂ , -C(=NH)NH ₂ and -NO ₂ , preferably containing 1 or 2 substituents selected from the group consisting of halogen, -OH, alkoxy, -NH ₂ , trifluoromethyl, -N(CH ₃ ) ₂ and -C(=O)OH, more preferably selected from the group consisting of halogen, alkoxy and -OH. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

When used in the present invention, the term "alkoxy group", when used alone or in combination with other terms, means, unless otherwise indicated, an alkyl group containing the specified number of carbon atoms as defined above, connected to the rest of the molecule through an oxygen atom, such as, for example , a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group (isopropoxy group), and higher homologues and isomers. Preferred are (C ₁ -C ₃ )alkoxy groups such as, but not limited to, ethoxy group and methoxy group.

When used in the present invention, the term "halogen" alone or as part of another substituent means, unless otherwise indicated, a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

When used in the present invention, the term "heteroalkyl", alone or in combination with another term, means, unless otherwise indicated, a stable linear or branched alkyl group containing the specified number of carbon atoms and 1 or 2 heteroatoms selected from the group consisting of O, N and S, and in which the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) may be at any position of the heteroalkyl group, including the position between the remainder of the heteroalkyl group and the fragment to which it is attached, and also attached to the outermost carbon atom of the heteroalkyl group. Examples include: -O-CH ₂ -CH ₂ -CH ₃ , -CH ₂ -CH ₂ -CH ₂ -OH, -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ and -CH ₂ CH ₂ -S(=O)-CH ₃ . Up to two heteroatoms can be arranged in series, for example, -CH ₂ -NH-OCH ₃ or -CH ₂ -CH ₂ -SS-CH ₃ .

When used in the present invention, the term "heteroalkenyl", alone or in combination with another term, means, unless otherwise indicated, a stable linear or branched monounsaturated or diunsaturated hydrocarbon group containing the specified number of carbon atoms and 1 or 2 heteroatoms selected from the group consisting of O, N and S, and in which the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms can be arranged in series. Examples include -CH=CH-O-CH ₃ , -CH=CH-CH ₂ -OH, -CH ₂ -CH=N-OCH ₃ , -CH=CH-N(CH ₃ )-CH ₃ and -CH ₂ -CH=CH-CH ₂ -SH.

When used in the present invention, the term "aromatic" means a carbocycle or heterocycle containing one or more polyunsaturated rings and having an aromatic character, i.e. containing (4n+2) delocalized π(pi) electrons, where n is an integer.

When used in the present invention, the term "aryl", when used alone or in combination with other terms, means, unless otherwise indicated, a carbocyclic aromatic system containing one or more rings (typically 1, 2 or 3 rings), where such rings can be bonded to each other, such as biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl and naphthyl. Preferred are phenyl and naphthyl, most preferred is phenyl.

When used in the present invention, the term "aryl-(C ₁ -C ₃ )alkyl" means a functional group where from 1 to 3 carbon alkyl chains are attached to the aryl group, for example, -CH ₂ CH ₂ -phenyl or -CH ₂ -phenyl (benzyl). Aryl-CH ₂ - and aryl-CH(CH ₃ )- are preferred. The term "substituted aryl-(C ₁ -C ₃ )alkyl" means an aryl-(C ₁ -C ₃ )alkyl functional group in which the aryl group is substituted. Substituted aryl(CH ₂ )- is preferred. Similarly, the term "heteroaryl-(C ₁ -C ₃ )alkyl" means a functional group where from 1 to 3 carbon alkyl chains are attached to a heteroaryl group, for example -CH ₂ CH ₂ -pyridyl. Heteroaryl-(CH ₂ )- is preferred. The term "substituted heteroaryl-(C ₁ -C ₃ )alkyl" means a heteroaryl-(C ₁ -C ₃ )alkyl functional group in which the heteroaryl group is substituted. Substituted heteroaryl-(CH ₂ )- is preferred.

When used in the present invention, the term "heterocycle" or "heterocyclyl" or "heterocyclic" alone or as part of another substituent means, unless otherwise indicated, an unsubstituted or substituted, stable, mono- or polycyclic heterocyclic ring system that contains carbon atoms and at least one heteroatom selected from the group consisting of N, O and S, and where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen atom may optionally be quaternized. The heterocyclic system may be attached, unless otherwise indicated, at any heteroatom or carbon atom, as long as this gives a stable structure. The heterocycle may be aromatic or non-aromatic in nature. In some other embodiments, the heterocycle is heteroaryl.

When used in the present invention, the term "heteroaryl" or "heteroaromatic" means a heterocycle having an aromatic character. The polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3 dihydrobenzofuryl.

Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine , 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1 ,3-dioxepane, 4,7-dihydro-1,3-dioxepine and hexamethylene oxide.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3 -triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4 -oxadiazolyl.

Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1 - and 5-isoquinolyl), 1,2,3,4-tetrahydrisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1, 4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1, 2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5 -benzothiazolyl), purinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl and quinolizidinyl.

The above list of heterocyclyl and heteroaryl moieties is representative and non-limiting.

When used in the present invention, the term "substituting" means that an atom or group of atoms is replaced by hydrogen as a substituent attached to another group. Non-limiting examples of "substituting" groups include C ₁ -C ₁₀ alkyl, halogen, perhaloalkyl, =O, -OH, alkoxy, -NH ₂ , -N(CH ₃ ) ₂ , -NH(CH ₃ ) ₂ , phenyl, benzyl, (1-methylimidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, -OC(=O) (C ₁ -C ₄ )alkyl , -C(=O)(C ₁ -C ₄ )alkyl, -C≡N, -C(=O)O(C ₁ -C ₄ )alkyl, -C(=O)NH ₂ , -C(= O)NH(C ₁ -C ₄ )alkyl, -C(=O)N((C ₁ -C ₄ )alkyl) _2, -SO ₂ NH ₂ , -C(=NH)NH ₂ and -NO ₂ .

For aryl, aryl-(C ₁ -C ₃ )alkyl and heterocyclyl groups, the term "substituted" in relation to the rings of these groups means any degree of substitution, namely, mono-, di-, tri-, tetra - or pentasubstitution, if such substitution is allowed. The substituents are independently chosen and substitution may occur at any chemically accessible position. In some other embodiments, the number of substituents ranges from 1 to 4. In other embodiments, the number of substituents ranges from 1 to 3. In other embodiments, the number of substituents ranges from 1 to 2. In other embodiments, the substituents are independently selected from the group consisting of C ₁ -C ₆ alkyl, -OH, C ₁ -C ₆ alkoxy group, halogen, amino group, acetamide group and nitro group. When used in the present invention, if the substituent is an alkyl or alkoxy group, the carbon chain may be linear, branched or cyclic, with linear being preferred. The terms "substituted heterocycle" and "substituted heteroaryl" as used herein means a heterocyclyl or heteroaryl group containing one or more substituents including halogen, CN, OH, NO ₂ , amino, alkyl, cycloalkyl, carboxyalkyl (C(O) O-alkyl), trifluoroalkyl such as CF ₃ , aryloxy, alkoxy, aryl or heteroaryl. A substituted heterocyclyl or heteroaryl group may contain 1, 2, 3 or 4 substituents.

In the present description, various aspects of the present invention may be represented as ranges. It should be understood that the description in terms of ranges is merely for convenience and brevity and should not be construed as an immutable limitation on the scope of the present invention. Accordingly, a description in terms of ranges should be considered as a specific disclosure of all possible subranges, as well as individual numerical values that are in this range, and, if appropriate, non-integer values that are in the ranges. For example, a range description such as 1 to 6 should be considered as specifically disclosing subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6 and so on, as well as individual values within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This is true regardless of the width of the range.

The following abbreviations are used in the present invention: Boc, t-butyloxycarbonyl; Cs₂CO₃, cesium carbonate; DCM, dichloromethane; DEA, diethylamine; DIPEA, N,N-diisopropylethylamine; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; EDC.HCl, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; ER, endoplasmic reticulum; ERAD, destruction associated with the endoplasmic reticulum; EtOAc, ethyl acetate; Et₂O, diethyl ether; HATU, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; HOBT, 1-hydroxybenzotriazole; HPLC, high performance liquid chromatography; IPA, 2-propanol; KOAc, potassium acetate; LC-MS, liquid chromatography-mass spectrometry; LiOH, lithium hydroxide; MDAP, automatic purification by weight fractionation; MeCN, acetonitrile; MeOH, methanol; MgSO₄, magnesium sulfate; Na₂SO₄, sodium sulfate; NBS, N-bromosuccinimide; Pd(dppf)Cl₂DCM, [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-DCM complex; Ph, phenyl; RP, retinitis pigmentosa; RT, room temperature; Rt, retention time; SCX-2, Biotage Isolute - highly cationic ion exchange resin; TEA, trimethylamine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; UPLC, Ultra High Performance Liquid Chromatography; UPR, unfolded protein reaction.

Compounds and compositions

The present invention includes a compound of formula (Ia), formula (Ib), or formula (Ic), or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof:

, где:

, Where:

и

;R ¹ is selected from the group consisting of

And

;

R ² is selected from the group consisting of H, methyl, ethyl, propyl, CF ₃ , CHF ₂ , 1-methylcyclopropyl, isopropyl, t-butyl, and C ₃ -C ₈ cycloalkyl, wherein each non-H substituent is independently optionally substituted one R ⁷ , provided that if R ⁷ is present, R ³ is H;

L is selected from the group consisting of a bond, -CH ₂ - and -C(=O)-;

R ³ is selected from the group consisting of H, optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₈ alkenyl, optionally substituted C ₂ -C ₈ alkynyl, optionally substituted C ₁ - C ₈ heteroalkyl, optionally substituted C ₃ -C ₈ heterocycloalkyl, optionally substituted C ₂ -C ₈ heteroalkenyl, optionally substituted benzyl, optionally substituted C ₂ -C ₈ cycloheteroalkenyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl (such as, but not limited to imidazolyl or pyrazolyl);

R ⁴ is selected from the group consisting of -H, -OH, C ₁ -C ₆ alkoxy, halogen, -NH ₂ and -NHR ⁸ ;

in each occurrence, R ⁵ is independently selected from the group consisting of halide, -OH, C ₁ -C ₆ alkoxy, optionally substituted phenyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkoxy, and optionally substituted heterocycloalkyl;

R ⁶ is selected from the group consisting of H and optionally substituted C ₁ -C ₆ alkyl;

R ⁷ is selected from the group consisting of optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₈ alkenyl, optionally substituted C ₂ -C ₈ alkynyl, optionally substituted C ₁ -C ₈ heteroalkyl, optionally substituted C ₃ -C ₈ heterocycloalkyl, optionally substituted C ₂ -C ₈ heteroalkenyl, optionally substituted aryl, optionally substituted heteroaryl (such as, but not limited to, imidazolyl or pyrazolyl), and benzyl;

R ⁸ means optionally substituted C ₁ -C ₃ alkyl;

Cy is selected from the group consisting of aryl, heteroaryl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkenyl, C ₃ -C ₁₀ heterocycloalkyl, C ₃ -C ₁₀ heterocycloalkenyl, polycyclic aryl, polycyclic heteroaryl, polycyclic C ₃ -C ₁₀ cycloalkyl, polycyclic C ₃ -C ₁₀ cycloalkenyl, polycyclic C ₃ -C ₁₀ heterocycloalkyl and polycyclic C ₃ -C ₁₀ heterocycloalkenyl;

;where Cy is substituted with 0 to 'n' X, in each occurrence X is independently selected from the group consisting of H, OH, halide, nitrile, optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, optionally substituted C ₁ -C ₆ alkoxy, optionally substituted aryl (such as, but not limited to, phenyl), optionally substituted heteroaryl, and

;

in each case, Z, if present, is independently selected from the group consisting of CH and N;

m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

n is an integer selected from the group consisting of 0, 1, 2, 3, 4 and 5; And

q means an integer selected from the group consisting of 0, 1, 2, 3, 4 and 5.

In some embodiments, an optionally substituted group is unsubstituted. In other embodiments, the optionally substituted group is substituted with at least one substituent provided herein.

In some embodiments, in each occurrence, an optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, heterocycloalkyl, heteroalkenyl, benzyl, heterocyclyl, or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of C ₁ -C ₆ alkyl, halogen, - OR ^a , optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -N(R ^a )C(=O)R ^a , -C(=O)NR ^a R ^a and -N(R ^a )(R ^a ) , where in each case R ^a is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, or two R ^a groups are combined with the N atom with which they linked to form a heterocycle.

In some embodiments, in each occurrence, the optionally substituted aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, halogen, - CN, -OR ^b , -N(R ^b )(R ^b ), -NO ₂ , -S(=O) ₂ N(R ^b )(R ^b ), acyl and C ₁ -C ₆ alkoxycarbonyl, where in each in the case of R ^b independently means H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl.

In some embodiments, in each occurrence, the optionally substituted aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, halogen, - CN, -OR ^c , -N(R ^c )(R ^c ) and C ₁ -C ₆ alkoxycarbonyl, where in each case R ^c independently means H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl.

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

и

.

And

.

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

.In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

.

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

.In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

.

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

.In other embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

.

In some embodiments, R ² is methyl. In some embodiments, R ² is ethyl. In some embodiments, R ² is isopropyl.

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления R³ означает

. В некоторых вариантах осуществления p является целым числом, равным 0-5. В некоторых вариантах осуществления в каждом случае R⁹ независимо выбран из группы, включающей H, оксетанил, C₁-C₆ гидроксиалкил, C₁-C₆ галогеналкил, C₁-C₆ карбоксамидоалкил, C₁-C₆ карбоксиалкил, C₁-C₆ карбокси(C₁-C₆)алкилалкил и C₁-C₆ цианоалкил.In some embodiments, R ³ is H. In some embodiments, R ³ is C ₁ -C ₈ alkyl. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, R ³ means

. In some embodiments, p is an integer equal to 0-5. In some embodiments, at each occurrence, R ⁹ is independently selected from the group consisting of H, oxetanyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ carboxamidoalkyl, C ₁ -C ₆ carboxyalkyl, C ₁ - C ₆ carboxy(C ₁ -C ₆ )alkylalkyl; and C ₁ -C ₆ cyanoalkyl.

. В некоторых вариантах осуществления L=связь и R³ означает

. В некоторых вариантах осуществления L=связь и R³ означает

.In some embodiments, L=bond and R ³ means

. In some embodiments, L=bond and R ³ means

. In some embodiments, L=bond and R ³ means

.

In some embodiments, R ⁴ is H. In some embodiments, R ⁴ is -NH ₂ .

In some embodiments, R ⁵ , if present, is halogen. In other embodiments, q=1 and R ⁵ is F.

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления R⁷ означает

. В некоторых вариантах осуществления p является целым числом, равным 0-5. В некоторых вариантах осуществления в каждом случае R⁹ независимо выбран из группы, включающей H, оксетанил, C₁-C₆ гидроксиалкил, C₁-C₆ галогеналкил, C₁-C₆ карбоксамидоалкил, C₁-C₆ карбоксиалкил, C₁-C₆ карбокси(C₁-C₆)алкилалкил и C₁-C₆ цианоалкил.In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, R ⁷ means

. In some embodiments, p is an integer equal to 0-5. In some embodiments, at each occurrence, R ⁹ is independently selected from the group consisting of H, oxetanyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ carboxamidoalkyl, C ₁ -C ₆ carboxyalkyl, C ₁ - C ₆ carboxy(C ₁ -C ₆ )alkylalkyl; and C ₁ -C ₆ cyanoalkyl.

In some embodiments, in each occurrence R ⁹ is independently selected from the group consisting of: H, oxetanyl, C ₁ -C ₈ alkyl,

и

.

And

.

, где R' означает R³, определенный в другой части настоящего изобретения. В некоторых вариантах осуществления соединение представляет собой

(Ib'), где R' означает R³, определенный в другой части настоящего изобретения. В некоторых вариантах осуществления соединение представляет собой

(Ic'), где R' означает R³, определенный в другой части настоящего изобретения. В некоторых вариантах осуществления R' означает необязательно замещенный гетероциклил. В некоторых вариантах осуществления R' означает необязательно замещенный -NH-(необязательно замещенный гетероциклил). В некоторых вариантах осуществления R' означает необязательно замещенный -N(C₁-C₆ алкил)-(необязательно замещенный гетероциклил). В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

. В некоторых вариантах осуществления R' означает

.In some embodiments, the connection is

where R' means R ³ defined in another part of the present invention. In some embodiments, the connection is

(Ib'), where R' means R ³ defined in another part of the present invention. In some embodiments, the connection is

(Ic'), where R' means R ³ defined in another part of the present invention. In some embodiments, R' is an optionally substituted heterocyclyl. In some embodiments, R' is an optionally substituted -NH- (optionally substituted heterocyclyl). In some embodiments, R' is optionally substituted -N(C ₁ -C ₆ alkyl)-(optionally substituted heterocyclyl). In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

. In some embodiments, R' means

.

(Ia''), где R'' означает H или C₁-C₆ алкил. В некоторых вариантах осуществления соединение представляет собой

(Ib''), где R'' означает H или C₁-C₆ алкил. В некоторых вариантах осуществления соединение представляет собой

(Ic''), где R'' означает H или C₁-C₆ алкил. В некоторых вариантах осуществления R'' означает H. В некоторых вариантах осуществления R'' означает C₁-C₆ алкил. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

. В некоторых вариантах осуществления R¹ означает

.In some embodiments, the connection is

(Ia''), where R'' means H or C ₁ -C ₆ alkyl. In some embodiments, the connection is

(Ib''), where R'' means H or C ₁ -C ₆ alkyl. In some embodiments, the connection is

(Ic''), where R'' means H or C ₁ -C ₆ alkyl. In some embodiments, R'' is H. In some embodiments, R'' is C ₁ -C ₆ alkyl. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

. In some embodiments, R ¹ means

.

(Ia'''), где R''' выбран из группы, включающей -OH, C₁-C₆ алкоксигруппу, -NH₂, -NH(C₁-C₆ алкил), -N(C₁-C₆ алкил)(C₁-C₆ алкил) и -NH(оксетанил), где каждый C₁-C₆ алкил необязательно замещен по меньшей мере одним заместителем, независимо выбранным из группы, включающей галоген, -C(=O)NH₂, -C(=O)N(C₁-C₆ алкил), -C(=O)N(C₁-C₆ алкил)(C₁-C₆ алкил), -OH и - C₁-C₆ алкоксигруппу. В некоторых вариантах осуществления соединение представляет собой

(Ib'''), где R''' выбран из группы, включающей -OH, C₁-C₆ алкоксигруппу, -NH₂, -NH(C₁-C₆ алкил), -N(C₁-C₆ алкил)(C₁-C₆ алкил) и -NH(оксетанил), где каждый C₁-C₆ алкил необязательно замещен по меньшей мере одним заместителем, независимо выбранным из группы, включающей галоген, -C(=O)NH₂, -C(=O)N(C₁-C₆ алкил), -C(=O)N(C₁-C₆ алкил)(C₁-C₆ алкил), -OH и - C₁-C₆ алкоксигруппу. В некоторых вариантах осуществления соединение представляет собой

(Ic'''), где R''' выбран из группы, включающей -OH, C₁-C₆ алкоксигруппу, -NH₂, -NH(C₁-C₆ алкил), -N(C₁-C₆ алкил)(C₁-C₆ алкил) и -NH(оксетанил), где каждый C₁-C₆ алкил необязательно замещен по меньшей мере одним заместителем, независимо выбранным из группы, включающей галоген, -C(=O)NH₂, -C(=O)N(C₁-C₆ алкил), -C(=O)N(C₁-C₆ алкил)(C₁-C₆ алкил), -OH и - C₁-C₆ алкоксигруппу. В некоторых вариантах осуществления R'' означает H. В некоторых вариантах осуществления R''' означает -OH. В некоторых вариантах осуществления R''' означает -NH₂. В некоторых вариантах осуществления R''' означает -NHCH₃. В некоторых вариантах осуществления R''' означает -N(CH₃)₂. В некоторых вариантах осуществления R''' означает -NHCH₂CH₂F. В некоторых вариантах осуществления R''' означает -N(Me)CH₂CH₂F. В некоторых вариантах осуществления R''' означает -NHCH₂CHF₂. В некоторых вариантах осуществления R''' означает -N(Me)CH₂CHF₂. В некоторых вариантах осуществления R''' означает -NHCH₂CF₃. В некоторых вариантах осуществления R''' означает -N(Me)CH₂CF₃. В некоторых вариантах осуществления R''' означает -NHCH₂CH₂CF₃. В некоторых вариантах осуществления R''' означает -N(Me)CH₂CH₂CF₃. В некоторых вариантах осуществления R''' означает -NHCH₂CH₂C(=O)NMe₂. В некоторых вариантах осуществления R''' означает -N(Me)CH₂CH₂C(=O)NMe₂. В некоторых вариантах осуществления R''' означает -NHCH₂CH₂C(=O)NH₂. В некоторых вариантах осуществления R''' означает -N(Me)CH₂CH₂C(=O)NH₂. В некоторых вариантах осуществления R''' означает -NHCH₂CH₂C(=O)NHMe. В некоторых вариантах осуществления R''' означает -N(Me)CH₂CH₂C(=O)NHMe₂. В некоторых вариантах осуществления R''' означает

.In some embodiments, the connection is

(Ia'''), where R''' is selected from the group consisting of -OH, C ₁ -C ₆ alkoxy, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl) and -NH(oxetanyl), where each C ₁ -C ₆ alkyl is optionally substituted with at least one substituent independently selected from the group consisting of halogen, -C(=O)NH ₂ , -C(=O)N(C ₁ -C ₆ alkyl), -C(=O)N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -OH and -C ₁ -C ₆ alkoxy group . In some embodiments, the connection is

(Ib'''), where R''' is selected from the group consisting of -OH, C ₁ -C ₆ alkoxy, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl) and -NH(oxetanyl), where each C ₁ -C ₆ alkyl is optionally substituted with at least one substituent independently selected from the group consisting of halogen, -C(=O)NH ₂ , -C(=O)N(C ₁ -C ₆ alkyl), -C(=O)N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -OH and -C ₁ -C ₆ alkoxy group . In some embodiments, the connection is

(Ic'''), where R''' is selected from the group consisting of -OH, C ₁ -C ₆ alkoxy, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl) and -NH(oxetanyl), where each C ₁ -C ₆ alkyl is optionally substituted with at least one substituent independently selected from the group consisting of halogen, -C(=O)NH ₂ , -C(=O)N(C ₁ -C ₆ alkyl), -C(=O)N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -OH and -C ₁ -C ₆ alkoxy group . In some embodiments, R'' is H. In some embodiments, R''' is -OH. In some embodiments, R''' is -NH ₂ . In some embodiments, R''' is -NHCH ₃ . In some embodiments, R''' means -N(CH ₃ ) ₂ . In some embodiments, R''' is -NHCH ₂ CH ₂ F. In some embodiments, R''' is -N(Me)CH ₂ CH ₂ F. In some embodiments, R''' is -NHCH ₂ CHF ₂ . In some embodiments, R''' is -N(Me)CH ₂ CHF ₂ . In some embodiments, R''' means -NHCH ₂ CF ₃ . In some embodiments, R''' means -N(Me)CH ₂ CF ₃ . In some embodiments, R''' means -NHCH ₂ CH ₂ CF ₃ . In some embodiments, R''' means -N(Me)CH ₂ CH ₂ CF ₃ . In some embodiments, R''' means -NHCH ₂ CH ₂ C(=O)NMe ₂ . In some embodiments, R''' means -N(Me)CH ₂ CH ₂ C(=O)NMe ₂ . In some embodiments, R''' means -NHCH ₂ CH ₂ C(=O)NH ₂ . In some embodiments, R''' means -N(Me)CH ₂ CH ₂ C(=O)NH ₂ . In some embodiments, R''' is -NHCH ₂ CH ₂ C(=O)NHMe. In some embodiments, R''' means -N(Me)CH ₂ CH ₂ C(=O)NHMe ₂ . In some embodiments, R''' means

.

