CN115697319A - Use of triterpenoid NRF2 inhibitors - Google Patents

Use of triterpenoid NRF2 inhibitors Download PDF

Info

Publication number
CN115697319A
CN115697319A CN202180026671.3A CN202180026671A CN115697319A CN 115697319 A CN115697319 A CN 115697319A CN 202180026671 A CN202180026671 A CN 202180026671A CN 115697319 A CN115697319 A CN 115697319A
Authority
CN
China
Prior art keywords
radical
alkyl
heterocycloalkyl
deuterium
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202180026671.3A
Other languages
Chinese (zh)
Inventor
金博翰
董晴
洪真
S·W·卡尔多
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Haisco Pharmaceutical Co Ltd
Original Assignee
Sichuan Haisco Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan Haisco Pharmaceutical Co Ltd filed Critical Sichuan Haisco Pharmaceutical Co Ltd
Publication of CN115697319A publication Critical patent/CN115697319A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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

Use of triterpenoid NRF2 inhibitor
Cross-referencing
This application claims the benefit of U.S. provisional application serial No. 63/003,719, filed on 4/1/2020 and incorporated herein by reference in its entirety.
Background
Kidney disease is highly prevalent worldwide and significantly reduces the quality of life of patients, and there is an urgent need for effective treatment modalities. Despite this significant unmet medical need, none of the drugs on the market 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 determining appropriate therapeutic targets for clinical trials. Recently, the us, european union and japan have considered the surrogate end point of clinical trials (i.e., the estimated glomerular filtration rate eGFR decreases by 30% or 40% from baseline over 2-3 years of observation), and this surrogate end point is expected to contribute to the progress of drug development for kidney disease. In addition, oxidative stress and inflammation are currently considered as key factors in the progression of kidney disease, thereby facilitating the study of more drugs targeting the mechanisms associated with these factors for treatment. The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap 1-Nrf 2) system has attracted attention in recent years because of its antioxidant and anti-inflammatory properties and its pharmacological potential for the treatment of kidney diseases, which potential has been widely studied in both clinical and non-clinical studies.
Many reports describe the association between Nrf2 and kidney disease. Furthermore, a review by Nezu et al discusses the role of Nrf2 in genetically modified animals (Nrf 2 knockdown [ KO ], keap1 knockdown [ KD ] and Keap1 conditional KO [ cKO ]) (Nezu, m., suzuki, n., yamamoto, m.,2017.Targeting the Keap1-Nrf2 system to present kidney disease progression [ targeting Keap1-Nrf2 system to prevent kidney disease progression ] am.j.nephrol [ american society of renal science ]45, 473-483). Nrf2-KO mutations cause exacerbation of lupus-like nephritis, streptozotocin-induced nephropathy (including renal function), iron nitrilotriacetate-induced nephrotoxicity, and Ischemia Reperfusion (IRI) -induced renal injury. In contrast, the Keap1-KD mutation was associated with reduction of IRI-induced renal tubular injury and reduction of unilateral ureteral obstruction-induced renal fibrosis.
Numerous studies have evaluated the effects of Nrf2 activators (e.g., sulforaphane, curcumin) and synthetic triterpenoids (CDDO) (e.g., bardoxolone methyl [ CDDO-Me ]) on kidney injury. Similar to the results in genetically modified animals, several other studies have also shown that Nrf2 activation leads to a reduction in kidney injury, suggesting therapeutic potential to target this pathway to treat kidney disease. There is a need for the treatment of kidney disease.
Disclosure of Invention
Disclosed herein are methods of treating a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), alport syndrome, focal Segmental Glomerulosclerosis (FSGS), pulmonary arterial hypertension, friedreich's ataxia, autosomal Dominant Polycystic Kidney Disease (ADPKD), or IgA nephropathy, comprising administering to a subject in need thereof a compound having formula (III):
Figure BDA0003874037850000021
wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 -Z-O-cycloalkyl, -Z-O-heterocycloalkyl, -Z-O-aryl, -Z-O-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) 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 is- (C) 1 -C 6 Alkylene) OP (= O) (OR) 5 )[N(R 5 ) 2 ](ii) a Wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
y is a bond, -O-, -S-, or-NR b -；
Z is a bond or C 1 -C 6 An alkylene group;
R x is hydrogen, -NO 2 -CN, or-S (= O) 2 R a ；
Each R 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl radical、C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000041
is that
Figure BDA0003874037850000042
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 Together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
R 12 and R 13 Independently of each other is hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 12 And R 13 Together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0 to 6R 14 Substitution;
each R 14 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
R 15 and R 16 Independently of each other is hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 15 And R 16 Together forming a cycloalkyl or hetero ringA cycloalkyl group; each of which is substituted by 0 to 6R 2 Substitution;
each R 2 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
Also disclosed herein are methods of treating a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), alport syndrome, focal Segmental Glomerulosclerosis (FSGS), pulmonary arterial hypertension, friedreich's ataxia, autosomal Dominant Polycystic Kidney Disease (ADPKD), or IgA nephropathy, comprising administering to a subject in need thereof a compound having formula (VIII):
Figure BDA0003874037850000061
Wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3b Substitution;
each R 3b Independently 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a Independently is 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000081
is that
Figure BDA0003874037850000082
Y 1 And Y 2 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
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 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, 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 with one, two or three R 13a Substitution;
each R 13a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 18 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 18a Substitution;
each R 18a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 19 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 19a Substitution;
each R 19a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 20 And R 21 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 20a Substitution;
each R 20a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 an optionally substituted one, two or three R 20b Substituted heterocycloalkyl;
each R 20b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 15 and R 16 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 15 And R 16 Together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0 to 6R 2 Substitution;
each R 2 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxy radicalAlkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
Is incorporated by reference
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purpose to which this specification pertains.
Drawings
Figure 1A shows spleen weight to body weight after treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
Figure 1B shows spleen mRNA expression fold after treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
Figure 2A shows serum BUN (blood urea nitrogen) levels after treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
Figure 2B shows urinary protein levels following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
Figure 3A shows kidney weight to body weight after treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
Figure 3B shows the kidney histopathological score after treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
Figure 3C shows NGAL expression in the kidney following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
Figure 3D shows CD11b expression in the kidney after treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
Detailed Description
Definition of
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, and reference to "a cell" includes reference to one or more cells (or a plurality of cells), and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), it is intended to include all combinations and subcombinations of ranges and specific embodiments therein. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or statistical experimental error), and thus in some cases the number or numerical range will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms, such as "comprising" or "comprises" or "having" or "including") is not intended to exclude the presence of "consisting of or" consisting essentially of the recited features "in other certain embodiments, such as the embodiments of any composition of matter, composition, method, or process described herein.
Unless indicated to the contrary, the following terms, as used in the present specification and appended claims, have the meanings indicated below.
"aliphatic chain" refers to a linear chemical moiety consisting only of carbon and hydrogen. In some embodiments, the fatty chain is saturated. In some embodiments, the fatty chain is unsaturated. In some embodiments, the unsaturated fatty chain contains one unsaturation. In some embodiments, the unsaturated fatty chain contains more than one 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" refers to an optionally substituted straight chain, or optionally substituted branched chain saturated hydrocarbon mono-radical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein sp of the alkyl residue 3 The hybridized carbon is attached to the rest of the molecule by a single bond. Examples include, but are not limited to: methyl radicalEthyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 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-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, as well as longer alkyl groups (e.g., heptyl, octyl, etc.). Whenever present herein, e.g. "C 1 -C 6 The numerical range of alkyl "means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also covers the occurrence of the term" alkyl "where no numerical range is specified. In some embodiments, alkyl is C 1 -C 10 Alkyl radical, C 1 -C 9 Alkyl radical, C 1 -C 8 Alkyl radical, C 1 -C 7 Alkyl radical, C 1 -C 6 Alkyl radical, C 1 -C 5 Alkyl radical, C 1 -C 4 Alkyl radical, C 1 -C 3 Alkyl radical, C 1 -C 2 Alkyl, or C 1 An alkyl group. Unless otherwise specifically stated in the specification, an alkyl group is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkyl is optionally oxo, halo, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, alkyl is optionally oxo, halo, -CN, -CF 3 -OH, or-OMe. In some embodiments, alkyl is optionally substituted with halo.
"alkenyl" means an optionally substituted straight chain, or optionally substituted branched chain hydrocarbon mono-radical having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein the sp of the alkenyl residue is 2 The hybridized carbon is attached to the rest of the molecule by a single bond. The groupMay be in either the cis or trans conformation about one or more double bonds and should be understood to include both isomers. Examples include, but are not limited to: vinyl (-CH = CH) 2 ) 1-propenyl (-CH) 2 CH＝CH 2 ) Isopropenyl [ -C (CH) 3 )＝CH 2 ]Butenyl, 1, 3-butadienyl and the like. Whenever present herein, e.g. "C 2 -C 6 The numerical range of "alkenyl" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also encompasses the occurrence of the term "alkenyl" without a specified numerical range. In some embodiments, alkenyl is C 2 -C 10 Alkenyl radical, C 2 -C 9 Alkenyl radical, C 2 -C 8 Alkenyl radical, C 2 -C 7 Alkenyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 5 Alkenyl radical, C 2 -C 4 Alkenyl radical, C 2 -C 3 Alkenyl, or C 2 An alkenyl group. Unless otherwise specifically stated in the specification, an alkenyl group is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkenyl is optionally substituted with oxo, halo, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, alkenyl is optionally substituted with oxo, halo, -CN, -CF 3 -OH, or-OMe. In some embodiments, the alkenyl is optionally substituted with halo.
"alkynyl" refers to an optionally substituted straight or optionally substituted branched chain hydrocarbon mono-radical 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 present herein, e.g. "C 2 -C 6 The numerical range of "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, but the present definition also encompasses techniques not specifying a numerical rangeThe term "alkynyl" appears. In some embodiments, 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 stated otherwise specifically in the specification, alkynyl groups are optionally substituted with, for example, oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halo, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, alkynyl is optionally substituted with oxo, halo, -CN, -CF 3 -OH, or-OMe. In some embodiments, alkynyl is optionally substituted with halo.
"alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, an alkylene group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkylene is optionally oxo, halo, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, alkylene is optionally oxo, halo, -CN, -CF 3 -OH, or-OMe. In some embodiments, the alkylene is optionally substituted with halogen.
"alkoxy" means having the formula-OR a In which R is a Is an alkyl radical as defined. Unless otherwise specifically stated in the specification, alkoxy groups may be optionally substituted with, for example, oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkoxy is optionally substituted with oxo, halo, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, alkoxy groupsOptionally substituted by oxo, halogen, -CN, -CF 3 -OH, or-OMe. In some embodiments, alkoxy is optionally substituted with halo.
"aminoalkyl" refers to an alkyl radical as defined above, substituted with one or more amines. In some embodiments, the alkyl group is substituted with one 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, the hydroxyalkyl group is an aminomethyl group.
"aryl" refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (the aryl group being bonded through an aromatic ring atom when fused to a cycloalkyl or heterocycloalkyl ring) or bridged ring systems. In some embodiments, the aryl is a 6-to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to: derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene,
Figure BDA0003874037850000141
Fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenalene, phenanthrene, obsidian, pyrene, and benzo [9,10]Aryl radicals of the hydrocarbon ring system of phenanthrenes. In some embodiments, aryl is phenyl. Unless otherwise specifically stated in the specification, aryl groups may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 -OH, or-OMe. In some embodiments, aryl is optionally substituted with halo.
"cycloalkyl" means stableA partially or fully saturated, monocyclic or polycyclic, carbocycle, which may include a fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring system. Representative cycloalkyl groups include, but are not limited to: cycloalkyl having three to fifteen carbon atoms (C) 3 -C 15 Cycloalkyl), cycloalkyl of 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), cycloalkyl of three to five carbon atoms (C) 3 -C 5 Cycloalkyl), or cycloalkyl of three to four carbon atoms (C) 3 -C 4 Cycloalkyl). In some embodiments, the cycloalkyl is a 3-to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5-to 6-membered cycloalkyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocycles include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo [3.3.0]Octane, bicyclo [4.3.0]Nonanes, cis-decalin, trans-decalin, bicyclo [2.1.1]Hexane, bicyclo [2.2.1 ]]Heptane, bicyclo [2.2.2]Octane, bicyclo [3.2.2]Nonanes, and bicyclo [3.3.2]Decane, and 7, 7-dimethyl-bicyclo [2.2.1]A heptalkyl group. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 -OH, or-OMe. In some embodiments, the cycloalkyl is optionally substituted with halo.
"deuterated alkyl" refers to an alkyl radical as defined above substituted with one or more deuterium. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, alkyl is substituted with one, two, or three deuterium. In some embodiments, alkyl is substituted with one, two, three, four, five, or six deuterium groups. Deuterated alkyl includes, for example, CD 3 、CH 2 D、CHD 2 、CH 2 CD 3 、CD 2 CD 3 、CHDCD 3 、CH 2 CH 2 D. Or CH 2 CHD 2 . In some embodiments, the deuterated alkyl is CD 3 。
"haloalkyl" refers to an alkyl radical as defined above, substituted with one or more halogens. In some embodiments, alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.
"halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.
"heteroalkyl" refers to an alkyl group in which one or more of the backbone atoms of the alkyl group is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N (alkyl) -), sulfur, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, heteroalkyl is C 1 -C 6 A 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 a carbon atom of the heteroalkyl group. Examples of such heteroalkyl radicals are, for example, -CH 2 OCH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 2 OCH 3 or-CH (CH) 3 )OCH 3 . Unless otherwise specifically stated in the specification, heteroalkanesThe groups are optionally substituted with, for example, oxo, halo, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroalkyl is optionally oxo, halo, methyl, ethyl, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 -OH, or-OMe. In some embodiments, the heteroalkyl is optionally substituted with halo.
"hydroxyalkyl" refers to an alkyl radical as defined above, which is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, alkyl is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.
"heterocycloalkyl" refers to a stable 3-to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and from one to 8 heteroatoms (selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur). Unless otherwise specifically stated in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom) or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized; the nitrogen atoms may optionally be quaternized.
Representative heterocycloalkyl groups include, but are not limited to: heterocycloalkyl having two to fifteen carbon atoms (C) 2 -C 15 Heterocycloalkyl), heterocycloalkyl of two to ten carbon atoms (C) 2 -C 10 Heterocycloalkyl group), heterocycloalkyl group of two to eight carbon atoms (C) 2 -C 8 Heterocycloalkyl), heterocycloalkyl of two to six carbon atoms (C) 2 -C 6 Heterocycloalkyl), heterocycloalkyl of two to five carbon atoms (C) 2 -C 5 Heterocycloalkyl radicals) Or heterocycloalkyl of two to four carbon atoms (C) 2 -C 4 Heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5-to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to: aziridinyl, azetidinyl, dioxolanyl, thienyl [1,3 ]]Dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxopenten-4-yl, and 2-oxo-1, 3-dioxopenten-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. It will be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group will be different from the total number of atoms (including heteroatoms) that make up the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, heterocycloalkyl is optionally substituted with, for example, oxo, halo, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 -OH, or-OMe. In some embodiments, the heterocycloalkyl group is optionally substituted with halo.
"heteroaryl" refers to a 5-to 14-membered ring system radical containing a hydrogen atom, one to thirteen carbon atoms, one to six hetero atomsAn atom selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. A heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (the heteroaryl group being bonded through an aromatic ring atom when fused to a cycloalkyl or heterocycloalkyl ring) or bridged ring systems; and the nitrogen, carbon or sulfur atom in the heteroaryl radical may be optionally oxidized; the nitrogen atoms may optionally be quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. Examples include, but are not limited to: azepatrienyl (aza)
