CN115697319A - Use of triterpenoid NRF2 inhibitors - Google Patents

Abstract

Described herein are terpenoid derivatives as NRF2 inhibitors for use in the treatment of systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS) , pulmonary hypertension, Friedreich's ataxia, autosomal dominant polycystic kidney disease (ADPKD) or IgA nephropathy.

Description

Uses of triterpenoid NRF2 inhibitors

cross reference

This application claims the benefit of U.S. Provisional Application Serial No. 63/003,719, filed April 1, 2020, which is hereby incorporated by reference in its entirety.

Background technique

Kidney disease is highly prevalent worldwide and significantly reduces the quality of life of patients, thus there is an urgent need for effective treatment modalities. Despite this significant unmet medical need, none of the drugs marketed to date have shown the potential to cure kidney disease. This may be due to the structural complexity of the kidney and the difficulty in setting appropriate endpoints and identifying appropriate therapeutic targets for clinical trials. More recently, surrogate endpoints for clinical trials (i.e., 30% or 40% reduction in estimated glomerular filtration rate [eGFR] from baseline after 2–3 years of Endpoints are expected to contribute to progress in drug development for kidney disease. In addition, oxidative stress and inflammation are now recognized as key factors in the progression of kidney disease, prompting the search for more therapeutic agents that target mechanisms related to these factors. The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) system has attracted much attention in recent years because of its antioxidant and anti-inflammatory properties, as well as its pharmacological potential for the treatment of renal diseases. It has been extensively studied in both research and nonclinical studies.

Many reports describe the association between Nrf2 and kidney disease. Furthermore, the review by Nezu et al. discusses the role of Nrf2 in genetically modified animals (Nrf2 knockout [KO], Keap1 knockdown [KD] and Keap1 conditional KO [cKO]) (Nezu, M., Suzuki, N. ., Yamamoto, M., 2017. Targeting the KEAP1-NRF2 system to prevent kidney disease progression. [Targeting the KEAP1-NRF2 system to prevent kidney disease progression] Am. J. Nephrol. [Journal of the American Society of Nephrology] 45, 473-483). Nrf2-KO mutations lead to exacerbation of lupus-like nephritis, streptozotocin-induced nephropathy (including renal function), ferric nitrilotriacetate-induced nephrotoxicity, and ischemia-reperfusion (IRI)-induced renal injury. In contrast, Keap1-KD mutations were associated with reduced IRI-induced renal tubular injury and reduced renal fibrosis induced by unilateral ureteral obstruction.

A number of studies have assessed the effects of Nrf2 activators (eg, sulforaphane, curcumin) and synthetic triterpenoids (CDDOs) (eg, bardoxolone-methyl [CDDO-Me]) on renal injury. Similar to the results in genetically modified animals, several other studies have also shown that Nrf2 activation leads to reduced kidney damage, suggesting the therapeutic potential of targeting this pathway to treat kidney disease. A need exists for the treatment of kidney disease.

Contents of the invention

Disclosed herein is a method of treating the disease systemic lupus nephritis, diabetic chronic kidney disease (CDK), Allport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Friedrich Ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprises administering a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof or stereoisomers:

in:

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ³ is N-linked heterocycloalkyl, N-linked heteroaryl, -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O )(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(= O)(=NR ^x )R ⁵ , -ZO-cycloalkyl, -ZO-heterocycloalkyl, -ZO-aryl, -ZO-heteroaryl, -Z-NR ⁵ -cycloalkyl, -Z -NR ⁵ -heterocycloalkyl, -Z-NR ⁵ -aryl, -Z-NR ⁵ -heteroaryl, -Y(C ₁ -C ₆ alkylene)S(=O)R ⁴ , -Y (C ₁ -C ₆ alkylene)S(=O) ₂ R ⁴ , -Y(C ₁ -C ₆ alkylene)P(=O)(R ⁴ ) ₂ , -Y(C ₁ -C ₆ Alkylene)P(=O)(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)B(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C( =NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)S(=O)( =NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S( =O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ C(=O)(C ₁ -C ₆ alkylene)S(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ C(=O )(C ₁ -C ₆ alkylene)S(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y( C ₂ -C ₆ alkenylene)S(=O) ₂ R ⁴ , -Y(C ₂ -C ₆ alkenylene)P(=O)(R ⁴ ) ₂ , -Y(C ₂ -C ₆ alkenylene) alkenyl)P(=O)(OR ⁵ ) ₂ , -Y(C ₂ -C ₆ alkenylene)B(OR ⁵ ) ₂ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ C(= NR ^x )R ⁵ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₂ -C ₆ alkenylene)S(=O)(= NR ^x )R ⁵ , -Y(C ₂ -C ₆ alkenylene )S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y(C ₂ -C ₆ alkenylene)cycloalkyl, -Y(C ₂ -C ₆ alkenylene ) heterocycloalkyl, -Y(C ₂ -C ₆ alkenylene) aryl, -Y(C ₂ -C ₆ alkenylene) heteroaryl, -(C ₁ -C ₆ alkylene) OP( =O)(OR ⁵ ) ₂ , -(C ₁ -C ₆ alkylene)O(C ₁ -C ₆ alkylene)OP(=O)(OR ⁵ ) ₂ , or -(C ₁ -C ₆ Alkylene) OP(=O)(OR ⁵ )[N(R ⁵ ) ₂ ]; wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

Y is a bond, -O-, -S-, or -NR ^b -;

Z is a bond or C ₁ -C ₆ alkylene;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹² and R ¹³ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹² and R ¹³ together form cycloalkyl or heterocycloalkyl; each of which is substituted by 0-6 R ¹⁴ ;

Each R ¹⁴ is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C(=O) ^Ra , -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ;

Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

Also disclosed herein is a method of treating the disease systemic lupus nephritis, diabetic chronic kidney disease (CDK), Allport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary arterial hypertension, Freed Reich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, a solvent to a subject in need thereof Compounds or Stereoisomers:

in:

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ³ is halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ^5. -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P( =O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)( =NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O) (=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R;

Each R ^3b is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C( ⁼ O)Ra, -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

Y ¹ and Y ² are independently hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹² is hydrogen, deuterium, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl base;

R ¹³ is -CN, -OR ¹⁹ , -S(=O) ₂ NR ²⁰ R ²¹ , -OC(=O)R ¹⁸ , -OC(=O)OR ¹⁹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkane radical, heterocycloalkyl, aryl, heteroaryl, -CH ₂ (cycloalkyl), -CH ₂ (heterocycloalkyl), -CH ₂ (aryl), or -CH ₂ (heteroaryl) ; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^13a ;

Each R ^13a is independently oxo, deuterium, halogen, -CN, -OR ¹⁹ , -SR ¹⁹ , -S(=O)R ¹⁸ , -S(=O) ₂ R ¹⁸ , -NO ₂ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -OC(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -OC(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hetero Alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ¹⁸ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^18a ;

Each R ^18a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ¹⁹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl Base, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^19a ;

Each R ^19a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ²⁰ and R ²¹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^20a ;

Each R ^20a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R ²⁰ and R ²¹ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three R ^20b ;

Each R ^20b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ;

Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

incorporated by reference

All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference for the specific purposes identified herein.

Description of drawings

Figure 1A shows spleen weight versus body weight after treatment with Compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.

Figure 1B shows the fold expression of spleen mRNA after treatment with Compound 26 in the imiquimod-induced systemic lupus nephritis mouse model.

Figure 2A shows serum BUN (blood urea nitrogen) levels after treatment with compound 26 in imiquimod-induced systemic lupus nephritis mouse model.

Figure 2B shows urinary protein levels after treatment with compound 26 in imiquimod-induced systemic lupus nephritis mouse model.

Figure 3A shows kidney weight versus body weight after treatment with Compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.

Figure 3B shows renal histopathology scores after treatment with Compound 26 in the imiquimod-induced systemic lupus nephritis mouse model.

Figure 3C shows the expression of NGAL in the kidney after treatment with compound 26 in the imiquimod-induced systemic lupus nephritis mouse model.

Figure 3D shows the expression of CD11b in the kidney after treatment with Compound 26 in the imiquimod-induced systemic lupus nephritis mouse model.

Detailed ways

definition

As used herein and in the appended claims, the singular forms "a, an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, while reference to a "cell" includes reference to one or more cell(s) and equivalents thereof known to those skilled in the art, and the like. When ranges are used herein for physical properties (eg, molecular weight) or chemical properties (eg, chemical formulae), all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. When referring to a number or a numerical range, the term "about" means that the referenced number or numerical range is an approximation within experimental variability (or statistical experimental error), so that in some cases the number or numerical range will be within the stated The number or value range varies between 1% and 15%. The term "comprising" (and related terms such as "comprises or comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as Any embodiment of a composition of matter, composition, method, process, etc. described herein "consists of" or "consists essentially of" described features.

Unless indicated to the contrary, the following terms, as used in the specification and appended claims, have the meanings indicated hereinafter.

"Aliphatic chain" refers to a linear chemical moiety composed only of carbon and hydrogen. In some embodiments, the fatty chains are saturated. In some embodiments, the fatty chains are unsaturated. In some embodiments, the unsaturated fatty chain contains one degree of unsaturation. In some embodiments, the unsaturated fatty chain contains more than one degree of unsaturation. In some embodiments, the unsaturated fatty chain contains two degrees of unsaturation. In some embodiments, the unsaturated fatty chain contains one double bond. In some embodiments, the unsaturated fatty chain contains two double bonds.

"Alkyl" means an optionally substituted straight chain, or an optionally substituted branched chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein alkane The sp ^hybridized carbon of the base residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1- Pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl -1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Pentyl, neopentyl, tert-pentyl, and hexyl, and longer alkyl groups (eg, heptyl, octyl, etc.). Whenever it appears herein, a numerical range such as "C ₁ -C ₆ alkyl" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, carbon atoms or consisting of 6 carbon atoms, but this definition also covers occurrences of the term "alkyl" where no numerical range is assigned. In some embodiments, the alkyl group is C ₁ -C ₁₀ alkyl, C ₁ -C ₉ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, or C ₁ alkyl. Unless specifically stated otherwise in this specification, an alkyl group is optionally replaced by, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkane Substituted by radicals, heteroaryls, etc. In some embodiments, alkyl is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, alkyl is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with halo.

"Alkenyl" means an optionally substituted straight chain, or optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, More preferred are two to about six carbon atoms, wherein the sp ^hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans configuration about one or more double bonds and it is understood that both isomers are included. Examples include, but are not limited to: ethenyl (-CH= _CH2 ), 1-propenyl ( _-CH2CH = _CH2 ), isopropenyl [-C( _CH3 )= _CH2 ], butenyl, 1 , 3-butadienyl, etc. Whenever it appears herein, a numerical range such as "C ₂ -C ₆ alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also covers occurrences of the term "alkenyl" where no numerical range is specified. In some embodiments, alkenyl is C ₂ -C ₁₀ alkenyl, C ₂ -C ₉ alkenyl, C ₂ -C ₈ alkenyl, C ₂ -C ₇ alkenyl, C ₂ -C ₆ alkenyl, C ₂ -C ₅ alkenyl, C ₂ -C ₄ alkenyl, C ₂ -C ₃ alkenyl, or C ₂ alkenyl. Unless specifically stated otherwise in this specification, an alkenyl group is optionally replaced by, for example, oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkane Substituted by radicals, heteroaryls, etc. In some embodiments, alkenyl is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, alkenyl is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halo.

"Alkynyl" means an optionally substituted straight chain or optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from two to about ten carbon atoms, more Preferably from two to about six carbon atoms. Examples include, but are not limited to: ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as "C ₂ -C ₆ alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. carbon atoms, but this definition also covers occurrences of the term "alkynyl" where no numerical range is specified. In some embodiments, the alkynyl is C ₂ -C ₁₀ alkynyl, C ₂ -C ₉ alkynyl, C ₂ -C ₈ alkynyl, C ₂ -C ₇ alkynyl, C ₂ -C ₆ alkynyl, C ₂ -C ₅ alkynyl, C ₂ -C ₄ alkynyl, C ₂ -C ₃ alkynyl, or C ₂ alkynyl. Unless specifically stated otherwise in this specification, an alkynyl group is optionally replaced by, for example, oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkane Substituted by radicals, heteroaryls, etc. In some embodiments, the alkynyl group is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, the alkynyl group is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with halo.

"Alkylene" means a straight or branched divalent hydrocarbon chain. Unless specifically stated otherwise in this specification, an alkylene group may optionally be replaced by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, hetero Substituted by cycloalkyl, heteroaryl, etc. In some embodiments, the alkylene group is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, the alkylene group is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halo.

"Alkoxy" means a radical of the formula _-ORa , where _Ra is an alkyl radical as defined. Unless specifically stated otherwise in this specification, an alkoxy group may optionally be replaced by, for example, oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, hetero Substituted by cycloalkyl, heteroaryl, etc. In some embodiments, alkoxy is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, alkoxy is optionally substituted with oxo, halo, -CN, _-CF3 , -OH, or -OMe. In some embodiments, alkoxy is optionally substituted with halo.

"Aminoalkyl" means an alkyl radical as defined above, substituted with one or more amines. In some embodiments, an alkyl group is substituted with an amine. In some embodiments, the alkyl group is substituted with one, two or three amines. Hydroxyalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, hydroxyalkyl is aminomethyl.

荧蒽、芴、不对称引达省、对称引达省、二氢化茚、茚、萘、非那烯、菲、七曜烯、芘、和苯并[9,10]菲的烃环系统的芳基自由基。在一些实施例中，芳基是苯基。除非在本说明书中另有特别说明，芳基可任选地被例如卤素、氨基、腈、硝基、羟基、烷基、烯基、炔基、卤代烷基、烷氧基、芳基、环烷基、杂环烷基、杂芳基等取代。在一些实施例中，芳基任选地被卤素、甲基、乙基、-CN、-CF₃、-OH、-OMe、-NH₂、或-NO₂取代。在一些实施例中，芳基任选地被卤素、甲基、乙基、-CN、-CF₃、-OH、或-OMe取代。在一些实施例中，芳基任选地被卤素取代。"Aryl" means a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. An aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fusion (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group passes through an aromatic ring atom Bonded) or bridged ring systems. In some embodiments, the aryl group is a 6-10 membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group. Aryl radicals include, but are not limited to: those derived from anthracenylene, naphthylene, phenanthrenylene, anthracene, azulene, benzene,

The hydrocarbon ring systems of fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenanthene, phenanthrene, heptadene, pyrene, and benzo[9,10]phenanthrene free radicals. In some embodiments, aryl is phenyl. Unless otherwise specifically stated in this specification, aryl can optionally be replaced by, for example, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkane Substituted by radical, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted with halo, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, aryl is optionally substituted with halo, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, aryl is optionally substituted with halo.

"Cycloalkyl" means a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl through a non- Aromatic ring atoms are bonded), bridged, or spiro ring systems. Representative cycloalkyl groups include, but are not limited to: cycloalkyl groups having three to fifteen carbon atoms (C ₃ -C ₁₅ cycloalkyl), cycloalkyl groups having three to ten carbon atoms (C ₃ -C ₁₀ cycloalkyl), cycloalkyl of three to eight carbon atoms (C ₃ -C ₈ cycloalkyl), cycloalkyl of three to six carbon atoms (C ₃ -C ₆ cycloalkyl), three A cycloalkyl group with 5 to 5 carbon atoms (C ₃ -C ₅ cycloalkyl group), or a cycloalkyl group with 3 to 4 carbon atoms (C ₃ -C ₄ cycloalkyl group). In some embodiments, the cycloalkyl group is a 3-6 membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5-6 membered cycloalkyl group. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Multicyclic cycloalkyl or carbocycles include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin Hydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-Dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in this specification, cycloalkyl is optionally replaced by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl , cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, cycloalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halo.

"Deuterioalkyl" means an alkyl radical as defined above, substituted with one or more deuteriums. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two or three deuteriums. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuteriums. Deuterioalkyl groups include, for example, _CD3 , _CH2D , _{CHD2, CH2CD3 , CD2CD3 , CHDCD3 , CH2CH2D ,} or _{CH2CHD2 .} In some embodiments, deuterioalkyl is CD ₃ .

"Haloalkyl" means an alkyl radical as defined above, which is substituted with one or more halogens. In some embodiments, the alkyl group is substituted with one, two or three halo. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six halo. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoro Propyl, 1,2-dibromoethyl, etc. In some embodiments, haloalkyl is trifluoromethyl.

"Halo" or "halogen" means bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

"Heteroalkyl" means an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-) , sulfur, or combinations thereof. A heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one aspect, a heteroalkyl group is a C ₁ -C ₆ heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g. oxygen, nitrogen (e.g. -NH- , -N(alkyl)-), sulfur, or combinations thereof), wherein the heteroalkyl group is attached to the remainder of the molecule at the heteroalkyl carbon atom. _{Examples of such} heteroalkyl groups _{are eg -CH2OCH3 , -CH2CH2OCH3} , _{-CH2CH2OCH2CH2OCH3} , or _-CH ( _CH3 ) _OCH3 . Unless specifically stated otherwise in this specification, heteroalkyl is optionally replaced by, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl , cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, heteroalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halo.

"Hydroxyalkyl" means an alkyl radical as defined above, substituted with one or more hydroxy groups. In some embodiments, an alkyl group is substituted with a hydroxy group. In some embodiments, the alkyl group is substituted with one, two or three hydroxyl groups. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, hydroxyalkyl is hydroxymethyl.

"Heterocycloalkyl" means a stable 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and from 1 to 8 heteroatoms (selected from nitrogen, oxygen, phosphorus, and group consisting of sulfur). Unless specifically stated otherwise in this specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring , the heterocycloalkyl radical is bonded through a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atom in the heterocycloalkyl radical can optionally be oxidized; the nitrogen atom can optionally to be quaternized.

Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having two to fifteen carbon atoms (C ₂ -C ₁₅ heterocycloalkyl groups), heterocycloalkyl groups having two to ten carbon atoms ( C ₂ -C ₁₀ heterocycloalkyl), heterocycloalkyl with two to eight carbon atoms (C ₂ -C ₈ heterocycloalkyl), heterocycloalkyl with two to six carbon atoms (C ₂ -C ₆ heterocycloalkyl), heterocycloalkyl with two to five carbon atoms (C ₂ -C ₅ heterocycloalkyl) or heterocycloalkyl with two to four carbon atoms (C ₂ -C ₄ heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. In some embodiments, the cycloalkyl group is a 5-6 membered heterocycloalkyl group. Examples of such heterocycloalkyl radicals include, but are not limited to: aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinoline Base, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxo Piperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, Tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-Dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxy heterocyclopentenyl-4-yl, and 2-oxo-1,3-dioxolyl-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is the same as that of the atoms (including heteroatoms) that make up the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). ) totals are different. Unless otherwise specifically stated in this specification, heterocycloalkyl is optionally replaced by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl Substituted by radical, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, heterocycloalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halo.

基)、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并间二氧杂环戊烯基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、苯并[b][1,4]二氧杂

基、1,4-苯并二噁烷基、苯并萘并呋喃基、苯并噁唑基、苯并间二氧杂环戊烯基、苯并二噁英基、苯并吡喃基、苯并吡喃基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(苯并苯硫基)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、二苯并硫苯基、呋喃基、呋喃酮基、异噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、异吲哚基、二氢吲哚基、异吲哚啉基、异喹啉基、吲哚嗪基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂环庚三烯基(氮杂

基)、噁唑基、环氧乙烷基、1-氧化吡啶基、1-氧化嘧啶基、1-氧化吡嗪基、1-氧化哒嗪基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、奎宁环基、异喹啉基、四氢喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基、和苯硫基(即噻吩基)。除非在本说明书中另有特别说明，杂芳基任选地被例如卤素、氨基、腈、硝基、羟基、烷基、烯基、炔基、卤代烷基、烷氧基、芳基、环烷基、杂环烷基、杂芳基等取代。在一些实施例中，杂芳基任选地被卤素、甲基、乙基、-CN、-CF₃、-OH、-OMe、-NH₂、或-NO₂取代。在一些实施例中，杂芳基任选地被卤素、甲基、乙基、-CN、-CF₃、-OH、或-OMe取代。在一些实施例中，杂芳基任选地被卤素取代。"Heteroaryl" means a 5- to 14-membered ring system radical containing hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms (selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur) ) and at least one aromatic ring. Heteroaryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fusion (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is ring atom bonded) or a bridged ring system; and the nitrogen, carbon, or sulfur atom in the heteroaryl radical can optionally be oxidized; the nitrogen atom can optionally be quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. Examples include, but are not limited to: azepanyl (azepine

base), acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuryl, benzoxazolyl, benzothiazolyl, Benzothiadiazolyl, Benzo[b][1,4]dioxa

1,4-benzodioxanyl, benzonaphthofuryl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzo Pyranyl, benzofuryl, benzofuranone, benzothienyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a] Pyridyl, carbazolyl, cinnolinyl, dibenzofuryl, dibenzothiophenyl, furyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, Isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indorazinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepanyl Alkenyl (aza

base), oxazolyl, oxiranyl, 1-oxypyridyl, 1-oxypyrimidinyl, 1-oxypyrazinyl, 1-oxypyridazinyl, 1-phenyl-1H-pyrrolyl, phen Azinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, Quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolyl, tetrahydroquinolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl ( ie thienyl). Unless specifically stated otherwise in this specification, heteroaryl is optionally replaced by, for example, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkane Substituted by radical, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halo, methyl, ethyl, -CN, _-CF3 , -OH, -OMe, _-NH2 , or _-NO2 . In some embodiments, heteroaryl is optionally substituted with halo, methyl, ethyl, -CN, _-CF3 , -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halo.

As used herein, the terms "treat", "prevent", "improvement" and "inhibit" and words derived therefrom do not necessarily imply 100% or complete treatment, prevention, amelioration or inhibition. Rather, there are varying degrees of treatment, prophylaxis, amelioration, and inhibition that are recognized by those of ordinary skill in the art as having potential benefits or therapeutic effects. In this regard, the disclosed methods may provide any amount and level of treatment, prevention, amelioration or inhibition of the disorder in the mammal. For example, the disorder (including symptoms or conditions thereof) can be reduced, for example, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or About 10%. Furthermore, treating, preventing, ameliorating or inhibiting provided by the methods disclosed herein can include treating, preventing, ameliorating or inhibiting one or more conditions or symptoms of a disorder (eg, cancer or inflammatory disease). Furthermore, for the purposes herein, "treating", "preventing", "improving" or "inhibiting" encompasses delaying the onset of a disorder or a symptom or condition thereof.

The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of a compound disclosed herein administered which will alleviate to some extent the disease or condition being treated (e.g., cancer or inflammatory disease ) of one or more symptoms. In some embodiments, the result is reduction and/or alleviation of a sign, symptom, or cause of a disease or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is that amount of a composition comprising a compound disclosed herein required to produce a clinically significant reduction in disease symptoms. In some embodiments, an appropriate "effective" amount is determined in any individual case using techniques such as dose escalation studies.

compound

Disclosed herein are compounds having formula (I), or pharmaceutically acceptable salts, solvates or stereoisomers thereof:

in:

Ring A is cycloalkyl or heterocycloalkyl;

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

n is 0-6;

R ³ is halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ^5. -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P( =O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)( =NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O) (=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R;

Each R ^3b is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C( ⁼ O)Ra, -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹² and R ¹³ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹² and R ¹³ together form cycloalkyl or heterocycloalkyl; each of which is substituted by 0-6 R ¹⁴ ;

Each R ¹⁴ is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C(=O) ^Ra , -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

In some embodiments of compounds of formula (I), R ¹ is -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (I), R ¹ is —CN or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (I), R ¹ is C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (I), R ¹ is -CN.

In some embodiments of compounds of formula (I), R ⁸ is hydrogen or deuterium. In some embodiments of compounds of formula (I), R ⁸ is hydrogen.

In some embodiments of compounds of formula (I), R ⁹ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (I), R ⁹ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (I), R ¹⁰ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (I), R ¹⁰ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (I), R ⁹ is C ₁ -C ₆ alkyl and R ¹⁰ is C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (I), R ¹⁰ is C ₁ -C ₆ alkyl and R ⁹ is C ₂ -C ₆ alkynyl.

是

在具有式(I)的化合物的一些实施例中，

是

In some embodiments of compounds of formula (I),

yes

In some embodiments of compounds of formula (I),

yes

In some embodiments of compounds of formula (I), R ¹¹ is hydrogen, halogen, or -OH. In some embodiments of compounds of formula (I), R ¹¹ is hydrogen or -OH. In some embodiments of compounds of formula (I), R ¹¹ is hydrogen.

In some embodiments of compounds of formula (I), R ¹² and R ¹³ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (I), R ¹² and R ¹³ are independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (I), R ¹² and R ¹³ are independently hydrogen or C ₁ -C ₆ deuteroalkyl. In some embodiments of compounds of formula (I), R ¹² and R ¹³ are independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (I), R ¹² and R ¹³ together form cycloalkyl. In some embodiments of compounds of formula (I), R ¹² and R ¹³ together form cycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (I), R ¹² and R ¹³ together form cycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (I), R ¹² and R ¹³ together form cycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (I), R ¹² and R ¹³ are taken together to form heterocycloalkyl. In some embodiments of compounds of formula (I), R ¹² and R ¹³ are taken together to form a heterocycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (I), R ¹² and R ¹³ are taken together to form a heterocycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (I), R ¹² and R ¹³ together form a heterocycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds having Formula (I), R ³ is halogen, -CN, -OR ⁵ , -NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(= O)OR ⁵ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O) R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ hetero Alkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted by one, two or three R ^3a . In some embodiments of compounds of formula (I), R ³ is -NR ⁵ C(=NR ^x )R ⁵ or -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ . In some embodiments of compounds having Formula (I), R ³ is -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds of formula (I), R ³ is C ₁ -C ₆ alkyl optionally substituted with one, two or three R ^3a . In some embodiments of compounds of formula (I), R ³ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of Formula (I), R ³ is -C(=O)OR ⁵ .

In some embodiments of compounds having Formula (I), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(= NR ^x ) NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C (=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , cycloalkyl, or heterocycloalkyl.

In some embodiments of compounds having Formula (I), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(= NR ^x ) NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C (=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formula (I), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -B(OR ⁵ ) ₂ , -S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ heteroalkyl, heterocycloalkyl, or heteroaryl base. In some embodiments of compounds of Formula (I), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C (=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x ) R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formula (I), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR 5 , -OC(=O)OR ⁵ , or -OC(=O)OR ⁵ , or - C(=O)NR ⁶ R ⁷ . In some embodiments of compounds of formula (I), each R ^3a is independently -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , or -B(OR ⁵ ) ₂ . In some embodiments of compounds having Formula (I), each R ^3a is independently -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S( =O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds having Formula (I), each R ^3b is independently deuterium, halogen, -CN, -OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (I), each R ^3b is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl .

In some embodiments of compounds of formula (I), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally replaced by one, Two or three R ^4a substitutions. In some embodiments of compounds having formula (I), each R ⁴ is independently C ₁ -C ₆ alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by one, two One or three R ^4a substitutions. In some embodiments of compounds of formula (I), each R ⁴ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^4a . In some embodiments of compounds of formula (I), each R ⁴ is independently C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (I), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds having Formula (I), each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I), each R ^4a is independently deuterium or halogen. In some embodiments of compounds of formula (I), each R ^4a is independently halogen.

In ^some embodiments of compounds having Formula (I), each R is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, cycloalkane A group, or a heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^5a . In some embodiments of compounds of formula (I), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by One, two or three R ^5a substitutions. In some embodiments of compounds of formula (I), each R ⁵ is independently hydrogen or C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of formula (I), each R ⁵ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of formula (I), each R ⁵ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formula (I), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds of formula (I), two R ⁵ are taken together to form optionally substituted heterocycloalkyl.

In some embodiments of compounds having Formula (I), each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I), each R ^5a is independently deuterium or halogen. In some embodiments of compounds of formula (I), each R ^5a is independently halogen. In some embodiments of compounds of Formula (I), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formula (I), each R ^5a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x )NR ^c R ^d .

In some embodiments of compounds of formula (I), _{each R and R is independently hydrogen, C 1 -C 6} ^alkyl _, ^C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl , cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds of formula (I), _each R and R is independently hydrogen, _{C 1} ^{-C 6} alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkane wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds having formula (I), each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; wherein the alkyl is independently any is optionally substituted by one, two or three R ^6a . In some embodiments of compounds of formula (I), each R ⁶ and R ⁷ is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having formula (I), each R and ^R is independently hydrogen, _{C 1} ^-C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterane base.

In some embodiments of compounds having Formula (I), each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I), each R ^6a is independently deuterium or halogen. In some embodiments of compounds of formula (I), each R ^6a is independently halogen. In some embodiments of compounds of Formula (I), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formula (I), each R ^6a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x )NR ^c R ^d .

In some embodiments of compounds of formula (I), R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with one, two or three R ^6b .

In some embodiments of compounds having Formula (I), each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I), each R ^6b is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (I), each R ^6b is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (I), R ^x is hydrogen, -NO ₂ , or -CN. In some embodiments of compounds of formula (I), R ^x is -NO ₂ or -CN. In some embodiments of compounds of formula (I), ^Rx is -CN.

In some embodiments of compounds of Formula (I), Ring A is cycloalkyl. In some embodiments of compounds of Formula (I), Ring A is heterocycloalkyl.

In some embodiments of compounds having Formula (I), each R ² is independently deuterium, halogen, -CN, -OR ^b , C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (I), each R ² is deuterium.

In some embodiments of compounds of formula (I), n is 0. In some embodiments of compounds of formula (I), n is 1. In some embodiments of compounds of formula (I), n is 2. In some embodiments of compounds of formula (I), n is 3. In some embodiments of compounds of formula (I), n is 4. In some embodiments of compounds of formula (I), n is 5. In some embodiments of compounds of formula (I), n is 6. In some embodiments of compounds of formula (I), n is 1-4. In some embodiments of compounds of formula (I), n is 1 or 2. In some embodiments of compounds of formula (I), n is 2-4.

Disclosed herein is a compound having formula (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

in:

Ring B is cycloalkyl or heterocycloalkyl;

Each R ¹⁴ is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C(=O) ^Ra , -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

m is 0-6;

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ³ is halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ^5. -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P( =O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)( =NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O) (=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R;

Each R ^3b is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C( ⁼ O)Ra, -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ;

Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

In some embodiments of compounds of formula (II), R ¹ is -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (II), R ¹ is —CN or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (II), R ¹ is C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (II), R ¹ is -CN.

In some embodiments of compounds of formula (II), R ⁸ is hydrogen or deuterium. In some embodiments of compounds of formula (II), R ⁸ is hydrogen.

In some embodiments of compounds of formula (II), R ⁹ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (II), R ⁹ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (II), R ¹⁰ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (II), R ¹⁰ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (II), R ⁹ is C ₁ -C ₆ alkyl and R ¹⁰ is C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (II), R ¹⁰ is C ₁ -C ₆ alkyl and R ⁹ is C ₂ -C ₆ alkynyl.

是

在具有式(II)的化合物的一些实施例中，

是

In some embodiments of compounds of formula (II),

yes

In some embodiments of compounds of formula (II),

yes

In some embodiments of compounds of formula (II), R ¹¹ is hydrogen, halogen, or -OH. In some embodiments of compounds of formula (II), R ¹¹ is hydrogen or -OH. In some embodiments of compounds of formula (II), R ¹¹ is hydrogen.

In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ are independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ are independently hydrogen or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ are independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ together form cycloalkyl. In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ are taken together to form heterocycloalkyl. In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (II), R ¹⁵ and R ¹⁶ together form a heterocycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds having Formula (II), R ³ is halogen, -CN, -OR ⁵ , -NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(= O)OR ⁵ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O) R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ hetero Alkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted by one, two or three R ^3a . In some embodiments of compounds of formula (II), R ³ is -NR ⁵ C(=NR ^x )R ⁵ or -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ . In some embodiments of compounds having Formula (II), R ³ is -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds of formula (II), R ³ is C ₁ -C ₆ alkyl optionally substituted with one, two or three R ^3a . In some embodiments of compounds of formula (II), R ³ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (II), R ³ is -C(=O)OR ⁵ .

In some embodiments of compounds having Formula (II), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(= NR ^x ) NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C (=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , cycloalkyl, or heterocycloalkyl.

In some embodiments of compounds having Formula (II), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(= NR ^x ) NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C (=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formula (II), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -B(OR ⁵ ) ₂ , -S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ heteroalkyl, heterocycloalkyl, or heteroaryl base. In some embodiments of compounds having Formula (II), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C (=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x ) R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formula (II), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR 5 , -OC(=O)OR ⁵ , or -OC(=O)OR ⁵ , or - C(=O)NR ⁶ R ⁷ . In some embodiments of compounds having Formula (II), each R ^3a is independently -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , or -B(OR ⁵ ) ₂ . In some embodiments of compounds having Formula (II), each R ^3a is independently -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S( =O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds having formula (II), each R ^3b is independently deuterium, halogen, -CN, -OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds having Formula (II), each R ^3b is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl .

In some embodiments of compounds having formula (II), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally replaced by one, Two or three R ^4a substitutions. In some embodiments of compounds having formula (II), each R ⁴ is independently C ₁ -C ₆ alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by one, two One or three R ^4a substitutions. In some embodiments of compounds of formula (II), each R ⁴ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^4a . In some embodiments of compounds of formula (II), each R ⁴ is independently C ₁ -C ₆ alkyl. In some embodiments of compounds having Formula (II), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds having Formula (II), each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II), each R ^4a is independently deuterium or halogen. In some embodiments of compounds of formula (II), each R ^4a is independently halogen.

In ^some embodiments of compounds having Formula (II), each R is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, cycloalkane A group, or a heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^5a . In some embodiments of compounds having formula (II), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by One, two or three R ^5a substitutions. In some embodiments of compounds of formula (II), each R ⁵ is independently hydrogen or C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds having formula (II), each R ⁵ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of formula (II), each R ⁵ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formula (II), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds of formula (II), two R ⁵ are taken together to form optionally substituted heterocycloalkyl.

In some embodiments of compounds having Formula (II), each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II), each R ^5a is independently deuterium or halogen. In some embodiments of compounds of formula (II), each R ^5a is independently halogen. In some embodiments of compounds having Formula (II), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formula (II), each R ^5a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x )NR ^c R ^d .

In some embodiments of compounds having Formula (II), each R and R _{is independently hydrogen, C 1 -C 6} ^alkyl _, ^C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl , cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds of formula (II), _each R and R is independently hydrogen, _{C 1} ^{-C 6} alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkane wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds having formula (II), each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; wherein the alkyl is independently any is optionally substituted by one, two or three R ^6a . In some embodiments of compounds of formula (II), each R ⁶ and R ⁷ is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having formula (II), each R and ^R is independently hydrogen, _{C 1} ^-C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterane base.

In some embodiments of compounds having Formula (II), each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II), each R ^6a is independently deuterium or halogen. In some embodiments of compounds of formula (II), each R ^6a is independently halogen. In some embodiments of compounds having Formula (II), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formula (II), each R ^6a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x )NR ^c R ^d .

In some embodiments of compounds having formula (II), R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with one, two or three R ^6b .

In some embodiments of compounds having Formula (II), each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (II), each R ^6b is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (II), each R ^6b is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (II), R ^x is hydrogen, -NO ₂ , or -CN. In some embodiments of compounds of formula (II), R ^x is -NO ₂ or -CN. In some embodiments of compounds of formula (II), ^Rx is -CN.

In some embodiments of compounds having Formula (II), Ring B is cycloalkyl. In some embodiments of compounds having Formula (II), Ring B is heterocycloalkyl.

In some embodiments of compounds of formula (II), each R ¹⁴ is independently deuterium, halogen, -CN, -OR ^b , C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (II), each R ¹⁴ is deuterium.

In some embodiments of compounds of formula (II), m is 0. In some embodiments of compounds of formula (II), m is 1. In some embodiments of compounds of formula (II), m is 2. In some embodiments of compounds having Formula (II), m is 3. In some embodiments of compounds having Formula (II), m is 4. In some embodiments of compounds of formula (II), m is 5. In some embodiments of compounds having Formula (II), m is 6. In some embodiments of compounds of formula (II), m is 1-4. In some embodiments of compounds of formula (II), m is 1 or 2. In some embodiments of compounds of formula (II), m is 2-4.

Disclosed herein is a compound having formula (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

in:

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ³ is N-linked heterocycloalkyl, N-linked heteroaryl, -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O )(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(= O)(=NR ^x )R ⁵ , -ZO-cycloalkyl, -ZO-heterocycloalkyl, -ZO-aryl, -ZO-heteroaryl, -Z-NR ⁵ -cycloalkyl, -Z -NR ⁵ -heterocycloalkyl, -Z-NR ⁵ -aryl, -Z-NR ⁵ -heteroaryl, -Y(C ₁ -C ₆ alkylene)S(=O)R ⁴ , -Y (C ₁ -C ₆ alkylene)S(=O) ₂ R ⁴ , -Y(C ₁ -C ₆ alkylene)P(=O)(R ⁴ ) ₂ , -Y(C ₁ -C ₆ Alkylene)P(=O)(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)B(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C( =NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)S(=O)( =NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S( =O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ C(=O)(C ₁ -C ₆ alkylene)S(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ C(=O )(C ₁ -C ₆ alkylene)S(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y( C ₂ -C ₆ alkenylene)S(=O) ₂ R ⁴ , -Y(C ₂ -C ₆ alkenylene)P(=O)(R ⁴ ) ₂ , -Y(C ₂ -C ₆ alkenylene) alkenyl)P(=O)(OR ⁵ ) ₂ , -Y(C ₂ -C ₆ alkenylene)B(OR ⁵ ) ₂ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ C(= NR ^x )R ⁵ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₂ -C ₆ alkenylene)S(=O)(= NR ^x )R ⁵ , -Y(C ₂ -C ₆ alkenylene )S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y(C ₂ -C ₆ alkenylene)cycloalkyl, -Y(C ₂ -C ₆ alkenylene ) heterocycloalkyl, -Y(C ₂ -C ₆ alkenylene) aryl, -Y(C ₂ -C ₆ alkenylene) heteroaryl, -(C ₁ -C ₆ alkylene) OP( =O)(OR ⁵ ) ₂ , -(C ₁ -C ₆ alkylene)O(C ₁ -C ₆ alkylene)OP(=O)(OR ⁵ ) ₂ , or -(C ₁ -C ₆ Alkylene) OP(=O)(OR ⁵ )[N(R ⁵ ) ₂ ]; wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

Y is a bond, -O-, -S-, or -NR ^b -;

Z is a bond or C ₁ -C ₆ alkylene;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹² and R ¹³ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹² and R ¹³ together form cycloalkyl or heterocycloalkyl; each of which is substituted by 0-6 R ¹⁴ ;

Each R ¹⁴ is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C(=O) ^Ra , -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ;

Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

In some embodiments of compounds of formula (III), R ¹ is -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (III), R ¹ is —CN or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (III), R ¹ is C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (III), R ¹ is -CN.

In some embodiments of compounds of formula (III), R ⁸ is hydrogen or deuterium. In some embodiments of compounds of formula (III), R ⁸ is hydrogen.

In some embodiments of compounds of formula (III), R ⁹ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (III), R ⁹ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (III), R ¹⁰ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (III), R ¹⁰ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (III), R ⁹ is C ₁ -C ₆ alkyl and R ¹⁰ is C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (III), R ¹⁰ is C ₁ -C ₆ alkyl and R ⁹ is C ₂ -C ₆ alkynyl.

是

在具有式(III)的化合物的一些实施例中，

是

In some embodiments of compounds of formula (III),

yes

In some embodiments of compounds of formula (III),

yes

In some embodiments of compounds of formula (III), R ¹¹ is hydrogen, halogen, or -OH. In some embodiments of compounds of formula (III), R ¹¹ is hydrogen or -OH. In some embodiments of compounds of formula (III), R ¹¹ is hydrogen.

In some embodiments of compounds of formula (III), R ¹² and R ¹³ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (III), R ¹² and R ¹³ are independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (III), R ¹² and R ¹³ are independently hydrogen or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (III), R ¹² and R ¹³ are independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (III), R ¹² and R ¹³ together form cycloalkyl. In some embodiments of compounds of formula (III), R ¹² and R ¹³ together form cycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (III), R ¹² and R ¹³ together form cycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (III), R ¹² and R ¹³ together form cycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (III), R ¹² and R ¹³ are taken together to form heterocycloalkyl. In some embodiments of compounds of formula (III), R ¹² and R ¹³ are taken together to form a heterocycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (III), R ¹² and R ¹³ are taken together to form a heterocycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (III), R ¹² and R ¹³ together form a heterocycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ are independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ are independently hydrogen or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ are independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ together form cycloalkyl. In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ are taken together to form heterocycloalkyl. In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (III), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (III), R ³ is -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ Alkyl)P(=O)(R ⁴ ) ₂ , -Y(C ₁ -C ₆ alkylene)P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene) B(OR ⁵ ) ₂ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -Y(C ₁ -C ₆ alkylene)S(=O) R ⁴ , -Y(C ₁ -C ₆ alkylene)S(=O) ₂ R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S (=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene) S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O)(=NR ^x )R ⁵ , N-linked heterocycloalkyl, or N-linked heteroaryl. In some embodiments of compounds of formula (III), R ³ is -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ Alkyl)P(=O)(R ⁴ ) ₂ , or -Y(C ₁ -C ₆ alkylene)P(=O)(OR ⁵ ) ₂ . In some embodiments of compounds of formula (III), R ³ is -B(OR ⁵ ) ₂ or -Y(C ₁ -C ₆ alkylene)B(OR ⁵ ) ₂ . In some embodiments of compounds having formula (III), R ³ is -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -Y(C ₁ -C ₆ alkylene)S( =O)R ⁴ , or -Y(C ₁ -C ₆ alkylene)S(=O) ₂ R ⁴ . In some embodiments of compounds of formula (III), R ³ is -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )R ⁵ , or -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ . In some embodiments of compounds of formula (III), R ³ is -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)( =NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S( =O) ₂ NR ⁵ C(=O)R ⁵ , or -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formula (III), R ³ is N-attached heterocycloalkyl or N-attached heteroaryl.

In some embodiments of compounds of formula (III), R ³ is -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ Alkyl)P(=O)(R ⁴ ) ₂ , -Y(C ₁ -C ₆ alkylene)P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene) B(OR ⁵ ) ₂ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -Y(C ₁ -C ₆ alkylene)S(=O) R ⁴ , -Y(C ₁ -C ₆ alkylene)S(=O) ₂ R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ C(=O)(C ₁ -C ₆ alkylene)S(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ C(=O)(C ₁ -C ₆ alkylene)S(=NR ^x )R ⁵ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O) R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )R ⁵ , -Y(C ₁ - C ₆ alkylene)S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O)(=NR ^x )R ⁵ , N-linked heterocycloalkyl, or N-linked heteroaryl.

In some embodiments of compounds having formula (III), R ³ is -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )R ⁵ or -Y(C ₁ -C ₆ alkylene group) NR ⁵ C(=NR ^x )NR ⁶ R ⁷ .

In some embodiments of compounds of formula (III), -Y is a bond. In some embodiments of compounds of formula (III), Y is a bond or -O-.

In some embodiments of compounds having formula (III), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally replaced by one, Two or three R ^4a substitutions. In some embodiments of compounds having formula (III), each R ⁴ is independently C ₁ -C ₆ alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by one, two One or three R ^4a substitutions. In some embodiments of compounds of formula (III), each R ⁴ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^4a . In some embodiments of compounds of formula (III), each R ⁴ is independently C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (III), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds having Formula (III), each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (III), each R ^4a is independently deuterium or halogen. In some embodiments of compounds of formula (III), each R ^4a is independently halogen.

In ^some embodiments of compounds having Formula (III), each R is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, cycloalkane A group, or a heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^5a . In some embodiments of compounds having formula (III), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by One, two or three R ^5a substitutions. In some embodiments of compounds of formula (III), each R ⁵ is independently hydrogen or C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of formula (III), each R ⁵ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of formula (III), each R ⁵ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (III), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds of formula (III), two R ⁵ are taken together to form optionally substituted heterocycloalkyl.

In some embodiments of compounds having Formula (III), each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^{c Rd} , or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (III), each R ^5a is independently halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)OR ^b , or C ₁ -C ₆ alkyl.

In some embodiments of compounds having Formula (III), each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (III), each R ^5a is independently deuterium or halogen. In some embodiments of compounds of formula (III), each R ^5a is independently halogen.

In some embodiments of compounds having formula (III), _{each R and R is independently hydrogen, C 1 -C 6} ^alkyl _, ^C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl , cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of _compounds having formula (III), each R and R is independently hydrogen, _{C 1} ^{-C 6} alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkane wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds having formula (III), each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; wherein the alkyl is independently any is optionally substituted by one, two or three R ^6a . In some embodiments of compounds of formula (III), each R ⁶ and R ⁷ is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having formula (III), each R and ^R is independently hydrogen, _{C 1} ^-C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterane base.

In some embodiments of compounds having Formula (III), each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (III), each R ^6a is independently deuterium or halogen. In some embodiments of compounds of formula (III), each R ^6a is independently halogen. In some embodiments of compounds of formula (III), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formula (III), each R ^6a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x )NR ^c R ^d .

In some embodiments of compounds of formula (III), R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with one, two or three R ^6b .

In some embodiments of compounds having Formula (III), each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (III), each R ^6b is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (III), each R ^6b is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (III), R ^x is hydrogen, -NO ₂ , or -CN. In some embodiments of compounds of formula (III), R ^x is -NO ₂ or -CN. In some embodiments of compounds of formula (III), ^Rx is -CN.

In some embodiments of compounds of formula (III), R ^is

In some embodiments of compounds of formula (III), R ^is

Disclosed herein is a compound having formula (IV), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

in:

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ³ is halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ^5. -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P( =O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)( =NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O) (=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R;

Each R ^3b is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C ⁽ =O)Ra, -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

with the proviso that one of R ⁹ or R ¹⁰ is C ₂ -C ₆ alkynyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹² and R ¹³ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹² and R ¹³ together form cycloalkyl or heterocycloalkyl; each of which is substituted by 0-6 R ¹⁴ ;

Each R ¹⁴ is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C(=O) ^Ra , -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane group, C ₁ -C ₆ deuterated alkyl group, or C ₁ -C ₆ hydroxyalkyl group;

or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ;

Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

In some embodiments of compounds of formula (IV), R ¹ is -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (IV), R ¹ is —CN or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (IV), R ¹ is C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (IV), R ¹ is -CN.

In some embodiments of compounds of formula (IV), R ⁸ is hydrogen or deuterium. In some embodiments of compounds of formula (IV), R ⁸ is hydrogen.

In some embodiments of compounds of formula (IV), R ⁹ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (IV), R ⁹ is C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (IV), R ⁹ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (IV), R ¹⁰ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (IV), R ¹⁰ is C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (IV), R ¹⁰ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (IV), R ⁹ is C ₁ -C ₆ alkyl and R ¹⁰ is C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (IV), R ¹⁰ is C ₁ -C ₆ alkyl and R ⁹ is C ₂ -C ₆ alkynyl.

是

在具有式(IV)的化合物的一些实施例中，

是

In some embodiments of compounds of formula (IV),

yes

In some embodiments of compounds of formula (IV),

yes

In some embodiments of compounds of formula (IV), R ¹¹ is hydrogen, halogen, or -OH. In some embodiments of compounds of formula (IV), R ¹¹ is hydrogen or -OH. In some embodiments of compounds of formula (IV), R ¹¹ is hydrogen.

In some embodiments of compounds of formula (IV), R ¹² and R ¹³ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (IV), R ¹² and R ¹³ are independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (IV), R ¹² and R ¹³ are independently hydrogen or C ₁ -C ₆ deuteroalkyl. In some embodiments of compounds of formula (IV), R ¹² and R ¹³ are independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (IV), R ¹² and R ¹³ together form cycloalkyl. In some embodiments of compounds of formula (IV), R ¹² and R ¹³ together form cycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (IV), R ¹² and R ¹³ together form cycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (IV), R ¹² and R ¹³ together form cycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (IV), R ¹² and R ¹³ are taken together to form heterocycloalkyl. In some embodiments of compounds of formula (IV), R ¹² and R ¹³ are taken together to form a heterocycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (IV), R ¹² and R ¹³ are taken together to form a heterocycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (IV), R ¹² and R ¹³ together form a heterocycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ are independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ are independently hydrogen or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ are independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ together form cycloalkyl. In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ are taken together to form heterocycloalkyl. In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (IV), R ¹⁵ and R ¹⁶ together form a heterocycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds having Formula (IV), R ³ is halogen, -CN, -OR ⁵ , -NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(= O)OR ⁵ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O) R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ hetero Alkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted by one, two or three R ^3a . In some embodiments of compounds of formula (IV), R ³ is -NR ⁵ C(=NR ^x )R ⁵ or -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ . In some embodiments of compounds having Formula (IV), R ³ is -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds of formula (IV), R ³ is C ₁ -C ₆ alkyl optionally substituted with one, two or three R ^3a . In some embodiments of compounds of formula (IV), R ³ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (IV), R ³ is -C(=O)OR ⁵ .

In some embodiments of compounds having Formula (IV), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(= NR ^x ) NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C (=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , cycloalkyl, or heterocycloalkyl.

In some embodiments of compounds having Formula (IV), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(= NR ^x ) NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C (=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formula (IV), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -B(OR ⁵ ) ₂ , -S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ heteroalkyl, heterocycloalkyl, or heteroaryl base. In some embodiments of compounds having Formula (IV), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C (=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x ) R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formula (IV), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR 5 , -OC(=O)OR ⁵ , or -OC(=O)OR ⁵ , or - C(=O)NR ⁶ R ⁷ . In some embodiments of compounds having Formula (IV), each R ^3a is independently -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , or -B(OR ⁵ ) ₂ . In some embodiments of compounds having Formula (IV), each R ^3a is independently -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S( =O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds having Formula (IV), each R ^3b is independently deuterium, halogen, -CN, -OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds having Formula (IV), each R ^3b is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl .

In some embodiments of compounds having formula (IV), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally replaced by one, Two or three R ^4a substitutions. In some embodiments of compounds having formula (IV), each R ⁴ is independently C ₁ -C ₆ alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by one, two One or three R ^4a substitutions. In some embodiments of compounds of formula (IV), each R ⁴ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^4a . In some embodiments of compounds of formula (IV), each R ⁴ is independently C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (IV), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds having Formula (IV), each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (IV), each R ^4a is independently deuterium or halogen. In some embodiments of compounds of formula (IV), each R ^4a is independently halogen.

In ^some embodiments of compounds having Formula (IV), each R is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, cycloalkane A group, or a heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^5a . In some embodiments of compounds having formula (IV), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by One, two or three R ^5a substitutions. In some embodiments of compounds of formula (IV), each R ⁵ is independently hydrogen or C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of formula (IV), each R ⁵ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of formula (IV), each R ⁵ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formula (IV), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds of formula (IV), two R ⁵ are taken together to form optionally substituted heterocycloalkyl.

In some embodiments of compounds having Formula (IV), each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (IV), each R ^5a is independently deuterium or halogen. In some embodiments of compounds of formula (IV), each R ^5a is independently halogen. In some embodiments of compounds of formula (IV), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formula (IV), each R ^5a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x )NR ^c R ^d .

In some embodiments of compounds having formula (IV), each R and R _{is independently hydrogen, C 1 -C 6} ^alkyl _, ^C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl , cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds having formula (IV), _each R and R is independently hydrogen, _{C 1} ^{-C 6} alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkane wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds having formula (IV), each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; wherein the alkyl is independently any is optionally substituted by one, two or three R ^6a . In some embodiments of compounds of formula (IV), each R ⁶ and R ⁷ is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having formula (IV), each R and ^R is independently hydrogen, _{C 1} ^-C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterane base.

In some embodiments of compounds having Formula (IV), each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (IV), each R ^6a is independently deuterium or halogen. In some embodiments of compounds of formula (IV), each R ^6a is independently halogen. In some embodiments of compounds of formula (IV), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formula (IV), each R ^6a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x )NR ^c R ^d .

In some embodiments of compounds of formula (IV), R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with one, two or three R ^6b .

In some embodiments of compounds having Formula (IV), each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (IV), each R ^6b is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (IV), each R ^6b is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (IV), R ^x is hydrogen, -NO ₂ , or -CN. In some embodiments of compounds of formula (IV), R ^x is -NO ₂ or -CN. In some embodiments of compounds of formula (IV), ^Rx is -CN.

Disclosed herein is a compound having formula (V), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

in:

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ³ is halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ^5. -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P( =O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)( =NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O) (=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R;

Each R ^3b is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C( ⁼ O)Ra, -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹² and R ¹³ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹² and R ¹³ together form cycloalkyl or heterocycloalkyl; each of which is substituted by 0-6 R ¹⁴ ;

Each R ¹⁴ is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C(=O) ^Ra , -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

R ¹⁷ is hydrogen, -S(=O)R ^a , -S(=O) ₂ R ^a , -S(=O) ₂ NR ^c R ^d , -C(=O)R ^a , -C(=O) )OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

In some embodiments of compounds of formula (V), R ¹ is -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (V), R ¹ is —CN or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (V), R ¹ is C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (V), R ¹ is -CN.

In some embodiments of compounds of formula (V), R ⁸ is hydrogen or deuterium. In some embodiments of compounds of formula (V), R ⁸ is hydrogen.

In some embodiments of compounds of formula (V), R ⁹ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (V), R ⁹ is C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (V), R ⁹ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (V), R ¹⁰ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (V), R ¹⁰ is C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (V), R ¹⁰ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (V), R ⁹ is C ₁ -C ₆ alkyl and R ¹⁰ is C ₂ -C ₆ alkynyl. In some embodiments of compounds of formula (V), R ¹⁰ is C ₁ -C ₆ alkyl and R ⁹ is C ₂ -C ₆ alkynyl.

是

在具有式(V)的化合物的一些实施例中，

是

In some embodiments of compounds of formula (V),

yes

In some embodiments of compounds of formula (V),

yes

In some embodiments of compounds of formula (V), R ¹¹ is hydrogen, halogen, or -OH. In some embodiments of compounds of formula (V), R ¹¹ is hydrogen or -OH. In some embodiments of compounds of formula (V), R ¹¹ is hydrogen.

In some embodiments of compounds of formula (V), R ¹² and R ¹³ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (V), R ¹² and R ¹³ are independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (V), R ¹² and R ¹³ are independently hydrogen or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (V), R ¹² and R ¹³ are independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (V), R ¹² and R ¹³ together form cycloalkyl. In some embodiments of compounds of formula (V), R ¹² and R ¹³ together form cycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (V), R ¹² and R ¹³ together form cycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (V), R ¹² and R ¹³ together form cycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (V), R ¹² and R ¹³ are taken together to form heterocycloalkyl. In some embodiments of compounds of formula (V), R ¹² and R ¹³ are taken together to form a heterocycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of formula (V), R ¹² and R ¹³ are taken together to form a heterocycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of formula (V), R ¹² and R ¹³ together form a heterocycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds of formula (V), R ¹⁷ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (V), R ¹⁷ is C ₁ -C ₆ alkyl.

In some embodiments of compounds having Formula (V), R ³ is halogen, -CN, -OR ⁵ , -NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(= O)OR ⁵ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O) R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ hetero Alkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted by one, two or three R ^3a . In some embodiments of compounds of formula (V), R ³ is -NR ⁵ C(=NR ^x )R ⁵ or -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ . In some embodiments of compounds having Formula (V), R ³ is -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds of formula (V), R ³ is C ₁ -C ₆ alkyl optionally substituted with one, two or three R ^3a . In some embodiments of compounds of formula (V), R ³ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (V), R ³ is -C(=O)OR ⁵ .

In some embodiments of compounds having Formula (V), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(= NR ^x ) NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C (=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , cycloalkyl, or heterocycloalkyl.

In some embodiments of compounds having Formula (V), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(= NR ^x ) NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C (=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formula (V), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -B(OR ⁵ ) ₂ , -S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ heteroalkyl, heterocycloalkyl, or heteroaryl base. In some embodiments of compounds having Formula (V), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C (=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x ) R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formula (V), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR 5 , -OC(=O)OR ⁵ , or -OC(=O)OR ⁵ , or - C(=O)NR ⁶ R ⁷ . In some embodiments of compounds having Formula (V), each R ^3a is independently -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , or -B(OR ⁵ ) ₂ . In some embodiments of compounds having Formula (V), each R ^3a is independently -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S( =O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds of formula (V), each R ^3b is independently deuterium, halogen, -CN, -OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds having Formula (V), each R ^3b is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl .

In some embodiments of compounds having formula (V), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally replaced by one, Two or three R ^4a substitutions. In some embodiments of compounds having formula (V), each R ⁴ is independently C ₁ -C ₆ alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by one, two One or three R ^4a substitutions. In some embodiments of compounds of formula (V), each R ⁴ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^4a . In some embodiments of compounds of formula (V), each R ⁴ is independently C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (V), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds having Formula (V), each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (V), each R ^4a is independently deuterium or halogen. In some embodiments of compounds of formula (V), each R ^4a is independently halogen.

In ^some embodiments of compounds having Formula (V), each R is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, cycloalkane A group, or a heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^5a . In some embodiments of compounds having formula (V), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally replaced by One, two or three R ^5a substitutions. In some embodiments of compounds of formula (V), each R ⁵ is independently hydrogen or C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of formula (V), each R ⁵ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of formula (V), each R ⁵ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (V), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds of formula (V), two R ⁵ are taken together to form optionally substituted heterocycloalkyl.

In some embodiments of compounds having Formula (V), each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (V), each R ^5a is independently deuterium or halogen. In some embodiments of compounds of formula (V), each R ^5a is independently halogen. In some embodiments of compounds of formula (V), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formula (V), each R ^5a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x )NR ^c R ^d .

In some embodiments of compounds having formula (V), _{each R and R is independently hydrogen, C 1 -C 6} ^alkyl _, ^C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl , cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of _compounds having formula (V), each R and R is independently hydrogen, _{C 1} ^{-C 6} alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkane wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds having formula (V), each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; wherein the alkyl is independently any is optionally substituted by one, two or three R ^6a . In some embodiments of compounds of formula (V), each R ⁶ and R ⁷ is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having formula (V), each R and ^R is independently hydrogen, _{C 1} ^-C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterane base.

In some embodiments of compounds of formula (V), each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (V), each R ^6a is independently deuterium or halogen. In some embodiments of compounds of formula (V), each R ^6a is independently halogen. In some embodiments of compounds of formula (V), each R ^6a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formula (V), each R ^6a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x )NR ^c R ^d .

In some embodiments of compounds of formula (V), R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with one, two or three R ^6b .

In some embodiments of compounds having Formula (V), each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (V), each R ^6b is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of formula (V), each R ^6b is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (V), R ^x is hydrogen, -NO ₂ , or -CN. In some embodiments of compounds of formula (V), R ^x is -NO ₂ or -CN. In some embodiments of compounds of formula (V), ^Rx is -CN.

Disclosed herein is a compound having formula (VI), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

in:

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ³ is halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ^5. -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P( =O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)( =NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O) (=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R;

Each R ^3b is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C( ⁼ O)Ra, -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

Y ¹ and Y ² are independently hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹² is hydrogen, deuterium, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl base; with the proviso that R ¹² is not -CH ₃ ;

R ¹³ is -OR ¹⁹ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -OC(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -OC(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C (=O)OR ¹⁹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , C ₁ -C ₆ alkane radical, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^13a ;

Each R ^13a is independently oxo, deuterium, halogen, -CN, -OR ¹⁹ , -SR ¹⁹ , -S(=O)R ¹⁸ , -S(=O) ₂ R ¹⁸ , -NO ₂ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -OC(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -OC(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

Each R ¹⁸ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^18a ;

Each R ^18a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ¹⁹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl Base, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^19a ;

Each R ^19a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ²⁰ and R ²¹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^20a ;

Each R ^20a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R ²⁰ and R ²¹ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three R ^20b ;

Each R ^20b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ;

Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

In some embodiments of compounds having formula (VI), Y ^{and Y} are independently hydrogen, deuterium, halogen, -OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (VI), Y ¹ and Y ² are independently hydrogen, deuterium, halogen, or -OR ^b . In some embodiments of compounds of formula (VI), Y ¹ and Y ² are independently hydrogen, deuterium, -OR ^b , or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (VI), Y ^{and Y} are independently hydrogen.

In some embodiments of compounds of formula (VI), R ¹² is hydrogen, deuterium, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, or cycloalkyl; with the proviso that R ¹² is not —CH ₃ . In some embodiments of compounds of formula (VI), R ¹² is hydrogen, deuterium, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl; with the proviso that R ¹² is not _-CH3 . In some embodiments of compounds of formula (VI), R ¹² is hydrogen or deuterium. In some embodiments of compounds of formula (VI), R ¹² is hydrogen. In some embodiments of compounds of formula (VI), R ¹² is hydrogen or C ₁ -C ₆ alkyl; with the proviso that R ¹² is not —CH ₃ . In some embodiments of compounds of formula (VI), R ¹² is C ₁ -C ₆ alkyl; with the proviso that R ¹² is not —CH ₃ .

In some embodiments of compounds having Formula (VI), R ¹³ is -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -C(=O) OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ^21. -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , C ₁ -C ₆ alkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two or Three R ^13a substitutions. In some embodiments of compounds having Formula (VI), R ¹³ is -C(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ S (=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , C ₁ -C ₆ alkyl, cycloalkyl, heterocycloalkyl, Aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^13a . In some embodiments of compounds having Formula (VI), R ¹³ is -C(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ S (=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , or -NR ¹⁹ C(=O)R ¹⁸ . In some embodiments of compounds having Formula (VI), R ¹³ is -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , or -NR ¹⁹ C(=O)R ¹⁸ . In some embodiments of compounds of formula (VI), R ¹³ is -C(=O)NR ²⁰ R ²¹ . In some embodiments of compounds of formula (VI), R ¹³ is -NR ¹⁹ C(═O)R ¹⁸ . In some embodiments of compounds of formula (VI), R ¹³ is C ₁ -C ₆ alkyl optionally substituted with one, two or three R ^13a . In some embodiments of compounds of formula (VI), R ¹³ is heteroaryl optionally substituted with one, two or three R ^13a .

In some embodiments of compounds having Formula (VI), each R ^13a is independently deuterium, halogen, -CN, -OR ¹⁹ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O) OR ¹⁹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ Heteroalkyl. In some embodiments of compounds having Formula (VI), each R ^13a is independently deuterium, halogen, -CN, -OR ¹⁹ , -NR ²⁰ R ²¹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl. In some embodiments of compounds having Formula (VI), each R ^13a is independently deuterium, halogen, -CN, -OR ¹⁹ , -NR ²⁰ R ²¹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl. In some embodiments of compounds of formula (VI), each R ^13a is independently -NR ¹⁹ S(=O) ₂ R ¹⁸ or -NR ¹⁹ C(=O)R ¹⁸ .

Disclosed herein is a compound having formula (VII), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

in:

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ³ is halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ^5. -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P( =O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)( =NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O) (=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R;

Each R ^3b is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C ⁽ =O)Ra, -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

Y ¹ and Y ² are independently hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl; with the proviso that one of Y ^{or Y} is not hydrogen;

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹² is hydrogen, deuterium, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl base;

R ¹³ is -OR ¹⁹ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -OC(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -OC(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C (=O)OR ¹⁹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , C ₁ -C ₆ alkane radical, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^13a ;

Each R ^13a is independently oxo, deuterium, halogen, -CN, -OR ¹⁹ , -SR ¹⁹ , -S(=O)R ¹⁸ , -S(=O) ₂ R ¹⁸ , -NO ₂ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -OC(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -OC(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl;

Each R ¹⁸ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^18a ;

Each R ^18a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ¹⁹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl Base, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^19a ;

Each R ^19a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ²⁰ and R ²¹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^20a ;

Each R ^20a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R ²⁰ and R ²¹ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three R ^20b ;

Each R ^20b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ;

Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

In some embodiments of compounds having formula (VII), Y ^{and Y} are independently hydrogen, deuterium, halogen, -OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuteroalkyl; with the proviso that one of Y ¹ or Y ² is not hydrogen. In some embodiments of compounds of formula (VII), Y ^{and Y} are independently hydrogen, deuterium, halogen, or ^-ORb ; with the proviso that one of ^Y or ^Y is not hydrogen. In some embodiments of compounds having Formula (VII), Y ^{and Y} are independently hydrogen, deuterium, -OR ^b , or C ₁ -C ₆ alkyl; with the proviso that one of Y ^{or Y} is not hydrogen.

In some embodiments of compounds having formula (VII), R ¹² is hydrogen, deuterium, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, or cycloalkyl. In some embodiments of compounds of formula (VII), R ¹² is hydrogen, deuterium, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (VII), R ¹² is hydrogen or deuterium. In some embodiments of compounds of formula (VII), R ¹² is hydrogen. In some embodiments of compounds of formula (VII), R ¹² is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (VII), R ¹² is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (VII), R ¹³ is -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -C(=O) OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ^21. -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , C ₁ -C ₆ alkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two or Three R ^13a substitutions. In some embodiments of compounds of formula (VII), R ¹³ is -C(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ S (=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , C ₁ -C ₆ alkyl, cycloalkyl, heterocycloalkyl, Aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^13a . In some embodiments of compounds of formula (VII), R ¹³ is -C(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ S (=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , or -NR ¹⁹ C(=O)R ¹⁸ . In some embodiments of compounds having Formula (VII), R ¹³ is -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , or -NR ¹⁹ C(=O)R ¹⁸ . In some embodiments of compounds of formula (VII), R ¹³ is -C(=O)NR ²⁰ R ²¹ . In some embodiments of compounds of formula (VII), R ¹³ is -NR ¹⁹ C(═O)R ¹⁸ . In some embodiments of compounds of formula (VII), R ¹³ is C ₁ -C ₆ alkyl optionally substituted with one, two or three R ^13a . In some embodiments of compounds of formula (VII), R ¹³ is heteroaryl optionally substituted with one, two or three R ^13a .

In some embodiments of compounds having Formula (VII), each R ^13a is independently deuterium, halogen, -CN, -OR ¹⁹ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O) OR ¹⁹ , -NR ¹⁹ S(=O) ₂ NR ²⁰ R ²¹ , -NR ¹⁹ S(=O) ₂ R ¹⁸ , -NR ¹⁹ C(=O)R ¹⁸ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ Heteroalkyl. In some embodiments of compounds of formula (VII), each R ^13a is independently deuterium, halogen, -CN, -OR ¹⁹ , -NR ²⁰ R ²¹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl. In some embodiments of compounds of formula (VII), each R ^13a is independently deuterium, halogen, -CN, -OR ¹⁹ , -NR ²⁰ R ²¹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl. In some embodiments of compounds of formula (VII), each R ^13a is independently -NR ¹⁹ S(=O) ₂ R ¹⁸ or -NR ¹⁹ C(=O)R ¹⁸ .

Disclosed herein is a compound having formula (VIII), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

in:

R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ³ is halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^3a ;

Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ^5. -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P( =O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)( =NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O) (=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R;

Each R ^3b is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C( ⁼ O)Ra, -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ;

Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ;

Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ;

or two R ⁵ together form an optionally substituted heterocycloalkyl;

Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ;

Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ;

Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

是

yes

Y ¹ and Y ² are independently hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl;

R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ;

or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

R ¹² is hydrogen, deuterium, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl base;

R ¹³ is -CN, -OR ¹⁹ , -S(=O) ₂ NR ²⁰ R ²¹ , -OC(=O)R ¹⁸ , -OC(=O)OR ¹⁹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkane radical, heterocycloalkyl, aryl, heteroaryl, -CH ₂ (cycloalkyl), -CH ₂ (heterocycloalkyl), -CH ₂ (aryl), or -CH ₂ (heteroaryl) ; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^13a ;

Each R ^13a is independently oxo, deuterium, halogen, -CN, -OR ¹⁹ , -SR ¹⁹ , -S(=O)R ¹⁸ , -S(=O) ₂ R ¹⁸ , -NO ₂ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -OC(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -OC(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hetero Alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ¹⁸ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^18a ;

Each R ^18a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ¹⁹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl Base, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^19a ;

Each R ^19a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Each R ²⁰ and R ²¹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^20a ;

Each R ^20a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R ²⁰ and R ²¹ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three R ^20b ;

Each R ^20b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl;

or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ;

Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl;

Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution;

Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and

Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution;

or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl.

In some embodiments of compounds having formula (VIII), Y ^{and Y} are independently hydrogen, deuterium, halogen, -OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (VIII), Y ¹ and Y ² are independently hydrogen, deuterium, halogen, or -OR ^b . In some embodiments of compounds of formula (VIII), Y ¹ and Y ² are independently hydrogen, deuterium, -OR ^b , or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (VIII), Y ^{and Y} are hydrogen.

In some embodiments of compounds of formula (VIII), R ¹² is hydrogen, deuterium, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, or cycloalkyl. In some embodiments of compounds of formula (VIII), R ¹² is hydrogen, deuterium, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of formula (VIII), R ¹² is hydrogen or deuterium. In some embodiments of compounds of formula (VIII), R ¹² is hydrogen. In some embodiments of compounds of formula (VIII), R ¹² is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of formula (VIII), R ¹² is C ₁ -C ₆ alkyl.

In some embodiments of compounds of formula (VIII), R ¹³ is -CN.

In some embodiments of compounds of formula (VIII), R ¹³ is C ₁ -C ₆ hydroxyalkyl optionally substituted with one, two or three R ^13a . In some embodiments of compounds having formula (VIII), R is ^cycloalkyl , heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl Aryl is independently optionally substituted with one, two or three R ^13a . In some embodiments of compounds of formula (VIII), R ¹³ is heteroaryl optionally substituted with one, two or three R ^13a .

In some embodiments of compounds having Formula (VIII), R ¹³ is -CN, heterocycloalkyl, heteroaryl, or -CH ₂ (heteroaryl); wherein the heterocycloalkyl and heteroaryl are independently is optionally substituted by one, two or three R ^13a . In some embodiments of compounds having formula (VIII), R is ^{heterocycloalkyl} or heteroaryl; wherein the heterocycloalkyl and heteroaryl are independently optionally replaced by one, two or three R ^13a substituted. In some embodiments of compounds of formula (VIII), R ¹³ is heteroaryl optionally substituted with one, two or three R ^13a . In some embodiments of compounds of formula (VIII), R ¹³ is heterocycloalkyl optionally substituted with one, two or three R ^13a .

In some embodiments of compounds having Formula (VIII), each R ^13a is independently deuterium, halogen, -CN, -OR ¹⁹ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl. In some embodiments of compounds of formula (VIII), each R ^13a is independently deuterium, halogen, -CN, -OR ¹⁹ , -NR ²⁰ R ²¹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl. In some embodiments of compounds of formula (VIII), each R ^13a is independently deuterium, halogen, -CN, -OR ¹⁹ , -NR ²⁰ R ²¹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl.

In some embodiments of compounds of formula (VIII), each R ^13a is independently oxo, -OR ¹⁹ , -NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -C(=O)OR ^19. -C(=O)NR ²⁰ R ²¹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ - C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, or aryl. In some embodiments of compounds having Formula (VIII), each R ^13a is independently oxo, -OR ¹⁹ , -NR ²⁰ R ²¹ , -C(=O)NR ²⁰ R ²¹ , C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, or aryl. In some embodiments of compounds of formula (VIII), each R ^13a is independently -OR ¹⁹ , -NR ²⁰ R ²¹ , or -C(=O)NR ²⁰ R ²¹ . In some embodiments of compounds of formula (VIII), each R ^13a is independently -OR ¹⁹ or -C(=O)NR ²⁰ R ²¹ . In some embodiments of compounds of formula (VIII), each R ^13a is independently -OR ¹⁹ .

In some embodiments of compounds of Formulas (VI)-(VIII), R ¹ is -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹ is —CN or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹ is C ₁ -C ₆ haloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹ is -CN.

In some embodiments of compounds of Formulas (VI)-(VIII), R ⁸ is hydrogen or deuterium. In some embodiments of compounds of Formulas (VI)-(VIII), R ⁸ is hydrogen.

In some embodiments of compounds of Formulas (VI)-(VIII), R ⁹ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ⁹ is C ₁ -C ₆ alkyl.

In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁰ is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkynyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁰ is C ₁ -C ₆ alkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), R ⁹ is C ₁ -C ₆ alkyl and R ¹⁰ is C ₂ -C ₆ alkynyl. In some embodiments of compounds having Formulas (VI)-(VIII), R ¹⁰ is C ₁ -C ₆ alkyl and R ⁹ is C ₂ -C ₆ alkynyl.

是

在具有式(VI)-(VIII)的化合物的一些实施例中，

是

In some embodiments of compounds having Formulas (VI)-(VIII),

yes

In some embodiments of compounds having Formulas (VI)-(VIII),

yes

In some embodiments of compounds of Formulas (VI)-(VIII), R ¹¹ is hydrogen, halogen, or -OH. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹¹ is hydrogen or -OH. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹¹ is hydrogen.

In some embodiments of compounds having Formulas (VI)-(VIII), each R ¹⁸ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally is substituted by one, two or three R ^18a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ¹⁸ is independently C ₁ -C ₆ alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally Substituted by one, two or three R ^18a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ¹⁸ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^18a . In some embodiments of compounds of Formulas (VI)-(VIII), each R ¹⁸ is independently C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (VI)-(VIII), each R ¹⁸ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl .

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^18a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^18a is independently deuterium or halogen. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^18a is independently halogen.

In some embodiments of compounds of Formulas (VI)-(VIII), each R ¹⁹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterane A group, a cycloalkyl group, or a heterocycloalkyl group; wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group are independently optionally substituted by one, two or three R ^19a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ¹⁹ is independently hydrogen, C ₁ -C ₆ alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently Optionally substituted with one, two or three R ^19a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ¹⁹ is independently hydrogen or C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^19a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ¹⁹ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^19a . In some embodiments of compounds of Formulas (VI)-(VIII), each R ¹⁹ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ¹⁹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterium alkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^19a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^19a is independently deuterium or halogen. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^19a is independently halogen.

In some embodiments of compounds having Formulas (VI)-(VIII), each R ²⁰ and R ²¹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^20a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ²⁰ and R ²¹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ²⁰ and R ²¹ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; wherein the alk The radicals are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds of Formulas (VI)-(VIII), each R ²⁰ and R ²¹ is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (VI)-(VIII), each R ²⁰ and R ²¹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ - C ₆ deuterated alkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^20a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^20a is independently deuterium or halogen. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^20a is independently halogen. In some embodiments of compounds having Formulas (VI)-(VIII), each R ^20a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formulas (VI)-(VIII), each R ^20a is independently -S(=O)(= ^NRx ) ^Rb or -S(=O)(= ^NRx ) NR ^c R ^d .

In some embodiments of compounds having Formulas (VI)-(VIII), R ²⁰ and R ²¹ together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three R ^20b alkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^20b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having Formulas (VI)-(VIII), each R ^20b is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In some embodiments of compounds having Formulas (VI)-(VIII), each R ^20b is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), R ³ is halogen, -CN, -OR ⁵ , -NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O )R ⁴ , -C(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(= NR ^x ) NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C (=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted by one, two or three R ^3a . In some embodiments of compounds having Formulas (VI)-(VIII), R ³ is -NR ⁵ C(=NR ^x )R ⁵ or -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ . In some embodiments of compounds having Formulas (VI)-(VIII), R ³ is -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds of Formulas (VI)-(VIII), R ³ is C ₁ -C ₆ alkyl or —C(═O)OR ⁵ . In some embodiments of compounds of Formulas (VI)-(VIII), R ³ is C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^3a . In some embodiments of compounds of Formulas (VI)-(VIII), R ³ is C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (VI)-(VIII), R ³ is -C(=O)OR ⁵ .

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O ) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having Formulas (VI)-(VIII), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -S(=O)R ⁴ , -S(=O ) ₂ R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formulas (VI)-(VIII), each R ^3a is independently deuterium, halogen, -CN, -OR ⁵ , -OC(=O)R ⁴ , -C(=O )OR ⁵ , -C(=O)NR ⁶ R ⁷ , -B(OR ⁵ ) ₂ , -S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ heteroalkyl, heterocycloalkyl , or heteroaryl. In some embodiments of compounds having Formulas (VI)-(VIII), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C( =NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ . In some embodiments of compounds having Formulas (VI)-(VIII), each R ^3a is independently -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , or -C(=O)NR ⁶ R ⁷ . In some embodiments of compounds having Formulas (VI)-(VIII), each R ^3a is independently -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , or -B(OR ⁵ ) ₂ . In some embodiments of compounds having Formulas (VI)-(VIII), each R ^3a is independently -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -NR ⁵ S(=O)(=NR ^x )R ⁵ .

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^3b is independently deuterium, halogen, -CN, -OR ^b , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane group, or C ₁ -C ₆ deuterated alkyl group. In some embodiments of compounds having Formulas (VI)-(VIII), each R ^3b is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally is substituted by one, two or three R ^4a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ⁴ is independently C ₁ -C ₆ alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally Substituted by one, two or three R ^4a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ⁴ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^4a . In some embodiments of compounds of Formulas (VI)-(VIII), each R ⁴ is independently C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (VI)-(VIII), each R is ^{independently} C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl .

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^4a is independently deuterium or halogen. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^4a is independently halogen.

In some embodiments of compounds having Formulas (VI)-(VIII), each R is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ¹ _{-C 6} deuterane A group, a cycloalkyl group, or a heterocycloalkyl group; wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group are independently optionally substituted by one, two or three R ^5a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently Optionally substituted with one, two or three R ^5a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ⁵ is independently hydrogen or C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ⁵ is independently C ₁ -C ₆ alkyl optionally substituted with one, two, or three R ^5a . In some embodiments of compounds of Formulas (VI)-(VIII), each R ⁵ is hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (VI)-(VIII), each R is independently hydrogen, C ₁ -C ₆ alkyl, C _{1 -C 6} ^haloalkyl , or C ₁ -C ₆ deuterium alkyl.

In some embodiments of compounds of Formulas (VI)-(VIII), two R ⁵ are taken together to form optionally substituted heterocycloalkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^5a is independently deuterium or halogen. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^5a is independently halogen. In some embodiments of compounds having Formulas (VI)-(VIII), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formulas (VI)-(VIII), each R ^5a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x ) NR ^c R ^d .

In some embodiments of compounds having Formulas (VI)-(VIII), each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C 6 ₆ deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds having Formulas ₍ VI)-(VIII), each R and R is independently hydrogen, C ₁ -C ⁶ alkyl, ^C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds having Formulas (VI)-(VIII), each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; wherein the alk The radicals are independently optionally substituted by one, two or three R ^6a . In some embodiments of compounds of Formulas (VI)-(VIII), each R ⁶ and R ⁷ is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ - C ₆ deuterated alkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^6a is independently deuterium or halogen. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^6a is independently halogen. In some embodiments of compounds having Formulas (VI)-(VIII), each R ^5a is independently -NR ^b C(=NR ^x )R ^b or -NR ^b C(=NR ^x )NR ^c R ^d . In some embodiments of compounds having Formulas (VI)-(VIII), each R ^6a is independently -S(=O)(=NR ^x )R ^b or -S(=O)(=NR ^x ) NR ^c R ^d .

In some embodiments of compounds having Formulas (VI)-(VIII), R ^{and R} together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or ^three R alkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^6b is independently C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), each R ^6b is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds of Formulas (VI)-(VIII), ^Rx is hydrogen, _-NO2 , or -CN. In some embodiments of compounds of Formulas (VI)-(VIII), R ^x is -NO ₂ or -CN. In some embodiments of compounds of Formulas (VI)-(VIII), ^Rx is -CN.

In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ are independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ are independently hydrogen or C ₁ -C ₆ deuterioalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ are independently C ₁ -C ₆ alkyl.

In some embodiments of compounds having Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ together form cycloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ together form cycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ are taken together to form cycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ together form a cycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds having Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ are taken together to form heterocycloalkyl. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 1-4 deuteriums. In some embodiments of compounds having Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 1 or 2 deuteriums. In some embodiments of compounds of Formulas (VI)-(VIII), R ¹⁵ and R ¹⁶ are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums.

In some embodiments of compounds having Formulas (I)-(VIII), each ^R is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkane , and heterocycloalkyl are independently optionally substituted with one, two or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (I)-(VIII), each ^R is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, Cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally replaced by one, two or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution. In some embodiments of compounds having Formulas (I)-(VIII), each R ^a is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl ; wherein the alkyl is independently optionally substituted by one, two or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (I)-(VIII), each R ^a independently is optionally replaced by one, two or three deuterium, halogen, -OH, -NH ₂ , or C ₁ C ₁ -C ₆ alkyl substituted by -C ₆ alkyl. In some embodiments of compounds having Formulas (I)-(VIII), each R ^a is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds having Formulas (I)-(VIII), each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterane group, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , Or C ₁ -C ₆ alkyl substitution. In some embodiments of compounds having Formulas (I)-(VIII), each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterium Alkyl; wherein the alkyl is independently optionally substituted by one, two or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (I)-(VIII), each R ^b independently is optionally replaced by one, two or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substituted hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (I)-(VIII), each R ^b is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of Formulas (I)-(VIII), each R ^b is independently hydrogen. In some embodiments of compounds having Formulas (I)-(VIII), each R ^b is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds having Formulas (I)-(VIII), each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally replaced by one, two or three deuterium, halogen, -OH, - NH ₂ , or C ₁ -C ₆ alkyl substitution. In some embodiments of compounds having Formulas (I)-(VIII), each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ - C ₆ deuterated alkyl; wherein the alkyl is independently optionally substituted by one, two or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (I)-(VIII), each R ^c and R ^d independently is optionally replaced by one, two or three deuterium, halogen, -OH, -NH ₂ , Or C ₁ -C ₆ alkyl substituted hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds having Formulas (I)-(VIII), each R ^c and R ^d is independently hydrogen or C ₁ -C ₆ alkyl. In some embodiments of compounds of Formulas (I)-(VIII), each R ^b is independently hydrogen. In some embodiments of compounds having Formulas (I)-(VIII), each R ^c and R ^d is independently C ₁ -C ₆ alkyl.

In some embodiments of compounds having Formulas (I)-(VIII), R ^c and R ^d together with the nitrogen atom to which they are attached form optionally surrounded by one, two or three deuterium, halogen, -OH , -NH ₂ , or C ₁ -C ₆ alkyl substituted heterocycloalkyl.

Disclosed herein is a compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Disclosed herein is a compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Other forms of the compounds disclosed herein

Isomers / Stereoisomers

In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, compounds described herein have one or more double bonds. Compounds presented herein include cis, trans, synonymous, antisense, hetero (E), and homo (Z) isomers and corresponding mixtures thereof. In some cases, compounds described herein have one or more chiral centers and each center exists in either the R-configuration or the S-configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms and corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers resulting from a single preparative step, combination or interconversion may be used in the applications described herein. In some embodiments, by reacting a racemic mixture of a compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer, The compounds described herein are prepared as their respective stereoisomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereoisomers have distinct physical properties (eg, melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereoisomers are separated by chiral chromatography or, preferably, by separation/resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then recovered with a resolving agent.

labeled compound

In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Accordingly, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those recited herein except that one or more atoms are labeled with an atomic mass or mass number different from that normally found in nature. Atoms of mass or mass number are substituted. Examples of isotopes that may be incorporated into the compounds described herein, or solvates or stereoisomers thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl. Compounds described herein, and pharmaceutically acceptable salts, solvates or stereoisomers thereof, containing the above isotopes and/or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopically labeled compounds, for example those into which radioactive isotopes such ^{as3H and14C} are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (ie, ^3H ) and carbon-14 (ie, ^14C ) isotopes are known for their ease of preparation and detectability. Furthermore, substitution with heavy isotopes, such as deuterium (ie, ^2H ), affords certain therapeutic advantages resulting from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements). In some embodiments, an isotopically labeled compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is prepared by any suitable method.

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

pharmaceutically acceptable salt

In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable Salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed to prepare.

Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with mineral acids, organic acids or inorganic bases, such salts include acetates, acrylates, adipates, alginates, Partiate, Benzoate, Besylate, Bisulfate, Bisulfite, Bromide, Butyrate, Butyne-1,4-dioate, Camphorate, Camphorsulfonate , caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentane propionate, caprate, digluconate, dihydrogen phosphate, dinitrobenzene Formate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucose enanthate, glycerophosphate, glycolate, hemisulfate, enanthate, caproate (hexanoate), hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, Iodide, isobutyrate, lactate, maleate, malonate, mesylate, mandelate, metaphosphate, mesylate, methoxybenzoate, methyl Benzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectate, persulfate, 3-phenylpropionate , phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonic acid Salt, Salicylate, Succinate, Sulfate, Sulfite, Succinate, Suberate, Sebacate, Sulfonate, Tartrate, Thiocyanate, Tosylate, Deca Monocarbonate and Xylene Sulfonate.

In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compounds with pharmaceutically acceptable inorganic or organic acids, including but not limited to inorganic acids, Such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid , malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, aryl Sulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octyl- 2-en-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butyl Glycolic Acid, Lauryl Sulfate, Gluconic Acid, Glutamic Acid, Hydroxynaphthoic Acid, Salicylic Acid, Stearic Acid, and Muconic Acid.

In some embodiments, those compounds described herein that contain a free acid group are reacted with a suitable base (e.g., a hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation) to react with Ammonia reaction, or reaction with pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amines. Representative salts include alkali or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium, aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ (C _1-4 alkyl) ₄ and the like.

Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

Solvate

In some embodiments, the compounds described herein exist as solvates. The present disclosure provides methods of treating diseases by administering such solvates. The present disclosure further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

Solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, solvates are formed during the process of crystallization with pharmaceutically acceptable solvents (eg, water, ethanol, etc.). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein may be conveniently prepared or formed in the methods described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Tautomer

In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerism is possible, there will be a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors including temperature, solvent, and pH.

Compound preparation

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" were obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, Wisconsin), including Sigma Chemicals and Vernon Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Ltd. ( BDH, Inc.) (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (Westchester, Pennsylvania), Crescent Chemical Company (Crescent Chemical Co. (Harpook, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Coss, CA) Tamesa), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. ( Cornwall, UK), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Connecticut), Polyorganics ( Polyorganix) (Houston, Texas), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Products, Inc. Inc.) (New Brunswick, NJ), TCI America (Portland, Ore.), Trans World Chemicals, Inc. (Rockville, Md.), and and Photochemical America Corporation (Wako Chemicals USA, Inc.) (Richmond, Virginia).

Suitable reference books and papers that describe in detail the synthesis of reactants that can be used to prepare the compounds described herein or provide references to articles describing such preparations include, for example: "Synthetic Organic Chemistry", John Wiley & Sons, Inc. [John Wiley & Sons], New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions [ Modern Synthetic Reactions]", 2nd ed., W.A. Benjamin, Inc. Menlo Park, CA 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd ed., John Wiley & Sons Lee & Sons], New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th ed., Wiley-Interscience, New York ,1992. Other suitable reference books and papers that describe in detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to articles describing such preparations include, for example: Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods , Starting Materials [Organic Synthesis: Concepts, Methods, Starting Materials]", Second Edition, Revised and Supplemented (1994) John Wiley & Sons [John Wiley & Sons] ISBN: 3-527-29074-5; Hoffman, R.V." Organic Chemistry, An Intermediate Text [Organic Chemistry, Intermediate Text]” (1996) Oxford University Press [Oxford University Press], ISBN 0-19-509618-5; Larock, R.C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations [ Comprehensive Organic Transformations: A Guide to Functional Group Preparation]" 2nd Edition (1999) Wiley-VCH [Wiley-VCH Company], ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure [Advanced Organic Chemistry: Reactions, Mechanisms, and Structure]" 4th Edition (1992) John Wiley & Sons [John Wiley & Sons], ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry [Modern Carbonyl Chemistry]" (2000) Wiley-VCH [Wiley-VCH Company], ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups [Patai 1992 Functional Group Chemistry Guide]" (1992) Interscience [International Science] ISBN: 0-471-93022-9; Solomons, T.W.G. "Organic Chemistry [Organic Chemistry]" 7th Edition (2000) John Wiley & Sons [John Wiley & Sons], ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry," 2nd Ed. (1993) W iley-Interscience [Willie International Science], ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia [Industrial Organic Chemicals: Starting Materials and Intermediates: Ullmann's Encyclopedia ]” (1999) John Wiley&Sons [John Wiley & Sons], ISBN: 3-527-29645-X, Volume 8; “Organic Reactions [organic reaction]” (1942-2000) John Wiley & Sons [John Wiley & Sons] , over 55 volumes; and "Chemistry of Functional Groups," John Wiley & Sons, 73 volumes.

An index of known chemicals prepared through the American Chemical Society's Chemical Abstract Service (available at most public and university libraries and online), optionally identifying specific and similar reactants. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, of which many standard chemical supply houses (eg, those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl and C.G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

pharmaceutical composition

In certain embodiments, the compounds described herein are administered as neat chemicals. In some embodiments, the compounds described herein are combined with a pharmaceutically suitable or pharmaceutically acceptable carrier (also referred to herein as pharmaceutically suitable (or Pharmaceutically acceptable) excipient, physiologically suitable (or acceptable) excipient or physiologically suitable (or physiologically acceptable) carrier) combination: for example Remington: The Science and Practice of Pharmacy[ Remington: The Science and Practice of Pharmacy] (Gennaro, 21st ed. Mack Pub. Co. [Mark Publishing Company], Easton, PA (2005)).

Accordingly, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, a compound provided herein is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules or, for example, in the synthesis process. Synthetic by-products produced during one or more steps.

Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. Typically, suitable dosages and treatment regimens are sufficient to provide therapeutic benefit and/or prophylactic benefit (e.g., improved clinical outcome, such as more frequent complete remission or partial remission, or longer disease-free and/or overall survival, or a reduction in the severity of symptoms) to provide one or more compositions. Optimal dosages are usually determined using experimental models and/or clinical trials. The optimal dose depends on the patient's body mass, body weight, or blood volume.

In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, epidural, or intranasal apply. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ocular administration. In some embodiments, pharmaceutical compositions are formulated for oral administration. In some embodiments, pharmaceutical compositions are formulated for intravenous injection. In some embodiments, pharmaceutical compositions are formulated as tablets, pills, capsules, liquids, inhalants, nasal spray solutions, suppositories, suspensions, gels, colloids, dispersions, suspensions, solutions, emulsions, Ointment, lotion, eye or ear drops. In some embodiments, pharmaceutical compositions are formulated as tablets.

Appropriate dosages and dosage regimens are determined by conventional range-finding techniques known to those skilled in the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compounds disclosed herein. Thereafter, the dosage is increased in small increments until the optimum effect for the particular situation is reached. In some embodiments, the methods involve administering from about 0.1 μg to about 50 mg of at least one compound described herein per kg body weight of the subject. For a 70 kg patient, doses of about 10 μg to about 200 mg of the compounds disclosed herein will more commonly be used, depending on the physiological response of the subject.

By way of example only, the dosage of a compound described herein for use in the method of treating a disease as described herein is from about 0.001 to about 1 mg/kg subject body weight/day, such as about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg /kg body weight/day. In some embodiments, the dose of a compound described herein used in the described methods is from about 1 to about 1000 mg/kg body weight/day of the subject being treated, for example about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

treatment method

Disclosed herein are methods of treating renal disease comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Also disclosed herein is a method of treating the disease systemic lupus nephritis, diabetic chronic kidney disease (CDK), Allport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary arterial hypertension, Freed Reich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereo isomer.

Also disclosed herein is a method of treating the kidney disease systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), autosomal dominant Polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

Disclosed herein is a method of treating systemic lupus nephritis comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. Lupus nephritis is inflammation of the kidneys caused by systemic lupus erythematosus (SLE). SLE, also known as lupus, is an autoimmune disease. With lupus, the body's immune system targets its own body tissues. Lupus nephritis occurs when lupus affects the kidneys.

Disclosed herein is a method of treating diabetic chronic kidney disease (CDK), the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, to a subject in need thereof.

Disclosed herein is a method of treating Alport syndrome comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Allport syndrome is a genetic disorder characterized by kidney disease, hearing loss, and eye abnormalities. People with Alport syndrome experience a progressive loss of kidney function. Nearly all affected individuals have blood in their urine (hematuria), which indicates abnormal kidney function. Many people with Allport syndrome also have high levels of protein in their urine (proteinuria). As this condition progresses, the kidneys become less and less functional, leading to end-stage renal disease (ESRD).

Disclosed herein is a method of treating focal segmental glomerulosclerosis (FSGS), the method comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof . Focal segmental glomerulosclerosis (FSGS) is a cause of nephrotic syndrome in children and adolescents and a leading cause of kidney failure in adults. It is also called "focal glomerulosclerosis" or "focal nodular glomerulosclerosis". It accounts for about one in six cases of nephrotic syndrome. In some embodiments, focal segmental glomerulosclerosis is primary focal segmental glomerulosclerosis when no underlying cause is found; usually manifests as nephrotic syndrome. In some embodiments, focal segmental glomerulosclerosis is secondary focal segmental glomerulosclerosis when the underlying cause is determined; usually presenting with renal failure and proteinuria. Secondary focal segmental glomerulosclerosis is a heterogeneous group that includes many causes such as: toxins and drugs, such as heroin and pamidronate, familial forms, and is secondary to nephron loss and ultrafiltration, Such as with chronic pyelonephritis and reflux, morbid obesity, diabetes.

Disclosed herein is a method of treating pulmonary hypertension comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. Pulmonary hypertension (PH or PHTN) is a condition in which blood pressure in the arteries of the lungs increases. Symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. This condition can make movement difficult. The cause is usually unknown. Risk factors include family history, previous blood clots in the lungs, HIV/AIDS, sickle cell disease, cocaine use, chronic obstructive pulmonary disease, sleep apnea, living at high altitudes, and mitral valve problems. The underlying mechanism typically involves inflammation of the pulmonary arteries. Diagnosis begins with the exclusion of other potential causes.

Disclosed herein is a method of treating Friedreich's ataxia comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. Friedreich's ataxia (FRDA or FA) is an autosomal recessive disorder that causes difficulty walking, loss of sensation in the arms and legs, and speech impairment that worsens over time. Symptoms can begin between the ages of 5 and 15. Many people develop hypertrophic cardiomyopathy and require mobility aids such as canes, walkers, or wheelchairs during their teenage years. As the disease progresses, vision and hearing are lost. Other complications include scoliosis and diabetes. This condition is caused by a mutation in the FXN gene on chromosome 9. The FXN gene produces a protein called frataxin. Degeneration of the neural tissue in the spinal cord leads to ataxia; particularly affected are sensory neurons that are critical for directing muscle movements in the arms and legs through connections with the cerebellum. The spinal cord becomes thinner, and nerve cells lose some of their myelin sheath.

Disclosed herein is a method of treating autosomal dominant polycystic kidney disease (ADPKD), the method comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the growth of massive cysts in the kidneys. The severity of symptoms and the age of onset vary, but usually develop between the ages of 30 and 40. ADPKD is a progressive disease, with symptoms worsening over time. The most common symptoms are kidney cysts, back and side pain, and headache. Other symptoms include cysts in the liver and pancreas, urinary tract infections, abnormal heart valves, high blood pressure, kidney stones and brain aneurysms. ADPKD is most commonly caused by changes in the PKD1 and PKD2 genes, and less commonly by changes in the GANAB and DNAJB11 genes. It is inherited in a dominant pattern. Treatment of ADPKD includes controlling symptoms and slowing disease progression. The most serious complications of ADPKD are kidney disease and kidney failure. ADPKD is the most common genetic disorder of the kidney.

Disclosed herein is a method of treating IgA nephropathy comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. IgA nephropathy, also known as Berger's disease, is a condition that causes damage to the tiny filters inside the kidneys. IgA is a protein that helps fight infection. In people with IgA nephropathy, these proteins accumulate and form clumps inside the tiny filters (glomeruli) of the kidneys. These protein clumps can damage the glomeruli. This damage can lead to chronic kidney disease and possibly kidney failure/ESRD.

combination therapy

In certain instances, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent.

In some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (also comprising a treatment regimen) that also has a therapeutic benefit.

In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvent The compound or stereoisomer and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than either therapeutic agent administered alone.

In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents, or the patient experiences a synergistic benefit.

In certain embodiments, when a compound disclosed herein is administered in combination with a second therapeutic agent, different therapeutically effective doses of a compound disclosed herein will be used to formulate a pharmaceutical composition and/or treatment regimen. Therapeutically effective doses of the drugs and other agents used in the combination treatment regimen are optionally determined in a manner similar to that listed herein for the compounds described herein. In addition, the methods of prophylaxis/treatment described herein encompass the use of rhythmic dosing, ie, providing more frequent, lower doses to minimize toxic side effects. In some embodiments, combination treatment regimens encompass treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is initiated before, during, or after treatment with a second agent described herein body and continue until any time during or after termination of treatment with the second agent. It also includes treatments wherein the compounds described herein, or pharmaceutically acceptable salts, solvates or stereoisomers thereof and the first combination used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Second drug. Combination therapy also includes periodic therapy that is started and stopped at different times to assist in the clinical management of the patient.

It will be appreciated that dosage regimens for the treatment, prevention or amelioration of the condition or conditions for which relief is sought will depend on a number of factors (e.g., the disease, disorder or condition afflicted by the subject; age, weight, sex of the subject; , diet, and medical conditions). Thus, in some cases, the actual dosage regimen employed differs and, in some embodiments, deviates from the dosage regimens set forth herein.

For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of combination drug used, the particular drug used, the disease or condition being treated, and the like. In additional embodiments, when a compound provided herein is co-administered with a second therapeutic agent, the compound provided herein and the second therapeutic agent are administered simultaneously or sequentially.

In combination therapy, multiple therapeutic agents, one of which is one of the compounds described herein, are administered in any order or even simultaneously. If administered simultaneously, by way of example only, the multiple therapeutic agents are provided in a single, unified form or in multiple forms (eg, as a single pill or as two separate pills).

The compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, and combination therapies are administered before, during, or after the onset of the disease or condition, and at various times when the compound-containing compositions are administered. Thus, in one embodiment, the compounds described herein are used as prophylactic agents and are administered continuously to a subject predisposed to develop a condition or disease to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In particular embodiments, the compounds described herein are administered for as long as feasible after the onset of a disease or condition is detected or suspected and continued for as long as necessary to treat the disease. In some embodiments, the length required for the treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in certain embodiments, administration of a compound described herein, or a formulation containing the compound, continues for at least 2 weeks, about 1 month, or about 5 years.

In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., an adjuvant that has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, has an overall therapeutic benefit to the patient be enhanced).

example

Example 1: Imiquimod-induced systemic lupus nephritis

Compound 26 formulated in sesame oil was orally administered to female BALB/c mice (7-9 weeks) at 3 mg/kg per day. Half an hour after compound 26 administration, the skin of the right ear of the mice was topically treated with 25 mg 5% imiquimod (IMQ) 3 times a week. The study was repeated for 8 weeks. At the conclusion of the study, mice were sacrificed, spleens and kidneys were weighed and divided into two parts, one part fixed in neutral buffered formalin and embedded in paraffin. Three-micron sections of liver and kidney were stained with hematoxylin and eosin. Another portion was snap frozen and subjected to gene expression analysis by qPCR.

Topical imiquimod treatment (model group) resulted in marked splenomegaly and increased expression of INFγ. Treatment with Compound 26 reduced splenomegaly and reduced INFγ expression (FIG. 1A and FIG. 1B). Topical imiquimod treatment also increased blood urea nitrogen (BUN) and proteinuria, signs of renal insufficiency. These levels were reduced by Compound 26 treatment (Figure 2A and Figure 2B).

Topical imiquimod treatment made the kidneys enlarged. Compound 26 treatment partially reversed kidney enlargement (Fig. 3A). Histological examination of the kidneys revealed hypercellularity of the glomeruli, increased mesangial matrix, and mild infiltration of peritubular mononuclear cells with concomitant increased deposition of IgG in the glomeruli. Significant increase in renal histopathology score indicated glomerulonephritis with immune complex deposition, and Compound 26 treatment significantly decreased renal histopathology score (Fig. 3B). Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is released by various cell types and is an attractive biomarker of kidney injury and inflammation. Another inflammatory biomarker, CD11b, is expressed on the surface of a variety of leukocytes, including monocytes, neutrophils, natural killer cells, granulocytes, and macrophages, and it regulates leukocyte adhesion and migration to mediate inflammation reaction. The expression of NGAL and CD11b in the kidney was examined by qPCR. Topical imiquimod treatment significantly increased their expression in the kidney, whereas compound 26 treatment significantly decreased this expression, suggesting that this compound has anti-inflammatory properties (Fig. 3C and Fig. 3D, respectively).

Compound 26 attenuated imiquimod-induced systemic lupus nephritis as indicated by improvement in spleen and kidney.

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in some embodiments will be included within the purview and scope of the disclosure of the appended claims.

Claims (70)

1. A method for treating a disease which is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Allport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary arterial hypertension, Freed Reich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound of formula (III) or a pharmaceutically acceptable salt thereof, a solvent to a subject in need thereof Compounds or Stereoisomers:

in: R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl; R ³ is N-linked heterocycloalkyl, N-linked heteroaryl, -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O )(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(= O)(=NR ^x )R ⁵ , -ZO-cycloalkyl, -ZO-heterocycloalkyl, -ZO-aryl, -ZO-heteroaryl, -Z-NR ⁵ -cycloalkyl, -Z -NR ⁵ -heterocycloalkyl, -Z-NR ⁵ -aryl, -Z-NR ⁵ -heteroaryl, -Y(C ₁ -C ₆ alkylene)S(=O)R ⁴ , -Y (C ₁ -C ₆ alkylene)S(=O) ₂ R ⁴ , -Y(C ₁ -C ₆ alkylene)P(=O)(R ⁴ ) ₂ , -Y(C ₁ -C ₆ Alkylene)P(=O)(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)B(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C( =NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)S(=O)( =NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S( =O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ C(=O)(C ₁ -C ₆ alkylene)S(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ C(=O )(C ₁ -C ₆ alkylene)S(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y( C ₂ -C ₆ alkenylene)S(=O) ₂ R ⁴ , -Y(C ₂ -C ₆ alkenylene)P(=O)(R ⁴ ) ₂ , -Y(C ₂ -C ₆ alkenylene) alkenyl)P(=O)(OR ⁵ ) ₂ , -Y(C ₂ -C ₆ alkenylene)B(OR ⁵ ) ₂ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ C(= NR ^x )R ⁵ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₂ -C ₆ alkenylene)S(=O)(= NR ^x )R ⁵ , -Y(C ₂ -C ₆ alkenylene )S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -Y(C ₂ -C ₆ alkenylene)NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y(C ₂ -C ₆ alkenylene)cycloalkyl, -Y(C ₂ -C ₆ alkenylene ) heterocycloalkyl, -Y(C ₂ -C ₆ alkenylene) aryl, -Y(C ₂ -C ₆ alkenylene) heteroaryl, -(C ₁ -C ₆ alkylene) OP( =O)(OR ⁵ ) ₂ , -(C ₁ -C ₆ alkylene)O(C ₁ -C ₆ alkylene)OP(=O)(OR ⁵ ) ₂ , or -(C ₁ -C ₆ Alkylene) OP(=O)(OR ⁵ )[N(R ⁵ ) ₂ ]; wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted by one, two or three R ^3a ; Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl; Y is a bond, -O-, -S-, or -NR ^b -; Z is a bond or C ₁ -C ₆ alkylene; R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ; Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ; Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ; or two R ⁵ together form an optionally substituted heterocycloalkyl; Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ; Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ; Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

yes

R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl; R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl; R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl; R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ; or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R ¹² and R ¹³ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl; or R ¹² and R ¹³ together form cycloalkyl or heterocycloalkyl; each of which is substituted by 0-6 R ¹⁴ ; Each R ¹⁴ is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C(=O) ^Ra , -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl; or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ; Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution; Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution; or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl. 2. The method of claim 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹ is -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl. 3. The method of claim 1 or 2, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹ is -CN. 4. The method of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: ^R8 is hydrogen or deuterium. 5. The method of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: ^R8 is hydrogen. 6. The method of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ⁹ is C ₁ -C ₆ alkyl. 7. The method of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹⁰ is C ₁ -C ₆ alkyl. 8. The method of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

yes

9. The method of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹¹ is hydrogen. 10. The method of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹² and R ¹³ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. 11. The method of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹² and R ¹³ are independently C ₁ -C ₆ alkyl. 12. The method of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹⁵ and R ¹⁶ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. 13. The method of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹⁵ and R ¹⁶ are independently C ₁ -C ₆ alkyl. 14. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)P(=O)(R ⁴ ) ₂ , -Y(C ₁ -C ₆ alkylene)P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)B(OR ⁵ ) ₂ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -Y(C ₁ -C ₆ alkylene)S(=O)R ⁴ , -Y(C ₁ -C ₆ alkylene )S(=O) ₂ R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ C(=O)(C ₁ -C ₆ alkylene group) S(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ C(=O)(C ₁ -C ₆ alkylene)S(=NR ^x )R ⁵ , -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ^5S (=O)(= ^NRx ) ^R5 , N-linked heterocycloalkyl, or N-linked heteroaryl. 15. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)P(=O)(R ⁴ ) ₂ , -Y(C ₁ -C ₆ alkylene)P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)B(OR ⁵ ) ₂ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -Y(C ₁ -C ₆ alkylene)S(=O)R ⁴ , -Y(C ₁ -C ₆ alkylene )S(=O) ₂ R ⁴ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , - Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O) (= ^NRx ) ^R5 , N-attached heterocycloalkyl, or N-attached heteroaryl. 16. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -Y(C ₁ -C ₆ alkylene)P(=O)(R ⁴ ) ₂ , or -Y(C ₁ -C ₆ alkylene)P(=O)(OR ⁵ ) ₂ . 17. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is -B(OR ⁵ ) ₂ or -Y(C ₁ -C ₆ alkylene)B(OR ⁵ ) ₂ . 18. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -Y(C ₁ -C ₆ alkylene)S(=O)R ⁴ , or -Y(C ₁ -C _6alkylene )S(=O) ₂ R ⁴ . 19. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )R ⁵ , or -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ . 20. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )R ⁵ or -Y(C ₁ -C ₆ alkylene)NR ⁵ C(=NR ^x )NR ⁶ R ⁷ . 21. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is -S(=O)(=NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ^5. -NR ⁵ S(=O)(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )R ⁵ , -Y(C ₁ -C ₆ alkylene)S(=O)(=NR ^x )NR ⁶ R ⁷ , -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , or -Y(C ₁ -C ₆ alkylene)NR ⁵ S(=O)(=NR ^x )R ⁵ . 22. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is -NR ⁵ C(=O)(C ₁ -C ₆ alkylene)S(=NR ^x )NR ⁶ R ⁷ or -NR ⁵ C(=O)(C ₁ -C ₆ alkylene) S(=NR ^x )R ⁵ . 23. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: ^R3 is N-linked heterocycloalkyl or N-linked heteroaryl. 24. The method of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Y is the key. 25. The method of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ^X is -CN. 26. The method of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. 27. The method of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. 28. The method of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Two R ⁵ are taken together to form optionally substituted heterocycloalkyl. 29. The method of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterioalkyl. 30. The method of any one of claims 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is:

or. 31. The method of any one of claims 1-30, wherein the disease is systemic lupus nephritis. 32. The method of any one of claims 1-30, wherein the disease is diabetic chronic kidney disease (CDK). 33. The method of any one of claims 1-30, wherein the disease is Alport syndrome. 34. The method of any one of claims 1-30, wherein the disease is focal segmental glomerulosclerosis (FSGS). 35. The method of any one of claims 1-30, wherein the disease is pulmonary hypertension. 36. The method of any one of claims 1-30, wherein the disease is Friedreich's ataxia. 37. The method of any one of claims 1-30, wherein the disease is autosomal dominant polycystic kidney disease (ADPKD). 38. The method of any one of claims 1-30, wherein the disease is IgA nephropathy. 39. A method of treating a disease which is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Allport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Freed Reich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, a solvent to a subject in need thereof Compounds or Stereoisomers:

in: R ¹ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -NR ^b S(=O) ₂ R ^a , -C(=O)R ^a , -C(=O)OR ^b , -C(=O)NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl; R ³ is halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ⁵ , -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P(=O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)(=NR ^x )R ⁵ , -S (=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O)(=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^3a ; Each R ^3a is independently oxo, deuterium, halogen, -CN, -OR ⁵ , -SR ⁵ , -S(=O)R ⁴ , -S(=O) ₂ R ⁴ , -NO ₂ , -NR ⁶ R ⁷ , -S(=O) ₂ NR ⁶ R ⁷ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁵ , -OC(=O)OR ^5. -C(=O)NR ⁶ R ⁷ , -OC(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)NR ⁶ R ⁷ , -NR ⁵ C(=O)OR ⁵ , -NR ⁵ S(=O) ₂ NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ R ⁴ , -NR ⁵ C(=O)R ⁴ , -P(=O)(R ⁴ ) ₂ , -P( =O)(OR ⁵ ) ₂ , -B(OR ⁵ ) ₂ , -NR ⁵ C(=NR ^x )R ⁵ , -NR ⁵ C(=NR ^x )NR ⁶ R ⁷ , -S(=O)( =NR ^x )R ⁵ , -S(=O)(=NR ^x )NR ⁶ R ⁷ , -NR ⁵ S(=O) ₂ NR ⁵ C(=O)R ⁵ , -NR ⁵ S(=O) (=NR ^x )R ⁵ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R; Each R ^3b is independently ^deuterium , halogen, -CN, ^-ORb , ^-NRcRd , -C( ⁼ O)Ra, -C(=O) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ^x is hydrogen, -NO ₂ , -CN, or -S(=O) ₂ R ^a ; Each R ⁴ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or ^three R ; Each R ^4a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^5a ; or two R ⁵ together form an optionally substituted heterocycloalkyl; Each R ^5a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ⁶ and R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^6a ; Each R ^6a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , -NR ^b C(=NR ^x )R ^b , -NR ^b C(=NR ^x )NR ^c R ^d , -S(=O)(=NR ^x )R ^b , -S(= O)(=NR ^x )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or ^R and ^R together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three ^R ; Each R ^6b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

yes

Y ¹ and Y ² are independently hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl; R ⁸ is hydrogen, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl; R ⁹ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl; R ¹⁰ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl; R ¹¹ is hydrogen, deuterium, halogen, or -OR ^b ; or R ^{and R} taken together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R ¹² is hydrogen, deuterium, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl base; R ¹³ is -CN, -OR ¹⁹ , -S(=O) ₂ NR ²⁰ R ²¹ , -OC(=O)R ¹⁸ , -OC(=O)OR ¹⁹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkane radical, heterocycloalkyl, aryl, heteroaryl, -CH ₂ (cycloalkyl), -CH ₂ (heterocycloalkyl), -CH ₂ (aryl), or -CH ₂ (heteroaryl) ; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^13a ; Each R ^13a is independently oxo, deuterium, halogen, -CN, -OR ¹⁹ , -SR ¹⁹ , -S(=O)R ¹⁸ , -S(=O) ₂ R ¹⁸ , -NO ₂ , -NR ²⁰ R ²¹ , -S(=O) ₂ NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -OC(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -OC(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , -OC(=O)NR ²⁰ R ²¹ , -NR ¹⁹ C(=O)OR ¹⁹ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ hetero Alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ¹⁸ is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^18a ; Each R ^18a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ¹⁹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl Base, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^19a ; Each R ^19a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R ²⁰ and R ²¹ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane Base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted by one, two or three R ^20a ; Each R ^20a is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R ²⁰ and R ²¹ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by one, two or three R ^20b ; Each R ^20b is independently oxo, deuterium, halogen, -CN, -OR ^b , -NR ^c R ^d , -C(=O)R ^a , -C(=O)OR ^b , -C(=O )NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ - C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ¹⁵ and R ¹⁶ are independently hydrogen, -OR ^b , -NR ^c R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkane Base, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, or C ₁ -C ₆ heteroalkyl; or R ¹⁵ and R ¹⁶ together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6 R ² ; Each ^R2 is ^{independently} deuterium, halogen, -CN, ^-ORb , ^-NRcRd , -C(=O)Ra, -C(= ^O ) ^ORb , -C(=O) ^NRc R ^d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxy Alkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; Each R ^a is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkane base substitution; Each R ^b is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterioalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl radical, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three halogens, -OH, -NH ₂ , or C ₁ -C ₆ alkane radical substitution; and Each R ^c and R ^d is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterium Alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkane radical, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally replaced by one, two, or three deuterium, halogen, -OH, -NH ₂ , or C ₁ -C ₆ alkyl substitution; or ^Rc and ^Rd together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted with one, two or three deuterium, halogen, -OH, _-NH2 , or _C1 - _C6 alkyl alkyl. 40. The method of claim 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹ is -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₁ -C ₆ deuterated alkyl. 41. The method of claim 39 or 40, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹ is -CN. 42. The method of any one of claims 39-41, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: ^R8 is hydrogen. 43. The method of any one of claims 39-42, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ⁹ is C ₁ -C ₆ alkyl. 44. The method of any one of claims 39-43, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹⁰ is C ₁ -C ₆ alkyl. 45. The method of any one of claims 39-44, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:

yes

46. The method of any one of claims 39-45, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: ^Y1 and ^Y2 are hydrogen. 47. The method of any one of claims 39-46, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹¹ is hydrogen, halogen, or -OH. 48. The method of any one of claims 39-47, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹¹ is hydrogen. 49. The method of any one of claims 39-48, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹² is hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. 50. The method of any one of claims 39-49, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹² is C ₁ -C ₆ alkyl. 51. The method of any one of claims 39-50, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹³ is -CN, heterocycloalkyl, heteroaryl, or -CH ₂ (heteroaryl); wherein the heterocycloalkyl and heteroaryl are independently optionally replaced by one, two or three R ^13a replace. 52. The method of any one of claims 39-51 , or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹³ is heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl are independently optionally substituted by one, two or three R ^13a . 53. The method of any one of claims 39-52, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹³ is heteroaryl optionally substituted with one, two or three R ^13a . 54. The method of any one of claims 39-53, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹³ is heterocycloalkyl optionally substituted by one, two or three R ^13a . 55. The method of any one of claims 39-54, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R ^13a is independently oxo, -OR ¹⁹ , -NR ²⁰ R ²¹ , -C(=O)R ¹⁸ , -C(=O)OR ¹⁹ , -C(=O)NR ²⁰ R ²¹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ deuterated alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ aminoalkyl, C ₁ -C ₆ heteroalkyl , or aryl. 56. The method of any one of claims 39-55, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R ^13a is independently oxo, -OR ¹⁹ , -NR ²⁰ R ²¹ , -C(=O)NR ²⁰ R ²¹ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ hydroxyalkyl, or aryl. 57. The method of any one of claims 39-56, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Each R ^13a is independently -OR ¹⁹ , -NR ²⁰ R ²¹ , or -C(=O)NR ²⁰ R ²¹ . 58. The method of any one of claims 39-57, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹⁵ and R ¹⁶ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ deuterioalkyl. 59. The method of any one of claims 39-58, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ¹⁵ and R ¹⁶ are independently C ₁ -C ₆ alkyl. 60. The method of any one of claims 39-59, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is C ₁ -C ₆ alkyl or -C(=O)OR ⁵ . 61. The method of any one of claims 39-60, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R ³ is C ₁ -C ₆ alkyl. 62. The method of claim 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is:

63. The method of any one of claims 39-62, wherein the disease is systemic lupus nephritis. 64. The method of any one of claims 39-62, wherein the disease is diabetic chronic kidney disease (CDK). 65. The method of any one of claims 39-62, wherein the disease is Alport syndrome. 66. The method of any one of claims 39-62, wherein the disease is focal segmental glomerulosclerosis (FSGS). 67. The method of any one of claims 39-62, wherein the disease is pulmonary hypertension. 68. The method of any one of claims 39-62, wherein the disease is Friedreich's ataxia. 69. The method of any one of claims 39-62, wherein the disease is autosomal dominant polycystic kidney disease (ADPKD). 70. The method of any one of claims 39-62, wherein the disease is IgA nephropathy.

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