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

Example 1: 3-{4-[8-Amino-3-methyl-5-(piperazin-1-carbonyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea;

Example 2: 3-{4-[8-amino-5-(4-aminopiperidin-1-carbonyl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1- [3-(trifluoromethyl)phenyl]urea);

Example 3: 8-amino-3-methyl-N-(piperidin-4-yl)-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1, 5-a]pyrazine-5-carboxamide;

Example 4 3-(4-{8-amino-5-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylimidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl )-1-[3-(trifluoromethyl)phenyl]urea;

Example 5: 3-(4-{8-amino-5-[(3S)-3-aminopiperidine-1-carbonyl]-3-methylimidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl )-1-[3-(trifluoromethyl)phenyl]urea);

Example 6 8-amino-3-methyl-N-[(3R)-piperidin-3-yl]-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl] imidazo[1,5-a]pyrazine-5-carboxamide;

Example 7: 8-amino-3-methyl-N-(piperidin-3-yl)-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1, 5-a]pyrazine-5-carboxamide;

Example 8: 8-amino-3-methyl-N-[(3S)-1-methylpiperidin-3-yl]-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1- yl]imidazo[1,5-a]pyrazine-5-carboxamide;

Example 9 8-amino-3-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1- yl]imidazo[1,5-a]pyrazine-5-carboxamide;

Example 10 3-{4-[8-Amino-3-methyl-5-(4-methylpiperazin-1-carbonyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -[3-(trifluoromethyl)phenyl]urea;

Example 11 3-{4-[8-Amino-3-methyl-5-(piperidin-4-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea;

Example 12 3-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea;

Example 13: 3-(4-{8-amino-5-[(4-aminopiperidin-1-yl)methyl]-3-methylimidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl) -1-[3-(trifluoromethyl)phenyl]urea;

Example 14 3-[4-(8-amino-3-methyl-5-{[(piperidin-4-yl)amino]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 15: 3-[4-(8-amino-5-{[(3R)-3-aminopiperidin-1-yl]methyl}-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene- 1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 16: 3-[4-(8-amino-5-{[(3S)-3-aminopiperidin-1-yl]methyl}-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene- 1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 17 3-[4-(8-amino-3-methyl-5-{[(piperidin-3-yl)amino]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 18 3-{4-[8-amino-3-methyl-5-({[(3S)-piperidin-3-yl]amino}methyl)imidazo[1,5-a]pyrazin-1-yl] naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 19 3-(4-{8-amino-3-methyl-5-[(4-methylpiperazin-1-yl)methyl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl )-1-[3-(trifluoromethyl)phenyl]urea;

Example 20 3-{4-[8-amino-3-ethyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea;

Example 21 3-{4-[8-amino-5-(piperazin-1-ylmethyl)-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1- yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 22 3-(4-{8-amino-3-ethyl-5-[(4-methylpiperazin-1-yl)methyl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl )-1-[3-(trifluoromethyl)phenyl]urea;

Example 23: 3-[4-(8-Amino-3-methyl-5-{[4-(methylamino)piperidin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene- 1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 24 3-[4-(8-Amino-3-methyl-5-{[(3R)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 25: 3-[4-(8-Amino-3-methyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 26 3-[4-(8-amino-5-{[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl}-3-methylimidazo[1,5-a]pyrazin-1- yl)naphthalene-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 27 3-[4-(8-Amino-3-ethyl-5-{[(3R)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 28 3-[4-(8-Amino-3-ethyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 29 3-{4-[8-amino-5-(1,4-diazepan-1-ylmethyl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}- 1-[3-(trifluoromethyl)phenyl]urea;

Example 30 3-[4-(8-Amino-5-{2,5-diazabicyclo[2.2.1]heptan-2-ylmethyl}-3-methylimidazo[1,5-a]pyrazin-1-yl )naphthalene-1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 31: 3-[4-(8-amino-3-methyl-5-{octahydropyrrolo[3,4-c]pyrrol-2-ylmethyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene- 1-yl]-1-[3-(trifluoromethyl)phenyl]urea;

Example 32 3-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-( 3-fluorophenyl)urea;

Example 33: 3-{4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-( 3-methylphenyl)urea;

Example 34 3-{4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl}-1-[3 -(trifluoromethyl)phenyl]urea;

Example 35 3-{4-[8-amino-3-ethyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl}-1-[3 -(trifluoromethyl)phenyl]urea;

Example 36 N-(4-(8-amino-3-isopropyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-1-(2 -chlorophenyl)methanesulfonamide;

Example 37 3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(piperazin-1-ylmethyl)imidazo[ 1,5-a]pyrazine-8-amine;

Example 38 2-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-N-[ 3-(trifluoromethyl)phenyl]acetamide;

Example 39 3-{4-[8-Amino-3-methyl-5-(1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene- 1-yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 40 3-{4-[8-amino-3-methyl-5-(piperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea;

Example 41 3-{4-[8-Amino-3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene- 1-yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 42 3-{4-[8-Amino-3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl]-3 -fluorophenyl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 43: 3-{4-[5-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl ]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 44: 3-{4-[5-(1-acetylpiperidin-3-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1- [3-(trifluoromethyl)phenyl]urea;

Example 45 3-{4-[5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl ]-3-fluorophenyl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 46 3-{4-[8-amino-5-(cyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}- 1-[3-(trifluoromethyl)phenyl]urea;

Example 47 3-{4-[8-Amino-3-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyrazin-1- yl]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 48 3-{4-[8-Amino-3-methyl-5-(pyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea;

Example 49 3-(4-{8-amino-3-methyl-5-[1-(prop-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl]imidazo[1,5- a]pyrazin-1-yl}naphthalene-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 50 3-{4-[8-amino-5-(4-aminophenyl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-( trifluoromethyl)phenyl]urea;

Example 51 3-{4-[8-amino-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1- yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 52 3-{4-[8-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1 -yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 53 3-{4-[8-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1 -yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 54 3-(4-{8-amino-3-methyl-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]imidazo[1,5-a]pyrazin-1- yl}naphthalene-1-yl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 55 3-{4-[8-Amino-3-methyl-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene- 1-yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 56 3-{4-[8-amino-5-(2-aminopyridin-4-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1- [3-(trifluoromethyl)phenyl]urea;

Example 57 2-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-N-(3-(trifluoromethyl)phenyl)acetamide;

Example 58 2-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide;

Example 59 2-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}naphthalene-1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide;

Example 60 2-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide;

Example 61 2-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 3-fluorophenyl)-N-[3-(trifluoromethyl)phenyl]acetamide;

Example 62 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-phenylacetamide;

Example 63: 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-N-(3-fluorophenyl)acetamide;

Example 64 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-fluorophenyl)acetamide;

Example 65 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-fluoro-5-methoxyphenyl)acetamide;

Example 66: 2-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-N-phenylacetamide;

Example 67 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-cyano-5-fluorophenyl)acetamide;

Example 68 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(pyridin-2-yl)acetamide;

Example 69 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(5-methoxypyridin-3-yl)acetamide;

Example 70 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-cyanophenyl)acetamide;

Example 71 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-methoxyphenyl)acetamide;

Example 72 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(pyridin-3-yl)acetamide;

Example 73 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(pyrazin-2-yl)acetamide;

Example 74 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(thiazol-5-yl)acetamide;

Example 75 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(1-methyl-1H-benzo[d]imidazol-5-yl)acetamide;

Example 76 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetamide;

Example 77 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide;

Example 78 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3,4-dimethoxyphenyl)acetamide;

Example 79 2-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(pyrimidin-5-yl)acetamide;

Example 80 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(5-fluoropyridin-3-yl)acetamide;

Example 81 2-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-fluorophenyl)acetamide;

Example 82 2-(5-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-phenylacetamide;

Example 83 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[3-(trifluoromethyl)phenyl]urea;

Example 84 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 85: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-ethylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-(3-(trifluoromethyl)phenyl)urea;

Example 86 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1- yl]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea;

Example 87: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-phenylurea;

Example 88 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[3,5-bis(trifluoromethyl)phenyl]urea;

Example 89 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-(3,5-dimethylphenyl)urea;

Example 90 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[4-chloro-3-(trifluoromethyl)phenyl]urea;

Example 91: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-benzylurea;

Example 92 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[(4-methylphenyl)methyl]urea;

Example 93: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-(2-chloro-5-(trifluoromethyl)phenyl)urea;

Example 94: 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-3-(5-chloro-2-methoxyphenyl)urea;

Example 95: 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-3-(2-methoxy-5-methylphenyl)urea;

Example 96 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-(5-chloro-2-methylphenyl)urea;

Example 97 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-(3-fluorophenyl)urea;

Example 98: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-(m-tolyl)urea;

Example 99: 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-3-(2-methoxyphenyl)urea;

Example 100: 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[4-(trifluoromethyl)phenyl]urea;

Example 101: N-(4-{8-amino-3-methyl-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1,5-a] pyrazin-5-yl}cyclohex-3-en-1-yl)acetamide;

Example 102: 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;

Example 103 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-(2,3-dihydro-1,4-benzodioxin-6-yl)urea;

Example 104 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl} -1-(2,3-dihydro-1,4-benzodioxin-6-yl)urea;

Example 105 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl} -3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;

Example 106 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 107 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-(trifluoromethyl)phenyl)urea;

Example 108 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 3-fluorophenyl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 109 3-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}-3-fluorophenyl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 110: 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 3-fluorophenyl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 111 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 3-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 112: 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 2-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 113: 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 5-fluoro-2-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 114 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 5-fluoro-2-methoxyphenyl)-1-[3-(trifluoromethyl)phenyl]urea;

Example 115 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-(3-methylphenyl)urea;

Example 116 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-(3-fluorophenyl)urea;

Example 117 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-(3-fluorophenyl)urea;

Example 118 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-(3-methylphenyl)urea;

Example 119 3-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}naphthalene-1-yl)-1-(3-methylphenyl)urea;

Example 120 3-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}naphthalene-1-yl)-1-(3-fluorophenyl)urea;

Example 121 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-phenylurea;

Example 122: 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(pyridin-3-yl)urea;

Example 123: 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-fluorophenyl)urea;

Example 124 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-(trifluoromethyl)phenyl)urea;

Example 125: 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea;

Example 126: 1-(4-(8-Amino-3-ethyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(3-fluorophenyl)urea;

Example 127 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-phenylurea;

Example 128 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea;

Example 129: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(3-fluorophenyl)urea;

Example 130: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-phenylurea;

Example 131 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(pyridin-2-yl)urea;

Example 132: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-methoxyphenyl)-3-(3-fluorophenyl)urea;

Example 133: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2-fluorophenyl)-3-phenylurea;

Example 134: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2-fluorophenyl)-3-(3-fluorophenyl)urea;

Example 135 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl )-3-(pyridin-3-yl)urea;

Example 136 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-cyano-5-fluorophenyl)urea;

Example 137 1-(5-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)isoquinoline -8-yl)-3-(3-fluorophenyl)urea;

Example 138: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(pyridin-3-yl)urea;

Example 139 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-benzylurea;

Example 140 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea;

Example 141 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-methoxyphenyl)urea;

Example 142: 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-cyanophenyl)urea;

Example 143: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3,4-dimethoxyphenyl)urea;

Example 144 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(pyridin-4-yl)urea;

Example 145: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(4-fluorophenyl)urea;

Example 146: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(3-fluoro-5-methoxyphenyl)urea;

Example 147 1-(4-(8-amino-3-methyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(pyridin-3-yl)urea;

Example 148: 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(5-methoxypyridin-3-yl)urea;

Example 149: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(5-fluoropyridin-3-yl)urea;

Example 150: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(thiophen-3-yl)urea;

Example 151 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3,5-difluorophenyl)urea;

Example 152 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(2-fluorophenyl)urea;

Example 153: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-methylphenyl)-3-(pyridin-3-yl)urea;

Example 154: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-chlorophenyl)-3-(pyridin-3-yl)urea;

Example 155: 1-(4-(3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-phenylurea;

Example 156: 3-Isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 157: 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-methyl-5-(4-(methylamino)cyclohex-1-en-1 -yl)imidazo[1,5-a]pyrazin-8-amine;

Example 158: 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)-2-fluorophenyl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazine-8-amine;

Example 159: 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1 -yl)imidazo[1,5-a]pyrazin-8-amine;

Example 160: 1-(5-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1 -yl)imidazo[1,5-a]pyrazin-8-amine;

Example 161: 1-(4-((4,6-difluoro-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex -1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 162: 1-(4-((4,6-dimethyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex -1-en-1-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 163 3-isopropyl-1-(4-((5-methoxy-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 164 2-((4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl) naphthalene-1-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

Example 165: 1-(4-((7-Fluoro-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 166: 1-(4-((1H-imidazo[4,5-c]pyridin-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 167: 1-(4-((7-Chloro-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 168 3-Isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)-1-(4-((5-phenyl-1H-imidazol-2-yl)methyl)naphthalene-1 -yl)imidazo[1,5-a]pyrazin-8-amine;

Example 169: N-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide;

Example 170: N-(4-(8-amino-3-methyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-chlorobenzenesulfonamide;

Example 171 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)benzenesulfonamide;

Example 172: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-fluorobenzenesulfonamide;

Example 173: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(2-chlorophenyl)methanesulfonamide;

Example 174: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-2-chlorobenzenesulfonamide;

Example 175: N-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-chlorobenzenesulfonamide;

Example 176: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-fluorobenzenesulfonamide;

Example 177: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonamide;

Example 178: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonamide;

Example 179: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2-fluorophenyl)-2-chlorobenzenesulfonamide;

Example 180: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide;

Example 181 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-chlorobenzenesulfonamide;

Example 182: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(3-fluorophenyl)methanesulfonamide;

Example 183: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-phenylmethanesulfonamide;

Example 184: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2,5-difluorobenzenesulfonamide;

Example 185: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-fluoro-5-methylbenzenesulfonamide;

Example 186 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-chloro-5-fluorobenzenesulfonamide;

Example 187: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(2-fluorophenyl)methanesulfonamide;

Example 188 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(2,5-difluorophenyl)methanesulfonamide;

Example 189: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(2-fluorophenyl)methanesulfonamide;

Example 190: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(2,5-difluorophenyl)methanesulfonamide;

Example 191: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(3,5-difluorophenyl)methanesulfonamide;

Example 192: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-fluoro-5-(trifluoromethyl)benzenesulfonamide;

Example 193: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(trifluoromethyl)benzenesulfonamide;

Example 194: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(trifluoromethyl)benzenesulfonamide;

Example 195: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-2,5-dichlorobenzenesulfonamide;

Example 196: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2,5-difluorophenyl)-1-(2-chlorophenyl)methanesulfonamide;

Example 197: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2,3-difluorophenyl)-1-(2-chlorophenyl)methanesulfonamide;

Example 198: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(pyridin-3-yl)methanesulfonamide;

Example 199 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(pyridin-3-yl)methanesulfonamide;

Example 200: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(3-methoxyphenyl)methanesulfonamide;

Example 201: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(3-methoxyphenyl)methanesulfonamide;

Example 202: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(3,5-difluorophenyl)methanesulfonamide;

Example 203: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(2-chlorophenyl)-N-methylmethanesulfonamide;

Example 204: 1-[(8-amino-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2- yl)imidazo[1,5-a]pyrazin-5-yl)methyl]piperidin-4-amine;

Example 205: (3S)-1-[(8-amino-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-( propan-2-yl)imidazo[1,5-a]pyrazin-5-yl)methyl]piperidin-3-amine;

Example 206: 1-{4-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-5-[4-(methylamino)cyclohex-1-en-1 -yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 207 4-(8-amino-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl )imidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-ol;

Example 208 5-[4-(dimethylamino)cyclohex-1-en-1-yl]-1-{4-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1 -yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 209 5-{4-[(2,2-difluoroethyl)(methyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol -2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 210 5-(4-aminocyclohex-1-en-1-yl)-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl} -3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 211 5-{4-[methyl(2,2,2-trifluoroethyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol -2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 212 5-{4-[(2,2-difluoroethyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2- yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 213: 5-{4-[(2-fluoroethyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl) methyl]naphthalen-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 214: 1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)-5-{4- [(2,2,2-trifluoroethyl)amino]cyclohex-1-en-1-yl}imidazo[1,5-a]pyrazine-8-amine;

Example 215: 5-{4-[(2-fluoroethyl)(methyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2 -yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 216 5-{4-[methyl(3,3,3-trifluoropropyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol -2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine;

Example 217: 3-((4-(8-amino-3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)imidazo [1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)amino)-N,N-dimethylpropanamide;

Example 218 N-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}-2-fluorophenyl)-2-fluoro-5-methylbenzene-1-sulfonamide;

Example 219: N-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}naphthalene-1-yl)-2-chloro-5-methylbenzene-1-sulfonamide;

Example 220: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide;

Example 221: 1-(4-((1H-Benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloro-3-(piperazin-1-ylmethyl)imidazo[1,5- a] pyrazine;

Example 222: 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloro-3-((4-methylpiperazin-1-yl)methyl)imidazo [1,5-a]pyrazine;

Example 223: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;

Example 224: N-(4-(8-amino-5-(4-hydroxycyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl) -1-(2-chlorophenyl)methanesulfonamide;

Example 225: N-(4-(8-amino-5-(4-hydroxycyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl) -2-chlorobenzenesulfonamide;

Example 226: N-(4-(8-amino-5-(4-((2,2-difluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazine -1-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;

Example 227: N-(4-(8-amino-3-isopropyl-5-(4-(oxetan-3-ylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide;

Example 228: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1 -yl)-2,5-difluorophenyl)-2-chlorobenzenesulfonamide;

Example 229: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-2-fluorobenzenesulfonamide;

Example 230: N-(4-(8-amino-5-(4-((2-fluoroethyl)(methyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a] pyrazin-1-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;

Example 231: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;

Example 232: N-(4-(8-amino-3-isopropyl-5-(4-(oxetan-3-ylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;

or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof.

In some embodiments, the compound is an IRE1 inhibitor. In other embodiments, the compound is an IRE1α inhibitor. In other embodiments, the compound is an inhibitor of IRE1α kinase activity. In other embodiments, the compound is an inhibitor of the RNase activity of IRE1α. In other embodiments, the compound binds to an ATP binding site in IRE1α. In other embodiments, the compound binds to IRE1α in a DFG-out conformation. In other embodiments, the compound binds to IRE1α in the DFG-in conformation. In other embodiments, the compound induces the formation of a DFG-out conformation for IRE1α. In other embodiments, the compound is an inhibitor of IRE1α oligomerization. In other embodiments, the compound is an inhibitor of IRE1α dimerization. In other embodiments, the compound is an inhibitor of IRE1α phosphorylation. In other embodiments, the compound is an inhibitor of IRE1α autophosphorylation. In other embodiments, the compound is an apoptosis inhibitor. In other embodiments, the compound is an inhibitor of IRE1α-induced apoptosis. In other embodiments, the compound is a cell death inhibitor. In other embodiments, the compound is an inhibitor of IRE1α-induced cell death. In other embodiments, the compound is an inhibitor of the pathway induced by phosphorylation of IRE1α. In other embodiments, the compound is an inhibitor of the pathway induced by IRE1α kinase activity. In other embodiments, the compound is an inhibitor of the pathway induced by the RNase activity of IRE1α. In other embodiments, the compound is a neuronal cell death inhibitor. In other embodiments, the compound is a cytotoxic agent. In other embodiments, the compound is an anticancer agent. In other embodiments, the compound is a demyelination inhibitor. In other embodiments, the compound is an antidiabetic agent. In other embodiments, the compound is a neuroprotective agent. In other embodiments, the compound protects against loss of photoreceptor cells. In other embodiments, the compound is a fibrosis inhibitor. In other embodiments, the compound reduces cell apoptosis during ER stress. In other embodiments, the compound reduces apoptosis of cells under ER stress, but not in cells that are under the same conditions, but not under ER stress. In other embodiments, the compound reduces apoptosis of cells under ER stress to a greater extent than cells that are under the same conditions, but not under ER stress. In other embodiments, the compound reduces miR-17 cleavage. In other embodiments, the compound reduces IRE1α-related miR-17 cleavage. In other embodiments, the compound reduces miR-34a cleavage. In other embodiments, the compound reduces IRE1α-related cleavage of miR-34a. In other embodiments, the compound reduces miR-96 cleavage. In other embodiments, the compound reduces IRE1α-related miR-96 cleavage. In other embodiments, the compound reduces miR-125b cleavage. In other embodiments, the compound reduces IRE1α-related cleavage of miR-125b. In other embodiments, the compound reduces splicing of the XBP1 mRNA. In other embodiments, the implementation of the connection reduces associated with IRE1α splicing XBP1 mRNA. In other embodiments, the connection weakens UPR signaling. In other embodiments, the connection attenuates IRE1α-related UPR signaling. In other embodiments, the connection weakens the signaling of the terminal UPR. In other embodiments, the connection attenuates IRE1α-related terminal UPR signaling.

The compounds described in the present invention may form salts with acids and/or bases, and such salts are included in the present invention. In some other embodiments, the salts are pharmaceutically acceptable salts. The term "salts" includes addition salts of free acids and/or bases, which are applicable in the methods proposed in the present invention. Pharmaceutically unacceptable salts may still have characteristics, such as high crystallinity, that are useful in the practice of the present invention, for example, used in the synthesis, purification, or preparation of compounds useful in the methods of the present invention.

Suitable addition salts with pharmaceutically acceptable acids can be obtained from an inorganic acid or from an organic acid. Examples of inorganic acid salts include sulfate, hydrogen sulfate, hemisulfate, and salts of hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids may be selected from the group consisting of the aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carbocyclic and sulfonic classes of organic acids, examples of which include formic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, almond, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic , sulfanilic, cyclohexylaminosulfonic , stearic, alginic, β-hydroxybutyric, salicylic, mucus, galacturonic acid, glycerophosphonic acids and saccharin (eg saccharinate, saccharate).

Suitable addition salts with pharmaceutically acceptable bases of the compounds of the present invention include, for example, metal salts, including alkali metal, alkaline earth metal and transition metal salts, such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts derived from basic amines such as, for example, ammonia, N,N'-dibenlylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

All of these salts can be obtained from the corresponding compound by reacting, for example, an appropriate acid or base with the compound. The salts may be less than one, one, or more than one molar equivalent of acid or base, based on any compound of the present invention.

In some other embodiments, at least one compound of the present invention is a component of a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.

The compounds of the present invention may contain one or more stereocenters, and each stereocenter may independently exist in the (R)- or (S)-configuration. In some other embodiments, the implementation of the compounds described in the present invention are contained in optically active or racemic forms. The compounds described in the present invention include racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof, which have the therapeutically useful characteristics described in the present invention. Obtaining optically active forms is carried out in any suitable manner, including, as a non-limiting example, resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In some other embodiments, a mixture of one or more isomers is used as the therapeutic compounds described in the present invention. In other embodiments, the implementation of the compounds described in the present invention contain one or more chiral centers. These compounds are prepared by any method, including stereoselective synthesis, enantioselective synthesis, and/or separation of a mixture of enantiomers and/or diastereoisomers. The separation of compounds and their isomers is carried out by any method including, but not limited to, chemical procedures, enzymatic procedures, fractional crystallization, distillation, and chromatography.

The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any of the compounds provided herein. invention, as well as metabolites and active metabolites of these compounds with the same type of activity. Solvates include water, ether (eg, tetrahydrofuran, methyl t-butyl ether) or alcohol (eg, ethanol), solvates, acetates, and the like. In some other embodiments, the compounds described in the present invention exist in solvated forms with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the implementation of the compounds described in the present invention exist in unsolvated form.