Figure BDA0003874037850000181
Base), acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ] benzo ][1,4]Dioxa medicine
Figure BDA0003874037850000182
A group, a 1, 4-benzodioxanyl group, a benzonaphthofuranyl group, a benzoxazolyl group, a benzodioxolyl group, a benzodioxinyl group, a benzopyran group, a benzofuranyl group, a benzofuranonyl group, a benzothiophenyl group (a benzothiophenyl group), a benzotriazolyl group, a benzo [4,6 ] group]Imidazo [1,2-a ]]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl (azacycloheptatrienyl)
Figure BDA0003874037850000183
Alkyl), oxazolyl, oxiranyl, 1-oxidopyridyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, and the like purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, and the like,Pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in the specification, heteroaryl is optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (4) substitution. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 -OH, or-OMe. In some embodiments, heteroaryl is optionally substituted with halo.
The terms "treat," "prevent," "improve," and "inhibit" and words derived therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, improvement, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition that one of ordinary skill in the art would consider to have a potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of a disorder in a mammal. For example, a disorder (including symptoms or conditions thereof) may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treating, preventing, ameliorating, or inhibiting one or more conditions or symptoms of a disorder (e.g., cancer or inflammatory disease). Furthermore, for purposes herein, "treating," "preventing," "ameliorating," or "inhibiting" encompasses delaying the onset of the disorder or a symptom or condition thereof.
The term "effective amount" or "therapeutically effective amount" as used herein refers to an amount of a compound disclosed herein administered that will alleviate one or more symptoms of the disease or disorder being treated (e.g., cancer or inflammatory disease) to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to reduce the symptoms of a disease significantly clinically. In some embodiments, in any individual case, an appropriate "effective" amount is determined using techniques (e.g., dose escalation studies).
Compound (I)
Disclosed herein are compounds having the formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure BDA0003874037850000191
wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
each R 2 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
n is 0 to 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 3b Substitution;
each R 3b Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000211
is that
Figure BDA0003874037850000212
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 Together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
R 12 and R 13 Independently of each other is hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 12 And R 13 Together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0 to 6R 14 Substitution;
each R 14 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
In some embodiments of compounds having formula (I), R 1 is-CN, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds of formula (I), R 1 is-CN or C 1 -C 6 A haloalkyl group. In some embodiments of compounds of formula (I), R 1 Is C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (I), R 1 is-CN.
In some embodiments of compounds having 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 having formula (I), R 9 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (I), R 9 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (I), R 10 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (I), R 10 Is C 1 -C 6 An alkyl group.
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 having formula (I), R 10 Is C 1 -C 6 Alkyl and R 9 Is C 2 -C 6 Alkynyl.
In some embodiments of the compounds having formula (I),
Figure BDA0003874037850000231
is that
Figure BDA0003874037850000232
In some embodiments of the compounds having formula (I),
Figure BDA0003874037850000233
is that
Figure BDA0003874037850000234
In some embodiments of compounds having formula (I), R 11 Is hydrogen, halogen, or-OH. In some embodiments of compounds having 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 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (I), R 12 And R 13 Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (I), R 12 And R 13 Independently is hydrogen or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (I), R 12 And R 13 Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (I), R 12 And R 13 Together form a cycloalkyl group. In some embodiments of compounds of formula (I), R 12 And R 13 Together form a cycloalkyl group substituted with 1-4 deuterium groups. In some embodiments of compounds having formula (I), R 12 And R 13 Together form a cycloalkyl group substituted with 1 or 2 deuterium groups. In some embodiments of compounds of formula (I), R 12 And R 13 Together form a cycloalkyl group substituted with 2-4 deuterium groups.
In some embodiments of compounds having formula (I), R 12 And R 13 Together form a heterocycloalkyl group. In some embodiments of compounds having formula (I), R 12 And R 13 Together form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds having formula (I), R 12 And R 13 Together form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of compounds having formula (I), R 12 And R 13 Together form a heterocycloalkyl substituted with 2-4 deuterium.
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 radical, C 2 -C 6 Alkenyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted with one, two, or three R 3a And (4) substitution. In some embodiments of compounds having 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 of 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 having formula (I), R 3 Is optionally substituted by one, two or three R 3a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (I), R 3 Is C 1 -C 6 An alkyl group.
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 is 3a Independently of each other, 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 is 3a Independently of each other, 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 is 3a Independently of each other, 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 formula (I), each R 3a Independently is-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 is 3a Independently is-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 formula (I), each R 3a Independently is-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 is 3a Independently is-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 Independently deuterium, halogen, -CN, -OR b 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (I), each R is 3b Independently of each other is deuterium, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (I), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, 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 substituted with one, two, or three R 4a Substitution. In some embodiments of compounds having formula (I), each R is 4 Independently is C 1 -C 6 Alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 4a And (4) substitution. In some embodiments of compounds having formula (I), each R is 4 Independently is optionally substituted by one, two or three R 4a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (I), each R is 4 Independently is C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (I), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (I), each R 4a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (I), each R 4a Independently is deuterium or halogen. In some embodiments of compounds having formula (I), each R 4a Independently a halogen.
In some embodiments of compounds having formula (I), each R is 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 5a And (4) substitution. In some embodiments of compounds having formula (I), each R is 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formula (I), each R is 5 Independently is optionally substituted by one, two or three R 5a Substituted hydrogen or C 1 -C 6 An alkyl group. In a compound having the formula (I)In some embodiments, each R 5 Independently is optionally substituted by one, two or three R 5a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (I), each R 5 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (I), each R 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (I), two R are 5 Together form an optionally substituted heterocycloalkyl.
In some embodiments of compounds having formula (I), each R is 5a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (I), each R is 5a Independently deuterium or halogen. In some embodiments of compounds having formula (I), each R is 5a Independently a halogen. In some embodiments of compounds having formula (I), each R 5a Independently is-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 is 5a Independently is-S (= O) (= NR) x )R b or-S (= O) (= NR) x )NR c R d 。
In some embodiments of compounds having formula (I), each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (I), each R 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (I), each R is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group; wherein the alkyl is independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (I), each R 6 And R 7 Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (I), each R is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (I), each R is 6a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (I), each R is 6a Independently deuterium or halogen. In some embodiments of compounds having formula (I), each R 6a Independently a halogen. In some embodiments of compounds having formula (I), each R 5a Independently is-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 Independently is-S (= O) (= NR) x )R b or-S (= O) (= NR) x )NR c R d 。
In some embodiments of compounds having formula (I), R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl group.
In some embodiments of compounds having formula (I), each R is 6b Independently is oxo,Deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (I), each R 6b Independently is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (I), each R is 6b Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (I), R x Is hydrogen, -NO 2 or-CN. In some embodiments of compounds having formula (I), R x is-NO 2 or-CN. In some embodiments of compounds of formula (I), R x is-CN.
In some embodiments of compounds having formula (I), ring a is cycloalkyl. In some embodiments of compounds having formula (I), ring a is heterocycloalkyl.
In some embodiments of compounds having formula (I), each R is 2 Independently of each other, deuterium, halogen, -CN, -OR b 、C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (I), each R is 2 Is deuterium.
In some embodiments of compounds having formula (I), n is 0. In some embodiments of compounds having formula (I), n is 1. In some embodiments of compounds having formula (I), n is 2. In some embodiments of compounds having formula (I), n is 3. In some embodiments of compounds having formula (I), n is 4. In some embodiments of compounds having formula (I), n is 5. In some embodiments of compounds having formula (I), n is 6. In some embodiments of compounds having formula (I), n is 1-4. In some embodiments of compounds having formula (I), n is 1 or 2. In some embodiments of compounds having formula (I), n is 2-4.
Disclosed herein are compounds having the formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure BDA0003874037850000281
wherein:
ring B is cycloalkyl or heterocycloalkyl;
each R 14 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
m is 0 to 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3b Substitution;
each R 3b Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 A halogenated alkyl group,C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000301
is that
Figure BDA0003874037850000302
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 Together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
R 15 and R 16 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group、C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 15 And R 16 Together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6R 2 Substitution;
each R 2 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogens, -OH、-NH 2 Or C 1 -C 6 Alkyl substitution; and is
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
In some embodiments of compounds having formula (II), R 1 is-CN, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (II), R 1 is-CN or C 1 -C 6 A haloalkyl group. In some embodiments of compounds of formula (II), R 1 Is C 1 -C 6 A haloalkyl group. In some embodiments of compounds having 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 having formula (II), R 8 Is hydrogen.
In some embodiments of compounds having formula (II), R 9 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (II), R 9 Is C 1 -C 6 An alkyl group.
In some embodiments of the compound of formula (II)In the examples, 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 An alkyl group.
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.
In some embodiments of the compounds having formula (II),
Figure BDA0003874037850000321
is that
Figure BDA0003874037850000322
In some embodiments of the compounds having formula (II),
Figure BDA0003874037850000323
is that
Figure BDA0003874037850000324
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 having formula (II), R 11 Is hydrogen.
In some embodiments of compounds of formula (II), R 15 And R 16 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (II), R 15 And R 16 Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds of formula (II), R 15 And R 16 Independently of each other is hydrogen or C 1 -C 6 A deuterated alkyl group. Some in the compounds of formula (II)In the examples, R 15 And R 16 Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (II), R 15 And R 16 Together form a cycloalkyl group. In some embodiments of compounds having formula (II), R 15 And R 16 Together form a cycloalkyl group substituted with 1-4 deuterium groups. In some embodiments of compounds of formula (II), R 15 And R 16 Together form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of compounds having formula (II), R 15 And R 16 Together form a cycloalkyl group substituted with 2-4 deuterium groups.
In some embodiments of compounds of formula (II), R 15 And R 16 Together form a heterocycloalkyl group. In some embodiments of compounds of formula (II), R 15 And R 16 Together form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds of formula (II), R 15 And R 16 Together form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of compounds of formula (II), R 15 And R 16 Together form a heterocycloalkyl substituted with 2-4 deuterium.
In some embodiments of compounds of 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 radical, C 2 -C 6 Alkenyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted with one, two, or three R 3a And (4) substitution. 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 having formula (II), R 3 Is optionally substituted by one, two or three R 3a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds of formula (II), R 3 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (II), R 3 is-C (= O) OR 5 。
In some embodiments of compounds having formula (II), each R is 3a 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 at least one position ofIn some embodiments of the compounds of formula (II), each R 3a Independently of each other, 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 is 3a Independently of each other, 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 formula (II), each R is 3a Independently is-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 is 3a independently-OC (= O) R 4 、-C(＝O)OR 5 、-OC(＝O)OR 5 or-C (= O) NR 6 R 7 . In some embodiments of the compounds having formula (II),each R 3a 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 is 3a Independently is-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 is 3b Independently of each other, deuterium, halogen, -CN, -OR b 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (II), each R is 3b Independently of each other is deuterium, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (II), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, 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 substituted with one, two or three R 4a And (4) substitution. In some embodiments of compounds having formula (II), each R is 4 Independently is C 1 -C 6 Alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 4a And (4) substitution. In some embodiments of compounds having formula (II), each R is 4 Independently is optionally substituted by one, two or three R 4a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (II), each R is 4 Independently is C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (II), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (II), each R is 4a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (II), each R is 4a Independently deuterium or halogen. In some embodiments of compounds having formula (II), each R is 4a Independently a halogen.
In some embodiments of compounds having formula (II), each R is 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formula (II), each R is 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formula (II), each R is 5 Independently is optionally substituted by one, two or three R 5a Substituted hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (II), each R is 5 Independently is optionally substituted by one, two or three R 5a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (II), each R is 5 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (II), each R is 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (II), two R are 5 Together form an optionally substituted heterocycloalkyl.
In some embodiments of compounds having formula (II), each R is 5a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (II), each R is 5a Independently is deuterium or halogen. In some embodiments of compounds having formula (II), each R is 5a Independently a halogen. In some embodiments of compounds having formula (II), each R is 5a Independently is-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 is 5a Independently is-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 is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (II), each R is 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (II), each R is 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group; wherein the alkyl is independently optionally substituted with one, two or three R 6a And (4) substitution. Some in the compounds of formula (II)In the examples, each R 6 And R 7 Independently of each other is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (II), each R is 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (II), each R is 6a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (II), each R is 6a Independently is deuterium or halogen. In some embodiments of compounds having formula (II), each R is 6a Independently a halogen. In some embodiments of compounds having formula (II), each R is 5a Independently is-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 is 6a Independently is-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 an optionally substituted one, two or three R 6b Substituted heterocycloalkyl group.
In some embodiments of compounds having formula (II), each R is 6b Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (II), each R is 6b Independently is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (II), each R is 6b Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (II), R x Is hydrogen, -NO 2 or-CN. In some embodiments of compounds having formula (II), R x is-NO 2 or-CN. In some embodiments of compounds having formula (II), R x 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 having formula (II), each R is 14 Independently of each other, deuterium, halogen, -CN, -OR b 、C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (II), each R is 14 Is deuterium.
In some embodiments of compounds having formula (II), m is 0. In some embodiments of compounds having formula (II), m is 1. In some embodiments of compounds having 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 having formula (II), m is 5. In some embodiments of compounds having formula (II), m is 6. In some embodiments of compounds having formula (II), m is 1-4. In some embodiments of compounds having formula (II), m is 1 or 2. In some embodiments of compounds having formula (II), m is 2 to 4.
Disclosed herein are compounds having the formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure BDA0003874037850000361
wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 -Z-O-cycloalkyl, -Z-O-heterocycloalkyl, -Z-O-aryl, -Z-O-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) 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 is- (C) 1 -C 6 Alkylene) OP (= O) (OR) 5 )[N(R 5 ) 2 ](ii) a Wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
y is a bond, -O-, -S-, or-NR b -；
Z is a bond or C 1 -C 6 An alkylene group;
R x is hydrogen, -NO 2 -CN, or-S (= O) 2 R a ；
Each R 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000381
is that
Figure BDA0003874037850000382
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 Together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
R 12 and R 13 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 12 And R 13 Together form a cycloalkyl or heterocycloalkyl; each of which is substituted by 0 to 6R 14 Substitution;
each R 14 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
R 15 and R 16 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 15 And R 16 Together form a cycloalkyl or heterocycloalkyl; each of which is substituted by 0 to 6R 2 Substitution;
each R 2 Independently of each other is 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is provided with
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
In some embodiments of compounds having formula (III), R 1 is-CN, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (III), R 1 is-CN or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (III), R 1 Is C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (III), R 1 is-CN.
In some embodiments of compounds having formula (III), R 8 Is hydrogen or deuterium. In some embodiments of compounds having formula (III), R 8 Is hydrogen.
In some embodiments of compounds having formula (III), R 9 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (III), R 9 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (III), R 10 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (III), R 10 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (III), R 9 Is C 1 -C 6 Alkyl and R 10 Is C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (III), R 10 Is C 1 -C 6 Alkyl and R 9 Is C 2 -C 6 Alkynyl.
In some embodiments of the compounds having formula (III),
Figure BDA0003874037850000401
is that
Figure BDA0003874037850000402
In some embodiments of the compounds having formula (III),
Figure BDA0003874037850000403
is that
Figure BDA0003874037850000404
In some embodiments of compounds having formula (III), R 11 Is hydrogen, halogen, or-OH. In some embodiments of compounds having formula (III), R 11 Is hydrogen or-OH. In some embodiments of compounds having formula (III), R 11 Is hydrogen.
In some embodiments of compounds having formula (III), R 12 And R 13 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (III), R 12 And R 13 Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (III), R 12 And R 13 Independently is hydrogen or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (III), R 12 And R 13 Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (III), R 12 And R 13 Together form a cycloalkyl group. In some embodiments of compounds having formula (III), R 12 And R 13 Together form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds having formula (III), R 12 And R 13 Together form a cycloalkyl group substituted with 1 or 2 deuterium groups. In some embodiments of compounds having formula (III), R 12 And R 13 Together form a cycloalkyl substituted with 2-4 deuterium.
In some embodiments of compounds having formula (III), R 12 And R 13 Together form a heterocycloalkyl group. In some embodiments of compounds having formula (III), R 12 And R 13 Together form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds having formula (III), R 12 And R 13 Together form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of compounds having formula (III), R 12 And R 13 Together form a heterocycloalkyl substituted with 2-4 deuterium.
In some embodiments of compounds having formula (III), R 15 And R 16 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (III), R 15 And R 16 Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (III), R 15 And R 16 Independently of each other is hydrogen or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (III), R 15 And R 16 Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (III), R 15 And R 16 Together form a cycloalkyl group. In some embodiments of compounds having formula (III), R 15 And R 16 Together form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds having formula (III), R 15 And R 16 Together form a cycloalkyl group substituted with 1 or 2 deuterium groups. In some embodiments of compounds having formula (III), R 15 And R 16 Together form a cycloalkyl group substituted with 2-4 deuterium groups.
In some embodiments of compounds having formula (III), R 15 And R 16 Together form a heterocycloalkyl group. In some embodiments of compounds having formula (III), R 15 And R 16 Together form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds having formula (III), R 15 And R 16 Together form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of compounds having formula (III), R 15 And R 16 Together form a heterocycloalkyl substituted with 2-4 deuterium.
In some embodiments of compounds having formula (III), 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)(＝NR x )R 5 An N-linked heterocycloalkyl, or an N-linked heteroaryl. In some embodiments of compounds having formula (III), 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 . In some embodiments of compounds having 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 having 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 having 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 an N-linked heterocycloalkyl or an N-linked heteroaryl.
On toolIn some embodiments of the compounds of formula (III), 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) 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 An N-linked heterocycloalkyl group, or an N-linked heteroaryl group.
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) NR 5 C(＝NR x )NR 6 R 7 。
In some embodiments of compounds having formula (III), -Y is a bond. In some embodiments of compounds having formula (III), Y is a bond or-O-.
In some embodiments of compounds having formula (III), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, 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 substituted with one, two, or three R 4a And (4) substitution. In some embodiments of compounds having formula (III), each R is 4 Independently is C 1 -C 6 Alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 4a And (4) substitution. In some embodiments of compounds having formula (III), each R is 4 Independently is optionally substituted by one, two or three R 4a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (III), each R is 4 Independently is C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (III), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (III), each R is 4a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (III), each R is 4a Independently is deuterium or halogen. In some embodiments of compounds having formula (III), each R is 4a Independently a halogen.
In some embodiments of compounds having formula (III), each R is 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formula (III), each R is 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formula (III), each R is 5 Independently is optionally substituted by one, two or three R 5a Substituted hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (III), each R is 5 Independently is optionally substituted by one, two or three R 5a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (III), each R is 5 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (III), each R is 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (III), two R are 5 Together form an optionally substituted heterocycloalkyl.
In some embodiments of compounds having formula (III), each R is 5a 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 Or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (III), each R is 5a Independently halogen, -CN, -OR b 、-NR c R d 、-C(＝O)OR b Or C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (III), each R is 5a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (III), each R is 5a Independently is deuterium or halogen. In some embodiments of compounds having formula (III), each R is 5a Independently a halogen.
In some embodiments of compounds having formula (III), each R is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a And (4) substitution. In some embodiments of compounds having formula (III), each R is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a And (4) substitution. In some embodiments of compounds having formula (III), each R is 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group; wherein the alkyl is independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (III), each R is 6 And R 7 Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (III), each R is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (III), each R is 6a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (III), each R is 6a Independently is deuterium or halogen. In some embodiments of compounds having formula (III), each R is 6a Independently a halogen. In some embodiments of compounds having formula (III), each R is 5a Independently is-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 is 6a Independently is-S (= O) (= NR) x )R b or-S (= O) (= NR) x )NR c R d 。
In some embodiments of compounds having formula (III), R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl group.
In some embodiments of compounds having formula (III), each R is 6b Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (III), each R is 6b Independently is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (III), each R is 6b Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (III), R x Is hydrogen, -NO 2 or-CN. In some embodiments of compounds having formula (III), R x is-NO 2 or-CN. In some embodiments of compounds having formula (III), R x is-CN.
In some embodiments of compounds having formula (III), R 3 Is that
Figure BDA0003874037850000451
Figure BDA0003874037850000452
Figure BDA0003874037850000461
In some embodiments of compounds having formula (III), R 3 Is that
Figure BDA0003874037850000462
Figure BDA0003874037850000463
Disclosed herein are compounds having the formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure BDA0003874037850000464
wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3b Substitution;
each R 3b Independently 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 4a Substitution;
each R 4a Independently is 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group,C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000481
is that
Figure BDA0003874037850000482
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
with the proviso that R 9 Or R 10 Is one of C 2 -C 6 An alkynyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 Together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
R 12 and R 13 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 12 And R 13 Together form a cycloalkyl or heterocycloalkyl; each of which is substituted by 0 to 6R 14 Substitution;
each R 14 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
R 15 and R 16 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, or C 1 -C 6 A hydroxyalkyl group;
or R 15 And R 16 Together form a cycloalkyl or heterocycloalkyl; each of which is substituted by 0-6R 2 Substitution;
each R 2 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form a halogen atom optionally substituted with one, two or three deuterium, halogen,-OH、-NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
In some embodiments of compounds having formula (IV), R 1 is-CN, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (IV), R 1 is-CN or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (IV), R 1 Is C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (IV), R 1 is-CN.
In some embodiments of compounds having formula (IV), R 8 Is hydrogen or deuterium. In some embodiments of compounds having formula (IV), R 8 Is hydrogen.
In some embodiments of compounds having formula (IV), R 9 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (IV), R 9 Is C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (IV), R 9 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (IV), R 10 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (IV), R 10 Is C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (IV), R 10 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (IV), R 9 Is C 1 -C 6 Alkyl and R 10 Is C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (IV), R 10 Is C 1 -C 6 Alkyl and R 9 Is C 2 -C 6 Alkynyl.
In some embodiments of the compound having formula (IV),
Figure BDA0003874037850000501
is that
Figure BDA0003874037850000502
In some embodiments of the compound having formula (IV),
Figure BDA0003874037850000503
is that
Figure BDA0003874037850000504
In some embodiments of compounds having formula (IV), R 11 Is hydrogen, halogen, or-OH. In some embodiments of compounds having formula (IV), R 11 Is hydrogen or-OH. In some embodiments of compounds having formula (IV), R 11 Is hydrogen.
In some embodiments of compounds having formula (IV), R 12 And R 13 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (IV), R 12 And R 13 Independently of each other is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (IV), R 12 And R 13 Independently of each other is hydrogen or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (IV), R 12 And R 13 Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (IV), R 12 And R 13 Together form a cycloalkyl group. In some embodiments of compounds having formula (IV), R 12 And R 13 Together form a cycloalkyl group substituted with 1-4 deuterium groups. In some embodiments of compounds having formula (IV), R 12 And R 13 Together form a cycloalkyl group substituted with 1 or 2 deuterium groups. In some embodiments of compounds having formula (IV), R 12 And R 13 Together form a cycloalkyl substituted with 2-4 deuterium.
In the formula (IV)In some embodiments of the compounds, R 12 And R 13 Together form a heterocycloalkyl group. In some embodiments of compounds having formula (IV), R 12 And R 13 Together form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds having formula (IV), R 12 And R 13 Together form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of compounds having formula (IV), R 12 And R 13 Together form a heterocycloalkyl substituted with 2-4 deuterium.
In some embodiments of compounds having formula (IV), R 15 And R 16 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (IV), R 15 And R 16 Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (IV), R 15 And R 16 Independently is hydrogen or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (IV), R 15 And R 16 Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (IV), R 15 And R 16 Together form a cycloalkyl group. In some embodiments of compounds having formula (IV), R 15 And R 16 Together form a cycloalkyl group substituted with 1-4 deuterium groups. In some embodiments of compounds having formula (IV), R 15 And R 16 Together form a cycloalkyl group substituted with 1 or 2 deuterium groups. In some embodiments of compounds having formula (IV), R 15 And R 16 Together form a cycloalkyl group substituted with 2-4 deuterium groups.
In some embodiments of compounds having formula (IV), R 15 And R 16 Together form a heterocycloalkyl group. In some embodiments of compounds having formula (IV), R 15 And R 16 Together form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds having formula (IV), R 15 And R 16 Together form a heterocycloalkyl substituted with 1 or 2 deuterions.In some embodiments of compounds having formula (IV), R 15 And R 16 Together form a heterocycloalkyl substituted with 2-4 deuterium.
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 radical, C 2 -C 6 Alkenyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted with one, two, or three R 3a And (4) substitution. In some embodiments of compounds having 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 having formula (IV), R 3 Is optionally substituted by one, two or three R 3a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (IV), R 3 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (IV), R 3 is-C (= O) OR 5 。
In some embodiments of compounds having formula (IV), each R 3a 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 is 3a Independently of each other, 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 is 3a Independently of each other, 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 formula (IV), each R 3a Independently is-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 is 3a Independently is-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 formula (IV), each R is 3a Independently is-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 Independently is-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 is 3b Independently of each other, deuterium, halogen, -CN, -OR b 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (IV), each R 3b Independently of each other is deuterium, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, orC 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (IV), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, 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 substituted with one, two, or three R 4a And (4) substitution. In some embodiments of compounds having formula (IV), each R is 4 Independently is C 1 -C 6 Alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 4a And (4) substitution. In some embodiments of compounds having formula (IV), each R is 4 Independently is optionally substituted by one, two or three R 4a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (IV), each R is 4 Independently is C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (IV), each R 4 Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (IV), each R is 4a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (IV), each R is 4a Independently deuterium or halogen. In some embodiments of compounds having formula (IV), each R 4a Independently a halogen.
In some embodiments of compounds having formula (IV), each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl groupsIndependently optionally substituted by one, two or three R 5a And (4) substitution. In some embodiments of compounds having formula (IV), each R is 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formula (IV), each R 5 Independently is optionally substituted by one, two or three R 5a Substituted hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (IV), each R 5 Independently is optionally substituted by one, two or three R 5a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (IV), each R is 5 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (IV), each R is 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (IV), two R are 5 Together form an optionally substituted heterocycloalkyl.
In some embodiments of compounds having formula (IV), each R is 5a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (IV), each R 5a Independently is deuterium or halogen. In some embodiments of compounds having formula (IV), each R is 5a Independently a halogen. In some embodiments of compounds having formula (IV), each R 5a Independently is-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 is 5a Independently is-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 is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (IV), each R is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (IV), each R is 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group; wherein the alkyl is independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (IV), each R 6 And R 7 Independently of each other is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (IV), each R is 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (IV), each R 6a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (IV), each R is 6a Independently is deuterium or halogen. In some embodiments of compounds having formula (IV), each R is 6a Independently a halogen. In some embodiments of compounds having formula (IV), each R is 5a Independently is-NR b C(＝NR x )R b or-NR b C(＝NR x )NR c R d . In the formulaIn some embodiments of the compounds of (IV), each R 6a Independently is-S (= O) (= NR) x )R b or-S (= O) (= NR) x )NR c R d 。