In some other embodiments, the compounds of the present invention exist as tautomers. All tautomers are included within the scope of the compounds listed in the present invention.

In some other embodiments, the implementation of the compounds described in the present invention, receive in the form of prodrugs. A "prodrug" is an agent that is converted in vivo to the parent drug. In some other embodiments, following in vivo administration, the prodrug is chemically converted to a biologically, pharmaceutically, or therapeutically active form of the compound. In other embodiments, the prodrug undergoes enzymatic metabolism through one or more steps or processes to form a biologically, pharmaceutically, or therapeutically active form of the compound.

In some other embodiments, the centers, for example, in the aromatic ring portion of the compounds of the present invention, enter into various metabolic reactions. The inclusion of suitable substituents on aromatic ring structures can shorten, minimize, or eliminate this metabolic pathway. In some other embodiments, a suitable substituent to reduce or eliminate the susceptibility of an aromatic ring to metabolic reactions is, for example, only deuterium, halogen, or an alkyl group.

The compounds described in the present invention also include isotopically labeled compounds in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature. . Examples of isotopes suitable for inclusion in the compounds described in the present invention include and are not limited to ² H, ³ H, ¹¹ C, ¹³ C, ^{14 C} , ³⁶ Cl, 18 F, ¹²³ I, ¹²⁵ I, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, and ³⁵ S. In some other embodiments, isotopically labeled compounds are useful for studying drug and/or substrate tissue distribution. In other embodiments, substitution with heavier isotopes, such as deuterium, provides greater metabolic stability (eg, increased in vivo half-life or the ability to use lower doses). In other embodiments, substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N is useful for positron emission tomography (PET) studies to study substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable procedure or procedures using an appropriate isotopically labeled reagent in place of the previously non-isotopically labeled reagent.

In some other embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent or chemiluminescent labels.

The compounds described in the present invention, and other related compounds having different substituents, are synthesized using the methods and materials described in the present invention and in the art. General methods for obtaining compounds described in the present invention, modified by using reagents and conditions suitable for the introduction of various fragments included in the formula given in the present invention.

Ways

The present invention includes methods for treating eating disorders associated with ER stress. In some embodiments, the present invention provides methods for treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the present invention, or pharmaceutically acceptable salts, solvates, enantiomers, diastereoisomers, or tautomers thereof. In other embodiments, the subject is in need of treatment.

In some embodiments, the disease or disorder is selected from the group consisting of neurodegenerative disease, demyelinating disease, cancer, eye disease, fibrotic disease, and diabetes.

In some embodiments, the disease is a neurodegenerative disease selected from the group consisting of retinitis pigmentosa, amyotrophic lateral sclerosis, retinal degeneration, macular degeneration, Parkinson's disease, Alzheimer's disease, Huntington's disease, prion disease, Creutzfeldt-Jakob disease, and kuru.

In some embodiments, the disease is a demyelinating disease selected from the group consisting of Wolfram syndrome, Pelizeus-Merzbacher disease, transverse myelitis, Charcot-Marie-Tooth disease, and multiple sclerosis.

In some embodiments, the disease is cancer. In other embodiments, the disease is multiple myeloma.

In some embodiments, the disease is diabetes. In other embodiments, the disease is selected from the group consisting of type I diabetes and type II diabetes.

In some embodiments, the disease is an eye disease selected from the group consisting of retinitis pigmentosa, retinal degeneration, macular degeneration, and Wolfram's syndrome.

In some embodiments, the disease is a fibrotic disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), myocardial infarction, cardiac hypertrophy, heart failure, cirrhosis, acetaminophen (Tylenol) liver toxicity, hepatitis C (liver disease), hepatosteatosis ( fatty infiltration of the liver) and liver fibrosis.

Without being limited by any one theory, it can be assumed that the compounds of the present invention treat the above diseases and disorders by modulating the activity of the IRE1 protein. In some embodiments, the compounds inhibit the activity of the IRE1 protein.

In some embodiments, the compounds of the present invention modulate the kinase activity of the IRE1 protein. In other embodiments, the compounds of the present invention modulate the autophosphorylation activity of the IRE1 protein. In other embodiments, the compounds of the present invention modulate the oligomerization activity of the IRE1 protein. In other embodiments, the compounds of the present invention modulate the dimerization activity of the IRE1 protein.

Administration/Dosage/Drugs

The mode of administration may affect what is an effective amount. Therapeutic drugs can be administered to a subject before or after the onset of the disease or disorder specified in the present invention. In addition, different divided doses, as well as doses spaced apart over time, can be administered daily or sequentially, or the dose can be continuously infused or performed as a bolus injection. In addition, the doses of therapeutic drugs can be proportionally increased or decreased in accordance with the need for a therapeutic or prophylactic case.

The introduction of the compositions proposed in the present invention, the patient, preferably a mammal, more preferably a human, can be carried out according to known procedures using doses and periods effective for the treatment of the disease or disorder considered in the present invention. The effective amount of a therapeutic compound required to provide a therapeutic effect may vary depending on such factors as the disease state or disorder of the patient, age, sex and body weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder of the present invention. Dosage regimens can be varied to obtain the optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally increased or decreased as needed for the therapeutic event. A non-limiting example of an effective dosage range for a therapeutic compound of the present invention is from about 1 to 5000 mg/kg body weight/day. Pharmaceutical compositions useful in the practice of the present invention may be administered to deliver a dose of 1 ng/kg/day to 100 mg/kg/day. One of ordinary skill in the art is able to study the relevant factors and determine the effective amount of the therapeutic compound without undue experimentation.

A physician, such as a physician or veterinarian with general training in the art, can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian may start with lower doses of the compounds of this invention used in a pharmaceutical composition than needed to provide the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

In preferred embodiments, it is useful to formulate the compound in dosage form for easy administration and uniformity of dose. Single dosage form when used in the present invention means individual portions, as single doses suitable for patients undergoing treatment; each serving contains a predetermined amount of the therapeutic compound judged to provide the desired therapeutic effect, together with a suitable pharmaceutical carrier.

In some other embodiments, the compositions of the present invention are prepared using one or more pharmaceutically acceptable excipients or carriers. In other embodiments, pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier. In other embodiments, the implementation of the connection proposed in the present invention is the only biologically active agent (ie, capable of treating or preventing diseases and disorders associated with IRE1) in the composition. In other embodiments, a compound of the present invention is the only biologically active agent (ie, capable of treating or preventing diseases and disorders associated with IRE1) in therapeutically effective amounts in the composition.

In some other embodiments, the implementation of the composition proposed in the present invention, administered to the patient in the modes, when the introduction is carried out from 1 to 5 or more times per day. In other embodiments, the compositions of the present invention are administered to a patient in administration ranges that include, but are not limited to, once daily, every two days, every three days to once a week, and once every 2 weeks. One skilled in the art will appreciate that the frequency of administration of various combinations of the compositions of the present invention varies from individual to individual, depending on many factors, including, but not limited to, age, disease or disorder being treated, gender, general health and other factors. Thus, the present invention should not be considered limited to any particular mode of administration and the precise dosage and composition to be administered to any patient will be determined by the attending physician, taking into account other factors related to the patient.

The dosage of the compounds of the present invention for administration may range from about 1 µg to about 10000 mg, from about 20 µg to about 9500 mg, from about 40 µg to about 9000 mg, from about 75 µg to about 8500 mg, from about 150 µg to about 7500 mg, from about 200 µg to about 7000 mg, from about 300 µg to about 6000 mg, from about 500 µg to about 5000 mg, from about 750 µg to about 4000 mg, from about 1 mg to about 3000 mg, from about 10 mg to about 2500 mg, from about 20 mg to about 2000 mg, from about 25 mg to about 1500 mg, from about 30 mg to about 1000 mg, from about 40 mg to about 900 mg, from about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all integer or non-integer values in between.

In some embodiments, the dosage of a compound of the present invention is between about 1 mg and about 2500 mg. In some embodiments, the dose of a compound of the present invention used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2000 mg, or less than about 1000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than about 1000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all integer or non-integer values in between.

In some other embodiments, the implementation, the present invention relates to the packaging of a pharmaceutical composition, including a container that contains a therapeutically effective amount of the compounds proposed in the present invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or ameliorate one or more of the symptoms of the disease or disorder of the present invention.

The preparations can be used in mixtures with common inert fillers, i.e. pharmaceutically acceptable organic or inorganic carriers suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral or any other suitable route of administration known in the art. Pharmaceutical preparations can be sterilized and optionally mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, osmotic salts, buffers, colorants, flavors and/or aromas, and the like. If desired, they can also be combined with other active agents.

Routes of administration of any of the compositions of the present invention include intravitreal, oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. Compounds for use in the present invention can be formulated for administration by any suitable route, such as oral or parenteral, e.g. transdermal, transmucosal (e.g. sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g. ), (intra)nasal and (trans)rectal), vitreous, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, lozenges, dispersions, suspensions, solutions, syrups, granules, boluses, transdermal patches, gels, powders, pellets, slurries, lozenges, creams, pastes, patches, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol preparations for inhalation, compositions and preparations for intravesical administration, and the like. It should be understood that the preparations and compositions that are applicable in the present invention are not limited to the specific preparations and compositions that are described in the present invention.

Oral administration

For oral administration, tablets, dragees, liquids, drops, suppositories or capsules, caplets and gel capsules are particularly suitable. Compositions intended for oral administration may be prepared by any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutical excipients which are suitable for tablet formulation. Such excipients include, for example, an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or may be coated by known techniques for visual appeal or to delay the release of the active ingredients. Oral preparations can also be made into hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

parenteral administration

As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by a mechanical rupture of the subject's tissue and administration of the pharmaceutical composition through the rupture into the tissue. Thus, parenteral administration includes, but is not limited to, administering the pharmaceutical composition by injecting the composition, by administering the composition through a surgical incision, by administering the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration includes, but is not limited to, subcutaneous, intravenous, intravitreal, intraperitoneal, intramuscular, epigastric injection, and renal dialysis infusion techniques.

Introduction to the vitreous

As used herein, "vitreous administration" of a pharmaceutical composition comprises administering to a vitreous fluid in the eye of a subject. Vitreous administration includes, but is not limited to, administering a pharmaceutical composition to the eye of a subject by injecting the composition. In some embodiments, the pharmaceutical composition may be administered using a hypodermic needle or through a surgical incision. Preferably the introduction through the sclera of the eye, so as not to damage the cornea or lens.

In some embodiments, the implementation of the pharmaceutical composition proposed in the present invention can be prepared for administration to the eye of a subject with a sustained release for 3-12 months.

Controlled release formulations and drug delivery systems

In some other embodiments, the formulations of the present invention may include, but are not limited to, short-acting, fast-acting, and controlled-release formulations, such as sustained release, delayed release, and intermittent release.

The term sustained release is used in its usual sense to refer to a drug product that provides a gradual release of the drug over an extended period of time and which may, although not necessarily, result in a substantially constant blood level of the drug over an extended period of time. The time period may be up to a month or more and the release may be longer than the release of the same amount of agent administered in bolus form. In some embodiments, the implementation of the compounds proposed in the present invention can be formulated for sustained release within 3-12 months.

For sustained release, compounds can be formulated with a suitable polymeric or hydrophobic material that provides sustained release of the compounds. As such, such compounds useful in the methods of the present invention may be administered in the form of microparticles, for example by injection, or in the form of wafers or discs by implantation.

In one embodiment of the present invention, the compounds of the present invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

The term delayed release is used in the present invention in its usual sense to refer to a drug product that provides initial drug release with some delay after drug administration, and which may include, although not necessarily include a delay of from about 10 minutes to about 12 hours.

The term intermittent release is used in the present invention in its usual sense to refer to a drug that provides drug release in such a way that after administration of the drug the plasma profiles of the drug are intermittent.

The term immediate release is used in its usual sense to refer to a drug product that releases the drug after administration of the drug.

As used herein, short term means any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes. , about 20 minutes, about 10 minutes, or about 1 minute, and has any and all integer or non-integer values after drug administration.

As used herein, prompt termination means any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 min, about 20 min, about 10 min, or about 1 min, and has any and all integer or non-integer values after drug administration.

Dosage

A therapeutically effective amount or dose of a compound of the present invention will depend on the age, sex, and body weight of the patient, the patient's current health status, and the progression of the disease or disorder of the present invention. One skilled in the art will be able to determine the appropriate dosage depending on these and other factors.

A suitable dose of a compound of the present invention may be in the range of from about 0.01 mg to about 5000 mg per day, such as from about 0.1 mg to about 1000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered as a single dose or multiple doses, for example 1 to 5 or more times per day. If multiple doses are used, the dose rates may be the same or different. For example, a dose of 1 mg per day can be administered as two doses of 0.5 mg with approximately 12 hours between doses.

It should be understood that the amount of the compound administered per day, as non-limiting examples, can be administered daily, every other day, 2 days later, 3 days later, 4 days later, or 5 days later.

In the event that the patient's condition does not improve, the inhibitor of the present invention is optionally administered continuously as prescribed by the physician; alternatively, the dose of the administered drug is temporarily reduced or temporarily canceled for a while (ie, take a break). The duration of the drug interruption is optionally between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days. The dose reduction during a drug interruption is 10%-100%, including, for example, only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% , 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

After the patient's condition has improved, if necessary, a maintenance dose is administered. The dose or frequency of administration, or both, is then reduced, depending on the disease or disorder, to values at which improvement in the course of the disease is maintained. In some other embodiments, patients require long-term intermittent treatment for any recurrence of symptoms and/or infection.

Compounds for use in the method of the present invention may be formulated in unit dosage form. The term "single dosage form" means single servings, as single doses suitable for patients undergoing treatment, each serving contains a predetermined amount of a therapeutic compound, estimated to provide the desired therapeutic effect, together with a suitable pharmaceutical carrier. The unit dosage form may be administered once a day or multiple times a day (eg, about 1 to 5 or more times a day). If administered several times a day, the unit dosage forms may be the same or different.

The toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined using cell cultures or experimental animals, including, but not limited to, determination of LD ₅₀ (dose lethal for 50% of the population) and ED ₅₀ (dose therapeutically effective for 50% of the population) . The dose ratio for toxic and therapeutic effects is a therapeutic index, which is expressed as the ratio of LD ₅₀ and ED ₅₀ . Data from cell culture and animal studies are not necessarily used to determine dosage ranges for humans. The dose of such compounds is preferably in the range of circulating concentrations that include the ED ₅₀ with minimal toxicity. The dose does not necessarily vary within this range depending on the dosage form used and the route of administration.

It is obvious to those skilled in the art, or using no more than standard experimentation, that they can determine numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of the present invention and are within the scope of the appended claims. For example, it should be understood that modifications to the reaction conditions, including, but not limited to, reaction time, reaction mixture size/volume, and reagents used in the experiment, such as solvents, catalysts, pressures, atmospheric conditions, such as nitrogen and reducing /oxidizing reagents, together with alternatives accepted in the art, established using no more than standard experiments, are included in the scope of this application.

The following examples further illustrate aspects of the present invention. However, they in no way limit the provisions or disclosure of the present invention given in the present invention.

Examples

The present invention is described using the following examples. These examples are provided for illustration only and the present invention is not limited to these examples, but includes all variations that are obvious from the provisions given in the present invention.

Materials and methods

General characteristics of the experiment

Reactions were not carried out under an inert atmosphere unless otherwise indicated, and all solvents and reagents purchased were used as received.

Purification by chromatography means purification using the CombiFlash® Companion Purification System or the Biotage SP1 Purification System. When products were purified using an Isolute® SPE Si II cartridge, an 'Isolute® SPE Si II cartridge' means a packed polypropylene column containing unbound activated silica with mixed particle sizes with an average size of 50 µm and a nominal porosity of 60Å. Fractions containing the desired product (identified by TLC and/or LCMS analysis) were combined, the organic fraction was removed by evaporation and the remaining aqueous fraction was lyophilized to give the final product. If thin layer chromatography (TLC) was used, this means TLC on silica gel using plates, typically 3 x 6 cm silica gel plates on aluminum foil with a fluorescent indicator (254 nm) (eg Fluka 60778). Operations using microwave radiation were performed using Biotage Initiator 60 ^TM , which uses a single-mode resonator and dynamic field control. Temperatures of 40-250°C and pressures of up to 30 bar can be provided.

NMR spectra were taken on a Bruker Avance 400 MHz instrument, 5 mm QNP probe H, C, F, P, single Z gradient, control of a dual-channel TopSpin 2.1 instrument, or on a Bruker Avance III 400 MHz instrument, 5 mm BBFO Plus probe, single Z gradient, control of a two-channel device TopSpin 3.0.

The names of the compounds were obtained according to the standard scheme using the Struct>Name function in the ChemDraw Professional 15.1 software.

Conditions of analysis using LC-MS

LC-MS Method 1: Acquity H-Class (quadruple pump/PDA detector) + QDa mass spectrometer. Column: Acquity UPLC BEH C18 (1.7 µm, 100×2.1 mm), maintained at 50°C. Conditions: 0.1% aqueous formic acid [eluent A]; MeCN (containing 0.1% formic acid) [eluent B]. Gradient mode: 3 to 99% B in 1.5 min at 1 ml/min

Conditions for QC LC-MS

Typically, any of the following LC-MS analysis methods were used.

QC LC-MS Method 1: Waters SQD2, with one UPLC-MS quadrupole lens. Column: Acquity UPLC HSS C18 (1.8 µm, 100 x 2.1 mm). Conditions: 0.1% aqueous formic acid [eluent A]; MeCN (containing 0.1% formic acid) [eluent B]. Gradient mode: 5 to 100% B in 4.9 min at 0.5 ml/min.

QC LC-MS Method 2: Waters SQD2, with one UPLC-MS quadrupole lens. Column: Acquity UPLC BEH Shield RP18 (1.7 µm, 100 x 2.1 mm). Conditions: 10 mM ammonium bicarbonate aqueous solution [eluent A]; MeCN [eluent B]. Gradient mode: 5 to 100% B in 4.9 min at 0.5 ml/min.

QC LC-MS Method 3: Acquity UPLC (dual pump/PDA detector) + Waters Micromass ZQ2000 mass spectrometer. Column: Acquity UPLC BEH C18 (1.7 µm, 100×2.1 mm), maintained at 40°C. Conditions: 0.1% aqueous formic acid [eluent A]; MeCN (containing 0.1% formic acid) [eluent B]. Gradient mode: 5 to 95% B in 6.8 min at 0.4 ml/min.

QC LC-MS Method 4: UPLC+Waters DAD+Waters SQD2, with one UPLC-MS quadrupole lens. Column: Acquity UPLC HSS C18 (1.8 µm 100×2.1 mm), maintained at 40°C. Conditions: 0.1% aqueous formic acid [eluent A]; MeCN (containing 0.1% formic acid) [eluent B]. Gradient Mode: 5 to 100% B in 3.5 min at 0.5 ml/min.

QC LC-MS Method 5: UPLC+Waters DAD+Waters SQD2, with one UPLC-MS quadrupole lens. Column: Acquity UPLC BEH Shield RP18 (1.7 µm 100×2.1 mm), maintained at 40°C. Conditions: 10 mM ammonium bicarbonate aqueous solution [eluent A]; MeCN [eluent B]. Gradient mode: isocratic mode with 5% B for 1.2 min, then from 5 to 100% B in 2.3 min at 0.5 ml/min.

SFC Methods

Preparative SFC: Waters Thar Prep100 SFC Preparative System (P200 CO ₂ Pump, 2545 Modifier Pump, 2998 UV/VIS Detector, 2767 Fluid Dispenser with Stacked Injection Module). Column: Phenomenex Lux Cellulose-4 or YMC Cellulose-SC (5 µm, 10-21.2×250 mm), maintained at 40°C. Conditions: CO ₂ supercritical fluid and eluents selected from the group consisting of MeOH, EtOH, IPA, MeCN, EtOAc, THF with modifiers selected from the group including Et ₂ NH or formic acid as directed. Gradient/Isocratic as directed at 100 ml/min, 120 bar (or whichever is appropriate).

The analytical SFC study was performed on a similar system using smaller columns and lower flow rates.

Getting a connection

Compounds of the present invention can be obtained by various methods, including well-known standard methods of synthesis. Illustrative general synthetic procedures are provided below and the specific compounds of the present invention are prepared in the working examples. One skilled in the art will understand that if a substituent described in the present invention is incompatible with the synthetic procedures described in the present invention, the substituent can be protected with an appropriate protecting group that is stable under the conditions of the reaction mixture. The protecting group can be removed at an appropriate stage in the reaction sequence to provide the desired intermediate or target compound. In all schemes below, protecting groups for sensitive or reactive groups are used, if necessary, in accordance with the general principles of synthetic chemistry. Protecting groups are used in accordance with standard organic synthesis techniques (T.W. Green and P.G.M. Wuts, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, which is incorporated herein by reference with respect to protecting groups).

In the procedures described below, some of the starting materials are indicated by a "step" or "example" number. This is done simply to assist the skilled chemist. The starting material may optionally be obtained from the specified batch.

When referring to the use of a "similar" or "similar" procedure, as those skilled in the art would understand, such procedure may include minor changes in, for example, reaction temperature, reagent/solvent amounts, reaction time, processing conditions, or chromatographic purification conditions.

The synthesis of compounds of general formula (Ia), (Ib), (Ic) and their pharmaceutically acceptable derivatives and salts can be carried out by those skilled in the art as described below in Schemes 1-8. Starting materials are commercially available or are prepared from commercially available starting materials by methods known to those skilled in the art.

Compounds of examples 1-10 can be obtained according to the general procedure presented in scheme 1. Treatment of 8-chloro-3-methylimidazo[1,5-a]pyrazine 1A with n-butyl lithium provides selective lithiation at C-5. Neutralization with carbon dioxide gives the carboxylic acid 1B and amide formation under standard conditions gives an amide such as 1C which is brominated and then treated with ammonium hydroxide to give 1D. Palladium-catalyzed coupling with arylboronic acid followed by deprotection gives the final product 1E.

Scheme 1:

Example 1 3-{4-[8-amino-3-methyl-5-(piperazin-1-carbonyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea 1E

Step 1: A solution of n-BuLi (1.2 eq) was added dropwise with stirring at -78°C to a slurry of 8-chloro-3-methylimidazo[1,5-a]pyrazine (6.0 g, 35.8 mmol) in THF (to give a 0.2 M solution) and the reaction mixture was stirred for 10 min. CO ₂ was passed through the reaction mixture with stirring for 30 minutes. After removal of the solvent, the title compound was purified by flash column chromatography to give 5.3 g (70%) of 8-chloro-3-methylimidazo[1,5-a]pyrazine-5-carboxylic acid 1B.

Step 2: 8-Chloro-3-methylimidazo[1,5-a]pyrazine-5-carboxylic acid 1B (200 mg, 0.945 mmol) was dissolved in DMF, HATU (1.2 eq) was added and stirred for 0, 5 hours, then DIPEA (2.0 eq.) was added followed by 1-Boc-piperazine. After extractive workup, the title compound was purified by flash column chromatography to give 73 mg (20%) of 8-chloro-3-methylimidazo[1,5-a]pyrazine-5-(N-Boc-piperazine)-1-carboxamide 1C .

Step 3: 8-Chloro-3-methylimidazo[1,5-a]pyrazine-5-(N-Boc-piperazine)-1-carboxamide 1C (1.7 g, 4.48 mmol) was dissolved in DMF and to solution NBS (1.1 eq) was added. The reaction mixture was stirred at RT for 2 hours. The title compound was purified by flash column chromatography to give 1.2 g. 900 mg Was dissolved in 1,4-dioxane and ammonium hydroxide was added to the solution. The reaction mixture was treated with microwave radiation at 100°C for 2 h. After removal of the solvent and purification by column chromatography, 500 mg (34%) of 8-amino-1-bromo-3-methylimidazo[1,5-a]pyrazine- 5-(N-Boc-piperazine)-1-carboxamide 1D.