In some embodiments of compounds having formula (IV), R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl group.
In some embodiments of compounds having formula (IV), each R is 6b Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (IV), each R is 6b Independently is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (IV), each R 6b Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (IV), R x Is hydrogen, -NO 2 or-CN. In some embodiments of compounds having formula (IV), R x is-NO 2 or-CN. In some embodiments of compounds having formula (IV), R x is-CN.
Disclosed herein are compounds having the formula (V) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure BDA0003874037850000551
wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3b Substitution;
each R 3b Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 A heteroalkyl group,Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R x is hydrogen, -NO 2 -CN, or-S (= O) 2 R a ；
Each R 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or the like, Aryl, and heteroaryl are independently optionally substituted with one, two or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000571
is that
Figure BDA0003874037850000572
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 Together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
R 12 and R 13 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 12 And R 13 Together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0 to 6R 14 Substitution;
each R 14 Independently 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH、-NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
In some embodiments of compounds having formula (V), R 1 is-CN, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (V), R 1 is-CN or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (V), R 1 Is C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (V), R 1 is-CN.
In some embodiments of compounds having formula (V), R 8 Is hydrogen or deuterium. In some embodiments of compounds having formula (V), R 8 Is hydrogen.
In some embodiments of compounds having formula (V), R 9 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (V), R 9 Is C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (V), R 9 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (V), R 10 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (V), R 10 Is C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (V), R 10 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (V), R 9 Is C 1 -C 6 Alkyl and R 10 Is C 2 -C 6 Alkynyl. In some embodiments of compounds having formula (V), R 10 Is C 1 -C 6 Alkyl and R 9 Is C 2 -C 6 Alkynyl.
In some embodiments of the compounds of formula (V),
Figure BDA0003874037850000591
is that
Figure BDA0003874037850000592
In some embodiments of the compounds having formula (V),
Figure BDA0003874037850000593
is that
Figure BDA0003874037850000594
In some embodiments of compounds having formula (V), R 11 Is hydrogen, halogen, or-OH. In some embodiments of compounds having formula (V), R 11 Is hydrogen or-OH. In some embodiments of compounds having formula (V), R 11 Is hydrogen.
In some embodiments of compounds having formula (V), R 12 And R 13 Independently of one another is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (V), R 12 And R 13 Independently of each other is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (V), R 12 And R 13 Independently is hydrogen or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (V), R 12 And R 13 Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (V), R 12 And R 13 Together form a cycloalkyl group. In some embodiments of compounds having formula (V), R 12 And R 13 Together form a cycloalkyl group substituted with 1-4 deuterium groups. In some embodiments of compounds having formula (V), R 12 And R 13 Taken together by 1 or 2 deuterium atomsSubstituted cycloalkyl groups. In some embodiments of compounds having formula (V), R 12 And R 13 Together form a cycloalkyl group substituted with 2-4 deuterium groups.
In some embodiments of compounds having formula (V), R 12 And R 13 Together form a heterocycloalkyl group. In some embodiments of compounds having formula (V), R 12 And R 13 Together form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds having formula (V), R 12 And R 13 Together form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of compounds having formula (V), R 12 And R 13 Together form a heterocycloalkyl substituted with 2-4 deuterium.
In some embodiments of compounds having formula (V), R 17 Is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (V), R 17 Is C 1 -C 6 An alkyl group.
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 radical, C 2 -C 6 Alkenyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Heteroalkyl, or heteroaryl; wherein the alkyl and alkenyl groupsAnd heteroaryl is independently optionally substituted with one, two or three R 3a And (4) substitution. In some embodiments of compounds having 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 having formula (V), R 3 Is optionally substituted by one, two or three R 3a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (V), R 3 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (V), R 3 is-C (= O) OR 5 。
In some embodiments of compounds having formula (V), each R is 3a 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 Independently of each other, 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 Independently of each other, 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 formula (V), each R is 3a Independently is-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 Independently is-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 formula (V), each R 3a independently-P (= O) (R) 4 ) 2 、-P(＝O)(OR 5 ) 2 OR-B (OR) 5 ) 2 . In the formula (II) In some embodiments of the compounds of V), each R 3a Independently is-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 3b Independently deuterium, halogen, -CN, -OR b 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (V), each R is 3b Independently of each other is deuterium, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (V), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, 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 substituted with one, two, or three R 4a And (4) substitution. In some embodiments of compounds having formula (V), each R is 4 Independently is C 1 -C 6 Alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 4a And (4) substitution. In some embodiments of compounds having formula (V), each R is 4 Independently is optionally substituted by one, two or three R 4a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (V), each R is 4 Independently is C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (V), each R 4 Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (V), each R 4a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (V), each R is 4a Independently is deuterium or halogen. In some embodiments of compounds having formula (V), each R is 4a Independently a halogen.
In some embodiments of compounds having formula (V), each R is 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formula (V), each R is 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formula (V), each R 5 Independently is optionally substituted by one, two or three R 5a Substituted hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (V), each R is 5 Independently is optionally substituted by one, two or three R 5a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (V), each R is 5 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (V), each R is 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (V), two R are 5 Together form an optionally substituted heterocycloalkyl.
In a way of havingIn some embodiments of the compound of formula (V), each R 5a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (V), each R 5a Independently is deuterium or halogen. In some embodiments of compounds having formula (V), each R 5a Independently a halogen. In some embodiments of compounds having formula (V), each R is 5a Independently is-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 is 5a Independently is-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 is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a And (4) substitution. In some embodiments of compounds having formula (V), each R is 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a And (4) substitution. In some embodiments of compounds having formula (V), each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group; wherein the alkyl is independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formula (V), each R is 6 And R 7 Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (V), each R is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (V), each R is 6a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (V), each R 6a Independently is deuterium or halogen. In some embodiments of compounds having formula (V), each R is 6a Independently a halogen. In some embodiments of compounds having formula (V), each R is 6a Independently is-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 is 6a Independently is-S (= O) (= NR) x )R b or-S (= O) (= NR) x )NR c R d 。
In some embodiments of compounds having formula (V), R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl group.
In some embodiments of compounds having formula (V), each R is 6b Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formula (V), each R is 6b Independently is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formula (V), each R is 6b Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (V), R x Is hydrogen, -NO 2 or-CN. In one of the compounds of the formula (V)In some embodiments, R x is-NO 2 or-CN. In some embodiments of compounds having formula (V), R x is-CN.
Disclosed herein are compounds having the formula (VI) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure BDA0003874037850000631
wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 3b Substitution;
each R 3b Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000661
is that
Figure BDA0003874037850000662
Y 1 And Y 2 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; provided that R is 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 Alkyl radical, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 13a Substitution;
each R 13a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
each R 18 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 18a Substitution;
each R 18a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 19 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groupsIndependently optionally substituted by one, two or three R 19a Substitution;
each R 19a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 20 And R 21 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 20a Substitution;
each R 20a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 an optionally substituted one, two or three R 20b Substituted heterocycloalkyl;
each R 20b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 15 and R 16 Independently of each other is hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 15 And R 16 Together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0 to 6R 2 Substitution;
each R 2 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is provided with
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
In some embodiments of compounds of formula (VI), Y 1 And Y 2 Independently hydrogen, deuterium, halogen, -OR b 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (VI), Y 1 And Y 2 Independently hydrogen, deuterium, halogen, OR-OR b . In some embodiments of compounds of formula (VI), Y 1 And Y 2 Independently hydrogen, deuterium, -OR b Or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (VI), Y 1 And Y 2 Independently hydrogen.
In some embodiments of compounds having formula (VI), R 12 Is hydrogen, deuterium, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl, or cycloalkyl; provided that R is 12 Is not-CH 3 . In some embodiments of compounds having formula (VI), R 12 Is hydrogen, deuterium, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group; provided that R is 12 Is not-CH 3 . In some embodiments of compounds having formula (VI), R 12 Is hydrogen or deuterium. In some embodiments of compounds having formula (VI), R 12 Is hydrogen. In some embodiments of compounds having formula (VI), R 12 Is hydrogen or C 1 -C 6 An alkyl group; provided that R is 12 Is not-CH 3 . In some embodiments of compounds having formula (VI), R 12 Is C 1 -C 6 An alkyl group; 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 radical, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 13a And (4) substitution. 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 with one, two or three R 13a And (4) substitution. 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 having formula (VI), R 13 is-C (= O) NR 20 R 21 . In some embodiments of compounds having formula (VI), R 13 is-NR 19 C(＝O)R 18 . In some embodiments of compounds having formula (VI), R 13 Is optionally substituted by one, two or three R 13a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (VI), R 13 Is optionally substituted by one, two or three R 13a A substituted heteroaryl group.
In some embodiments of compounds having formula (VI), each R is 13a 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 radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group. In some embodiments of compounds having formula (VI), each R 13a Independently of each other, deuterium, halogen, -CN, -OR 19 、-NR 20 R 21 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group. In some embodiments of compounds having formula (VI), each R is 13a Independently deuterium, halogen, -CN, -OR 19 、-NR 20 R 21 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (VI), each R 13a Independently is-NR 19 S(＝O) 2 R 18 or-NR 19 C(＝O)R 18 。
Disclosed herein are compounds having the formula (VII):
Figure BDA0003874037850000701
wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Amino alkaneBase, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3b Substitution;
each R 3b Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000721
is that
Figure BDA0003874037850000722
Y 1 And Y 2 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group; provided that Y is 1 Or Y 2 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
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 Alkyl radical, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 13a Substitution;
each R 13a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 A heteroalkyl group;
each R 18 Independent of each otherGround is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 18a Substitution;
each R 18a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 19 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 19a Substitution;
each R 19a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 20 And R 21 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 20a Substitution;
each R 20a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 an optionally substituted one, two or three R 20b Substituted heterocycloalkyl;
each R 20b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group,C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 15 and R 16 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 15 And R 16 Together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0-6R 2 Substitution;
each R 2 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is provided with
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
In some embodiments of compounds having formula (VII), Y 1 And Y 2 Independently hydrogen, deuterium, halogen, -OR b 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group; provided that Y is 1 Or Y 2 Is not hydrogen. In some embodiments of compounds having formula (VII), Y 1 And Y 2 Independently hydrogen, deuterium, halogen, OR-OR b (ii) a Provided that Y is 1 Or Y 2 Is not hydrogen. In one of the compounds of the formula (VII)In some embodiments, Y 1 And Y 2 Independently hydrogen, deuterium, -OR b Or C 1 -C 6 An alkyl group; provided that Y is 1 Or Y 2 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 radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl, or cycloalkyl. In some embodiments of compounds having formula (VII), R 12 Is hydrogen, deuterium, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (VII), R 12 Is hydrogen or deuterium. In some embodiments of compounds having formula (VII), R 12 Is hydrogen. In some embodiments of compounds having formula (VII), R 12 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (VII), R 12 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having 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 radical, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 13a And (4) substitution. In some embodiments of compounds having 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 with one, two or three R 13a And (4) substitution. In some embodiments of compounds having 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 having formula (VII), R 13 is-C (= O) NR 20 R 21 . In some embodiments of compounds having formula (VII), R 13 is-NR 19 C(＝O)R 18 . In some embodiments of compounds having formula (VII), R 13 Is optionally substituted by one, two or three R 13a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (VII), R 13 Is optionally substituted by one, two or three R 13a A substituted heteroaryl group.
In some embodiments of compounds having formula (VII), each R is 13a Independently of each other, 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 radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group. In some embodiments of compounds having formula (VII), each R is 13a Independently deuterium, halogen, -CN, -OR 19 、-NR 20 R 21 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group. In some embodiments of compounds having formula (VII), each R is 13a Independently deuterium, halogen, -CN, -OR 19 、-NR 20 R 21 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (VII), each R is 13a Independently is-NR 19 S(＝O) 2 R 18 or-NR 19 C(＝O)R 18 。
Disclosed herein are compounds having the formula (VIII):
Figure BDA0003874037850000771
wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 3b Substitution;
each R 3b Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure BDA0003874037850000791
is that
Figure BDA0003874037850000792
Y 1 And Y 2 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
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 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CH 2 (cycloalkyl), -CH 2 (heterocycloalkyl), -CH 2 (aryl), or-CH 2 (heteroaryl); wherein the alkyl, cycloalkyl, heterocycloalkyl, arylIndependently, and heteroaryl are optionally substituted with one, two or three R 13a Substitution;
each R 13a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 18 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 18a Substitution;
each R 18a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Amino groupAlkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 19 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 19a Substitution;
each R 19a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 20 And R 21 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 20a Substitution;
each R 20a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 an optionally substituted one, two or three R 20b Substituted heterocycloalkyl;
each R 20b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 15 and R 16 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 15 And R 16 Together form a cycloalkyl or heterocycloalkyl; each of which is substituted by 0 to 6R 2 Substitution;
each R 2 Independently of each other, 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, aryl, heteroaryl, and heteroaryl,C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkaneIndependently, the group, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
In some embodiments of compounds having formula (VIII), Y 1 And Y 2 Independently hydrogen, deuterium, halogen, -OR b 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (VIII), Y 1 And Y 2 Independently hydrogen, deuterium, halogen, OR-OR b . In some embodiments of compounds having formula (VIII), Y 1 And Y 2 Independently hydrogen, deuterium, -OR b Or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (VIII), Y 1 And Y 2 Is hydrogen.
In some embodiments of compounds having formula (VIII), R 12 Is hydrogen, deuterium, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl, or cycloalkyl. In some embodiments of compounds having formula (VIII), R 12 Is hydrogen, deuterium, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formula (VIII), R 12 Is hydrogen or deuterium. In some embodiments of compounds having formula (VIII), R 12 Is hydrogen. In some embodiments of compounds having formula (VIII), R 12 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formula (VIII), R 12 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formula (VIII), R 13 is-CN.
In some embodiments of compounds having formula (VIII), R 13 Is optionally substituted by one, two or three R 13a Substituted C 1 -C 6 A hydroxyalkyl group. In some embodiments of compounds having formula (VIII), R 13 Is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 13a And (4) substitution. In some embodiments of compounds having formula (VIII), R 13 Is optionally substituted by one, two or three R 13a A substituted heteroaryl group.
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 optionally substituted with one, two or three R 13a And (4) substitution. In some embodiments of compounds having formula (VIII), R 13 Is heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl are independently optionally substituted with one, two or three R 13a And (4) substitution. In some embodiments of compounds having formula (VIII), R 13 Is optionally substituted by one, two or three R 13a A substituted heteroaryl group. In some embodiments of compounds having formula (VIII), R 13 Is optionally substituted by one, two or three R 13a Substituted heterocycloalkyl group.
In some embodiments of compounds having formula (VIII), each R is 13a Independently of each other, 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 radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Amino groupAlkyl, or C 1 -C 6 A heteroalkyl group. In some embodiments of compounds having formula (VIII), each R is 13a Independently of each other, deuterium, halogen, -CN, -OR 19 、-NR 20 R 21 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group. In some embodiments of compounds having formula (VIII), each R 13a Independently of each other, deuterium, halogen, -CN, -OR 19 、-NR 20 R 21 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formula (VIII), each R 13a 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 radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, or aryl. In some embodiments of compounds having formula (VIII), each R 13a Independently oxo, -OR 19 、-NR 20 R 21 、-C(＝O)NR 20 R 21 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, or aryl. In some embodiments of compounds having formula (VIII), each R is 13a Independently is-OR 19 、-NR 20 R 21 or-C (= O) NR 20 R 21 . In some embodiments of compounds having formula (VIII), each R is 13a Independently is-OR 19 or-C (= O) NR 20 R 21 . In some embodiments of compounds having formula (VIII), each R 13a Independently is-OR 19 。
In some embodiments of compounds having formulas (VI) - (VIII), R 1 is-CN, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), R 1 is-CN or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formulas (VI) - (VIII), R 1 Is C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formulas (VI) - (VIII), R 1 is-CN.
In some embodiments of compounds having formulas (VI) - (VIII), R 8 Is hydrogen or deuterium. In some embodiments of compounds having formulas (VI) - (VIII), R 8 Is hydrogen.
In some embodiments of compounds having formulas (VI) - (VIII), R 9 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formulas (VI) - (VIII), R 9 Is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), R 10 Is C 1 -C 6 Alkyl or C 2 -C 6 Alkynyl. In some embodiments of compounds having formulas (VI) - (VIII), R 10 Is C 1 -C 6 An alkyl group.
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.
In some embodiments of compounds having formulas (VI) - (VIII),
Figure BDA0003874037850000841
is that
Figure BDA0003874037850000842
In some embodiments of compounds having formulas (VI) - (VIII),
Figure BDA0003874037850000843
is that
Figure BDA0003874037850000844
In some embodiments of compounds having formulas (VI) - (VIII), R 11 Is hydrogen, halogen, or-OH. In some embodiments of compounds having formulas (VI) - (VIII), R 11 Is hydrogen or-OH. In some embodiments of compounds having formulas (VI) - (VIII), R 11 Is hydrogen.
In some embodiments of compounds having formulas (VI) - (VIII), each R is 18 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, 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 substituted with one, two or three R 18a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R 18 Independently is C 1 -C 6 Alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 18a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R 18 Independently is optionally substituted by one, two or three R 18a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R 18 Independently is C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 18 Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), each R 18a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formulas (VI) - (VIII), each R 18a Independently is deuterium or halogen. In some embodiments of compounds having formulas (VI) - (VIII), each R 18a Independently a halogen.
In some embodiments of compounds having formulas (VI) - (VIII), each R 19 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 19a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R is 19 Independently of one another is hydrogen, C 1 -C 6 Alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 19a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R is 19 Independently is optionally substituted by one, two or three R 19a Substituted hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 19 Independently is optionally substituted by one, two or three R 19a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 19 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 19 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), each R is 19a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In a compound of formulae (VI) to (VIII)In some embodiments of the compounds, each R 19a Independently is deuterium or halogen. In some embodiments of compounds having formulas (VI) - (VIII), each R is 19a Independently a halogen.
In some embodiments of compounds having formulas (VI) - (VIII), each R is 20 And R 21 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 20a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R 20 And R 21 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R is 20 And R 21 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group; wherein the alkyl is independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R is 20 And R 21 Independently of each other is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 20 And R 21 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), each R is 20a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formulas (VI) - (VIII), each R is 20a Independently is deuterium or halogen. In the presence of compounds of formulae (VI) to (VIII)In some embodiments, each R 20a Independently a halogen. In some embodiments of compounds having formulas (VI) - (VIII), each R is 20a Independently is-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 is 20a Independently is-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 20 And R 21 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 20b Substituted heterocycloalkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), each R is 20b Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formulas (VI) - (VIII), each R is 20b Independently is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 20b Independently is C 1 -C 6 An alkyl group.
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 radical, C 2 -C 6 Alkenyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted with one, two, or three R 3a And (4) substitution. 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 having formulas (VI) - (VIII), R 3 Is C 1 -C 6 Alkyl OR-C (= O) OR 5 . In some embodiments of compounds having formulas (VI) - (VIII), R 3 Is optionally substituted by one, two or three R 3a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), R 3 Is C 1 -C 6 An alkyl group. 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 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 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 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 Independently is-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 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 is 3a Independently is-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 is 3a Independently is-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 is 3b Independently of each other, deuterium, halogen, -CN, -OR b 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R 3b Independently of one another is deuterium, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, 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 substituted with one, two, or three R 4a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R is 4 Independently is C 1 -C 6 Alkyl or cycloalkaneA group; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 4a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R 4 Independently is optionally substituted by one, two or three R 4a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 4 Independently is C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 4 Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), each R is 4a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formulas (VI) - (VIII), each R is 4a Independently is deuterium or halogen. In some embodiments of compounds having formulas (VI) - (VIII), each R is 4a Independently a halogen.
In some embodiments of compounds having formulas (VI) - (VIII), each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R is 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two or three R 5a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R is 5 Independently is optionally substituted by one, two or three R 5a Substituted hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 5 Independently is optionally substituted by one, two or three R 5a Substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 5 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), two R 5 Together form an optionally substituted heterocycloalkyl.
In some embodiments of compounds having formulas (VI) - (VIII), each R 5a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formulas (VI) - (VIII), each R 5a Independently deuterium or halogen. In some embodiments of compounds having formulas (VI) - (VIII), each R 5a Independently a halogen. In some embodiments of compounds having formulas (VI) - (VIII), each R is 5a Independently is-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 is 5a Independently is-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 is 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R is 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A haloalkyl group; wherein the alkyl is independently optionally substituted with one, two or three R 6a And (4) substitution. In some embodiments of compounds having formulas (VI) - (VIII), each R 6 And R 7 Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R is 6 And R 7 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), each R is 6a Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formulas (VI) - (VIII), each R 6a Independently is deuterium or halogen. In some embodiments of compounds having formulas (VI) - (VIII), each R is 6a Independently a halogen. In some embodiments of compounds having formulas (VI) - (VIII), each R is 5a Independently is-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 Independently is-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 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), each R is 6b Independently oxo, deuterium, halogen, -CN, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds having formulas (VI) - (VIII), each R 6b Independently is C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of compounds having formulas (VI) - (VIII), each R 6b Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), R x Is hydrogen, -NO 2 or-CN. In some embodiments of compounds having formulas (VI) - (VIII), R x is-NO 2 or-CN. In some embodiments of compounds having formulas (VI) - (VIII), R x is-CN.
In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Independently of each other is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Independently is hydrogen or C 1 -C 6 A deuterated alkyl group. In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Together form a cycloalkyl group. In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Together form a cycloalkyl group substituted with 1-4 deuterium groups. In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Together form a cycloalkyl substituted with 1 or 2 deuterium. In the formula (VI)In some embodiments of compounds of (VIII), R 15 And R 16 Together form a cycloalkyl group substituted with 2-4 deuterium groups.
In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Together form a heterocycloalkyl group. In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Together form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Together form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of compounds having formulas (VI) - (VIII), R 15 And R 16 Together form a heterocycloalkyl substituted with 2-4 deuterium.
In some embodiments of compounds having formulas (I) - (VIII), each R a Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 And (3) alkyl substitution. In some embodiments of compounds having formulas (I) - (VIII), each R a Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with 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 Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group; wherein the alkyl is independently optionally substituted with one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution. In the formula(I) Some embodiments of the Compounds of (VIII), each R a Independently by one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substituted C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (I) - (VIII), each R a Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formulas (I) - (VIII), each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 And (3) alkyl substitution. In some embodiments of compounds having formulas (I) - (VIII), each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group; wherein the alkyl is independently optionally substituted with one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 And (3) alkyl substitution. In some embodiments of compounds having formulas (I) - (VIII), each R b Independently by one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (I) - (VIII), each R b Independently is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (I) - (VIII), each R b Independently hydrogen. In some embodiments of compounds having formulas (I) - (VIII), each R b Independently is C 1 -C 6 An alkyl group.
In some embodiments of compounds having formulas (I) - (VIII), each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, cycloalkyl, orA heterocycloalkyl group; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with 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 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group; wherein the alkyl is independently optionally substituted with one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 And (3) alkyl substitution. In some embodiments of compounds having formulas (I) - (VIII), each R c And R d Independently by one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (I) - (VIII), each R c And R d Independently of each other is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of compounds having formulas (I) - (VIII), each R b Independently hydrogen. In some embodiments of compounds having formulas (I) - (VIII), each R c And R d Independently is C 1 -C 6 An alkyl group.
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 an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
Disclosed herein are compounds selected from the group consisting of:
Figure BDA0003874037850000911
Figure BDA0003874037850000921
Figure BDA0003874037850000931
Figure BDA0003874037850000941
Figure BDA0003874037850000951
Figure BDA0003874037850000961
disclosed herein are compounds selected from the group consisting of:
Figure BDA0003874037850000962
Figure BDA0003874037850000971
Figure BDA0003874037850000981
Figure BDA0003874037850000991
Figure BDA0003874037850001001
Figure BDA0003874037850001011
Figure BDA0003874037850001021
Figure BDA0003874037850001031
Figure BDA0003874037850001041
Figure BDA0003874037850001051
Figure BDA0003874037850001061
Figure BDA0003874037850001071
other forms of the compounds disclosed herein
Isomers/stereoisomers
In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include cis, trans, synonymous, antisense, ipsilateral (E), and ipsilateral (Z) isomers, as well as corresponding mixtures thereof. In some cases, a compound described herein has one or more chiral centers and each center is present in the R configuration or the S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms as well as corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers resulting from a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as their respective stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and are separated by utilizing these different points. In some embodiments, the diastereomers are separated by chiral chromatography or, preferably, by separation/resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer is then recovered with a resolving agent.
Labelled compounds
In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease 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. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into a compound described herein, or a solvate or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, for example 2 H、 3 H、 13 C、 14 C、 l5 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F. And 36 and (4) Cl. Compounds described herein and pharmaceutically acceptable salts, solvates, or stereoisomers thereof that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labelled compounds, e.g. in which are incorporated, e.g. 3 H and 14 a compound of a radioisotope of C,can be used for drug and/or substrate tissue distribution determination. Tritiated (i.e. by tritiation) 3 H) And carbon 14 (i.e. 14 C) Isotopologues are distinguished by their ease of preparation and detectability. In addition, heavy isotopes such as deuterium (i.e., 2 h) Substitution offers certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, the isotopically labeled compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is prepared by any suitable method.
In some embodiments, the 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 salts
In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. 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 salts. 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.
Examples of pharmaceutically acceptable salts include those salts prepared by reacting a compound described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1, 4-dioate, camphorate, camphorsulfonate, hexanoate (caprate), octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucose heptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate (hexanoate), hexyne-1, 6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, salicylate, and mixtures thereof, thiocyanate, tosylate, undecanoate, and xylenesulfonate.
In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts, which are formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid and the like; and organic acids such as acetic acid, propionic acid, hexanoic 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, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, pivalic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.
In some embodiments, 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), with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts and the like. Illustrative examples of the base include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl radical) 4 And so on.
Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It is to 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.
Solvates
In some embodiments, the compounds described herein are present as solvates. The disclosure provides methods of treating diseases by administering such solvates. The 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, the solvate is formed during the process of crystallization with a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein may be conveniently prepared or formed in the processes described herein. In addition, the compounds provided herein can exist in unsolvated forms as well as solvated forms. In general, the solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.