Step 4: 8-Amino-1-bromo-3-methylimidazo[1,5-a]pyrazine-5-(N-Boc-piperazine)-1-carboxamide 1D (500 mg, 1.14 mmol), 1-( 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)-3-(3-(trifluoromethyl)phenyl)urea (1.5 eq.) and Cs ₂ CO ₃ (3 eq.) were suspended in DME (12 ml) and H ₂ O (3 ml) and Pd(PPh ₃ ) ₄ (0.05 eq.) were added. The mixture was refluxed for 2 hours under N ₂ atmosphere. After cooling, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel flash column chromatography to give 3-{4-[8-amino-3-methyl-5-(N-Boc-piperazine-1-carbonyl)imidazo[1,5-a]pyrazine-1 -yl]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea (300 mg) as a solid, which was dissolved in DCM and TFA and the mixture was stirred for 3 h. The solvent was removed and the residue was neutralized with saturated NaHCO ₃ solution. The title compound was purified by C-18 column chromatography to give 91 mg of end product 3-{4-[8-amino-3-methyl-5-(piperazine-1-carbonyl)imidazo[1,5-a]pyrazine-1 -yl]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]ureas 1E, ES-LCMS m/z 589.4 (M+H).

The examples below were carried out by similar procedures with the replacement of the appropriate protected amine intermediate in step 2.

Example 2 3-{4-[8-amino-5-(4-aminopiperidin-1-carbonyl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1- [3-(trifluoromethyl)phenyl]urea); ES-LCMS m/z 602.4 (M+H).

Example 3 8-amino-3-methyl-N-(piperidin-4-yl)-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1, 5-a]pyrazine-5-carboxamide; ES-LCMS m/z 603.6 (M+H).

Example 4 3-(4-{8-amino-5-[(3R)-3-aminopiperidine-1-carbonyl]-3-methylimidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl )-1-[3-(trifluoromethyl)phenyl]urea; ES-LCMS m/z 603.3 (M+H).

Example 5 3-(4-{8-amino-5-[(3S)-3-aminopiperidin-1-carbonyl]-3-methylimidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl )-1-[3-(trifluoromethyl)phenyl]urea; ES-LCMS m/z 603.5 (M+H).

Example 6 8-amino-3-methyl-N-[(3R)-piperidin-3-yl]-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl] imidazo[1,5-a]pyrazine-5-carboxamide; ES-LCMS m/z 603.5 (M+H).

Example 7 8-amino-3-methyl-N-(piperidin-3-yl)-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1, 5-a]pyrazine-5-carboxamide; ES-LCMS m/z 603.8 (M+H).

Example 8 8-amino-3-methyl-N-[(3S)-1-methylpiperidin-3-yl]-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1- yl]imidazo[1,5-a]pyrazine-5-carboxamide; ES-LCMS m/z 617.6 (M+H).

Example 9 8-amino-3-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1- yl]imidazo[1,5-a]pyrazine-5-carboxamide; ES-LCMS m/z 617.6 (M+H).

Example 10 3-{4-[8-amino-3-methyl-5-(4-methylpiperazin-1-carbonyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -[3-(trifluoromethyl)phenyl]urea; ES-LCMS m/z 602.7 (M+H).

In another embodiment, alkyl analogs such as 2E can be prepared as described in Scheme 2. Treatment of lithiated 8-chloro-3-methylimidazo[1,5-a]pyrazine aldehyde gives the alcohol 2B. Treatment with mesyl chloride and then with sodium borohydride gives the reduced compound 2C, which is introduced into the bromination, ammonolysis and Pd(0) catalyzed coupling reactions described above to give the final product 2E.

Scheme 2:

Example 11 3-{4-[8-Amino-3-methyl-5-(piperidin-4-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea 2E

Step 1: A solution of n-BuLi (1.2 eq) was added dropwise with stirring to a slurry of 8-chloro-3-methylimidazo[1,5-a]pyrazine (2.0 g, 11.9 mmol) at -78 °C in THF (to give a 0.2 M solution) and the reaction mixture was stirred for 10 min. 1-N-Boc-4-formylpiperidine (1.3 eq.) was added dropwise and the reaction mixture was stirred for another 15 min, the reaction was stopped with NH ₄ Cl (5 ml, saturated aqueous solution) and cooling was stopped and heated to room temperature for 15-20 minutes. Purification by flash column chromatography gave 3.8 g (83%) of 8-chloro-3-methylimidazo[1,5-a]pyrazin-5-(N-Boc-piperidin-4-ylmethyl)-methanol 2B.

Step 2: 8-chloro-3-methylimidazo[1,5-a]pyrazine-5-(N-Boc-piperidin-4-ylmethyl)-methanol 2B (1.0 g, 2.62 mmol) and TEA (1 3 eq) was dissolved in DCM. MsCl (1.2 eq.) was added to the solution. The mixture was stirred at RT for 2 h. 8-Chloro-3-methylimidazo[1,5-a]pyrazine-5-(N-Boc-piperidin-4-ylmethyl)-methanol mesylate (0.9 g, 75%) was obtained using flash column chromatography.

Step 3: 8-chloro-3-methylimidazo[1,5-a]pyrazine-5-(N-Boc-piperidin-4-ylmethyl)-methanol mesylate (20 mg, 0.044 mmol) was dissolved in DMF, NaBH was added to the solution ₄ (1.5 eq.). The mixture was heated at 50°C overnight. 8-Chloro-3-methylimidazo[1,5-a]pyrazin-5-(N-Boc-piperidin-4-ylmethyl) 2C (31%) was detected by LC-MS.

Step 4: 8-chloro-3-methylimidazo[1,5-a]pyrazin-5-(N-Boc-piperidin-4-ylmethyl) 2C (50 mg, 0.137 mmol) was dissolved in DMF (5 ml) and to a solution added NBS (1.5 eq.) in DMF. The mixture was stirred at RT for 1 h. The title compound 8-chloro-1-bromo-3-methylimidazo[1,5-a]pyrazin-5-(N-Boc-piperidin-4-ylmethyl) was purified by column chromatography.

Step 5: 8-chloro-1-bromo-3-methylimidazo[1,5-a]pyrazine-5-(N-Boc-piperidin-4-ylmethyl) was dissolved in 1,4-dioxane, ammonium hydroxide was added to the solution. The reaction mixture was treated with microwave radiation at 100°C for 2 h and 8-amino-1-bromo-3-methylimidazo[1,5-a]pyrazin-5-(N-Boc-piperidin-4-ylmethyl) 2D was isolated with using column chromatography (35 mg, 60% over 2 steps).

Step 6: 8-amino-1-bromo-3-methylimidazo[1,5-a]pyrazine-5-(N-Boc-piperidin-4-ylmethyl) (120 mg, 0.28 mmol) 2D 1-(4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)-3-(3-(trifluoromethyl)phenyl)urea (1.5 eq) and Cs ₂ CO ₃ (3 eq.) was suspended in DME (12 ml) and H ₂ O (3 ml). Added Pd(PPh ₃ ) ₄ (0.05 eq.). The mixture was heated at 90° C. for 2 hours in a microwave oven. 3-{4-[8-Amino-3-methyl-5-(N-Boc-piperidin-4-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1- [3-(trifluoromethyl)phenyl]urea was obtained (100 mg, 54%) using column chromatography.

Step 7: 3-{4-[8-amino-3-methyl-5-(N-Boc-piperidin-4-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl} -1-[3-(trifluoromethyl)phenyl]urea (100 mg, 0.15 mmol) was dissolved in dioxane, HCl (37%) was added dropwise to the solution, the mixture was stirred for 3 h. using C-18 column chromatography and isolated 3-{4-[8-amino-3-methyl-5-(piperidin-4-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1- hydrochloride yl}-1-[3-(trifluoromethyl)phenyl]urea 2E (25 mg, 29% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.26 (d, 1H), 8.04 (d, 2H), 7.79 (d, 1H), 7.71-7.51 (m, 5H ), 7.36 (d, 1H), 6.81 (s, 1H), 3.50 (d, 2H), 3.09-3.02 (m, 4H), 3.02 (s, 3H) , 2.14 (m, 3H), 1.60 (m, 2H); ES-LCMS m/z 573.4 (M+H).

Scheme 3:

Compounds exemplifying another aspect of the present invention can be prepared by the reactions shown in Scheme 3. Treatment of 8-chloro-3-isopropylimidazo[1,5-a]pyrazine 3A with n-butyllithium followed by ethyl formate gives the aldehyde 3B. Bromination and reaction with ammonium hydroxide gives 3D, which can be put into a reductive amination to give an amine derivative such as 3E. Pd(0) catalyzed coupling and deprotection gives the final product 3G.

Example 36 N-(4-(8-amino-3-isopropyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-1-(2 -chlorophenyl)methanesulfonamide 3G

Stage 1: 8-Chloro-3-isopropylimidazo[1,5-a]pyrazine-5-carbaldehyde 3B

To a solution of 8-chloro-3-isopropylimidazo[1,5-a]pyrazine 3A (1.00 g, 5.11 mmol) in THF at -65°C was added a solution of n-butyllithium (2.5 M solution in THF, 2.9 ml, 7.16 mmol) keeping the temperature below -55°C. The resulting dark brown solution was stirred at -78°C for 1 h, then ethyl formate (0.62 ml, 7.67 mmol) was added dropwise and the mixture was stirred at -78°C for 1.5 h. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc in isohexane to give the title compound 3B as a yellow oil which crystallized on standing (900 mg, 79%). LC-MS (method 1): Rt=1.06 min, m/z=224.1 [M( ³⁵ Cl)+H] ⁺ .

Stage 2: 1-Bromo-8-chloro-3-isopropylimidazo[1,5-a]pyrazine-5-carbaldehyde 3C

To a solution of 8-chloro-3-isopropylimidazo[1,5-a]pyrazine-5-carbaldehyde 3B (900 mg, 4.02 mmol) in MeCN (20 ml) was added NBS (788 mg, 4.43 mmol) and the mixture stirred at RT for 1.5 h. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give the title compound 3C as a yellow solid (1.23 g, 100%). LC-MS (method 1): Rt=1.29 min, m/z=302.0 [M( ³⁵ Cl ⁷⁹ Br)+H] ⁺ .

Stage 3: 8-Amino-1-bromo-3-isopropylimidazo[1,5-a]pyrazine-5-carbaldehyde 3D

A solution of 1-bromo-8-chloro-3-isopropylimidazo[1,5-a]pyrazine-5-carbaldehyde 3C (1.23 g, 4.07 mmol) in IPA (3 ml) and aqueous ammonium hydroxide solution (33% , 3 ml) was heated in a microwave oven at 130°C for 15 min. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to give the title compound 3D (535 mg, 47%). LC-MS (method 1): Rt=0.95 min, m/z=283.1 [M( ⁷⁹ Br)+H] ⁺ .

Step 4: tert-Butyl-4-((8-amino-1-bromo-3-isopropylimidazo[1,5-a]pyrazin-5-yl)methyl)piperazin-1-carboxylate 3E

Solution of 8-amino-1-bromo-3-isopropylimidazo[1,5-a]pyrazine-5-carbaldehyde 3D (468 mg, 1.65 mmol), 1-N-Boc-piperazine (770 mg, 4.13 mmol ) and acetic acid (0.19 ml, 3.31 mmol) in THF (10 ml) was stirred at 60° C. for 10 min. Sodium triacetoxyborohydride (1.051 g, 4.96 mmol) was then added and the mixture was stirred at 60° C. for 24 h. The reaction mixture was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane, then repurified with chromatography on silica gel eluting with 0-4% MeOH in DCM gave the title compound 3E (206 mg, 28%). LC-MS (method 1): Rt=1.01 min, m/z=453.3 [M( ⁷⁹ Br)+H] ⁺ .

Stage 5: tert-butyl-4-((8-amino-1-(4-(((2-chlorophenyl)methyl)sulfonamido)-3-fluorophenyl)-3-isopropylimidazo[1,5-a]pyrazine-5 -yl)methyl)piperazine-1-carboxylate 3F

The desired compound 3F was obtained by a method similar to that described in example 169, stage 3, using tert-butyl-4-((8-amino-1-bromo-3-isopropylimidazo[1,5-a]pyrazin-5-yl) methyl)piperazine-1-carboxylate 3E (100 mg, 0.221 mmol) to give product 3F (124 mg, 84%). LC-MS (method 1): Rt=1.17 min, m/z=672.5 [M( ³⁵ Cl)+H] ⁺ .

Step 6: N-(4-(8-amino-3-isopropyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-1-(2 -chlorophenyl)methanesulfonamide 3G

A solution of tert-butyl-4-((8-amino-1-(4-(((2-chlorophenyl)methyl)sulfonamido)-3-fluorophenyl)-3-isopropylimidazo[1,5-a]pyrazin-5-yl )methyl)piperazine-1-carboxylate 3F (124 mg, 0.184 mmol) in methanol (3 mL) and 4N. HCl in 1,4-dioxane (1 mL, 4.0 mmol) was stirred at RT for 1.5 h. Solvents were concentrated in vacuo and the residue was dissolved in methanol and passed through an SCX-2 cartridge eluting with 2 N NH ₃ in MeOH. The residue was purified by MDAP (method B) and the product was re-passed through an SCX-2 cartridge eluting with 2N HCl. NH ₃ in MeOH to give the title compound 3F (45 mg, 43%). QC LC-MS (method 3): Rt=2.50 min, m/z=572.3 [M( ³⁵ Cl)+H] ⁺ .

The following examples were carried out in a manner similar to that used in Example 36:

Example 12 3-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea

Example 13: 3-(4-{8-amino-5-[(4-aminopiperidin-1-yl)methyl]-3-methylimidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl) -1-[3-(trifluoromethyl)phenyl]urea

Example 14 3-[4-(8-amino-3-methyl-5-{[(piperidin-4-yl)amino]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 15: 3-[4-(8-amino-5-{[(3R)-3-aminopiperidin-1-yl]methyl}-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene- 1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 16: 3-[4-(8-amino-5-{[(3S)-3-aminopiperidin-1-yl]methyl}-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene- 1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 17 3-[4-(8-amino-3-methyl-5-{[(piperidin-3-yl)amino]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 18 3-{4-[8-amino-3-methyl-5-({[(3S)-piperidin-3-yl]amino}methyl)imidazo[1,5-a]pyrazin-1-yl] naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea

Example 19 3-(4-{8-amino-3-methyl-5-[(4-methylpiperazin-1-yl)methyl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl )-1-[3-(trifluoromethyl)phenyl]urea

Example 20 3-{4-[8-amino-3-ethyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea

Example 21 3-{4-[8-amino-5-(piperazin-1-ylmethyl)-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1- yl}-1-[3-(trifluoromethyl)phenyl]urea

Example 22 3-(4-{8-amino-3-ethyl-5-[(4-methylpiperazin-1-yl)methyl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl )-1-[3-(trifluoromethyl)phenyl]urea

Example 23: 3-[4-(8-Amino-3-methyl-5-{[4-(methylamino)piperidin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene- 1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 24 3-[4-(8-Amino-3-methyl-5-{[(3R)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 25: 3-[4-(8-Amino-3-methyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 26 3-[4-(8-amino-5-{[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl}-3-methylimidazo[1,5-a]pyrazin-1- yl)naphthalene-1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 27 3-[4-(8-Amino-3-ethyl-5-{[(3R)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 28 3-[4-(8-Amino-3-ethyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 29 3-{4-[8-amino-5-(1,4-diazepan-1-ylmethyl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}- 1-[3-(trifluoromethyl)phenyl]urea

Example 30 3-[4-(8-Amino-5-{2,5-diazabicyclo[2.2.1]heptan-2-ylmethyl}-3-methylimidazo[1,5-a]pyrazin-1-yl )naphthalene-1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 31: 3-[4-(8-amino-3-methyl-5-{octahydropyrrolo[3,4-c]pyrrol-2-ylmethyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene- 1-yl]-1-[3-(trifluoromethyl)phenyl]urea

Example 32 3-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-( 3-fluorophenyl)urea

Example 33: 3-{4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-( 3-methylphenyl)urea

Example 34 3-{4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl}-1-[3 -(trifluoromethyl)phenyl]urea

Example 35 3-{4-[8-amino-3-ethyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl}-1-[3 -(trifluoromethyl)phenyl]urea

Example 37 3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(piperazin-1-ylmethyl)imidazo[ 1,5-a]pyrazine-8-amine

Example 38 2-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-N-[ 3-(trifluoromethyl)phenyl]acetamide

Example 204: 1-[(8-amino-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2- yl)imidazo[1,5-a]pyrazin-5-yl)methyl]piperidin-4-amine

Example 205: (3S)-1-[(8-amino-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-( propan-2-yl)imidazo[1,5-a]pyrazin-5-yl)methyl]piperidin-3-amine

Table 1

Example R' ^R2 X ^R1 LCMS m/z (M+H) 12

CH ₃ 2,3- _{( C4H4} )

574.7 13

CH ₃ 2,3- _{( C4H4} )

589.4 14

CH ₃ 2,3- _{( C4H4} )

589.3 15

CH ₃ 2,3- _{( C4H4} )

589.4 16

CH ₃ 2,3- _{( C4H4} )

589.3 17

CH ₃ 2,3- _{( C4H4} )

589.3 18

CH ₃ 2,3- _{( C4H4} )

589.4 19

CH ₃ 2,3- _{( C4H4} )

589.1 20

CH ₂ CH ₃ 2,3- _{( C4H4} )

589.3 21

CH( _CH3 ) ₂ 2,3- _{( C4H4} )

603.5 22

CH ₂ CH ₃ 2,3- _{( C4H4} )

603.6 23

CH ₃ 2,3- _{( C4H4} )

603.6 24

CH ₃ 2,3- _{( C4H4} )

589.2 25

CH ₃ 2,3- _{( C4H4} )

589.3 26

CH ₃ 2,3- _{( C4H4} )

603.1 27

CH ₂ CH ₃ 2,3- _{( C4H4} )

602.8 28

CH ₂ CH ₃ 2,3- _{( C4H4} )

603.3 29

CH ₃ 2,3- _{( C4H4} )

589.4 thirty

CH ₃ 2,3- _{( C4H4} )

586.9 31

CH ₃ 2,3- _{( C4H4} )

600.6 32

CH ₃ 3-F

525.6 33

CH ₃ 2,3- _{( C4H4} )

521.6 34

CH ₃ 3-F

543.0 35

CH ₂ CH ₃ 3-F

557.0 36

CH( _CH3 ) ₂ 2-F

572.3 37

CH( _CH3 ) ₂ 2,3- _{( C4H4} )

545.5 38

CH ₃ 2,3- _{( C4H4} )

575.6 204

CH( _CH3 ) ₂ 2,3- _{( C4H4} )

559.4 205

CH( _CH3 ) ₂ 2,3- _{( C4H4} )

559.4

Compounds of another object of the present invention can be prepared by the reactions shown in Scheme 4. Pd(0) catalyzed coupling of 8-chloro-5-iodo-3-methylimidazo[1,5-a]pyrazine 4A with vinyl or aryl boronate gives C-5 substituted vinyl analog 4B. Iodization and then treatment with ammonium hydroxide gives 4C, which is sent to a second Pd(0) catalyzed coupling with an aryl boronate to give 4D. Removal of the protecting group with TFA gives the vinyl analogue of 4F, which can be acetylated to give 4G. Alternatively, reaction of 4D with triethylsilane in TFA gives the reduced analogue of 4E.

Scheme 4:

Example 39 1-yl}-1-[3-(trifluoromethyl)phenyl]urea 4F

Stage 1: 8-Chloro-5-iodo-3-methylimidazo[1,5-a]pyrazine 4A (760 mg, 2.59 mmol), tert-butyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 2.59 mmol) and Cs ₂ CO ₃ (2.50 g, 7.77 mmol) were suspended in DME (120 ml) and H ₂ O (30 ml). Pd(PPh ₃ ) ₄ (150 mg) was added. The mixture was heated at 60° C. for 0.5 h in a microwave oven. The title compound 8-chloro-3-methylimidazo[1,5-a]pyrazine-5-N-Boc-(1,2,5,6-tetrahydropyridine) 4B (500 mg, 55%) was purified by column chromatography.

Step 2: 8-chloro-3-methylimidazo[1,5-a]pyrazine-5-N-Boc-(1,2,5,6-tetrahydropyridine) 4B (1.3 g, 3.73 mmol) was dissolved in DMF (5 ml) and NIS (2 eq.) in DMF was added to the solution. The mixture was heated at 55°C overnight. The title compound was purified by column chromatography, then dissolved in 1,4-dioxane, and ammonia was added to the solution. The reaction mixture was microwaved at 100° C. for 2 h. Purification by flash chromatography gave a total of 610 mg (36%) of 8-amino-3-iodimidazo[1,5-a]pyrazine-5-N-Boc- (1,2,5,6-tetrahydropyridine) 4C.

Step 3: 8-amino-3-iodimidazo[1,5-a]pyrazine-5-N-Boc-(1,2,5,6-tetrahydropyridine) (610 mg, 1.34 mmol) 4C, 1-( 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)-3-(3-(trifluoromethyl)phenyl)urea (1.0 eq.) and Cs ₂ CO ₃ (4 eq.) were suspended in DME (1 ml) and H ₂ O (0.25 ml). Pd(PPh ₃ ) ₄ (0.05.equiv.) was added. The mixture was heated at 100° C. for 60 minutes in a microwave oven. After cooling, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel flash column chromatography to give 3-{4-[8-amino-3-methyl-5-(N-Boc-(1,2,5,6-tetrahydropyridine)-imidazo[1,5 -a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea (250mg, 29%) 4D as solid, 200mg Substances were dissolved in DCM and TFA and mixture was stirred for 3 hours, the Solvent was removed and the residue was neutralized with saturated solution of NaHCO _3. The title compound 4F was purified using C-18 column chromatography to give 80 mg of the final product 3-{4-[8-amino-3-methyl-5-( 1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 558.5 (M+H).

Example 40 3-{4-[8-amino-3-methyl-5-(piperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea 4E

3-{4-[8-amino-3-methyl-5-(N-Boc-(1,2,5,6-tetrahydropyridine)-imidazo[1,5-a]pyrazin-1-yl]naphthalene-1 -yl}-1-[3-(trifluoromethyl)phenyl]urea 4D (280 mg) was dissolved in TFA and triethylsilane (10 eq.) was added The mixture was stirred at RT for 2 h, concentrated and purified to give 50 mg of the title compound 4E, ES-LCMS m/z 560.7 (M+H).

Example 43: 3-{4-[5-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl ]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea 4G

3-{4-[8-Amino-3-methyl-5-(1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[3-(trifluoromethyl)phenyl]urea 4F (80 mg) and 18-crown-6 (2.0 equiv.) were dissolved in 0.5 M Ac ₂ O in DCM (4 ml) at 0° C. TEA (1.5 eq.) was added and the reaction mixture was stirred for 1 h. Purification gave 32 mg of the title product 4G, ES-LCMS m/z 600.6 (M+H).

The following examples were carried out according to similar methods.

Example 41 3-{4-[8-Amino-3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene- 1-yl}-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 558.7 (M+H).

Example 42 3-{4-[8-Amino-3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl]-3 -fluorophenyl}-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 526.5 (M+H).

Example 44: 3-{4-[5-(1-acetylpiperidin-3-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1- [3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 602.6 (M+H).

Example 45 3-{4-[5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl ]-3-fluorophenyl}-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 568.6 (M+H).

Example 46 3-{4-[8-amino-5-(cyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}- 1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 557.6 (M+H).

Example 47 3-{4-[8-Amino-3-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyrazin-1- yl]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 571.2 (M+H).