Tautomers
In some cases, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein. Tautomers are compounds that interconvert by the migration of a hydrogen atom, with the conversion of a single bond and an adjacent double bond. In a linkage arrangement where tautomerism is likely to occur, there will be a chemical equilibrium of the 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.
Preparation of the Compounds
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" are obtained from standard commercial sources and include akroso Organic (Acros Organics, pittsburgh, pennsylvania), aldrich Chemical (Aldrich Chemical), milwaukee, wi, sigma Chemical and freuke (Sigma Chemical and Fluka), apin Chemicals ltd.) (milton park, uk), ava Research (Avocado Research) (luckshire, uk), BDH limited (BDH, inc. (Toronto, canada), poynet (Bionet) (Comvorel, UK), chemical services Inc. (Chem Service Inc.) (Wichester, pa.), krauser Chemical Company (Crecent Chemical Co., U.S.), harpagk, ishmann Organic Chemicals (Eastman Organic Chemicals), eastman Kodak Company (Eastman Kodak Company) (Rochester, N.Y.), fisher Scientific Co., ltd (Fisher Scientific Co., P.C.), fisher Chemical Company (Fisons Chemicals) (Larstuk, U.K.), frontier Scientific Company (Frontier Scientific) (Rough, U.S.), ICN biomedicine Company (ICN Biomedicals, inc.) (California Sporo., valley), saway Key Organic Chemicals (Oriental) (Laternal, inc.), new Zernist Karman Corp., inc. (New Zernist Co., inc.) United states bridge Chemical company, ltd. (combale, uk), textbook Chemical company (Parish Chemical co.) (orem, utah), fartz and pall ltd. (Pfaltz & Bauer, inc.) (walibbury, connecticut), polyorgano company (Polyorganix) (houston, tx), pierce Chemical company (Pierce Chemical co.) (rockford, illinois), riedlhyd haiton company (Riedel haede AG) (hannover, germany), spectral Quality products company (Spectrum Quality Product, inc.) (new lungo, nj), TCI company (TCI America) (portland, USA), cross-World Chemicals (Trans, world, inc.), and wauk Chemical company (wallau, inc., USA).
Detailed description synthesis of reactants useful in the preparation of the compounds described herein or suitable references and papers providing reference to articles describing the preparation include, for example: "Synthetic Organic Chemistry," John Wiley & Sons, inc. [ John Willi father, N.Y.; sandler et al, "Organic Functional Group precursors [ organofunctional agents ]", 2 nd edition, academic Press [ Academic Press ], new york, 1983; H.O.House, "Modern Synthetic Reactions", 2 nd edition, W.A.Benjamin, inc. [ W.A. Benjamin, inc. ] California Ropak, 1972; l.l. gilchrist, "Heterocyclic Chemistry, 2 nd edition, john Wiley & Sons [ John Wiley parent company ], new york, 1992; march, "Advanced Organic Chemistry: reactions, mechanics and Structure [ Advanced Organic Chemistry: reaction, mechanism and structure ] ", 4 th edition, wiley-Interscience [ Weili International science ], new York, 1992. Other suitable references and articles that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide a reference to an article describing the preparation include, for example: fuhrhop, J. And Penzlin G. "Organic Synthesis: conjugates, methods, staring Materials [ Organic Synthesis: concept, method, starting materials ] ", second edition, revised addendum edition (1994) John Wiley & Sons [ John Willi father-son ] ISBN:3-527-29074-5; hoffman, R.V. "Organic Chemistry, an Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group precursors [ Comprehensive Organic Transformations: guide to functional group preparation ] "Wiley-VCH [ Wiley-VCH company, 2 nd edition (1999) ], ISBN:0-471-19031-4; march, J. "Advanced Organic Chemistry: reactions, mechanics, and Structure [ Advanced Organic Chemistry: reaction, mechanism and Structure ] "4 th edition (1992) John Wiley & Sons [ John Wiley father, inc. ], ISBN:0-471-60180-2; otera, J. (eds.) "Modern Carbonyl Chemistry" (2000) Wiley-VCH [ Willi-VCH company ], ISBN:3-527-29871-1; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups [ Patai 1992Guide for Functional Groups ]" (1992) Interscience [ International science ] ISBN:0-471-93022-9; solomons, T.W.G. "Organic Chemistry" 7 th edition (2000) John Wiley & Sons [ John Willi father, ISBN:0-471-19095-0; stowell, J.C., "Intermediate Organic Chemistry [ Intermediate Organic Chemistry ]" 2 nd edition (1993) Wiley-Interscience [ Wili International science ], ISBN:0-471-57456-2; "Industrial Organic Chemicals: staring Materials and Intermediates: an Ullmann's Encyclopedia [ Industrial Organic Chemicals: starting materials and intermediates: ullmann encyclopedia ] "(1999) John Wiley & Sons [ John Willi father, inc. ], ISBN:3-527-29645-X, vol.8; "Organic Reactions ]" (1942-2000) John Wiley & Sons John Willi father, over volume 55; and "Chemistry of Functional Groups [ Functional group Chemistry ]" John Wiley & Sons [ John Willi father, inc. ], volume 73.
Specific and similar reactants may optionally be identified by an index of known chemicals (available in most public and university libraries and online) prepared by the Chemical abstracts Service (Chemical Abstract Service) of the American Chemical Society. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses (custom chemical synthesis houses), where many standard chemical supply houses (e.g., those listed above) provide custom synthesis services. References to the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are p.h.stahl and c.g.wermuth "Handbook of Pharmaceutical Salts [ Handbook of pharmaceutically acceptable Salts ]", verlag Helvetica Chimica Acta [ swertia chem ], zurich, 2002.
Pharmaceutical composition
In certain embodiments, the compounds described herein are applied as pure chemicals. In some embodiments, the compounds described herein are combined with a pharmaceutically suitable or pharmaceutically acceptable carrier (also referred to herein as a pharmaceutically suitable (or pharmaceutically acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or physiologically acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice as described below: for example, remington, the Science and Practice of Pharmacy [ Remington: science and practice of pharmacy (Gennaro, 21 st edition 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 synthetic byproducts, e.g., produced in one or more steps of a synthetic process.
The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration will be determined by 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, and like factors. Generally, suitable dosages and treatment regimens provide one or more compositions in an amount sufficient to provide a therapeutic benefit and/or a prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remission, or longer periods of disease free and/or overall survival, or reduction in severity of symptoms). The optimal dosage is typically determined using experimental models and/or clinical trials. The optimal dosage depends on the body mass, body weight or blood volume of the patient.
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 administration. 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, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drop, or ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.
Suitable dosages and dosage regimens are determined by conventional range finding techniques known to those skilled in the art. Typically, treatment is initiated at smaller doses than the optimal dose of the compounds disclosed herein. Thereafter, the dosage is increased in small increments until the optimum effect under the particular circumstances is achieved. In some embodiments, the methods involve administering from about 0.1 μ g to about 50mg of at least one compound described herein per kg of body weight of the subject. For a 70kg patient, a dose of about 10 μ g to about 200mg of the compounds disclosed herein will be more commonly used depending on the physiological response of the subject.
By way of example only, a dose of a compound described herein for use in a method of treating a disease as described herein is from about 0.001 to about 1mg/kg body weight of a subject per day, e.g., about 0.001mg, about 0.002mg, about 0.005mg, about 0.010mg, 0.015mg, about 0.020mg, about 0.025mg, about 0.050mg, about 0.075mg, about 0.1mg, about 0.15mg, about 0.2mg, about 0.25mg, about 0.5mg, about 0.75mg, or about 1mg/kg body weight per day. In some embodiments, the dose of a compound described herein for use in the described methods is from about 1 to about 1000mg/kg body weight of the subject treated per day, e.g., about 1mg, about 2mg, about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, about 250mg, about 500mg, about 750mg, or about 1000 mg/day.
Method of treatment
Disclosed herein are methods of treating kidney 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 are methods of treating a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), alport syndrome, focal Segmental Glomerulosclerosis (FSGS), pulmonary arterial hypertension, friedreich's ataxia, autosomal Dominant Polycystic Kidney Disease (ADPKD), or IgA nephropathy, comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
Also disclosed herein are methods of treating a kidney disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), alport syndrome, focal Segmental Glomerulosclerosis (FSGS), autosomal Dominant Polycystic Kidney Disease (ADPKD), or IgA nephropathy, comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
Disclosed herein are methods of treating systemic lupus nephritis, comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Lupus nephritis is an inflammation of the kidney caused by Systemic Lupus Erythematosus (SLE). SLE, also known as lupus, is an autoimmune disease. For lupus, the body's immune system targets its own body tissues. Lupus nephritis occurs when lupus affects the kidneys.
Disclosed herein are methods of treating diabetic chronic kidney disease (CDK) comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
Disclosed herein are methods 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. Alport 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. Almost all affected individuals have blood in their urine (hematuria), which indicates renal dysfunction. High levels of protein (proteinuria) also occur in the urine of many people with alport syndrome. As this condition progresses, the function of the kidney becomes increasingly poor, leading to end-stage renal disease (ESRD).
Disclosed herein are methods of treating Focal Segmental Glomerulosclerosis (FSGS) 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 is also a major cause of renal failure in adults. It is also known as "focal glomerulosclerosis" or "focal nodular glomerulosclerosis". It accounts for about one sixth of the cases of nephrotic syndrome. In some embodiments, when the root cause is not found, the focal segmental glomerulosclerosis is primary focal segmental glomerulosclerosis; usually manifested as nephrotic syndrome. In some embodiments, when the root cause is determined, focal segmental glomerulosclerosis is secondary focal segmental glomerulosclerosis; renal failure and proteinuria are commonly manifested. Secondary focal segmental glomerulosclerosis is a heterogeneous population that includes many causes, such as: toxins and drugs such as heroin and pamidronate, familial forms, and secondary to nephron loss and ultrafiltration, such as with chronic pyelonephritis and reflux, morbid obesity, diabetes.
Disclosed herein are methods 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 of elevated blood pressure in the pulmonary arteries. Symptoms include shortness of breath, syncope, tiredness, chest pain, swelling of the legs, and increased heartbeat. This situation may make the movement difficult. The reason is usually unknown. Risk factors include family history, previous pulmonary thrombosis, HIV/AIDS, sickle cell disease, cocaine use, chronic obstructive pulmonary disease, sleep apnea, living in high altitude areas, and mitral valve problems. The underlying mechanism typically involves inflammation of the pulmonary artery. The diagnosis is primarily to exclude other potential causes.
Disclosed herein are methods of treating friedreich 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 genetic disorder that results in walking difficulties, loss of arm and leg sensation, and speech impairment that worsens over time. Symptoms may begin between 5 and 15 years of age. Many people suffer from hypertrophic cardiomyopathy and in the teenage years need mobility aids such as walking sticks, walking aids or wheelchairs. As the disease progresses, vision and hearing are lost. Other complications include scoliosis and diabetes. This is caused by mutation of the FXN gene on chromosome 9. The FXN gene produces a protein called ataxin. Degeneration of spinal nervous tissue leading to ataxia; particularly affected are sensory neurons, which are essential for guiding the motor of the muscles of the arms and legs by connecting to the cerebellum. The spinal cord thins and the nerve cells lose some myelin.
Disclosed herein are methods of treating Autosomal Dominant Polycystic Kidney Disease (ADPKD) 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 numerous cysts in the kidney. The severity of symptoms and age of onset vary, but usually progresses between 30 and 40 years of age. ADPKD is a progressive disease, and symptoms worsen over time. The most common symptoms are renal cysts, back and side pain, and headache. Other symptoms include liver and pancreatic cysts, urinary tract infections, heart valve abnormalities, hypertension, kidney stones, and cerebral aneurysms. ADPKD is most often caused by alterations in the PKD1 and PKD2 genes, and a few by alterations 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 renal failure. ADPKD is the most common genetic disorder of the kidney.
Disclosed herein are methods 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 disease that causes damage to the microfilters in the kidney. IgA is a protein that helps to fight infection. In IgA nephropathy patients, these proteins accumulate and form clumps within the microfilter (glomerulus) of the kidney. These protein clumps can damage the glomeruli. This damage can lead to chronic kidney disease and may lead to renal 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 the patient is increased by administering one of the compounds described herein with a second therapeutic agent (also including a treatment regimen) that also has therapeutic benefit.
In a particular 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, solvate, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing greater overall benefit than either therapeutic agent administered alone.
In any event, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply the addition 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 the compound disclosed herein will be used to formulate a pharmaceutical composition and/or a treatment regimen. Therapeutically effective doses of drugs and other agents for use in combination treatment regimens are optionally determined in a manner similar to that set forth herein for the compounds described herein. Furthermore, the prophylactic/therapeutic methods described herein encompass the use of a rhythmic administration, i.e. providing more frequent, lower doses to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses a treatment regimen wherein 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 and continued until any time during or after termination of treatment with the second agent. It also includes treatments wherein a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second agent used in combination are administered simultaneously or at different times and/or with decreasing or increasing intervals during the treatment. Combination therapy also includes periodic treatments that are started and stopped at different times to assist in the clinical management of the patient.
It will be appreciated that the dosage regimen for treating, preventing or ameliorating the one or more conditions for which remission is sought will be modified depending upon a variety of factors (e.g., the disease, disorder or condition from which the subject is suffering; the age, weight, sex, diet and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed is different, and in some embodiments, deviates from the dosage regimen set forth herein.
For the combination therapies described herein, the dosage of the co-administered compounds varies depending on the type of combination drug used, the particular drug used, the disease or disorder being treated, and the like. In further embodiments, when a compound provided herein is co-administered with a second therapeutic agent, the compound provided herein is administered simultaneously or sequentially with the second therapeutic agent.
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, the multiple therapeutic agents are provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only.
The compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, and the combination therapy, are administered before, during, or after the onset of the disease or condition, and at different times for the administration of the composition containing the compound. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to a subject predisposed to developing a disorder or disease to prevent the development of the disease or disorder. In another embodiment, the compounds and compositions are administered to the subject during or as soon as possible after the onset of symptoms. In particular embodiments, following detection or suspicion of onset of a disease or disorder, a compound described herein is administered whenever feasible and for the length of time required to treat the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the particular needs of each subject. For example, in particular embodiments, administration of a compound described herein or a formulation containing the compound is 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 administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
Examples of the invention
Example 1: systemic lupus nephritis induced by imiquimod
Compound 26 formulated in sesame oil was orally administered to female BALB/c mice at 3mg/kg per day (7-9 weeks). Half an hour after compound 26 administration, mice were topically treated with 25mg of 5% Imiquimod (IMQ) 3 times per week on the skin of the right ear. The study was repeated for 8 weeks. At the end of the study, mice were sacrificed and the spleen and kidney were weighed and divided into two portions, one portion fixed with neutral buffered formalin and embedded in paraffin. Three-micron sections of liver and kidney were stained with hematoxylin and eosin. The other part was snap frozen and analyzed for gene expression by qPCR.
Topical imiquimod treatment (model group) resulted in marked splenomegaly and increased INF γ expression. Treatment with compound 26 reduced splenomegaly and reduced INF γ expression (fig. 1A and 1B). Topical imiquimod treatment also increases Blood Urea Nitrogen (BUN) and proteinuria, which are signs of renal insufficiency. These levels were reduced by treatment with compound 26 (fig. 2A and 2B).
Topical imiquimod treatment enlarged the kidney. Compound 26 treatment partially reversed kidney enlargement (fig. 3A). Histological examination of the kidney showed glomerular cytosis, increased mesangial matrix, mild peritubular mononuclear cell infiltration with increased intraglomerular IgG deposition. A significant increase in kidney histopathology score indicated glomerulonephritis with immune complex deposition and compound 26 treatment significantly reduced kidney histopathology score (fig. 3B). Lipocalin-2 (LCN 2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is released by a variety of cell types and is an attractive biomarker for 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), which regulate leukocyte adhesion and migration to mediate inflammatory responses. The kidney was examined for NGAL and CD11b expression by qPCR. Topical imiquimod treatment significantly increased their expression in the kidney, while compound 26 treatment significantly decreased this expression, indicating that the compound has anti-inflammatory function (fig. 3C and 3D, respectively).
Compound 26 reduced 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, in some embodiments, various modifications or changes will be included within the scope and purview of the disclosure in the appended claims.

Claims (70)

1. A method of treating a disease that is 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, comprising administering to a subject in need thereof a compound having formula (III):
Figure FDA0003874037840000011
wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 -Z-O-cycloalkyl, -Z-O-heterocycloalkyl, -Z-O-aryl, -Z-O-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 (= n)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) 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 is- (C) 1 -C 6 Alkylene) OP (= O) (OR) 5 )[N(R 5 ) 2 ](ii) a Wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
y is a bond, -O-, -S-, or-NR b -；
Z is a bond or C 1 -C 6 An alkylene group;
R x is hydrogen, -NO 2 CN, -or-S (= O) 2 R a ；
Each R 4 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure FDA0003874037840000031
is that
Figure FDA0003874037840000032
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 Together form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
R 12 and R 13 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 12 And R 13 Together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0 to 6R 14 Substitution;
each R 14 Independently 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
R 15 and R 16 Independently hydrogen, -OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 15 And R 16 Together form a cycloalkyl or heterocycloalkyl group; each of which is substituted by 0 to 6R 2 Substitution;
each R 2 Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is
Each R c And R d Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
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 radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
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:
R 8 is hydrogen or deuterium.
5. The method of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 8 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 An alkyl group.
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 An alkyl group.
8. The method of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Figure FDA0003874037840000051
Is that
Figure FDA0003874037840000052
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 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group.
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 Independently is C 1 -C 6 An alkyl group.
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 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group.
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 Independently is C 1 -C 6 An alkyl group.
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) 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 An N-linked heterocycloalkyl, or an 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)(＝NR x )R 5 An N-linked heterocycloalkyl, or an N-linked 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 6 Alkylene) 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:
R 3 is an N-linked heterocycloalkyl or an 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 a bond.
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 Independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
27. The method of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
28. The method of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
two R 5 Together form an 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 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
30. The method of any one of claims 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:
Figure FDA0003874037840000091
Figure FDA0003874037840000101
Figure FDA0003874037840000111
Figure FDA0003874037840000121
Figure FDA0003874037840000122
Or (b).
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 that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), alport syndrome, focal Segmental Glomerulosclerosis (FSGS), pulmonary arterial hypertension, friedreich's ataxia, autosomal Dominant Polycystic Kidney Disease (ADPKD), or IgA nephropathy, comprising administering to a subject in need thereof a compound having formula (VIII):
Figure FDA0003874037840000131
Wherein:
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 3a Substitution;
each R 3a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independentlyOptionally substituted by one, two or three R 3b Substitution;
each R 3b Independently of each other, 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 4a Substitution;
each R 4a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 5 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 5a Substitution;
or two R 5 Together form an optionally substituted heterocycloalkyl;
each R 5a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 6 And R 7 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroAn aryl group; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a Substitution;
each R 6a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R 6 And R 7 Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R 6b Substituted heterocycloalkyl;
each R 6b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure FDA0003874037840000151
Is that
Figure FDA0003874037840000152
Y 1 And Y 2 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 9 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 10 is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group;
R 11 is hydrogen, deuterium, halogen, OR-OR b ；
Or R 3 And R 11 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
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 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, 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 with one, two or three R 13a Substitution;
Each R 13a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 18 Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 18a Substitution;
each R 18a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 19 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three R 19a Substitution;
each R 19a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 20 And R 21 Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 20a Substitution;
each R 20a 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 an optionally substituted one, two or three R 20b Substituted heterocycloalkyl;
each R 20b 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 15 and R 16 Independently of hydrogen、-OR b 、-NR c R d 、C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl, or C 1 -C 6 A heteroalkyl group;
or R 15 And R 16 Together form a cycloalkyl or heterocycloalkyl; each of which is substituted by 0-6R 2 Substitution;
each R 2 Independently 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 radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R a Independently is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
each R b Independently of each other is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogens, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution; and is provided with
Each R c And R d Independently of one another is hydrogen, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl substitution;
or R c And R d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three deuterium, halogen, -OH, -NH 2 Or C 1 -C 6 Alkyl-substituted heterocycloalkyl.
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 radical, C 1 -C 6 Haloalkyl, or C 1 -C 6 A deuterated alkyl group.
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:
R 8 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 An alkyl group.
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 An alkyl group.
45. The method of any one of claims 39-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Figure FDA0003874037840000191
is that
Figure FDA0003874037840000192
46. The method of any one of claims 39-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Y 1 and Y 2 Is 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 A deuterated alkyl group.
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 An alkyl group.
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 substituted with one, two or three R 13a And (4) substitution.
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 with one, two or three R 13a And (4) substitution.
53. The method of any one of claims 39-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 13 is optionally substituted by one, two or three R 13a A substituted heteroaryl group.
54. The method of any one of claims 39-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 13 is optionally substituted by one, two or three R 13a Substituted heterocycloalkyl group.
55. The method of any one of claims 39-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R 13a 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 radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterium alkyl group, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Aminoalkyl radical, 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 Independently oxo, -OR 19 、-NR 20 R 21 、-C(＝O)NR 20 R 21 、C 1 -C 6 Alkyl radical, 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 Independently is-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 Independently of each other is hydrogen, C 1 -C 6 Alkyl, or C 1 -C 6 A deuterated alkyl group.
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 Independently is C 1 -C 6 An alkyl group.
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 An alkyl group.
62. The method of claim 39, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is:
Figure FDA0003874037840000221
Figure FDA0003874037840000231
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.
CN202180026671.3A 2020-04-01 2021-03-31 Use of triterpenoid NRF2 inhibitors Pending CN115697319A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US202063003719P 2020-04-01 2020-04-01
US63/003,719 2020-04-01
PCT/US2021/025158 WO2021202720A1 (en) 2020-04-01 2021-03-31 Use of triterpenoid nrf2 inhibitors