Example 48 3-{4-[8-Amino-3-methyl-5-(pyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 553.7 (M+H).

Example 49 3-(4-{8-amino-3-methyl-5-[1-(prop-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl]imidazo[1,5- a]pyrazin-1-yl}naphthalene-1-yl)-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 612.3 (M+H).

Example 50 3-{4-[8-amino-5-(4-aminophenyl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-( trifluoromethyl)phenyl]urea, ES-LCMS m/z 568.5 (M+H).

Example 51 3-{4-[8-amino-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1- yl}-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 557.3 (M+H).

Example 52 3-{4-[8-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1 -yl}-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 569.3 (ES-).

Example 53 3-{4-[8-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1 -yl}-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 570.7 (M+H).

Example 54 3-(4-{8-amino-3-methyl-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]imidazo[1,5-a]pyrazin-1- yl}naphthalene-1-yl)-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 625.7 (M+H).

Example 55 3-{4-[8-Amino-3-methyl-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene- 1-yl}-1-[3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 608.7 (M+H).

Example 56 3-{4-[8-amino-5-(2-aminopyridin-4-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1- [3-(trifluoromethyl)phenyl]urea, ES-LCMS m/z 569.2 (M+H).

Scheme 5:

Additional compounds of the present invention can be prepared from the reactions shown in Scheme 5. Treatment of 8-chloro-3-isopropylimidazo[1,5-a]pyrazine 3A with n-butyllithium followed by iodine treatment gives the iodine-containing intermediate 5B, which can be enter into Pd(0) catalyzed coupling with vinyl or aryl boronates to form a coupling product such as 5C. Bromination and reaction with ammonium hydroxide gives 5E, which can be introduced into another Pd(0) catalyzed coupling with arylboronates to give 5F. Hydrolysis of the ester gives the 5G acid, which can be coupled with various amines to give amides such as 5H. Deprotection of the acid gives the final product 5I.

Example 71 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-methoxyphenyl)acetamide 5I

Step 1: 8-Chloro-5-iodo-3-isopropylimidazo[1,5-a]pyrazine 5B

n-Butyllithium (2 5 M in hexanes, 82.4 ml, 206 mmol) keeping the internal temperature below -65°C. After stirring for 30 min, a solution of iodine (56.3 g, 221.8 mmol) in THF (50 ml) was added dropwise over 10 min, maintaining the internal temperature below -65°C during the addition. The resulting suspension was stirred for 1 h while warming to -10°C, then the reaction was stopped by adding a saturated aqueous solution of NH ₄ Cl and was extracted with 2-methyltetrahydrofuran (×3). The combined organic extracts were washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by passing through a plug of silica gel eluting with 0-20% EtOAc in DCM to give an orange solid which was triturated with Et ₂ O to give the title compound 5B as a yellow solid (41.2 g, 81%). LC-MS: Rt=1.29 min, m/z=322.0 [M+H] ⁺

Stage 2: tert-Butyl-(4-(8-chloro-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5C

A mixture of 8-chloro-5-iodine-3-isopropylimidazo[1,5-a]pyrazine 5B 32.5 g, 101.1 mmol), tert-butylmethyl (4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate (35.8 g, 106.15 mmol), PdCl ₂ (dppf). DCM (8.3 g, 10.1 mmol) and cesium carbonate (65.9 g, 202.2 mmol) in a mixture of dioxane (500 ml) and water (100 ml) was purged with argon under sonication, then heated at 100°C for 16 h. The reaction mixture was diluted with water and was extracted with EtOAc (×2) and the combined organic extract was washed with brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc in isohexane to give a solid which was triturated with Et ₂ O to give the title compound 5C as a yellow solid (22.1 g, 54%). LC-MS: Rt=1.55 min, m/z=405.4 [M+H] ⁺ .

Step 3: tert-Butyl-(4-(1-bromo-8-chloro-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5D

With stirring, to a suspension of tert-butyl-(4-(8-chloro-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5C (22, 1 g, 54.58 mmol) in MeCN (200 ml) was added NBS (10.69 g, 60.03 mmol). After 15 min most of the solids had dissolved and then a fine precipitate formed. DCM (20 ml) was added to promote dissolution and after another 5 minutes the reaction was complete. The reaction mixture was concentrated in vacuo and the resulting residue triturated with water and the solid was collected by filtration and dried in vacuo to give the title compound 5D which was used without further purification (24.8 g, 94%). LC-MS: Rt=1.69 min, m/z=483.3 [M( ⁷⁹ Br)+H] ⁺ .

Step 4: tert-Butyl-(4-(8-amino-1-bromo-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5E

The reaction mixture was separated and placed in 9 microwave vials: -1-yl)(methyl)carbamate 5D (24.8 g, 51.2 mmol) in [1:1] IPA:ammonia (180 ml) heated by microwave at 130°C for 1 h. diluted with water and extracted with EtOAc (×2) and the combined organic extract was washed with brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo. The resulting residue was triturated with Et ₂ O to give the title compound 5E as a dark yellow solid (18 g, 76%). LC-MS: Rt=1.01 min, m/z=464.3 [M( ⁷⁹ Br)+H] ⁺

Stage 5: Methyl-2-(4-(8-amino-5-(4-((tert-butoxycarbonyl)(methyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5- a]pyrazin-1-yl)naphthalen-1-yl)acetate 5F

Solution of tert-butyl-(4-(1-bromo-8-chloro-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5E (2 .4 g, 5.2 mmol), methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)acetate (1, 70 g, 5.2 mmol), PdCl ₂ (dppf). DCM (378 mg, 0.52 mmol) and cesium carbonate (2.5 g, 7.7 mmol) in a mixture of dioxane (15 ml) and water (2 .9 ml) was purged with nitrogen, then heated at 100° C. for 18 hours. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to give the title product 5F (1.9 g, 63%). LC-MS: Rt=1.29 min, m/z=584.3 [M+H] ⁺

Step 6: 2-(4-(8-Amino-5-(4-((tert-butoxycarbonyl)(methyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a] pyrazin-1-yl)naphthalene-1-yl)acetic acid 5G

With stirring, to a solution of methyl 2-(4-(8-amino-5-(4-((tert-butoxycarbonyl)(methyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1.5 -a]pyrazin-1-yl)naphthalen-1-yl)acetate 5F (1.9 g, 3.2 mmol) in MeOH (15 ml) was added 1 M NaOH aqueous solution (8 ml) and the resulting mixture was sonicated to promoting dissolution. After 3 hours, the reaction mixture was concentrated in vacuo and extracted with EtOAc (×3), then dried (MgSO ₄ ), filtered and concentrated in vacuo to give the title compound 5G as a brown solid (1.5 g, 82%). LC-MS: Rt=1.24 min, m/z=570.3 [M+H] ⁺ .

Step 7: tert-Butyl-(4-(8-amino-3-isopropyl-1-(4-(2-((3-methoxyphenyl)amino)-2-oxoethyl)naphthalene-1-yl)imidazo[1, 5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5H

To a solution of 2-(4-(8-amino-5-(4-((tert-butoxycarbonyl)(methyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazine -1-yl)naphthalen-1-yl)acetic acid 5G (115 mg, 0.20 mmol) in DCM (3.5 ml) at 0°C was added 2-chloro-1-methylpyridinium iodide (77 mg, 0.30 mmol), TEA (0.14 ml, 1.00 mmol), then 3-methoxyaniline (68 μl, 0.61 mmol). The resulting solution was allowed to warm to RT and stirred for 2 h. 1 M aqueous HCl was added and the mixture was extracted with DCM (2×). The combined organic extracts were concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexane to give the title compound 5H (80 mg, 59%). LC-MS: Rt=3.22 min, m/z=675.3 [M+H] ⁺ .

Step 8: 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-methoxyphenyl)acetamide (Example 71) 5I

To a solution of tert-butyl-(4-(8-amino-3-isopropyl-1-(4-(2-((3-methoxyphenyl)amino)-2-oxoethyl)naphthalen-1-yl)imidazo[1.5 -a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5H (80 mg, 0.12 mmol) in methanol (4 ml) was added 4 M HCl in 1,4-dioxane ( 1 ml) and the resulting solution was stirred at RT for 2.5 h. The solvents were concentrated in vacuo and the residue was passed through an SCX-2 cartridge (5 g). Major fractions were concentrated in vacuo and the residue was purified with MDAP to give the title compound (42 mg, 62%). QC LC-MS (method 2): Rt=3.13 min, m/z=575.4 [M+H] ⁺ .

The examples in Table 2 below were carried out in a manner analogous to that used in Example 71. Other central bridges were prepared in a similar manner by replacing the 4-bromonaphthyl acetate moiety with the appropriate 5-bromonaphthyl acetates or substituted 4-bromophenylacetates.

table 2

Example R'' ^R2 X Ar LCMS m/z (M+H) HPLC Rt (min)/method 57 H CH ₃ 2,3- _{( C4H4} ) 3- _CF3 -Ph 571.2 2.57/1 58 CH ₃ CH ₂ CH ₃ 2,3- _{( C4H4} ) 3- _CF3 -Ph 599.5 7.3/1 59 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3- _CF3 -Ph 613.3 2.66/1 60 CH ₃ CH ₃ 2,3- _{( C4H4} ) 3- _CF3 -Ph 585.7 7.25/1 61 CH ₃ CH ₃ 3-F 3- _CF3 -Ph 553.7 5.04/1 62 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) Ph 545.4 2.99/2 63 CH ₃ CH( _CH3 ) ₂ 3-F 3-F-Ph 531.4 2.94/2 64 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-F-Ph 563.5 3.07/2 65 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-F-5-CH ₃ O-Ph 593.5 3.00/2 66 CH ₃ CH( _CH3 ) ₂ 3-F Ph 513.3 2.58/1 67 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-F-5-CN-Ph 588.5 2.98/2 68 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

546.4 2.96/2 69 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

576.4 2.87/2 70 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-CN-Ph 570.4 3.10/2 72 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

546.4 2.82/2 73 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

547.4 2.49/1 74 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

552.4 2.32/1 75 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

599.6 2.20/1 76 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

625.3 2.64/1 77 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

549.3 2.29/1 78 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

605.6 2.44/1 79 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

547.3 2.28/1 80 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

564.4 2.40/1

Table 2 (continued)

Example R'' ^R2 Ar LCMS m/z (M+H) HPLC Rt (min)/method 81 CH ₃ CH( _CH3 ) ₂

563.5 2.94/2 82 CH ₃ CH( _CH3 ) ₂

545.3 2.87/2

Example 57 2-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-N-(3-(trifluoromethyl)phenyl)acetamide

Example 58 2-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide

Example 59 2-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}naphthalene-1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide

Example 60 2-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide

Example 61 2-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 3-fluorophenyl)-N-[3-(trifluoromethyl)phenyl]acetamide

Example 62 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-phenylacetamide

Example 63: 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-N-(3-fluorophenyl)acetamide

Example 64 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-fluorophenyl)acetamide

Example 65 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-fluoro-5-methoxyphenyl)acetamide

Example 66: 2-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-N-phenylacetamide

Example 67 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-cyano-5-fluorophenyl)acetamide

Example 68 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(pyridin-2-yl)acetamide

Example 69 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(5-methoxypyridin-3-yl)acetamide

Example 70 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-cyanophenyl)acetamide

Example 72 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(pyridin-3-yl)acetamide

Example 73 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(pyrazin-2-yl)acetamide

Example 74 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(thiazol-5-yl)acetamide

Example 75 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(1-methyl-1H-benzo[d]imidazol-5-yl)acetamide

Example 76 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetamide

Example 77 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide

Example 78 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3,4-dimethoxyphenyl)acetamide

Example 79 2-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(pyrimidin-5-yl)acetamide

Example 80 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(5-fluoropyridin-3-yl)acetamide

Example 81 2-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-(3-fluorophenyl)acetamide

Example 82 2-(5-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-N-phenylacetamide

Scheme 6:

Another set of compounds of the present invention can be prepared from the reactions shown in Scheme 6. Treatment of 4-bromonaphthalene-1-amine 6A with an isocyanate such as phenyl isocyanate gives the urea intermediate 6B which can be converted to the boronate 6C using standard conditions. 6C is coupled with a Pd(0) catalyzed coupling with a heterocyclic bromide such as above to give a coupling product such as 6D. Deprotection of the acid gives the final product 6E.

Example 121 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-phenylurea 6E

Step 1: 1-(4-Bromonaphthalene-1-yl)-3-phenylurea 6B

To a solution of 4-bromonaphthalene-1-amine (5.0 g, 22.5 mmol) in THF (50 ml) was added phenyl isocyanate (2.57 ml, 23.6 mmol) and the resulting mixture was stirred at RT for 18 h. The reaction mixture was diluted with Et ₂ O and the solid precipitated was collected by filtration to give the title compound 6B as a tan solid (7.4 g, 96%). QC LC-MS (method 1): Rt=3.88 min, m/z=341.1 [M( ⁷⁹ Br)+H] ⁺ .

Step 2: 1-Phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)urea 6C

With stirring, a mixture of 1-(4-bromonaphthalene-1-yl)-3-phenylurea 6B (2.50 g, 7.33 mmol), bis(pinacolato)diboron (1.87 g, 8.06 mmol), PdCl ₂ (dppf). DCM (0.27 g, 0.40 mmol) and potassium acetate (1.31 g, 14.7 mmol) in 1,4-dioxane (40 ml, purged with nitrogen for 10 min before use) were heated at 115° C. for 5 hours. The reaction mixture was concentrated in vacuo then partitioned between EtOAc and water. The organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to give the title compound 6C as a solid (2.27 g, 80%). LC-MS: Rt=1.72 min, m/z=389.2 [M+H] ⁺ . ¹H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.99 (s, 1H), 8.82-8.75 (m, 1H), 8.25-8.20 (m, 2H), 8.03-8.00 (m, 1H), 7.68-7.54 (m, 4H), 7.40-7.35 (m, 2H), 7.08-7 .04 (m, 1H), 1.43 (s, 12H).

Step 3: tert-Butyl-(4-(8-amino-3-isopropyl-1-(4-(3-phenylureido)naphthalene-1-yl)imidazo[1,5-a]pyrazin-5-yl)cyclohex -3-en-1-yl)(methyl)carbamate 6D

With stirring, a solution of tert-butyl-(4-(8-amino-1-bromo-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5E (100 mg, 0.22 mmol), 1-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)urea 6C (92 mg, 0.24 mmol), PdCl ₂ (dppf). DCM (9 mg, 0.01 mmol) and cesium carbonate (211 mg, 0.65 mmol) in DME (3 ml) were purged with nitrogen, then boiled with reflux for 2 hours. The reaction mixture was diluted with EtOAc and washed with water, then dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to give the title compound 6D as a green-yellow solid (80 mg, 56%). LC-MS Rt=1.31 min, m/z=646.4 [M+H] ⁺ .

Step 4: 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-phenylurea (example 121) 6E

With stirring to a solution of tert-butyl-(4-(8-amino-3-isopropyl-1-(4-(3-phenylureido)naphthalen-1-yl)imidazo[1,5-a]pyrazin-5-yl) cyclohex-3-en-1-yl)(methyl)carbamate 6D (80 mg, 0.12 mmol) in dioxane (2 ml) was added dropwise with 4 M HCl in dioxane (1 ml) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with EtOAc and the resulting mixture was stirred with saturated aqueous NaHCO ₃ . The organic layer was collected and concentrated in vacuo and the residue was purified with MDAP to give the title compound 6E as a yellow solid, (22 mg, 34%). QC LC-MS (method 1): Rt=2.48 min, m/z=546.5 [M+H] ⁺ .

The examples in Table 3 below were carried out in a similar manner to that used in Example 121. Other central bridges were prepared in a similar manner by replacing 4-bromonaphthalene-1-amine with 5-bromonaphthylamines, 5-bromoisoquinoline, or substituted 4-bromoanilines.

Table 3

Example R'' ^R2 X Ar LCMS m/z (M+H) 83 H CH ₃ 2,3- _{( C4H4} ) 3- _CF3 -Ph 572.4 84 CH ₃ CH ₃ 2,3- _{( C4H4} ) 3- _CF3 -Ph 586.7 85 H CH ₂ CH ₃ 2,3- _{( C4H4} ) 3- _CF3 -Ph 586.4 86 H CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3- _CF3 -Ph 599.8 87 H CH ₃ 2,3- _{( C4H4} ) Ph 503.0(ES-) 88 H CH ₃ 2,3- _{( C4H4} ) 3-5-(CF ₃ ) ₂ -Ph 641.5 89 H CH ₃ 2,3- _{( C4H4} ) 3-5-(CH ₃ ) ₂ -Ph 532.6 90 H CH ₃ 2,3- _{( C4H4} ) 3- _CF3-4 -Cl-Ph 606.4 91 H CH ₃ 2,3- _{( C4H4} ) CH ₂ Ph 518.2 92 H CH ₃ 2,3- _{( C4H4} ) CH ₂ (4-CH ₃ -Ph) 532.6 93 H CH ₃ 2,3- _{( C4H4} ) 3- _CF3-6 -Cl-Ph 606.1 94 H CH ₃ 2,3- _{( C4H4} ) 3-Cl-2-OCH ₃ -Ph 568.5 95 H CH ₃ 2,3- _{( C4H4} ) 3-CH ₃ -2-OCH ₃ -Ph 548.2 96 H CH ₃ 2,3- _{( C4H4} ) 3-Cl-5-CH ₃ -Ph 552.6 97 H CH ₃ 2,3- _{( C4H4} ) 3-F-Ph 519.7(ES-) 98 H CH ₃ 2,3- _{( C4H4} ) 3- _CH3 -Ph 518.2 99 H CH ₃ 2,3- _{( C4H4} ) 2- _OCH3 -Ph 534.6 100 H CH ₃ 2,3- _{( C4H4} ) 4- _CF3 -Ph 570.3(ES-) 101 AC CH ₃ 2,3- _{( C4H4} ) 2- _CF3 -Ph 614.5 102 H CH ₃ 2,3- _{( C4H4} )

616.6 103 H CH ₃ 2,3- _{( C4H4} )

562.5 104 H CH ₃ 3-F

530.5 105 H CH ₃ 3-F

584.6 106 CH ₃ CH ₂ CH ₃ 2,3- _{( C4H4} ) 3- _CF3 -Ph 600.1 107 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3- _CF3 -Ph 614.4 108 CH ₃ CH ₂ CH ₃ 3-F 3- _CF3 -Ph 568.6 109 CH ₃ CH( _CH3 ) ₂ 3-F 3- _CF3 -Ph 582.6 110 CH ₃ CH ₃ 3-F 3- _CF3 -Ph 554.7 111 CH ₃ CH ₃ 3- _CH3 3- _CF3 -Ph 550.6 112 CH ₃ CH ₃ 2- _CH3 3- _CF3 -Ph 550.6 113 CH ₃ CH ₃ 3-F, 6-CH ₃ 3- _CF3 -Ph 568.5 114 CH ₃ CH ₃ 3-F, 6-OCH ₃ 3- _CF3 -Ph 584.2 115 CH ₃ CH ₃ 2,3- _{( C4H4} ) 3- _CH3 -Ph 532.4 116 CH ₃ CH ₃ 2,3- _{( C4H4} ) 3-F-Ph 536.7 117 CH ₃ CH ₂ CH ₃ 2,3- _{( C4H4} ) 3-F 550.6 118 CH ₃ CH ₂ CH ₃ 2,3- _{( C4H4} ) 3- _CH3 546.8 119 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3- _CH3 560.8 120 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-F 564.7 122 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-pyridyl 547.5 125 CH ₃ CH( _CH3 ) ₂ 3-F

572.3 126 CH ₃ CH ₂ CH ₃ 3-F 3-F-Ph 518.4 129 CH ₃ CH( _CH3 ) ₂ 3-F 3-F-Ph 532.4 130 CH ₃ CH( _CH3 ) ₂ 3-F Ph 514.4 131 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 2-pyridyl 547.5 132 CH ₃ CH( _CH3 ) ₂ 3-OCH ₃ 3-F-Ph 544.5 133 CH ₃ CH( _CH3 ) ₂ 2-F Ph 514.5 134 CH ₃ CH( _CH3 ) ₂ 2-F 3-F-Ph 532.4 135 CH ₃ CH( _CH3 ) ₂ H 3-pyridyl 497.4 136 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-F,5-CN-Ph 589.4 138 CH ₃ CH( _CH3 ) ₂ 3-F 3-pyridyl 515.3 139 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) _CH2 -Ph 560.4 140 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

604.4 141 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3- _OCH3 -Ph 576.4 142 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-CN-Ph 571.4 143 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

606.3 144 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 4-pyridyl 547.4 145 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 4-F-Ph 564.4 146 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-F,5-CH ₃ O-Ph 562.3 147 CH ₃ CH ₃ 2,3- _{( C4H4} ) 3-pyridyl 519.3 148 CH ₃ CH( _CH3 ) ₂ 3-F

545.3 149 CH ₃ CH( _CH3 ) ₂ 3-F

533.3 150 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

552.4 151 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3,5-Di-F-Ph 582.4 152 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 2-F-Ph 564.5 153 CH ₃ CH( _CH3 ) ₂ 3- _CH3 3-pyridyl 511.3 154 CH ₃ CH( _CH3 ) ₂ 3-Cl 3-pyridyl 529.3 155 CH ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} ) Ph 531.4

Table 3 (continued)

Example R'' ^R2 Y LCMS m/z (M+H) 123 CH ₃ CH( _CH3 ) ₂

564.5 124 CH ₃ CH( _CH3 ) ₂

614.3 127 CH ₃ CH( _CH3 ) ₂

546.3 128 CH ₃ CH( _CH3 ) ₂

604.3 137 CH ₃ CH( _CH3 ) ₂

565.4

Example 83 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[3-(trifluoromethyl)phenyl]urea

Example 84 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-[3-(trifluoromethyl)phenyl]urea

Example 85: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-ethylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-(3-(trifluoromethyl)phenyl)urea

Example 86 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1- yl]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl]urea

Example 87: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-phenylurea

Example 88 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[3,5-bis(trifluoromethyl)phenyl]urea

Example 89 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-(3,5-dimethylphenyl)urea

Example 90 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[4-chloro-3-(trifluoromethyl)phenyl]urea

Example 91: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-benzylurea

Example 92 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[(4-methylphenyl)methyl]urea

Example 93: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-(2-chloro-5-(trifluoromethyl)phenyl)urea

Example 94: 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-3-(5-chloro-2-methoxyphenyl)urea

Example 95: 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-3-(2-methoxy-5-methylphenyl)urea

Example 96 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-(5-chloro-2-methylphenyl)urea

Example 97 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-(3-fluorophenyl)urea

Example 98: 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-(m-tolyl)urea

Example 99: 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-3-(2-methoxyphenyl)urea

Example 100: 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[4-(trifluoromethyl)phenyl]urea

Example 101: N-(4-{8-amino-3-methyl-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1,5-a] pyrazin-5-yl}cyclohex-3-en-1-yl)acetamide

Example 102: 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea

Example 103 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-(2,3-dihydro-1,4-benzodioxin-6-yl)urea

Example 104 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl} -1-(2,3-dihydro-1,4-benzodioxin-6-yl)urea

Example 105 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl} -3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea

Example 106 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-[3-(trifluoromethyl)phenyl]urea

Example 107 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-(trifluoromethyl)phenyl)urea

Example 108 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 3-fluorophenyl)-1-[3-(trifluoromethyl)phenyl]urea

Example 109 3-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}-3-fluorophenyl)-1-[3-(trifluoromethyl)phenyl]urea

Example 110: 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 3-fluorophenyl)-1-[3-(trifluoromethyl)phenyl]urea

Example 111 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 3-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea

Example 112: 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 2-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea

Example 113: 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 5-fluoro-2-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea

Example 114 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}- 5-fluoro-2-methoxyphenyl)-1-[3-(trifluoromethyl)phenyl]urea

Example 115 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-(3-methylphenyl)urea

Example 116 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-(3-fluorophenyl)urea

Example 117 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-(3-fluorophenyl)urea

Example 118 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-(3-methylphenyl)urea

Example 119 3-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}naphthalene-1-yl)-1-(3-methylphenyl)urea

Example 120 3-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}naphthalene-1-yl)-1-(3-fluorophenyl)urea

Example 122: 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(pyridin-3-yl)urea

Example 123: 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-fluorophenyl)urea

Example 124 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-(trifluoromethyl)phenyl)urea

Example 125: 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea

Example 126: 1-(4-(8-Amino-3-ethyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(3-fluorophenyl)urea

Example 127 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-phenylurea

Example 128 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea

Example 129: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(3-fluorophenyl)urea

Example 130: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-phenylurea

Example 131 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(pyridin-2-yl)urea

Example 132: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-methoxyphenyl)-3-(3-fluorophenyl)urea

Example 133: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2-fluorophenyl)-3-phenylurea

Example 134: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2-fluorophenyl)-3-(3-fluorophenyl)urea

Example 135 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl )-3-(pyridin-3-yl)urea

Example 136 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-cyano-5-fluorophenyl)urea

Example 137 1-(5-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)isoquinoline -8-yl)-3-(3-fluorophenyl)urea

Example 138: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(pyridin-3-yl)urea

Example 139 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-benzylurea

Example 140 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea

Example 141 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-methoxyphenyl)urea

Example 142: 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3-cyanophenyl)urea

Example 143: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3,4-dimethoxyphenyl)urea

Example 144 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(pyridin-4-yl)urea

Example 145: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(4-fluorophenyl)urea

Example 146: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(3-fluoro-5-methoxyphenyl)urea

Example 147 1-(4-(8-amino-3-methyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(pyridin-3-yl)urea

Example 148: 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(5-methoxypyridin-3-yl)urea

Example 149: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(5-fluoropyridin-3-yl)urea

Example 150: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(thiophen-3-yl)urea

Example 151 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(3,5-difluorophenyl)urea

Example 152 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(2-fluorophenyl)urea

Example 153: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-methylphenyl)-3-(pyridin-3-yl)urea

Example 154: 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-chlorophenyl)-3-(pyridin-3-yl)urea

Example 155: 1-(4-(3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-phenylurea

Step 1: tert-Butyl-(4-(1-bromo-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate

To a solution of tert-butyl-(4-(8-amino-1-bromo-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5E ( 0.30 g, 0.648 mmol) in THF (6 ml) in two test tubes, tert-butyl nitrite (0.31 ml, 2.57 mmol) was added to carry out the reaction and the mixture was heated at 60°C for 30 min. The mixture was cooled to RT and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to give the title compound (0.22 g, 76%). LC-MS: Rt=1.70 min, m/z=449.2 [M( ⁷⁹ Br)+H] ⁺ .

Step 2: tert-Butyl-(4-(3-isopropyl-1-(4-(3-phenylureido)naphthalen-1-yl)imidazo[1,5-a]pyrazin-5-yl)cyclohex-3-ene -1-yl)(methyl)carbamate

tert-Butyl-(4-(1-bromo-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate mixture (Example 155, step 1) (0.21 g, 0.47 mmol), 1-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl) urea 6C (0.20 g, 0.52 mmol) and cesium carbonate (0.5038 g, 1.55 mmol) in DME (4.5 ml) and water (1.15 ml) were purged with nitrogen for 2 min, then PdCl ₂ (dppf).DCM (19.1 mg, 0.023 mmol) was added. The mixture was purged for another 30 seconds, then heated at 90° C. overnight. The reaction mixture was subjected to distribution between EtOAc and brine. The aqueous layer was further extracted with EtOAc (2×) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to give the title compound (0.1021 g, 35%). LC-MS: Rt=1.61 min, m/z=631.4 [M+H] ⁺ .

Step 3: 1-(4-(3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl )-3-phenylurea (example 155)

The desired compound was obtained from tert-butyl-(4-(3-isopropyl-1-(4-(3-phenylureido)naphthalen-1-yl)imidazo[1,5-a]pyrazin-5-yl)cyclohex-3- en-1-yl)(methyl)carbamate (Example 155, Step 2) (100 mg, 0.16 mmol) in a manner similar to that described in Example 121, Step 4 to give the product as a yellow-orange solid (12 mg , 14%). QC LC-MS (method 1): Rt=2.65 min, m/z=531.4 [M+H] ⁺ .

Another set of compounds of the present invention can be prepared from the reactions shown in Scheme 7. Treatment of 2-(4-bromonaphthalene-1-yl)acetic acid 7A with a phenylenediamine such as 2,3-diaminotoluene gives the intermediate amide 7B which can be converted to benzimidazole 7C using standard conditions. 7C can be converted to boronate 7D which is coupled with a Pd(0) catalyzed coupling with a heterocyclic bromide such as above to give a coupling product such as 7E. Deprotection of the acid gives the final product 7F.

Scheme 7:

Example 156: 3-Isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine 7F

Stage 1: N-(2-Amino-3-methylphenyl)-2-(4-bromonaphthalen-1-yl)acetamide 7B

To a solution of 2-(4-bromonaphthalen-1-yl)acetic acid (5.00 g, 18.9 mmol), 2,3-diaminotoluene (3.46 g, 28.3 mmol) and TEA (5.3 ml , 37.7 mmol) in DMF (75 ml) was added HATU (7.89 g, 20.8 mmol) and the resulting solution was stirred at RT for 10 min. The mixture was poured into water (750 ml) and the resulting solid was collected by filtration, washed with water and dried in vacuo overnight. The solid was then washed with Et ₂ O-MeCN (3:1) and dried in vacuo at 40° C. to give the title compound 7B as a tan solid (6.39 g, 92%). LC-MS (method 1): Rt=1.85 and 1.95 min, m/z=369.1 [M( ⁷⁹ Br)+H] ⁺ .

Step 2: 2-((4-Bromonaphthalen-1-yl)methyl)-7-methyl-1H-benzo[d]imidazole 7C

A solution of N-(2-amino-3-methylphenyl)-2-(4-bromonaphthalen-1-yl)acetamide 7B (6.39 g, 17.3 mmol) in glacial acetic acid (100 ml) was heated at 130°C within 90 min. After cooling to RT, the solvent was concentrated in vacuo and the residue taken up in EtOAc and washed with 1N HCl. NaOH (x2) then brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting solid was triturated with water, collected by filtration, washed with water and dried in vacuo at 40° C. to give the title compound 7C as a tan solid (5.86 g, 96%). LC-MS (method 1): Rt=1.36 min, m/z=351.0 [M( ⁷⁹ Br)+H] ⁺ .

Stage 3: 7-Methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)methyl)-1H-benzo[d ]imidazole 7D

Mixture of 2-((4-bromonaphthalene-1-yl)methyl)-7-methyl-1H-benzo[d]imidazole 7C (5.86 g, 16.7 mmol), bis(pinacolato)diboron (6.35 g , 25.0 mmol), PdCl ₂ (dppf). DCM (680 mg, 0.84 mmol) and potassium acetate (4.09 g, 41.7 mmol) in dioxane (150 ml) were purged with argon for 10 min then heated at 95°C for 22 hours After cooling to RT the solvent was concentrated in vacuo and the residue was diluted with EtOAc, washed with water, then brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 25% EtOAc in isohexane. The residue was taken up in a minimal volume of EtOAc and the solid was precipitated by adding isohexane. The solid was collected by filtration, washed with isohexane and dried in vacuo at 45° C. to give the title compound 7D as a tan solid, (5.08 g, 76%). LC-MS (method 1): Rt=1.54 min, m/z=399.2 [M+H] ⁺ .

Step 4: tert-Butyl-(4-(8-amino-3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl) imidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 7E

A mixture of tert-butyl-(4-(8-amino-1-bromo-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5E (5 .08 g, 10.9 mmol), 7-methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)methyl )-1H-benzo[d]imidazole 7D (5.66 g, 14.2 mmol), PdCl ₂ (dppf).DCM (0.89 g, 1.09 mmol) and cesium carbonate (10.68 g, 32 .8 mmol) in 1,4-dioxane (100 ml) was purged with argon for 10 min, then heated at 95°C for 2.5 h. The reaction mixture was allowed to cool to RT, diluted with EtOAc (200 ml) and washed with water then brine, dried (Na ₂ SO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% 2N HCl. NH ₃ in MeOH/DCM, then re-purified by silica gel chromatography eluting with 0-15% MeOH/EtOAc to give the title compound 7E as an orange solid (5.35 g, 75%). LC-MS (method 1): Rt=1.33 min, m/z=656.4 [M+H] ⁺ .

Step 5: 3-Isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine (example 156) 7F

To a mixture of tert-butyl-(4-(8-amino-3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)imidazo [1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 7E (5.35 g, 8.16 mmol) with methanol (20 ml) was added 4N. HCl in 1,4-dioxane (20.4 mL, 81.6 mmol) and the resulting solution was stirred at RT for 60 min during which time a solid precipitated. The solvent was concentrated in vacuo and the residue was dissolved in a minimum amount of water, filtered and then added dropwise to aqueous ammonia (800 ml). The solid was collected by filtration, washed with water and dried in vacuo at 45° C. to give the title compound 7F (4.47 g, 99%). QC LC-MS (method 3) Rt=2.01 min, m/z=556.3 [M+H] ⁺ .

The examples in Table 4 below were carried out in a similar manner to that used in Example 156. Other central bridges were prepared in a similar manner by replacing 4-bromonaphthylacetic acid with 5-bromonaphthylacetic acid or substituted 4-bromophenylacetic acids.

Table 4

Example R''' ^R2 X Ar LCMS m/z (M+H) HPLC Rt (min)/method 157 _NHCH3 CH ₃ 2,3- _{( C4H4} )

514.5 2.69/2 158 _NHCH3 CH( _CH3 ) ₂ 3-F

510.5 2.74/2 159 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

542.3 2.39/1 161 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

578.3 2.46/1 162 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

570.3 2.32/1 163 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

572.3 1.97/3 164 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

567.3 2.33/3 165 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

560.3 2.28/3 166 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

543.3 1.67/3 167 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

576.3 2.46/3 168 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

568.3 2.26/1 206 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

556.5 1.98/3 207 Oh CH( _CH3 ) ₂ 2,3- _{( C4H4} )

543.3 2.53/3 208 N(CH ₃ ) ₂ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

570.3 2.00/3 209 N(CH ₃ )-CH ₂ CHF ₂ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

620.4 2.29/3 210 _NH2 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

542.3 1.97/3 211 N(CH ₃ )-CH ₂ CF ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

638.4 3.21/3 212 NH-CH ₂ CHF ₂ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

606.4 2.08/3 213 NH-CH ₂ CH ₂ F CH( _CH3 ) ₂ 2,3- _{( C4H4} )

588.4 2.02/3 214 NH-CH ₂ CF ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

624.4 2.68/3 215 N(CH ₃ )-CH ₂ CH ₂ F CH( _CH3 ) ₂ 2,3- _{( C4H4} )

602.4 2.06/3 216 N(CH ₃ )-CH ₂ CH ₂ -CF ₃ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

652.4 2.28/3 217 NH-CH ₂ CH ₂ -CONMe ₂ CH( _CH3 ) ₂ 2,3- _{( C4H4} )

641.4 2.23/3

Table 4 (continued)

Example R''' ^R2 Ar LCMS m/z (M+H) HPLC Rt (min)/method 160 _NHCH3 CH( _CH3 ) ₂

542.4 2.19/1

Example 157: 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-methyl-5-(4-(methylamino)cyclohex-1-en-1 -yl)imidazo[1,5-a]pyrazin-8-amine

Example 158: 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)-2-fluorophenyl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1- yl)imidazo[1,5-a]pyrazine-8-amine

Example 159: 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1 -yl)imidazo[1,5-a]pyrazin-8-amine

Example 160: 1-(5-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1 -yl)imidazo[1,5-a]pyrazin-8-amine

Example 161: 1-(4-((4,6-difluoro-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex -1-en-1-yl)imidazo[1,5-a]pyrazine-8-amine

Example 162: 1-(4-((4,6-dimethyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex -1-en-1-yl)imidazo[1,5-a]pyrazine-8-amine

Example 163 3-isopropyl-1-(4-((5-methoxy-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine

Example 164 2-((4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl) naphthalene-1-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Example 165: 1-(4-((7-Fluoro-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine

Example 166: 1-(4-((1H-imidazo[4,5-c]pyridin-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine

Example 167: 1-(4-((7-Chloro-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1 -en-1-yl)imidazo[1,5-a]pyrazin-8-amine

Example 168 3-Isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)-1-(4-((5-phenyl-1H-imidazol-2-yl)methyl)naphthalene-1 -yl)imidazo[1,5-a]pyrazin-8-amine

Step 1: 2-((4-Bromonaphthalene-1-yl)methyl)-5-phenyl-1H-imidazole

To a solution of 2-(4-bromonaphthalen-1-yl)acetic acid (250 mg, 0.94 mmol) in methanol (7 mL) was added cesium carbonate (153.6 mg, 0.47 mmol) and the mixture was stirred at RT for for 1 h. The solvent was concentrated in vacuo and the residue suspended in DMF (5 ml). 2-bromo-1-phenylethan-1-one (197.1 mg, 0.99 mmol) was added and the mixture was stirred at RT for 1 h. The solvent was concentrated in vacuo and the residue was suspended in EtOAc, the inorganic salts were filtered off, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in xylene (7.5 mL), ammonium acetate (1.454 g, 18.9 mmol) was added and the mixture was refluxed for 16 h. The mixture was cooled, diluted with EtOAc, washed successively with water, aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified on an SCX cartridge eluting with 10% 4 M NH ₃ in MeOH/DCM to give the title compound as a yellow foam (296 mg, 86%). LC-MS: Rt 1.23=min, m/z=363.0 [M( ⁷⁹ Br)+H] ⁺ .

Step 2: tert-Butyl-(4-(8-amino-3-isopropyl-1-(4-((5-phenyl-1H-imidazol-2-yl)methyl)naphthalene-1-yl)imidazo[1, 5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate

To a mixture of 2-((4-bromonaphthalen-1-yl)methyl)-5-phenyl-1H-imidazole (Example 168, step 1) (129.0 mg, 0.355 mmol), potassium acetate (95 mg, 0.97 mmol) and bis(neopentylglycolate)diboron (109 mg, 0.48 mmol) in DMF (2.5 ml, pre-purged with nitrogen for 10 min) was added Pd(dppf)Cl ₂ (24 mg, 0.032 mmol) and the mixture was purged nitrogen for 10 s, then heated at 80°C for 2 h. The mixture was allowed to cool to RT and tert-butyl pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5E (150 mg, 0.32 mmol) followed by aqueous cesium carbonate solution (3.7 M, 0.19 mL, 0.70 mmol) and Pd(dppf)Cl ₂ (23.6 mg, 0.032 mmol). The mixture was purged with nitrogen and heated at 90° C. overnight. The mixture was diluted with EtOAc and washed with water then brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in isohexane to give the title compound as a brown oil (176 mg, 74%). LC-MS: Rt=1.23 min, m/z=668.4 [M+H] ⁺ .

Step 3: 3-Isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)-1-(4-((5-phenyl-1H-imidazol-2-yl)methyl)naphthalene-1 -yl)imidazo[1,5-a]pyrazin-8-amine

It was obtained from tert-butyl-(4-(8-amino-3-isopropyl-1-(4-((5-phenyl-1H-imidazol-2-yl)methyl)naphthalen-1-yl)imidazo[1, 5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate (176 mg, 0.264 mmol) by the same procedure as described for 6E. This was purified with MDAP followed by SFC (LUX CELLULOSE-4 40-60% EtOH+0.1% DEA) to give the two enantiomers of the title compound as off-white solids (48 mg, 32%). Isomer A: 25 mg; QC LC-MS (method 1): Rt=2.26 min, m/z=568.3 [M+H] ⁺ ; SFC Assay (LUX CELLULOSE-4 40% EtOH+ 0.1% DEA) Rt=6.22 min ee=100%. Isomer B: 23 mg; QC LC-MS (method 1): Rt=2.26 min, m/z=568.3 [M+H] ⁺ ; SFC Assay (LUX CELLULOSE-4 40% EtOH+0.1% DEA) Rt=7.65 min; ee=94.9%.

Example 206: 1-{4-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-5-[4-(methylamino)cyclohex-1-en-1 -yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine

Example 207 4-(8-amino-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl )imidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-ol

Example 208 5-[4-(dimethylamino)cyclohex-1-en-1-yl]-1-{4-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1 -yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine

Example 209 5-{4-[(2,2-difluoroethyl)(methyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol -2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine

Example 210 5-(4-aminocyclohex-1-en-1-yl)-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl} -3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine

Example 211 5-{4-[methyl(2,2,2-trifluoroethyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol -2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine

Example 212 5-{4-[(2,2-difluoroethyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2- yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine

Example 213: 5-{4-[(2-fluoroethyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl) methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine

Example 214: 1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)-5-{4- [(2,2,2-trifluoroethyl)amino]cyclohex-1-en-1-yl}imidazo[1,5-a]pyrazine-8-amine

Example 215: 5-{4-[(2-fluoroethyl)(methyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2 -yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine

Example 216 5-{4-[methyl(3,3,3-trifluoropropyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol -2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine

Example 217: 3-((4-(8-amino-3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)imidazo [1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)amino)-N,N-dimethylpropanamide

Additional compounds of the present invention may be prepared by the reactions shown in Scheme 8. Treatment of 4-bromo-2-fluoroaniline 8A with a sulfonyl chloride such as (2-chlorophenyl)methanesulfonyl chloride gives the intermediate sulfonamide 8B which can be converted to the boronate 8C, which is then coupled with a Pd(0) catalyzed coupling with a heteroaromatic bromide such as above to give a coupling product such as 8D. Deprotection of the acid gives the final product 8E.

Scheme 8:

Example 169: N-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide 8E

Step 1: N-(4-Bromo-2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide 8B

To an ice-cold solution of 4-bromo-2-fluoroaniline (3.52 g, 18.5 mmol) in DCM (100 mL) was added pyridine (4.5 mL, 55.5 mmol) followed by (2-chlorophenyl)methanesulfonyl chloride ( 5.00 g, 22.2 mmol). The mixture was stirred at 0°C for 30 min, then at RT for 10 min. The mixture was diluted with 1N. HCl and extracted with DCM. The combined organic extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound 8B (7.46 g, 89%). LC-MS (method 1): Rt=1.44 min, m/z=376.0 [M( ⁷⁹ Br ³⁵ Cl)-H] ^- .

Step 2: 1-(2-Chlorophenyl)-N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide 8C

A mixture of N-(4-bromo-2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide (8B (7.46 g, 19.7 mmol), bis(pinacolato)diboron (6.00 g, 23.6 mmol ), PdCl ₂ (dppf). DCM (0.80 g, 0.99 mmol) and potassium acetate (4.83 g, 49.3 mmol) in dioxane (100 ml) were purged with argon under sonication, then heated at 100 °C for 2 hours After cooling to RT the mixture was diluted with water and extracted with EtOAc The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo The residue was purified by silica gel chromatography eluting with 0 -50% EtOAc in isohexane The oily residue was triturated with isohexane and collected by filtration to give the title compound 8C as an off-white solid (6.28 g, 75%) LC-MS (Method 1): Rt=1.56 min , m/z=424.2 [M( ³⁵ Cl)-H] ^- .

Step 3: tert-Butyl-(4-(8-amino-1-(4-(((2-chlorophenyl)methyl)sulfonamido)-3-fluorophenyl)-3-isopropylimidazo[1,5-a]pyrazine-5 -yl)cyclohex-3-en-1-yl)(methyl)carbamate 8D

A mixture of tert-butyl-(4-(8-amino-1-bromo-3-isopropylimidazo[1,5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)(methyl)carbamate 5E (2 .00 g, 4.31 mmol), 1-(2-chlorophenyl)-N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)methanesulfonamide 8C (2.02 g, 4.74 mmol), PdCl ₂ (dppf). DCM (0.35 g, 0.43 mmol) and cesium carbonate (2.81 g, 8.61 mmol) in 1 ,4-dioxane (40 ml) and water (10 ml) were purged with argon under sonication, then heated at 100° C. for 30 min. After cooling to RT, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-5% MeOH in DCM to give the title compound 8D (2.97 g, 100%). LC-MS (method 1): Rt=1.18 min, m/z=683.5 [M( ³⁵ Cl)+H] ⁺ .

Step 4: N-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide (Example 169) 8E

To a solution of tert-butyl-(4-(8-amino-1-(4-(((2-chlorophenyl)methyl)sulfonamido)-3-fluorophenyl)-3-isopropylimidazo[1,5-a]pyrazine-5- yl)cyclohex-3-en-1-yl)(methyl)carbamate 8D (5.40 g, 7.90 mmol) in 1,4-dioxane (20 ml) was added 4N. HCl in 1,4-dioxane (20 mL, 80 mmol) which precipitated a sticky solid. Methanol (20 ml) was added to promote dissolution and the mixture was stirred for 1.5 h. Solvents were evaporated in vacuo and the residue was dissolved in water (20 ml) and added dropwise to aqueous ammonia (30%) with vigorous stirring. The resulting solid was collected by filtration to give the title compound 8E (4.11 g, 89%). QC LC-MS (method 3): Rt=2.55 min, m/z=583.4 [M( ³⁵ Cl)+H] ⁺ .

The examples in Table 5 below were carried out in a similar manner to that used in Example 169. Other central bridges were prepared in a similar manner by replacing 4-bromo-2-fluoroaniline with appropriately substituted 4-bromoanilines or bromonaphthylamines.

Table 5

Example R''' ^R2 X Ar LCMS m/z (M+H) HPLC Rt (min)/method 170 _NHCH3 CH ₃ 2,3- _{( C4H4} ) 2-Cl-Ph 573.4 2.51/1 171 _NHCH3 CH( _CH3 ) ₂ 3-F Ph 535.3 2.43/1 172 _NHCH3 CH( _CH3 ) ₂ 3-F 3-F-Ph 542.3 2.39/1 173 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) CH ₂ -(2-Cl-Ph) 615.4 2.91/2 174 _NHCH3 CH( _CH3 ) ₂ 3-F-Ph 2-Cl-Ph 569.3 2.66/2 176 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-F-Ph 585.4 2.53/1 177 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} )

625.3 2.77/2 178 _NHCH3 CH( _CH3 ) ₂ 3-F

593.4 2.65/2 179 _NHCH3 CH( _CH3 ) ₂ 2-F 2-Cl-Ph 569.4 2.53/1 180 _NHCH3 CH( _CH3 ) ₂ 3-F CH ₂ -(2-Cl-Ph) 583.4 2.48/1 181 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 2-Cl-Ph 601.4 2.57/1 182 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) CH ₂ -(3-F-Ph) 599.4 2.49/1 183 _NHCH3 CH( _CH3 ) ₂ 3-F _CH2 -Ph 549.3 2.41/1 184 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 2.5- _F2 -Ph 603.5 2.48/1 185 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 2-F,5-CH ₃ -Ph 599.3 2.79/2 186 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 2-Cl,5-F-Ph 619.2 2.69/2 187 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) CH ₂ -(2-F-Ph) 599.3 2.54/3 188 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) CH ₂ -(2.5-F ₂ -Ph) 617.2 2.59/3 189 _NHCH3 CH( _CH3 ) ₂ 3-F CH ₂ -(2-F-Ph) 567.2 2.41/3 190 _NHCH3 CH( _CH3 ) ₂ 3-F CH ₂ -(2.5-F ₂ -Ph) 585.2 2.47/3 191 _NHCH3 CH( _CH3 ) ₂ 3-F CH ₂ -(3.5-F ₂ -Ph) 585.2 2.53/3 192 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 2-F,5-CF ₃ -Ph 653.3 2.83/3 193 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3- _CF3 -Ph 635.4 2.81/3 194 _NHCH3 CH( _CH3 ) ₂ 3-F 3- _CF3 -Ph 603.3 2.74/3 195 _NHCH3 CH( _CH3 ) ₂ 3-F 2,5-Cl ₂ -Ph 603.2 2.72/3 196 _NHCH3 CH( _CH3 ) ₂ 3.6- _F2 CH ₂ -(2-Cl-Ph) 601.3 2.59/3 197 _NHCH3 CH( _CH3 ) ₂ 2,3- _F2 CH ₂ -(2-Cl-Ph) 601.3 2.56/3 198 _NHCH3 CH( _CH3 ) ₂ 3-F CH ₂ -(3-pyridyl) 550.2 1.83/3 199 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) CH ₂ -(3-pyridyl) 582.2 1.9/3 200 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 3-CH ₃ O-Ph 611.2 2.53/3 201 _NHCH3 CH( _CH3 ) ₂ 3-F CH ₂ -(3-CH ₃ O-Ph) 579.3 2.42/3 202 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) CH ₂ -(3.5-F ₂ -Ph) 617.2 2.65/3 218 _NHCH3 CH( _CH3 ) ₂ 2-F 2-F,5-CH ₃ -Ph 567.2 2.50/3 219 _NHCH3 CH( _CH3 ) ₂ 2,3- _{( C4H4} ) 2-Cl,5-CH ₃ -Ph 615.3 2.81/3 220 NHCH ₂ CH ₂ F CH( _CH3 ) ₂ 2-F CH ₂ -(2-Cl-Ph) 615.3 2.72/3 223 NHCH ₂ CH ₂ F CH( _CH3 ) ₂ 2-F 2-Cl-Ph 601.3 2.66/3 224 Oh CH( _CH3 ) ₂ 2-F CH ₂ -(2-Cl-Ph) 570.3 3.22/3 225 Oh CH( _CH3 ) ₂ 2-F 2-Cl-Ph 556.3 3.36/3 226 NHCH ₂ CHF ₂ CH( _CH3 ) ₂ 2-F 2-Cl-Ph 619.3 2.72/3 227

CH( _CH3 ) ₂ 2-F CH ₂ -(2-Cl-Ph) 625.3 2.64/3 228 NHCH ₂ CH ₂ F CH( _CH3 ) ₂ 2.5- _F2 2-Cl-Ph 619.3 2.46/4 229 NHCH ₂ CH ₂ F CH( _CH3 ) ₂ 2-F 2-F-Ph 585.4 2.81/5 230 NMeCH ₂ CH ₂ F CH( _CH3 ) ₂ 2-F 2-Cl-Ph 615.2 2.65/3 231 NHCH ₂ CH ₂ F CH ₃ 2-F 2-Cl-Ph 573.2 2.34/3 232

CH( _CH3 ) ₂ 2-F 2-Cl-Ph 611.4 2.68/3

Table 5 (continued)

Example R''' ^R2 Y LCMS m/z (M+H) HPLC Rt (min)/method 175 _NHCH3 CH( _CH3 ) ₂

601.4 2.83/2 203 _NHCH3 CH( _CH3 ) ₂

629.3 2.88/3

Example 170: N-(4-(8-amino-3-methyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-chlorobenzenesulfonamide

Example 171 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)benzenesulfonamide

Example 172: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-fluorobenzenesulfonamide

Example 173: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(2-chlorophenyl)methanesulfonamide

Example 174: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-2-chlorobenzenesulfonamide

Example 175: N-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-chlorobenzenesulfonamide

Example 176: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-fluorobenzenesulfonamide

Example 177: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonamide

Example 178: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonamide

Example 179: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2-fluorophenyl)-2-chlorobenzenesulfonamide

Example 180: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide

Example 181 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-chlorobenzenesulfonamide

Example 182: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(3-fluorophenyl)methanesulfonamide

Example 183: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-phenylmethanesulfonamide

Example 184: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2,5-difluorobenzenesulfonamide

Example 185: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-fluoro-5-methylbenzenesulfonamide

Example 186 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-chloro-5-fluorobenzenesulfonamide

Example 187: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(2-fluorophenyl)methanesulfonamide

Example 188 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(2,5-difluorophenyl)methanesulfonamide

Example 189: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(2-fluorophenyl)methanesulfonamide

Example 190: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(2,5-difluorophenyl)methanesulfonamide

Example 191: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(3,5-difluorophenyl)methanesulfonamide

Example 192: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-2-fluoro-5-(trifluoromethyl)benzenesulfonamide

Example 193: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-3-(trifluoromethyl)benzenesulfonamide

Example 194: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-3-(trifluoromethyl)benzenesulfonamide

Example 195: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-2,5-dichlorobenzenesulfonamide

Example 196: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2,5-difluorophenyl)-1-(2-chlorophenyl)methanesulfonamide

Example 197: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 2,3-difluorophenyl)-1-(2-chlorophenyl)methanesulfonamide

Example 198: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(pyridin-3-yl)methanesulfonamide

Example 199 N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(pyridin-3-yl)methanesulfonamide

Example 200: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(3-methoxyphenyl)methanesulfonamide

Example 201: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)- 3-fluorophenyl)-1-(3-methoxyphenyl)methanesulfonamide

Example 202: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(3,5-difluorophenyl)methanesulfonamide

Example 203: N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl)-1-(2-chlorophenyl)-N-methylmethanesulfonamide

Example 218 N-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}-2-fluorophenyl)-2-fluoro-5-methylbenzene-1-sulfonamide

Example 219: N-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazine -1-yl}naphthalene-1-yl)-2-chloro-5-methylbenzene-1-sulfonamide

Example 220: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide

Example 223: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide

Example 224: N-(4-(8-amino-5-(4-hydroxycyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl) -1-(2-chlorophenyl)methanesulfonamide

Example 225: N-(4-(8-amino-5-(4-hydroxycyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl) -2-chlorobenzenesulfonamide

Example 226: N-(4-(8-amino-5-(4-((2,2-difluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazine -1-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide

Example 227: N-(4-(8-amino-3-isopropyl-5-(4-(oxetan-3-ylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide

Example 228: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1 -yl)-2,5-difluorophenyl)-2-chlorobenzenesulfonamide

Example 229: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-2-fluorobenzenesulfonamide

Example 230: N-(4-(8-amino-5-(4-((2-fluoroethyl)(methyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a] pyrazin-1-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide

Example 231: N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide

Example 232: N-(4-(8-amino-3-isopropyl-5-(4-(oxetan-3-ylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide

Additional compounds of the present invention may be prepared from the reactions shown in Scheme 9. Coupling of (3-chloropyrazin-2-yl)methanamine 9A with an acid such as 4-Boc-1-piperazinoacetic acid gives the amide intermediate 9B, which can be cyclize to imidazopyrazine 9C. It is then brominated to give 9D, then treated with ammonia to give 9E, which is coupled with Pd(0) catalyzed in situ boronate to give a coupling product such as 9F. Removal of the protecting group from the acid gives the final product 9G, which can then be alkylated to give products such as 9H.

Scheme 9:

Example 221: 1-(4-((1H-Benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloro-3-(piperazin-1-ylmethyl)imidazo[1,5- a] Pyrazine 9G

Stage 1: tert-Butyl-4-(2-(((3-chloropyrazin-2-yl)methyl)amino)-2-oxoethyl)piperazine-1-carboxylate 9B

A mixture of 4-Boc-1-piperazinoacetic acid (2.7 g, 11.1 mmol), HOBT (1.6 g, 12.0 mmol), EDC.HCl (2.3 g, 12.0 mmol) and DIPEA (4.0 ml, 25 mmol)) in DMF (30 ml) was stirred at RT for 5 min, then (3-chloropyrazin-2-yl)methanamine (1.4 g, 10.0 mmol) was added and stirred at RT for 18 hours The mixture was subjected to distribution between water and DCM and the combined organic extracts were washed with saturated aqueous NaCl, dried (MgSO ₄ ), filtered and evaporated in vacuum. The residue was purified by silica gel chromatography eluting with 0-50% ethyl acetate in hexane. The residue was taken up in DCM, washed twice with water then brine and evaporated in vacuo to give the title compound 9B (2.21 g, 67%). ¹H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, 1H, J=2.4 Hz), 8.33 (m, 1H), 8.28 (br s, 1H), 4.75 (d , 2H, J=5.2 Hz), 3.51 (m, 4H), 3.14 (s, 2H), 2.55 (m, 4H), 1.47 (s, 9H).

Stage 2: tert-Butyl-4-((8-chloroimidazo[1,5-a]pyrazin-3-yl)methyl)piperazine-1-carboxylate 9C

To a solution of tert-butyl 4-(2-(((3-chloropyrazin-2-yl)methyl)amino)-2-oxoethyl)piperazine-1-carboxylate 9B (2.21 g, 5.98 mmol) in DCM (20 ml) at 0°C was added pyridine (1.45 ml, 17.9 mmol), then dropwise over 10 min trifluoromethanesulfonic anhydride (3.02 ml, 18.0 mmol). The resulting slurry was heated at RT, more DCM (10 mL) was added to aid stirring, then stirred for 2.5 h. NaHCO ₃ aqueous solution was added and the mixture was extracted twice with DCM, then EtOAc. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-15% methanol in DCM to give the title compound 9C (1.0 g, 86%). LC-MS: Rt=1.11 min, m/z=352.2 [M( ³⁵ Cl)+H] ⁺ .

Stage 3: tert-Butyl-4-((1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)methyl)piperazine-1-carboxylate 9D

To a solution of tert-butyl 4-((8-chloroimidazo[1,5-a]pyrazin-3-yl)methyl)piperazin-1-carboxylate 9C (1.0 g, 2.84 mmol) in THF (7, 7 ml) and acetonitrile (18.9 ml) at 0°C was added NBS (0.6 g, 3.37 mmol). The mixture was allowed to warm to RT and stirred for 2 h. The mixture was concentrated in vacuo and the residue suspended in DCM and filtered. The filtrate was evaporated in vacuo and purified by silica gel chromatography eluting with 0-15% methanol in DCM to give the title compound 9D (700 mg, 57%). LC-MS: Rt=1.34 min, m/z=430.1 [M( ³⁵ Cl ⁷⁹ Br)+H] ⁺ .

Step 4: tert-Butyl-4-((8-amino-1-bromimidazo[1,5-a]pyrazin-3-yl)methyl)piperazine-1-carboxylate 9E

It was obtained in 64% yield by a procedure similar to that described for 5E using tert-butyl-4-((1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)methyl)piperazin-1- carboxylate 9D. LC-MS: Rt=1.14 min, m/z=411.1 [M( ⁷⁹ Br)+H] ⁺ .

Stage 5: tert-Butyl-4-((1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloroimidazo[1,5-a]pyrazine -3-yl)methyl)piperazine-1-carboxylate 9F

A mixture of 2-((4-bromonaphthalen-1-yl)methyl)-1H-benzo[d]imidazole (prepared by a procedure similar to that described for 7C (160 mg, 0.47 mmol), tetrahydroxydiboron (128 mg, 1.42 mmol), potassium acetate (140 mg, 1.42 mmol), XPhos Pd G2 (11 mg, 0.01 mmol), ethylene glycol (80 µl, 1.42 mmol) in methanol (4.7 ml) in a test tube reaction was purged with nitrogen for 30 min then heated at 90° C. for 1.5 h The mixture was filtered through celite and the filtrate was evaporated in vacuo The residue was dissolved in 1,4-dioxane (2.4 ml) and tert-butyl was added -4-((8-Amino-1-bromimidazo[1,5-a]pyrazin-3-yl)methyl)piperazin-1-carboxylate 9E (117 mg, 0.28 mmol), cesium carbonate (3.7 M solution in water, 385 μl, 1.42 mmol) and Pd(dppf)Cl ₂ .DCM (39 mg, 0.05 mmol) The mixture was purged with nitrogen for 30 min, then heated at 80°C for 18 h. The mixture was concentrated in vacuo and the residue partitioned between DCM and aqueous NaHCO _3. The aqueous layer was extracted twice more with DCM and the combined organic layers were passed through a phase separator and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-50% ethyl acetate in hexane to give the title compound 9F (99 mg, 59%). LC-MS: Rt=1.16 min, m/z=589.2 [M+H] ⁺ .

Step 6: 1-(4-((1H-Benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloro-3-(piperazin-1-ylmethyl)imidazo[1,5- a] Pyrazine 9G

To a solution of tert-butyl-4-((1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloroimidazo[1,5-a]pyrazin- 3-yl)methyl)piperazin-1-carboxylate 9F (99 mg, 0.20 mmol) in methanol (2 ml) was added with 4 M HCl in 1,4-dioxane (2 ml) and the resulting solution was stirred at RT for 1 .5 h. The solvents were concentrated in vacuo and the residue was passed through an SCX-2 cartridge (5 g). Major fractions were concentrated in vacuo and the residue was purified with MDAP to give the title compound 9G (11.6 mg, 14%). QC LC-MS (method 1): Rt=2.07 min, m/z=489.3 [M+H] ⁺ .

Example 222: 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloro-3-((4-methylpiperazin-1-yl)methyl)imidazo [1,5-a]pyrazine 9H

To a solution of 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloro-3-(piperazin-1-ylmethyl)imidazo[1,5-a ]pyrazine (Example 220) 9G (40 mg, 0.082 mmol) in methanol (2 ml) was added formaldehyde (37% solution in water, 0.1 ml, 1.3 mmol) and acetic acid (0.1 ml). The mixture was stirred for 10 min, then sodium cyanoborohydride (8 mg, 0.12 mmol) was added and the mixture was stirred for another 1.5 h. Water (0.4 ml) was added and the mixture was loaded into an SCX-2 cartridge (5 g ). The cartridge was washed with methanol, then eluted with 1 M ammonia in methanol. Major fractions were concentrated in vacuo and the residue was purified with MDAP to give the title compound 9H. QC LC-MS (method 2): Rt=2.71 min, m/z=503.4 [M+H] ⁺ .

Example 233: Biochemical Assays for Detecting Inhibition of IRE1α Kinase Activity

Kinase reactions were performed in ProxiPlate-384 Plus 384-well white plates (PERKIN Elmer 6008280) using 25 mM MOPS assay buffer with 1 mM dithiothreitol, 25 mM MgCl ₂ , 12.5 mM β-glycerophosphate, 5 mM EGTA and 50 μg /ml BSA. Test compounds were received on the day of analysis and dosed twice using the D300 digital pipette as a series of 10 ½ log dilutions, normalized to a final DMSO concentration of 3%. Test compounds were pre-incubated for 30 min at room temperature with 10 nM IRE1α kinase (E31-11G from Signal Chem) in 2.5 µl of assay buffer and the reaction was initiated by adding 2.5 µl of ATP to the assay buffer to give the final an ATP concentration of 100 μM and 5 nM for IRE1α kinase. After 4 hours incubation at room temperature, the reactions were stopped and kinase activity was determined using Promega's ADP-Glo™ reagent according to the manufacturer's instructions. Luminescence was examined with a luminometer (EnVision, PerkinElmer) and IC ₅₀ values were calculated by fitting with a sigmoidal curve the percent control inhibition versus Log ₁₀ compound concentration. The inhibitory activity of each compound against IRE1α kinase is shown in Table 6.

Table 6

Example IRE1α kinase IC ₅₀ (µM) Example IRE1α kinase IC ₅₀ (µM) 1 0.083 112 0.086 2 1.0 113 0.053 3 2.7 114 10-100 4 0.75 115 0.083 5 1.5 116 0.022 6 2.6 117 0.015 7 0.072 118 0.025 8 1.63 119 0.014 9 0.33 120 0.020 10 10-50 121 0.003 eleven 0.042 122 0.010 12 0.088 123 0.009 13 0.057 124 0.007 14 1.42 125 0.001 15 0.50 126 0.001 16 0.028 127 0.028 17 0.57 128 0.004 18 0.20 129 0.001 19 0.18 130 0.001 20 0.016 131 0.015 21 0.027 132 0.031 22 0.047 133 0.027 23 0.44 134 0.011 24 0.029 135 0.007 25 0.41 136 0.003 26 1.27 137 0.009 27 0.013 138 0.001 28 0.15 139 0.009 29 0.10 140 0.003 thirty 0.18 141 0.001 31 0.11 142 0.002 32 0.10 143 0.005 33 0.26 144 0.005 34 0.039 145 0.004 35 0.027 146 0.001 36 0.021 147 0.007 37 0.10 148 0.001 38 0.10 149 0.001 39 0.056 150 0.002 40 0.026 151 0.001 41 0.047 152 0.003 42 0.654 153 0.009 43 0.076 154 0.002 44 0.047 155 0.019 45 0.80 156 0.003 46 1.16 157 0.078 47 0.59 158 0.104 48 50-100 159 0.009 49 0.83 160 0.019 50 0.15 161 0.002 51 0.91 162 0.005 52 0.48 163 0.003 53 0.82 164 0.004 54 0.23 165 0.003 55 1.47 166 0.018 56 0.93 167 0.007 57 0.027 168 0.02 58 0.060 169 0.002 59 0.043 170 0.075 60 0.060 171 0.080 61 10-50 172 0.065 62 0.010 173 0.009 63 0.039 174 0.010 64 0.004 175 1-10 65 0.002 176 0.009 66 0.066 177 0.241 67 0.002 178 0.250 68 0.008 179 0.013 69 0.002 180 0.009 70 0.002 181 0.027 71 0.002 182 0.010 72 0.009 183 0.020 73 0.021 184 0.012 74 0.009 185 0.005 75 0.005 186 0.005 76 0.021 187 0.011 77 0.020 188 0.016 78 0.010 189 0.012 79 0.023 190 0.012 80 0.008 191 0.026 81 0.008 192 0.011 82 0.007 193 0.019 83 0.033 194 0.027 84 0.023 195 0.004 85 0.006 196 0.009 86 0.008 197 0.017 87 0.032 198 0.028 88 0.55 199 0.042 89 0.043 200 0.017 90 0.032 201 0.015 91 0.88 202 0.024 92 0.55 203 0.57 93 0.053 204 0.10 94 0.022 205 0.15 95 0.042 206 0.017 96 0.13 207 0.037 97 0.008 208 0.033 98 0.012 209 0.17 99 0.12 210 0.012 100 0.029 211 1-10 101 0.22 212 0.085 102 0.10 213 0.055 103 0.028 214 0.65 104 0.043 215 0.16 105 0.019 216 0.17 106 0.003 217 0.08 107 0.014 218 0.007 108 0.026 219 0.0114 109 0.016 220 0.097 110 0.084 221 0.65 111 0.12 222 0.86 223 0.010 227 0.003 224 0.085 230 0.004 225 0.118 231 0.011

Example 234: In Vitro Pharmacological Assays

Biochemical analysis: Inhibition of RNase activity of IRE1α

RNase reactions were performed in ProxiPlate-384 Plus 384-well black plates (PERKIN Elmer) using 50 mM Tris assay buffer with 0.5 mM MgCl ₂ , 10 mM KCl, 0.03% Tween, 2 mM DTT, and 1% DMSO . Test compounds were received on the day of analysis and dosed twice using the D300 digital pipette as a series of 10 ½ log dilutions, normalized to a final DMSO concentration of 4%. Test compounds were pre-incubated for 30 min at room temperature with IRE1α kinase (E31-11G from Signal Chem) in 2.5 µl of assay buffer. Then 2.5 µl of assay buffer containing substrate (5' Alexa Fluor 647 - rCrArU rGrUrC rCrGrC rArGrC rGrCrArUrG - Iowa Black RQ quencher 3') was added to give a final enzyme concentration of 0.325 nM and substrate of 100 nM. After 20 min incubation at room temperature, reactions were stopped by adding 5 µl of 5M urea, incubated at room temperature for 10 min and fluorescence was examined with a plate reader (EnVision, PerkinElmer) and IC ₅₀ values were calculated by fitting with a sigmoidal curve expressed as a percentage of the degree of inhibition of the control from the concentration of the compound.

Example 235: In Vitro Cell Assays

XBP-1 splicing analysis using cells

ARPE-19 cells stably expressing XBP-1 (aa 1-376) with the nanoluciferase gene sequence linked so that it is in-frame when XBP-1 is spliced were grown in F12 media, 10% FBS, 0.044% sodium bicarbonate , 150 μg/ml hygromycin B and seeded for analysis in 5000 cells in 384-well plates in culture media without hygromycin B and incubated at 37°C/5% CO ₂ . After overnight incubation, test compounds were added to the cell plate as two series of 10 ½ log dilutions (0.117% final DMSO concentration). After an additional 30 min incubation, thapsigargin (final concentration 150 nM) was added and then incubated for another 4 h. Nanoluciferase assay (Promega) was performed according to the manufacturer's instructions for luciferase detection and luminescence was examined with a luminometer (EnVision, PerkinElmer). IC ₅₀ values were calculated by fitting a sigmoid curve to the percentage of control inhibition versus compound concentration.

Cell Apoptosis Analysis

INS-19 cells expressing mIRE-1 were grown in RPMI, 10% FCS, 0.0003% β-mercaptoethanol, and 150 μg/ml hygromycin B and seeded for assays at 10,000 cells/well in 384-well plates in media without hygromycin B After a 24 hour incubation, test compounds were added to the plate as two series of 10 ½ log dilutions and incubated for 30 minutes. Doxycycline (final concentration 100 nM) was added and the plates were incubated for a further 72 hours. Hoechst 33342 (final concentration 10 μg/ml) was added to determine the content of apoptotic cells, then after 30 minutes cells were imaged and analyzed in an imaging apparatus at great content incell.

Table 7

Example IRE1 (RNase IC50 (µM) Cell Assay IC50 (µM) Example IRE1 (RNase IC50 (µM) Cell Assay IC50 (µM) 20 0.011 0.47 146 0.006 0.24 36 0.156 1.53 147 0.007 3.1 37 0.007 0.32 148 0.001 1.3 40 0.020 0.28 149 0.001 0.78 67 0.001 0.21 150 0.001 0.090 68 0.003 0.43 151 0.001 0.060 69 0.001 0.35 152 0.001 0.10 70 0.001 0.14 155 0.019 0.64 71 0.001 0.062 156 0.001 0.016 81 0.005 0.29 168 0.003 0.096 82 0.006 0.40 169 0.001 0.031 121 0.001 0.089 185 0.002 0.21 123 0.002 0.23 195 0.002 0.066 124 0.005 0.43 218 0.017 0.025 125 0.001 0.30 219 0.002 0.020 126 0.001 0.45 220 0.002 0.050 129 0.001 0.28 224 0.010 0.042 130 0.001 0.41 225 0.121 0.25 139 0.003 0.38 226 0.213 0.33 140 0.001 0.078 227 0.073 0.087 141 0.001 0.059 228 0.006 0.010 142 0.001 0.094 229 0.025 0.025 143 0.002 0.21 230 0.012 0.019 144 0.002 0.49 231 0.029 0.019 145 0.004 0.074 232 0.060 0.20

Cell-based assays (IC ₅₀ values) were performed for XBP1 splicing assay or apoptosis assay

The disclosures of each and all patents, patent applications and publications cited in the present invention are incorporated herein by reference in their entirety. While the present invention has been disclosed using specific embodiments, it is clear that other embodiments and variations of the present invention may be proposed by those skilled in the art without deviating from the true spirit and scope of the present invention. The appended claims are intended to include all such embodiments and equivalents.

Claims (296)

1. Compound of formula (Ia), formula (Ib) or formula (Ic):

(Ia)

(Ib),

(Ic), Where: R ¹ is selected from the group consisting of

,

,

,

,

And

; R ² is selected from the group consisting of H, methyl, ethyl, propyl, CF ₃ , CHF ₂ , 1-methylcyclopropyl, isopropyl, t-butyl and C ₃ -C ₈ cycloalkyl; L is selected from the group consisting of a bond, -CH ₂ - and -C(=O)-; R ³ is selected from the group consisting of

,

,

,

,

,

,

,

,

,

,

, C ₃ -C ₈ cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl and oxadiazolyl; or -LR ³ is

where R''' is selected from the group consisting of -OH, C ₁ -C ₆ alkoxy, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl) and -NH(oxetanyl); R ⁴ is selected from the group consisting of halogen, -NH ₂ and -NHR ⁸ ; in each occurrence, R ⁵ is independently selected from the group consisting of halide, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; R ⁶ is H; in each occurrence R ⁹ is independently selected from the group consisting of H, C ₁ -C ₈ alkyl, oxetanyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ carboxamidoalkyl, C ₁ -C ₆ carboxyalkyl and C ₁ -C ₆ cyanoalkyl ; R ⁸ means C ₁ -C ₃ alkyl; Cy is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidinyl, thienyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl,

,

,

,

And

; where Cy is substituted with 0 to 'n' X, in each occurrence X is independently selected from the group consisting of H, OH, halide, nitrile, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy groups, phenyl and

; in each case, Z, if present, is independently selected from the group consisting of CH and N; m means an integer selected from the group consisting of 0, 1, 2, 3 and 4; n is an integer selected from the group consisting of 0, 1, 2, 3, 4 and 5; q means an integer selected from the group consisting of 0, 1, 2, 3, 4 and 5; p means an integer selected from the group consisting of 0, 1, 2, 3, 4 and 5; And in each case alkyl, cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl , isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, oxetanyl and benzimidazolyl are optionally substituted with at least one substituent selected from the group consisting of C ₁ -C ₁₀ alkyl, halogen, perhaloalkyl, =O, -OH, alkoxy groups, -NH ₂ , -N(CH ₃ ) ₂ , -NH(CH ₃ ) ₂ , phenyl, benzyl, (1-methylimidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, - C(=O)OH, -OC(=O) (C ₁ -C ₄ )alkyl, -C(=O)(C ₁ -C ₄ )alkyl, -C≡N, -C(=O)O( C ₁ -C ₄ )alkyl, -C(=O)NH ₂ , -C(=O)NH(C ₁ -C ₄ )alkyl, -C(=O)N((C ₁ -C ₄ )alkyl) _2, -SO ₂ NH ₂ , -C (= NH) NH ₂ and -NO ₂ or a pharmaceutically acceptable salt or enantiomer thereof. 2. The compound according to claim 1, wherein Cy is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

. 3. The compound according to claim 1, wherein R ¹ is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

. 4. The compound according to claim 3, wherein R ¹ is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

. 5. The compound according to claim 1, wherein R ³ is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

. 6. A compound according to claim 1 or 5, wherein R ³ is selected from the group consisting of:

,

And

. 7. A compound according to claim 1, wherein R ⁴ is -NH ₂ , or wherein R ⁵ , if present, is -F. 8. The compound according to claim 1 or 5, in which in each case R ⁹ is independently selected from the group consisting of: H, oxetanyl, C ₁ -C ₈ alkyl,

,

,

,

,

,

And

. 9. The compound according to claim 1, which is selected from the group consisting of:

(Ia'),

(Ib') and

(Ic'), where R' means R ³ . 10. The compound of claim 9 wherein R' is selected from the group consisting of

,

,

,

,

,

,

,

,

,

,

,

,

And

. 11. The compound according to claim 1, which is selected from the group consisting of:

(Ia''),

(Ib'') and

(Ic''), where in each case R'' independently means H or C ₁ -C ₆ alkyl. 12. The compound according to claim 1, which is selected from the group consisting of:

(Ia'''),

(Ib''') and

(Ic'''), where in each case R''' is independently selected from the group consisting of -OH, C ₁ -C ₆ alkoxy, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) and -NH(oxetanyl) wherein each C ₁ -C ₆ alkyl is optionally substituted with at least one substituent independently selected from the group consisting of halo, -C(=O)NH ₂ , - C(=O)NH(C ₁ -C ₄ alkyl), -C(=O)N(C ₁ -C ₄ alkyl)(C ₁ -C ₄ alkyl), -OH and -C ₁ -C ₆ alkoxy groups. 13. The compound of claim 12 wherein R''' is selected from the group consisting of -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₂ F, -N(Me )CH ₂ CH ₂ F, -NHCH ₂ CHF ₂ , -N(Me)CH ₂ CHF ₂ , -NHCH ₂ CF ₃ , -N(Me)CH ₂ CF ₃ , -NHCH ₂ CH ₂ CF ₃ , -N( Me)CH ₂ CH ₂ CF ₃ , -NHCH ₂ CH ₂ C(=O)NMe ₂ , -N(Me)CH ₂ CH ₂ C(=O)NMe ₂ , -NHCH ₂ CH ₂ C(=O)NH ₂ , -N(Me)CH ₂ CH ₂ C(=O)NH ₂ , -NHCH ₂ CH ₂ C(=O)NHMe, -N(Me)CH ₂ CH ₂ C(=O)NHMe ₂ and

. 14. A compound selected from the group consisting of the following: 3-{4-[8-Amino-3-methyl-5-(piperazin-1-carbonyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-( trifluoromethyl)phenyl]urea; 3-{4-[8-amino-5-(4-aminopiperidin-1-carbonyl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3- (trifluoromethyl)phenyl]urea); 8-amino-3-methyl-N-(piperidin-4-yl)-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1,5-a ]pyrazine-5-carboxamide; 3-(4-{8-amino-5-[(3R)-3-aminopiperidin-1-carbonyl]-3-methylimidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl)-1 -[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-5-[(3S)-3-aminopiperidin-1-carbonyl]-3-methylimidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl)-1 -[3-(trifluoromethyl)phenyl]urea); 8-amino-3-methyl-N-[(3R)-piperidin-3-yl]-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1 ,5-a]pyrazine-5-carboxamide; 8-amino-3-methyl-N-(piperidin-3-yl)-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1,5-a ]pyrazine-5-carboxamide; 8-amino-3-methyl-N-[(3S)-1-methylpiperidin-3-yl]-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo [1,5-a]pyrazine-5-carboxamide; 8-amino-3-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo [1,5-a]pyrazine-5-carboxamide; 3-{4-[8-amino-3-methyl-5-(4-methylpiperazin-1-carbonyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3 -(trifluoromethyl)phenyl]urea; 3-{4-[8-amino-3-methyl-5-(piperidin-4-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-( trifluoromethyl)phenyl]urea; 3-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-( trifluoromethyl)phenyl]urea; 3-(4-{8-amino-5-[(4-aminopiperidin-1-yl)methyl]-3-methylimidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl)-1- [3-(trifluoromethyl)phenyl]urea; 3-[4-(8-amino-3-methyl-5-{[(piperidin-4-yl)amino]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl]- 1-[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-amino-5-{[(3R)-3-aminopiperidin-1-yl]methyl}-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl ]-1-[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-amino-5-{[(3S)-3-aminopiperidin-1-yl]methyl}-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl ]-1-[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-amino-3-methyl-5-{[(piperidin-3-yl)amino]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl]- 1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-Amino-3-methyl-5-({[(3S)-piperidin-3-yl]amino}methyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1 -yl}-1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[(4-methylpiperazin-1-yl)methyl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl)-1 -[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-Amino-3-ethyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-( trifluoromethyl)phenyl]urea; 3-{4-[8-amino-5-(piperazin-1-ylmethyl)-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}- 1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-ethyl-5-[(4-methylpiperazin-1-yl)methyl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1-yl)-1 -[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-Amino-3-methyl-5-{[4-(methylamino)piperidin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl ]-1-[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-Amino-3-methyl-5-{[(3R)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl]-1-[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-Amino-3-methyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl]-1-[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-amino-5-{[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl}-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene -1-yl]-1-[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-Amino-3-ethyl-5-{[(3R)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl]-1-[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-Amino-3-ethyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl]-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-amino-5-(1,4-diazepan-1-ylmethyl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea; 3-[4-(8-amino-5-{2,5-diazabicyclo[2,2,1]heptan-2-ylmethyl}-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene- 1-yl]-1-[3-(trifluoromethyl)phenyl]urea; 3-[4-(8-amino-3-methyl-5-{octahydropyrrolo[3,4-c]pyrrol-2-ylmethyl}imidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl ]-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-(3-fluorophenyl )urea; 3-{4-[8-amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalen-1-yl}-1-(3-methylphenyl )urea; 3-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl}-1-[3-(trifluoromethyl )phenyl]urea; 3-{4-[8-amino-3-ethyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl}-1-[3-(trifluoromethyl )phenyl]urea; N-(4-(8-amino-3-isopropyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-1-(2-chlorophenyl) methanesulfonamide; 3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(piperazin-1-ylmethyl)imidazo[1,5 -a]pyrazine-8-amine; 2-{4-[8-Amino-3-methyl-5-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-N-[3-( trifluoromethyl)phenyl]acetamide; 3-{4-[8-Amino-3-methyl-5-(1,2,5,6-tetrahydropyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-Amino-3-methyl-5-(piperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-( trifluoromethyl)phenyl]urea; 3-{4-[8-Amino-3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-amino-3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl} -1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[5-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene- 1-yl}-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[5-(1-acetylpiperidin-3-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3- (trifluoromethyl)phenyl]urea; 3-{4-[5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl]-3 -fluorophenyl}-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-amino-5-(cyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[ 3-(trifluoromethyl)phenyl]urea; 3-{4-[8-Amino-3-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene -1-yl}-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-Amino-3-methyl-5-(pyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-( trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[1-(prop-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl]imidazo[1,5-a]pyrazine -1-yl}naphthalene-1-yl)-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-amino-5-(4-aminophenyl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3-(trifluoromethyl)phenyl ]urea; 3-{4-[8-amino-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}- 1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl} -1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl} -1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene -1-yl)-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-Amino-3-methyl-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl }-1-[3-(trifluoromethyl)phenyl]urea; 3-{4-[8-amino-5-(2-aminopyridin-4-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1-[3- (trifluoromethyl)phenyl]urea; 2-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl)-N -(3-(trifluoromethyl)phenyl)acetamide; 2-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1- yl)-N-[3-(trifluoromethyl)phenyl]acetamide; 2-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1- yl}naphthalene-1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide; 2-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1- yl)-N-[3-(trifluoromethyl)phenyl]acetamide; 2-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluorophenyl )-N-[3-(trifluoromethyl)phenyl]acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-phenylacetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-N-(3-fluorophenyl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(3-fluorophenyl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(3-fluoro-5-methoxyphenyl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-N-phenylacetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(3-cyano-5-fluorophenyl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(pyridin-2-yl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(5-methoxypyridin-3-yl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(3-cyanophenyl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(3-methoxyphenyl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(pyridin-3-yl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(pyrazin-2-yl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(thiazol-5-yl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(1-methyl-1H-benzo[d]imidazol-5-yl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(3,4-dimethoxyphenyl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(pyrimidin-5-yl)acetamide; 2-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(5-fluoropyridin-3-yl)acetamide; 2-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-(3-fluorophenyl)acetamide; 2-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-N-phenylacetamide; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1- yl)-1-[3-(trifluoromethyl)phenyl]urea; 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-ethylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl)-3 -(3-(trifluoromethyl)phenyl)urea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1-yl]naphthalene -1-yl}-1-[3-(trifluoromethyl)phenyl]urea; 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl)-3 -phenylurea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -[3,5-bis(trifluoromethyl)phenyl]urea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -(3,5-dimethylphenyl)urea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -[4-chloro-3-(trifluoromethyl)phenyl]urea; 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl)-3 - benzylurea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -[(4-methylphenyl)methyl]urea; 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl)-3 -(2-chloro-5-(trifluoromethyl)phenyl)urea; 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-3 -(5-chloro-2-methoxyphenyl)urea; 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-3 -(2-methoxy-5-methylphenyl)urea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -(5-chloro-2-methylphenyl)urea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -(3-fluorophenyl)urea; 1-(4-(8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl)-3 -(m-tolyl)urea; 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-3 -(2-methoxyphenyl)urea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -[4-(trifluoromethyl)phenyl]urea; N-(4-{8-amino-3-methyl-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)naphthalene-1-yl]imidazo[1,5-a]pyrazine-5 -yl}cyclohex-3-en-1-yl)acetamide; 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-3 -{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]naphthalene-1-yl}-1 -(2,3-dihydro-1,4-benzodioxin-6-yl)urea; 3-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl}-1- (2,3-dihydro-1,4-benzodioxin-6-yl)urea; 1-{4-[8-amino-5-(4-aminocyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl]-3-fluorophenyl}-3- {4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea; 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1- yl)-1-[3-(trifluoromethyl)phenyl]urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(3-(trifluoromethyl)phenyl)urea; 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluorophenyl )-1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1- yl}-3-fluorophenyl)-1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluorophenyl )-1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methylphenyl )-1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}-2-methylphenyl )-1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}-5-fluoro -2-methylphenyl)-1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}-5-fluoro -2-methoxyphenyl)-1-[3-(trifluoromethyl)phenyl]urea; 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1- yl)-1-(3-methylphenyl)urea; 3-(4-{8-amino-3-methyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1- yl)-1-(3-fluorophenyl)urea; 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1- yl)-1-(3-fluorophenyl)urea; 3-(4-{8-amino-3-ethyl-5-[4-(methylamino)cyclohex-1-en-1-yl]imidazo[1,5-a]pyrazin-1-yl}naphthalene-1- yl)-1-(3-methylphenyl)urea; 3-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1- yl}naphthalene-1-yl)-1-(3-methylphenyl)urea; 3-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1- yl}naphthalene-1-yl)-1-(3-fluorophenyl)urea; 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-phenylurea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(pyridin-3-yl)urea; 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(3-fluorophenyl)urea; 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea; 1-(4-(8-Amino-3-ethyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-(3-fluorophenyl)urea; 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-phenylurea; 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-(3-fluorophenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-phenylurea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(pyridin-2-yl)urea; 1-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-methoxyphenyl )-3-(3-fluorophenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl )-3-phenylurea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl )-3-(3-fluorophenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-3 -(pyridin-3-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(3-cyano-5-fluorophenyl)urea; 1-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)isoquinolin-8- yl)-3-(3-fluorophenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-(pyridin-3-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-benzylurea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(3-methoxyphenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(3-cyanophenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(3,4-dimethoxyphenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(pyridin-4-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(4-fluorophenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-(3-fluoro-5-methoxyphenyl)urea; 1-(4-(8-Amino-3-methyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(pyridin-3-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-(5-methoxypyridin-3-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-(5-fluoropyridin-3-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(thiophen-3-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(3,5-difluorophenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(2-fluorophenyl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl )-3-(pyridin-3-yl)urea; 1-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-chlorophenyl )-3-(pyridin-3-yl)urea; 1-(4-(3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1-yl)-3 -phenylurea; 3-Isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(4-(methylamino)cyclohex-1-en- 1-yl)imidazo[1,5-a]pyrazin-8-amine; 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-methyl-5-(4-(methylamino)cyclohex-1-en-1-yl) imidazo[1,5-a]pyrazine-8-amine; 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)-2-fluorophenyl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo [1,5-a]pyrazine-8-amine; 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl) imidazo[1,5-a]pyrazine-8-amine; 1-(5-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl) imidazo[1,5-a]pyrazine-8-amine; 1-(4-((4,6-difluoro-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1- en-1-yl)imidazo[1,5-a]pyrazin-8-amine; 1-(4-((4,6-dimethyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1- en-1-yl)imidazo[1,5-a]pyrazin-8-amine; 3-isopropyl-1-(4-((5-methoxy-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-5-(4-(methylamino)cyclohex-1-en- 1-yl)imidazo[1,5-a]pyrazin-8-amine; 2-((4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1 -yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile; 1-(4-((7-fluoro-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en- 1-yl)imidazo[1,5-a]pyrazin-8-amine; 1-(4-((1H-imidazo[4,5-c]pyridin-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en- 1-yl)imidazo[1,5-a]pyrazin-8-amine; 1-(4-((7-chloro-1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-3-isopropyl-5-(4-(methylamino)cyclohex-1-en- 1-yl)imidazo[1,5-a]pyrazin-8-amine; 3-Isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)-1-(4-((5-phenyl-1H-imidazol-2-yl)methyl)naphthalene-1-yl) imidazo[1,5-a]pyrazine-8-amine; N-(4-(8-Amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl )-1-(2-chlorophenyl)methanesulfonamide; N-(4-(8-amino-3-methyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-2-chlorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )benzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-fluorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-1-(2-chlorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-2-chlorobenzenesulfonamide; N-(5-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-2-chlorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-fluorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl )-2-chlorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-1-(2-chlorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-2-chlorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-1-(3-fluorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-1-phenylmethanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-2,5-difluorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-2-fluoro-5-methylbenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-2-chloro-5-fluorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-1-(2-fluorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-1-(2,5-difluorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-1-(2-fluorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-1-(2,5-difluorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-1-(3,5-difluorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-2-fluoro-5-(trifluoromethyl)benzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-3-(trifluoromethyl)benzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-3-(trifluoromethyl)benzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-2,5-dichlorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-2.5 -difluorophenyl)-1-(2-chlorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-2,3 -difluorophenyl)-1-(2-chlorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-1-(pyridin-3-yl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-1-(pyridin-3-yl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-1-(3-methoxyphenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)-3-fluorophenyl )-1-(3-methoxyphenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-1-(3,5-difluorophenyl)methanesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(methylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl)naphthalene-1- yl)-1-(2-chlorophenyl)-N-methylmethanesulfonamide; 1-[(8-amino-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo [1,5-a]pyrazin-5-yl)methyl]piperidin-4-amine; (3S)-1-[(8-amino-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2 -yl)imidazo[1,5-a]pyrazin-5-yl)methyl]piperidin-3-amine; 1-{4-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalen-1-yl}-5-[4-(methylamino)cyclohex-1-en-1-yl] -3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine; 4-(8-amino-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[ 1,5-a]pyrazin-5-yl)cyclohex-3-en-1-ol; 5-[4-(dimethylamino)cyclohex-1-en-1-yl]-1-{4-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl} -3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine; 5-{4-[(2,2-difluoroethyl)(methyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2- yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine; 5-(4-aminocyclohex-1-en-1-yl)-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3- (propan-2-yl)imidazo[1,5-a]pyrazin-8-amine; 5-{4-[methyl(2,2,2-trifluoroethyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2- yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine; 5-{4-[(2,2-difluoroethyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl ]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine; 5-{4-[(2-fluoroethyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene -1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine; 1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)-5-{4-[(2 ,2,2-trifluoroethyl)amino]cyclohex-1-en-1-yl}imidazo[1,5-a]pyrazine-8-amine; 5-{4-[(2-fluoroethyl)(methyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2-yl) methyl]naphthalen-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine; 5-{4-[methyl(3,3,3-trifluoropropyl)amino]cyclohex-1-en-1-yl}-1-{4-[(4-methyl-1H-1,3-benzodiazol-2- yl)methyl]naphthalene-1-yl}-3-(propan-2-yl)imidazo[1,5-a]pyrazin-8-amine; 3-((4-(8-amino-3-isopropyl-1-(4-((7-methyl-1H-benzo[d]imidazol-2-yl)methyl)naphthalen-1-yl)imidazo[1, 5-a]pyrazin-5-yl)cyclohex-3-en-1-yl)amino)-N,N-dimethylpropanamide; N-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1- yl}-2-fluorophenyl)-2-fluoro-5-methylbenzene-1-sulfonamide; N-(4-{8-amino-5-[4-(methylamino)cyclohex-1-en-1-yl]-3-(propan-2-yl)imidazo[1,5-a]pyrazin-1- yl}naphthalene-1-yl)-2-chloro-5-methylbenzene-1-sulfonamide; N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl) -2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide; 1-(4-((1H-Benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloro-3-(piperazin-1-ylmethyl)imidazo[1,5-a]pyrazine ; 1-(4-((1H-benzo[d]imidazol-2-yl)methyl)naphthalene-1-yl)-8-chloro-3-((4-methylpiperazin-1-yl)methyl)imidazo[1, 5-a] pyrazine; N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl) -2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(8-amino-5-(4-hydroxycyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-1- (2-chlorophenyl)methanesulfonamide; N-(4-(8-amino-5-(4-hydroxycyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl)-2-fluorophenyl)-2- chlorobenzenesulfonamide; N-(4-(8-amino-5-(4-((2,2-difluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1- yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(oxetan-3-ylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl) -2-fluorophenyl)-1-(2-chlorophenyl)methanesulfonamide; N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl) -2,5-difluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1-yl) -2-fluorophenyl)-2-fluorobenzenesulfonamide; N-(4-(8-amino-5-(4-((2-fluoroethyl)(methyl)amino)cyclohex-1-en-1-yl)-3-isopropylimidazo[1,5-a]pyrazin-1 -yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(8-amino-5-(4-((2-fluoroethyl)amino)cyclohex-1-en-1-yl)-3-methylimidazo[1,5-a]pyrazin-1-yl) -2-fluorophenyl)-2-chlorobenzenesulfonamide; N-(4-(8-amino-3-isopropyl-5-(4-(oxetan-3-ylamino)cyclohex-1-en-1-yl)imidazo[1,5-a]pyrazin-1-yl) -2-fluorophenyl)-2-chlorobenzenesulfonamide; or a pharmaceutically acceptable salt or enantiomer thereof. 15. Pharmaceutical composition having inhibitory activity against IRE1α kinase, containing a therapeutically effective amount of at least one compound according to any one of paragraphs. 1-14 and at least one pharmaceutically acceptable carrier. 16. A method of treating an IRE1α-associated disease in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or enantiomer thereof according to any one of paragraphs. 1-14. 17. The method of claim 16 wherein the disease is selected from the group consisting of neurodegenerative disease, demyelinating disease, cancer, eye disease, fibrotic disease, and diabetes. 18. The method according to claim 17, in which (a) the neurodegenerative disease is selected from the group consisting of retinitis pigmentosa, amyotrophic lateral sclerosis, retinal degeneration, macular degeneration, Parkinson's disease, Alzheimer's disease, Huntington's disease, prion disease, Creutzfeldt-Jakob disease, and kuru; (b) the demyelinating disease is selected from the group consisting of Wolfram syndrome, Pelizeus-Merzbacher disease, transverse myelitis, Charcot-Marie-Tooth disease, and multiple sclerosis; (c) the cancer is multiple myeloma; (d) the diabetes is selected from the group consisting of type I diabetes and type II diabetes; (e) the eye disease is selected from the group consisting of retinitis pigmentosa, retinal degeneration, macular degeneration, and Wolfram's syndrome; (f) the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), myocardial infarction, cardiac hypertrophy, heart failure, cirrhosis, acetaminophen (Tylenol) liver toxicity, hepatitis C liver disease, hepatosteatosis (fatty liver), or liver fibrosis. 19. A method of inhibiting the activity of the IRE1 protein, where the method includes the interaction of the IRE1 protein with an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-14, wherein the activity is selected from the group consisting of kinase activity and RNase activity. 20. The method of claim 19 wherein the IRE1 protein is present in the cell. 21. The method according to claim 20, in which at least one is applicable: (a) cell apoptosis is prevented or minimized; (b) the cell is in an organism that has an IRE1α associated disease or disorder. 22. The method of claim 21, wherein in (b) the disease or disorder is a neurodegenerative disease, a demyelinating disease, cancer, an eye disease, a fibrotic disease, or diabetes.