Publications (1)

Publication Number Publication Date
CN115697319A true CN115697319A (en) 2023-02-03

Family

ID=77929803

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202180026671.3A Pending CN115697319A (en) 2020-04-01 2021-03-31 Use of triterpenoid NRF2 inhibitors

Country Status (2)

Country Link
CN (1) CN115697319A (en)
WO (1) WO2021202720A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117050134A (en) * 2022-05-05 2023-11-14 中国科学院上海有机化学研究所 Synthesis of amide compounds and uses thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RS55631B1 (en) * 2008-04-18 2017-06-30 Reata Pharmaceuticals Inc Antioxidant inflammation modulators: c-17 homologated oleanolic acid derivatives
JP2015527407A (en) * 2012-09-10 2015-09-17 アッヴィ・インコーポレイテッド Glycyrrhetinic acid derivatives and methods of use thereof
CN112870202A (en) * 2013-08-23 2021-06-01 里亚塔医药公司 Methods of treating and preventing renal disease using bardoxolone methyl or analogs thereof
KR102486434B1 (en) * 2016-11-08 2023-01-09 리아타 파마슈티컬즈 홀딩스, 엘엘씨 Methods of treating Alport syndrome using bardoxolone methyl or analogs thereof

Also Published As

Publication number Publication date
WO2021202720A1 (en) 2021-10-07

Similar Documents

Publication Publication Date Title
AU2014298051B2 (en) Novel quinazolinones as bromodomain inhibitors
CN107406438B (en) Inhibitors of bromodomains
CA2915622C (en) Novel substituted bicyclic compounds as bromodomain inhibitors
US9284283B2 (en) Macrocyclic compounds for modulating IL-17
US20130281396A1 (en) Treatment of diseases by epigenetic regulation
US10676438B2 (en) KCNQ2-5 channel activator
KR20200030126A (en) Substituted 3-haloallylamine inhibitors of ssao and uses thereof
JP2012514655A (en) Fluorine-containing compounds and methods of use
TWI828644B (en) Tubulin inhibitors
US20230138663A1 (en) Eaat2 activators and methods of using thereof
EA028818B1 (en) Amide derivatives as lysophosphatidic acid receptor antagonists
CA3030232A1 (en) Pyrimidinone derivatives and uses thereof to neutralize the biological activity of chemokines
CN115697319A (en) Use of triterpenoid NRF2 inhibitors
JP6434506B2 (en) Substituted pyrimidine compounds and their use as SYK inhibitors
US11780862B2 (en) Inhibitors of MEK kinase
WO2016176562A1 (en) Novel epha4 inhibitors targeting its ligand binding domain
WO2022184685A1 (en) Nicotinamide mononucleotide derivatives and use thereof for the treatment and/or prevention of long covid-19
CN112279778B (en) Substituted phenoxyamide derivative, application and medicine for treating Parkinson's disease
AU2019292207B2 (en) Pyridopyrimidinone derivatives for use as Axl inhibitors
EP4259148A1 (en) Phosphonates as inhibitors of enpp1 and cdnp
US20240010620A1 (en) Arylazabicyclo[2.1.1]hexylmethanols derivatives and medical uses thereof
EA043296B1 (en) PYRIDOPYRIMIDINONE DERIVATIVES FOR USE AS AXL INHIBITORS
WO2018232160A1 (en) Methods of treating metabolic diseases with phenoxyethylamides

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination