CN117794940A

CN117794940A - Fused heteroaryl compounds useful as anticancer agents

Info

Publication number: CN117794940A
Application number: CN202280056111.7A
Authority: CN
Inventors: 李连生; 朱秀文; 任平达; 刘异
Original assignee: Kumquat Biotechnology Co
Current assignee: Kumquat Biotechnology Co
Priority date: 2021-06-14
Filing date: 2022-06-13
Publication date: 2024-03-29

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof, and methods of using the same. The compounds and methods have utility as therapeutic, diagnostic and research toolsColumn use. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic proteins.

Description

Fused heteroaryl compounds useful as anticancer agents

Cross reference

The present application claims priority from U.S. provisional application No. 63/210,474 filed on day 14, 6, 2021, U.S. provisional application No. 63/291,320 filed on day 17, 12, 2021, and U.S. provisional application No. 63/313,132 filed on day 23, 2, 2022, each of which is incorporated by reference in its entirety.

Background

Cancer (e.g., tumor, neoplasm, metastasis) is the second leading cause of death worldwide, estimated to be about 1000 tens of thousands of deaths each year. Many types of cancer are marked by mutations in one or more proteins that are involved in various signaling pathways, resulting in uncontrolled growth of cancer cells. In some cases, about 25% to 30% of tumors are known to contain rat sarcoma (Ras) mutations. In particular, mutations in the Kirsten Ras oncogene (K-Ras) are one of the most common Ras mutations detected in human cancers, including lung adenocarcinoma (LUAD) and Pancreatic Ductal Adenocarcinoma (PDAC).

Although Kras is known to be an oncogenic driver, to date, there is no clinically approved targeted therapy for Ras mutated cancers. Ras proteins have long been considered "non-patentable" in part due to their high affinity for their substrate guanosine 5' -triphosphate (GTP) and/or their smooth surface without any distinct targeting regions. Recently, a specific G12C Ras gene mutation has been identified as a potential patentable (drug) target. However, such therapeutic approaches remain limited because the G12C mutation in Ras has a low prevalence (e.g., about 3% in PDAC) compared to other known Ras mutations.

Disclosure of Invention

In view of the foregoing, there remains a considerable need for new designs of therapeutic and diagnostic agents that can specifically target Ras mutants and/or related proteins of Ras to reduce Ras pathway signaling. Such compositions and methods may be particularly useful for treating a variety of diseases, including, but not limited to, cancer and neoplasia conditions. The present disclosure meets these needs and provides additional advantages for diagnosis, prognosis, and treatment of a variety of diseases.

In one aspect, there is provided a compound of formula (I):

Wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

V is C (R) ¹⁷ ) And J is C (R ¹⁶ ) Or V is C (R ¹⁷ ) And J is N, or J is C (R ¹⁷ ) And V is C (R ¹⁶ ) Or J is C (R ¹⁷ ) And V is N;

R ¹⁰ is-L ⁷ -R ⁷ ；

L ⁷ Is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₂ -C ₆ Alkynyl group, wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl and C ₂ -C ₆ Alkynyl is optionally substituted with one, two or three R ^20a Substitution;

R ⁷ is a 3-12 membered nitrogen-containing heterocycloalkyl or a 5-12 membered nitrogen-containing heteroaryl, wherein the 3-12 membered nitrogen-containing heterocycloalkyl or the 5-12 membered nitrogen-containing heteroaryl is optionally substituted with one or moreMultiple R' s ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution;

wherein the bond to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

each R ¹ Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _1-11 Heterocyclylalkyl, -CH ₂ -C _1-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _1-11 Heterocyclylalkyl, -CH ₂ -C _1-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

each R ⁴ Independently selected from hydrogen, halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) (e.g., wherein R ⁴ Optionally an electrophilic moiety capable of forming a covalent bond with a cysteine, serine or aspartic acid residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

R ⁶ is-L ² -R ⁵ ；

Each L ² Independently selected from bond, C ₁ -C ₆ Alkyl, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、-OCON(R ¹⁴ )-、-N(R ¹⁴ ) C (O) O-and-N (R) ¹⁴ )C(O)N(R ¹⁴ )-；

Each R ⁵ Independently hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with a cysteine residue at position 12 of a KRAS protein;

R ⁸ selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20c Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

L ¹ Selected from bonds, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、-OCON(R ¹⁴ )-、-N(R ¹⁴ )C(O)O-、N(R ^1e )、C(O)N(R ^1c )、S(O) ₂ N(R ^1c )、S(O)N(R ^1c )、C(R ^1f )(R ^1g )O、C(R ^1f )(R ^1g )N(R ^1c ) And C (R) ^1f )(R ^1g )；

R ^1e 、R ^1f And R is ^1g Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 NaphtheneRadical, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R is ^1f And R is ^1g To form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or the 4-7 membered cycloalkyl ring is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ^1c selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ¹⁹ selected from C _3-12 Cycloalkyl (e.g., monocyclic, bicyclic, or polycyclic), C _2-11 Heterocycloalkyl (e.g., monocyclic, bicyclic, or polycyclic)、C _6-12 Aryl (e.g., monocyclic, bicyclic, or polycyclic) and C _2-12 Heteroaryl (e.g., monocyclic, bicyclic, or polycyclic), wherein C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl is optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ Substitution;

each R ¹ⁱ Independently selected from halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ¹⁶ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20g Substitution;

R ² is-C (O) OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ 、-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ )、–(C ₁ -C ₆ Alkyl) -R ^12b 、–(C _2-6 Alkenyl) -R ^12b 、–(C _2-6 Alkynyl) -R ^12b 、-O-R ^12a 、-N(R ¹⁴ )-R ^12b 、-S-R ^12b 、-(C _3-10 Cycloalkyl) -R ^12b 、-(C _2-9 Heterocycloalkyl) -R ^12b 、-(C _6-10 Aryl) -R ^12b Or-

(C _1-9 Heteroaryl) -R ^12b Wherein said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

R ^12a selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

R ^12b selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

x is C (R) ³ ) Or N;

R ³ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20b Substitution;

each R ¹² Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl radicals、-CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

each R ¹³ Independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; or R is ¹² And R is ¹³ Together with the nitrogen to which they are attached form a group which is optionally substituted with one, two or three R groups ^20e Substituted C _2-9 A heterocycloalkyl ring;

each R ¹⁴ Independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group;

each R ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f Substitution;

each R ^20a 、R ^20b 、R ^20c 、R ^20d 、R ^20e 、R ^20f 、R ^20g And R is ²⁰ⁱ Each independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

Each R ²¹ Independently selected from H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl;

each R ²² Independently selected from H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

each R ²⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl; and is also provided withRepresents a single bond or a double bond such that all valences are satisfied.

In embodiments, X is C (R ³ ). In embodiments, X is N. In embodiments, J is C (R ¹⁶ ) And V is C (R ¹⁷ ). In embodiments, W is C (O).

In embodiments, the compound or pharmaceutically acceptable salt or solvate thereof has the structure:

in embodiments, L ⁷ Is a key.

In embodiments, L ⁷ is-NH-.

In embodiments, R ⁷ Is a 3-12 membered nitrogen-containing heterocycloalkyl group, in whichThe 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution; and wherein the bonding to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In embodiments, R ⁷ Is that

p is an integer from 0 to 12; x is X ¹ Selected from CH ₂ 、C(R ⁴ )(R ⁶ )、C＝N-OR ⁴ 、C＝NN(R ⁴ )(R ⁶ )、C(O)N(R ⁴ )、N(R ⁴ )、N(R ⁶ )、O、S、S(O)、S(＝O)(＝NR ⁴ )、S(O) ₂ N(R ⁴ )、N(R ⁴ )S(O)N(R ⁴ )、N(R ⁴ )S(O) ₂ N(R ⁴ )、S(O)N(R ⁴ )、OC(O)N(R ⁴ )、N(R ⁴ )C(O)N(R ⁴ )、S(O) ₂ 、CH ₂ C(R ⁴ )(R ⁶ )、CH ₂ C(R ⁴ )(R ⁶ )CH ₂ 、C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )C＝N-OR ⁴ 、CH ₂ C＝NN(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁶ )、C(R ⁴ )(R ⁶ )O、C(R ⁴ )(R ⁶ )OC(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S、C(R ⁴ )(R ⁶ )SC(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S(O)、C(R ⁴ )(R ⁶ )S(O)C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S(O) ₂ C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S(＝O)(＝NR ⁴ )、C(R ⁴ )(R ⁶ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁶ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )OC(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )S(O) ₂ 、C＝NN(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )、C(O)N(R ⁴ )C(R ⁴ )(R ⁶ )、S(O) ₂ N(R ⁴ )C(R ⁴ )(R ⁶ )、S(O)N(R ⁴ )C(R ⁴ )(R ⁶ )、OC(O)N(R ⁴ )C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁴ )、C＝N-OR ⁴ 、C＝NN(R ⁴ )(R ⁴ )、CH ₂ C(R ⁴ )(R ⁴ )、CH ₂ C(R ⁴ )(R ⁴ )CH ₂ 、C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C＝N-OR ⁴ 、CH ₂ C＝NN(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁶ )、C(R ⁴ )(R ⁴ )O、C(R ⁴ )(R ⁴ )OC(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S、C(R ⁴ )(R ⁴ )SC(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S(O)、C(R ⁴ )(R ⁴ )S(O)C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S(O) ₂ C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S(＝O)(＝NR ⁴ )、C(R ⁴ )(R ⁴ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁴ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )OC(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )S(O) ₂ 、C＝NN(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )、C(O)N(R ⁴ )C(R ⁴ )(R ⁴ )、S(O) ₂ N(R ⁴ )C(R ⁴ )(R ⁴ )、S(O)N(R ⁴ )C(R ⁴ )(R ⁴ ) And OC (O) N (R) ⁴ )C(R ⁴ )(R ⁴ )；X ² Selected from N, C, C (R) ⁶ )、C(R ⁴ )、CH、N(R ¹ )、N(R ⁴ )、N(R ⁶ )、O、S、S(O)、C(H)(R ⁶ )、C(R ⁴ ) ₂ 、CH ₂ 、C(R ⁴ )(R ⁶ )、S(＝O)(＝NR ⁴ )、S(O) ₂ The method comprises the steps of carrying out a first treatment on the surface of the And X is ³ Selected from N, C, C (R) ⁶ ) And C (R) ⁴ )。

In embodiments, R ⁷ Is that

And p is an integer of 0 to 12.

In embodiments, R ¹⁶ Independently selected from hydrogen and halogen. In embodiments, R ¹⁶ Independent and independentIs selected from hydrogen and fluorine.

In embodiments, R ⁸ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 The heterocycloalkyl groups are optionally substituted with one, two or three R independently selected from ^20c Substitution: halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group. In embodiments, R ⁸ Selected from the group consisting of methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R independently selected from ^20c Substitution: fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl. In embodiments, R ⁸ Selected from methyl, cyclopropyl, cyclobutyl and oxetanyl.

In embodiments, R ³ Is hydrogen or CN.

In embodiments, L ¹ Is a key. In embodiments, L ¹ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -C (O) -, -NHC (O) -, -C (O) NH-, CH ₂ O、CH ₂ NH and CH ₂ 。

In embodiments, R ¹⁹ Is a single ring. In embodiments, R ¹⁹ Is a bicyclic ring system. In embodiments, R ¹⁹ Is a polycyclic system.

In embodiments, R ¹⁹ The method comprises the following steps:

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

X ⁴ 、X ⁵ 、X ⁶ 、X ⁹ 、X ¹⁰ 、X ¹¹ 、X ¹² And X ¹⁶ Independently selected from C (R) ^1a ) Or N;

X ⁷ and X ⁸ Independently selected from C (R) ^1a )、C(R ^1a )(R ^1b ) N, N or N (R) ^1c )；

X ¹³ Selected from bond, C (O), C (R) ^1a )(R ^1b )、C(O)C(R ^1a )(R ^1b )、C(R ^1a )(R ^1b )C(R ^1a )(R ^1b )、C(R ^1a )(R ^1b )N(R ^1c ) And N (R) ^1c )；

X ¹⁴ And X ¹⁵ Independently selected from bond, C (O), C (R) ^1a )(R ^1b ) And N (R) ^1c )；

Each R ^1a 、R ^1b 、R ^1d 、R ^1f 、R ^1g And R is ^1h Each independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R bonded to the same carbon ^1a And R is ^1b To form a 3-to 10-membered heterocycloalkyl ring or C _3-10 Cycloalkyl rings, wherein 3-10 membered heterocycloalkyl ring or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or two R's bonded to adjacent atoms ^1a To form a 3-to 10-membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring wherein 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or R is ^1h With R bound to adjacent atoms ^1a 、R ^1b 、R ^1c And R is ^1d Is linked to form a 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring wherein 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring and C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or R is ^1f And R is ^1g To form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or the 4-7 membered cycloalkyl ring is optionally substituted with one, two or three R ²⁰ⁱ Substitution; and is also provided with

Each R ^1c Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ And (3) substitution.

In embodiments, R ¹⁹ The method comprises the following steps:

/>

in embodiments, R ² Selected from the group consisting of

/>

In embodiments, each L ² Independently a key.

In embodiments, each R ⁵ Independently selected from: -H, -NH ₂ 、-OH、-NH(C _1-6 Alkyl group),

/>

And m is 0, 1, 2 or 3 when present.

In embodiments, R ⁴ independently-C (O) R ¹⁵ . In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently selected from C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl, wherein C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f And (3) substitution. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently C _2-6 Alkenyl group, wherein C _2-6 Alkenyl is optionally substituted with one, two or three R ^20f And (3) substitution. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently C _2-9 Heterocycloalkyl, wherein C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20f And (3) substitution. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently C _1-9 Heteroaryl, wherein C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f And (3) substitution. In embodiments, R ⁴ Is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine or aspartic acid residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein.

In one aspect, a composition having the formula A-L ^AB -a compound of B, wherein a is a monovalent form of a compound described herein; l (L) ^AB Are covalent linkers that bind to a and B; and B is a monovalent form of a degradation enhancer.

In embodiments, the degradation enhancer is capable of binding a protein selected from the group consisting of: E3A, mdm, APC, EDD1, SOCS/BC-boxEach of the following materials may be selected from the group consisting of/eloBC/CUL 5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE C, UBE3D, UBE4A, UBE4B, UBOX5 UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WWP1, WWP2, parkinson's protein, MKRN1, CMA (chaperone-mediated autophagy), SCFB-TRCP (jump-hysteresis-F box (. Beta. -TRCP) ubiquitin complex), b-TRCP (b-transduced repeat-containing protein), cIAP1 (apoptosis inhibitor protein 1), APC/C (late promoting complex/cell cycle body), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL 4) ^CRBN ) Ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, ahR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, atorvastatin, ibbean and CC-885.

In embodiments, the degradation enhancer is capable of binding a protein selected from the group consisting of: UBE2A, UBE2B, UBE2C, UBE D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE V2U, UBE V1, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.

In embodiments, L ^AB is-L ^AB1 -L ^AB2 -L ^AB3 -L ^AB4 -L ^AB5 -；L ^AB1 、L ^AB2 、L ^AB3 、L ^AB4 And L ^AB5 Independently is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C _1-6 Alkylene, (-O-C) _1-6 Alkyl group _z -、(-C _1-6 Alkyl group-O) _z -、C _2-6 Alkenylene, C _2-6 Alkynylene, C _1-6 Halogenated alkylene, C _3-12 Cycloalkylene, C _1-11 Heterocycloalkylene, C _6-12 Arylene or C _1-11 Heteroarylene group, wherein C _1-6 Alkylene, C _2-6 Alkenylene, C _2-6 Alkynylene, C _1-6 Halogenated alkylene, C _3-12 Cycloalkylene, C _1-11 Heterocycloalkylene, C _6-12 Arylene or C _1-11 Heteroarylene is optionally substituted with one, two or three R ^20j Substitution; wherein (-O-C) _1-6 Alkyl group _z -and (-C) _1-6 alkyl-O) _z -each C _1-6 Alkyl is optionally substituted with one, two or three R ^20j Substitution; z is independently an integer from 0 to 10; each R ¹² Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution; each R ¹³ Independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; or R is ¹² And R is ¹³ Together with the nitrogen to which they are attached form a group which is optionally substituted with one, two or three R groups ^20e Substituted C _2-9 A heterocycloalkyl ring; each R ¹⁴ Independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; each R ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f Substitution; each R ^20d 、R ^20e 、R ^20f And R is ^20j Each independently selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ The method comprises the steps of carrying out a first treatment on the surface of the Each R ²¹ Independently selected from H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl; each R ²² Independently selected from H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl; each R ²³ Independently selected from H and C _1-6 An alkyl group; each R ²⁴ Independently selected from H and C _1-6 An alkyl group; and each R ²⁵ Selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl groups. In embodiments, L ^AB Is- (O-C) ₂ Alkyl group _z -, and z is an integer from 1 to 10. In embodiments, L ^AB Is- (C) ₂ alkyl-O-) _z -, and z is an integer from 1 to 10. In embodiments, L ^AB Is- (CH) ₂ ) _z1 L ^AB2 (CH ₂ O) _z2 -, wherein L ^AB2 Is a bond, 5-or 6-membered heterocycloalkylene or heteroarylene, phenylene, - (C) ₂ -C ₄ ) Alkynylene, -SO ₂ -or-NH-; and z1 and z2 are independently integers from 0 to 10. In embodiments, L ^AB Is- (CH) ₂ ) _z1 (CH ₂ O) _z2 -wherein z1 and z2 are each independently integers from 0 to 10. In embodiments, L ^AB Is a PEG linker. In embodiments, B is a compound selected fromMonovalent form of the substance:

in one aspect, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

In one aspect, there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, a method of modulating the activity of a Ras protein is provided, the method comprising contacting the Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.

In embodiments, the method comprises administering an additional agent or therapy.

In one aspect, a method of inhibiting cell growth is provided, the method comprising administering to a cell expressing a Ras protein an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting growth of the cell.

In embodiments, the method comprises administering an additional agent to the cell.

In some embodiments, the additional agent comprises (1) an inhibitor of MEK; (2) Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and/or mutants thereof; (3) an immunotherapeutic agent; (4) a taxane; (5) an antimetabolite; (6) Inhibitors of FGFR1 and/or FGFR2 and/or FGFR3 and/or mutants thereof; (7) mitotic kinase inhibitors; (8) an anti-angiogenic drug; (9) a topoisomerase inhibitor; (10) a platinum-containing compound; (12) inhibitors of c-MET and/or mutants thereof; (13) inhibitors of BCR-ABL and/or mutants thereof; (14) inhibitors of ErbB2 (Her 2) and/or mutants thereof; (15) inhibitors of AXL and/or mutants thereof; (16) inhibitors of NTRK1 and/or mutants thereof; (17) inhibitors of RET and/or mutants thereof; (18) Inhibitors of A-Raf and/or B-Raf and/or C-Raf and/or mutants thereof; (19) inhibitors of ERK and/or mutants thereof; (20) an MDM2 inhibitor; (21) inhibitors of mTOR; (23) inhibitors of IGF1/2 and/or IGF 1-R; (24) inhibitors of CDK 9; (25) inhibitors of farnesyl transferase; (26) inhibitors of the SHIP pathway; (27) inhibitors of SRC; (28) inhibitors of JAK; (29) PARP inhibitors; (31) ROS1 inhibitors; (32) inhibitors of the SHP pathway; or (33) an inhibitor of Src, FLT3, HDAC, VEGFR, PDGFR, LCK, bcr-Abl or AKT; (34) inhibitors of KrasG12C mutants; (35) SHC inhibitors (e.g., PP2, AID 371185); (36) a GAB inhibitor; (38) PI-3 kinase inhibitors; (39) a MALPK inhibitor; (40) a CDK4/6 inhibitor; (41) MAPK inhibitors; (42) an SHP2 inhibitor; (43) checkpoint immune blocker; (44) SOS1 inhibitors; or (45) an SOS2 inhibitor. In some embodiments, the additional agent comprises an SHP2 inhibitor selected from the group consisting of RMC-4630, TNO155, JAB-3068, IACS-13909/BBP-398, SHP099, ERAS-601, and RMC-4550. In some embodiments, the additional agent comprises an SOS inhibitor selected from the group consisting of RMC-5845, BI-3406, BI-1701963, MRTX0902 and BAY 293. In some embodiments, the additional agent comprises an EGFR inhibitor selected from the group consisting of: afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, octreotide, omrotinib and EGF-816. In some embodiments, the additional agent comprises an inhibitor of MEK selected from the group consisting of: trametinib, kemeltinib, bemetinib, semetinib, remimetinib and AZD6244. In some embodiments, the additional agent comprises an ERK inhibitor selected from the group consisting of: ulitinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996 and ravoxertiinib. In some embodiments, the additional agent comprises an inhibitor of CDK4/6 selected from the group consisting of: palbociclib, rebabociclib and abbe-cilib. In some embodiments, the additional agent comprises an inhibitor of BRAF selected from the group consisting of: sorafenib (sorafenib), vitamin Mo Feini (vemurafenib), dapafinib (dabrafenib), kang Naifei of ni (encorafenib), regrafenib (regorafenib) and GDC-879.

In one aspect, there is provided a Ras protein bound by a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the activity of the Ras protein is reduced compared to a Ras protein not bound to the compound.

In one aspect, there is provided a compound of formula (I):

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

R ¹⁰ is-L ⁷ -R ⁷ ；

R ⁷ is a 3-12 membered nitrogen containing heterocycloalkyl or a 5-12 membered nitrogen containing heteroaryl, wherein 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substitution;

each R ⁴ Independently selected from hydrogen, halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

R ⁶ is-L ² -R ⁵ ；

R ⁸ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20c Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

R ^1e 、R ^1f And R is ^1g Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R is ^1f And R is ^1g To form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or the 4-7 membered cycloalkyl ring is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ¹⁹ selected from C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl, wherein C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl is optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ Substitution;

each R ¹ⁱ Independently selected from halogen,-CN、C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

x is C (R) ³ ) Or N;

each R ¹² Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

each R ¹³ Independently selected from hydrogen, C _1-6 Alkyl groupAnd C _1-6 A haloalkyl group; or R is ¹² And R is ¹³ Together with the nitrogen to which they are attached form a group which is optionally substituted with one, two or three R groups ^20e Substituted C _2-9 A heterocycloalkyl ring;

each R ^20a 、R ^20b 、R ^20c 、R ^20d 、R ^20e 、R ^20f 、R ^20g And R is ²⁰ⁱ Each independently selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

each R ²⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl; and is also provided with

Represents a single bond or a double bond such that all valences are satisfied.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, X is C (R ³ ). In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, X is N.

In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, V is C (R ¹⁶ ) And J is C (R ¹⁷ ). In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, V is N and J is C (R ¹⁷ ). In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, J is N and V is C (R ¹⁷ ). In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, J is C (R ¹⁶ ) And V is C (R ¹⁷ ). In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, W is C (O). In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, W is S (O). In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, W is S (O) ₂ 。

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the following structure:

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in embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the following structure:

in further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ⁷ Is a key. In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ⁷ is-NH-.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substitution; and wherein the bonding to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is that

p is an integer from 0 to 12;

X ¹ selected from CH ₂ 、C(R ⁴ )(R ⁶ )、C＝N-OR ⁴ 、C＝NN(R ⁴ )(R ⁶ )、C(O)N(R ⁴ )、N(R ⁴ )、N(R ⁶ )、O、S、S(O)、S(＝O)(＝NR ⁴ )、S(O) ₂ N(R ⁴ )、N(R ⁴ )S(O)N(R ⁴ )、N(R ⁴ )S(O) ₂ N(R ⁴ )、S(O)N(R ⁴ )、OC(O)N(R ⁴ )、N(R ⁴ )C(O)N(R ⁴ )、S(O) ₂ 、CH ₂ C(R ⁴ )(R ⁶ )、CH ₂ C(R ⁴ )(R ⁶ )CH ₂ 、C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )C＝N-OR ⁴ 、CH ₂ C＝NN(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁶ )、C(R ⁴ )(R ⁶ )O、C(R ⁴ )(R ⁶ )OC(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S、C(R ⁴ )(R ⁶ )SC(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S(O)、C(R ⁴ )(R ⁶ )S(O)C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S(O) ₂ C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S(＝O)(＝NR ⁴ )、C(R ⁴ )(R ⁶ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁶ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )OC(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )S(O) ₂ 、C＝NN(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )、C(O)N(R ⁴ )C(R ⁴ )(R ⁶ )、S(O) ₂ N(R ⁴ )C(R ⁴ )(R ⁶ )、S(O)N(R ⁴ )C(R ⁴ )(R ⁶ )、OC(O)N(R ⁴ )C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁴ )、C＝N-OR ⁴ 、C＝NN(R ⁴ )(R ⁴ )、CH ₂ C(R ⁴ )(R ⁴ )、CH ₂ C(R ⁴ )(R ⁴ )CH ₂ 、C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C＝N-OR ⁴ 、CH ₂ C＝NN(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁶ )、C(R ⁴ )(R ⁴ )O、C(R ⁴ )(R ⁴ )OC(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S、C(R ⁴ )(R ⁴ )SC(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S(O)、C(R ⁴ )(R ⁴ )S(O)C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S(O) ₂ C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S(＝O)(＝NR ⁴ )、C(R ⁴ )(R ⁴ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁴ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )OC(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )S(O) ₂ 、C＝NN(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )、C(O)N(R ⁴ )C(R ⁴ )(R ⁴ )、S(O) ₂ N(R ⁴ )C(R ⁴ )(R ⁴ )、S(O)N(R ⁴ )C(R ⁴ )(R ⁴ ) And OC (O) N (R) ⁴ )C(R ⁴ )(R ⁴ )；

X ² Selected from N, C, C (R) ⁶ )、C(R ⁴ )、CH、N(R ¹ )、N(R ⁴ )、N(R ⁶ )、O、S、S(O)、C(H)(R ⁶ )、C(R ⁴ ) ₂ 、CH ₂ 、C(R ⁴ )(R ⁶ )、S(＝O)(＝NR ⁴ )、S(O) ₂ The method comprises the steps of carrying out a first treatment on the surface of the And X is ³ Selected from N, C, C (R) ⁶ ) And C (R) ⁴ )。

In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is that

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And p is an integer of 0 to 12.

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is that

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl group, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl is optionally substituted with one, two or three R' s ^20g And (3) substitution. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen and halogen. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen and fluorine.

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20c And (3) substitution. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 The heterocycloalkyl groups are optionally substituted with one, two or three R independently selected from ^20c Substitution: halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from the group consisting of methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R independently selected from ^20c Substitution: fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from methyl, cyclopropyl, cyclobutyl and oxetanyl.

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ³ Is hydrogen or CN. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ³ Is hydrogen.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ¹ Is a key. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ¹ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -C (O) -, -NHC (O) -, -C (O) NH-, CH ₂ O、CH ₂ NH and CH ₂ 。

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is a single ring. In the subject compounds orIn some embodiments of pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is a bicyclic ring system. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is a polycyclic system. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ The method comprises the following steps:/>

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

X ⁴ 、X ⁵ 、X ⁶ 、X ⁹ 、X ¹⁰ 、X ¹¹ And X ¹² Independently selected from C (R) ^1a ) Or N;

Each R ^1a 、R ^1b 、R ^1d And R is ^1h Each independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R bonded to the same carbon ^1a And R is ^1b To form a 3-to 10-membered heterocycloalkyl ring or C _3-10 Cycloalkyl rings, wherein 3-10 membered heterocycloalkyl ring or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or two R's bonded to adjacent atoms ^1a To form a 3-to 10-membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring wherein 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or R is ^1h With R bound to adjacent atoms ^1a 、R ^1b 、R ^1c And R is ^1d Is linked to form a 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring wherein 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring and C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; and is also provided with

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ The method comprises the following steps:

/>

in embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ² Selected from the group consisting of

/>

In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, each R ⁵ Independently selected from:

-H、-NH ₂ 、-OH、-NH(C _1-6 alkyl group),

And m is 0, 1, 2 or 3 when present.

In one aspect, there is provided a compound of formula (II):

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

V is C (R) ¹⁶ ) Or N;

R ¹⁰ is-L ⁷ -R ⁷ ；

R ⁷ is a 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl, wherein 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substitution;

bonded to the same or adjacent atoms and selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to two substituents of (2)To form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

R ⁶ is-L ² -R ⁵ ；

R ¹⁷ is-L ¹ -R ¹⁹ ；

R ^12a selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl group、C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

x is C (R) ³ ) Or N;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, V is C (R ¹⁶ ). In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, V is N.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, W is C (O). In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, W is S (O). In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, W is S (O) ₂ 。

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in embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ⁷ Is a key. In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ⁷ is-NH-.

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is a 3-12 membered heterocycloalkyl, wherein 3-12 membered heterocycloalkyl is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substitution; and wherein the bonding to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

p is an integer from 0 to 12;

In some embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereofWherein R is ⁷ Is that

And p is an integer of 0 to 12.

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In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl group, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl is optionally substituted with one, two or three R' s ^20g And (3) substitution. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen and halogen. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereofWherein R is ¹⁶ Independently selected from hydrogen and fluorine.

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20c And (3) substitution. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 The heterocycloalkyl groups are optionally substituted with one, two or three R independently selected from ^20c Substitution: halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group. In some embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereofWherein R is ⁸ Selected from the group consisting of methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R independently selected from ^20c Substitution: fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from methyl, cyclopropyl, cyclobutyl, oxetane methyl and oxetane groups. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from methyl, cyclopropyl, cyclobutyl and oxetanyl.

In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ³ Is hydrogen or CN. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ³ Is hydrogen.

In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ¹ Is a key. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ¹ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -C (O) -, -NHC (O) -, -C (O) NH-, CH ₂ O、CH ₂ NH and CH ₂ 。

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is a single ring. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is a bicyclic ring system. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is a polycyclic system. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ The method comprises the following steps:

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

In embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof,

in some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ² Selected from the group consisting of

/>

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, each R ⁵ Independently selected from:

-H、-NH ₂ 、-OH、-NH(C _1-6 alkyl group),

And m is 0, 1, 2 or 3 when present.

In one aspect, a composition having the formula A-L ^AB -B compounds wherein A is of the formula I, IA, IA2, IA3,Monovalent forms of compounds of IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; l (L) ^AB Are covalent linkers that bind to a and B; and B is a monovalent form of a degradation enhancer.

In one aspect, a composition having the formula A-L ^AB -a compound of B, wherein a is a monovalent form of a compound of formula I, IA, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX; l (L) ^AB Are covalent linkers that bind to a and B; and B is a monovalent form of a degradation enhancer.

In embodiments, the degradation enhancer is capable of binding a protein selected from the group consisting of: E3A, mdm2, APC, EDD1, SOCS/BC-box/eloBC/CUL 5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE B, UBOX5 UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WWP1, WWP2, parkinson's protein, MKRN1, CMA (chaperone-mediated autophagy), SCFB-TRCP (jump-hysteresis-F box (. Beta. -TRCP) ubiquitin complex), b-TRCP (b-transduced repeat-containing protein), cIAP1 (apoptosis inhibitor protein 1), APC/C (late promoting complex/cell cycle body), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL 4) ^CRBN ) Ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, ahR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, atorvastatin, illitePolyamine and CC-885.

In embodiments, L ^AB is-L ^AB1 -L ^AB2 -L ^AB3 -L ^AB4 -L ^AB5 -；

L ^AB1 、L ^AB2 、L ^AB3 、L ^AB4 And L ^AB5 Independently is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C _1-6 Alkylene, (-O-C) _1-6 Alkyl group _z -、(-C _1-6 alkyl-O) _z -、C _2-6 Alkenylene, C _2-6 Alkynylene, C _1-6 Halogenated alkylene, C _3-12 Cycloalkylene, C _1-11 Heterocycloalkylene, C _6-12 Arylene or C _1-11 Heteroarylene group, wherein C _1-6 Alkylene, C _2-6 Alkenylene, C _2-6 Alkynylene, C _1-6 Halogenated alkylene, C _3-12 Cycloalkylene, C _1-11 Heterocycloalkylene, C _6-12 Arylene or C _1-11 Heteroarylene is optionally substituted with one, two or three R ^20j Substitution; wherein (-O-C) _1-6 Alkyl group _z -and (-C) _1-6 alkyl-O) _z -each C _1-6 Alkyl is optionally substituted with one, two or three R ^20j Substitution;

z is independently an integer from 0 to 10;

each R ^20d 、R ^20e 、R ^20f And R is ^20j Each independently selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

Each R ²¹ Independently selected from H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl groupA base;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group; and is also provided with

Each R ²⁵ Selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl groups.

In embodiments, L ^AB Is- (O-C) ₂ Alkyl group _z -, and z is an integer from 1 to 10.

In embodiments, L ^AB Is- (C) ₂ alkyl-O-) _z -, and z is an integer from 1 to 10.

In embodiments, L ^AB Is- (CH) ₂ ) _z1 L ^AB2 (CH ₂ O) _z2 -, wherein L ^AB2 Is a bond, 5-or 6-membered heterocycloalkylene or heteroarylene, phenylene, - (C) ₂ -C ₄ ) Alkynylene, -SO ₂ -or-NH-; and z1 and z2 are independently integers from 0 to 10.

In embodiments, L ^AB Is- (CH) ₂ ) _z1 (CH ₂ O) _z2 -wherein z1 and z2 are each independently integers from 0 to 10.

In embodiments, L ^AB Is a PEG linker (e.g., a divalent linker of 1 to 10 ethylene glycol subunits).

In embodiments, B is a monovalent form of a compound selected from the group consisting of:

in one aspect, a pharmaceutical composition is provided that comprises a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

In one aspect, a method of treating cancer in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, a method of modulating the activity of a protein of Ras (e.g., K-Ras) is provided, comprising contacting the Ras protein with an effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; formulas I ', II ', I ', II ', I-1', I-3, I-4 a compound of II-1, XVI, XVII, XVIII or XIX) or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of a Ras (e.g., K-Ras) protein.

In some embodiments, the subject methods comprise administering an additional agent or therapy.

In one aspect, a method of inhibiting cell growth is provided, the method comprising administering to a cell expressing a Ras (e.g., K-Ras) protein an effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII or XIX) or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting the growth of said cells. In embodiments, the subject methods comprise administering an additional agent to the cells.

In one aspect, there is provided a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the activity of the Ras (e.g., K-Ras) protein is reduced compared to a Ras (e.g., K-Ras) protein that is not bound to the compound.

Incorporation by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Detailed Description

Practice of some embodiments disclosed herein employs, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA within the skill of the art. See, e.g., sambrook and Green, molecular Cloning: laboratory Manual, 4 th edition (2012); current Protocols in Molecular Biology series (F.M. Ausubel et al); methods In Enzymology series (Academic Press, inc.); PCR 2:Practical Approach (M.J.MacPherson, B.D.Hames and G.R.Taylor et al (1995)); harlow and Lane et al (1988) Antibodies, laboratory Manual; and Culture of Animal Cells: manual of Basic Technique and Specialized Applications, 6 th edition (R.I. Freshney, eds. (2010)).

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood in the art to which claimed subject matter belongs. If there are multiple definitions of the terms herein, those in this section control. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. When referring to a URL or other such identifier or address, it should be understood that such identifier may vary and that specific information on the internet may vary, but equivalent information may be found by searching the internet. Reference thereto demonstrates the availability and public dissemination of such information.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "include" and other forms, such as "include", "include" and "included", are not limiting.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Definitions of standard chemical terms can be found in references including, but not limited to, carey and Sundberg, "Advanced Organic Chemistry, 4 th edition," volumes a (2000) and B (2001), plenum Press, new york. Mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and conventional methods of pharmacology, unless otherwise indicated.

Unless specifically defined otherwise, nomenclature that and laboratory procedures and techniques employed in connection with the analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are those recognized in the art. Standard techniques may be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, tissue culture and transformation (e.g., electroporation, lipofection). The reaction and purification techniques may be performed, for example, using a kit with manufacturer's instructions, or as commonly accomplished in the art, or as described herein. The foregoing techniques and procedures may generally be carried out according to conventional methods and as described in various general and more specific references cited and discussed throughout the present specification.

It is to be understood that the methods and compositions described herein are not limited to the particular methods, protocols, cell lines, constructs, and reagents described herein, and, therefore, may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

As used herein, C ₁ -C _x Comprises C ₁ -C ₂ 、C ₁ -C ₃ …C ₁ -C _x 。C ₁ -C _x Refers to the number of carbon atoms (excluding optional substituents) that make up the moiety to which it is assigned.

"alkyl" group refers to a straight or branched hydrocarbon radical consisting of only carbon and hydrogen atoms, and containing no unsaturation. In some embodiments, an "alkyl" group may beHaving 1 to 18, 1 to 12, 1 to 10, 1 to 8, or 1 to 6 carbon atoms (whenever present herein, a numerical range such as "1 to 6" means each integer within a given range; e.g., "1 to 6 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where a numerical range is not specified). The alkyl groups of the compounds described herein may be designated as "C" ₁ -C ₆ Alkyl "or the like. Merely by way of example, "C ₁ -C ₆ Alkyl "indicates the presence of one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl. The alkyl group may be substituted or unsubstituted. The alkyl groups may be mono-or di-radicals (i.e., alkylene groups) depending on the structure.

"alkoxy" refers to an "-O-alkyl" group, wherein alkyl is as defined herein.

The term "alkenyl" refers to a straight or branched hydrocarbon chain radical consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include-ch=ch ₂ 、-C(CH ₃ )＝CH ₂ 、-CH＝CHCH ₃ 、-CH＝C(CH ₃ ) ₂ and-C (CH) ₃ )＝CHCH ₃ . In some embodiments, the alkenyl group may have 2 to 6 carbons. The alkenyl group may be substituted or unsubstituted. Depending on the structure, the alkenyl groups may be mono-or di-radicals (i.e., alkenylene groups).

The term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include-C.ident.CH, -C.ident.CCH ₃ 、–C≡CCH ₂ CH ₃ and-C.ident.CCH ₂ CH ₂ CH ₃ . In some embodiments, an alkynyl group may have 2 to 6 carbons. Alkynyl groups may be substituted or unsubstituted. Depending on the structureAlkynyl groups may be mono-or di-radicals (i.e., alkynylene groups).

"amino" means-NH ₂ A group.

The term "alkylamine" or "alkylamino" refers to-N (alkyl) _x H _y A group wherein alkyl is as defined herein and x and y are selected from x=1, y=1 and x=2, y=0. When x=2, the alkyl groups together with the nitrogen to which they are attached may optionally form a cyclic ring system. "dialkylamino" means-N (alkyl) ₂ A group wherein alkyl is as defined herein.

The term "aromatic" refers to a planar ring having a delocalized pi electron system comprising 4n+2 pi electrons, where n is an integer. The aromatic ring may be formed from five, six, seven, eight, nine or more than nine atoms. The aromatic compound may be optionally substituted. The term "aromatic" includes aryl groups (e.g., phenyl, naphthyl) and heteroaryl groups (e.g., pyridyl, quinolinyl).

As used herein, the term "aryl" refers to a monocyclic aromatic ring in which each atom forming the ring is a carbon atom (e.g., phenyl) or a polycyclic ring system (e.g., bicyclic or tricyclic), wherein 1) at least one ring is carbocyclic and aromatic, 2) the bonds of the remainder of the compound are directly bonded to the carbocyclic aromatic ring of the aryl ring system, and 3) the carbocyclic aromatic ring of the aryl ring system of 2) is not directly bonded (e.g., fused) to a heteroaryl ring in the polycyclic ring system. The aryl ring may be formed from five, six, seven, eight, nine or more than nine carbon atoms. The aryl group may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Depending on the structure, the aryl group may be a mono-radical or a di-radical (i.e., arylene group). As used herein, aryl radicals are monocyclic, bicyclic or tricyclic ring systems. In embodiments, aryl is a single ring. In embodiments, aryl is a fused ring polycyclic ring system. In embodiments, aryl is a bridged polycyclic ring system. In some embodiments, aryl is a "fused ring aryl" in which the aryl ring is fused to a cycloalkyl or heterocycloalkyl ring.

"carboxy" means-CO ₂ H. In one placeIn some embodiments, the carboxyl moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as the carboxylic acid moiety. The carboxylic acid bioisostere has biological properties similar to those of the carboxylic acid group. The compound having a carboxylic acid moiety may have a carboxylic acid moiety that is bioisostere exchanged with a carboxylic acid and has similar physical and/or biological properties when compared to the compound containing a carboxylic acid. For example, in one embodiment, the carboxylic acid bioisostere will ionize to about the same extent as the carboxylic acid group at physiological pH. Examples of bioisosteres of carboxylic acids include, but are not limited to

Etc.

The term "cycloalkyl" refers to a monocyclic carbocyclic saturated or partially unsaturated non-aromatic ring or polycyclic carbocyclic (i.e., excluding heteroatoms) ring system (e.g., bicyclic or tricyclic), wherein 1) at least one ring is a carbocyclic saturated or partially unsaturated non-aromatic ring, 2) the bond to the remainder of the compound is directly bonded to the carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system, and 3) the carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system of 2) is not directly bonded (e.g., fused or spiro) to the heterocycloalkyl ring in the polycyclic ring system. Cycloalkyl groups may be saturated or partially unsaturated. In some embodiments, the cycloalkyl ring is a spiro cycloalkyl ring. In embodiments, cycloalkyl is a single ring. In embodiments, cycloalkyl is a fused ring polycyclic ring system. In embodiments, cycloalkyl is a bridged polycyclic ring system. In embodiments, cycloalkyl is a spiro polycyclic ring system. In some embodiments, cycloalkyl groups include groups having 3 to 10 ring atoms. Depending on the structure, the cycloalkyl group may be a mono-radical or a di-radical (i.e., a cycloalkylene group).

The term "heteroaryl" or alternatively "heteroaromatic" refers to a monocyclic aryl group comprising one or more ring heteroatoms selected from nitrogen, oxygen and sulfur; or polycyclic ring systems (e.g., bicyclic or tricyclic), wherein 1) at least one ring is aromatic and includes one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and 2) bonds to the remainder of the compound are directly bonded to an aromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, or are directly bonded (e.g., fused) to an aromatic ring of an aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical may be a monocyclic, bicyclic, or tricyclic ring system, wherein at least one ring in the ring system is fully unsaturated (i.e., aromatic) and includes heteroatoms. In embodiments, heteroaryl is a single ring. In embodiments, heteroaryl groups are fused ring polycyclic ring systems. In embodiments, heteroaryl groups are bridged ring polycyclic systems. In some embodiments is a "fused ring heteroaryl" in which the heteroaryl ring is fused to a cycloalkyl, aryl, or heterocycloalkyl ring. An "heteroaromatic" or "heteroaryl" moiety containing N refers to an aromatic group in which at least one backbone atom of the ring is a nitrogen atom. Depending on the structure, the heteroaryl group may be a mono-radical or a di-radical (i.e., heteroarylene group).

"heterocycloalkyl" group or "heteroalicyclic" group refers to a heterocycloalkyl group in which at least one backbone ring atom of a saturated or partially unsaturated non-aromatic ring is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. Heterocycloalkyl refers to a monocyclic saturated or partially unsaturated non-aromatic or polycyclic ring system (e.g., bicyclic or tricyclic) comprising one or more heteroatoms, wherein 1) at least one ring is a saturated or partially unsaturated non-aromatic ring and comprises one or more heteroatoms, and 2) the bond to the remainder of the compound is directly bonded to a ring of the ring system, which ring is a saturated or partially unsaturated non-aromatic ring comprising one or more heteroatoms, or is a non-aromatic ring directly bonded (e.g., fused) to a saturated or partially unsaturated non-aromatic ring comprising one or more heteroatoms of the ring system. Heterocycloalkyl groups may be saturated or partially unsaturated. The term heterocycloalkyl also includes all cyclic forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl ring is a spirocycloalkyl ring. In embodiments, the heterocycloalkyl group is a single ring. In embodiments, heterocycloalkyl is a fused ring polycyclic ring system. In embodiments, heterocycloalkyl is a bridged polycyclic ring system. In embodiments, heterocycloalkyl is a spiro polycyclic ring system. Unless otherwise indicated, heterocycloalkyl groups have from 2 to 13 carbons in the ring or ring system. It will be appreciated that when referring to the number of carbon atoms in the heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is different from the total number of atoms (including heteroatoms) that make up the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). Depending on the structure, the heterocycloalkyl group may be a mono-radical or a di-radical (i.e., a heterocycloalkylene group).

The term "halo" or alternatively "halogen" refers to fluoro, chloro, bromo and iodo.

The abbreviations "Fmoc", "Ac", "Bn", "PMB", "Tr", "Ts", "Boc" and "Cbz" are used according to their common meaning well known in chemistry and mean the monovalent chemical substituents fluorenylmethoxycarbonyl, acetyl, benzyl, p-methoxybenzyl, trityl or triphenylmethyl, tosyl, t-butoxycarbonyl and carbonylbenzyloxy, respectively.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens may be the same or they may be different. Non-limiting examples of haloalkyl groups include-CH ₂ Cl、-CF ₃ 、-CHF ₂ 、-CH ₂ CF ₃ 、-CF ₂ CF ₃ Etc.

The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups, respectively, substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl groups include-CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CF ₃ 、-CF ₂ CF ₃ 、-CF ₂ CF ₂ CF ₃ 、-CF(CH ₃ ) ₃ Etc. Non-limiting examples of fluoroalkoxy groupscomprises-OCF ₃ 、-OCHF ₂ 、-OCH ₂ F、-OCH ₂ CF ₃ 、-OCF ₂ CF ₃ 、-OCF ₂ CF ₂ CF ₃ 、-OCF(CH ₃ ) ₂ Etc.

The term "heteroalkylene linker" refers to a divalent alkyl group where one or more backbone atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. In some embodiments, the heteroatom may be located at any internal position of the heteroalkyl group. In some embodiments, the heteroatom may be located at one or both terminal positions of the alkylene linker (i.e., directly bonded to a portion of the molecule other than the alkylene linker). Examples include, but are not limited to, -CH ₂ -O-CH ₂ -、-CH ₂ -CH ₂ -O-CH ₂ -、-CH ₂ -NH-CH ₂ -、-CH ₂ -CH ₂ -NH-CH ₂ -、-CH ₂ -N(CH ₃ )-CH ₂ -、-CH ₂ -CH ₂ -N(CH ₃ )-CH ₂ -、-CH ₂ -S-CH ₂ -CH ₂ -、-CH ₂ -CH ₂ -S(O)-CH ₂ -、-CH ₂ -CH ₂ -S(O) ₂ -CH ₂ -、-CH ₂ -NH-O-CH ₂ -、–CH ₂ -O-Si(CH ₃ ) ₂ -、-CH ₂ -CH＝N-O-CH ₂ -and-ch=ch-N (CH ₃ )-CH ₂ -. Examples include, but are not limited to, -CH ₂ -O-、-CH ₂ -CH ₂ -O-、-CH ₂ -NH-、-CH ₂ -CH ₂ -NH-、-CH ₂ -N(CH ₃ )-、-CH ₂ -CH ₂ -N(CH ₃ )-、-CH ₂ -S-、-CH ₂ -CH ₂ -S-、-CH ₂ -CH ₂ -S(O)-、-CH ₂ -CH ₂ -S(O) ₂ -、-CH ₂ -S(O)-、-CH ₂ -S(O) ₂ -、-CH ₂ -CH ₂ -CH ₂ -S(O)-、-CH ₂ -CH ₂ -CH ₂ -S(O) ₂ -、-CH ₂ -CH ₂ -CH ₂ -O-、-CH ₂ -CH ₂ -CH ₂ -O-、-CH ₂ -CH ₂ -CH ₂ -S-、-CH ₂ -CH ₂ -CH ₂ -S-、-CH ₂ -CH ₂ -CH ₂ -NH-、-CH ₂ -CH ₂ -CH ₂ -NH-、-CH ₂ -CH ₂ -CH ₂ -N(CH ₃ )-、-CH ₂ -CH ₂ -CH ₂ -N(CH ₃ )-、-CH ₂ -NH-O-、-O-Si(CH ₃ ) ₂ -、-CH ₂ -ch=n-O-and-ch=ch-N (CH ₃ ) -. Examples include, but are not limited to, the-O-CH ₂ -、-O-CH ₂ -CH ₂ -、-NH-CH ₂ -、-NH-CH ₂ -CH ₂ -、-N(CH ₃ )-CH ₂ -、-N(CH ₃ )-CH ₂ -CH ₂ -、-S-CH ₂ -、-S-CH ₂ -CH ₂ -、-S(O)-CH ₂ -CH ₂ -、-S(O) ₂ -CH ₂ -CH ₂ -、-S(O)-CH ₂ -、-S(O) ₂ -CH ₂ -、-S(O)-CH ₂ -CH ₂ -CH ₂ -、-S(O) ₂ -CH ₂ -CH ₂ -CH ₂ -、-O-CH ₂ -CH ₂ -CH ₂ -、-O-CH ₂ -CH ₂ -CH ₂ -、-S-CH ₂ -CH ₂ -CH ₂ -、-S-CH ₂ -CH ₂ -CH ₂ -、-NH-CH ₂ -CH ₂ -CH ₂ -、-NH-CH ₂ -CH ₂ -CH ₂ -、-N(CH ₃ )-CH ₂ -CH ₂ -CH ₂ -、-N(CH ₃ )-CH ₂ -CH ₂ -CH ₂ -、-O-NH-CH ₂ -、-Si(CH ₃ ) ₂ -O-、-O-N＝CH-CH ₂ -and-N (CH) ₃ ) -ch=ch-. Furthermore, up to two heteroatoms may be consecutive, e.g., as an example, -CH ₂ -NH-O-and-O-Si (CH) ₃ ) ₂ -. Examples include, but are not limited to, -P (O) (CH ₃ )-CH ₂ -、-P(O)(CH ₃ )-CH ₂ -CH ₂ -、-P(O)(CH ₃ )-CH ₂ -CH ₂ -CH ₂ -、-CH ₂ -P(O)(CH ₃ )-、-CH ₂ -CH ₂ -P(O)(CH ₃ ) -and-CH ₂ -CH ₂ -CH ₂ -P(O)(CH ₃ ) -. In addition, up to two hetero sourcesThe sub-groups may be contiguous, e.g., -CH as an example ₂ -NH-O-and-O-Si (CH) ₃ ) ₂ -. Unless otherwise indicated, the "heteroalkylene linker" may have 2 to 4 backbone atoms.

The term "heteroalkyl" refers to an alkyl radical in which one or more backbone atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom may be located at any internal position of the heteroalkyl group. Examples include, but are not limited to, -CH ₂ -O-CH ₃ 、-CH ₂ -CH ₂ -O-CH ₃ 、-CH ₂ -NH-CH ₃ 、-CH ₂ -CH ₂ -NH-CH ₃ 、-CH ₂ -N(CH ₃ )-CH ₃ 、-CH ₂ -CH ₂ -NH-CH ₃ 、-CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ 、-CH ₂ -S-CH ₂ -CH ₃ 、-CH ₂ -CH ₂ -S(O)-CH ₃ 、-CH ₂ -CH ₂ -S(O) ₂ -CH ₃ 、-CH ₂ -NH-OCH ₃ 、–CH ₂ -O-Si(CH ₃ ) ₃ 、-CH ₂ -CH＝N-OCH ₃ and-ch=ch-N (CH ₃ )-CH ₃ . Furthermore, up to two heteroatoms may be consecutive, e.g. as an example-CH ₂ -NH-OCH ₃ and-CH ₂ -O-Si(CH ₃ ) ₃ . Excluding the number of heteroatoms, a "heteroalkyl" may have from 1 to 6 carbon atoms.

The term "oxo" refers to an =o radical.

The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms joined by the bond are considered part of a larger substructure.

The term "moiety" refers to a particular segment or functional group of a molecule. Chemical moieties are often considered chemical entities that are embedded in or attached to a molecule.

The suffix "-diyl" will be understood to mean that the substituent or linker is a divalent substituent or linker.

As used herein, a substituent "R" that appears alone and without a numerical designation refers to a substituent selected from the group consisting of alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when it does not.

Unless otherwise specified, the term "optionally substituted" or "substituted" means that the group referred to may be substituted with one or more additional groups independently and independently selected from the following: alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, -CN, alkyne, C ₁ -C ₆ Alkyl alkyne, halo, acyl, acyloxy, -CO ₂ H、-CO ₂ Alkyl, nitro, haloalkyl, fluoroalkyl, and amino (including mono-and di-substituted amino groups (e.g., -NH ₂ 、-NHR、-N(R) ₂ ) And protected derivatives thereof. For example, the optional substituent may be L ^s R ^s Wherein each L ^s Independently selected from the group consisting of bond, -O-, -C (=o) -, -S (=o) ₂ -、-NH-、-NHC(O)-、-C(O)NH-、S(＝O) ₂ NH-、-NHS(＝O) ₂ 、-OC(O)NH-、-NHC(O)O-、-(C ₁ -C ₆ Alkyl) -or- (C ₂ -C ₆ Alkenyl) -; and each R ^s Independently selected from H, (C) ₁ -C ₆ Alkyl), (C ₃ -C ₈ Cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C ₁ -C ₆ A heteroalkyl group. Protecting groups that can form protective derivatives of the above substituents are found in sources such as Greene and Wuts above.

"pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the compounds described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"pharmaceutically acceptable acid addition salts" refers to salts of: it retains the bioavailability and properties of the free base, is not undesirable in biological or other respects, and is formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts with organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Salts of amino acids such as arginine salts, gluconate and galacturonate are also contemplated (see, e.g., berge s.m. et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science,66:1-19 (1997)). In some embodiments, the acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to the skilled artisan.

"pharmaceutically acceptable base addition salt" refers to the salt: it retains the bioavailability and properties of the free acid and is not undesirable in biological or other respects. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, the pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, salts of: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine (caffeine), procaine, N-dibenzylethylenediamine, chloroprocaine, hydrabamine (hydrabamine), choline, betaine, ethylenediamine, ethylenediphenylamine, N-methyl-reduced glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al (supra).

The terms "polypeptide", "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and may be interrupted by non-amino acids. The term also encompasses amino acid polymers that have been modified (e.g., disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component). As used herein, the term "amino acid" refers to natural and/or unnatural or synthetic amino acids, including glycine and D or L optical isomers, as well as amino acid analogs and peptidomimetics.

The terms "polynucleotide", "nucleotide sequence", "nucleic acid" and "oligonucleotide" are used interchangeably. They refer to polymeric forms of any length of deoxyribonucleotides or ribonucleotides or analogs thereof. Polynucleotides may have any three-dimensional structure and may perform any known or unknown function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci defined by linkage analysis (loci/locus), exons, introns, messenger RNAs (mRNA), transfer RNAs, ribosomal RNAs, short interfering RNAs (siRNA), short hairpin RNAs (shRNA), micrornas (miRNA), ribozymes, cdnas, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNAs of any sequence, nucleic acid probes and primers. Polynucleotides may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as Peptide Nucleic Acids (PNAs), morpholino oligonucleotides and Locked Nucleic Acids (LNAs), glycerol Nucleic Acids (GNAs), threose Nucleic Acids (TNAs), 2 '-fluoro nucleic acids, 2' -OMe nucleic acids, and phosphorothioated DNA. Modification of the nucleotide structure, if present, may be imparted either before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. The polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

As used herein, "expression" refers to the process by which a polynucleotide is transcribed from a DNA template (e.g., into mRNA or other RNA transcript) and/or the subsequent translation of the transcribed mRNA into a peptide, polypeptide, or protein. Transcripts and encoded polypeptides may be collectively referred to as "gene products". If the polynucleotide is derived from genomic DNA, expression may include splicing of mRNA in eukaryotic cells.

The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, apes, humans, farm animals, sports animals, and pets. Tissues, cells and their progeny obtained in vivo or cultured in vitro of a biological entity are also contemplated.

The terms "therapeutic agent (therapeutic agent)", "therapeutic agent (therapeutic capable agent)" or "therapeutic agent" are used interchangeably and refer to a molecule or compound that imparts a certain beneficial effect upon administration to a subject. Beneficial effects include enabling diagnostic determinations; improving a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder, or condition; and against diseases, symptoms, disorders or pathological conditions in general.

As used herein, "treatment" or "alleviating" or "improving" are used interchangeably. These terms refer to methods for achieving beneficial or desired results including, but not limited to, therapeutic benefits and/or prophylactic benefits. Therapeutic benefit means any therapeutically relevant improvement or effect on one or more diseases, conditions or symptoms under treatment. For prophylactic benefit, the composition may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more physiological symptoms of a disease, although the disease, condition, or symptom may not have been manifested. Generally, prophylactic benefits include reducing the occurrence and/or worsening of one or more diseases, conditions, or symptoms under treatment (e.g., as between a treated population and an untreated population, or between a treated state and an untreated state of a subject).

The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to achieve a beneficial or desired result. The therapeutically effective amount may vary according to one or more of the following: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, which can be readily determined by one of ordinary skill in the art. An effective amount of the active agent may be administered in a single dose or in multiple doses. A component may be described herein as having at least an effective amount or at least an effective amount, such as an amount associated with a particular target or purpose, such as any of the targets or purposes described herein. The term "effective amount" also applies to a dose that will provide a detection image by a suitable imaging method. The specific dosage may vary depending on one or more of the following: the particular agent selected, the dosing regimen to be followed, whether it is to be administered in combination with other compounds, the time of administration, the tissue to be imaged, and the physical delivery system in which it is to be carried.

The term "in vivo" refers to an event that occurs in the body of a subject.

The term "ex vivo" refers to an event that first occurs outside the body of a subject for subsequent in vivo application into the body of the subject. For example, ex vivo preparation may involve preparing cells outside of the body of a subject for the purpose of introducing the prepared cells into the body of the same or a different subject.

The term "in vitro" refers to an event that occurs outside the body of a subject. For example, an in vitro assay encompasses any assay that runs outside of the body of a subject. In vitro assays encompass cell-based assays in which living or dead cells are employed. In vitro assays also encompass cell-free assays in which intact cells are not employed.

The term "Ras" or "Ras" refers to a protein in the rat sarcoma (Ras) superfamily of small gtpases, such as a protein in the Ras subfamily. Ras superfamily includes, but is not limited to, ras subfamily, rho subfamily, rab subfamily, rap subfamily, arf subfamily, ran subfamily, rheb subfamily, RGK subfamily, rit subfamily, miro subfamily, and unclassified subfamilies. In some embodiments, the Ras protein is selected from KRAS (also used interchangeably herein as K-Ras, kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras 2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as selected from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

The terms "mutant Ras" and "Ras mutant" as used interchangeably herein refer to Ras proteins having one or more amino acid mutations, such as with respect to a common reference sequence, such as a wild-type (WT) sequence. In some embodiments, the mutant Ras is selected from the group consisting of mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT1, and any combination thereof, such as selected from the group consisting of mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof. In some embodiments, the mutation may be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, the mutation may be a substitution (e.g., a substituted amino acid), an insertion (e.g., an addition of one or more amino acids), or a deletion (e.g., a removal of one or more amino acids). In some embodiments, two or more mutations may be continuous, discontinuous, or a combination thereof. In some embodiments, the mutation may be present at any position in Ras. In some embodiments, when optimally aligned, the mutation may be present at positions 12, 13, 62, 92, 95 or any combination thereof relative to Ras of SEQ ID No. 1. In some embodiments, mutant Ras can contain about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, mutant Ras can contain up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations. In some embodiments, the mutant Ras is about or up to about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50, or less than 50 amino acids in length. In some embodiments, the mutated amino acid is a protein amino acid, a natural amino acid, a standard amino acid, a non-standard amino acid, an atypical amino acid, an essential amino acid, a non-essential amino acid, or a non-natural amino acid. In some embodiments, the mutated amino acid has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a nonpolar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain. In some embodiments, the mutation comprises a reactive moiety. In some embodiments, the substituted amino acid comprises a reactive moiety. In some embodiments, mutant Ras can be further modified, for example, by conjugation with a detectable label. In some embodiments, mutant Ras is a full length or truncated polypeptide. For example, mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of mutant RALA or mutant RALB).

Represents the attachment location of the chemical formula or atom to a substituent, another component of a molecule, or atom (e.g., the location of a bond to another atom). />May be located at the end of the key or overlap the key.

The term "corresponding to" or "corresponding to" amino acid or protein residues as used herein should be understood as the selected residue occupies the same basic structural position in the protein as the given residue. The substantially identical structural positions in the protein may be in the three-dimensional conformation of the folded protein, or may be positions of residues in the primary sequence of the protein. For example, when a selected residue occupies the same basic space or other structural position as Cys12 in a human Ras (e.g., human K-Ras) protein, the selected residue in the protein corresponds to Cys12 of the human Ras (e.g., human K-Ras) protein. In some embodiments, in the case of a selected protein with a human Ras (e.g., human K-Ras) protein for maximum homology alignment, the position in the selected protein aligned with Cys12 is considered to correspond to Cys12. In addition to primary sequence alignment, three dimensional structure alignment can also be used, for example, wherein the structure of the selected protein and human K-Ras protein is maximally aligned, and the overall structure is compared. In this case, the amino acid occupying the same basic position as Cys12 in the structural model is considered to correspond to Cys12 residue. For example, when a selected residue occupies the same basic space or other structural position as Cys13 in a human Ras (e.g., human K-Ras) protein, the selected residue in the protein corresponds to Cys13 of a human Ras (e.g., human K-Ras) protein, similar to the examples of Cys12 described above.

In embodiments, C _3-10 Cycloalkyl is 3-membered cycloalkyl. In embodiments, C _3-10 Cycloalkyl is 4-membered cycloalkyl. In embodiments, C _3-10 Cycloalkyl is 5 membered cycloalkyl. In embodiments, C _3-10 Cycloalkyl is 6 membered cycloalkyl. In embodiments, C _3-10 Cycloalkyl is 7 membered cycloalkyl. In embodiments, C _3-10 Cycloalkyl is 8 membered cycloalkyl. In embodiments, C _3-10 Cycloalkyl is 9 membered cycloalkyl. In embodiments, C _3-10 Cycloalkyl is 10 membered cycloalkyl. In embodiments, C _3-10 Cycloalkyl is 3-10 membered cycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is a 3-membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is a 5 membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is an 8 membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is 11 membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, C _2-9 Heterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is a 3-membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is a 5 membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is an 8 membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is 11 membered heterocycloalkyl. In practiceIn embodiments, C _2-11 Heterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, C _2-11 Heterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is a 3-membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is a 5 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is an 8 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is 11 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, C _1-11 Heterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, C _6-12 Aryl is 6 membered aryl. In embodiments, C _6-12 Aryl is 7 membered aryl. In embodiments, C _6-12 Aryl is 8 membered aryl. In embodiments, C _6-12 Aryl is a 9-membered aryl. In embodiments, C _6-12 Aryl is 10 membered aryl. In embodiments, C _6-12 Aryl is 11 membered aryl. In embodiments, C _6-12 Aryl is a 12 membered aryl. In embodiments, C _6-12 Aryl is a 6-12 membered aryl. In embodiments, C _1-11 Heteroaryl is a 5 membered heterocycloalkyl. In embodiments, C _1-11 Heteroaryl is a 6 membered heterocycloalkyl. In embodiments, C _1-11 Heteroaryl is a 7 membered heterocycloalkyl. In embodiments, C _1-11 Heteroaryl is an 8 membered heterocycloalkyl. In embodiments, C _1-11 Heteroaryl is a 9 membered heterocycloalkyl. In embodiments, C _1-11 Heteroaryl is a 10 membered heterocycloalkyl. In embodiments, C _1-11 Heteroaryl is 11 membered heterocycloalkyl. In embodiments, C _1-11 Heteroaryl is a12 membered heterocycloalkyl. In embodiments, C _1-11 Heteroaryl is a 5-12 membered heterocycloalkyl. In embodiments, C _3-6 Cycloalkyl is 3-membered cycloalkyl. In embodiments, C _3-6 Cycloalkyl is 4-membered cycloalkyl. In embodiments, C _3-6 Cycloalkyl is 5 membered cycloalkyl. In embodiments, C _3-6 Cycloalkyl is 6 membered cycloalkyl. In embodiments, C _6-10 Aryl is 6 membered aryl. In embodiments, C _6-10 Aryl is 7 membered aryl. In embodiments, C _6-10 Aryl is 8 membered aryl. In embodiments, C _6-10 Aryl is a 9-membered aryl. In embodiments, C _6-10 Aryl is 10 membered aryl. In embodiments, C _1-9 Heteroaryl is a5 membered heterocycloalkyl. In embodiments, C _1-9 Heteroaryl is a6 membered heterocycloalkyl. In embodiments, C _1-9 Heteroaryl is a7 membered heterocycloalkyl. In embodiments, C _1-9 Heteroaryl is an 8 membered heterocycloalkyl. In embodiments, C _1-9 Heteroaryl is a9 membered heterocycloalkyl. In embodiments, C _1-9 Heteroaryl is a10 membered heterocycloalkyl. In embodiments, C _1-9 Heteroaryl is 11 membered heterocycloalkyl. In embodiments, C _1-9 Heteroaryl is a12 membered heterocycloalkyl. In embodiments, C _1-9 Heteroaryl is a 5-12 membered heterocycloalkyl.

Compounds of formula (I)

The compounds of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX, or a pharmaceutically acceptable salt or solvate thereof, are modulators of Ras (e.g., K-Ras WT, or K-Ras G12D), and have wide applicability in therapeutic, diagnostic, and other biomedical research.

In one aspect, there is provided a compound of formula (I):

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

R ¹⁰ is-L ⁷ -R ⁷ ；

R ⁶ is-L ² -R ⁵ ；

R ¹⁷ is-L ¹ -R ¹⁹ ；

x is C (R) ³ ) Or N;

each R ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl group,C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f Substitution;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

each R ²⁵ Selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl; and is also provided with

Represents a single bond or a double bond such that all valences are satisfied.

In one aspect, there is provided a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

R ¹⁰ is-L ⁷ -R ⁷ ；

L ⁷ Is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or 2-to 4-membered heteroalkylene linker wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and 2-to 4-membered alkylene linkers are optionally substituted with one, two or three R ^20a Substitution;

R ⁷ is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl each contain one or more ring nitrogen atoms or one or more epoxy atoms, and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution;

R ⁶ is-L ² -R ⁵ ；

R ⁸ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl group、C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20c Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

R ^12a selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl group,C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

R ^12b selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

R ^12c independently selected from hydrogen and R ^20k ；

X is C (R) ³ ) Or N;

each R ^20a 、R ^20b 、R ^20c 、R ^20d 、R ^20e 、R ^20f 、R ^20g 、R ²⁰ⁱ And R is ^20k Each independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied。

/>

In embodiments, L ⁷ Is a key. In embodiments, L ⁷ is-O-. In embodiments, L ⁷ is-N (R) ¹⁴ ) -. In embodiments, L ⁷ is-C (O) -. In embodiments, L ⁷ is-N (R) ¹⁴ ) C (O) -. In embodiments, L ⁷ is-C (O) N (R) ¹⁴ ) -. In embodiments, L ⁷ is-S-. In embodiments, L ⁷ is-S (O) ₂ -. In embodiments, L ⁷ is-S (O) -. In embodiments, L ⁷ is-S (O) ₂ N(R ¹⁴ ) -. In embodiments, L ⁷ is-S (O) N (R) ¹⁴ ) -. In embodiments, L ⁷ is-N (R) ¹⁴ ) S (O) -. In embodiments, L ⁷ is-N (R) ¹⁴ )S(O) ₂ -. In embodiments, L ⁷ Is C ₁ -C ₆ An alkyl group. In embodiments, L ⁷ Is C ₂ -C ₆ Alkenyl groups. In embodiments, L ⁷ Is C ₂ -C ₆ Alkynyl groups. In embodiments, L ⁷ Is a 2-to 4-membered alkylene linker. In embodiments, L ⁷ Is optionally substituted with one, two or three R ^20a Substituted C ₁ -C ₆ An alkyl group. In embodiments, L ⁷ Is optionally substituted with one, two or three R ^20a Substituted C ₂ -C ₆ Alkenyl groups. In embodiments, L ⁷ Is optionally substituted with one, two or three R ^20a Substituted C ₂ -C ₆ Alkynyl groups. In embodiments, L ⁷ Is optionally substituted with one, two or three R ^20a Substituted 2-to 4-membered alkylene linkers. In embodiments, L ⁷ is-N (H) -. In embodiments, L ⁷ is-N (H) C (O) -. In embodiments, L ⁷ is-C (O) N (H) -. In embodiments, L ⁷ is-S (O) ₂ N (H) -. In the implementation modeIn the case of L ⁷ is-S (O) N (H) -. In embodiments, L ⁷ is-N (H) S (O) -. In embodiments, L ⁷ is-N (H) S (O) ₂ -。

In some embodiments of formula (I') or a pharmaceutically acceptable salt or solvate thereof, R ⁷ Is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl and 5-12 membered heteroaryl each contain one or more ring nitrogen atoms or one or more epoxy atoms, and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution; wherein the bond to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is a 3-12 membered nitrogen containing heterocycloalkyl, wherein said 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution; and wherein the bonding to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In embodiments, R ⁷ Is a 3-12 membered cycloalkyl group. In embodiments, R ⁷ Is a 5-12 membered cycloalkyl group. In embodiments, R ⁷ Is a 3-12 membered heterocycloalkyl. In embodiments, R ⁷ Is a 6-12 membered aryl group. In embodiments, R ⁷ Is a 7-12 membered aryl group. In embodiments, R ⁷ Is a 5-12 membered heteroaryl.

In embodiments, R ⁷ Is a 3-12 membered cycloalkyl group containing one or more ring nitrogen atoms. In embodiments, R ⁷ Is a 5-12 membered cycloalkyl group containing one or more ring nitrogen atoms. In embodiments, R ⁷ Is a 3-12 membered heterocycloalkyl containing one or more ring nitrogen atoms. In embodiments, R ⁷ Is a 6-12 membered aryl group containing one or more ring nitrogen atoms. In embodiments, R ⁷ Is a 7-12 membered aryl group containing one or more ring nitrogen atoms. In embodiments, R ⁷ Is a 5-12 membered heteroaryl group containing one or more ring nitrogen atoms.

In embodiments, R ⁷ Is a 3-12 membered cycloalkyl group containing one or more epoxide atoms. In embodiments, R ⁷ Is a 5-12 membered cycloalkyl group containing one or more epoxide atoms. In embodiments, R ⁷ Is a 3-12 membered heterocycloalkyl containing one or more epoxide atoms. In embodiments, R ⁷ Is a 6-12 membered aryl group containing one or more epoxy atoms. In embodiments, R ⁷ Is composed of a7-12 membered aryl of one or more epoxy atoms. In embodiments, R ⁷ Is a 5-12 membered heteroaryl group containing one or more epoxy atoms.

In embodiments, R ⁷ Is optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ Substituted 3-12 membered cycloalkyl. In embodiments, R ⁷ Is optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ Substituted 5-12 membered cycloalkyl. In embodiments, R ⁷ Is optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ Substituted 3-12 membered heterocycloalkyl. In embodiments, R ⁷ Is optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ Substituted 6-12 membered aryl. In embodiments, R ⁷ Is optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ Substituted 7-12 membered aryl. In embodiments, R ⁷ Is optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ Substituted 5-12 membered heteroaryl.

In embodiments, R ⁷ Is a 3-12 membered cycloalkyl containing one or more ring nitrogen atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 5-12 membered cycloalkyl containing one or more ring nitrogen atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 3-12 membered heterocycloalkyl containing one or more ring nitrogen atoms, optionally substituted with one or more R ¹ Substitution ofOptionally by one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 6-12 membered aryl group containing one or more ring nitrogen atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 7-12 membered aryl group containing one or more ring nitrogen atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 5-12 membered heteroaryl group containing one or more ring nitrogen atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution.

In embodiments, R ⁷ Is a 3-12 membered cycloalkyl group containing one or more epoxide atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 5-12 membered cycloalkyl group containing one or more epoxide atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 3-12 membered heterocycloalkyl containing one or more epoxide atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 6-12 membered aryl group containing one or more epoxide atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 7-12 membered aryl group containing one or more epoxide atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution. In embodiments, R ⁷ Is a 5-12 membered heteroaryl group containing one or more epoxide atoms, optionally substituted with one or more R ¹ Optionally substituted with one or more R ⁴ Substituted and optionally substituted with one or more R ⁶ And (3) substitution.

In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₃ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₄ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₃ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₄ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substitution ofAnd optionally by one or more R ⁴ Substituted monocyclic C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₁₀ Cycloalkyl groups.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is comprised ofAt least one nitrogen atom and optionally by one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Cycloalkyl groups. In embodiments R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₁₀ Cycloalkyl groups.

In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₃ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₄ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₃ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₄ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or moreR is a number of ⁴ Substituted monocyclic C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₁₀ Cycloalkyl groups.

In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Cycloalkyl groups.

In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₁₀ Cycloalkyl groups.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₆ Cycloalkyl radicals. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted by one or moreMultiple R' s ⁴ Substituted bridged bicyclic ring C ₅ Cycloalkyl groups. In embodiments R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or moreR ⁴ Substituted spirocyclic bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₁₀ Cycloalkyl groups.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is comprised of At least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Cycloalkyl groups. In embodiments R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substitution and optionalOptionally by one or more R ⁴ Substituted spirocyclic bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₁₀ Cycloalkyl groups.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Cycloalkyl groups. In embodiments R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is comprised ofWith one oxygen atom less and optionally by one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₅ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₆ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₇ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₈ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₉ Cycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic ring C ₁₀ Cycloalkyl groups.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9-membered cycloalkyl. In embodiments, R ⁷ Is composed of at least one nitrogenAn atom and optionally by one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 5 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 11-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or moreR is a number of ⁴ Substituted 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ SubstitutedFused bicyclic 10 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 5 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is one containing at least one nitrogen atom and anyOptionally by one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 11-membered cycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 7-membered cycloalkyl. In embodiments, R ⁷ Is a composition comprising at least one oxygen atomAnd optionally by one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10-membered cycloalkyl. In embodiments, R ⁷ Is one containing at least one oxygen atom and any Optionally by one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 5 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 5-memberedCycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 11-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 8-memberedCycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11-membered ringCycloalkyl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 5 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 5-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 11-membered cycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 12 membered cycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 3-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 4-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 5 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one nitrogen atom and optionallyIs covered by one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 7 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 8 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 9 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 3-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 4-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 6-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 10-membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 5 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substitution and substitutionOptionally by one or more R ⁴ Substituted spirocyclic bicyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 3-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 4-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 5 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 7 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 8 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 9 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 3-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 4-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 6-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 10-membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 5 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substitution ofAnd optionally by one or more R ⁴ Substituted spirocyclic bicyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 3-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 4-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 5 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 7 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 8 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 9 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 3-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 4-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 6-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substitution of And optionally by one or more R ⁴ Substituted monocyclic 10-membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 5 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substitution ofAnd optionally by one or more R ⁴ Substituted spirocyclic bicyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 3-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 4-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 5 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 7 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 8 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 9 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substitution and substitutionOptionally by one or more R ⁴ Substituted 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 3-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 4-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 6-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 10-membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionallyGround cover R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 5 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 5-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9-membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substitution ofAnd optionally by one or more R ⁴ Substituted spirocyclic bicyclic 10 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 11 membered heterocycloalkyl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 12 membered heterocycloalkyl.

In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₆ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₆ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₇ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₈ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₉ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₁₀ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Aryl groups.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted withOne or more R ⁴ Substituted C ₇ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Aryl groups. In embodiments R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Aryl groups. In embodiments R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Aryl groups.

In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₆ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₆ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₇ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted by one or moreMultiple R' s ⁴ Substituted monocyclic C ₈ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₉ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic C ₁₀ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionallyGeodesic one or more R ⁴ Substituted bridged bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is optionally covered with one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Aryl groups.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Aryl groups. In embodiments R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally oneR ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Aryl groups. In embodiments R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Aryl groups.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Aryl groups. In embodiments R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Aryl groups. In embodiments R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Aryl groups.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₇ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₈ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₉ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted C ₁₀ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₇ Aryl groups. In embodiments R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally aR is a number of ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic ring C ₁₀ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₅ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₆ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₇ Aryl groups. In embodiments R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₈ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₉ Aryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic ring C ₁₀ Aryl groups.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 7-membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 8-membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 9-membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered aryl. In embodiments, R ⁷ Is composed of at least one nitrogenAn atom and optionally by one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered aryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered aryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered aryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 7-membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 8-membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 9-membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered aryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered aryl. In embodiments, R ⁷ Is comprised of at leastA nitrogen atom and optionally by one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered aryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered aryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered aryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 7-membered aryl. In implementationIn the scheme, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 8-membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 9-membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered aryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered aryl.

In embodimentsWherein R is ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered aryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 7-membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 8-membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 9-membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 11 membered aryl. In embodiments, R ⁷ Is composed of at least one oxygenAn atom and optionally by one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 12 membered aryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8-membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered aryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered aryl. In embodiments，R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered aryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered aryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 5 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 7 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 8 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 9 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 5-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 6-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 7-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 8-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 9-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 11 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 12 membered heteroaryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 11 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 12 membered heteroaryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 11 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 12 membered heteroaryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 5 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 7 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 8 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 9 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 5-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 6-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 7-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 8-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 9-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is comprised ofAt least one nitrogen atom and optionally by one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound containing at least one nitrogen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 5 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 7 membered heteroaryl.In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 8 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 9 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 5-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 6-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 7-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 8-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 9-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7-membered heterogeniesAryl groups. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ⁶ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 5 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 6 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 7 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 8 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 9 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 5-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 6-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 7-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 8-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 9-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted monocyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 8 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted fused bicyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 8 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted bridged bicyclic 10 membered heteroaryl.

In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 6 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 7 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 8-membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 9 membered heteroaryl. In embodiments, R ⁷ Is a compound comprising at least one oxygen atom and optionally one R ¹ Substituted and optionally substituted with one or more R ⁴ Substituted spirocyclic bicyclic 10 membered heteroaryl.

In embodiments, R ⁴ Independently halogen. In embodiments, R ⁴ Independently oxo. In embodiments, R ⁴ Independently is-CN. In embodiments, R ⁴ Independently C _1-6 An alkyl group. In embodiments, R ⁴ Independently C _2-6 Alkenyl groups. In embodiments, R ⁴ Independently C _2-6 Alkynyl groups. In embodiments, R ⁴ Independently C _1-6 A haloalkyl group. In embodiments, R ⁴ Independently C _3-12 NaphtheneA base. In embodiments, R ⁴ Is independently-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ⁴ Independently C _1-11 A heterocycloalkyl group. In embodiments, R ⁴ Is independently-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ⁴ Independently C _6-12 Aryl groups. In embodiments, R ⁴ Is independently-CH ₂ -C _6-12 Aryl groups. In embodiments, R ⁴ Is independently-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ⁴ Independently C _1-11 Heteroaryl groups. In embodiments, R ⁴ Independently is-OR ¹² . In embodiments, R ⁴ independently-SR ¹² . In embodiments, R ⁴ Is independently-N (R) ¹² )(R ¹³ ). In embodiments, R ⁴ Independently is-C (O) OR ¹² . In embodiments, R ⁴ independently-OC (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁴ Is independently-N (R) ¹⁴ )C(O)N(R ¹² )(R ¹³ ). In embodiments, R ⁴ Is independently-N (R) ¹⁴ )C(O)OR ¹⁵ . In embodiments, R ⁴ Is independently-N (R) ¹⁴ )S(O) ₂ R ¹⁵ . In embodiments, R ⁴ independently-C (O) R ¹⁵ . In embodiments, R ⁴ Independently is-S (O) R ¹⁵ . In embodiments, R ⁴ independently-OC (O) R ¹⁵ . In embodiments, R ⁴ independently-C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁴ independently-C (O) C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁴ Is independently-N (R) ¹⁴ )C(O)R ¹⁵ . In embodiments, R ⁴ Independently is-S (O) ₂ R ¹⁵ . In embodiments, R ⁴ Independently is-S (O) ₂ N(R ¹² )(R ¹³ ) -. In embodiments, R ⁴ Independently S (=o) (=nh) N (R ¹² )(R ¹³ ). In embodiments, R ⁴ Is independently-CH ₂ C(O)N(R ¹² )(R ¹³ ). In embodiments, R ⁴ Is independently-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ . In embodiments, R ⁴ Is independently-CH ₂ S(O) ₂ R ¹⁵ . In embodiments, R ⁴ Is independently-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ )。

In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 An alkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-6 Alkenyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-6 Alkynyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 A haloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C _3-12 Cycloalkyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-11 A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C _6-12 Aryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _6-12 Aryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-11 Heteroaryl groups.

In embodiments, L ² Is a key. In embodiments, L ² Is C ₁ -C ₆ An alkyl group. In embodiments, L ² is-O-. In embodiments, L ² is-N (R) ¹⁴ ) -. In embodiments, L ² is-C (O) -. In embodiments, L ² is-N (R) ¹⁴ ) C (O) -. In embodiments, L ² is-C (O) N (R) ¹⁴ ) -. In embodiments, L ² is-S-. In embodiments, L ² is-S (O) ₂ -. In embodiments, L ² is-S (O) -. In embodiments, L ² is-S (O) ₂ N(R ¹⁴ ) -. In embodiments, L ² is-S (O) N (R) ¹⁴ ) -. In embodiments, L ² is-N (R) ¹⁴ ) S (O) -. In embodiments, L ² is-N (R) ¹⁴ )S(O) ₂ -. In embodiments, L ² is-OCON (R) ¹⁴ ) -. In embodiments, L ² is-N (R) ¹⁴ ) C (O) O-. In embodiments, L ² is-N (R) ¹⁴ )C(O)N(R ¹⁴ ) -. In embodiments, L ² is-N (H) -. In embodiments, L ² is-N (H) C (O) -. In embodiments, L ² is-C (O) N (H) -. In embodiments, L ² is-S (O) ₂ N (H) -. In embodiments, L ² is-S (O) N (H) -. In embodiments, L ² is-N (H) S (O) -. In embodiments, L ² is-N (H) S (O) ₂ -. In embodiments, L ² is-OCON (H) -. In embodiments, L ² is-N (H) C (O) O-. In embodiments, L ² is-N (H) C (O) N (R) ¹⁴ )-。

In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁ An alkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ An alkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ An alkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ An alkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ An alkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ An alkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ Alkenyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Alkenyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Alkenyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Alkenyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Alkenyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ Alkynyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Alkynyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Alkynyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Alkynyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Alkynyl groups. In embodiments, R ⁴ Independently C ₁ A haloalkyl group. In embodiments, R ⁴ Independently C ₂ A haloalkyl group. In embodiments, R ⁴ Independently C ₃ A haloalkyl group. In embodiments, R ⁴ Independently C ₄ A haloalkyl group. In embodiments, R ⁴ Independently C ₅ A haloalkyl group. In embodiments, R ⁴ Independently C ₆ A haloalkyl group.

In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Cycloalkyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Cycloalkyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Cycloalkyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Cycloalkyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ Cycloalkyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ Cycloalkyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ Cycloalkyl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₀ Cycloalkyl groups.

In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ A heterocycloalkyl group. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Aryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ Aryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ Aryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ Aryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₀ Aryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₁ Aryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₂ Aryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ Heteroaryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Heteroaryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Heteroaryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Heteroaryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Heteroaryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ Heteroaryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ Heteroaryl groups. In embodiments, R ⁴ Independently is optionally covered withOne, two or three R ^20a Substituted C ₉ Heteroaryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₀ Heteroaryl groups. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₁ Heteroaryl groups.

In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 3-membered cycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 4-membered cycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 5-membered cycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 6 membered cycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 7-membered cycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 8-membered cycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 9-membered cycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 10 membered cycloalkyl.

In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 3-membered heterocycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 4-membered heterocycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 5 membered heterocycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 6 membered heterocycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 7 membered heterocycloalkyl. In embodiments, R ⁴ Independent and independentOptionally by one, two or three R ^20a Substituted 8 membered heterocycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 9 membered heterocycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 10 membered heterocycloalkyl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 6 membered aryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 7-membered aryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 8-membered aryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 9-membered aryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 10 membered aryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 11 membered aryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 12 membered aryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 5 membered heteroaryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 6 membered heteroaryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 7 membered heteroaryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 8 membered heteroaryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 9 membered heteroaryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 10 membered heteroaryl. In embodiments, R ⁴ Independently are optionally substituted with one, two or three R ^20a Substituted 11 membered heteroaryl. In the context of an embodiment of the present invention,R ⁴ independently are optionally substituted with one, two or three R ^20a Substituted 12 membered heteroaryl.

In embodiments, R ⁴ independently-OH. In embodiments, R ⁴ Independently is-SH. In embodiments, R ⁴ independently-NH ₂ . In embodiments, R ⁴ independently-C (O) OH. In embodiments, R ⁴ independently-OC (O) NH ₂ . In embodiments, R ⁴ independently-N (H) C (O) NH ₂ . In embodiments, R ⁴ independently-N (H) C (O) OH. In embodiments, R ⁴ independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ⁴ independently-C (O) H. In embodiments, R ⁴ Is independently-S (O) CH ₃ . In embodiments, R ⁴ independently-OC (O) CH ₃ . In embodiments, R ⁴ independently-C (O) NH ₂ . In embodiments, R ⁴ independently-C (O) C (O) NH ₂ . In embodiments, R ⁴ independently-N (H) C (O) H. In embodiments, R ⁴ Independently is-S (O) ₂ CH ₃ . In embodiments, R ⁴ Independently is-S (O) ₂ NH ₂ -. In embodiments, R ⁴ Independently S (=o) (=nh) NH ₂ . In embodiments, R ⁴ Is independently-CH ₂ C(O)NH ₂ . In embodiments, R ⁴ Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ⁴ Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ⁴ Is independently-CH ₂ S(O) ₂ NH ₂ . In embodiments, R ⁴ Is independently-OCH ₃ . In embodiments, R ⁴ Independently is-SCH ₃ . In embodiments, R ⁴ Is independently-N (CH) ₃ ) (H). In embodiments, R ⁴ Is independently-C (O) OCH ₃ . In embodiments, R ⁴ independently-OC (O) N (CH) ₃ ) (H). In embodiments, R ⁴ independently-N (H) C (O) N (CH) ₃ ) (H). In embodiments, R ⁴ Is independently-N (H) C (O) OCH ₃ . In embodiments, R ⁴ independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ⁴ independently-C (O) CH ₃ . In embodiments, R ⁴ Is independently-S (O) CH ₃ . In embodiments, R ⁴ independently-OC (O) CH ₃ . In embodiments, R ⁴ independently-C (O) N (CH) ₃ ) (H). In embodiments, R ⁴ independently-C (O) C (O) N (CH) ₃ ) (H). In embodiments, R ⁴ independently-N (H) C (O) CH ₃ . In embodiments, R ⁴ Independently is-S (O) ₂ CH ₃ . In embodiments, R ⁴ Independently is-S (O) ₂ N(CH ₃ ) (H) -. In embodiments, R ⁴ Independently S (=o) (=nh) N (CH ₃ ) (H). In embodiments, R ⁴ Is independently-CH ₂ C(O)N(CH ₃ ) (H). In embodiments, R ⁴ Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ⁴ Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ⁴ Is independently-CH ₂ S(O) ₂ N(CH ₃ ) (H). In embodiments, R ⁴ independently-OC (O) N (CH) ₃ ) ₂ . In embodiments, R ⁴ independently-N (H) C (O) N (CH) ₃ ) ₂ . In embodiments, R ⁴ independently-C (O) (CH ₃ ). In embodiments, R ⁴ independently-C (O) N (CH) ₃ ) ₂ . In embodiments, R ⁴ independently-C (O) C (O) N (CH) ₃ ) ₂ . In embodiments, R ⁴ independently-N (H) C (O) (CH ₃ ). In embodiments, R ⁴ Independently is-S (O) ₂ N(CH ₃ ) ₂ . In embodiments, R ⁴ Independently S (=o) (=nh) N (CH ₃ ) ₂ . In embodiments, R ⁴ Is independently-CH ₂ C(O)N(CH ₃ ) ₂ . In embodiments, R ⁴ Is independently-CH ₂ S(O) ₂ N(CH ₃ ) ₂ . In embodiments, R ⁴ Is independently-CH ₃ . In embodiments, R ⁴ Independently is-CF ₃ . In embodiments, R ⁴ independently-CHF ₂ . In embodiments, R ⁴ Independently is-CFH ₂ . In embodiments, R ⁴ Independently ethyl. In embodiments, R ⁴ Independently is propyl. In embodiments, R ⁴ Independently isopropyl. In embodiments, R ⁴ Independently butyl. In embodiments, R ⁴ Independently t-butyl.

In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 12 of the G12D KRas mutant. In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 12 of the G12C KRas mutant. In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 12 of the G12S KRas mutant. In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 13 of the G13D KRa mutant. In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 13 of the G13C KRa mutant. In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 13 of the G13S KRa mutant.

In embodiments, R ⁴ Selected from the group consisting of

Wherein each R is ^a Independently hydrogen, C _1-6 Alkyl, carboxyl, C _1-6 Alkoxycarbonyl, phenyl, C _2-7 Carbonylalkyl radicals R ^c -(C(R ^b ) ₂ ) _z -、R ^c -(C(R ^b ) ₂ ) _w -M-(C(R ^b ) ₂ ) _r -、(R ^d )(R ^e )CH-M-(C(R ^b ) ₂ ) _r -or Het-J ³ -(C(R ^b ) ₂ ) _r -; each R ^b Independently hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-7 Carbonyl alkyl, C _2-7 Carboxyalkyl, phenyl or phenyl optionally substituted by one or more halogens, C _1-6 Alkoxy, trifluoromethyl, amino, C _1-3 Alkylamino, C _2-6 Dialkylamino, nitro, azido, halomethyl, C _2-7 Alkoxymethyl, C _2-7 Alkanoyloxymethyl, C _1-6 Alkylthio, hydroxy, carboxyl, C _2-7 Alkoxycarbonyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, C _1-6 Alkanoylamino or C _1-6 An alkyl group; each R ^c Is independently-NR ^b R ^b OR-OR ^b ；R ^d And R is ^e Each independently is- (C (R) ^b ) ₂ ) _r -NR ^b R ^b Or- (C (R) ^b ) ₂ ) _r -OR ^b The method comprises the steps of carrying out a first treatment on the surface of the Each J ¹ Independently hydrogen, chlorine, fluorine or bromine; j (J) ² Is C _1-6 Alkyl or hydrogen; each M is independently-N (R ^b )-、-O-、-N[(C(R ^b ) ₂ ) _w -NR ^b R ^b ]-or-N [ (C (R) ^b ) ₂ ) _w -OR ^b ]-; each J ³ Is independently-N (R) ^b ) -, -O-or a bond; each Het is independently a heterocycle optionally substituted on carbon or nitrogen with R ^b Monosubstituted or disubstituted and optionally substituted on carbon by-CH ₂ OR ^b Mono-substitution; wherein the heterocycle is selected from morpholine, thiomorpholine S-oxide, thiomorpholine S, S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2, 3-triazole, 1,2, 4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran; each r is independently 1-4; each w is independently 2-4; x is 0-1; y is 0 to 4 and each z is independently 1 to 6; wherein the sum of x+y is 2 to 4.

In implementationIn the scheme, R ⁴ Independently selected from Wherein each R is ^b Independently selected from hydrogen, hydroxy, C ₁ -C ₆ Alkoxy and C ₁ -C ₆ Alkyl, or two R ^b Optionally linked to form a heterocycle having 3 to 12 ring atoms or C ₃ -C ₆ Cycloalkyl groups. In embodiments, R ⁴ Independently selected from->

In embodiments, R ⁴ independently-C (O) N (R) ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ or-C (O) R ¹⁵ . In embodiments, R ⁴ independently-C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁴ Is independently-N (R) ¹⁴ )C(O)R ¹⁵ . In embodiments, R ⁴ independently-C (O) R ¹⁵ 。

In embodiments, R ⁴ Independently selected from -C(O)R ¹⁵ Wherein R is ¹⁵ Is optionally substituted with one, two or three R ^20f Substituted C _1-6 Alkyl group,-C(O)R ¹⁵ Wherein R is ¹⁵ Is optionally substituted with one, two or three R ^20f Substituted C _2-6 Alkenyl, -C (O) R ¹⁵ Wherein R is ¹⁵ Is optionally substituted with one, two or three R ^20f Substituted C _2-6 Alkynyl, -C (O) R ¹⁵ Wherein R is ¹⁵ Is optionally substituted with one, two or three R ^20f Substituted C _3-6 Cycloalkyl, -C (O) R ¹⁵ Wherein R is ¹⁵ Is optionally substituted with one, two or three R ^20f Substituted C _2-9 Heterocyclylalkyl, -C (O) R ¹⁵ Wherein R is ¹⁵ Is optionally substituted with one, two or three R ^20f Substituted C _6-10 Aryl and-C (O) R ¹⁵ Wherein R is ¹⁵ Is optionally substituted with one, two or three R ^20f Substituted C _1-9 Heteroaryl groups.

In embodiments, R ⁴ Is independently-C (O) NH (R) ¹² ) And R is ¹² Independently C _1-9 Heteroaryl, wherein C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d And (3) substitution. In embodiments, R ⁴ Is independently-C (O) NH (R) ¹² ) And R is ¹² Independently C _1-5 Heteroaryl, wherein C _1-5 Heteroaryl is optionally substituted with one, two or three R ^20d And (3) substitution. In embodiments, R ⁴ Is independently-C (O) NH (R) ¹² ) And R is ¹² Independently C _1-5 Heteroaryl groups.

In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₁ An alkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ An alkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ An alkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ An alkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ An alkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ An alkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ Alkenyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ Alkenyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ Alkenyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ Alkenyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Alkenyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ Alkynyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ Alkynyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ Alkynyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ Alkynyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Alkynyl groups. In embodiments, R ¹² Independently C ₁ A haloalkyl group. In embodiments, R ¹² Independently C ₂ A haloalkyl group. In embodiments, R ¹² Independently C ₃ A haloalkyl group. In embodiments, R ¹² Independently C ₄ A haloalkyl group. In embodiments, R ¹² Independently C ₅ A haloalkyl group. In embodiments, R ¹² Independently C ₆ A haloalkyl group.

In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ Cycloalkyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ Cycloalkyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ Cycloalkyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Cycloalkyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₇ Cycloalkyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₈ Cycloalkyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₉ Cycloalkyl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₁₀ Cycloalkyl groups.

In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ A heterocycloalkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ A heterocycloalkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ A heterocycloalkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ A heterocycloalkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ A heterocycloalkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₇ A heterocycloalkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₈ A heterocycloalkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₉ A heterocycloalkyl group. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Aryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₇ Aryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₈ Aryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₉ Aryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₁₀ Aryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₁₁ Aryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₁₂ Aryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ Heteroaryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ Heteroaryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ Heteroaryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ Heteroaryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Heteroaryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₇ Heteroaryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₈ Heteroaryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₉ Heteroaryl groups. In embodiments, R ¹² Independently are optionally one, twoOr three R ^20d Substituted C ₁₀ Heteroaryl groups. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₁₁ Heteroaryl groups.

In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 3-membered cycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 4-membered cycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 5-membered cycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 6 membered cycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 7-membered cycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 8-membered cycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 9-membered cycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 10 membered cycloalkyl.

In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 3-membered heterocycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 4-membered heterocycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 5 membered heterocycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 6 membered heterocycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 7 membered heterocycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 8 membered heterocycloalkyl. In embodiments, R ¹² Independently and separatelyIs optionally substituted with one, two or three R ^20d Substituted 9 membered heterocycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 10 membered heterocycloalkyl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 6 membered aryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 7-membered aryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 8-membered aryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 9-membered aryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 10 membered aryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 11 membered aryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 12 membered aryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 5 membered heteroaryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 6 membered heteroaryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 7 membered heteroaryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 8 membered heteroaryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 9 membered heteroaryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 10 membered heteroaryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 11 membered heteroaryl. In embodiments, R ¹² Independently are optionally substituted with one, two or three R ^20d Substituted 12 membered heteroaryl.

In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₁ An alkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ An alkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ An alkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ An alkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ An alkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ An alkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ Alkenyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Alkenyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Alkenyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ Alkenyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Alkenyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ Alkynyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Alkynyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Alkynyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ Alkynyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Alkynyl groups. In embodiments, R ¹⁵ Independently C ₁ A haloalkyl group. In embodiments, R ¹⁵ Independently C ₂ A haloalkyl group. In embodiments, R ¹⁵ Independently C ₃ A haloalkyl group. In embodiments, R ¹⁵ Independently C ₄ A haloalkyl group. In embodiments, R ¹⁵ Independently C ₅ A haloalkyl group. In embodiments, R ¹⁵ Independently C ₆ A haloalkyl group.

In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Cycloalkyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Cycloalkyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ Cycloalkyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Cycloalkyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₇ Cycloalkyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₈ Cycloalkyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₉ Cycloalkyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₁₀ Cycloalkyl groups.

In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ A heterocycloalkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ A heterocycloalkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ A heterocycloalkyl group. In the context of an embodiment of the present invention,R ¹⁵ independently are optionally substituted with one, two or three R ^20f Substituted C ₅ A heterocycloalkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ A heterocycloalkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₇ A heterocycloalkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₈ A heterocycloalkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₉ A heterocycloalkyl group. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Aryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₇ Aryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₈ Aryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₉ Aryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₁₀ Aryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₁₁ Aryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₁₅ Aryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ Heteroaryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Heteroaryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Heteroaryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ Heteroaryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Heteroaryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₇ Heteroaryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₈ Heteroaryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₉ Heteroaryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₁₀ Heteroaryl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₁₁ Heteroaryl groups.

In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 3-membered cycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 4-membered cycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 5-membered cycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 6 membered cycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 7-membered cycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 8-membered cycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 9-membered cycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 10 membered cycloalkyl.

In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 3-membered heterocycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 4-membered heterocycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 5 membered heterocycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 6 membered heterocycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 7 membered heterocycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 8 membered heterocycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 9 membered heterocycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 10 membered heterocycloalkyl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 6 membered aryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 7-membered aryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 8-membered aryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 9-membered aryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 10 membered aryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 11 membered aryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 12 membered aryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 5 membered heteroaryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 6 membered heteroaryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted7 membered heteroaryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 8 membered heteroaryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 9 membered heteroaryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 10 membered heteroaryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 11 membered heteroaryl. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted 12 membered heteroaryl.

In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently selected from C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl, wherein C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f And (3) substitution. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ Alkenyl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Alkenyl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Alkenyl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ Alkenyl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Alkenyl groups.

In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ Alkynyl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Alkynyl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Alkynyl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ Alkynyl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Alkynyl groups.

In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₇ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₈ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₉ A heterocycloalkyl group.

In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₁ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₇ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₈ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₉ Heteroaryl groups.

In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently selected from C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl, wherein C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f And (3) substitution. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ Alkenyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Alkenyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Alkenyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ Alkenyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Alkenyl groups.

In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ Alkynyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Alkynyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Alkynyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally one, twoOne or three R ^20f Substituted C ₅ Alkynyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Alkynyl groups.

In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₇ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₈ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₉ A heterocycloalkyl group.

In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₁ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₂ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₃ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₄ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₅ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₆ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₇ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₈ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹⁵ And R is ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C ₉ Heteroaryl groups.

In embodiments, R ⁴ Selected from the group consisting of Wherein each R is ^a Independently hydrogen, C _1-6 Alkyl, carboxyl, C _1-6 Alkoxycarbonyl radicalsPhenyl, C _2-7 Carbonylalkyl radicals R ^c -(C(R ^b ) ₂ ) _z -、R ^c -(C(R ^b ) ₂ ) _w -M-(C(R ^b ) ₂ ) _r -、(R ^d )(R ^e )CH-M-(C(R ^b ) ₂ ) _r -or Het-J ³ -(C(R ^b ) ₂ ) _r -; each R ^b Independently hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-7 Carbonyl alkyl, C _2-7 Carboxyalkyl, phenyl or phenyl optionally substituted by one or more halogens, C _1-6 Alkoxy, trifluoromethyl, amino, C _1-3 Alkylamino, C _2-6 Dialkylamino, nitro, azido, halomethyl, C _2-7 Alkoxymethyl, C _2-7 Alkanoyloxymethyl, C _1-6 Alkylthio, hydroxy, carboxyl, C _2-7 Alkoxycarbonyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, C _1-6 Alkanoylamino or C _1-6 An alkyl group; each R ^c Is independently-NR ^b R ^b OR-OR ^b ；R ^d And R is ^e Each independently is- (C (R) ^b ) ₂ ) _r -NR ^b R ^b Or- (C (R) ^b ) ₂ ) _r -OR ^b The method comprises the steps of carrying out a first treatment on the surface of the Each J ¹ Independently hydrogen, chlorine, fluorine or bromine; j (J) ² Is C _1-6 Alkyl or hydrogen; each M is independently-N (R ^b )-、-O-、-N[(C(R ^b ) ₂ ) _w -NR ^b R ^b ]-or-N [ (C (R) ^b ) ₂ ) _w -OR ^b ]-; each J ³ Is independently-N (R) ^b ) -, -O-or a bond; each Het is independently a heterocycle optionally substituted on carbon or nitrogen with R ^b Monosubstituted or disubstituted and optionally substituted on carbon by-CH ₂ OR ^b Mono-substitution; wherein the heterocycle is selected from morpholine, thiomorpholine S-oxide, thiomorpholine S, S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2, 3-triazole, 1,2, 4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran; each of whichR is independently 1-4; each w is independently 2-4; x is 0-1; y is 0 to 4 and each z is independently 1 to 6; wherein the sum of x+y is 2 to 4.

In embodiments, R ⁴ Can form covalent bonds with Ras amino acid side chains. In embodiments, R ⁴ Capable of forming a covalent bond with KRas amino acids. In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 12 of human KRas protein. In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 12 of a mutant KRas protein selected from KRas G12D, KRas G12C and KRas G12S. In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 13 of human KRas protein. In embodiments, R ⁴ Capable of forming a covalent bond with amino acid 13 of a mutant KRas protein selected from KRas G13D, KRas G13C and KRas G13S.

In embodiments, R ⁴ Selected from the group consisting of

/>

In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently C optionally substituted by one, two or three halogens _2-6 Alkenyl groups.In embodiments, R ¹⁵ Independently C optionally substituted with one, two or three F _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently is optionally-OR ²¹ Substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Is independently optionally substituted with-N (R ²² )(R ²³ ) Substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently is optionally C _2-9 Heterocycloalkyl substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkenyl group, the C _1-5 Heteroaryl is optionally substituted with one, two or three C _1-6 Alkyl substitution. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkenyl group, the C _1-5 Heteroaryl is optionally substituted with methyl. In embodiments, R ¹⁵ Independently C optionally substituted with-CN _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkenyl group, the C _1-5 Heteroaryl is optionally substituted with-N (R ²⁴ )C(O)R ²⁵ And (3) substitution. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl and/or CN substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently C optionally substituted by one, two or three halogens _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently C optionally substituted with one, two or three F _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently is optionally-OR ²¹ Substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Is independently optionally substituted with-N (R ²² )(R ²³ ) Substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently is optionally C _2-9 Heterocycloalkyl substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently isOptionally by C _1-5 Heteroaryl substituted C _2-6 Alkenyl group, the C _1-5 Heteroaryl is optionally substituted with one, two or three C _1-6 Alkyl substitution. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkenyl group, the C _1-5 Heteroaryl is optionally substituted with methyl. In embodiments, R ¹⁵ Independently C optionally substituted with-CN _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkenyl group, the C _1-5 Heteroaryl is optionally substituted with-N (R ²⁴ )C(O)R ²⁵ And (3) substitution. In embodiments, R ¹⁵ Is independently optionally substituted with-C (O) N (R ²² )(R ²³ ) Substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently substituted by Cl and optionally by one or two R ^20f Substituted C _2-6 Alkenyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently C optionally substituted by one, two or three halogens _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently C optionally substituted with one, two or three F _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently is optionally-OR ²¹ Substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Is independently optionally substituted with-N (R ²² )(R ²³ ) Substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently is optionally C _2-9 Heterocycloalkyl substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkynyl group, said C _1-5 Heteroaryl is optionally substituted with one, two or three C _1-6 Alkyl substitution. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkynyl group, said C _1-5 Heteroaryl is optionally substituted with methyl. In embodiments, R ¹⁵ Independently C optionally substituted with-CN _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkynyl group, said C _1-5 Heteroaryl is optionally substituted with-N (R ²⁴ )C(O)R ²⁵ And (3) substitution. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl and/or CN substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently C optionally substituted by one, two or three halogens _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently C optionally substituted with one, two or three F _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently is optionally-OR ²¹ Substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Is independently optionally substituted with-N (R ²² )(R ²³ ) Substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently is optionally C _2-9 Heterocycloalkyl substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkynyl group, said C _1-5 Heteroaryl is optionally substituted with one, two or three C _1-6 Alkyl substitution. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkynyl group, said C _1-5 Heteroaryl is optionally substituted with methyl. In embodiments, R ¹⁵ Independently C optionally substituted with-CN _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently is optionally C _1-5 Heteroaryl substituted C _2-6 Alkynyl group, said C _1-5 Heteroaryl is optionally substituted with-N (R ²⁴ )C(O)R ²⁵ And (3) substitution. In embodiments, R ¹⁵ Is independently optionally substituted with-C (O) N (R ²² )(R ²³ ) Substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently substituted by Cl and optionally by one or two R ^20f Substituted C _2-6 Alkynyl groups. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C _3-5 Cycloalkyl groups. In embodiments, R ¹⁵ Independently is optionally C _1-6 Alkyl substituted C _3-5 Cycloalkyl group, the C _1-6 The alkyl group is optionally substituted with one, two or three halogens. In embodiments, R ¹⁵ Independently is optionally C _1-6 Alkyl substituted C _3-5 Cycloalkyl group, the C _1-6 The alkyl group is optionally substituted with one, two or three F. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C _1-5 A heterocycloalkyl group. In embodiments, R ¹⁵ Independently is optionally C _1-6 Alkyl substituted C _1-5 Heterocycloalkyl, said C _1-6 The alkyl group is optionally substituted with one, two or three halogens. In embodiments, R ¹⁵ Independently is optionally C _1-6 Alkyl substituted C _1-5 Heterocycloalkyl, said C _1-6 The alkyl group is optionally substituted with one, two or three F. In embodiments, R ¹⁵ Independently are optionally substituted with one, two or three R ^20f Substituted C _1-6 An alkyl group. In embodiments, R ¹⁵ Independently substituted by Cl and optionally by one, two or three R ^20f Substituted C _1-6 An alkyl group. In embodiments, R ⁴ Independently is-CN.

In embodiments, L ² Independently is a bond, -C (O) NH-, -NHC (O) -or-C (O) -; and R is ⁵ Independently selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _1-11 Heterocyclylalkyl, -CH ₂ -C _1-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _1-11 Heterocyclylalkyl, -CH ₂ -C _1-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In embodiments, L ² Independently is-C (O) -; and R is ⁵ Independently C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _1-11 Heterocyclylalkyl, -CH ₂ -C _1-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl or C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _1-11 Heterocyclylalkyl, -CH ₂ -C _1-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In embodiments, L ² Independently is-C (O) -; and R is ⁵ Independently C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In embodiments, L ² Independently is a bond, -C (O) NH-, -NHC (O) -or-C (O) -; l (L) ² Independently bond to R ⁵ Carbon atoms of (2); and R is ⁵ Independently selected from-CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In embodiments, L ² Independently is-C (O) -; l (L) ² Independently bond to R ⁵ Carbon atoms of (2); and R is ⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-12 Cycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In embodiments, L ² Independently is-C (O) -; l (L) ² Independently bond to R ⁵ Carbon atoms of (2); and R is ⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and 5-6 membered heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and 5-6 membered heteroaryl are optionally substituted with one, two or three R ^20a And (3) substitution. In embodiments，L ² Independently is-C (O) -; r is R ⁵ Independently is a heteroaryl group having the formula:R ^5a is independently O, S, CH, C (R) ^20a ) N, NH or N (R) ^20a )；R ⁵ Comprising 0-3 independent R ^20a The method comprises the steps of carrying out a first treatment on the surface of the And 0 to 4R ^5a Is independently N, NH or N (R) ^20a ). In embodiments, L ² Independently is-C (O) -; and R is ⁵ Independently is a heteroaryl group having the formula: />R ^5a Is independently CH, C (R) ^20a ) N, NH or N (R) ^20a )；R ⁵ Comprising 0-3 independent R ^20a The method comprises the steps of carrying out a first treatment on the surface of the And 0 to 4R ^5a Is independently N, NH or N (R) ^20a ). In embodiments, L ² Independently is-C (O) -; r is R ⁵ Independently is->R ^5a Is independently CH, C (R) ^20a )、CH(R ^20a )、CH ₂ 、C(R ^20a ) ₂ N, NH or N (R) ^20a )；R ⁵ Comprising 0-3 independent R ^20a The method comprises the steps of carrying out a first treatment on the surface of the And 0 to 4R ^5a Is independently N, NH or N (R) ^20a )。

In embodiments, L ² Independently is-C (O) -; and R is ⁵ Independently C _3-10 Cycloalkyl group, wherein C _3-10 Cycloalkyl groups are independently optionally substituted with one, two or three R ^20a And (3) substitution. In embodiments, L ² Independently is-C (O) -; and R is ⁵ Independently is cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two or three F. In embodiments, L ² Independently is-C (O) -; and R is ⁵ Independently is cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two or three CNs. In embodiments, L ² Independently is-C (O) -; and R is ⁵ Independently isCyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two or three halogens.

In embodiments, R ⁵ Independently hydrogen. In embodiments, R ⁵ Independently halogen. In embodiments, R ⁵ Independently oxo. In embodiments, R ⁵ Independently is-CN. In embodiments, R ⁵ Independently C _1-6 An alkyl group. In embodiments, R ⁵ Independently C _2-6 Alkenyl groups. In embodiments, R ⁵ Independently C _2-6 Alkynyl groups. In embodiments, R ⁵ Independently C _1-6 A haloalkyl group. In embodiments, R ⁵ Independently C _3-12 Cycloalkyl groups. In embodiments, R ⁵ Is independently-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ⁵ Independently C _1-11 A heterocycloalkyl group. In embodiments, R ⁵ Is independently-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ⁵ Independently C _6-12 Aryl groups. In embodiments, R ⁵ Is independently-CH ₂ -C _6-12 Aryl groups. In embodiments, R ⁵ Is independently-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ⁵ Independently C _1-11 Heteroaryl groups. In embodiments, R ⁵ Independently is-OR ¹² . In embodiments, R ⁵ independently-SR ¹² . In embodiments, R ⁵ Is independently-N (R) ¹² )(R ¹³ ). In embodiments, R ⁵ Independently is-C (O) OR ¹² . In embodiments, R ⁵ independently-OC (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁵ Is independently-N (R) ¹⁵ )C(O)N(R ¹² )(R ¹³ ). In embodiments, R ⁵ Is independently-N (R) ¹⁵ )C(O)OR ¹⁵ . In embodiments, R ⁵ Is independently-N (R) ¹⁵ )S(O) ₂ R ¹⁵ . In embodiments, R ⁵ independently-C (O) R ¹⁵ . In embodiments, R ⁵ Independently is-S(O)R ¹⁵ . In embodiments, R ⁵ independently-OC (O) R ¹⁵ . In embodiments, R ⁵ independently-C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁵ independently-C (O) C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁵ Is independently-N (R) ¹⁵ )C(O)R ¹⁵ . In embodiments, R ⁵ Independently is-S (O) ₂ R ¹⁵ . In embodiments, R ⁵ Independently is-S (O) ₂ N(R ¹² )(R ¹³ ) -. In embodiments, R ⁵ Independently S (=o) (=nh) N (R ¹² )(R ¹³ ). In embodiments, R ⁵ Is independently-CH ₂ C(O)N(R ¹² )(R ¹³ ). In embodiments, R ⁵ Is independently-CH ₂ N(R ¹⁵ )C(O)R ¹⁵ . In embodiments, R ⁵ Is independently-CH ₂ S(O) ₂ R ¹⁵ . In embodiments, R ⁵ Is independently-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ). In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 An alkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-6 Alkenyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-6 Alkynyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 A haloalkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C _3-12 Cycloalkyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-11 A heterocycloalkyl group. In embodiments, R ⁵ Independently is optionally oneTwo or three R ^20a substituted-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C _6-12 Aryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _6-12 Aryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-11 Heteroaryl groups.

In further embodiments of the subject compounds, R ⁵ Independently selected from hydrogen, halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, -OR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ ) and-C (O) R ¹² Wherein C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with one, two or three R ^20a And (3) substitution. In embodiments of the subject compounds, R ⁵ Independently hydrogen. In further embodiments of the subject compounds, R ⁵ Independently halogen. In some embodiments of the subject compounds, R ⁵ Independently oxo. In some embodiments of the subject compounds, R ⁵ Independently is-CN. In further embodiments of the subject compounds, R ⁵ Independently C _1-6 An alkyl group. In embodiments of the subject compounds, R ⁵ Independently C _2-6 Alkenyl groups. In some embodiments of the subject compounds, R ⁵ Independently C _2-6 Alkynyl groups. In further embodiments of the subject compounds, R ⁵ Independently is-OR ¹² . In selected embodiments of the subject compounds, R ⁵ Is independently-N (R) ¹² )(R ¹³ ). In further embodiments of the subject compounds, R ⁵ Independently is-C (O) OR ¹² . In the practice of the subject compoundsIn embodiments, R ⁵ independently-OC (O) N (R) ¹² )(R ¹³ ). In some embodiments of the subject compounds, R ⁵ independently-C (O) R ¹² . In selected embodiments of the subject compounds, R ⁵ independently-NH ₂ . In further embodiments of the subject compounds, R ⁵ independently-C (O) OH. In further embodiments of the subject compounds, R ⁵ independently-OC (O) NH ₂ . In embodiments of the subject compounds, R ⁵ independently-C (O) CH ₃ 。

In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁ An alkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ An alkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ An alkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ An alkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ An alkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ An alkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ Alkenyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Alkenyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Alkenyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Alkenyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Alkenyl groups. In embodiments, R ⁵ Independently optionally one, two or threeR is a number of ^20a Substituted C ₂ Alkynyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Alkynyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Alkynyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Alkynyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Alkynyl groups. In embodiments, R ⁵ Independently C ₁ A haloalkyl group. In embodiments, R ⁵ Independently C ₂ A haloalkyl group. In embodiments, R ⁵ Independently C ₃ A haloalkyl group. In embodiments, R ⁵ Independently C ₄ A haloalkyl group. In embodiments, R ⁵ Independently C ₅ A haloalkyl group. In embodiments, R ⁵ Independently C ₆ A haloalkyl group.

In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Cycloalkyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Cycloalkyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Cycloalkyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Cycloalkyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ Cycloalkyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ Cycloalkyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ Cycloalkyl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₀ Cycloalkyl groups.

In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ A heterocycloalkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ A heterocycloalkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ A heterocycloalkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ A heterocycloalkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ A heterocycloalkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ A heterocycloalkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ A heterocycloalkyl group. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ A heterocycloalkyl group.

In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Aryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ Aryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ Aryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ Aryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₀ Aryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₁ Aryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₂ Aryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₀ Heteroaryl groups. In embodiments, R ⁵ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₁ Heteroaryl groups. In embodiments, R ⁵ independently-OH. In embodiments, R ⁵ Independently is-SH. In embodiments, R ⁵ independently-NH ₂ . In embodiments, R ⁵ independently-C (O) OH. In embodiments, R ⁵ independently-OC (O) NH ₂ . In embodiments, R ⁵ independently-N (H) C (O) NH ₂ . In embodiments, R ⁵ independently-N (H) C (O) OH. In embodiments, R ⁵ independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ⁵ independently-C (O) H. In embodiments, R ⁵ Is independently-S (O) CH ₃ . In embodiments, R ⁵ independently-OC (O) CH ₃ . In embodiments, R ⁵ independently-C (O) NH ₂ . In embodiments, R ⁵ independently-C (O) C (O) NH ₂ . In embodiments, R ⁵ independently-N (H) C (O) H. In embodiments, R ⁵ Independently is-S (O) ₂ CH ₃ . In embodiments, R ⁵ Independently is-S (O) ₂ NH ₂ -. In embodiments, R ⁵ Independently S (=o) (=nh) NH ₂ . In embodiments, R ⁵ Is independently-CH ₂ C(O)NH ₂ . In embodiments, R ⁵ Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ⁵ Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ⁵ Is independently-CH ₂ S(O) ₂ NH ₂ 。

In embodiments, R ⁵ Is independently-OCH ₃ . In embodiments, R ⁵ Independently is-SCH ₃ . In embodiments, R ⁵ Is independently-N (CH) ₃ ) (H). In embodiments, R ⁵ Is independently-C (O) OCH ₃ . In embodiments, R ⁵ independently-OC (O) N (CH) ₃ ) (H). In embodiments, R ⁵ independently-N (H) C (O) N (CH) ₃ ) (H). In embodiments, R ⁵ Is independently-N (H) C (O) OCH ₃ . In embodiments, R ⁵ independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ⁵ independently-C (O) CH ₃ . In embodiments, R ⁵ Is independently-S (O) CH ₃ . In embodiments, R ⁵ independently-OC (O) CH ₃ . In embodiments, R ⁵ independently-C (O) N (CH) ₃ ) (H). In embodiments, R ⁵ independently-C (O) C (O) N (CH) ₃ ) (H). In embodiments, R ⁵ independently-N (H) C (O) CH ₃ . In embodiments, R ⁵ Independently is-S (O) ₂ CH ₃ . In embodiments, R ⁵ Independently is-S (O) ₂ N(CH ₃ ) (H) -. In embodiments, R ⁵ Independently and separatelyIs S (=o) (=nh) N (CH ₃ ) (H). In embodiments, R ⁵ Is independently-CH ₂ C(O)N(CH ₃ ) (H). In embodiments, R ⁵ Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ⁵ Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ⁵ Is independently-CH ₂ S(O) ₂ N(CH ₃ )(H)。

In embodiments, R ⁵ independently-OC (O) N (CH) ₃ ) ₂ . In embodiments, R ⁵ independently-N (H) C (O) N (CH) ₃ ) ₂ . In embodiments, R ⁵ independently-C (O) (CH ₃ ). In embodiments, R ⁵ independently-C (O) N (CH) ₃ ) ₂ . In embodiments, R ⁵ independently-C (O) C (O) N (CH) ₃ ) ₂ . In embodiments, R ⁵ independently-N (H) C (O) (CH ₃ ). In embodiments, R ⁵ Independently is-S (O) ₂ N(CH ₃ ) ₂ . In embodiments, R ⁵ Independently S (=o) (=nh) N (CH ₃ ) ₂ . In embodiments, R ⁵ Is independently-CH ₂ C(O)N(CH ₃ ) ₂ 。

In embodiments, R ⁵ Is independently-CH ₂ S(O) ₂ N(CH ₃ ) ₂ 。

In embodiments, R ⁵ Is independently-CH ₃ . In embodiments, R ⁵ Independently is-CF ₃ . In embodiments, R ⁵ independently-CHF ₂ . In embodiments, R ⁵ Independently is-CFH ₂ . In embodiments, R ⁵ Independently ethyl. In embodiments, R ⁵ Independently is propyl. In embodiments, R ⁵ Independently isopropyl. In embodiments, R ⁵ Independently butyl. In embodiments, R ⁵ Independently t-butyl.

In embodiments, R ⁶ Independently halogen. In embodiments, R ⁶ Independently oxo. In embodiments, R ⁶ Independently is-CN. In embodiments, R ⁶ Independently C _1-6 An alkyl group. In embodiments, R ⁶ Independently C _2-6 Alkenyl groups. In embodiments, R ⁶ Independently C _2-6 Alkynyl groups. In embodiments, R ⁶ Independently C _1-6 A haloalkyl group. In embodiments, R ⁶ Independently C _3-12 Cycloalkyl groups. In embodiments, R ⁶ Is independently-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ⁶ Independently C _1-11 A heterocycloalkyl group. In embodiments, R ⁶ Is independently-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ⁶ Independently C _6-12 Aryl groups. In embodiments, R ⁶ Is independently-CH ₂ -C _6-12 Aryl groups. In embodiments, R ⁶ Is independently-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ⁶ Independently C _1-11 Heteroaryl groups. In embodiments, R ⁶ Independently is-OR ¹² . In embodiments, R ⁶ independently-SR ¹² . In embodiments, R ⁶ Is independently-N (R) ¹² )(R ¹³ ). In embodiments, R ⁶ Independently is-C (O) OR ¹² . In embodiments, R ⁶ independently-OC (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁶ Is independently-N (R) ¹⁶ )C(O)N(R ¹² )(R ¹³ ). In embodiments, R ⁶ Is independently-N (R) ¹⁶ )C(O)OR ¹⁵ . In embodiments, R ⁶ Is independently-N (R) ¹⁶ )S(O) ₂ R ¹⁵ . In embodiments, R ⁶ independently-C (O) R ¹⁵ . In embodiments, R ⁶ Independently is-S (O) R ¹⁵ . In embodiments, R ⁶ independently-OC (O) R ¹⁵ . In embodiments, R ⁶ independently-C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁶ independently-C (O) C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁶ Is independently-N (R) ¹⁶ )C(O)R ¹⁵ . In embodiments, R ⁶ Independently is-S (O) ₂ R ¹⁵ . In embodiments, R ⁶ Independently is-S (O) ₂ N(R ¹² )(R ¹³ ) -. In embodiments, R ⁶ Independently S (=o) (=nh) N (R ¹² )(R ¹³ ). In embodiments, R ⁶ Is independently-CH ₂ C(O)N(R ¹² )(R ¹³ ). In embodiments, R ⁶ Is independently-CH ₂ N(R ¹⁶ )C(O)R ¹⁵ . In embodiments, R ⁶ Is independently-CH ₂ S(O) ₂ R ¹⁵ . In embodiments, R ⁶ Is independently-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ). In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 An alkyl group. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-6 Alkenyl groups. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-6 Alkynyl groups. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 A haloalkyl group. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a Substituted C _3-12 Cycloalkyl groups. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-11 A heterocycloalkyl group. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a Substituted C _6-12 Aryl groups. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _6-12 Aryl groups. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ⁶ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-11 Heteroaryl groups.

In further embodiments of the subject compounds, R ¹ Independently hydrogen. In selected embodiments of the compounds, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 An alkyl group. In embodiments of the compounds, R ¹ Independently are optionally substituted with one or two R ^20a Substituted methyl. In further embodiments of the compounds, R ¹ Independently methyl. In some embodiments of the compounds, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted ethyl. In embodiments of the compounds, R ¹ Independently ethyl. In some embodiments of the compounds, R ¹ Independently are optionally substituted with one, two or three R ^20a A substituted propyl group. In embodiments of the compounds, R ¹ Independently is propyl. In some embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _2-9 A heterocycloalkyl group. In some embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ - (single ring C) _2-8 Heterocycloalkyl). In some embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ - (single ring C) _3-5 Heterocycloalkyl). In some embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ - (spiro C) _2-11 Heterocycloalkyl). In some embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ - (spiro ring)C _3-11 Heterocycloalkyl). In some embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ - (condensed C) _2-11 Heterocycloalkyl). In some embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ - (spiro C) _6-8 Heterocycloalkyl). In embodiments, R ¹ Independently C _1-6 An alkyl group. In embodiments, R ¹ Independently C _2-6 Alkenyl groups. In embodiments, R ¹ Independently C _2-6 Alkynyl groups. In embodiments, R ¹ Independently C _3-10 Cycloalkyl groups. In embodiments, R ¹ Is independently-CH ₂ -C _3-10 Cycloalkyl groups. In embodiments, R ¹ Independently C _2-9 A heterocycloalkyl group. In embodiments, R ¹ Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ¹ Independently C _6-10 Aryl groups. In embodiments, R ¹ Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ¹ Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ¹ Independently C _1-9 Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 An alkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-6 Alkenyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-6 Alkynyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _3-10 Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _3-10 Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-9 A heterocycloalkyl group. In the implementation modeIn the scheme, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _6-10 Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _6-10 Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-9 Heteroaryl groups.

In embodiments, R ¹ Independently C _1-6 An alkyl group. In embodiments, R ¹ Independently C _2-6 Alkenyl groups. In embodiments, R ¹ Independently C _2-6 Alkynyl groups. In embodiments, R ¹ Independently C _1-6 A haloalkyl group. In embodiments, R ¹ Independently C _3-12 Cycloalkyl groups. In embodiments, R ¹ Is independently-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ¹ Independently C _1-11 A heterocycloalkyl group. In embodiments, R ¹ Is independently-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ¹ Independently C _6-12 Aryl groups. In embodiments, R ¹ Is independently-CH ₂ -C _6-12 Aryl groups. In embodiments, R ¹ Is independently-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ¹ Independently C _1-11 Heteroaryl groups.

In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 An alkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _2-6 Alkenyl groups. In embodiments, R ¹ Independently are optionally one, two orThree R ^20a Substituted C _2-6 Alkynyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-6 A haloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _3-12 Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-11 A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _6-12 Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _6-12 Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C _1-11 Heteroaryl groups.

In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁ An alkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ An alkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ An alkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ An alkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ An alkyl group. In embodiments, R ¹ Independently isOptionally by one, two or three R ^20a Substituted C ₆ An alkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ Alkenyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Alkenyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Alkenyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Alkenyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Alkenyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ Alkynyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Alkynyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Alkynyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Alkynyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Alkynyl groups. In embodiments, R ¹ Independently C ₁ A haloalkyl group. In embodiments, R ¹ Independently C ₂ A haloalkyl group. In embodiments, R ¹ Independently C ₃ A haloalkyl group. In embodiments, R ¹ Independently C ₄ A haloalkyl group. In embodiments, R ¹ Independently C ₅ A haloalkyl group. In embodiments, R ¹ Independently C ₆ A haloalkyl group.

In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally one, two orThree R ^20a Substituted C ₄ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₀ Cycloalkyl groups.

In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ A heterocycloalkyl group.

In embodiments, R ¹ Independently is optionally oneTwo or three R ^20a Substituted C ₆ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₀ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₁ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₂ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₂ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₃ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₄ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₅ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₆ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₇ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₈ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₉ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₀ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a Substituted C ₁₁ Heteroaryl groups.

In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₃ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₄ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₅ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₆ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₇ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₈ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₉ Cycloalkyl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₁₀ Cycloalkyl groups.

In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₂ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₃ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₄ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₅ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₆ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₇ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₈ A heterocycloalkyl group. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₉ A heterocycloalkyl group.

In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₆ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₇ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₈ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₉ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₁₀ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₁₁ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₁₂ Aryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₂ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₃ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₄ Heteroaryl groups. In embodiments, R ¹ Independently is optionally covered withOne, two or three R ^20a substituted-CH ₂ -C ₅ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₆ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₇ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₈ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₉ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₁₀ Heteroaryl groups. In embodiments, R ¹ Independently are optionally substituted with one, two or three R ^20a substituted-CH ₂ -C ₁₁ Heteroaryl groups.

In embodiments, R ¹ Is independently-CH ₃ . In embodiments, R ¹ Independently is-CF ₃ . In embodiments, R ¹ independently-CHF ₂ . In embodiments, R ¹ Independently is-CFH ₂ . In embodiments, R ¹ Independently ethyl. In embodiments, R ¹ Independently is propyl. In embodiments, R ¹ Independently isopropyl. In embodiments, R ¹ Independently butyl. In embodiments, R ¹ Independently t-butyl.

/>

p is an integer from 0 to 12;

X ¹ selected from CH ₂ 、C(R ⁴ )(R ⁶ )、C＝N-OR ⁴ 、C＝NN(R ⁴ )(R ⁶ )、C(O)N(R ⁴ )、

N(R ⁴ )、N(R ⁶ )、O、S、S(O)、S(＝O)(＝NR ⁴ )、S(O) ₂ N(R ⁴ )、

N(R ⁴ )S(O)N(R ⁴ )、N(R ⁴ )S(O) ₂ N(R ⁴ )、S(O)N(R ⁴ )、OC(O)N(R ⁴ )、N(R ⁴ )C(O)N(R ⁴ )、S(O) ₂ 、CH ₂ C(R ⁴ )(R ⁶ )、CH ₂ C(R ⁴ )(R ⁶ )CH ₂ 、C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )C＝N-OR ⁴ 、CH ₂ C＝NN(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁶ )、C(R ⁴ )(R ⁶ )O、C(R ⁴ )(R ⁶ )OC(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S、C(R ⁴ )(R ⁶ )SC(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S(O)、C(R ⁴ )(R ⁶ )S(O)C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S(O) ₂ C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S(＝O)(＝NR ⁴ )、C(R ⁴ )(R ⁶ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁶ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )OC(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁶ )S(O) ₂ 、C＝NN(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )、C(O)N(R ⁴ )C(R ⁴ )(R ⁶ )、S(O) ₂ N(R ⁴ )C(R ⁴ )(R ⁶ )、S(O)N(R ⁴ )C(R ⁴ )(R ⁶ )、OC(O)N(R ⁴ )C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁴ )、C＝N-OR ⁴ 、C＝NN(R ⁴ )(R ⁴ )、CH ₂ C(R ⁴ )(R ⁴ )、CH ₂ C(R ⁴ )(R ⁴ )CH ₂ 、C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C＝N-OR ⁴ 、CH ₂ C＝NN(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁶ )、C(R ⁴ )(R ⁴ )O、C(R ⁴ )(R ⁴ )OC(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S、C(R ⁴ )(R ⁴ )SC(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S(O)、C(R ⁴ )(R ⁴ )S(O)C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S(O) ₂ C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )S(＝O)(＝NR ⁴ )、C(R ⁴ )(R ⁴ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )S(O) ₂ N(R ⁴ )、C(R ⁴ )(R ⁴ )S(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )OC(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )S(O) ₂ 、C＝NN(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )、C(O)N(R ⁴ )C(R ⁴ )(R ⁴ )、S(O) ₂ N(R ⁴ )C(R ⁴ )(R ⁴ )、S(O)N(R ⁴ )C(R ⁴ )(R ⁴ ) And OC (O) N (R) ⁴ )C(R ⁴ )(R ⁴ )；

/>

In some embodiments, R ⁷ Is that

p is an integer from 0 to 12;

X ² Selected from N, C, C (R) ⁶ )、C(R ⁴ )、CH、N(R ¹ )、N(R ⁴ )、N(R ⁶ )、O、S、S(O)、C(H)(R ⁶ )、C(R ⁴ ) ₂ 、CH ₂ 、C(R ⁴ )(R ⁶ )、S(＝O)(＝NR ⁴ )、S(O) ₂ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

X ³ Selected from N, C, C (R) ⁶ ) And C (R) ⁴ )。

In embodiments, R ⁷ Is that

In some embodiments, R ⁷ Is that

In some embodiments, R ⁷ Is that/>

And p is independently an integer from 0 to 12.

In some embodiments, R ⁷ Is that/>

And p is independently an integer from 0 to 12.

In some embodiments, R ⁷ Is that/>

In some embodiments, R ⁷ Is that

And p is an integer of 0 to 12.

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl group, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl is optionally substituted with one, two or three R' s ^20g And (3) substitution. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen and halogen. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen and fluorine. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Is hydrogen. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Is fluorine.

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20c And (3) substitution. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from hydrogen, C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 The heterocycloalkyl groups are optionally substituted with one, two or three R independently selected from ^20c Substitution: halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from the group consisting of hydrogen, methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R independently selected from the group consisting of ^20c Substitution: fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from the group consisting of hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments, R ⁸ Selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20c And (3) substitution. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 The heterocycloalkyl groups are optionally substituted with one, two or three R independently selected from ^20c Substitution: halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from the group consisting of methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R independently selected from ^20c Substitution: fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from methyl, cyclopropyl, cyclobutyl and oxetanyl.

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ³ Is hydrogen or CN. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ³ Is hydrogen. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ³ Is CN.

In the subject compounds or pharmaceutically acceptable thereofIn some embodiments of the salts or solvates of L ¹ Is a key. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ¹ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -C (O) -, -NHC (O) -, -C (O) NH-, CH ₂ O、CH ₂ NH and CH ₂ 。

In embodiments, L ¹ Is a key. In embodiments, L ¹ Is C ₁ -C ₆ An alkyl group. In embodiments, L ¹ Is C ₂ -C ₆ Alkenyl groups. In embodiments, L ¹ Is C ₂ -C ₆ Alkynyl groups. In embodiments, L ¹ is-O-. In embodiments, L ¹ is-N (R) ¹⁴ ) -. In embodiments, L ¹ is-C (O) -. In embodiments, L ¹ is-N (R) ¹⁴ ) C (O) -. In embodiments, L ¹ is-C (O) N (R) ¹⁴ ) -. In embodiments, L ¹ is-S-. In embodiments, L ¹ is-S (O) ₂ -. In embodiments, L ¹ is-S (O) -. In embodiments, L ¹ is-S (O) ₂ N(R ¹⁴ ) -. In embodiments, L ¹ is-S (O) N (R) ¹⁴ ) -. In embodiments, L ¹ is-N (R) ¹⁴ ) S (O) -. In embodiments, L ¹ is-N (R) ¹⁴ )S(O) ₂ -. In embodiments, L ¹ is-OCON (R) ¹⁴ ) -. In embodiments, L ¹ is-N (R) ¹⁴ ) C (O) O-. In embodiments, L ¹ Is N (R) ^1e ). In embodiments, L ¹ Is C (O) N (R) ^1c ). In embodiments, L ¹ Is S (O) ₂ N(R ^1c ). In embodiments, L ¹ Is S (O) N (R) ^1c ). In embodiments, L ¹ Is C (R) ^1f )(R ^1g ) O. In embodiments, L ¹ Is C (R) ^1f )(R ^1g )N(R ^1c ). In embodiments, L ¹ Is C (R) ^1f )(R ^1g ). In embodiments, L ¹ is-N (H) -. In the context of an embodiment of the present invention,L ¹ is-N (H) C (O) -. In embodiments, L ¹ is-C (O) N (H) -. In embodiments, L ¹ is-S (O) ₂ N (H) -. In embodiments, L ¹ is-S (O) N (H) -. In embodiments, L ¹ is-N (H) S (O) -. In embodiments, L ¹ is-N (H) S (O) ₂ -. In embodiments, L ¹ is-OCON (H) -. In embodiments, L ¹ is-N (H) C (O) O-. In embodiments, L ¹ is-N (H) -. In embodiments, L ¹ is-C (O) N (H) -. In embodiments, L ¹ is-S (O) ₂ N (H) -. In embodiments, L ¹ is-S (O) N (H) -. In embodiments, L ¹ is-CH ₂ O-. In embodiments, L ¹ is-CH ₂ N (H) -. In embodiments, L ¹ is-CH ₂ -。

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is a single ring. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is a bicyclic ring system. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is a polycyclic system. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ The method comprises the following steps:

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

Each R ^1a 、R ^1b 、R ^1d And R is ^1h Each independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R bonded to the same carbon ^1a And R is ^1b To form a 3-to 10-membered heterocycloalkyl ring or C _3-10 Cycloalkyl rings, wherein 3-10 membered heterocycloalkyl ring or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or two R's bonded to adjacent atoms ^1a To form a 3-to 10-membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring wherein 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroarylRing or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or R is ^1h With R bound to adjacent atoms ^1a 、R ^1b 、R ^1c And R is ^1d Is linked to form a 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring wherein 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring and C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; and is also provided with

/>

In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, each R ⁵ Independently selected from: -H, -NH ₂ 、-OH、-NH(C _1-6 Alkyl group),

And m is 0, 1, 2 or 3 when present.

In one aspect, there is provided a compound of formula (II):

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

V is C (R) ¹⁶ ) Or N;

R ¹⁰ is-L ⁷ -R ⁷ ；

Bonded to the same or adjacent atoms and selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

R ⁶ is-L ² -R ⁵ ；

Each R ⁵ Independently hydrogen or other than at position 12 capable of interacting with the KRAS proteinThe cysteine residues form groups other than the electrophilic moiety of the covalent bond;

R ¹⁷ is-L ¹ -R ¹⁹ ；

x is C (R) ³ ) Or N;

each R ¹² Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl group、C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

Each R ^20a 、R ^20b 、R ^20c 、R ^20d 、R ^20e 、R ^20f 、R ^20g And R is ²⁰ⁱ Each independently selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl, C _1-9 Heteroaryl group、-OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

In one aspect, there is provided a compound of formula (II'):

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

V is C (R) ¹⁶ ) Or N;

R ¹⁰ is-L ⁷ -R ⁷ ；

L ⁷ Is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or 2-to 4-membered heteroalkylene linker wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl groupsThe 2-to 4-membered alkylene linker is optionally substituted with one, two or three R ^20a Substitution;

each R ⁴ Independently selected from hydrogen, halogenPlain, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

R ⁶ is-L ² -R ⁵ ；

R ¹⁷ is-L ¹ -R ¹⁹ ；

L ¹ Selected from bonds, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、-OCON(R ¹⁴ )-、-N(R ¹⁴ )C(O)O-、N(R ^1e )、C(O)N(R ^1c )、S(O) ₂ N(R ^1c )、S(O)N(R ^1c )、C(R ^1f )(R ^1g )O、C(R ^1f )(R ^1g )N(R ^1c ) AndC(R ^1f )(R ^1g )；

R ^12a selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

R ^12c independently selected from hydrogen and R ^20k ；

X is C (R) ³ ) Or N;

Each R ²¹ Independently selected from H、C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

In some embodiments of formula (II') or a pharmaceutically acceptable salt or solvate thereof, R ⁷ Is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl and 5-12 membered heteroaryl each contain one or more ring nitrogen atoms or one or more epoxy atoms, and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution; wherein the bond to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 NaphtheneRadical, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In one aspect, there is provided a compound of formula (I "), or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

R ¹⁰ is-L ⁷ -R ⁷ ；

L ⁷ Is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or 2-to 4-membered heteroalkylene linker wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and 2-to 4-membered alkylene linkers are unsubstituted or optionally substituted;

R ⁷ is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each contain one or more ring nitrogen atoms or one or more epoxy atoms, and wherein 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl is unsubstituted or optionally substituted;

R ⁸ Selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl groups、C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

R ¹⁷ is-L ¹ -R ¹⁹ ；

R ^1e 、R ^1f And R is ^1g Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted; or R is ^1f And R is ^1g To form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or the 4-7 membered cycloalkyl ring is unsubstituted or optionally substituted;

R ^1c selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

R ¹⁹ selected from C _3-12 Cycloalkyl group, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl, wherein C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl is unsubstituted or optionally substituted;

R ¹⁶ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

R ² is-C (O) OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ 、-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ )、–(C ₁ -C ₆ Alkyl) -R ^12b 、–(C _2-6 Alkenyl) -R ^12b 、–(C _2-6 Alkynyl) -R ^12b 、-O-R ^12a 、-N(R ¹⁴ )-R ^12b 、-S-R ^12b 、-(C _3-10 Cycloalkyl) -R ^12b 、-(C _2-9 Heterocycloalkyl) -R ^12b 、-(C _6-10 Aryl) -R ^12b Or- (C) _1-9 Heteroaryl) -R ^12b Wherein said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted; r is R ^12a Selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

R ^12b selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -C (R) ^12c ) ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -C (R) ^12c ) ₂ -C _6-10 Aryl, -C (R) ^12c ) ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

R ^12c selected from hydrogen, halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

each R ²⁵ Selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl;

x is C (R) ³ ) Or N;

R ³ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

each R ¹² Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

each R ¹³ Independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; or R is ¹² And R is ¹³ Together with the nitrogen to which they are attached form an unsubstituted or optionally substituted C _2-9 A heterocycloalkyl ring;

each R ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

represents a single bond or a double bond such that all valences are satisfied.

In some embodiments of formula (II "), or a pharmaceutically acceptable salt or solvate thereof, R ⁷ Is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each contain one or more ring nitrogen atoms or one or more epoxy atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl is optionally substituted or unsubstituted.

In one aspect, there is provided a compound of formula (II') or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

V is C (R) ¹⁶ ) Or N;

R ¹⁰ is-L ⁷ -R ⁷ ；

R ⁸ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is unsubstituted or optionally substituted;

R ¹⁷ is-L ¹ -R ¹⁹ ；

R ¹⁹ selected from C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl, wherein C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl is unsubstituted or optionally substituted;

R ¹⁶ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is not takenSubstituted or optionally substituted;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

x is C (R) ³ ) Or N;

Each R ¹³ Independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; or R is ¹² And R is ¹³ Together with the nitrogen to which they are attached form an unsubstituted or optionallyC substituted with ground _2-9 A heterocycloalkyl ring;

represents a single bond or a double bond such that all valences are satisfied.

In one aspect, there is provided a compound of formula (I-1), or a pharmaceutically acceptable salt or solvate thereof:

Wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

R ¹⁰ is-L ⁷ -R ⁷ ；

R ⁷ is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl and 5-12 membered heteroaryl each contain one or more ring nitrogen atoms or one or more epoxy atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution;

wherein the bond to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl, wherein 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

each R ¹ Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _2-11 Heterocyclylalkyl, -CH ₂ -C _2-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl groupC _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _2-11 Heterocyclylalkyl, -CH ₂ -C _2-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

each R ⁴ Independently selected from hydrogen, halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹² 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹² 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

R ⁶ is-L ² -R ⁵ ；

Each L ² Independently selected from bond, C ₁ -C ₆ Alkyl radicalsO-、-N(R ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、-OCON(R ¹⁴ )-、-N(R ¹⁴ ) C (O) O-and-N (R) ¹⁴ )C(O)N(R ¹⁴ )-；

R ⁸ selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20c Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

R ^1e 、R ^1f And R is ^1g Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R is ^1f And R is ^1g To form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or the 4-7 membered cycloalkyl ring is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ^1c selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

each R ¹ⁱ Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ¹⁶ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20g Substitution;

R ² is-C (O) OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ 、-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ )、–(C ₁ -C ₆ Alkyl) -R ^12b 、–(C _2-6 Alkenyl) -R ^12b 、–(C _2-6 Alkynyl) -R ^12b 、-O-R ^12a 、-N(R ¹⁴ )-R ^12b 、-S-R ^12b 、-(C _3-10 Cycloalkyl) -R ^12b 、-(C _2-9 Heterocycloalkyl) -R ^12b 、-(C _6-10 Aryl) -R ^12b Or- (C) _1-9 Heteroaryl) -R ^12b Wherein said C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

R ^12c independently selected from hydrogen and R ^20k ；

X is C (R) ³ ) Or N;

R ³ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20b Substitution;

each R ¹² Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20d Substitution;

each R ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 A heteroaryl group, which is a group,wherein C is _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20f Substitution;

each R ^20a 、R ^20b 、R ^20c 、R ^20d 、R ^20e 、R ^20f 、R ^20g 、R ²⁰ⁱ And R is ^20k Each independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

Each R ²¹ Independently selected from H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl;

each R ²² Independently selected from H, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

each R ²⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl; and is also provided with

Represents a single bond or a double bond such that all valences are satisfied.

In one aspect, there is provided a compound of formula (II-1), or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

V is C (R) ¹⁶ ) Or N;

R ¹⁰ is-L ⁷ -R ⁷ ；

bonded to the same or adjacent atoms and selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl, wherein 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

each R ¹ Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _2-11 Heterocyclylalkyl, -CH ₂ -C _2-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _2-11 Heterocyclylalkyl, -CH ₂ -C _2-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

each R ⁴ Independently selected from hydrogen, halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹² 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹² 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted withOne, two or three R ^20a Substitution;

R ⁶ is-L ² -R ⁵ ；

R ⁸ selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl groups are optionallyIs one, two or three R ^20c Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

R ^12c independently selected from hydrogen and R ^20k ；

X is C (R) ³ ) Or N;

each R ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20f Substitution;

each R ^20a 、R ^20b 、R ^20c 、R ^20d 、R ^20e 、R ^20f 、R ^20g 、R ²⁰ⁱ And R is ^20k Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with And each, two or three are independently substituted with a group selected from the group consisting of: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

In the formulaIn an embodiment of I-1, one R ⁴ Is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine or aspartic acid residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;

in an embodiment of formula II-1, one R ⁴ Is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine or aspartic acid residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;

In one aspect, there is provided a compound of formula (I-1'), or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

W is C (O); v is C (R) ¹⁷ ) And J is C (R ¹⁶ )；

R ¹⁰ is-L ⁷ -R ⁷ ；

L ⁷ Is a bond, -O-or-N (R) ¹⁴ )-；

R ⁷ Is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl contains one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution;

each R ⁴ Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹² 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹² 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

r is R ⁴ Optionally independently an electrophilic moiety capable of forming a covalent bond with a cysteine, serine or aspartic acid residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;

R ⁶ is-L ² -R ⁵ ；

Each L ² Independently selected from the group consisting of bond and-C (O) -;

each R ⁵ Independently selected from hydrogen, halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl, C _1-11 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹² 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹² 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

R ⁸ selected from-CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl and-C (O) R ¹² Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20c Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

L ¹ Is a bond;

R ¹⁹ selected from C _6-12 Aryl and C _2-12 Heteroaryl, wherein C _6-12 Aryl and C _2-12 Heteroaryl is optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ Substitution;

each R ¹ⁱ Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-5 Heterocyclylalkyl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-C(O)R ¹² 、-C(O)N(R ¹² )(R ¹³ ) and-N (R) ¹⁴ )C(O)R ¹² Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl and C _2-5 Heterocycloalkyl is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ¹⁶ selected from hydrogen and halogen;

R ² is-O-R ^12a ；

R ^12a is-C (R) ^12c ) ₂ -C _2-9 Heterocycloalkyl, wherein-C (R ^12c ) ₂ -C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20d Substitution;

R ^12c independently selected from hydrogen and C _1-3 An alkyl group;

x is C (R) ³ ) Or N;

R ³ selected from hydrogen and-CN;

each R ¹³ Independently selected from hydrogen, C _1-6 Alkyl and C _1-6 A haloalkyl group;

each R ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 NaphtheneRadical, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20f Substitution;

each R ^20a 、R ^20c 、R ^20d 、R ^20e 、R ^20f And R is ²⁰ⁱ Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

In one aspect, there is provided a compound of formula (I-1') or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

W is C (O); v is C (R) ¹⁷ ) And (2) andj is C (R) ¹⁶ )；

R ¹⁰ is-L ⁷ -R ⁷ ；

L ⁷ Is a bond, -O-or-N (R) ¹⁴ )-；

R ⁷ Is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirobicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirobicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each contain one or more ring nitrogen atoms and wherein 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirobicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each optionally substituted with one or more R ⁴ Substitution;

R ⁴ independently selected from halogen, oxo, -CN, -C (O) R ¹² 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl and-OR ¹² Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20a Substitution;

R ⁸ selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20c Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

L ¹ Is a bond;

R ¹⁹ selected from C _6-12 Aryl and 9-10 membered heteroaryl, wherein C _6-12 Aryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ Substitution;

each R ¹ⁱ Independently selected from halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, -OH、-NH ₂ Wherein C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ¹⁶ selected from hydrogen and halogen;

R ² is-O-R ^12a ；

R ^12a is-C (R) ^12c ) ₂ - (5-8 membered heterocycloalkyl), wherein-C (R ^12c ) ₂ - (5-8 membered heterocycloalkyl) optionally substituted by one, two or three R ^20d Substitution;

R ^12c independently selected from hydrogen and methyl;

x is N;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

wherein the method comprises the steps of

W is C (O); v is C (R) ¹⁷ ) And J is C (R ¹⁶ )；

R ¹⁰ is-L ⁷ -R ⁷ ；

L ⁷ Is a bond, -O-or-N (R) ¹⁴ )-；

R ⁷ Is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirobicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirobicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each contain one or more ring nitrogen atoms and wherein 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirobicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each substituted with one or more R ⁴ Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

L ¹ Is a bond;

each R ¹ⁱ Independently selected from halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, -OH, -NH ₂ Wherein C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ¹⁶ selected from hydrogen and halogen;

R ² is-O-R ^12a ；

R ^12c independently selected from hydrogen and methyl;

x is N;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

each R ²⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-12 Aryl and C _1-11 Heteroaryl; and is also provided withRepresents a single bond or a double bond such that all valences are satisfied.

In embodiments, R ⁴ independently-C (O) N (R) ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹² or-C (O) R ¹² . In embodiments, R ⁴ independently-C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁴ Is independently-N (R) ¹⁴ )C(O)R ¹² . In embodiments, R ⁴ independently-C (O) R ¹² 。

In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently selected from C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl, wherein C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d And (3) substitution. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Is optionally substituted with one, two or three R ^20d Substituted C ₂ Alkenyl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Is optionally substituted with one, two or three R ^20d Substituted C ₃ Alkenyl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Is optionally substituted with one, two or three R ^20d Substituted C ₄ Alkenyl groups. In embodiments, R ⁴ is-C (O) R ¹² And R is ¹² Is optionally substituted with one, two or three R ^20d Substituted C ₅ Alkenyl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Is optionally substituted with one, two or three R ^20d Substituted C ₆ Alkenyl groups.

In embodiments, R ⁴ Independently is-C(O)R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ Alkynyl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ Alkynyl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ Alkynyl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ Alkynyl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Alkynyl groups.

In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ A heterocycloalkyl group.

In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₇ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₈ A heterocycloalkyl group. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₉ A heterocycloalkyl group.

In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₁ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₇ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₈ Heteroaryl groups. In embodiments, R ⁴ independently-C (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₉ Heteroaryl groups.

In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently selected from C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl, wherein C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20d And (3) substitution. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ Alkenyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ Alkenyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ Alkenyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ Alkenyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Alkenyl groups.

In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ Alkynyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ Alkynyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ Alkynyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ Alkynyl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Alkynyl groups.

In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₇ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₈ A heterocycloalkyl group. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₉ A heterocycloalkyl group.

In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₁ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₂ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₃ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₄ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₅ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₆ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₇ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₈ Heteroaryl groups. In embodiments, R ⁴ Is independently-NHC (O) R ¹² And R is ¹² Independently are optionally substituted with one, two or three R ^20d Substituted C ₉ Heteroaryl groups.

In one aspect, there is provided a compound of formula (I-1' ") or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

W is C (O); v is C (R) ¹⁷ ) And J is C (R ¹⁶ )；

R ¹⁰ is-L ⁷ -R ⁷ ；

L ⁷ Is a bond;

R ⁴ independently selected from halogen; c (C) _1-6 Alkyl, wherein C _1-6 Alkyl is optionally substituted with one, two or three R ^20a Substitution; and-C (O) R ¹⁵ Wherein said R is ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally substituted by one, two or three R ^20f Substitution;

R ⁸ selected from C _1-4 Alkyl and C _3-4 Cycloalkyl group, wherein C _1-4 Alkyl and C _3-4 Cycloalkyl is optionally substituted with one, two or three R' s ^20c Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

L ¹ Is a bond;

R ¹⁹ selected from naphthyl and 9-10 membered heteroaryl, wherein naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ Substitution;

each R ¹ⁱ Independently selected from halogen, -CN, C _1-3 Alkyl, C _1-3 Haloalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, -OH, -NH ₂ Wherein C _1-3 Alkyl, C _1-3 Haloalkyl, C _2-3 Alkenyl and C _2-3 Alkynyl is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ¹⁶ selected from hydrogen and F;

R ² is-O-R ^12a ；

R ^12c independently selected from hydrogen and methyl;

x is N; and is also provided with

Each R ^20a 、R ^20c 、R ^20d 、R ^20e 、R ^20f And R is ²⁰ⁱ Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ 。

/>

wherein the method comprises the steps of

W is C (O); v is C (R) ¹⁷ ) And J is C (R ¹⁶ )；

R ¹⁰ is-L ⁷ -R ⁷ ；

L ⁷ Is a bond;

R ¹⁷ is-L ¹ -R ¹⁹ ；

L ¹ Is a bond;

R ¹⁶ selected from hydrogen and F;

R ² is-O-R ^12a ；

R ^12c independently selected from hydrogen and methyl;

x is N; and is also provided with

In one aspect, there is provided a compound of formula (I-3), or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

R ⁸ selected from cyclopropyl, fluoro-substituted cyclopropyl, methyl, ethyl, n-propyl, -CH ₂ CH ₂ CN and-CH ₂ CH ₂ CH ₂ CN；

R ¹⁹ Selected from the group consisting ofR ² Selected from->And is also provided with

Each R ^20a And R is ^20f Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ 。

In one aspect, there is provided a compound of formula (I-4), or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

R ⁴ independently selected from-C (O) R ¹⁵ Wherein said R is ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally substituted by one, two or three R ^20f Substitution; halogen; and C _1-6 Alkyl, wherein C _1-6 Alkyl is optionally substituted with one, two or three R ^20a Substitution;

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, X is C (R3). In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, X is N.

wherein the method comprises the steps of

W is C (O); v is C (R) ¹⁷ ) And J is C (R ¹⁶ )；R ¹⁰ is-L ⁷ -R ⁷ ；L ⁷ Is a bond;

R ⁷ is a compound containing one or more ring nitrogen atoms5-7 membered monocyclic heterocycloalkyl and wherein 5-7 membered monocyclic heterocycloalkyl is optionally substituted with one or more R ⁴ Substitution;

R ⁴ independently selected from 1) -C (O) R ¹⁵ Wherein said R is ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally substituted by one, two or three R ^20f Substitution; 2) Halogen; and 3) optionally one, two or three R ^20a Substituted C _1-6 An alkyl group;

R ⁸ selected from C _1-4 Alkyl and cyclopropyl, wherein C _1-4 The alkyl and cyclopropyl groups are optionally substituted with one, two or three R groups ^20c Substitution;

R ¹⁷ is that

R ¹⁶ Selected from hydrogen and F;

R ² is that

X is N; and is also provided with

Each R ^20a 、R ^20c And R is ^20f Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl group、-OH、-OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ 。

wherein the method comprises the steps of

R ⁷ is a 7-12 membered fused bicyclic heterocycloalkyl containing one or more ring nitrogen atoms and wherein 7-12 membered fused bicyclic heterocycloalkyl is optionally substituted with one or more R ⁴ Substitution;

R ⁴ independently selected from 1) -C (O) R ¹⁵ Wherein said R is ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroarylThe radicals being optionally substituted by one, two or three R ^20f Substitution; 2) Halogen; and 3) optionally one, two or three R ^20a Substituted C _1-6 An alkyl group;

R ¹⁷ is that

R ¹⁶ Selected from hydrogen and F;

R ² is that

X is N; and is also provided with

Each R ^20a 、R ^20c And R is ^20f Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one,Two or three of the groups independently selected from the following are substituted: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ 。

wherein the method comprises the steps of

R ⁷ is a 7-10 membered spirocyclic bicycloheterocycloalkyl containing one or more ring nitrogen atoms and wherein 7-10 membered spirocyclic bicycloheterocycloalkyl is optionally substituted with one or more R ⁴ Substitution;

R ¹⁷ is that

R ¹⁶ Selected from hydrogen and F;

R ² is that

X is N; and is also provided with

Each R ^20a 、R ^20c And R is ^20f Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ 。

wherein the method comprises the steps of

R ⁷ is a 7-10 membered bridged bicyclic heterocycloalkyl containing one or more ring nitrogen atoms and wherein the 7-10 membered bridged bicyclic heterocycloalkyl is optionally substituted with one or more R ⁴ Substitution;

R ¹⁷ is that

R ¹⁶ Selected from hydrogen and F;

R ² is that

X is N; and is also provided with

Each of which isR ^20a 、R ^20c And R is ^20f Independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ 。

wherein the method comprises the steps of

R ⁷ is a 5-8 membered monocyclic heterocycloalkyl containing one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl is optionally substituted with one or more R ⁴ Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond;

R ¹⁶ selected from hydrogen and F;

R ² is-O-R ^12a ；R ^12a is-C (R) ^12c ) ₂ - (5-8 membered heterocycloalkyl), wherein-C (R ^12c ) ₂ - (5-8 membered heterocycloalkyl) optionally substituted by one, two or three R ^20d Substitution; r is R ^12c Independently selected from hydrogen and methyl;

x is N; and is also provided with

wherein the method comprises the steps of

R ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond;

R ¹⁶ selected from hydrogen and F;

x is N; and is also provided with

Each R ^20a 、R ^20c 、R ^20d 、R ^20e 、R ^20f And R is ²⁰ⁱ Independently selected from halogen, oxo,-CN、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl, C _1-11 Heteroaryl, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, -CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OH, -OCH ₃ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-C(O)OH、-C(O)NH ₂ -NHC (O) H, -C (O) H and-C (O) CH ₃ 。

wherein the method comprises the steps of

R ⁷ is a 7-10 membered spirocyclic bicycloheterocycloalkyl containing one or more ring nitrogen atoms and wherein 7-10 membered spirocyclic bicycloheterocycloalkyl is optionally substituted with one or more R4;

R ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond;

R ¹⁶ selected from hydrogen and F;

x is N; and is also provided with

Wherein the method comprises the steps of

R ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond;

R ¹⁶ selected from hydrogen and F;

x is N; and is also provided with

In one aspect, there is provided a compound of formula (I):

wherein the method comprises the steps of

W is C (O);

v is C (R) ¹⁷ ) And J is C (R ¹⁶ )；

R ¹⁰ is-L ⁷ -R ⁷ ；

R ⁷ is a 6-10 membered nitrogen containing heterocycloalkyl, wherein the 6-10 membered nitrogen containing heterocycloalkyl is substituted with one or more R ⁴ Substitution;

each R ⁴ Independently selected from CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-9 Heterocyclylalkyl, -C (O) OR ¹² and-C (O) R ¹⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl and C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20a Substitution;

R ⁸ selected from C _1-6 Alkyl and C _3-6 Cycloalkyl group, wherein C _1-6 Alkyl and C _3-6 Cycloalkyl is optionally substituted with one, two or three R' s ^20c Substitution;

R ¹⁷ is-L ¹ -R ¹⁹ ；

L ¹ Is a bond;

R ¹⁹ is one, two, three, four, five, six or seven R ¹ⁱ Substituted fused bicyclic 9-10 membered heterocycloalkyl;

each R ¹ⁱ Independently selected from halogen, -CN and-N (R) ¹² )(R ¹³ )；

R ¹⁶ Is halogen;

R ² selected from- (C) ₁ -C ₆ Alkyl) -R ^12b 、-O-R ^12a And- (C) _2-9 Heterocycloalkyl) -R ^12b Wherein said C _1-6 Alkyl and C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20d Substitution;

R ^12a selected from-CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl and C _6-10 Aryl, wherein-CH ₂ -C _3-10 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl and C _6-10 Aryl is optionally substituted with one, two or three R ^20d Substitution;

R ^12b independently selected from hydrogen and C _2-9 Heterocycloalkyl, wherein C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20d Substitution;

x is N;

each R ¹⁵ Independently selected from C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocyclic ringAlkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f Substitution;

each R ^20a 、R ^20c 、R ^20d 、R ^20e And R is ^20f Each independently selected from halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, W is C (O). In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, W is S (O). On the subject ofIn further embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, W is S (O) ₂ 。

p is an integer from 0 to 12;

/>

And p is an integer of 0 to 12.

Additional entities in the subject compounds or pharmaceutically acceptable salts or solvates thereofIn embodiments, R ⁷ Is that

In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl group, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl is optionally substituted with one, two or three R' s ^20g And (3) substitution. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen and halogen. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Independently selected from hydrogen and fluorine.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20c And (3) substitution. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from hydrogen, C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl group, its preparation methodMiddle C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 The heterocycloalkyl groups are optionally substituted with one, two or three R independently selected from ^20c Substitution: halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from the group consisting of hydrogen, methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R independently selected from the group consisting of ^20c Substitution: fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from the group consisting of hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments, R ⁸ Selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl group、C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20c And (3) substitution. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 The heterocycloalkyl groups are optionally substituted with one, two or three R independently selected from ^20c Substitution: halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from the group consisting of methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R independently selected from ^20c Substitution: fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Selected from methyl, cyclopropyl, cyclobutyl and oxetanyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is methyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is cyclopropyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is cyclobutyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is oxetanyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is a fluorine substituted cyclopropyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is a fluorine substituted methyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is a fluorine substituted ethyl group. In the subject compounds or pharmaceutically acceptable thereof In some embodiments of the salt or solvate, R ⁸ Is CN substituted cyclopropyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is CN substituted methyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is CN substituted ethyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is CN substituted n-propyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is CN substituted n-butyl.

In embodiments, R ⁸ Independently selected from

Me、Et、n-Pr、n-Bu、t-Bu、iPR、

In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ¹ Is a key. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ¹ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -C (O) -, -NHC (O) -, -C(O)NH-、CH ₂ O、CH ₂ NH and CH ₂ 。

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

Each R ^1c Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocyclic ringAlkyl, C _6-10 Aryl, C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ And (3) substitution.

In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ The method comprises the following steps:

/>

-H、-NH ₂ 、-OH、-NH(C _1-6 alkyl group),

/>

And m is 0, 1, 2 or 3 when present.

In some embodiments of the subject compounds, L ⁷ Is a key. In embodiments of the subject compounds, L ⁷ is-N (R) ¹⁴ ) -. In further embodiments of the subject compounds, L ⁷ Is C ₁ -C ₆ An alkyl group. In further embodiments of the subject compounds, L ⁷ Is methylene. In some embodiments of the subject compounds, L ⁷ Is ethylene.

In embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted 3-12 membered nitrogen-containing heterocycloalkyl. In some embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ¹ Substituted 3-12 membered nitrogen-containing heterocycloalkyl. In further embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ⁴ Substituted 3-12 membered nitrogen-containing heterocycloalkyl. In further embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ⁶ Substituted 3-12 membered nitrogen-containing heterocycloalkyl.

In some embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted 6-9 membered nitrogen-containing heterocycloalkyl. In embodiments of the subject compounds, R ⁷ Is optionally one or more ofR ¹ Substituted 6-9 membered nitrogen-containing heterocycloalkyl. In some embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ⁴ Substituted 6-9 membered nitrogen-containing heterocycloalkyl. In further embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ⁶ Substituted 6-9 membered nitrogen-containing heterocycloalkyl. In some embodiments of the subject compounds, R ⁷ Is unsubstituted 6-9 membered nitrogen-containing heterocycloalkyl.

In further embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted 5-12 membered nitrogen containing heteroaryl. In embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ¹ Substituted 5-12 membered nitrogen containing heteroaryl. In some embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ⁴ Substituted 5-12 membered nitrogen containing heteroaryl. In further embodiments of the subject compounds, R ⁷ Is optionally substituted with one or more R ⁶ Substituted 5-12 membered nitrogen containing heteroaryl. In embodiments of the subject compounds, R ⁷ Is unsubstituted 5-12 membered nitrogen containing heteroaryl.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is a 3-12 membered heterocycloalkyl, wherein 3-12 membered heterocycloalkyl is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ And (3) substitution. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is a 3-12 membered heterocycloalkyl, wherein 3-12 membered heterocycloalkyl is optionally substituted with one or more R ¹ And (3) substitution. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is a 3-12 membered heterocycloalkyl, wherein 3-12 membered heterocycloalkyl is optionally substituted with one or more R ⁴ And (3) substitution. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is a 3-12 membered heterocycloalkyl, wherein 3-12 membered heterocycloalkyl is optionally substituted with one or more R ⁶ Substitution of. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is 4-9 membered heterocycloalkyl, wherein 4-9 membered heterocycloalkyl is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ And (3) substitution. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is 4-9 membered heterocycloalkyl, wherein 4-9 membered heterocycloalkyl is optionally substituted with one or more R ¹ And (3) substitution. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is 4-9 membered heterocycloalkyl, wherein 4-9 membered heterocycloalkyl is optionally substituted with one or more R ⁴ And (3) substitution. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is 4-9 membered heterocycloalkyl, wherein 4-9 membered heterocycloalkyl is optionally substituted with one or more R ⁶ And (3) substitution. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is unsubstituted 3-12 membered heterocycloalkyl. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is unsubstituted 4-9 membered heterocycloalkyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted monocyclic C _1-8 A heterocycloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted monocyclic C _1-5 Heteroaryl groups. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted spirocyclic ring C _2-11 A heterocycloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted condensed C _2-11 A heterocycloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted fused 6-to 12-membered aryl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted fused 5-to 12-membered heteroaryl.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted monocyclic nitrogen-containing C _1-8 A heterocycloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted monocyclic nitrogen-containing C _1-5 Heteroaryl groups. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted spirocyclic nitrogen-containing C _2-11 A heterocycloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted condensed nitrogen-containing C _2-11 A heterocycloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted condensed nitrogen-containing C _6-12 Aryl groups. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is optionally covered withOne or more R ¹ One or more R ⁴ Or one or more R ⁶ Substituted fused nitrogen-containing 5-to 12-membered heteroaryl groups.

In a further embodiment of the subject compounds, the groups bonded to the same atom are selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _3-12 Cycloalkyl or C _1-11 Heterocycloalkyl, wherein C _3-12 Cycloalkyl and C _1-11 Heterocycloalkyl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, two R's bonded to the same atom ⁴ Substituents are linked to form C _3-5 Cycloalkyl group, wherein C _3-5 Cycloalkyl is optionally substituted with one, two or three R' s ^20a And (3) substitution. In embodiments of the subject compounds, two R's bonded to the same atom ⁴ Substituents are linked to form C _3-5 Cycloalkyl groups. In a further embodiment of the subject compounds, two R's bonded to the same atom ⁴ Substituents are linked to form C _3-4 Cycloalkyl group, wherein C _3-4 Cycloalkyl is optionally substituted with one, two or three R' s ^20a And (3) substitution. In some embodiments of the subject compounds, two R's bonded to the same atom ⁴ Substituents are linked to form C _3-4 Cycloalkyl groups. In embodiments of the subject compounds, two R's bonded to the same atom ⁴ Substituents are linked to form a 4-to 5-membered heterocycloalkyl, wherein 4-to 5-membered heterocycloalkyl is optionally substituted with one, two or three R ^20a And (3) substitution. In a further embodiment of the subject compounds, two R's bonded to the same atom ⁴ The substituents are linked to form a 4-to 5-membered heterocycloalkyl. ThemeingIn a further embodiment of the compound, two R's bonded to the same atom ⁴ Substituents are linked to form a 4 membered heterocycloalkyl, wherein the 4 membered heterocycloalkyl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, two R's bonded to the same atom ⁴ The substituents are linked to form a 4-membered heterocycloalkyl. In some embodiments of the subject compounds, the groups bonded to the same atom are selected from R ¹ And R is ⁴ Is linked to form C _3-12 Cycloalkyl or C _1-11 Heterocycloalkyl, wherein C _3-12 Cycloalkyl and C _1-11 Heterocycloalkyl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, the groups bonded to the same atom are selected from R ⁴ Is linked to form C _3-12 Cycloalkyl or C _1-11 Heterocycloalkyl, wherein C _3-12 Cycloalkyl and C _1-11 Heterocycloalkyl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, the groups bonded to the same atom are selected from R ¹ And R is ⁶ Is linked to form C _3-12 Cycloalkyl or C _1-11 Heterocycloalkyl, wherein C _3-12 Cycloalkyl and C _1-11 Heterocycloalkyl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, the groups bonded to the same atom are selected from R ⁴ And R is ⁶ Is linked to form C _3-12 Cycloalkyl or C _1-11 Heterocycloalkyl, wherein C _3-12 Cycloalkyl and C _1-11 Heterocycloalkyl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ And R is ⁴ Is linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compoundsIn the scheme, the group bonded to adjacent atoms is selected from R ¹ And R is ⁴ Is linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl groups. In some embodiments of the subject compounds, two R's bonded to adjacent atoms ⁴ Substituents are linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, two R's bonded to adjacent atoms ⁴ Substituents are linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl groups. In some embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ And R is ⁶ Is linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ And R is ⁶ Is linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl groups. In some embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ⁴ And R is ⁶ Is linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ⁴ And R is ⁶ Is a combination of two of (2)Substituents are linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl groups.

In a further embodiment of the subject compounds, the groups bonded to the same atom are selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _3-12 Cycloalkyl or C _1-11 Heterocycloalkyl, wherein C _3-12 Cycloalkyl and C _1-11 Heterocycloalkyl is optionally substituted with one, two or three R ^20a And (3) substitution. In a further embodiment of the subject compounds, the groups bonded to the same atom are selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _3-12 Cycloalkyl or C _1-11 A heterocycloalkyl group. In further embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution. In further embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl groups. In some embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _3-12 Cycloalkyl group, wherein C _3-12 Cycloalkyl is optionally substituted with one, two or three R' s ^20a And (3) substitution. In further embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _3-12 Cycloalkyl groups. In further embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _1-11 Heterocycloalkyl, wherein C _1-11 Heterocycloalkyl is optionally substituted with one, two or three R ^20a And (3) substitution. In some embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _1-11 A heterocycloalkyl group. In further embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _6-12 Aryl group, wherein C _6-12 Aryl is optionally substituted with one, two or three R ^20a And (3) substitution. In embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _6-12 Aryl groups. In further embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _1-11 Heteroaryl, wherein C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

In further embodiments of the subject compounds, the group bonded to adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Is linked to form C _1-11 Heteroaryl groups.

In some embodiments of the subject compounds, R ¹ Is hydrogen.

In further embodiments of the subject compounds, R ⁴ Independently selected from hydrogen, halogen, oxo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, -OR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ ) and-C (O) R ¹⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with one, two or three R ^20a And (3) substitution. In embodiments of the subject compounds, R ⁴ Independently hydrogen. In further embodiments of the subject compounds, R ⁴ Independently halogen. In some embodiments of the subject compounds, R ⁴ Independently oxo. In some embodiments of the subject compounds, R ⁴ Independently is-CN. In further embodiments of the subject compounds, R ⁴ Independently C _1-6 An alkyl group. In embodiments of the subject compounds, R ⁴ Independently C _2-6 Alkenyl groups. In some embodiments of the subject compounds, R ⁴ Independently C _2-6 Alkynyl groups. In further embodiments of the subject compounds, R ⁴ Independently is-OR ¹² . In selected embodiments of the subject compounds, R ⁴ Is independently-N (R) ¹² )(R ¹³ ). In further embodiments of the subject compounds, R ⁴ Independently is-C (O) OR ¹² . In embodiments of the subject compounds, R ⁴ independently-OC (O) N (R) ¹² )(R ¹³ ). In some embodiments of the subject compounds, R ⁴ independently-C (O) R ¹⁵ . In selected embodiments of the subject compounds, R ⁴ independently-NH ₂ . In further embodiments of the subject compounds, R ⁴ independently-C (O) OH. In further embodiments of the subject compounds, R ⁴ independently-OC (O) NH ₂ . In embodiments of the subject compounds, R ⁴ independently-C (O) CH ₃ 。

In some embodiments of the subject compounds, R ⁶ Is hydrogen.

In selected embodiments of the subject compounds, L ² Is a key. In further embodiments of the subject compounds, L ² Is C ₁ -C ₆ An alkyl group.

In further embodiments of the subject compounds, R ⁵ Independently hydrogen.

In embodiments of the subject compounds, R ⁸ Is hydrogen. In some embodiments of the subject compounds, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _1-6 An alkyl group. In selected embodiments of the subject compounds, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _2-6 Alkenyl groups. In the subject compoundsIn further embodiments of (2), R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _2-6 Alkynyl groups. In some embodiments of the subject compounds, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _3-6 Cycloalkyl groups. In embodiments of the subject compounds, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _2-9 A heterocycloalkyl group. In further embodiments of the subject compounds, R ⁸ Is C _1-6 An alkyl group. In selected embodiments of the subject compounds, R ⁸ Is C _2-6 Alkenyl groups. In further embodiments of the subject compounds, R ⁸ Is C _2-6 Alkynyl groups. In some embodiments of the subject compounds, R ⁸ Is C _3-6 Cycloalkyl groups. In embodiments of the subject compounds, R ⁸ Is C _2-9 A heterocycloalkyl group.

In selected embodiments of the subject compounds, L ¹ Is a key. In further embodiments of the subject compounds, L ¹ Is C ₁ -C ₆ An alkyl group. In further embodiments of the subject compounds, L ¹ is-C (O) -. In some embodiments of the subject compounds, L ¹ Is C (R) ^1f )(R ^1g ) O. In embodiments of the subject compounds, L ¹ Is CH ₂ O。

In selected embodiments of the subject compounds, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _3-12 Cycloalkyl groups. In further embodiments of the subject compounds, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _2-11 A heterocycloalkyl group. In further embodiments of the subject compounds, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _6-12 Aryl groups. In some embodiments of the subject compounds, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _2-12 Heteroaryl groups. In embodiments of the subject compounds, R ¹⁹ Is C _3-12 Cycloalkyl groups. In selected embodiments of the subject compounds, R ¹⁹ Is C _2-11 A heterocycloalkyl group. In further embodiments of the subject compounds, R ¹⁹ Is C _6-12 Aryl groups. In some embodiments of the subject compounds, R ¹⁹ Is C _2-12 Heteroaryl groups. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted monocyclic C _3-9 Cycloalkyl groups. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted monocyclic C _1-8 A heterocycloalkyl group. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is optionally substituted with one, two, three, four or five R ¹ⁱ Substituted monocyclic phenyl. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is optionally substituted with one, two, three, four or five R ¹ⁱ Substituted monocyclic C _1-5 Heteroaryl groups. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted spirocyclic ring C _5-12 Cycloalkyl groups. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted spirocyclic ring C _2-11 A heterocycloalkyl group. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted condensed C _4-12 Cycloalkyl groups. In the subject compounds or pharmaceutically acceptable salts or solvents thereofIn further embodiments of the compounds, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted condensed C _2-11 A heterocycloalkyl group. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted condensed C _6-12 Aryl groups. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted fused 5-to 12-membered heteroaryl.

In further embodiments of the subject compounds, R ¹⁶ Is hydrogen. In embodiments of the subject compounds, R ¹⁶ Is halogen. In selected embodiments of the subject compounds, R ¹⁶ Is C _1-6 An alkyl group. In some embodiments of the subject compounds, R ¹⁶ is-OR ¹² 。

In further embodiments of the subject compounds, R ² is-O-R ^12a 。

In selected embodiments of the subject compounds, R ^12a Is optionally substituted with one, two or three R ^20d Substituted C _1-6 An alkyl group. In embodiments of the subject compounds, R ^12a Is optionally covered by one or two R ^20d Substituted methylene groups. In further embodiments of the subject compounds, R ^12a Is methylene. In some embodiments of the subject compounds, R ^12a Is optionally substituted with one, two or three R ^20d A substituted ethylene group. In embodiments of the subject compounds, R ^12a Is ethylene. In some embodiments of the subject compounds, R ^12a Is optionally substituted with one, two or three R ^20d A substituted propylene group. In embodiments of the subject compounds, R ^12a Is propylene. In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _2-9 A heterocycloalkyl group.In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (single ring C) _2-8 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (single ring C) _3-5 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (spiro C) _2-11 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (spiro C) _3-11 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (condensed C) _2-11 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (spiro C) _6-8 Heterocycloalkyl).

In selected embodiments of the compounds, R ^12a Is optionally substituted with one, two or three R ^20d Substituted C _1-6 An alkyl group. In embodiments of the compounds, R ^12a Is optionally covered by one or two R ^20d Substituted methylene groups. In further embodiments of the compounds, R ^12a Is methylene. In some embodiments of the compounds, R ^12a Is optionally substituted with one, two or three R ^20d A substituted ethylene group. In embodiments of the compounds, R ^12a Is ethylene. In some embodiments of the compounds, R ^12a Is optionally substituted with one, two or three R ^20d A substituted propylene group. In embodiments of the compounds, R ^12a Is propylene. In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _2-9 A heterocycloalkyl group. In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (single ring C) _2-8 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (single ring C) _3-5 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (spiro C) _2-11 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (spiro C) _3-11 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (condensed C) _2-11 Heterocycloalkyl). In some embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (spiro C) _6-8 Heterocycloalkyl).

In embodiments, R ^12a Is C _1-6 An alkyl group. In embodiments, R ^12a Is C _2-6 Alkenyl groups. In embodiments, R ^12a Is C _2-6 Alkynyl groups. In embodiments, R ^12a Is C _3-10 Cycloalkyl groups. In embodiments, R ^12a is-CH ₂ -C _3-10 Cycloalkyl groups. In embodiments, R ^12a Is C _2-9 A heterocycloalkyl group. In embodiments, R ^12a is-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^12a Is C _6-10 Aryl groups. In embodiments, R ^12a is-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^12a is-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^12a Is C _1-9 Heteroaryl groups.

In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d Substituted C _1-6 An alkyl group. In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d Substituted C _2-6 Alkenyl groups. In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d Substituted C _2-6 Alkynyl groups. In embodiments, R ^12a Is optionally covered withTwo or three R ^20d Substituted C _3-10 Cycloalkyl groups. In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _3-10 Cycloalkyl groups. In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d Substituted C _2-9 A heterocycloalkyl group. In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d Substituted C _6-10 Aryl groups. In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^12a Is optionally substituted with one, two or three R ^20d Substituted C _1-9 Heteroaryl groups.

In further embodiments of the subject compounds, R ^12b Is hydrogen. In selected embodiments of the compounds, R ^12b Is optionally substituted with one, two or three R ^20d Substituted C _1-6 An alkyl group. In embodiments of the compounds, R ^12b Is optionally covered by one or two R ^20d Substituted methylene groups. In further embodiments of the compounds, R ^12b Is methylene. In some embodiments of the compounds, R ^12b Is optionally substituted with one, two or three R ^20d A substituted ethylene group. In embodiments of the compounds, R ^12b Is ethylene. In some embodiments of the compounds, R ^12b Is optionally substituted with one, two or three R ^20d A substituted propylene group. In embodiments of the compounds, R ^12b Is propylene. In some embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _2-9 A heterocycloalkyl group. In some embodiments, R ^12b Is optionally covered withOne, two or three R ^20d substituted-CH ₂ - (single ring C) _2-8 Heterocycloalkyl). In some embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (single ring C) _3-5 Heterocycloalkyl). In some embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (spiro C) _2-11 Heterocycloalkyl). In some embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (spiro C) _3-11 Heterocycloalkyl). In some embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (condensed C) _2-11 Heterocycloalkyl). In some embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ - (spiro C) _6-8 Heterocycloalkyl).

In embodiments, R ^12b Is C _1-6 An alkyl group. In embodiments, R ^12b Is C _2-6 Alkenyl groups. In embodiments, R ^12b Is C _2-6 Alkynyl groups. In embodiments, R ^12b Is C _3-10 Cycloalkyl groups. In embodiments, R ^12b is-CH ₂ -C _3-10 Cycloalkyl groups. In embodiments, R ^12b Is C _2-9 A heterocycloalkyl group. In embodiments, R ^12b is-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^12b Is C _6-10 Aryl groups. In embodiments, R ^12b is-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^12b is-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^12b Is C _1-9 Heteroaryl groups.

In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d Substituted C _1-6 An alkyl group. In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d Substituted C _2-6 Alkenyl groups. In embodiments, R ^12b Is optionallyIs one, two or three R ^20d Substituted C _2-6 Alkynyl groups. In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d Substituted C _3-10 Cycloalkyl groups. In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _3-10 Cycloalkyl groups. In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d Substituted C _2-9 A heterocycloalkyl group. In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d Substituted C _6-10 Aryl groups. In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d substituted-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^12b Is optionally substituted with one, two or three R ^20d Substituted C _1-9 Heteroaryl groups.

In further embodiments of the subject compounds, X is C (R ³ ). In selected embodiments of the subject compounds, X is N.

In some embodiments of the subject compounds, R ³ Is hydrogen. In embodiments of the subject compounds, R ³ is-CN. In embodiments of the subject compounds, R ³ Is C _1-6 An alkyl group. In further embodiments of the subject compounds, R ³ Is methyl. In embodiments, R ³ Is optionally substituted with one, two or three R ^20b Substituted C _1-6 An alkyl group. In embodiments, R ³ Is optionally substituted with one, two or three R ^20b Substituted C _2-6 Alkenyl groups. In embodiments, R ³ Is optionally substituted with one, two or three R ^20b Substituted C _2-6 Alkynyl groups. In embodiments, R ³ Is optionally covered with one,Two or three R' s ^20b Substituted C _3-10 Cycloalkyl groups. In embodiments, R ³ Is optionally substituted with one, two or three R ^20b Substituted C _2-9 A heterocycloalkyl group. In embodiments, R ³ Is optionally substituted with one, two or three R ^20b Substituted C _6-10 Aryl groups. In embodiments, R ³ Is optionally substituted with one, two or three R ^20b Substituted C _1-9 Heteroaryl groups. In embodiments, R ³ is-OR ¹² . In embodiments, R ³ is-C (O) OR ¹² . In embodiments, R ³ is-OC (O) N (R) ¹² )(R ¹³ ). In embodiments, R ³ is-C (O) R ¹⁵ . In embodiments, R ³ Is halogen. In embodiments, R ³ is-N (R) ¹² )(R ¹³ ). In embodiments, R ³ is-NH ₂ 。

In further embodiments of the subject compounds, each R ¹² Independently selected from hydrogen, C _1-6 Alkyl and C _3-6 Cycloalkyl groups. In some embodiments of the subject compounds, each R ¹² Independently selected from hydrogen or C _1-6 An alkyl group. In embodiments of the subject compounds, R ¹² Independently hydrogen. In selected embodiments of the subject compounds, each R ¹³ Independently selected from hydrogen and C _1-4 An alkyl group. In some embodiments of the subject compounds, each R ¹⁴ Independently selected from hydrogen and C _1-4 An alkyl group. In further embodiments of the subject compounds, each R ¹⁵ Independently C _1-4 An alkyl group.

In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structureWherein R is ² 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In selected embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure Wherein R is ² 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure +.>Wherein R is ² 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure +.>Wherein R is ² 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In selected embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structureWherein R is ² 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In a further embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure +.>Wherein R is ² 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In a further embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure +.>Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof,the compound has the structure Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure +.>Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In selected embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure +. >Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure +.>Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structureWherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein.

In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structureWherein R is ² 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure +.>Wherein R is ² 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In selected embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure +.>Wherein R is ² 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In further embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structureWherein R is ² 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure +.>Wherein R is ² 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In selected embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure +. >Wherein R is ² 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure +.>Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In a further embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure +.>Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure +.>Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ As described herein. In selected embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structureWherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In a further embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure +.> Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ² 、R ³ 、R ⁸ 、R ¹⁰ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ¹⁰ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +. >Wherein R is ⁸ 、W、R ¹⁶ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ⁸ 、W、R ¹⁶ And R is ¹⁷ As described herein. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure orWherein R is ⁸ W and R ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ⁸ 、W、R ³ 、R ¹⁶ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ⁸ 、W、R ³ 、R ¹⁶ And R is ¹⁷ As described herein. In the practice of the subject compounds or pharmaceutically acceptable salts or solvates thereofIn the scheme, the compound has a structure orWherein R is ⁸ 、W、R ³ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ¹⁶ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ¹⁶ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +. >Wherein R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ³ 、R ¹⁶ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ³ 、R ¹⁶ And R is ¹⁷ As described herein. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.>Wherein R is ³ And R is ¹⁷ As described herein.

In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, the compounds have the structure orWherein R is ¹⁶ And R is ¹⁰ As described herein. In an embodiment of formula (XVI), R ¹⁶ Is F and R ¹⁰ Is covered by one R ⁶ Substituted and optionally substituted by one, two or three R ⁴ Substituted 10 membered spirocyclic bicycloheterocycloalkyl. In an embodiment of formula (XVI), R ¹⁶ Is F and R ¹⁰ Is optionally substituted with one, two or three R ⁴ Substituted 10 membered fused bicyclic heterocycloalkyl. In an embodiment of formula (XVI), R ¹⁶ Is F and R ¹⁰ Is optionally substituted with one, two or three R ⁴ Substituted 11-membered fused bicyclic heterocycloalkyl. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +. >Wherein R is ¹⁶ And R is ¹⁰ As described herein. In an embodiment of formula (XVII), R ¹⁶ Is F and R ¹⁰ Is covered by one R ⁶ Substituted and optionally substituted by one, two or three R ⁴ Substituted 10 membered spirocyclic bicycloheterocycloalkyl. In an embodiment of formula (XVII), R ¹⁶ Is F and R ¹⁰ Is optionally substituted with one, two or three R ⁴ Substituted 10 membered fused bicyclic heterocycloalkyl. In an embodiment of formula (XVII), R ¹⁶ Is F and R ¹⁰ Is optionally substituted with one, two or three R ⁴ Substituted 11-membered fused bicyclic heterocycloalkyl. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +.> Wherein R is ¹⁶ And R is ¹⁰ As described herein. In an embodiment of formula (XVIII), R ¹⁶ Is F and R ¹⁰ Is covered by one R ⁶ Substituted and optionally substituted by one, two or three R ⁴ Substituted 10 membered spirocyclic bicycloheterocycloalkyl. In an embodiment of formula (XVIII), R ¹⁶ Is F and R ¹⁰ Is optionally substituted with one, two or three R ⁴ Substituted 10 membered fused bicyclic heterocycloalkyl. In an embodiment of formula (XVIII), R ¹⁶ Is F and R ¹⁰ Is optionally substituted with one, two or three R ⁴ Substituted 11-membered fused bicyclic heterocycloalkyl. In an embodiment of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or +. >Wherein R is ¹⁶ And R is ¹⁰ As described herein. In an embodiment of formula (XIX), R ¹⁶ Is F and R ¹⁰ Is covered by one R ⁶ Substituted and optionally substituted by one, two or three R ⁴ Substituted 10 membered spirocyclic bicycloheterocycloalkyl. In an embodiment of formula (XIX), R ¹⁶ Is F and R ¹⁰ Is optionally substituted with one, two or three R ⁴ Substituted 10 membered fused bicyclic heterocycloalkyl. In an embodiment of formula (XIX), R ¹⁶ Is F and R ¹⁰ Is optionally substituted with one, two or three R ⁴ Substituted 11-membered fused bicyclic heterocycloalkyl.

In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is thatWherein X is ¹ 、X ² 、X ³ 、R ⁴ And p is as described herein. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is->Wherein X is ¹ 、X ² 、X ³ 、R ⁴ And p is as described herein. In selected embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is->Wherein X is ² 、X ³ 、R ⁴ And p is as described herein. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is->Wherein X is ² 、X ³ 、R ⁴ And p is as described herein. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is->Wherein X is ² 、X ³ 、R ⁴ And p is as described herein. In selected embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is->Wherein X is ¹ 、X ² 、X ³ 、R ⁴ And p is as described herein. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is thatWherein X is ¹ 、X ² 、R ⁴ And p is as described herein.

In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is thatWherein X is ¹ 、X ² 、X ³ 、R ⁴ And p is asAs described herein. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is->Wherein X is ¹ 、X ² 、X ³ 、R ⁴ And p is as described herein. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is->Wherein X is ² 、X ³ 、R ⁴ And p is as described herein. In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is thatWherein X is ² 、X ³ 、R ⁴ And p is as described herein. In selected embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is->Wherein X is ² 、X ³ 、R ⁴ And p is as described herein. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is->Wherein X is ¹ 、X ² 、X ³ 、R ⁴ And p is as described herein. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁷ Is thatWherein X is ¹ 、X ² 、R ⁴ And p is as described herein. />

In further embodiments of the subject compounds, p is an integer from 0 to 4. In embodiments of the subject compounds, p is 0. In selected embodiments of the subject compounds, p is 1. In some embodiments of the subject compounds, p is 2. In embodiments of the subject compounds, p is 3. In further embodiments of the subject compounds, p is 4.

In embodiments of the subject compounds, X ¹ Selected from CH ₂ 、C(R ⁴ )(R ⁶ )、CH ₂ C(R ⁴ )(R ⁶ )、CH ₂ C(R ⁴ )(R ⁶ )CH ₂ 、C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )N(R ⁴ )、C(R ⁴ )(R ⁶ )N(R ⁶ )、C(R ⁴ )(R ⁶ )O、C(R ⁴ )(R ⁶ )OC(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁶ )S、C(R ⁴ )(R ⁶ )SC(R ⁴ )(R ⁶ )、C(R ⁴ )(R ⁴ )、CH ₂ C(R ⁴ )(R ⁴ )、CH ₂ C(R ⁴ )(R ⁴ )CH ₂ 、C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ )C(O)N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁴ )、C(R ⁴ )(R ⁴ )N(R ⁶ )、C(R ⁴ )(R ⁴ )O、C(R ⁴ )(R ⁴ )OC(R ⁴ )(R ⁴ )、C(R ⁴ )(R ⁴ ) S and C (R) ⁴ )(R ⁴ )SC(R ⁴ )(R ⁴ )。

In further embodiments of the subject compounds, X ¹ Is CH ₂ . In some embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁶ ). In selected embodiments of the subject compounds, X ¹ Is CH ₂ C(R ⁴ )(R ⁶ ). In further embodiments of the subject compounds, X ¹ Is CH ₂ C(R ⁴ )(R ⁶ )CH ₂ . In embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁶ ). In selected embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁶ )N(R ⁴ ). In further embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁶ )N(R ⁶ ). In some embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁶ ) O. In selected embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁶ )OC(R ⁴ )(R ⁶ ). In embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁶ ) S, S. In further embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁶ )SC(R ⁴ )(R ⁶ ). In embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁴ ). In further embodiments of the subject compounds, X ¹ Is CH ₂ C(R ⁴ )(R ⁴ ). In selected embodiments of the subject compounds, X ¹ Is CH ₂ C(R ⁴ )(R ⁴ )CH ₂ . In embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁴ )C(R ⁴ )(R ⁶ )C(R ⁴ )(R ⁴ ). In some embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ )C(R ⁴ )(R ⁴ ). In embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁴ )C(O)N(R ⁴ ). In further embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁴ )N(R ⁴ ). In further embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁴ )N(R ⁶ ). In embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁴ ) O. In some embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁴ )OC(R ⁴ )(R ⁴ ). In selected embodiments of the subject compounds，X ¹ Is C (R) ⁴ )(R ⁴ ) S, S. In some embodiments of the subject compounds, X ¹ Is C (R) ⁴ )(R ⁴ )SC(R ⁴ )(R ⁴ )。

In selected embodiments of the subject compounds, X ² Is N. In embodiments of the subject compounds, X ² Is C. In further embodiments of the subject compounds, X ² Is C (R) ⁶ ). In further embodiments of the subject compounds, X ² Is C (R) ⁴ ). In some embodiments of the subject compounds, X ² Is CH. In selected embodiments of the subject compounds, X ² Is N (R) ¹ ). In embodiments of the subject compounds, X ² Is N (R) ⁴ ). In selected embodiments of the subject compounds, X ² Is N (R) ⁶ ). In further embodiments of the subject compounds, X ² Is O. In further embodiments of the subject compounds, X ² Is S. In some embodiments of the subject compounds, X ² S (O). In embodiments of the subject compounds, X ² Is C (H) (R) ⁶ ). In embodiments of the subject compounds, X ² Is C (R) ⁴ ) ₂ . In embodiments of the subject compounds, X ² Is CH ₂ . In selected embodiments of the subject compounds, X ² Is C (R) ⁴ )(R ⁶ ). In further embodiments of the subject compounds, X ² Is S (=O) (=NR ⁴ ). In embodiments of the subject compounds, X ² Is S (O) ₂ 。

In further embodiments of the subject compounds, X ³ Is N. In some embodiments of the subject compounds, X ³ Is C. In selected embodiments of the subject compounds, X ³ Is C (R) ⁶ ). In selected embodiments of the subject compounds, X ³ Is C (R) ⁴ )。

In embodiments of the subject compounds, R ⁷ Is thatWherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ⁷ Is thatWherein R is ⁴ And p is as described herein. In selected embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In selected embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In selected embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ⁷ Is->Wherein the method comprises the steps ofR ⁴ And p is as described herein. In further embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ⁷ Is thatWherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In selected embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ⁷ Is->Wherein R is ⁴ And p is as described herein.

In some embodiments of the subject compounds, R ⁷ Is thatIn embodiments of the subject compounds, R ⁷ Is thatIn further embodiments of the subject compounds, R ⁷ Is->In further embodiments of the subject compounds, R ⁷ Is->In selected embodiments of the subject compounds, R ⁷ Is->In some embodiments of the subject compounds, R ⁷ Is->In embodiments of the subject compounds, R ⁷ Is->In embodiments of the subject compounds, R ⁷ Is->In further embodiments of the subject compounds, R ⁷ Is->In selected embodiments of the subject compounds, R ⁷ Is->In further embodiments of the subject compounds, R ⁷ Is->In some embodiments of the subject compounds, R ⁷ Is->In embodiments of the subject compounds, R ⁷ Is->In the subject compoundsIn some embodiments, R ⁷ Is thatIn further embodiments of the subject compounds, R ⁷ Is->In selected embodiments of the subject compounds, R ⁷ Is->In some embodiments of the subject compounds, R ⁷ Is->In further embodiments of the subject compounds, R ⁷ Is->In embodiments of the subject compounds, R ⁷ Is->In some embodiments of the subject compounds, R ⁷ Is->In further embodiments of the subject compounds, R ⁷ Is->In selected embodiments of the subject compounds, R ⁷ Is->In some embodiments of the subject compounds, R ⁷ Is->In embodiments of the subject compounds, R ⁷ Is->In embodiments of the subject compounds, R ⁷ Is->In further embodiments of the subject compounds, R ⁷ Is->In further embodiments of the subject compounds, R ⁷ Is->

In selected embodiments of the subject compounds, R ¹⁰ Is thatWherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ¹⁰ Is thatWherein R is ⁴ And p is as described herein. In selected embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ¹⁰ Is thatWherein R is ⁴ And p is as described herein. In selected embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein.In further embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In selected embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In some embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In embodiments of the subject compounds, R ¹⁰ Is thatWherein R is ⁴ And p is as described herein. In further embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein. In selected embodiments of the subject compounds, R ¹⁰ Is->Wherein R is ⁴ And p is as described herein.

In further embodiments of the subject compounds, R ¹⁰ Is thatIn some embodiments of the subject compounds, R ¹⁰ Is->In embodiments of the subject compounds, R ¹⁰ Is->In embodiments of the subject compounds, R ¹⁰ Is thatIn selected embodiments of the subject compounds, R ¹⁰ Is->In further embodiments of the subject compounds, R ¹⁰ Is->In further embodiments of the subject compounds, R ¹⁰ Is->In embodiments of the subject compounds, R ¹⁰ Is thatIn some embodiments of the subject compounds, R ¹⁰ Is->In some embodiments of the subject compounds, R ¹⁰ Is thatIn selected embodiments of the subject compounds, R ¹⁰ Is->In some embodiments of the subject compounds, R ¹⁰ Is->In embodiments of the subject compounds, R ¹⁰ Is->In further embodiments of the subject compounds, R ¹⁰ Is->In further embodiments of the subject compounds, R ¹⁰ Is->In some embodiments of the subject compounds, R ¹⁰ Is->In selected embodiments of the subject compounds, R ¹⁰ Is->In embodiments of the subject compounds, R ¹⁰ Is->In some embodiments of the subject compounds, R ¹⁰ Is->In further embodiments of the subject compounds, R ¹⁰ Is->In embodiments of the subject compounds, R ¹⁰ Is->In further embodiments of the subject compounds, R ¹⁰ Is->In embodiments of the subject compounds, R ¹⁰ Is->In selected embodiments of the subject compounds, R ¹⁰ Is->In some embodiments of the subject compounds, R ¹⁰ Is thatIn further embodiments of the subject compounds, R ¹⁰ Is->In some embodiments of the subject compounds, R ¹⁰ Is->

In embodiments of the subject compounds, R ¹⁰ Is thatIn selected embodiments of the subject compounds, R ¹⁰ Is->

In embodiments, R ¹⁰ Independently selected from/>

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Is hydrogen. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Is halogen. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ¹⁶ Is fluorine.

In embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is hydrogen. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is methyl. In selected embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is cyclopropyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is cyclobutyl. In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is oxetanyl.

In further embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted methyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted cyclopropyl. In selected embodiments of the subject compounds or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted cyclobutyl. At the position ofIn some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted oxetanyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ is-CN. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ is-CH ₂ CN. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ is-CH ₂ CH ₂ CN. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ is-CH ₂ CH ₂ CH ₂ CN. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ is-CH ₂ CH ₂ CH ₂ CH ₂ CN. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is- (C) ₁ -C ₆ Alkyl) -CN. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted cyclopropyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is cyclopropyl substituted with CN. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is quilt- (C) ₁ -C ₆ Alkyl) -CN substituted cyclopropyl. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is C ₁ -C ₆ A haloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is C ₁ -C ₂ A haloalkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is C ₁ -C ₆ An alkyl group. In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is- (C) ₁ -C ₆ Alkyl) -C (O) NH ₂ . In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is- (C) ₁ -C ₆ Alkyl) - (C ₃ -C ₆ Cycloalkyl). In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, R ⁸ Is- (C) ₁ -C ₂ Alkyl) - (C ₃ -C ₄ Cycloalkyl). In embodiments, R ⁸ Is hydrogen. In embodiments, R ⁸ Is halogen. In embodiments, R ⁸ is-CN. In embodiments, R ⁸ Is C _1-6 An alkyl group. In embodiments, R ⁸ Is C _2-6 Alkenyl groups. In embodiments, R ⁸ Is C _2-6 Alkynyl groups. In embodiments, R ⁸ Is C _3-6 Cycloalkyl groups. In embodiments, R ⁸ Is C _2-9 A heterocycloalkyl group. In embodiments, R ⁸ Is C _6-10 Aryl groups. In embodiments, R ⁸ Is C _1-9 Heteroaryl groups. In embodiments, R ⁸ is-OR ¹² . In embodiments, R ⁸ is-SR ¹² . In embodiments, R ⁸ is-N (H) (R) ¹² ). In embodiments, R ⁸ is-C (O) OR ¹² . In embodiments, R ⁸ is-OC (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁸ is-N (R) ¹⁴ )C(O)N(R ¹² )(R ¹³ ). In embodiments, R ⁸ is-N (R) ¹⁴ )C(O)OR ¹⁵ . In embodiments, R ⁸ is-N (R) ¹⁴ )S(O) ₂ R ¹⁵ . In embodiments, R ⁸ is-C (O) R ¹⁵ . In embodiments, R ⁸ is-S (O) R ¹⁵ . In embodiments, R ⁸ is-OC (O) R ¹⁵ . In embodiments, R ⁸ is-C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁸ is-C (O) C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ⁸ is-N (R) ¹⁴ )C(O)R ¹⁵ . In embodiments, R ⁸ is-S%O) ₂ R ¹⁵ . In embodiments, R ⁸ is-S (O) ₂ N(R ¹² )(R ¹³ ) -. In embodiments, R ⁸ Is S (=o) (=nh) N (R ¹² )(R ¹³ ). In embodiments, R ⁸ is-CH ₂ C(O)N(R ¹² )(R ¹³ ). In embodiments, R ⁸ is-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ . In embodiments, R ⁸ is-CH ₂ S(O) ₂ R ¹⁵ . In embodiments, R ⁸ is-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ). In embodiments, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _1-6 An alkyl group. In embodiments, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _2-6 Alkenyl groups. In embodiments, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _2-6 Alkynyl groups. In embodiments, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _3-6 Cycloalkyl groups. In embodiments, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _2-9 A heterocycloalkyl group. In embodiments, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _6-10 Aryl groups. In embodiments, R ⁸ Is optionally substituted with one, two or three R ^20c Substituted C _1-9 Heteroaryl groups.

In some embodiments, L ¹ Is a key. In some embodiments, L ¹ Is C ₁ -C ₆ An alkyl group. In some embodiments, L ¹ Is C ₂ -C ₆ Alkenyl groups. In some embodiments, L ¹ Is C ₂ -C ₆ Alkynyl groups. In some embodiments, L ¹ is-O-. In some embodiments, L ¹ is-N (R) ¹⁴ ) -. In some embodiments, L ¹ is-C (O) -. In some embodiments, L ¹ is-N (R) ¹⁴ ) C (O) -. In some embodiments, L ¹ is-C (O) N (R) ¹⁴ ) -. In some embodiments, L ¹ is-S-. In some embodiments, L ¹ is-S (O) ₂ -. In some embodiments, L ¹ is-S (O) -. In some embodiments, L ¹ is-S (O) ₂ N(R ¹⁴ ) -. In some embodiments, L ¹ is-S (O) N (R) ¹⁴ ) -. In some embodiments, L ¹ is-N (R) ¹⁴ ) S (O) -. In some embodiments, L ¹ is-N (R) ¹⁴ )S(O) ₂ -. In some embodiments, L ¹ is-OCON (R) ¹⁴ ) -. In some embodiments, L ¹ is-N (R) ¹⁴ ) C (O) O-. In some embodiments, L ¹ Is N (R) ^1e ). In some embodiments, L ¹ Is C (O) N (R) ^1c ). In some embodiments, L ¹ Is S (O) ₂ N(R ^1c ). In some embodiments, L ¹ Is S (O) N (R) ^1c ). In some embodiments, L ¹ Is C (R) ^1f )(R ^1g ) O. In some embodiments, L ¹ Is C (R) ^1f )(R ^1g )N(R ^1c ). In some embodiments, L ¹ Is C (R) ^1f )(R ^1g ). In some embodiments, L ¹ is-NH-. In some embodiments, L ¹ is-NHC (O) -. In some embodiments, L ¹ is-C (O) NH-. In some embodiments, L ¹ is-S (O) ₂ NH-. In some embodiments, L ¹ is-S (O) NH-. In some embodiments, L ¹ is-NHS (O) -. In some embodiments, L ¹ is-NHS (O) ₂ -. In some embodiments, L ¹ is-OCONH-. In some embodiments, L ¹ is-NHC (O) O-. In some embodiments, L ¹ Is CH ₂ O. In some embodiments, L ¹ Is CH ₂ NH. In some embodiments, L ¹ Is CH ₂ . In some embodiments of the subject compounds, or pharmaceutically acceptable salts or solvates thereof, L ¹ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -C (O) -, -NHC (O) -, -C (O) NH-, CH ₂ O、CH ₂ NH and CH ₂ 。

In embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, R ¹⁹ The method comprises the following steps:

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

Each R ^1a 、R ^1b 、R ^1d 、R ^1f 、R ^1g And R is ^1h Each independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R bonded to the same carbon ^1a And R is ^1b To form a 3-to 10-membered heterocycloalkyl ring or C _3-10 Cycloalkyl rings, wherein 3-10 membered heterocycloalkyl ring or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or two R's bonded to adjacent atoms ^1a To form a 3-to 10-membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring wherein 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or R is ^1h With R bound to adjacent atoms ^1a 、R ^1b 、R ^1c And R is ^1d Is linked to form a 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring wherein 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring and C _3-10 Cycloalkyl ring radicalOptionally by one, two or three R ²⁰ⁱ Substitution; or R is ^1f And R is ^1g To form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or the 4-7 membered cycloalkyl ring is optionally substituted with one, two or three R ²⁰ⁱ Substitution; and is also provided with

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

In embodiments, R ^1h Selected from hydrogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, -N (R) ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-C(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ C(O)N(R ¹² )(R ¹³ ) and-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with one, two or three R ²⁰ⁱ And (3) substitution.

In embodiments, R ^1h Selected from hydrogen and-N (R) ¹² )(R ¹³ ). In embodiments, R ^1h Is hydrogen. In embodiments, R ^1h is-N (R) ¹² )(R ¹³ ). In embodiments, R ^1h is-NH ₂ 。

In embodiments, R ^1d Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution. In embodiments, R ^1d Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution. In embodiments, R ^1d Independently selected from hydrogen, -CN, C _1-6 Alkyl and C _1-6 Haloalkyl group wherein C _1-6 Alkyl is optionally substituted with one, two or three R ²⁰ⁱ And (3) substitution. In embodiments, R ^1d Independently hydrogen. In embodiments, R ^1d Independently is-CN.

In some embodiments, R ¹⁹ Selected from:/>

/>

in some embodiments, R ¹⁹ Selected from the group consisting of

/>

In some embodiments, R ¹⁹ Selected from:

/>

in some embodiments, R ¹⁹ Selected from the group consisting of

/>

In some embodiments of the compound or pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is a single ring. In some embodiments of the compound or pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is a bicyclic ring system. In some embodiments of the compound or pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is a polycyclic system.

In selected embodiments of the compounds, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _3-12 Cycloalkyl groups. In further embodiments of the compounds, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _2-11 A heterocycloalkyl group. In further embodiments of the compounds, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _6-12 Aryl groups. In some embodiments of the compounds, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _2-12 Heteroaryl groups. In embodiments of the compounds, R ¹⁹ Is C _3-12 Cycloalkyl groups. In selected embodiments of the compounds, R ¹⁹ Is C _2-11 A heterocycloalkyl group. In further embodiments of the compounds, R ¹⁹ Is C _6-12 Aryl groups. In some embodiments of the compounds, R ¹⁹ Is C _2-12 Heteroaryl groups. In some embodiments of the compound or pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted monocyclic C _3-9 Cycloalkyl groups. In embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted monocyclic C _1-8 A heterocycloalkyl group. In further embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally covered withTwo, three, four or five R' s ¹ⁱ Substituted monocyclic phenyl. In further embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally substituted with one, two, three, four or five R ¹ⁱ Substituted monocyclic C _1-5 Heteroaryl groups. In some embodiments of the compound or pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted spirocyclic ring C _5-12 Cycloalkyl groups. In embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted spirocyclic ring C _2-11 A heterocycloalkyl group. In further embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted condensed C _5-12 Cycloalkyl groups. In further embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted condensed C _2-11 A heterocycloalkyl group. In further embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted condensed C _6-12 Aryl groups. In some embodiments of the compound or pharmaceutically acceptable salt or solvate thereof, R ¹⁹ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted fused 5-to 12-membered heteroaryl.

In embodiments, R ¹⁹ Is thatIn embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is thatIn embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is thatIn embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is thatIn embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is thatIn embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is thatIn embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is thatIn embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is thatIn embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is thatIn embodiments, R ¹⁹ Is->In embodiments, R ¹⁹ Is->

In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is- >In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some implementationsIn embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is thatIn some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In some embodiments, R ¹⁹ Is->In one placeIn some embodiments, R ¹⁹ Is->

In some embodiments of the compound or pharmaceutically acceptable salt or solvate thereof, R ¹⁹ The method comprises the following steps:

in embodiments of the subject compounds, R ¹⁹ Is thatWherein X is ⁴ 、X ⁵ 、X ⁶ 、X ⁹ And X ¹⁰ As described herein. In embodiments of the subject compounds, R ¹⁹ Is->Wherein X is ⁴ 、X ⁵ 、X ⁶ 、X ⁹ 、X ¹⁰ 、X ¹¹ And X ¹² As described herein. In embodiments of the subject compounds, R ¹⁹ Is->Wherein X is ⁴ 、X ⁵ 、X ⁶ 、Q ¹ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is->Wherein X is ⁴ 、X ⁵ 、X ⁶ 、Q ¹ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is- >Wherein X is ⁹ 、X ¹⁰ 、X ¹¹ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is->Wherein X is ⁹ 、X ¹⁰ 、X ¹¹ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is->Wherein X is ⁷ 、X ⁸ 、X ¹² 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is->Wherein X is ⁷ 、X ⁸ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is->Wherein X is ⁷ 、X ⁸ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is->Wherein X is ⁷ 、X ⁸ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is thatWherein Q is ³ 、Q ⁴ 、Q ⁵ 、Q ⁶ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is thatWherein X is ⁴ 、X ⁵ 、X ⁶ 、Q ³ And Q ⁴ As described herein. In embodiments of the subject compounds, R ¹⁹ Is thatWherein X is ⁴ 、X ⁵ 、X ⁶ 、Q ³ And Q ⁴ As described herein. In embodiments of the subject compounds, R ¹⁹ Is thatWherein, Q ³ 、Q ⁴ 、Q ⁵ 、Q ⁶ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁹ Is->Wherein, Q ³ 、Q ⁴ 、X ¹³ 、X ¹⁴ 、X ¹⁵ 、R ^1a And R is ^1h As described herein.

In embodiments of the subject compounds, R ¹⁹ Is thatIn some embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is->In selected embodiments of the subject compounds, R ¹⁹ Is thatIn embodiments of the subject compounds, R ¹⁹ Is->In some embodiments of the subject compounds, R ¹⁹ Is->In some embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is->In selected embodiments of the subject compounds, R ¹⁹ Is thatIn embodiments of the subject compounds, R ¹⁹ Is->In some embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is->In some embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is->In embodiments of the subject compounds, R ¹⁹ Is->In selected embodiments of the subject compounds, R ¹⁹ Is thatIn some embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is->In embodiments of the subject compounds, R ¹⁹ Is->In embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is->In selected embodiments of the subject compounds, R ¹⁹ Is->In some embodiments of the subject compounds, R ¹⁹ Is thatIn further embodiments of the subject compounds, R ¹⁹ Is- >In embodiments of the subject compounds, R ¹⁹ Is->In some embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is->In selected embodiments of the subject compounds, R ¹⁹ Is thatIn some embodiments of the subject compounds, R ¹⁹ Is->In embodiments of the subject compounds, R ¹⁹ Is->In some embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is->In further embodiments of the subject compounds, R ¹⁹ Is thatIn the subject compoundsIn selected embodiments, R ¹⁹ Is->In embodiments of the subject compounds, R ¹⁹ Is->In some embodiments of the subject compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is thatIn some embodiments of the compounds, R ¹⁹ Is- >In some embodiments of the compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is->In some embodiments of the compounds, R ¹⁹ Is->In embodiments of the compounds, R ¹⁹ Is->In embodiments of the compounds, R ¹⁹ Is thatIn embodiments of the compounds, R ¹⁹ Is->In embodiments of the compounds, R ¹⁹ Is thatIn embodiments of the compounds, R ¹⁹ Is->In embodiments of the compounds, R ¹⁹ Is thatIn embodiments of the compounds, R ¹⁹ Is->In embodiments of the compounds, R ¹⁹ Is thatIn embodiments of the compounds, R ¹⁹ Is->In embodiments of the compounds, R ¹⁹ Is thatIn embodiments of the compounds, R ¹⁹ Is->In embodiments of the compounds, R ¹⁹ Is->In embodiments of the compounds, R ¹⁹ Is->In embodiments of the compounds, R ¹⁹ Is that

In embodiments, R ¹⁹ Selected from the group consisting of

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In some embodiments, R ¹⁹ Selected from:

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in some embodiments, R ¹⁹ Selected from:

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in some embodiments, R ¹⁹ Selected from:

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in embodiments, R ¹⁷ Is a fused bicyclic ring C _5-12 Cycloalkyl groups. In embodiments, R ¹⁷ Is a fused bicyclic ring C _2-11 A heterocycloalkyl group. In embodiments, R ¹⁷ Is a fused bicyclic ring C _7-12 Aryl groups. In embodiments, R ¹⁷ Is a fused bicyclic ring C _2-12 Heteroaryl groups.

In embodiments, R ¹⁷ Is one, two, three, four, five, six or seven R ¹ⁱ Substituted fused bicyclic ring C _5-12 Cycloalkyl groups. In embodiments, R ¹⁷ Is one, two, three, four, five, six or seven R ¹ⁱ Substituted fused bicyclic ring C _2-11 A heterocycloalkyl group. In embodiments, R ¹⁷ Is one, two, three, four, five, six or seven R ¹ⁱ Substituted fused bicyclic ring C _7-12 Aryl groups. In embodiments, R ¹⁷ Is one, two, three, four, five, six or seven R ¹ⁱ Substituted fused bicyclic ring C _2-12 Heteroaryl groups.

In embodiments, R ¹⁷ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted fused bicyclic ring C _5-12 Cycloalkyl groups. In embodiments, R ¹⁷ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted fused bicyclic ring C _2-11 A heterocycloalkyl group. In embodiments, R ¹⁷ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted fused bicyclic ring C _7-12 Aryl groups. In embodiments, R ¹⁷ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted fused bicyclic ring C _2-12 Heteroaryl groups.

In embodiments, R ¹⁷ Is C _3-12 Cycloalkyl groups. In embodiments, R ¹⁷ Is C _2-11 A heterocycloalkyl group. In embodiments, R ¹⁷ Is C _6-12 Aryl groups. In embodiments, R ¹⁷ Is C _2-12 Heteroaryl groups.

In embodiments, R ¹⁷ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _3-12 Cycloalkyl groups. In embodiments, R ¹⁷ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _2-11 A heterocycloalkyl group. In embodiments, R ¹⁷ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _6-12 Aryl groups. In embodiments, R ¹⁷ Is optionally substituted with one, two, three, four, five, six or seven R' s ¹ⁱ Substituted C _2-12 Heteroaryl groups.

In embodiments, R ¹⁷ Is one, two, three, four, five, six or seven R ¹ⁱ Substituted C _3-12 Cycloalkyl groups. In embodiments, R ¹⁷ Is one, two, three, four, five, six or seven R ¹ⁱ Substituted C _2-11 A heterocycloalkyl group. In embodiments, R ¹⁷ Is one, two, three, four, five, six or seven R ¹ⁱ Substituted C _6-12 Aryl groups. In embodiments, R ¹⁷ Is one, two, three, four, five, six or seven R ¹ⁱ Substituted C _2-12 Heteroaryl groups.

In embodiments, R ¹ⁱ Independently hydrogen. In embodiments, R ¹ⁱ Independently halogen. In embodiments, R ¹ⁱ Independently oxo. In embodiments, R ¹ⁱ Independently is-CN. In embodiments, R ¹ⁱ Independently C _1-6 An alkyl group. In embodiments, R ¹ⁱ Independently C _2-6 Alkenyl groups. In embodiments, R ¹ⁱ Independently C _2-6 Alkynyl groups. In embodiments, R ¹ⁱ Independently C _3-10 Cycloalkyl groups. In embodiments, R ¹ⁱ Independently C _2-9 A heterocycloalkyl group. In embodiments, R ¹ⁱ Independently C _6-10 Aryl groups. In embodiments, R ¹ⁱ Independently C _1-9 Heteroaryl groups.

In embodiments, R ¹ⁱ Independently are optionally substituted with one, two or three R ²⁰ⁱ Substituted C _1-6 An alkyl group. In embodiments, R ¹ⁱ Independently are optionally substituted with one, two or three R ²⁰ⁱ Substituted C _2-6 Alkenyl groups. In embodiments, R ¹ⁱ Independently are optionally substituted with one, two or three R ²⁰ⁱ Substituted C _2-6 Alkynyl groups. In embodiments, R ¹ⁱ Independently are optionally substituted with one, two or three R ²⁰ⁱ Substituted C _3-10 Cycloalkyl groups. In embodiments, R ¹ⁱ Independently are optionally substituted with one, two or three R ²⁰ⁱ Substituted C _2-9 A heterocycloalkyl group. In embodiments, R ¹ⁱ Independently are optionally substituted with one, two or three R ²⁰ⁱ Substituted C _6-10 Aryl groups. In embodiments, R ¹ⁱ Independently are optionally substituted with one, two or three R ²⁰ⁱ Substituted C _1-9 Heteroaryl groups.

In embodiments, R ¹ⁱ Independently is-OR ¹² . In embodiments, R ¹ⁱ independently-SR ¹² . In embodiments, R ¹ⁱ Is independently-N (R) ¹² )(R ¹³ ). In embodiments, R ¹ⁱ Independently is-C (O) OR ¹² . In embodiments, R ¹ⁱ independently-OC (O) N (R) ¹² )(R ¹³ ). In embodiments, R ¹ⁱ Is independently-N (R) ¹⁴ )C(O)N(R ¹² )(R ¹³ ). In embodiments, R ¹ⁱ Is independently-N (R) ¹⁴ )C(O)OR ¹⁵ . In embodiments, R ¹ⁱ Is independently-N (R) ¹⁴ )S(O) ₂ R ¹⁵ . In embodiments, R ¹ⁱ independently-C (O) R ¹⁵ . In embodiments, R ¹ⁱ Independently is-S (O) R ¹⁵ . In embodiments, R ¹ⁱ independently-OC (O) R ¹⁵ . In embodiments, R ¹ⁱ independently-C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ¹ⁱ independently-C (O) C (O) N (R) ¹² )(R ¹³ ). In embodiments, R ¹ⁱ Is independently-N (R) ¹⁴ )C(O)R ¹⁵ . In embodiments, R ¹ⁱ Independently is-S (O) ₂ R ¹⁵ . In embodiments, R ¹ⁱ Independently is-S (O) ₂ N(R ¹² )(R ¹³ ). In embodiments, R ¹ⁱ Independently S (=o) (=nh) N (R ¹² )(R ¹³ ). In embodiments, R ¹ⁱ Is independently-CH ₂ C(O)N(R ¹² )(R ¹³ ). In embodiments, R ¹ⁱ Is independently-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ . In embodiments, R ¹ⁱ Is independently-CH ₂ S(O) ₂ R ¹⁵ . In embodiments, R ¹ⁱ Is independently-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ )。

In embodiments of the subject compounds, R ¹⁷ Is thatWherein X is ⁴ 、X ⁵ 、X ⁶ 、X ⁹ And X ¹⁰ As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein X is ⁴ 、X ⁵ 、X ⁶ 、X ⁹ 、X ¹⁰ 、X ¹¹ And X ¹² As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein X is ⁴ 、X ⁵ 、X ⁶ 、Q ¹ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein X is ⁴ 、X ⁵ 、X ⁶ 、Q ¹ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein X is ⁹ 、X ¹⁰ 、X ¹¹ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein X is ⁹ 、X ¹⁰ 、X ¹¹ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein X is ⁷ 、X ⁸ 、X ¹² 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein X is ⁷ 、X ⁸ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein X is ⁷ 、X ⁸ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein X is ⁷ 、X ⁸ 、Q ³ 、Q ⁴ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is thatWherein Q is ³ 、Q ⁴ 、Q ⁵ 、Q ⁶ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is thatWherein X is ⁴ 、X ⁵ 、X ⁶ 、Q ³ And Q ⁴ As described herein. In embodiments of the subject compounds, R ¹⁷ Is thatWherein X is ⁴ 、X ⁵ 、X ⁶ 、Q ³ And Q ⁴ As described herein. In embodiments of the subject compounds, R ¹⁷ Is thatWherein Q is ³ 、Q ⁴ 、Q ⁵ 、Q ⁶ And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein Q is ³ 、Q ⁴ 、X ¹³ 、X ¹⁴ 、X ¹⁵ 、R ^1a And R is ^1h As described herein. In embodiments of the subject compounds, R ¹⁷ Is->Wherein Q is ³ 、Q ⁴ 、X ¹³ 、X ¹⁴ 、X ¹⁵ 、X ¹⁶ 、R ^1a And R is ^1h As described herein.

In some embodiments of the subject compounds, R ¹⁷ Is thatIn the subject matter of chemical combinationIn selected embodiments of the substance, R ¹⁷ Is->In further embodiments of the subject compounds, R ¹⁷ Is->In embodiments of the subject compounds, R ¹⁷ Is->In further embodiments of the subject compounds, R ¹⁷ Is thatIn some embodiments of the subject compounds, R ¹⁷ Is->In embodiments of the subject compounds, R ¹⁷ Is->In selected embodiments of the subject compounds, R ¹⁷ Is->In embodiments of the subject compounds, R ¹⁷ Is->In further embodiments of the subject compounds, R ¹⁷ Is thatIn some embodiments of the subject compounds, R ¹⁷ Is->In further embodiments of the subject compounds, R ¹⁷ Is->In some embodiments of the subject compounds, R ¹⁷ Is->In embodiments of the subject compounds, R ¹⁷ Is->In selected embodiments of the subject compounds, R ¹⁷ Is->In further embodiments of the subject compounds, R ¹⁷ Is->In some embodiments of the subject compounds, R ¹⁷ Is->In embodiments of the subject compounds, R ¹⁷ Is->In embodiments of the subject compounds, R ¹⁷ Is thatIn further embodiments of the subject compounds, R ¹⁷ Is->In selected embodiments of the subject compounds, R ¹⁷ Is->In further embodiments of the subject compounds, R ¹⁷ Is->In some embodiments of the subject compounds, R ¹⁷ Is->In embodiments of the subject compounds, R ¹⁷ Is->In some embodiments of the subject compounds, R ¹⁷ Is->In further embodiments of the subject compounds, R ¹⁷ Is thatIn selected embodiments of the subject compounds, R ¹⁷ Is->In further embodiments of the subject compounds, R ¹⁷ Is->In embodiments of the subject compounds, R ¹⁷ Is->In some embodiments of the subject compounds, R ¹⁷ Is->In some embodiments of the subject compounds, R ¹⁷ Is thatIn further embodiments of the subject compounds, R ¹⁷ Is->In selected embodiments of the subject compounds, R ¹⁷ Is->In embodiments of the subject compounds, R ¹⁷ Is->In further embodiments of the subject compounds, R ¹⁷ Is->In some embodiments of the subject compounds, R ¹⁷ Is thatIn embodiments of the subject compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In some embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In the process of chemical conversionIn embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is->In embodiments of the compounds, R ¹⁷ Is thatIn embodiments of the compounds, R ¹⁷ Is->

In some embodiments, R ¹⁷ Selected from:

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in some embodiments, R ¹⁷ Selected from:

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in embodiments of the compound or a pharmaceutically acceptable salt or solvate thereof, R ² Selected from the group consisting of

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And

in embodiments, R ² Is thatIn embodiments, R ² Is->In embodiments, R ² Is->In embodiments, R ² Is->In embodiments, R ² Is->In embodiments, R ² Is->In embodiments, R ² Is->In embodiments, R ² Is->In further embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is thatIn selected embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is thatIn embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is- >In further embodiments of the subject compounds, R ² Is thatIn some embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is thatIn further embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is thatOn the subject ofIn some embodiments of the compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is that In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is thatIn some embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is thatIn further embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is thatIn selected embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->On the subject ofIn some embodiments of the compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is thatIn further embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is thatIn some embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is thatIn selected embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In some embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is thatIn some embodiments of the subject compounds, R ² Is->In further embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In embodiments of the subject compounds, R ² Is->In selected embodiments of the subject compounds, R ² Is thatIn embodiments, R ² Is->In embodiments, R ² Independently selected from/>

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In the subject compounds or pharmaceutically acceptable thereofIn further embodiments of the salt or solvate, R ⁵ Is hydrogen.

In some embodiments, R ^20a Independently selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In some embodiments, R ^20a Independently selected from halogen, -CN, C _1-6 Alkyl, -OR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)R ²⁵ and-OC (O) R ²⁵ Wherein C _1-6 The alkyl group is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In some embodiments, R ^20d Independently selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In some embodiments, R ^20d Independently selected from halogen, -CN, C _1-6 Alkyl, -OR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)R ²⁵ and-OC (O) R ²⁵ Wherein C _1-6 The alkyl group is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In some embodiments, R ^20f Independently selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In some embodiments, R ^20f Independently selected from halogen, -CN, C _1-6 Alkyl, -OR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)R ²⁵ and-OC (O) R ²⁵ Wherein C _1-6 The alkyl group is optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20a Independently halogen. In embodiments, R ^20a Independently oxo. In embodiments, R ^20a Independently is-CN. In embodiments, R ^20a Independently C _1-6 An alkyl group. In embodiments, R ^20a Independently C _2-6 Alkenyl groups. In embodiments, R ^20a Independently C _2-6 Alkynyl groups. In embodiments, R ^20a Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20a Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20a Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20a Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20a Independently C _6-10 Aryl groups. In embodiments, R ^20a Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20a Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20a Independently C _1-9 Heteroaryl groups. In embodiments, R ^20a Independently is-OR ²¹ . In embodiments, R ^20a independently-SR ²¹ . In embodiments, R ^20a Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20a Independently is-C (O) OR ²² . In embodiments, R ^20a independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20a independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20a independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20a Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20a Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20a Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20a Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20a independently-C (O) R ²⁵ . In embodiments, R ^20a Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20a Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20a Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20a independently-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _3-6 Cycloalkyl groups, which are optionally covered byOne, two or three of the groups are independently selected from the following: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20a Independently halogen. In embodiments, R ^20a Independently oxo. In embodiments, R ^20a Independently is-CN. In embodiments, R ^20a Independently C _1-6 An alkyl group. In embodiments, R ^20a Independently C _2-6 Alkenyl groups. In embodiments, R ^20a Independently C _2-6 Alkynyl groups. In embodiments, R ^20a Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20a Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20a Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20a Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20a Independently C _6-10 Aryl groups. In embodiments, R ^20a Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20a Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20a Independently C _1-9 Heteroaryl groups. In embodiments, R ^20a Independently is-OR ²¹ . In embodiments, R ^20a independently-SR ²¹ . In embodiments, R ^20a Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20a Independently is-C (O) OR ²² . In embodiments, R ^20a independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20a independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20a independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20a Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20a Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20a Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20a Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20a independently-C (O) R ²⁵ . In embodiments, R ^20a Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20a Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20a Is independently-OCH ₂ C(O)OR ²² . In practiceIn embodiments, R ^20a independently-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In further embodiments of the subject compounds, R ^20a Independently halogen. In some embodiments of the subject compounds, R ^20a Independently oxo. In some embodiments of the subject compounds, R ^20a Independently is-CN. In further embodiments of the subject compounds, R ^20a Independently C _1-6 An alkyl group. In embodiments of the subject compounds, R ^20a Independently C _2-6 Alkenyl groups. In some embodiments of the subject compounds, R ^20a Independently C _2-6 Alkynyl groups. In further embodiments of the subject compounds, R ^20a Independently is-OR ²² . In selected embodiments of the subject compounds, R ^20a Is independently-N (R) ²² )(R ²³ ). In further embodiments of the subject compounds, R ^20a Independently is-C (O) OR ²² . In embodiments of the subject compounds, R ^20a independently-OC (O) N (R) ²² )(R ²³ ). In some embodiments of the subject compounds, R ^20a independently-C (O) R ²⁵ . In selected embodiments of the subject compounds, R ^20a independently-NH ₂ . In further embodiments of the subject compounds, R ^20a independently-C (O) OH. In further embodiments of the subject compounds, R ^20a independently-OC (O) NH ₂ . In embodiments of the subject compounds, R ^20a independently-C (O) CH ₃ 。

In embodiments, R ^20a Independently halogen. In embodiments, R ^20a Independently oxo. In embodiments, R ^20a Independently is-CN. In embodiments, R ^20a Independently C _1-6 An alkyl group. In embodiments, R ^20a Independently C _2-6 Alkenyl groups. In embodiments, R ^20a Independently C _2-6 Alkynyl groups. In embodiments, R ^20a Independently C _1-6 A haloalkyl group. In embodiments, R ^20a Independently C _3-12 Cycloalkyl groups. In embodiments, R ^20a Is independently-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ^20a Independently C _1-11 A heterocycloalkyl group. In embodiments, R ^20a Is independently-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ^20a Independently C _6-12 Aryl groups. In embodiments, R ^20a Is independently-CH ₂ -C _6-12 Aryl groups. In embodiments, R ^20a Is independently-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ^20a Independently C _1-11 Heteroaryl groups. In embodiments, R ^20a Independently is-OR ²² . In embodiments, R ^20a independently-SR ²² . In embodiments, R ^20a Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20a Independently is-C (O) OR ²² . In embodiments, R ^20a independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20a Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20a Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20a Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20a independently-C (O) R ²⁵ . In embodiments, R ^20a Independently is-S (O) R ²⁵ . In embodiments, R ^20a independently-OC (O) R ²⁵ . In embodiments, R ^20a independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20a independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20a Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20a Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20a Independently is-S (O) ₂ N(R ²² )(R ²³ ) -. In embodiments, R ^20a Independently S (=o) (=nh) N (R ²² )(R ²³ ). In embodiments, R ^20a Is independently-CH ₂ C(O)N(R ²² )(R ²³ ). In embodiments, R ^20a Is independently-CH ₂ N(R ²⁴ )C(O)R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ S(O) ₂ R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ S(O) ₂ N(R ²² )(R ²³ )。

In embodiments, R ^20a Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _1-6 Halogenated compoundsAlkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _3-12 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _3-12 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _1-11 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _1-11 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _6-12 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _6-12 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C _1-11 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Halogenated compoundsAlkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C _1-11 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20a Independently C ₁ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₂ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₃ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₄ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxoCN、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₅ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₆ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₂ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₃ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₄ Alkenyl, optionally one, two or moreThree groups independently selected from the following are substituted: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₅ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₆ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₂ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₃ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₄ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₅ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₆ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₁ A haloalkyl group. In embodiments, R ^20a Independently C ₂ A haloalkyl group. In embodiments, R ^20a Independently C ₃ A haloalkyl group. In embodiments, R ^20a Independently C ₄ A haloalkyl group. In embodiments, R ^20a Independently C ₅ A haloalkyl group. In embodiments, R ^20a Independently C ₆ A haloalkyl group.

In embodiments, R ^20a Independently C ₃ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₄ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₅ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₆ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₇ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₈ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₉ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₁₀ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20a Independently C ₂ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₃ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₄ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₅ Heterocycloalkyl groups, optionally one, twoOr three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₆ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₇ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₈ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₉ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In the implementation modeIn the scheme, R ^20a Independently C ₆ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₇ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₈ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₉ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₁₀ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₁₁ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₁₂ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₂ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₃ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₄ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₅ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₆ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₇ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₈ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₉ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₁₀ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independently C ₁₁ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a independently-OH. In embodiments, R ^20a Independently is-SH. In embodiments, R ^20a independently-NH ₂ . In embodiments, R ^20a independently-C (O) OH. In embodiments, R ^20a independently-OC (O) NH ₂ . In embodiments, R ^20a independently-N (H) C (O) NH ₂ . In embodiments, R ^20a independently-N (H) C (O) OH. In embodiments, R ^20a independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ^20a independently-C (O) H. In embodiments, R ^20a Is independently-S (O) CH ₃ . In embodiments, R ^20a independently-OC (O) CH ₃ . In embodiments, R ^20a independently-C (O) NH ₂ . In embodiments, R ^20a independently-C (O) C (O) NH ₂ . In embodiments, R ^20a independently-N (H) C (O) H. In embodiments, R ^20a Independently is-S (O) ₂ CH ₃ . In embodiments, R ^20a Independently is-S (O) ₂ NH ₂ -. In embodiments, R ^20a Independently S (=o) (=nh) NH ₂ . In embodiments, R ^20a Is independently-CH ₂ C(O)NH ₂ . In embodiments, R ^20a Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ^20a Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ^20a Is independently-CH ₂ S(O) ₂ NH ₂ . In embodiments, R ^20a Is independently-OCH ₃ . In embodiments, R ^20a Independently is-SCH ₃ . In embodiments, R ^20a Is independently-N (CH) ₃ ) (H). In embodiments, R ^20a Is independently-C (O) OCH ₃ . In embodiments, R ^20a independently-OC (O) N (CH) ₃ ) (H). In embodiments, R ^20a independently-N (H) C (O) N (CH) ₃ ) (H). In embodiments, R ^20a Is independently-N (H) C (O) OCH ₃ . In embodiments, R ^20a independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ^20a independently-C (O) CH ₃ . In the implementation modeIn the scheme, R ^20a Is independently-S (O) CH ₃ . In embodiments, R ^20a independently-OC (O) CH ₃ . In embodiments, R ^20a independently-C (O) N (CH) ₃ ) (H). In embodiments, R ^20a independently-C (O) C (O) N (CH) ₃ ) (H). In embodiments, R ^20a independently-N (H) C (O) CH ₃ . In embodiments, R ^20a Independently is-S (O) ₂ CH ₃ . In embodiments, R ^20a Independently is-S (O) ₂ N(CH ₃ ) (H) -. In embodiments, R ^20a Independently S (=o) (=nh) N (CH ₃ ) (H). In embodiments, R ^20a Is independently-CH ₂ C(O)N(CH ₃ ) (H). In embodiments, R ^20a Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ^20a Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ^20a Is independently-CH ₂ S(O) ₂ N(CH ₃ ) (H). In embodiments, R ^20a independently-OC (O) N (CH) ₃ ) ₂ . In embodiments, R ^20a independently-N (H) C (O) N (CH) ₃ ) ₂ . In embodiments, R ^20a independently-C (O) (CH ₃ ). In embodiments, R ^20a independently-C (O) N (CH) ₃ ) ₂ . In embodiments, R ^20a independently-C (O) C (O) N (CH) ₃ ) ₂ . In embodiments, R ^20a independently-N (H) C (O) (CH ₃ ). In embodiments, R ^20a Independently is-S (O) ₂ N(CH ₃ ) ₂ . In embodiments, R ^20a Independently S (=o) (=nh) N (CH ₃ ) ₂ . In embodiments, R ^20a Is independently-CH ₂ C(O)N(CH ₃ ) ₂ . In embodiments, R ^20a Is independently-CH ₂ S(O) ₂ N(CH ₃ ) ₂ . In embodiments, R ^20a Is independently-CH ₃ . In embodiments, R ^20a Independently is-CF ₃ . In embodiments, R ^20a independently-CHF ₂ . In embodiments, R ^20a Independently is-CFH ₂ . In embodiments, R ^20a Independently ethyl. In embodiments, R ^20a Independently is propyl. In embodiments, R ^20a Independently isopropyl. In embodiments, R ^20a Independently butyl. In embodiments, R ^20a Independently t-butyl.

In embodiments, R ^20a Is independently-CH ₂ -C ₃ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₄ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₅ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₆ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₇ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₈ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₉ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₁₀ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20a Is independently-CH ₂ -C ₂ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₃ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₄ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₅ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₆ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₇ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₈ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₉ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20a Is independently-CH ₂ -C ₆ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₇ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₈ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₉ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₁₀ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Independent and independentGround is-CH ₂ -C ₁₁ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₁₂ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₂ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₃ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₄ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₅ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₆ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₇ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₈ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₉ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₁₀ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20a Is independently-CH ₂ -C ₁₁ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20b Independently halogen. In embodiments, R ^20b Independently oxo. In embodiments, R ^20b Independently is-CN. In embodiments, R ^20b Independently C _1-6 An alkyl group. In embodiments, R ^20b Independently C _2-6 Alkenyl groups. In embodiments, R ^20b Independently C _2-6 Alkynyl groups. In embodiments, R ^20b Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20b Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20b Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20b Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20b Independently C _6-10 Aryl groups. In embodiments, R ^20b Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20b Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20b Independently C _1-9 Heteroaryl groups. In embodiments, R ^20b Independently is-OR ²¹ . In embodiments, R ^20b independently-SR ²¹ . In embodiments, R ^20b Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20b Independently is-C (O) OR ²² . In embodiments, R ^20b independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20b independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20b independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20b Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20b Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20b Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20b Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20b independently-C (O) R ²⁵ . In embodiments，R ^20b Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20b Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20b Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20b independently-OC (O) R ²⁵ . In embodiments, R ^20b Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20b Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20c Independently halogen. In embodiments, R ^20c Independently oxo. In embodiments, R ^20c Independently is-CN. In embodiments, R ^20c Independently C _1-6 An alkyl group. In embodiments, R ^20c Independently C _2-6 Alkenyl groups. In embodiments, R ^20c Independently C _2-6 Alkynyl groups. In embodiments, R ^20c Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20c Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20c Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20c Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20c Independently C _6-10 Aryl groups. In embodiments, R ^20c Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20c Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20c Independently C _1-9 Heteroaryl groups. In embodiments, R ^20c Independently is-OR ²¹ . In embodiments, R ^20c independently-SR ²¹ . In embodiments, R ^20c Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20c Independently is-C (O) OR ²² . In embodiments, R ^20c independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20c independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20c independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20c Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20c Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20c Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20c Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20c independently-C (O) R ²⁵ . In embodiments, R ^20c Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20c Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20c Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20c independently-OC (O) R ²⁵ . In embodiments, R ^20c Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen (halogen) Oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20c Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20d Independently halogen. In embodiments, R ^20d Independently oxo. In embodiments, R ^20d Independently is-CN. In embodiments, R ^20d Independently C _1-6 An alkyl group. In embodiments, R ^20d Independently C _2-6 Alkenyl groups. In embodiments, R ^20d Independently C _2-6 Alkynyl groups. In embodiments, R ^20d Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20d Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20d Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20d Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20d Independently C _6-10 Aryl groups. In embodiments, R ^20d Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20d Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20d Independently C _1-9 Heteroaryl groups. In embodiments, R ^20d Independently is-OR ²¹ . In embodiments, R ^20d independently-SR ²¹ . In embodimentsWherein R is ^20d Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20d Independently is-C (O) OR ²² . In embodiments, R ^20d independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20d independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20d independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20d Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20d Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20d Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20d Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20d independently-C (O) R ²⁵ . In embodiments, R ^20d Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20d Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20d Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20d independently-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In the implementation modeIn the scheme, R ^20d Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radicalRadical, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20d Independently halogen. In embodiments, R ^20d Independently oxo. In embodiments, R ^20d Independently is-CN. In embodiments, R ^20d Independently C _1-6 An alkyl group. In embodiments, R ^20d Independently C _2-6 Alkenyl groups. In embodiments, R ^20d Independently C _2-6 Alkynyl groups. In embodiments, R ^20d Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20d Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20d Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20d Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20d Independently C _6-10 Aryl groups. In embodiments, R ^20d Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20d Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20d Independently C _1-9 Heteroaryl groups. In embodiments, R ^20d Independently is-OR ²¹ . In embodiments, R ^20d independently-SR ²¹ . In embodiments, R ^20d Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20d Independently is-C (O) OR ²² . In embodiments, R ^20d independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20d independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20d independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20d Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20d Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20d Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20d Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20d independently-C (O) R ²⁵ . In embodiments, R ^20d Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20d Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20d Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20d independently-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _3-6 Cycloalkyl groups, optionally one, two or three of which are independentlySubstitution of a group selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In further embodiments of the subject compounds, R ^20d Independently halogen. In some embodiments of the subject compounds, R ^20d Independently oxo. In some embodiments of the subject compounds, R ^20d Independently is-CN. In further embodiments of the subject compounds, R ^20d Independently C _1-6 An alkyl group. In embodiments of the subject compounds, R ^20d Independently C _2-6 Alkenyl groups. In some embodiments of the subject compounds, R ^20d Independently C _2-6 Alkynyl groups. In further embodiments of the subject compounds, R ^20d Independently is-OR ²² . In selected embodiments of the subject compounds, R ^20d Is independently-N (R) ²² )(R ²³ ). In further embodiments of the subject compounds, R ^20d Independently is-C (O) OR ²² . In embodiments of the subject compounds, R ^20d independently-OC (O) N (R) ²² )(R ²³ ). In some embodiments of the subject compounds, R ^20d independently-C (O) R ²⁵ . In selected embodiments of the subject compounds, R ^20d independently-NH ₂ . In further embodiments of the subject compounds, R ^20d independently-C (O) OH. In further embodiments of the subject compounds, R ^20d independently-OC (O) NH ₂ . In embodiments of the subject compounds, R ^20d independently-C (O) CH ₃ 。

In embodiments, R ^20d Independently halogen. In embodiments, R ^20d Independently oxo. In embodiments, R ^20d Independently is-CN. In embodiments, R ^20d Independently C _1-6 An alkyl group. In embodiments, R ^20d Independently C _2-6 Alkenyl groups. In embodiments, R ^20d Independently C _2-6 Alkynyl groups. In embodiments, R ^20d Independently C _1-6 A haloalkyl group. In embodiments, R ^20d Independently C _3-12 Cycloalkyl groups. In embodiments, R ^20d Is independently-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ^20d Independently C _1-11 A heterocycloalkyl group. In embodiments, R ^20d Is independently-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ^20d Independently C _6-12 Aryl groups. In embodiments, R ^20d Is independently-CH ₂ -C _6-12 Aryl groups. In embodiments, R ^20d Is independently-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ^20d Independently C _1-11 Heteroaryl groups. In embodiments, R ^20d Independently is-OR ²² . In embodiments, R ^20d independently-SR ²² . In embodiments, R ^20d Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20d Independently is-C (O) OR ²² . In embodiments, R ^20d independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20d Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20d Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20d Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20d independently-C (O) R ²⁵ . In embodiments, R ^20d Independently is-S (O) R ²⁵ . In embodiments, R ^20d independently-OC (O) R ²⁵ . In embodiments, R ^20d independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20d independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20d Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20d Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20d Independently is-S (O) ₂ N(R ²² )(R ²³ ) -. In embodiments, R ^20d Independently S (=o) (=nh) N (R ²² )(R ²³ ). In embodiments, R ^20d Is independently-CH ₂ C(O)N(R ²² )(R ²³ ). In embodiments, R ^20d Is independently-CH ₂ N(R ²⁴ )C(O)R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ S(O) ₂ R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ S(O) ₂ N(R ²² )(R ²³ )。

In embodiments, R ^20d Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _1-6 Haloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _3-12 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _3-12 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _1-11 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _1-11 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _6-12 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _6-12 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C _1-11 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C _1-11 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20d Independently C ₁ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₂ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₃ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₄ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₅ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₆ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₂ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₃ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₄ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₅ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₆ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₂ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₃ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₄ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₅ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₆ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₁ A haloalkyl group. In embodiments, R ^20d Independently C ₂ A haloalkyl group. In embodiments, R ^20d Independently C ₃ A haloalkyl group. In embodiments, R ^20d Independently C ₄ A haloalkyl group. In embodiments, R ^20d Independently C ₅ A haloalkyl group. In embodiments, R ^20d Independently C ₆ A haloalkyl group.

In embodiments, R ^20d Independently C ₃ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₄ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₅ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₆ Cycloalkyl groups, optionally one, two or three of which are independently selected fromIs substituted by a group of: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₇ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₈ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₉ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₁₀ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments，R ^20d Independently C ₂ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₃ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₄ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₅ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₆ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₇ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₈ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₉ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₆ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₇ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₈ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₉ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₁₀ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl、C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₁₁ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₁₂ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₂ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₃ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₄ Heteroaryl optionally substituted with one, two or three groups independently selected from:halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₅ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₆ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₇ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₈ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₉ A heteroaryl group, which is a group,optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₁₀ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Independently C ₁₁ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d independently-OH. In embodiments, R ^20d Independently is-SH. In embodiments, R ^20d independently-NH ₂ . In embodiments, R ^20d independently-C (O) OH. In embodiments, R ^20d independently-OC (O) NH ₂ . In embodiments, R ^20d independently-N (H) C (O) NH ₂ . In embodiments, R ^20d independently-N (H) C (O) OH. In embodiments, R ^20d independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ^20d independently-C (O) H. In embodiments, R ^20d Is independently-S (O) CH ₃ . In embodiments, R ^20d independently-OC (O) CH ₃ . In embodiments, R ^20d independently-C (O) NH ₂ . In embodiments, R ^20d independently-C (O) C (O) NH ₂ . In embodiments, R ^20d independently-N (H) C (O) H. In embodiments, R ^20d Independently is-S (O) ₂ CH ₃ . In embodiments, R ^20d Independently is-S (O) ₂ NH ₂ -. In embodiments, R ^20d Independently S (=o) (=nh) NH ₂ . In embodiments, R ^20d Is independently-CH ₂ C(O)NH ₂ . In embodiments, R ^20d Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ^20d Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ^20d Is independently-CH ₂ S(O) ₂ NH ₂ . In embodiments, R ^20d Is independently-OCH ₃ . In embodiments, R ^20d Independently is-SCH ₃ . In embodiments, R ^20d Is independently-N (CH) ₃ ) (H). In embodiments, R ^20d Is independently-C (O) OCH ₃ . In embodiments, R ^20d independently-OC (O) N (CH) ₃ ) (H). In embodiments, R ^20d independently-N (H) C (O) N (CH) ₃ ) (H). In embodiments, R ^20d Is independently-N (H) C (O) OCH ₃ . In embodiments, R ^20d independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ^20d independently-C (O) CH ₃ . In embodiments, R ^20d Is independently-S (O) CH ₃ . In embodiments, R ^20d independently-OC (O) CH ₃ . In embodiments, R ^20d independently-C (O) N (CH) ₃ ) (H). In embodiments, R ^20d independently-C (O) C (O) N (CH) ₃ ) (H). In embodiments, R ^20d independently-N (H) C (O) CH ₃ . In embodiments, R ^20d Independently is-S (O) ₂ CH ₃ . In embodiments, R ^20d Independently is-S (O) ₂ N(CH ₃ ) (H) -. In embodiments, R ^20d Independently S (=o) (=nh) N (CH ₃ ) (H). In embodiments, R ^20d Is independently-CH ₂ C(O)N(CH ₃ ) (H). In embodiments, R ^20d Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ^20d Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ^20d Is independently-CH ₂ S(O) ₂ N(CH ₃ ) (H). In embodiments, R ^20d independently-OC (O) N (CH) ₃ ) ₂ . In embodiments, R ^20d independently-N (H) C (O) N (CH) ₃ ) ₂ . In embodiments, R ^20d independently-C (O) (CH ₃ ). In embodiments, R ^20d independently-C (O) N (CH) ₃ ) ₂ . In embodiments, R ^20d independently-C (O) C (O) N (CH) ₃ ) ₂ . In embodiments, R ^20d independently-N (H) C (O) (CH ₃ ). In implementationIn the scheme, R ^20d Independently is-S (O) ₂ N(CH ₃ ) ₂ . In embodiments, R ^20d Independently S (=o) (=nh) N (CH ₃ ) ₂ . In embodiments, R ^20d Is independently-CH ₂ C(O)N(CH ₃ ) ₂ . In embodiments, R ^20d Is independently-CH ₂ S(O) ₂ N(CH ₃ ) ₂ . In embodiments, R ^20d Is independently-CH ₃ . In embodiments, R ^20d Independently is-CF ₃ . In embodiments, R ^20d independently-CHF ₂ . In embodiments, R ^20d Independently is-CFH ₂ . In embodiments, R ^20d Independently ethyl. In embodiments, R ^20d Independently is propyl. In embodiments, R ^20d Independently isopropyl. In embodiments, R ^20d Independently butyl. In embodiments, R ^20d Independently t-butyl.

In embodiments, R ^20d Is independently-CH ₂ -C ₃ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₄ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl group、C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₅ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₆ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₇ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₈ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₉ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₁₀ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20d Is independently-CH ₂ -C ₂ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₃ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₄ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₅ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₆ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₇ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo、-CN、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₈ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₉ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20d Is independently-CH ₂ -C ₆ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₇ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₈ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₉ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₁₀ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₁₁ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₁₂ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₂ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₃ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₄ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo,-CN、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₅ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₆ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₇ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₈ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₉ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₁₀ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20d Is independently-CH ₂ -C ₁₁ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20e Independently halogen. In embodiments, R ^20e Independently oxo. In embodiments, R ^20e Independently is-CN. In embodiments, R ^20e Independently C _1-6 An alkyl group. In embodiments, R ^20e Independently C _2-6 Alkenyl groups. In embodiments, R ^20e Independently C _2-6 Alkynyl groups. In embodiments, R ^20e Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20e Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20e Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20e Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20e Independently C _6-10 Aryl groups. In embodiments, R ^20e Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20e Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20e Independently C _1-9 Heteroaryl groups. In embodiments, R ^20e Independently is-OR ²¹ . In embodiments, R ^20e independently-SR ²¹ . In embodiments, R ^20e Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20e Independently is-C (O) OR ²² . In embodiments, R ^20e independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20e independently-C (O) C (O) N (R) ²² )(R ²³ ). At the position ofIn embodiments, R ^20e independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20e Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20e Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20e Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20e Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20e independently-C (O) R ²⁵ . In embodiments, R ^20e Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20e Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20e Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20e independently-OC (O) R ²⁵ . In embodiments, R ^20e Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20e Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20f Independently halogen. In practiceIn embodiments, R ^20f Independently oxo. In embodiments, R ^20f Independently is-CN. In embodiments, R ^20f Independently C _1-6 An alkyl group. In embodiments, R ^20f Independently C _2-6 Alkenyl groups. In embodiments, R ^20f Independently C _2-6 Alkynyl groups. In embodiments, R ^20f Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20f Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20f Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20f Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20f Independently C _6-10 Aryl groups. In embodiments, R ^20f Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20f Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20f Independently C _1-9 Heteroaryl groups. In embodiments, R ^20f Independently is-OR ²¹ . In embodiments, R ^20f independently-SR ²¹ . In embodiments, R ^20f Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20f Independently is-C (O) OR ²² . In embodiments, R ^20f independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20f independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20f independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20f Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20f Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20f Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20f Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20f independently-C (O) R ²⁵ . In embodiments, R ^20f Independently is-S(O) ₂ R ²⁵ . In embodiments, R ^20f Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20f Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20f independently-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _2-6 Alkynyl, optionally substituted withAnd each, two or three are independently substituted with a group selected from the group consisting of: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20f Independently halogen. In embodiments, R ^20f Independently oxo. In embodiments, R ^20f Independently is-CN. In embodiments, R ^20f Independently C _1-6 An alkyl group. In embodiments, R ^20f Independently C _2-6 Alkenyl groups. In embodiments, R ^20f Independently C _2-6 Alkynyl groups. In embodiments, R ^20f Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20f Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20f Independently C _2-9 A heterocycloalkyl group. In the context of an embodiment of the present invention,R ^20f is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20f Independently C _6-10 Aryl groups. In embodiments, R ^20f Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20f Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20f Independently C _1-9 Heteroaryl groups. In embodiments, R ^20f Independently is-OR ²¹ . In embodiments, R ^20f independently-SR ²¹ . In embodiments, R ^20f Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20f Independently is-C (O) OR ²² . In embodiments, R ^20f independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20f independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20f independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20f Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20f Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20f Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20f Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20f independently-C (O) R ²⁵ . In embodiments, R ^20f Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20f Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20f Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20f independently-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In further embodiments of the subject compounds, R ^20f Independently halogen. In some embodiments of the subject compounds, R ^20f Independently oxo. In some embodiments of the subject compounds, R ^20f Independently is-CN. In further embodiments of the subject compounds, R ^20f Independently C _1-6 An alkyl group. In embodiments of the subject compounds, R ^20f Independently C _2-6 Alkenyl groups. In some embodiments of the subject compounds, R ^20f Independently C _2-6 Alkynyl groups. In further embodiments of the subject compounds, R ^20f Independently is-OR ²² . In selected embodiments of the subject compounds, R ^20f Is independently-N (R) ²² )(R ²³ ). In further embodiments of the subject compounds, R ^20f Independently is-C (O) OR ²² . In embodiments of the subject compounds, R ^20f independently-OC (O) N (R) ²² )(R ²³ ). In some embodiments of the subject compounds, R ^20f independently-C (O) R ²⁵ . In selected embodiments of the subject compounds, R ^20f independently-NH ₂ . In further embodiments of the subject compounds, R ^20f independently-C (O) OH. In addition to the subject compoundsIn embodiments of (2), R ^20f independently-OC (O) NH ₂ . In embodiments of the subject compounds, R ^20f independently-C (O) CH ₃ 。

In embodiments, R ^20f Independently halogen. In embodiments, R ^20f Independently oxo. In embodiments, R ^20f Independently is-CN. In embodiments, R ^20f Independently C _1-6 An alkyl group. In embodiments, R ^20f Independently C _2-6 Alkenyl groups. In embodiments, R ^20f Independently C _2-6 Alkynyl groups. In embodiments, R ^20f Independently C _1-6 A haloalkyl group. In embodiments, R ^20f Independently C _3-12 Cycloalkyl groups. In embodiments, R ^20f Is independently-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ^20f Independently C _1-11 A heterocycloalkyl group. In embodiments, R ^20f Is independently-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ^20f Independently C _6-12 Aryl groups. In embodiments, R ^20f Is independently-CH ₂ -C _6-12 Aryl groups. In embodiments, R ^20f Is independently-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ^20f Independently C _1-11 Heteroaryl groups. In embodiments, R ^20f Independently is-OR ²² . In embodiments, R ^20f independently-SR ²² . In embodiments, R ^20f Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20f Independently is-C (O) OR ²² . In embodiments, R ^20f independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20f Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20f Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20f Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20f Independently is-C(O)R ²⁵ . In embodiments, R ^20f Independently is-S (O) R ²⁵ . In embodiments, R ^20f independently-OC (O) R ²⁵ . In embodiments, R ^20f independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20f independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20f Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20f Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20f Independently is-S (O) ₂ N(R ²² )(R ²³ ) -. In embodiments, R ^20f Independently S (=o) (=nh) N (R ²² )(R ²³ ). In embodiments, R ^20f Is independently-CH ₂ C(O)N(R ²² )(R ²³ ). In embodiments, R ^20f Is independently-CH ₂ N(R ²⁴ )C(O)R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ S(O) ₂ R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ S(O) ₂ N(R ²² )(R ²³ )。

In embodiments, R ^20f Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _1-6 Haloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _3-12 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _3-12 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _1-11 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _1-11 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _6-12 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _6-12 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C _1-11 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C _1-11 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20f Independently C ₁ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₂ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₃ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₄ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₅ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₆ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₂ Alkenyl groups, which are optionallySubstituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₃ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₄ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₅ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₆ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments，R ^20f Independently C ₂ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₃ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₄ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₅ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₆ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₁ A haloalkyl group. In embodiments, R ^20f Independently C ₂ A haloalkyl group. In embodiments, R ^20f Independently C ₃ A haloalkyl group. In embodiments, R ^20f Independently C ₄ A haloalkyl group. In embodiments, R ^20f Independently C ₅ A haloalkyl group. In embodiments, R ^20f Independently C ₆ A haloalkyl group.

In embodiments, R ^20f Independently C ₃ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₄ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₅ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₆ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₇ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₈ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₉ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₁₀ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20f Independently C ₂ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₃ Heterocycloalkyl, optionally substituted with oneTwo or three of the groups independently selected from the following are substituted: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₄ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₅ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₆ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₇ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . At the position ofIn embodiments, R ^20f Independently C ₈ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₉ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₆ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₇ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₈ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₉ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₁₀ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₁₁ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₁₂ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₂ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₃ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₄ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₅ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₆ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₇ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₈ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₉ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₁₀ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen-free foodPlain, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Independently C ₁₁ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f independently-OH. In embodiments, R ^20f Independently is-SH. In embodiments, R ^20f independently-NH ₂ . In embodiments, R ^20f independently-C (O) OH. In embodiments, R ^20f independently-OC (O) NH ₂ . In embodiments, R ^20f independently-N (H) C (O) NH ₂ . In embodiments, R ^20f independently-N (H) C (O) OH. In embodiments, R ^20f independently-N (H) S (O) ₂ CH ₃ . In practiceIn embodiments, R ^20f independently-C (O) H. In embodiments, R ^20f Is independently-S (O) CH ₃ . In embodiments, R ^20f independently-OC (O) CH ₃ . In embodiments, R ^20f independently-C (O) NH ₂ . In embodiments, R ^20f independently-C (O) C (O) NH ₂ . In embodiments, R ^20f independently-N (H) C (O) H. In embodiments, R ^20f Independently is-S (O) ₂ CH ₃ . In embodiments, R ^20f Independently is-S (O) ₂ NH ₂ -. In embodiments, R ^20f Independently S (=o) (=nh) NH ₂ . In embodiments, R ^20f Is independently-CH ₂ C(O)NH ₂ . In embodiments, R ^20f Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ^20f Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ^20f Is independently-CH ₂ S(O) ₂ NH ₂ . In embodiments, R ^20f Is independently-OCH ₃ . In embodiments, R ^20f Independently is-SCH ₃ . In embodiments, R ^20f Is independently-N (CH) ₃ ) (H). In embodiments, R ^20f Is independently-C (O) OCH ₃ . In embodiments, R ^20f independently-OC (O) N (CH) ₃ ) (H). In embodiments, R ^20f independently-N (H) C (O) N (CH) ₃ ) (H). In embodiments, R ^20f Is independently-N (H) C (O) OCH ₃ . In embodiments, R ^20f independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ^20f independently-C (O) CH ₃ . In embodiments, R ^20f Is independently-S (O) CH ₃ . In embodiments, R ^20f independently-OC (O) CH ₃ . In embodiments, R ^20f independently-C (O) N (CH) ₃ ) (H). In embodiments, R ^20f independently-C (O) C (O) N (CH) ₃ ) (H). In embodiments, R ^20f independently-N (H) C (O) CH ₃ . In implementationIn the scheme, R ^20f Independently is-S (O) ₂ CH ₃ . In embodiments, R ^20f Independently is-S (O) ₂ N(CH ₃ ) (H) -. In embodiments, R ^20f Independently S (=o) (=nh) N (CH ₃ ) (H). In embodiments, R ^20f Is independently-CH ₂ C(O)N(CH ₃ ) (H). In embodiments, R ^20f Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ^20f Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ^20f Is independently-CH ₂ S(O) ₂ N(CH ₃ ) (H). In embodiments, R ^20f independently-OC (O) N (CH) ₃ ) ₂ . In embodiments, R ^20f independently-N (H) C (O) N (CH) ₃ ) ₂ . In embodiments, R ^20f independently-C (O) (CH ₃ ). In embodiments, R ^20f independently-C (O) N (CH) ₃ ) ₂ . In embodiments, R ^20f independently-C (O) C (O) N (CH) ₃ ) ₂ . In embodiments, R ^20f independently-N (H) C (O) (CH ₃ ). In embodiments, R ^20f Independently is-S (O) ₂ N(CH ₃ ) ₂ . In embodiments, R ^20f Independently S (=o) (=nh) N (CH ₃ ) ₂ . In embodiments, R ^20f Is independently-CH ₂ C(O)N(CH ₃ ) ₂ . In embodiments, R ^20f Is independently-CH ₂ S(O) ₂ N(CH ₃ ) ₂ . In embodiments, R ^20f Is independently-CH ₃ . In embodiments, R ^20f Independently is-CF ₃ . In embodiments, R ^20f independently-CHF ₂ . In embodiments, R ^20f Independently is-CFH ₂ . In embodiments, R ^20f Independently ethyl. In embodiments, R ^20f Independently is propyl. In embodiments, R ^20f Independently isopropyl. In embodiments, R ^20f Independently butyl. In embodiments, R ^20f Independently t-butyl.

In embodiments, R ^20f Is independently-CH ₂ -C ₃ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₄ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₅ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₆ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₇ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₈ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₉ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₁₀ Cycloalkyl groups, optionally one, two or moreThree groups independently selected from the following are substituted: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20f Is independently-CH ₂ -C ₂ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₃ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₄ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₅ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₆ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₇ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₈ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₉ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20f Is independently-CH ₂ -C ₆ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₇ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₈ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₉ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₁₀ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₁₁ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₁₂ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₂ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₃ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₄ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₅ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₆ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₇ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₈ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₉ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₁₀ Heteroaryl, any of whichOptionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20f Is independently-CH ₂ -C ₁₁ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20g Independently halogen. In embodiments, R ^20g Independently oxo. In embodiments, R ^20g Independently is-CN. In embodiments, R ^20g Independently C _1-6 An alkyl group. In embodiments, R ^20g Independently C _2-6 Alkenyl groups. In embodiments, R ^20g Independently C _2-6 Alkynyl groups. In the context of an embodiment of the present invention,R ^20g independently C _3-6 Cycloalkyl groups. In embodiments, R ^20g Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20g Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20g Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20g Independently C _6-10 Aryl groups. In embodiments, R ^20g Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20g Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20g Independently C _1-9 Heteroaryl groups. In embodiments, R ^20g Independently is-OR ²¹ . In embodiments, R ^20g independently-SR ²¹ . In embodiments, R ^20g Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20g Independently is-C (O) OR ²² . In embodiments, R ^20g independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20g independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20g independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20g Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20g Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20g Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20g Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20g independently-C (O) R ²⁵ . In embodiments, R ^20g Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20g Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20g Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20g independently-OC (O) R ²⁵ . In embodiments, R ^20g Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20g Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ²⁰ⁱ Independently halogen. In embodiments, R ²⁰ⁱ Independently oxo. In embodiments, R ²⁰ⁱ Independently is-CN. In embodiments, R ²⁰ⁱ Independently C _1-6 An alkyl group. In embodiments, R ²⁰ⁱ Independently C _2-6 Alkenyl groups. In embodiments, R ²⁰ⁱ Independently C _2-6 Alkynyl groups. In embodiments, R ²⁰ⁱ Independently C _3-6 Cycloalkyl groups. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ²⁰ⁱ Independently C _2-9 A heterocycloalkyl group. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ²⁰ⁱ Independently C _6-10 Aryl groups. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodimentsWherein R is ²⁰ⁱ Independently C _1-9 Heteroaryl groups. In embodiments, R ²⁰ⁱ Independently is-OR ²¹ . In embodiments, R ²⁰ⁱ independently-SR ²¹ . In embodiments, R ²⁰ⁱ Is independently-N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Independently is-C (O) OR ²² . In embodiments, R ²⁰ⁱ independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ²⁰ⁱ independently-C (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ R ²⁵ . In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ²⁰ⁱ independently-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ²⁰ⁱ Independently halogen. In embodiments, R ²⁰ⁱ Independently oxo. In embodiments, R ²⁰ⁱ Independently is-CN. In embodiments, R ²⁰ⁱ Independently C _1-6 An alkyl group. In embodiments, R ²⁰ⁱ Independently C _2-6 Alkenyl groups. In embodiments, R ²⁰ⁱ Independently C _2-6 Alkynyl groups. In embodiments, R ²⁰ⁱ Independently C _3-6 Cycloalkyl groups. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ²⁰ⁱ Independently C _2-9 A heterocycloalkyl group. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ²⁰ⁱ Independently C _6-10 Aryl groups. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ²⁰ⁱ Independently C _1-9 Heteroaryl groups. In embodiments, R ²⁰ⁱ Independently is-OR ²¹ . In embodiments, R ²⁰ⁱ independently-SR ²¹ . In embodiments, R ²⁰ⁱ Is independently-N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Independently is-C (O) OR ²² . In embodiments, R ²⁰ⁱ independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Independently is-OC(O)N(R ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ²⁰ⁱ independently-C (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ R ²⁵ . In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ²⁰ⁱ independently-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In further embodiments of the subject compounds, R ²⁰ⁱ Independently halogen. In the subject compoundsIn some embodiments, R ²⁰ⁱ Independently oxo. In some embodiments of the subject compounds, R ²⁰ⁱ Independently is-CN. In further embodiments of the subject compounds, R ²⁰ⁱ Independently C _1-6 An alkyl group. In embodiments of the subject compounds, R ²⁰ⁱ Independently C _2-6 Alkenyl groups. In some embodiments of the subject compounds, R ²⁰ⁱ Independently C _2-6 Alkynyl groups. In further embodiments of the subject compounds, R ²⁰ⁱ Independently is-OR ²² . In selected embodiments of the subject compounds, R ²⁰ⁱ Is independently-N (R) ²² )(R ²³ ). In further embodiments of the subject compounds, R ²⁰ⁱ Independently is-C (O) OR ²² . In embodiments of the subject compounds, R ²⁰ⁱ independently-OC (O) N (R) ²² )(R ²³ ). In some embodiments of the subject compounds, R ²⁰ⁱ independently-C (O) R ²⁵ . In selected embodiments of the subject compounds, R ²⁰ⁱ independently-NH ₂ . In further embodiments of the subject compounds, R ²⁰ⁱ independently-C (O) OH. In further embodiments of the subject compounds, R ²⁰ⁱ independently-OC (O) NH ₂ . In embodiments of the subject compounds, R ²⁰ⁱ independently-C (O) CH ₃ 。

In embodiments, R ²⁰ⁱ Independently halogen. In embodiments, R ²⁰ⁱ Independently oxo. In embodiments, R ²⁰ⁱ Independently is-CN. In embodiments, R ²⁰ⁱ Independently C _1-6 An alkyl group. In embodiments, R ²⁰ⁱ Independently C _2-6 Alkenyl groups. In embodiments, R ²⁰ⁱ Independently C _2-6 Alkynyl groups. In embodiments, R ²⁰ⁱ Independently C _1-6 A haloalkyl group. In embodiments, R ²⁰ⁱ Independently C _3-12 Cycloalkyl groups. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _3-12 Cycloalkyl groups. In embodiments, R ²⁰ⁱ Independently C _1-11 A heterocycloalkyl group. In embodiments，R ²⁰ⁱ Is independently-CH ₂ -C _1-11 A heterocycloalkyl group. In embodiments, R ²⁰ⁱ Independently C _6-12 Aryl groups. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _6-12 Aryl groups. In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _1-11 Heteroaryl groups. In embodiments, R ²⁰ⁱ Independently C _1-11 Heteroaryl groups. In embodiments, R ²⁰ⁱ Independently is-OR ²² . In embodiments, R ²⁰ⁱ independently-SR ²² . In embodiments, R ²⁰ⁱ Is independently-N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Independently is-C (O) OR ²² . In embodiments, R ²⁰ⁱ independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ²⁰ⁱ independently-C (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently is-S (O) R ²⁵ . In embodiments, R ²⁰ⁱ independently-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ R ²⁵ . In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ N(R ²² )(R ²³ ) -. In embodiments, R ²⁰ⁱ Independently is

S(＝O)(＝NH)N(R ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-CH ₂ C(O)N(R ²² )(R ²³ ). In embodiments, R ²⁰ⁱ Is independently-CH ₂ N(R ²⁴ )C(O)R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ S(O) ₂ R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ S(O) ₂ N(R ²² )(R ²³ )。

In embodiments, R ²⁰ⁱ Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _2-6 Alkynyl groups, optionally one, twoAnd each or three are independently substituted with groups selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _1-6 Haloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _3-12 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _3-12 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _1-11 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _1-11 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _6-12 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _6-12 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C _1-11 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C _1-11 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ²⁰ⁱ Independently C ₁ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₂ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₃ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl group,C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₄ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₅ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₆ Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₂ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₃ Alkenyl groups, optionally one, two or three of which are independently selected fromGroup substitution: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₄ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₅ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₆ Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₂ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₃ An alkynyl group, an amino group,optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₄ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₅ Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₆ Alkynyl optionally substituted with one, two or three groups independently selected from:

halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₁ A haloalkyl group. In embodiments, R ²⁰ⁱ Independently C ₂ A haloalkyl group. In embodiments, R ²⁰ⁱ Independently C ₃ A haloalkyl group. In embodiments, R ²⁰ⁱ Independently C ₄ A haloalkyl group. In embodiments, R ²⁰ⁱ Independently C ₅ A haloalkyl group. In embodiments, R ²⁰ⁱ Independently C ₆ A haloalkyl group.

In embodiments, R ²⁰ⁱ Independently C ₃ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₄ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₅ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₆ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₇ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₈ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₉ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₁₀ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ²⁰ⁱ Independently C ₂ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₃ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₄ Heterocycloalkyl, optionally substituted by one, two or moreThree groups independently selected from the following are substituted: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₅ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₆ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₇ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₈ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodimentsWherein R is ²⁰ⁱ Independently C ₉ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₆ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₇ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₈ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₉ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₁₀ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₁₁ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₁₂ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₂ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₃ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₄ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₅ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₆ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy radicalRadical, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₇ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₈ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₉ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₁₀ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Independently C ₁₁ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo,-CN、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ independently-OH. In embodiments, R ²⁰ⁱ Independently is-SH. In embodiments, R ²⁰ⁱ independently-NH ₂ . In embodiments, R ²⁰ⁱ independently-C (O) OH. In embodiments, R ²⁰ⁱ independently-OC (O) NH ₂ . In embodiments, R ²⁰ⁱ independently-N (H) C (O) NH ₂ . In embodiments, R ²⁰ⁱ independently-N (H) C (O) OH. In embodiments, R ²⁰ⁱ independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ²⁰ⁱ independently-C (O) H. In embodiments, R ²⁰ⁱ Is independently-S (O) CH ₃ . In embodiments, R ²⁰ⁱ independently-OC (O) CH ₃ . In embodiments, R ²⁰ⁱ independently-C (O) NH ₂ . In embodiments, R ²⁰ⁱ independently-C (O) C (O) NH ₂ . In embodiments, R ²⁰ⁱ independently-N (H) C (O) H. In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ CH ₃ . In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ NH ₂ -. In embodiments, R ²⁰ⁱ Independently S (=o) (=nh) NH ₂ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ C(O)NH ₂ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ S(O) ₂ NH ₂ . In embodiments, R ²⁰ⁱ Is independently-OCH ₃ . In embodiments, R ²⁰ⁱ Independently is-SCH ₃ . In embodiments, R ²⁰ⁱ Is independently-N (CH) ₃ ) (H). In embodiments, R ²⁰ⁱ Is independently-C (O) OCH ₃ . In embodiments, R ²⁰ⁱ independently-OC (O) N (CH) ₃ ) (H). In embodiments, R ²⁰ⁱ independently-N (H) C (O) N (CH) ₃ ) (H). In embodiments, R ²⁰ⁱ Is independently-N (H) C (O) OCH ₃ . In embodiments, R ²⁰ⁱ independently-N (H) S (O) ₂ CH ₃ . In embodiments, R ²⁰ⁱ independently-C (O) CH ₃ . In embodiments, R ²⁰ⁱ Is independently-S (O) CH ₃ . In embodiments, R ²⁰ⁱ independently-OC (O) CH ₃ . In embodiments, R ²⁰ⁱ independently-C (O) N (CH) ₃ ) (H). In embodiments, R ²⁰ⁱ independently-C (O) C (O) N (CH) ₃ ) (H). In embodiments, R ²⁰ⁱ independently-N (H) C (O) CH ₃ . In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ CH ₃ . In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ N(CH ₃ ) (H) -. In embodiments, R ²⁰ⁱ Independently S (=o) (=nh) N (CH ₃ ) (H). In embodiments, R ²⁰ⁱ Is independently-CH ₂ C(O)N(CH ₃ ) (H). In embodiments, R ²⁰ⁱ Is independently-CH ₂ N(H)C(O)CH ₃ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ S(O) ₂ CH ₃ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ S(O) ₂ N(CH ₃ ) (H). In embodiments, R ²⁰ⁱ independently-OC (O) N (CH) ₃ ) ₂ . In embodiments, R ²⁰ⁱ independently-N (H) C (O) N (CH) ₃ ) ₂ . In embodiments, R ²⁰ⁱ independently-C ]O)(CH ₃ ). In embodiments, R ²⁰ⁱ independently-C (O) N (CH) ₃ ) ₂ . In embodiments, R ²⁰ⁱ independently-C (O) C (O) N (CH) ₃ ) ₂ . In embodiments, R ²⁰ⁱ independently-N (H) C (O) (CH ₃ ). In embodiments, R ²⁰ⁱ Independently is-S (O) ₂ N(CH ₃ ) ₂ . In embodiments, R ²⁰ⁱ Independently S (=o) (=nh) N (CH ₃ ) ₂ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ C(O)N(CH ₃ ) ₂ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ S(O) ₂ N(CH ₃ ) ₂ . In embodiments, R ²⁰ⁱ Is independently-CH ₃ . In embodiments, R ²⁰ⁱ Independently is-CF ₃ . In embodiments, R ²⁰ⁱ independently-CHF ₂ . In embodiments, R ²⁰ⁱ Independently is-CFH ₂ . In embodiments, R ²⁰ⁱ Independently ethyl. In embodiments, R ²⁰ⁱ Independently is propyl. In embodiments, R ²⁰ⁱ Independently isopropyl. In embodiments, R ²⁰ⁱ Independently butyl. In embodiments, R ²⁰ⁱ Independently t-butyl.

In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₃ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₄ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₅ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₆ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₇ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₈ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₉ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₁₀ Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₂ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₃ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₄ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₅ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₆ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₇ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₈ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₉ Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl、C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₆ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₇ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₈ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₉ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₁₀ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₁₁ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₁₂ Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₂ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₃ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₄ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₅ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₆ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₇ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₈ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₉ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₁₀ Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ²⁰ⁱ Is independently-CH ₂ -C ₁₁ Heteroaryl groupOptionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^20k Independently halogen. In embodiments, R ^20k Independently is-CN. In embodiments, R ^20k Independently C _1-6 An alkyl group. In embodiments, R ^20k Independently C _2-6 Alkenyl groups. In embodiments, R ^20k Independently C _2-6 Alkynyl groups. In embodiments, R ^20k Independently C _3-6 Cycloalkyl groups. In embodiments, R ^20k Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^20k Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^20k Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^20k Independently C _6-10 Aryl groups. In embodiments, R ^20k Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^20k Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^20k Independently C _1-9 Heteroaryl groups. In embodiments, R ^20k Independently is-OR ²¹ . In embodiments, R ^20k independently-SR ²¹ . In embodiments, R ^20k Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^20k Independently is-C (O) OR ²² . In embodiments, R ^20k independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20k independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^20k independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^20k Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^20k Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^20k Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^20k Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^20k independently-C (O) R ²⁵ . In embodiments, R ^20k Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^20k Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^20k Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^20k independently-OC (O) R ²⁵ . In embodiments, R ^20k Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20k Independently C _2-6 Alkenyl groups, optionally one, two or three independentlyIs substituted with a group selected from the group consisting of: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20k Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20k Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20k Is independently-CH ₂ -C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20k Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodimentsWherein R is ^20k Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20k Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20k Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20k Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^20k Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In embodiments, R ^12c Independently hydrogen. In embodiments, R ^12c Independently methyl. In embodiments, R ^12c Independently ethyl. In embodiments, R ^12c Independently halogen. In embodiments, R ^12c Independently is-CN. In embodiments, R ^12c Independently C _1-6 An alkyl group. In embodiments, R ^12c Independently C _2-6 Alkenyl groups. In embodiments, R ^12c Independently C _2-6 Alkynyl groups. In embodiments, R ^12c Independently C _3-6 Cycloalkyl groups. In embodiments, R ^12c Is independently-CH ₂ -C _3-6 Cycloalkyl groups. In embodiments, R ^12c Independently C _2-9 A heterocycloalkyl group. In embodiments, R ^12c Is independently-CH ₂ -C _2-9 A heterocycloalkyl group. In embodiments, R ^12c Independently C _6-10 Aryl groups. In embodiments, R ^12c Is independently-CH ₂ -C _6-10 Aryl groups. In embodiments, R ^12c Is independently-CH ₂ -C _1-9 Heteroaryl groups. In embodiments, R ^12c Independently C _1-9 Heteroaryl groups. In embodiments, R ^12c Independently is-OR ²¹ . In embodiments, R ^12c independently-SR ²¹ . In embodiments, R ^12c Is independently-N (R) ²² )(R ²³ ). In embodiments, R ^12c Independently is-C (O) OR ²² . In embodiments, R ^12c independently-C (O) N (R) ²² )(R ²³ ). In embodiments, R ^12c independently-C (O) C (O) N (R) ²² )(R ²³ ). In embodiments, R ^12c independently-OC (O) N (R) ²² )(R ²³ ). In embodiments, R ^12c Is independently-N (R) ²⁴ )C(O)N(R ²² )(R ²³ ). In embodiments, R ^12c Is independently-N (R) ²⁴ )C(O)OR ²⁵ . In embodiments, R ^12c Is independently-N (R) ²⁴ )C(O)R ²⁵ . In embodiments, R ^12c Is independently-N (R) ²⁴ )S(O) ₂ R ²⁵ . In embodiments, R ^12c independently-C (O) R ²⁵ . In embodiments, R ^12c Independently is-S (O) ₂ R ²⁵ . In embodiments, R ^12c Independently is-S (O) ₂ N(R ²² )(R ²³ ). In embodiments, R ^12c Is independently-OCH ₂ C(O)OR ²² . In embodiments, R ^12c independently-OC (O) R ²⁵ . In embodiments, R ^12c Independently C _1-6 Alkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Independently C _2-6 Alkenyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Independently C _2-6 Alkynyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Independently C _3-6 Cycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Is independently-CH ₂ -C _3-6 Cycloalkyl groups, optionally one, two or three independentlyIs substituted with a group selected from the group consisting of: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Independently C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Is independently-CH ₂ -C _2-9 Heterocycloalkyl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Independently C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Is independently-CH ₂ -C _6-10 Aryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Is independently-CH ₂ -C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ . In embodiments, R ^12c Independently C _1-9 Heteroaryl optionally substituted with one, two or three groups independently selected from: halogen, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ 。

In some embodiments, the compound is selected from

/>

In some embodiments, the compound is selected from

Atropisomer 1,/-or->/>

Is trans-atropisomer 2 of (2).

In some embodiments, the compound is selected from/>

In some embodiments, the compound is selected from

/>

In some embodiments, the compound is selected from

/>

In embodiments, the compound is a compound described herein (e.g., one of compounds 101-372). In embodiments, the compound is a compound described herein (e.g., one of compounds 101-442). In embodiments, the compound is a compound described herein (e.g., one of compounds 101-454). In embodiments, the compound is a compound described herein.

In one aspect, a composition having the formula A-L ^AB -a compound of B, wherein a is a monovalent form of a compound of formula I, IA, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV;

L ^AB Are covalent linkers that bind to a and B; and is also provided with

B is a monovalent form of a degradation enhancer.

In one aspect, a composition having the formula A-L ^AB -a compound of B, wherein a is a monovalent form of a compound of formula I, I', IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV;

L ^AB are covalent linkers that bind to a and B; and is also provided with

B is a monovalent form of a degradation enhancer.

In one aspect, a composition having the formula A-L ^AB -a compound of B, wherein a is a monovalent form of a compound of formula I, IA, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX;

L ^AB are covalent linkers that bind to a and B; and is also provided with

B is a monovalent form of a degradation enhancer.

A "degradation enhancer" is a compound capable of binding to an ubiquitin ligase protein (e.g., E3 ubiquitin ligase protein), or a compound capable of binding to an ubiquitin ligase protein to form a protein complex capable of conjugating ubiquitin protein to a target protein. In embodiments, the degradation enhancer is capable of binding to an E3 ubiquitin ligase protein or a protein complex comprising an E3 ubiquitin ligase protein. In embodiments, the degradation enhancer is capable of binding to the E2 ubiquitin conjugating enzyme. In embodiments, the degradation enhancer is capable of binding to a protein complex comprising an E2 ubiquitin conjugating enzyme and an E3 ubiquitin ligase protein.

In embodiments, the degradation enhancer is capable of binding a protein selected from the group consisting of: E3A, mdm, APC, EDD1, SOCS/BC-box/eloBC/CUL 5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX, UBR5, UBL (von-Hippel-sudau-ligustrase), P1, WWP2, parkinson's protein, KRN1, chaperone (CMB-mediated protein), and the protein (TRIAP-1-mediated apoptosis-factor) protein (TRIAB-mediated by the protein), the protein (TRIAP-containing protein (TRIAB-1-carried out by the apoptosis-promoting factor) and the protein (TRIAB-1-mediated apoptosis-inducing protein (TRCPP-1) Compound/cell cycle body), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL 4) ^CRBN ) Ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, ahR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, atorvastatin, ibbean and CC-885.

In embodiments, the degradation enhancers are compounds described in Ishida and ciuli, SLAS discover 2021, vol.25 (4) 484-502, which are incorporated by reference in their entirety for any purpose, such as VH032, VH101, VH298, thalidomide, ubenimex (betatin), ubenimex, nutlelin, idasalutinin (idasanutrlin), bardoxolone, methylbardoxolone, mide Su Lam (indailam) (E7070), E7820, chloroquinoxaline sulfonamide (chloroquinoxaline sulfonamide) (CQS), azadirachtin (nimble), KB02, ASTX660, lenalidomide (lenalidomide) or pomalidomide (pomalidomide).

In embodiments, the degradation enhancer is a compound described in US20180050021, WO2016146985, WO2018189554, WO2018119441, WO2018140809, WO2018119448, WO2018119357, WO2018118598, WO2018102067, WO201898280, WO201889736, WO201881530, WO201871606, WO201864589, WO201852949, WO2017223452, WO2017204445, WO2017197055, WO2017197046, WO2017180417, WO2017176958, WO201711371, WO2018226542, WO2018223909, WO2018189554, WO2016169989, WO2016146985, CN105085620B, CN106543185B, US10040804, US9938302, US10144745, US10145848, US9938264, US9632089, US9821068, US9758522, US9500653, US9765019, US8507488, US8299057, US20180298027, US20180215731, US20170065719, US20170037004, US20160272639, US20150291562 or US20140356322 (which are incorporated by reference in their entirety for any purpose).

In embodiments, L ^AB is-L ^AB1 -L ^AB2 -L ^AB3 -L ^AB4 -L ^AB5 -；L ^AB1 、L ^AB2 、L ^AB3 、L ^AB4 And L ^AB5 Independently is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C _1-6 Alkylene, (-O-C) _1-6 Alkyl group _z -、(-C _1-6 alkyl-O) _z -、C _2-6 Alkenylene, C _2-6 Alkynylene, C _1-6 Halogenated alkylene, C _3-12 Cycloalkylene, C _1-11 Heterocycloalkylene, C _6-12 Arylene or C _1-11 Heteroarylene group, wherein C _1-6 Alkylene, C _2-6 Alkenylene, C _2-6 Alkynylene, C _1-6 Halogenated alkylene, C _3-12 Cycloalkylene, C _1-11 Heterocycloalkylene, C _6-12 Arylene or C _1-11 Heteroarylene is optionally substituted with one, two or three R ^20j Substitution; wherein (-O-C) _1-6 Alkyl group _z -and (-C) _1-6 alkyl-O) _z -each C _1-6 Alkyl is optionally substituted with one, two or three R ^20j Substitution;

z is independently an integer from 0 to 10;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

the formula of the compounds of Table 1

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TABLE 2R ¹⁰ Description of the embodiments

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TABLE 3L ¹ Description of the embodiments

	A	B	C
				1	Key with a key	C ₁ -C ₆ Alkyl group	C ₂ -C ₆ Alkenyl groups
2	C ₂ -C ₆ Alkynyl group	-C(O)-	-NHC(O)-
				3	-C(O)NH-	CH ₂ O	CH ₂ NH
4	CH ₂

Watch 4.R ¹⁹ Description of the embodiments

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TABLE 5R ² Description of the embodiments

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TABLE 8R ⁴

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TABLE 9R ⁸

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In embodiments, the subject compounds are of the formula of Table 1 (e.g., one selected from 1A-12B) and one R of Table 2 ¹⁰ Embodiments (e.g., selected from 1A-9C, 10A) in combination with one L of Table 3 ¹ Embodiments (e.g., selected from 1A-3C, 4A) in combination with one R of Table 4 ¹⁹ Embodiments (e.g., selected from 1A-11E) (wherein L ¹ And R is ¹⁹ R combined to form the formula of Table 1 ¹⁷ ) Combination with one R of Table 5 ² Embodiments (e.g., compounds selected from the group consisting of 1A-27D, 28A, 28B) in combination. R is R ³ 、R ⁸ And R is ¹⁶ As described herein, included in any embodiment herein.

In embodiments, the subject compounds are of the formula of Table 1 (e.g., one selected from 1A-12B) and one R of Table 2 ¹⁰ Embodiments (e.g., selected from 1A-12C) in combination with one L of Table 3 ¹ Embodiments (e.g., selected from 1A-3C, 4A) in combination with one R of Table 4 ¹⁹ Embodiments (e.g., selected from 1A-16E) (wherein L ¹ And R is ¹⁹ R combined to form the formula of Table 1 ¹⁷ ) Combination with one R of Table 5 ² Embodiment (e.g., selected from the group consisting of 1A-36D) compounds. R is R ³ 、R ⁸ And R is ¹⁶ As described herein, included in any embodiment herein.

In embodiments, the subject compounds are of the formula of Table 1 (e.g., one selected from 1A-12B) and one R of Table 2 ¹⁰ Embodiments (e.g., selected from 1A-20C) in combination with one L of Table 3 ¹ Embodiments (e.g., selected from 1A-3C, 4A) in combination with one R of Table 4 ¹⁹ Embodiments (e.g., selected from 1A-16E) (wherein L ¹ And R is ¹⁹ R combined to form the formula of Table 1 ¹⁷ ) Combination with one R of Table 5 ² Embodiment (e.g., selected from the group consisting of 1A-36D) compounds. R is R ³ 、R ⁸ And R is ¹⁶ As described herein, included in any embodiment herein.

In embodiments, the subject compounds are of the formula of Table 1 (e.g., one selected from 1A-12B) and one R of Table 2 ¹⁰ Embodiments (e.g., selected from 1A-35D, 36A, 36B, 36C) in combination with one L of Table 3 ¹ Embodiments (e.g., selected from 1A-3C, 4A) in combination with one R of Table 4 ¹⁹ Embodiments (e.g., selected from 1A-16E) (wherein L ¹ And R is ¹⁹ R combined to form the formula of Table 1 ¹⁷ ) Combination with one R of Table 5 ² Embodiments (e.g., selected from 1A-36D, 37A, 37B) in combination with one R of Table 8 ⁴ Embodiment (e.g., selected from 1A-14D) in combination with one R of Table 9 ⁸ Embodiment (e.g., selected from the group consisting of 1A-6D) combinations. R is R ³ And R is ¹⁶ As described herein, included in any embodiment herein. p is an integer from 0 to 12. In an embodiment, p is 0. In an embodiment, p is 1. In an embodiment, p is 2. In an embodiment, p is 3. In an embodiment, p is 4. In an embodiment, p is 5. In an embodiment, p is 6.

In addition to the inhibition and high potency in reducing Kras signaling output by targeting Kras (including Kras mutants such as Kras G12D), the compounds disclosed herein exhibit one or more advantageous DMPK properties. Exemplary superior DMPK properties associated with the subject compounds include, but are not limited to, improved metabolic stability, reduced serum protein binding (thus increasing free and available compounds circulating in the subject's blood after administration of the compound), and/or increased oral exposure. The fine-tuning pharmacological properties embodied in the subject compounds are of great importance for improving the efficacy and/or safety of Kras inhibitors in therapeutic clinical applications.

In some embodiments, the substituted aryl groups are similar or identical to those having a different 6 membered heteroaryl bicyclic core (e.g., quinazoline core)Radical R ² 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ In comparison with the compound of the formula (I), formulae I, I ', I ', I-1 '; the compounds of I-1' or I-1' show an increase in unbound/free compounds present in the plasma. In one embodiment, R is the same or different as R having a different 6 membered heteroaryl bicyclic core (e.g., quinazoline core) ² 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ The subject compounds of formula I, I ', I ", I-1', I-1", or I-1 '"exhibit at least 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700-fold or more increase in unbound/free compounds present in the plasma compared to the corresponding compounds of formula I, I', I", I-1', I-1", or I-1'". In another embodiment, R is the same or different as R having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) ² 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ The subject compounds of formula I, I ', I ", I-1', I-1", or I-1 '"exhibit at least a 10%, 20%, 30%, 40%, 50%, 100%, 200%, 300%, 400%, 500% or even higher increase in unbound/free compounds present in the plasma as compared to the corresponding compounds of formula I, I', I", I-1', I-1", or I-1'".

In one embodiment, R is the same or different from R having a different core backbone but having similar or identical substituents ² 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ In comparison with the compound of the formula (I), formulae I, I ', I ', I-1 '; the subject compounds of I-1' or I-1' exhibit reduced serum protein binding.

In one embodiment, R is the same as R ² 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ But compared to compounds having a different 6 membered heteroaryl bicyclic core backbone, in the formulae I, I ', I ', I-1 '; reduced serum protein binding was observed in compounds of I-1' or I-1 '.

In one embodiment of the present invention, in one embodiment, the increase in unbound/free compounds present in the plasma is in accordance with formula I, I ': compounds of I', I-1 'or I-1', wherein R is ¹⁰ is-L ⁷ -R ⁷ ；L ⁷ Is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or 2-to 4-membered heteroalkylene linker wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and 2-to 4-membered alkylene linkers are optionally substituted with one, two or three R ^20a Substitution; and R is ⁷ Is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl and 5-12 membered heteroaryl each contain one or more ring nitrogen atoms or one or more epoxy atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ And (3) substitution.

In one embodiment of the present invention, in one embodiment, the increase in unbound/free compounds present in the plasma is in accordance with formula I, I ': compounds of I', I-1 'or I-1', wherein R is ¹⁰ is-L ⁷ -R ⁷ ；L ⁷ Is a bond, -O-or-N (R) ¹⁴ ) -; and R is ⁷ Is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl contains one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R ⁴ Substituted, and optionally with one or more R ⁶ And (3) substitution.

In one embodiment of the present invention, in one embodiment, the increase in unbound/free compounds present in the plasma is in accordance with formula I, I ': compounds of I', I-1 'or I-1', wherein R is ¹⁰ is-L ⁷ -R ⁷ ；L ⁷ Is a bond; and R is ⁷ Is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl contains one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or moreR ⁴ Substituted, and optionally with one or more R ⁶ And (3) substitution.

In one embodiment of the present invention, in one embodiment, the increase in unbound/free compounds present in the plasma is in accordance with formula I, I ': compounds of I', I-1 'or I-1', wherein R is ¹⁰ is-L ⁷ -R ⁷ ；L ⁷ Is a bond; and R is ⁷ Is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl contains one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R ⁴ And (3) substitution.

In one embodiment of the present invention, in one embodiment, the increase in unbound/free compounds present in the plasma is in accordance with formula I, I ': compounds of I', I-1 'or I-1', wherein R is ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Selected from bonds, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、-OCON(R ¹⁴ )-、-N(R ¹⁴ )C(O)O-、N(R ^1e )、C(O)N(R ^1c )、S(O) ₂ N(R ^1c )、S(O)N(R ^1c )、C(R ^1f )(R ^1g )O、C(R ^1f )(R ^1g )N(R ^1c ) And C (R) ^1f )(R ^1g )；R ¹⁹ Selected from C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl, wherein C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl is optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ And (3) substitution.

In one embodiment of the present invention, in one embodiment, the increase in unbound/free compounds present in the plasma is in accordance with formula I, I ': compounds of I', I-1 'or I-1', wherein R is ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond; r is R ¹⁹ Selected from C _6-12 Aryl and 9-10 membered heteroaryl, wherein C _6-12 Aryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ And (3) substitution.

In one embodiment of the present invention, in one embodiment, the increase in unbound/free compounds present in the plasma is in accordance with formula I, I ': compounds of I', I-1 'or I-1', wherein R is ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond; r is R ¹⁹ Selected from naphthyl and 9-10 membered heteroaryl, wherein naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ And (3) substitution.

In one embodiment of the present invention, in one embodiment, the increase in unbound/free compounds present in the plasma is in accordance with formula I, I ': compounds of I', I-1 'or I-1', wherein R is ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond; r is R ¹⁹ Selected from naphthyl and 9-10 membered heteroaryl, wherein naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ Substitution; each R ¹ⁱ Independently selected from halogen, -CN, C _1-3 Alkyl, C _1-3 Haloalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, -OH, -NH ₂ Wherein C _1-3 Alkyl, C _1-3 Haloalkyl, C _2-3 Alkenyl and C _2-3 Alkynyl is optionally substituted with one, two or three R ²⁰ⁱ And (3) substitution.

In one embodiment, the increase in unbound/free compounds present in the plasma is associated with a compound of formula (I-1), (I '-1), (Ia' -1), (Ib '-1), (Ic-1) or (Ic' -1), wherein R ² is-O-R ^12a ；R ^12a is-C (R) ^12c ) ₂ - (5-8 membered heterocycloalkyl), wherein-C (R ^12c ) ₂ - (5-8 membered heterocycloalkyl) optionally substituted by one, two or three R ^20d And (3) substitution.

In one embodiment, the increase in unbound/free compounds present in the plasma is greater than that of formula (I-1), (I' -1), (Ia-1), (I) a ' -1), (Ib ' -1), (Ic-1) or (Ic ' -1), wherein R ² is-O-R ^12a ；R ^12a is-C (R) ^12c ) ₂ - (5-8 membered heterocycloalkyl), wherein-C (R ^12c ) ₂ - (5-8 membered heterocycloalkyl) optionally substituted by one, two or three R ^20d Substitution; r is R ^12c Independently selected from hydrogen and methyl.

In one embodiment, the increase in unbound/free compounds present in plasma is compared to the corresponding compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) to formula (XVI)Related to the compounds of (2).

In some embodiments, R is the same or different as R having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) ² 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ In comparison with the compound of the formula (I), formulae I, I ', I ', I-1 '; the compounds of I-1' or I-1' exhibit excellent metabolic stability. For example, the subject compounds exhibit significantly longer metabolic stability as determined by T1/2 of liver microsomal metabolism (see example 12 of the experimental procedure). In one embodiment, an increase in microsomal metabolic stability of at least 10%, 20%, 30%, 40%, 50%, 100%, 200%, 300%, 400%, 500% or even higher is observed compared to such corresponding compounds.

In one embodiment, an increase in microsomal metabolic stability of at least 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700 or more fold is observed as compared to such corresponding compounds.

In one embodiment, R is the same or different from R having a different core backbone but having similar or identical substituents ² 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ In comparison with the compound of the formula (I), formulae I, I ', I ', I-1 '; the subject compounds of I-1' or I-1' exhibit excellent metabolic stability.

In one implementationIn the scheme, R is the same as the substituent R ² 、R ¹⁰ 、R ¹⁶ And R is ¹⁷ But compared to compounds having a different 6 membered heteroaryl bicyclic core backbone, in the formulae I, I ', I ', I-1 '; excellent metabolic stability was observed in compounds of I-1' or I-1 '.

In one embodiment of the present invention, in one embodiment, improved microsomal metabolic stability and formula I, I ', I ', I-1 Compounds of I-1', I-1' or I-1', wherein R is ¹⁰ is-L ⁷ -R ⁷ ；L ⁷ Is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl or 2-to 4-membered heteroalkylene linker wherein C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and 2-to 4-membered alkylene linkers are optionally substituted with one, two or three R ^20a Substitution; and R is ⁷ Is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl and 5-12 membered heteroaryl each contain one or more ring nitrogen atoms or one or more epoxy atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl or 5-12 membered heteroaryl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ And (3) substitution.

In one embodiment of the present invention, in one embodiment, improved microsomal metabolic stability and formula I, I ', I ', I-1 Compounds of I-1', I-1' or I-1', wherein R is ¹⁰ is-L ⁷ -R ⁷ ；L ⁷ Is a bond, -O-or-N (R) ¹⁴ ) -; and R is ⁷ Is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl contains one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R ⁴ Substituted, and optionally with one or more R ⁶ And (3) substitution.

In one embodiment of the present invention, in one embodiment, improved microsomal metabolic stability and formula I, I ', I ', I-1 Compounds of I-1', I-1' or I-1', wherein R is ¹⁰ is-L ⁷ -R ⁷ ；L ⁷ Is a bond; and R is ⁷ Is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl contains one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R ⁴ Substituted, and optionally with one or more R ⁶ And (3) substitution.

In one embodiment of the present invention, in one embodiment, improved microsomal metabolic stability and formula I, I ', I ', I-1 Compounds of I-1', I-1' or I-1', wherein R is ¹⁰ is-L ⁷ -R ⁷ ；L ⁷ Is a bond; and R is ⁷ Is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl contains one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R ⁴ And (3) substitution.

In one embodiment of the present invention, in one embodiment, improved microsomal metabolic stability and formula I, I ', I ', I-1 Compounds of I-1', I-1' or I-1', wherein R is ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Selected from bonds, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、-OCON(R ¹⁴ )-、-N(R ¹⁴ )C(O)O-、N(R ^1e )、C(O)N(R ^1c )、S(O) ₂ N(R ^1c )、S(O)N(R ^1c )、C(R ^1f )(R ^1g )O、C(R ^1f )(R ^1g )N(R ^1c ) And C (R) ^1f )(R ^1g )；R ¹⁹ Selected from C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl, wherein C _3-12 Cycloalkyl radicals、C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl is optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ And (3) substitution.

In one embodiment of the present invention, in one embodiment, improved microsomal metabolic stability and formula I, I ', I ', I-1 Compounds of I-1', I-1' or I-1', wherein R is ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond; r is R ¹⁹ Selected from C _6-12 Aryl and 9-10 membered heteroaryl, wherein C _6-12 Aryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ And (3) substitution.

In one embodiment of the present invention, in one embodiment, improved microsomal metabolic stability and formula I, I ', I ', I-1 Compounds of I-1', I-1' or I-1', wherein R is ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond; r is R ¹⁹ Selected from naphthyl and 9-10 membered heteroaryl, wherein naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ And (3) substitution.

In one embodiment of the present invention, in one embodiment, improved microsomal metabolic stability and formula I, I ', I ', I-1 Compounds of I-1', I-1' or I-1', wherein R is ¹⁷ is-L ¹ -R ¹⁹ ；L ¹ Is a bond; r is R ¹⁹ Selected from naphthyl and 9-10 membered heteroaryl, wherein naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ Substitution; each R ¹ⁱ Independently selected from halogen, -CN, C _1-3 Alkyl, C _1-3 Haloalkyl, C _2-3 Alkenyl, C _2-3 Alkynyl, -OH, -NH ₂ Wherein C _1-3 Alkyl, C _1-3 Haloalkyl, C _2-3 Alkenyl and C _2-3 Alkynyl is optionally substituted with one, two or three R ²⁰ⁱ And (3) substitution.

In one embodiment, improved microsomal metabolic stability is associated with a compound of formula (I-1), (I '-1), (Ia' -1), (Ib '-1), (Ic-1) or (Ic' -1) wherein R ² is-O-R ^12a ；R ^12a is-C (R) ^12c ) ₂ - (5-8 membered heterocycloalkyl), wherein-C (R ^12c ) ₂ - (5-8 membered heterocycloalkyl) optionally substituted by one, two or three R ^20d And (3) substitution.

In one embodiment, improved microsomal metabolic stability is associated with a compound of formula (I-1), (I '-1), (Ia' -1), (Ib '-1), (Ic-1) or (Ic' -1) wherein R ² is-O-R ^12a ；R ^12a is-C (R) ^12c ) ₂ - (5-8 membered heterocycloalkyl), wherein-C (R ^12c ) ₂ - (5-8 membered heterocycloalkyl) optionally substituted by one, two or three R ^20d Substitution; r is R ^12c Independently selected from hydrogen and methyl.

In one embodiment, the improved microsomal metabolic stability is compared to a corresponding compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) and formula (XVI)Related to the compounds of (2).

It should be understood that the different aspects of the invention may be understood individually, collectively, or in combination with each other. The various aspects of the invention described herein may be applied to any particular application disclosed herein. Compositions of matter comprising compounds of any of the formulae disclosed herein in the compositions section of this disclosure can be used in the methods section, including methods of use and production disclosed herein, or vice versa.

Additional embodiments

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

Wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

R ¹⁰ is-L ⁷ -R ⁷ ；

each R ¹ Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _1-11 Heterocyclylalkyl, -CH ₂ -C _1-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl groups、C _2-6 Alkynyl, C _1-6 Haloalkyl, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, C _1-11 Heterocyclylalkyl, -CH ₂ -C _1-11 Heterocycloalkyl, C _6-12 Aryl, -CH ₂ -C _6-12 Aryl, -CH ₂ -C _1-11 Heteroaryl and C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution;

R ⁶ is-L ² -R ⁵ ；

R ¹⁷ is-L ¹ -R ¹⁹ ；

R ^1e 、R ^1f And R is ^1g Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R is ^1f And R is ^1g To form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein 4-7 membered is heterolepticCycloalkyl rings or 4-7 membered cycloalkyl rings optionally substituted with one, two or three R' s ²⁰ⁱ Substitution;

x is C (R) ³ ) Or N;

R ³ selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl groups are optionallyIs one, two or three R ^20b Substitution;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

2. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C (R ³ )。

3. The compound according to embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

4. The compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein V is C (R ¹⁶ ) And J is C (R ¹⁷ )。

5. The compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein V is N and J is C (R ¹⁷ )。

6. The compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt or solvent thereof A compound wherein J is N and V is C (R ¹⁷ )。

7. The compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein J is C (R ¹⁶ ) And V is C (R ¹⁷ )。

8. The compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C (O).

9. The compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S (O).

10. The compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S (O) ₂ 。

11. A compound according to embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure:

12. a compound according to embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure:

/>

13. the compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein L ⁷ Is a key.

14. The compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein L ⁷ is-NH-.

15. The compound according to any one of embodiments 1 to 14 or a pharmaceutically acceptable thereof Salts or solvates of R ⁷ Is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substitution; and is also provided with

Wherein the bond to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

16. The compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein

R ⁷ Is that/>

p is an integer from 0 to 12;

X ³ Selected from N, C, C (R) ⁶ ) And C (R) ⁴ )。

17. The compound of embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein

R ⁷ Is that

18. The compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ Is that/>

And p is an integer of 0 to 12.

19. The compound of embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ Is that

20. The compound of embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ Is that

21. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁶ Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl group, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl is optionally substituted with one, two or three R' s ^20g And (3) substitution.

22. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁶ Independently selected from hydrogen and halogen.

23. The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁶ Independently selected from hydrogen and fluorine.

24. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20c And (3) substitution.

25. According to embodiment 1-23 or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 The heterocycloalkyl groups are optionally substituted with one, two or three R independently selected from ^20c Substitution: halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group.

26. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from the group consisting of methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R independently selected from ^20c Substitution: fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl.

27. The compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from methyl, cyclopropyl, cyclobutyl and oxetanyl.

28. The compound of any one of embodiments 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein R ³ Is hydrogen or CN.

29. The compound of any one of embodiments 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein R ³ Is hydrogen.

30. The compound of any one of embodiments 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein L ¹ Is a key.

31. The compound of any one of embodiments 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein L ¹ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -C (O) -, -NHC (O) -, -C (O) NH-, CH ₂ O、CH ₂ NH and CH ₂ 。

32. According to realityThe compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ Is a single ring.

33. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ Is a bicyclic ring system.

34. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ Is a polycyclic system.

35. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ The method comprises the following steps:

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

Each R ^1c Independently selected from hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl group、C _6-10 Aryl, C _1-9 Heteroaryl, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ And (3) substitution.

36. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ The method comprises the following steps:

37. the compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein R ² Selected from the group consisting of

/>

38. The compound of any one of embodiments 1 to 7 and 10 to 37, or a pharmaceutically acceptable salt or solvate thereof, wherein each R ⁵ Independently selected from:

-H、-NH ₂ 、-OH、-NH(C _1-6 alkyl group),/>

And m is 0, 1, 2 or 3 when present.

39. A compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

V is C (R) ¹⁶ ) Or N;

R ¹⁰ is-L ⁷ -R ⁷ ；

R ⁶ is-L ² -R ⁵ ；

R ¹⁷ is-L ¹ -R ¹⁹ ；

x is C (R) ³ ) Or N;

each R ^20a 、R ^20b 、R ^20c 、R ^20d 、R ^20e 、R ^20f 、R ^20g And R is ²⁰ⁱ Each independently selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl, C _1-9 Heteroaryl, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ )、-OCH ₂ C(O)OR ²² and-OC (O) R ²⁵ Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, C _2-9 Heterocyclylalkyl, -CH ₂ -C _2-9 Heterocycloalkyl, C _6-10 Aryl, -CH ₂ -C _6-10 Aryl, -CH ₂ -C _1-9 Heteroaryl and C _1-9 Heteroaryl is optionally substituted with one, two or three groups independently selected from: halogen-free foodPlain, oxo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -OR ²¹ 、-SR ²¹ 、-N(R ²² )(R ²³ )、-C(O)OR ²² 、-C(O)N(R ²² )(R ²³ )、-C(O)C(O)N(R ²² )(R ²³ )、-OC(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)N(R ²² )(R ²³ )、-N(R ²⁴ )C(O)OR ²⁵ 、-N(R ²⁴ )C(O)R ²⁵ 、-N(R ²⁴ )S(O) ₂ R ²⁵ 、-C(O)R ²⁵ 、-S(O) ₂ R ²⁵ 、-S(O) ₂ N(R ²² )(R ²³ ) and-OC (O) R ²⁵ ；

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

40. The compound of embodiment 39 or a pharmaceutically acceptable salt or solvate thereofWherein X is C (R) ³ )。

41. A compound according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

42. The compound of any one of embodiments 39 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein V is C (R ¹⁶ )。

43. The compound according to any one of embodiments 39 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein V is N.

44. The compound according to any one of embodiments 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C (O).

45. The compound according to any one of embodiments 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S (O).

46. The compound of any one of embodiments 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S (O) ₂ 。

47. A compound according to embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, having the structure:

48. the compound according to any one of embodiments 39 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein L ⁷ Is a key.

49. The compound according to any one of embodiments 39 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein L ⁷ is-NH-.

50. The compound of any one of embodiments 39 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ Is a 3-12 membered heterocycloalkyl, wherein 3-12 membered heterocycloalkyl is optionally substituted with one or more R ¹ One or more R ⁴ Or one or more R ⁶ Substitution; and is also provided with

Wherein is bonded toSelected from the group consisting of R of identical or adjacent atoms ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

51. The compound of any one of embodiments 39 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein

R ⁷ Is that

p is an integer from 0 to 12;

X ³ Selected from N, C, C (R) ⁶ ) And C (R) ⁴ )。

52. The compound of embodiment 51, or a pharmaceutically acceptable salt or solvate thereof, wherein

R ⁷ Is that

53. The compound of any one of embodiments 39 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein

R ⁷ Is that

And p is an integer of 0 to 12.

54. The compound of embodiment 51, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ Is that

/>

55. The compound of embodiment 51, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ Is that

56. The compound of any one of embodiments 39 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁶ Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl group, wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl and C _3-6 Cycloalkyl is optionally substituted with one, two or three R' s ^20g And (3) substitution.

57. The compound of any one of embodiments 39 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁶ Independently selected from hydrogen and halogen.

58. According to embodiment 39 to55 or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁶ Independently selected from hydrogen and fluorine.

59. The compound of any one of embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from halogen, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(H)(R ¹² )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20c And (3) substitution.

60. The compound of any one of embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 The heterocycloalkyl groups are optionally substituted with one, two or three R independently selected from ^20c Substitution: halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group.

61. The compound of any one of embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from the group consisting of methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R independently selected from ^20c Substitution: fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl.

62. The compound of any one of embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from methyl, cyclopropyl, cyclobutyl and oxetanyl.

63. The compound according to any one of embodiments 39 to 62, or a pharmaceutically acceptable salt or solvate thereof, wherein R ³ Is hydrogen or CN.

64. The compound according to any one of embodiments 39 to 62, or a pharmaceutically acceptable salt or solvate thereof, wherein R ³ Is hydrogen.

65. The compound of any one of embodiments 39 to 64, or a pharmaceutically acceptable salt or solvate thereof, wherein L ¹ Is a key.

66. The compound of any one of embodiments 39 to 64, or a pharmaceutically acceptable salt or solvate thereof, wherein L ¹ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -C (O) -, -NHC (O) -, -C (O) NH-, CH ₂ O、CH ₂ NH and CH ₂ 。

67. The compound according to any one of embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ Is a single ring.

68. The compound according to any one of embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ Is a bicyclic ring system.

69. A compound according to any one of embodiments 39 to 66 or a compound thereofPharmaceutically acceptable salts or solvates, wherein R ¹⁹ Is a polycyclic system.

70. The compound according to any one of embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ The method comprises the following steps:

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

71. The compound of any one of embodiments 39 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ The method comprises the following steps:

/>

72. the compound of any one of embodiments 39 to 71, or a pharmaceutically acceptable salt or solvate thereof, wherein R ² Selected from the group consisting of

/>

73. The compound of any one of embodiments 39 to 50 and 56 to 72, or a pharmaceutically acceptable salt or solvate thereof, wherein each R ⁵ Independently selected from:

-H、-NH ₂ 、-OH、-NH(C _1-6 alkyl group),

And m is 0, 1, 2 or 3 when present.

74. Having the formula A-L ^AB -a compound of B wherein

A is a monovalent form of a compound of any one of embodiments 1 to 73;

L ^AB are covalent linkers that bind to a and B; and is also provided with

B is a monovalent form of a degradation enhancer.

75. The compound of embodiment 74, wherein the degradation enhancer is capable of binding a protein selected from the group consisting of: E3A, mdm2, APC, EDD1, SOCS/BC-box/eloBC/CUL 5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE B, UBOX5 UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WWP1, WWP2, parkinson's protein, MKRN1, CMA (chaperone-mediated autophagy), SCFB-TRCP (jump-hysteresis-F box (. Beta. -TRCP) ubiquitin complex), b-TRCP (b-transduced repeat-containing protein), cIAP1 (apoptosis inhibitor protein 1), APC/C (late promoting complex/cell cycle body), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL 4) ^CRBN ) Ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, ahR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, atorvastatin, ibbean and CC-885.

76. The compound of embodiment 74, wherein the degradation enhancer is capable of binding a protein selected from the group consisting of: UBE2A, UBE2B, UBE2C, UBE D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE V2U, UBE V1, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.

77. The compound of any of embodiments 74 to 76, wherein L ^AB is-L ^AB1 -L ^AB2 -L ^AB3 -L ^AB4 -L ^AB5 -；

z is independently an integer from 0 to 10;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

78. The compound of any of embodiments 74 to 76, wherein L ^AB Is- (O-C) ₂ Alkyl group _z -, and z is an integer from 1 to 10.

79. The compound of any of embodiments 74 to 76, wherein L ^AB Is- (C) ₂ alkyl-O-) _z -, and z is an integer from 1 to 10.

80. The compound of any of embodiments 74 to 76, wherein L ^AB Is- (CH) ₂ ) _z1 L ^AB2 (CH ₂ O) _z2 -, wherein L ^AB2 Is a bond, 5-or 6-membered heterocycloalkylene or heteroarylene, phenylene, - (C) ₂ -C ₄ ) Alkynylene, -SO ₂ -or-NH-; and z1 and z2 are independently integers from 0 to 10.

81. The compound of any of embodiments 74 to 76, wherein L ^AB Is- (CH) ₂ ) _z1 (CH ₂ O) _z2 -wherein z1 and z2 are each independently integers from 0 to 10.

82. The compound of any of embodiments 74 to 76, wherein L ^AB Is a PEG linker.

83. The compound of any of embodiments 74 to 82, wherein B is a monovalent form of the compound selected from the group consisting of:

84. a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

85. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof.

86. A method of modulating the activity of a Ras protein, the method comprising contacting the Ras protein with an effective amount of a compound according to any one of embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.

87. The method of embodiment 85 or embodiment 86, comprising administering an additional agent or therapy.

88. A method of inhibiting cell growth, the method comprising administering to a cell expressing a Ras protein an effective amount of a compound according to any one of embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting growth of the cell.

89. The method of any one of embodiments 85 to 88, comprising administering to the cell an additional agent.

90. A Ras protein bound by the compound of any one of embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof, wherein the activity of the Ras protein is reduced compared to a Ras protein not bound to the compound.

Additional forms of the compounds disclosed herein

Isomers of

Furthermore, in some embodiments, the compounds described herein exist in geometric isomeric forms. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (E) and cis (Z) isomers, as well as their corresponding mixtures. In some cases, the compounds exist in tautomeric forms. The compounds described herein include all possible tautomers within the formulae described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in either the R configuration or the S configuration. The compounds described herein include all diastereoisomeric, enantiomeric and epimeric forms and their corresponding mixtures. 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 are used in the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of a racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by: reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereoisomers, and recovering the optically pure enantiomer. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and are separated by exploiting these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or, preferably, by separation/resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer as well as the resolving agent is then recovered by any practical means that does not result in racemization.

Labeled 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 a disease by administering such isotopically-labeled compounds in the form of 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 having an atomic mass or mass number different from the atomic mass or mass number usually found in natureAtomic substitution of mass numbers. Examples of isotopes incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as respectively ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ^l5 N、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. The compounds described herein, and pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, containing the above-mentioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds (e.g., radioisotopes such as ³ H and ¹⁴ those into which C is incorporated) are used in drug and/or substrate tissue distribution assays. Tritiated (i.e ³ H) And carbon-14 (i.e ¹⁴ C) Isotopes are particularly preferred because of their ease of preparation and detectability. Furthermore, the use of heavy isotopes such as deuterium (i.e ² H) The substitution of (c) yields certain therapeutic advantages derived from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically-labeled compounds, pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof are prepared by any suitable method.

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

Pharmaceutically acceptable salts

In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a number 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 described herein, or by separately reacting the purified compounds in their free form with a suitable acid or base, and isolating the salts formed thereby.

Solvates of the formula

In some embodiments, the compounds described herein exist in the form of solvates. In some embodiments are methods of treating diseases by administering such solvates. Also described herein are methods of treating diseases by administering such solvates in the form of pharmaceutical compositions.

Solvates contain a stoichiometric or non-stoichiometric amount of solvent and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. When the solvent is water, hydrates are formed, or when the solvent is an alcohol, alcoholates are formed. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from aqueous solvent/organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. Furthermore, the compounds provided herein exist in unsolvated forms as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

Synthesis of Compounds

In some embodiments, the synthesis of the compounds described herein is achieved using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, the solvents, temperatures, and other reaction conditions described herein may vary.

In other embodiments, the starting materials and reagents used to synthesize the compounds described herein are synthetic or obtained from commercial sources such as, but not limited to, sigma-Aldrich, fischerScientific (Fischer Chemicals) and Acros Organics.

In other embodiments, the compounds described herein and other related compounds having different substituents are synthesized by using the techniques and materials described herein and those recognized in the art, such as described, for example, in the following: fieser and Fieser's Reagents for Organic Synthesis, volumes 1-17 (John Wiley and Sons, 1991); rodd's Chemistry of Carbon Compounds, volumes 1-5 and journals (Elsevier Science Publishers, 1989); organic Reactions, volumes 1-40 (John Wiley and Sons, 1991), larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), march, advanced Organic Chemistry, 4 th edition, (Wiley 1992); carey and Sundberg, advanced Organic Chemistry, 4 th edition, volumes A and B (Plenum 2000, 2001), and Green and Wuts, protective Groups in Organic Synthesis, 3 rd edition, (Wiley 1999), all of which are incorporated herein by reference for such disclosure. The general methods for preparing the compounds as disclosed herein may originate from the reaction, and the reaction may be modified by the use of appropriate reagents and conditions for introducing the various moieties present in the formulae as provided herein. In some embodiments, the following synthetic methods may be utilized.

In some embodiments, the compounds of the invention exhibit one or more of the functional characteristics disclosed herein. For example, the subject compounds bind to Ras proteins, kras proteins, or mutant forms thereof. In some embodiments, the subject compounds specifically bind to and inhibit Ras proteins, kras proteins, or mutant forms thereof. In some embodiments, the subject compounds selectively inhibit Kras mutants relative to wild-type Kras. In some embodiments, the subject compounds selectively inhibit KrasG12D and/or KrasG12V relative to wild-type Kras. In some embodiments, the subject compounds have an IC50 for Kras mutants (e.g., including G12D) of less than about 5 μm, less than about 1 μm, less than about 50nM, less than about 10nM, less than about 1nM, less than about 0.5nM, less than about 100pM, or less than about 50pM, as measured in vitro assays known in the art or exemplified herein.

In some embodiments, the presently disclosed subject compounds are capable of reducing Ras signaling output. Such a decrease can be demonstrated by one or more members of (i) an increase in steady state levels of GDP-bound Ras protein; (ii) A decrease in phosphorylated AKTs473, (iii) a decrease in phosphorylated ERKT202/y204, (iv) a decrease in phosphorylated S6S235/236, and (v) a decrease (e.g., inhibition) in cell growth of Ras-driven tumor cells (e.g., tumor cells derived from the tumor cell lines disclosed herein). In some cases, the reduction in Ras signaling output can be demonstrated by two, three, four, or all of (i) - (v) above.

Method

In one aspect, a method of treating cancer in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject methods comprise administering an additional agent or therapy.

In one aspect, a method of modulating the activity of a Ras (e.g., K-Ras) protein is provided, comprising contacting the Ras protein with an effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; formulas I ', II ', I ', II ', I-1', I-3, I-4 a compound of II-1, XVI, XVII, XVIII or XIX) or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of a Ras (e.g., K-Ras) protein.

In some embodiments is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor or hematological cancer. In some embodiments is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor. In some embodiments is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from the group consisting of prostate cancer, brain cancer, colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head cancer or neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, hodgkin's disease, non-hodgkin's lymphoma, cancer of the endocrine system, thyroid cancer, parathyroid gland cancer, adrenal gland cancer, sarcoma of soft tissue, urinary tract cancer, penile cancer, childhood solid tumor, bladder cancer, renal or ureteral cancer, renal cell carcinoma, CNS cancer, central Nervous System (CNS) tumors, primary tumor of the nervous system (CNS), tumor angiogenesis, spinal axis (glioblastoma), shaft (glioblastoma), brain-axis (Kappy tumor, adenoma, squamous cell carcinoma, adenoma, carcinoma of the like, carcinoma of the pituitary cell, carcinoma of the like Environmentally induced cancer, combinations of such cancers, and metastatic lesions of such cancers. In some embodiments is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematologic cancer. In some embodiments is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer selected from one or more of: chronic Lymphocytic Leukemia (CLL), acute leukemia, acute Lymphoblastic Leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic Myelogenous Leukemia (CML), B-cell pre-lymphoblastic leukemia, blast plasmacytoid dendritic cell tumor, burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small or large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-hodgkin's lymphoma, plasmablastoid dendritic cell tumor, waldenstrom macroglobulinemia and promulgated leukemia. In some embodiments is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from Chronic Lymphocytic Leukemia (CLL), acute Myelogenous Leukemia (AML), T-cell acute lymphocytic leukemia (T-ALL), B-cell acute lymphocytic leukemia (B-ALL), and/or one or more of the cancers (ALL).

Any of the methods of treatment disclosed herein can be administered alone or in combination or association with another therapy or another agent. "combination" is meant to include (a) formulating a subject composition comprising a subject compound and another agent, and (b) using the subject composition separately from the other agent as an overall treatment regimen. By "in combination" is meant that another therapy or agent is administered simultaneously, concurrently or sequentially (without specific time limitations) with the subject compositions comprising the compounds disclosed herein, wherein such combination administration provides a therapeutic effect.

In some embodiments, the subject therapeutic methods are combined with surgical, cell therapy, chemotherapy, radiation, and/or immunosuppressive agents. In addition, the compositions of the present disclosure may be combined with other therapeutic agents, such as other anticancer agents, antiallergic agents, anti-nausea agents (or antiemetics), analgesics, cytoprotective agents, immunostimulants, and combinations thereof.

In one embodiment, the subject therapeutic methods are combined with a chemotherapeutic agent.

Exemplary chemotherapeutic agents include anthracyclines (anthracyclines) (e.g., doxorubicin (e.g., liposomal doxorubicin)), vinca alkaloids (e.g., vinblastine, vincristine, vindesine, vinorelbine), alkylating agents (e.g., cyclophosphamide, dacarbazine (decobazine), melphalan (melphalan), ifosfamide (ifosfamide), temozolomide), immune cell antibodies (e.g., alemtuzumab), gemtuzumab (gemtuzumab), rituximab (rituximab), oxamtuzumab (ofatumaab), tositumomab), busitumomab (brentuximab)), antimetabolites (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase (e.g., fludarabine), TNFR-induced by (temozolomide), or other drugs (e.g., fludarabine), or other drugs (e.g., granzyme) that induce a factor of the enzyme (e.g., gizomib), or other drugs (e.g., granzyme) such as the toxin (gizomib) or the derivatives of the enzyme may be used to treat the same conditions as the other drugs (e.g., the one or the derivatives of the enzyme-related toxin (gizotoxin (e.g., gizotoxin-62) Busulfan injection>Cladribine>CyclophosphamideOr->) Cytarabine, cytosine arabinoside (cytosine arabinoside)Cytarabine liposome injection>Daunorubicin hydrochloride (daunorubicin hydrochloride)>Daunorubicin citrate liposome injection (Daun oxo->) Dexamethasone, doxorubicin hydrochloride->Etoposide->Fludarabine phosphateHydroxyurea (hydroxyurea)>Idarubicin (Idarubicin)>Mitoxantrone->Auzocine Mi Xingji tobulab (Gemtuzumab Ozogamicin) in the presence of a drug>Anastrozole (anastrozole)>Bicalutamide (bicalutamide)>Bleomycin sulfate (bleomycin)sulfate)/>Busulfan injection>Capecitabine->N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin +.>Carmustine (carmustine)>Chlorambucil->Cisplatin->Dacarbazine->Dactinomycin (dactinomycin) (actinomycin D (Actinomycin D), cosmegan, dexamethasone, docetaxel->5-fluorouracil->Flutamide (flutamide)>Tizalcitabine, gemcitabine, ifosfamide>IrinotecanL-asparaginase (L-asparginase)>Calcium leucovorin (leucovorin calcium), melphalan->6-mercaptopurine->Methotrexate (methotrexate) >Mitoxantrone->Milotatag (mylotarg), paclitaxel +.>Phoenix (yttrium 90/MX-DTPA), penstatin, polifeprosan 20 and carmustine implant +.>Tamoxifen citrate->Teniposide->6-thioguanine (6-thioguanine), thiotepa, tirapazamine (tirapaz amine)>Topotecan hydrochloride for injection>Vinca alkaloid->Vincristine->And vinorelbine>

Particularly interesting anti-cancer agents for combination with the compounds of the present invention include: anthracyclines; an alkylating agent; antimetabolites; an agent that inhibits the calcium-dependent phosphatase calcineurin (calcineuretin) or the p70S6 kinase FK506 or inhibits the p70S6 kinase; an mTOR inhibitor; an immunomodulator; anthracyclines; vinca alkaloids; a proteasome inhibitor;

GITR agonists; protein tyrosine phosphatase inhibitors; inhibitors of CDK4 kinase; BTK inhibitors; MKN kinase inhibitors; DGK kinase inhibitors; or oncolytic viruses.

Exemplary antimetabolites include, but are not limited to, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors: methotrexate5-fluorouracil (/ -)>Fluorine->) FluorouridineCytarabine (> Tarabine PFS), 6-mercaptopurine +.>6-Thioguanine (thioguraine- >) Fludarabine phosphate->Pennisetum>Pemetrexed (pemetrexed)>Raltitrexed->Cladribine>Clofarabine (clofaabine)>Azacytidine->Decitabine and gemcitabinePreferred antimetabolites include cytarabine, clofarabine and fludarabine.

Exemplary alkylating agents include, but are not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes: uracil mustard (aerosil) Uracil nitrogen/> ) Nitrogen mustard (chlorethine)>Cyclophosphamide (/ -s)> Revimmune ^TM ) Ifosfamide->Melphalan->Chlorambucil->Pipobromine (pipobroman)>Triethylenemelamine (triethylene melamine)Triethylenethiophosphoric acid amine), temozolomide (Temozolomide)Thiotepa->Busulfan->Carmustine>Lomustine (lomustine)>Streptozocin (streptozocin)>And dacarbazineAdditional exemplary alkylating agents include, but are not limited to, oxaliplatin +.>Temozolomide ]And->) The method comprises the steps of carrying out a first treatment on the surface of the Dactinomycin (also known as actinomycin-D,>) The method comprises the steps of carrying out a first treatment on the surface of the Melphalan (also known as L-PAM, L-lysosarcosine (L-sarcosine) and melphalan,)>) The method comprises the steps of carrying out a first treatment on the surface of the Altretamine (also known as Hexamethylmelamine (HMM)), ->) The method comprises the steps of carrying out a first treatment on the surface of the Carmustine >Bendamustine (Bendamustine)>Busulfan (/ -herba)>And->) The method comprises the steps of carrying out a first treatment on the surface of the Carboplatin->Lomustine (also called CCNU,>) The method comprises the steps of carrying out a first treatment on the surface of the Cisplatin (also known as CDDP, <' > cisplatin>And->-AQ); chlorambucil->Cyclophosphamide (/ -s)>And->) The method comprises the steps of carrying out a first treatment on the surface of the Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, +.>) The method comprises the steps of carrying out a first treatment on the surface of the Altretamine (also known as altretamine (HMM)) @>) The method comprises the steps of carrying out a first treatment on the surface of the IfosfamidePrednisomustine (Prednumustine);procarbazine (Procarbazine)>Dichloromethyldiethylamine (also known as nitrogen mustard (nitrogen mustard), nitrogen mustard (mustine) and dichloromethyldiethylamine hydrochloride,) The method comprises the steps of carrying out a first treatment on the surface of the Streptozotocin->Thiotepa (also known as thiophosphamide), TESPA and TSPA>) The method comprises the steps of carrying out a first treatment on the surface of the Cyclophosphamide->Bendamustine hydrochloride (Bendamustine HCl) is added>

In one aspect, the compositions provided herein may be administered in combination with radiation therapy, such as radiation. Systemic radiation can be administered at 12 Gy. The radiation dose may include a 12Gy cumulative dose to the whole body including healthy tissue. The radiation dose may include 5Gy to 20Gy. The radiation dose may be 5Gy, 6Gy, 7Gy, 8Gy, 9Gy, 10Gy, 11Gy, 12Gy, 13Gy, 14Gy, 15Gy, 16Gy, 17Gy, 18Gy, 19Gy, or up to 20Gy. The radiation may be whole body radiation or partial body radiation. In the case where the radiation is whole body radiation, it may be uniform or non-uniform. For example, a narrower region of the body, such as the neck, may receive a higher dose than a wider region, such as the buttocks, when the radiation may not be uniform.

Immunosuppressants can be used in combination with the subject therapeutic methods when desired. Exemplary immunosuppressants include, but are not limited to, cyclosporine (cycloporin), azathioprine (azathioprine), methotrexate, mycophenolic acid esters, and FK506, antibodies or other immune ablators (immunoablative agent) such as CAMPATH, anti-CD 3 antibodies (e.g., murominab, oxuzumab) or other antibody therapies, cytotoxins, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and radiation, peptide vaccines, and any combination thereof. In accordance with the presently disclosed subject matter, the various methods described above can include administering at least one immunomodulatory agent. In certain embodiments, the at least one immunomodulatory agent is selected from the group consisting of an immunostimulant, a checkpoint immune blocker (e.g., an blocker or inhibitor of an immune checkpoint gene such as, for example, PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIR, and CD 39), a radiotherapeutic agent, a chemotherapeutic agent, and combinations thereof. In some embodiments, the immunostimulant is selected from the group consisting of IL-12, agonist co-stimulatory monoclonal antibodies, and combinations thereof. In one embodiment, the immunostimulant is IL-12. In some embodiments, the agonist co-stimulatory monoclonal antibody is selected from the group consisting of an anti-4-lBB antibody (e.g., wu Ruili You Shan anti (urelumab), PF-05082566), an anti-OX 40 antibody (pogalizumab), tamoxizumab (tavolizumab), PF-04518600), an anti-ICOS antibody (BMS 986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. In one embodiment, the agonist co-stimulatory monoclonal antibody is an anti-4-l BB antibody. In some embodiments, the checkpoint immune blocker is selected from the group consisting of an anti-PD-L1 antibody (atezolizumab), an avermectin Li Youshan antibody (avelumab), a dulcis You Shan antibody, BMS-936559), an anti-CTLA-4 antibody (e.g., tremelimumab, ipilimumab), an anti-PD-1 antibody (e.g., pamtezumab (pembrolizumab), a nano Wu Liyou mab (nivolumab)), an anti-LAG 3 antibody (e.g., C9B7W, 410C 9), an anti-B7-H3 antibody (e.g., DS-5573 a), an anti-TIM 3 antibody (e.g., F38-2E 2), and combinations thereof. In one embodiment, the checkpoint immune blocker is an anti-PD-Ll antibody. In some cases, compounds of the present disclosure may be administered to a subject in combination (e.g., before, concurrently with, or after) bone marrow transplantation, T cell decontamination therapy using a chemotherapeutic agent such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide, or an antibody such as OKT3 or CAMPATH. In some cases, the expanded cells may be administered before or after surgery. Alternatively, a composition comprising a compound described herein may be administered with an immunostimulant. The immunostimulant may be a vaccine, colony stimulating agent, interferon, interleukin, virus, antigen, co-stimulatory agent, immunogenic agent, immunomodulator or immunotherapeutic agent. The immunostimulant may be a cytokine such as an interleukin. One or more cytokines may be introduced with the modified cells provided herein. Cytokines can be used to boost the function of modified T lymphocytes (including adoptively metastasized tumor-specific cytotoxic T lymphocytes) to expand within the tumor microenvironment. In some cases, IL-2 can be used to facilitate the expansion of modified cells described herein. Cytokines such as IL-15 may also be employed. Other relevant cytokines in the field of immunotherapy may also be utilized, such as IL-2, IL-7, IL-12, IL-15, IL-21, or any combination thereof. The interleukin may be IL-2 or aldeskin (aldeskeukin). The aldesleukin may be administered in low or high doses. The high dose aldi interleukin regimen may involve intravenous administration of aldi interleukin at about 0.037mg/kg (600,000IU/kg) every 8 hours for up to about 14 doses when tolerated. The immunostimulant (e.g., aldesleukin) may be administered within 24 hours after the administration of the cells. The immunostimulant (e.g., aldesleukin) may be administered as an infusion for up to about 4 days within about 15 minutes about every 8 hours after cell infusion. The immunostimulant (e.g., aldesleukin) may be administered at a dose of about 100,000iu/kg, 200,000iu/kg, 300,000IU/kg, 400,000IU/kg, 500,000iu/kg, 600,000IU/kg, 700,000IU/kg, 800,000IU/kg, 900,000IU/kg, or up to about 1,000,000IU/kg. In some cases, the aldesleukin may be administered at a dose of about 100,000iu/kg to 300,000IU/kg, 300,000IU/kg to 500,000iu/kg, 500,000iu/kg to 700,000IU/kg, 700,000IU/kg to about 1,000,000IU/kg.

In some embodiments, the present context can be combined with a Ras protein (e.g., KRAS) to regulate the activity of such Ras protein any compoundOr a combination or co-administration of a plurality of pharmacologically active agents including (1) inhibitors of MEK (e.g., MEK1, MEK 2) or mutants thereof (e.g., trametinib, kemetinib, bemetinib, semetinib, remimetinib); (2) Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and/or mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, octyinib, omutinib, EGF-816); (3) Immunotherapeutic agents (e.g., checkpoint immune blockers, as disclosed herein); (4) Taxane (taxane) (e.g., paclitaxel, docetaxel); (5) Antimetabolites (e.g., antifolates such as methotrexate, raltitrexed, pyrimidine analogs such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and jestistatin, cytarabine (ara C), fludarabine); (6) Inhibitors of FGFR1 and/or FGFR2 and/or FGFR3 and/or mutants thereof (e.g., nidanib); (7) Mitotic kinase inhibitors (e.g., CDK4/6 inhibitors such as, for example, palbociclib, rebabociclib, abbe's) and; (8) Anti-angiogenic drugs (e.g., anti-VEGF antibodies, such as, for example, bevacizumab); (9) Topoisomerase inhibitors (e.g., epipodophyllotoxins such as, for example, etoposide and vanpichia, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone); (10) Platinum-containing compounds (e.g., cisplatin, oxaliplatin, carboplatin); (11) Inhibitors of ALK and/or mutants thereof (e.g., crizotinib, albetinib, emtrictinib, bucatinib); (12) Inhibitors of c-MET and/or mutants thereof (e.g., K252a, SU11274, PHA665752, PF 2341066); (13) Inhibitors of BCR-ABL and/or mutants thereof (e.g., imatinib, dasatinib, nilotinib); (14) Inhibitors of ErbB2 (Her 2) and/or mutants thereof (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (15) Inhibitors of AXL and/or mutants thereof (e.g., R428, an Mfa tenib, XL-880); (16) Inhibitors of NTRK1 and/or mutants thereof (e.g., mersatinib); (17) Inhibitors of RET and/or mutants thereof (e.g., BLU-667, lenvatinib); (18) Inhibitors of A-Raf and/or B-Raf and/or C-Raf and/or mutants thereof (RAF-709, LY-3009120); (19) Inhibitors of ERK and/or mutants thereof (e.g., ulitinib); (20) MDM2 inhibitors (e.g., HDM-201, NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (21) Inhibitors of mTOR (e.g., rapamycin, temsirolimus, everolimus, dipholimus); (22) Inhibitors of BET (e.g., I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS 645); (23) Inhibitors of IGF1/2 and/or IGF1-R (e.g., trastuzumab, MEDI-573); (24) Inhibitors of CDK9 (e.g., DRB, huang Tongbi alcohol, CR8, AZD 5438, pravalano B, AT7519, dinaproxen, SNS-032); (25) Inhibitors of farnesyl transferase (e.g., tipifarnib); (26) Inhibitors of the SHIP pathway, including SHIP2 inhibitors and SHIP1 inhibitors; an inhibitor of SRC (e.g., dasatinib); (28) inhibitors of JAK (e.g., tofacitinib); (29) PARP inhibitors (e.g., olaparib, revapab, nilaparib, tazopanib); (30) BTK inhibitors (e.g., ibrutinib, acartinib, zebutinib); (31) ROS1 inhibitors (e.g., emtrictinib); (32) Inhibitors of the SHP pathway, including SHP2 inhibitors (e.g., 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine) and SHP1 inhibitors; (33) Inhibitors of Src, FLT3, HDAC, VEGFR, PDGFR, LCK, bcr-Abl or AKT; or (34) inhibitors of the KrasG12C mutant (e.g., including but not limited to AMG510, MRTX849 and any covalent inhibitors of cysteine residue 12 binding to Kras, the structure of which is well known) (e.g., as in US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206539, WO20191107519, WO2019141250, WO2019150305, US9862701, US20170197945, US20180086753, US10144724, US20190055211, US20190092767, US20180127396, US20180273523, US10280172, US20180319775, US20180273515, US20180282307, US20180282308, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO2019241157, WO2019217307, WO2020047192, WO 201708) 7528. Ras G12C inhibitors as described in WO2018218070, WO2018218069, WO2018218071, WO2020027083, WO2020027084, WO2019215203, WO2019155399, WO2020035031, WO2014160200, WO2018195349, WO2018112240, WO2019204442, WO2019204449, WO2019104505, WO2016179558, WO2016176338 or related patents and applications, each of which is incorporated by reference in its entirety); (35) SHC inhibitors (e.g., PP2, AID 371185); (36) a GAB inhibitor (e.g., GAB-0001); (37) GRB inhibitors; (38) PI-3 kinase inhibitors (e.g., idola Li Xibu, ku Pan Lixi cloth, du Weili sibutra, acephate Li Xibu, tamsulosin Li Xibu, pirifaxine, bupirinotecan, erbu Li Xibu, NVP-BEZ 235-AN); (39) a MALPK inhibitor; (40) CDK4/6 (e.g., palbociclib), ribociclib, abbe ciclib); or (41) MAPK inhibitors (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323, GW-856553, RWJ67657, BCT-197); or (42) an inhibitor of the SHP pathway, including SHP2 inhibitors (e.g., 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine, RMC-4630, TNO 155) JAB-3068/>IACS-13909/BBP-398/>SHP099/>ERAS-601 and RMC-4550SHP1 inhibitors. In some embodiments, the present text can be combined with Ras proteins (e.g., kras) to regulate the activity of such Ras proteins of any compound can be combined with one or more checkpoint immune blockers (e.g., anti-PD-1 andor anti-PD-L1 antibodies, anti-CLTA-4 antibodies) in combination or in combination. In some embodiments, any compound herein capable of binding to a Ras protein (e.g., KRAS) to modulate the activity of such a Ras protein can be administered in combination or association with one or more pharmacologically active agents, including inhibitors against one or more targets selected from the group consisting of: MEK, epidermal Growth Factor Receptor (EGFR), FGFR1, FGFR2, FGFR3, mitokinase, topoisomerase, ALK, C-MET, erbB2, AXL, NTRK1, RET, a-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1/2, IGF1-R, CDK9, SHIP1, SHIP2, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, bcr-Abl, AKT, krasG C mutants, and ROS1. When desired, the additional agent may be an inhibitor against one or more targets selected from the group consisting of: MEK, epidermal Growth Factor Receptor (EGFR), FGFR1, FGFR2, FGFR3, mitokinase, topoisomerase, ALK, C-MET, erbB2, AXL, NTRK1, RET, a-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1/2, IGF1-R, CDK9, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, bcr-Abl, AKT, krasG12C mutants, and ROS1. In some embodiments, any compound herein capable of binding to a Ras protein (e.g., KRAS, mutant Ras proteins) to modulate the activity of such Ras mutants (e.g., G12C, G12D, G3512S, G12V, G C or G13D) can be combined or co-administered with one or more additional pharmacologically active agents, including inhibitors of SOS (e.g., SOS1, SOS 2) or mutants thereof. In embodiments, the additional pharmacologically active agent that is combined or co-administered with a compound described herein (e.g., a compound that is capable of binding a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS 2). In embodiments, the additional pharmacologically active agent that is combined or co-administered with a compound described herein (e.g., a compound that is capable of binding a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS 2). In embodiments, the compound (e.g., capable of binding to Ras protein) in combination or combined administration with additional pharmacologically active agent is selected from the group consisting of SOS (example Such as inhibitors of SOS1, SOS 2): RMC-5845, BI-3406->BI-1701963、MRTX0902/>And BAY 293->In embodiments, the additional pharmacologically active agent that is combined or co-administered with a compound described herein (e.g., a compound that is capable of binding a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS 2) described in WO2021092115, WO2018172250, WO2019201848, WO2019122129, WO2018115380, WO2021127429, WO2020180768, or WO2020180770, which are incorporated herein by reference in their entirety for all purposes.

In some embodiments, any compound herein capable of binding to a Ras protein (e.g., kras) to modulate the activity of such a Ras protein can be combined or administered in combination with one or more checkpoint immune blockers (e.g., anti-PD-1 and/or anti-PD-L1 antibodies, anti-CLTA-4 antibodies).

In some embodiments, any of the compounds described herein that are capable of binding to a Ras protein (e.g., KRAS) can be combined or administered in combination with one or more pharmacologically active agents, including the following inhibitors: (1) SOS1 or a mutant thereof (e.g., RMC-5845, BI-3406, BAY-293, MRTX0902, BI-1701963); (2) SHP2 or mutants thereof (e.g., 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine, TNO155, RMC-4630, ERAS-601, JAB-3068, IACS-13909/BBP-398, SHP099, RMC-4550); (3) SHC or mutants thereof (e.g., PP2, AID 371185); (4) GAB or a mutant thereof (e.g., GAB-0001); (5) GRB or mutant thereof; (6) JAK or a mutant thereof (e.g., tofacitinib); (7) A-RAF, B-RAF, C-RAF, or mutants thereof (e.g., RAF-709, LY-3009120); (8) BRAF or a mutant thereof (e.g., sorafenib, vitamin Mo Feini, dapafinib, kang Naifei, regorafenib, GDC-879); (9) MEK or a mutant thereof (e.g., trametinib, kemetinib, bemetinib, semetinib, remimetinib, AZD 6244); (10) ERK or mutants thereof (e.g., ulitinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, ravoxertiinib); (11) PI3K or mutants thereof (e.g., idola Li Xibu, ku Pan Lixi cloth, du Weili sibutra, acephate Li Xibu, tambour Li Xibu, pirifaxine, bupirinotecan, erbu Li Xibu, NVP-BEZ 235-AN); (12) MAPK or a mutant thereof (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323, GW-856553, RWJ67657, BCT-197); (13) EGFR or a mutant thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, octtinib, omutinib, EGF-816); (14) c-MET or mutants thereof (e.g., K252a, SU11274, PHA665752, PF 2341066); (15) ALK or a mutant thereof (e.g., crizotinib, albantinib, emtrictinib, bucatinib); (16) FGFR1, FGFR-2, FGFR-3, FGFR-4, or mutants thereof (e.g., nidamib); (17) BCR-ABL or a mutant thereof (e.g., imatinib, dasatinib, nilotinib); (18) ErbB2 (Her 2) or a mutant thereof (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (19) AXL or a mutant thereof (e.g., R428, an Mfa tinib, XL-880); (20) NTRK1 or a mutant thereof (e.g., mersatinib); (21) ROS1 or a mutant thereof (e.g., emtrictinib); (22) RET or a mutant thereof (e.g., BLU-667, lenvatinib); (23) MDM2 or a mutant thereof (e.g., HDM-201, NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (24) mTOR or a mutant thereof (e.g., rapamycin, temsirolimus, everolimus, dipholimus); (25) BET or mutants thereof (e.g., I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS 645); (26) IGF1, IGF2, IGF1R, or mutants thereof (e.g., zhantuzumab, MEDI-573); (27) CDK9 or a mutant thereof (e.g., DRB, huang Tongbi alcohol, CR8, AZD 5438, pravastatin B, AT7519, dixic, SNS-032); or (28) CDK4/6 (e.g., palbociclib, rebabociclib, abbe west).

In combination therapy, the compounds provided herein and other anti-cancer agents can be administered simultaneously, concurrently or sequentially without specific time constraints, wherein such administration provides therapeutically effective levels of both compounds in the body of the patient.

In some embodiments, the compounds of the present disclosure and other anti-cancer agents are administered sequentially in any order, typically by infusion or oral administration. The dosing regimen will vary depending on the stage of the disease, the patient's physical health level, the safety profile of the individual drugs and the tolerability of the individual drugs, as well as other criteria well known to the attending physician and medical practitioner administering the combination. Depending on the particular period to be used for treatment, the compounds of the invention and other anti-cancer agents may be administered minutes, hours, days, or even weeks apart from each other. Furthermore, the cycle may include more frequent administration of one drug than another during the treatment cycle, as well as administration at a different dose each time the drug is administered.

Antibiotics may be administered to a subject as part of a therapeutic regimen. The antibiotic may be administered in a therapeutically effective dose. Antibiotics may kill bacteria or inhibit the growth of bacteria. The antibiotic may be a broad spectrum antibiotic that can target a wide range of bacteria. The 3 rd or 4 th generation broad spectrum antibiotic may be cephalosporin (cephalosporin) or quinolone (quinolone). The antibiotic may also be a narrow spectrum antibiotic that can target a specific type of bacteria. Antibiotics can target bacterial cell walls such as penicillin (penicillin) and cephalosporins. Antibiotics can target cell membranes such as polymyxin (polymyxin). Antibiotics can interfere with essential bacterial enzymes, such as antibiotics: rifamycin (rifamycin), leap-year mycin (lipiarmycin), quinolones, and sulfonamides. Antibiotics may also be protein synthesis inhibitors such as macrolides (macrolide), lincosamide (lincosamide) and tetracyclines (tetracyclines). The antibiotic may also be a cyclic lipopeptide such as daptomycin, glycylcycline such as tigecycline, oxazolidone such as linezolid, and leap-year mycin such as fidaxomicin. In some cases, the antibiotic may be generation 1, generation 2, generation 3, generation 4, or generation 5. The first generation antibiotics can have a narrow spectrum. Examples of the 1 st generation antibiotics may be penicillin (penicillin G or penicillin V), cephalosporin (cefazolin), cephalothin (Cephalothin), cefpirin (cephalexin), cefalexin (Cephalothin), cefradine (Cephradin) or cefadroxil (cephaldroxin)). In some cases, the antibiotic may be generation 2. The 2 nd generation antibiotic may be penicillin (Amoxicillin) or Ampicillin (Ampicillin)), cephalosporin (Cefuroxime), cefamandole (cephalomandole), cefoxitin (Cephoxitin), cefaclor (cephaloclor), cefprozil (cefrozil), chlorocarbon cephalosporin (Loracarbef)). In some cases, the antibiotic may be generation 3. The 3 rd generation antibiotics may be penicillin (carbocilin and ticarcillin) or cephalosporins (cefixime), ceftriaxone (ceftriaxone), cefotaxime (cefphotaxime), ceftizoxime (ceftizoxime) and ceftazidime (ceftazidime)). The antibiotic may also be a 4 th generation antibiotic. The 4 th generation antibiotic may be cefepime (cephime). The antibiotic may also be generation 5. The 5 th generation antibiotic may be ceftaroline (Cephtaloline) or cefpiramide (Cephtobiprole).

In some cases, the antiviral agent can be administered as part of a therapeutic regimen. In some cases, a herpesvirus prophylactic agent may be administered to a subject as part of a therapeutic regimen. The herpesvirus prophylaxis agent may be valacyclovir (Valtrex). Valtrex can be orally administered to prevent herpes virus infection in subjects with positive HSV serology. It may be provided in 500mg tablets. Valacyclovir can be administered in a therapeutically effective amount.

In some cases, the treatment regimen may be administered according to the weight of the subject. After being determined to be obese (BMI>35 A) may need to utilize the actual body weight. BMI was calculated by: bmi=weight (kg)/[ height (m) ]] ² 。

The body weight may be calculated as 50kg+2.3 inches (over 60 inches) for men or 45.5kg+2.3 inches for women. For subjects exceeding 20% of their ideal body weight, the adjusted body weight can be calculated. The adjusted body weight may be the sum of ideal body weight + (0.4× (actual body weight-ideal body weight)). In some cases, body surface area may be used to calculate the dose. Body Surface Area (BSA) can be calculated by: BSA (m 2) = vheight (cm) weight (kg)/3600.

In some embodiments is a method of modulating the activity of a Ras protein, the method comprising contacting the Ras protein with an effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compounds of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the modulation comprises inhibiting Ras (e.g., K-Ras) protein activity. In some embodiments is a method of modulating the activity of a Ras (e.g., K-Ras) protein, the method comprising contacting the Ras protein with an effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; formulas I ', II ', I ', II ', I-1', I-3, I-4 a compound of II-1, XVI, XVII, XVIII or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is a K-Ras protein. In some embodiments is a method of modulating the activity of a Ras (e.g., K-Ras) protein, the method comprising contacting the Ras protein with an effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; formulas I ', II ', I ', II ', I-1', I-3, I-4 a compound of II-1, XVI, XVII, XVIII or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is G12D or G12V mutant K-Ras. In some embodiments is a method of modulating the activity of a Ras (e.g., K-Ras) protein, the method comprising contacting the Ras protein with an effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; formulas I ', II ', I ', II ', I-1', I-3, I-4 a compound of II-1, XVI, XVII, XVIII or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is G12D mutant K-Ras. In some embodiments is a method of modulating the activity of a Ras (e.g., K-Ras) protein, the method comprising contacting the Ras protein with an effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; formulas I ', II ', I ', II ', I-1', I-3, I-4 a compound of II-1, XVI, XVII, XVIII or XIX) or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is G12V mutant K-Ras.

In some embodiments, there is provided a method of treating a disorder by contacting a cell with a compound described herein (e.g., a compound of formula I, IA, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; formulas I ', II ', I ', II ', I-1 '; I-1', I-1', I-3, I-4 II-1, XVI, XVII, XVIII or XIX) to reduce Ras signaling output in a cell. The reduction in Ras signaling can be demonstrated by one or more of the following members: (i) an increase in steady state levels of the GDP-bound Ras protein; (ii) a reduction of phosphorylated AKTs 473; (iii) a reduction in phosphorylated ERKT202/y 204; (iv) a reduction in phosphorylated S6S 235/236; and (v) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., tumor cells from a tumor cell line). In some cases, the decrease in Ras signaling output can be demonstrated by two, three, four, or all of (i) - (v) above. In some embodiments, the decrease in any one or more of (i) - (v) may be 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more, as compared to a control not treated with the subject compound. The reduction in cell growth can be demonstrated using tumor cells or cell lines. The tumor cell line may originate from a tumor in one or more tissues such as pancreas, lung, ovary, biliary tract, intestine (e.g., small intestine, large intestine (i.e., colon)), endometrium, stomach, hematopoietic tissue (e.g., lymphoid tissue), and the like. Examples of tumor cell lines with K-Ras mutations can include, but are not limited to, A549 (e.g., K-Ras G12S), AGS (e.g., K-Ras G12D), ASPC1 (e.g., K-Ras G12D), calu-6 (e.g., K-Ras Q61K), CFPAC-1 (e.g., K-Ras G12V), CL40 (e.g., K-Ras G12D), COLO678 (e.g., K-Ras G12D), COR-L23 (e.g., K-Ras G12V), DAN-G (e.g., K-Ras G12V), GP2D (e.g., K-Ras G12D), GSU (e.g., K-Ras G12F), HCT116 (e.g., K-Ras G13D), HEC1A (e.g., K-Ras G12D), COLO678 (e.g., K-Ras G12D) HEC1B (e.g., K-Ras G12F), HEC50B (e.g., K-Ras G12F), HEYA8 (e.g., K-Ras G12D or G13D), HPAC (e.g., K-Ras G12D), HPAII (e.g., K-Ras G12D), HUCCT1 (e.g., K-Ras G12D), KARPAS620 (e.g., K-Ras G13D), KOPN8 (e.g., K-Ras G13D), KP-3 (e.g., K-Ras G12V), KP-4 (e.g., K-Ras G12D), L3.3 (e.g., K-Ras G12D), lovo (e.g., K-Ras G13D), LS180 (e.g., K-Ras G12D), LS513 (e.g., K-Ras G12D), MCAS (e.g., K-Ras G12D), NB4 (e.g., K-Ras A18D), NCI-H1355 (e.g., K-Ras G13C), NCI-H1573 (e.g., K-Ras G12A), NCI-H1944 (e.g., K-Ras)

G13D), NCI-H2009 (e.g., K-Ras G12A), NCI-H441 (e.g., K-Ras)

G12V), NCI-H747 (e.g., K-Ras G13D), NOMO-1 (e.g., K-Ras G12D), OV7 (e.g., K-Ras G12D), PANC0203 (e.g., K-Ras G12D), PANC0403 (e.g., K-Ras G12D), PANC0504 (e.g., K-Ras G12D), PANC0813 (e.g., K-Ras G12D), PANC1 (e.g., K-Ras G12D), panc-10.05 (e.g., K-Ras G12D), paTu-8902 (e.g., K-Ras G12V), PK1 (e.g., K-Ras G12D), PK45H (e.g., K-Ras G12D), PK59 (e.g., K-Ras G12D), SK-CO-1 (e.g., K-Ras G12V) SKLU1 (e.g., K-Ras G12D), SKM-1 (e.g., K-Ras K117N), SNU1 (e.g., K-Ras G12D), SNU1033 (e.g., K-Ras G12D), SNU1197 (e.g., K-Ras G12D), SNU407 (e.g., K-Ras G12D), SNU410 (e.g., K-Ras G12D), SNU601 (e.g., K-Ras G12D), SNU61 (e.g., K-Ras G12D), SNU8 (e.g., K-Ras G12D), SNU869 (e.g., K-Ras G12D), SNU-C2A (e.g., K-Ras G12D), SUI.86.86 (e.g., K-Ras G12D), SUIT2 (e.g., K-Ras G12D), SNU601 (e.g., K-Ras G12D), SW1990 (e.g., K-Ras G12D), SW403 (e.g., K-Ras G12V), SW480 (e.g., K-Ras G12V), SW620 (e.g., K-Ras G12V), SW948 (e.g., K-Ras Q61L), T3M10 (e.g., K-Ras G12D), TCC-PAN2 (e.g., K-Ras G12R), TGBC11TKB (e.g., K-Ras G12D), and MIA Pa-Ca (e.g., MIA Pa-Ca 2 (e.g., K-Ras G12C)).

In some embodiments is a method of inhibiting the activity of a KrasG12D mutein comprising contacting the KrasG12D mutein with a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a method of inhibiting the activity of a KrasG12D mutein comprising contacting the KrasG12D mutein with a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of inhibiting the activity of a KrasG12D mutein comprising contacting the KrasG12D mutein with a compound of formula I, I', II ", IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of inhibiting the activity of a KrasG12D mutein comprising contacting the KrasG12D mutein with the formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV; i ', II', I ', II', I-1I-1 ', I-1', the compounds I-3, I-4, II-1, XVI, XVII, XVIII or XIX.

Pharmaceutical compositions and methods of administration

The compounds described herein (e.g., compounds of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compounds of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or pharmaceutically acceptable salts or solvates thereof are administered to a subject in a biocompatible form suitable for administration to treat or prevent a disease, disorder, or condition. Administration of the compounds described herein can be in any pharmacological form, including a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; a compound of formula I ', II', I ", II", I-1', I-1", I-1'", I-3, I-4, II-1, XVI, XVII, XVIII, or XIX) or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with a pharmaceutically acceptable carrier.

In certain embodiments, the compounds described herein are administered in pure chemical form. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier selected based on the route of administration selected and standard pharmaceutical practice, as described, for example, in remington: the Science and Practice of Pharmacy (Gennaro, 21 st edition Mack pub. Co., easton, PA) (2005) of pennsylvania.

Accordingly, provided herein is a pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt described herein and one or more pharmaceutically acceptable excipients. Excipients (or carriers) are acceptable or suitable if they are compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I, I ', II', IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV; i ', II ', I ', II ', I-1 '; I-1', I-1', I-3, I-4 a compound of II-1, XVI, XVII, XVIII or XIX or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA2 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA3 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA4 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA5 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA6 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA7 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA8 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA9 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA10 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA11 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IA12 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula II or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA2 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA3 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA4 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA5 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA6 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA7 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA8 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA9 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA10 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA11 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula IIA12 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I', or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula II', or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I ", or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula II ", or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I-1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula II-1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula XVI or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula XVII or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula XVIII or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula XIX or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments of the methods described herein, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in the form of a pharmaceutical composition. Administration of the compounds and compositions described herein can be accomplished by any method that enables delivery of the compounds to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intra-arterial, intra-cardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including intradermal, dermal, enema, eye drops, ear drops, intranasal, vaginal), although the most suitable route may depend on, for example, the condition and disorder of the recipient. By way of example only, the compounds described herein may be topically applied to an area in need of treatment by, for example, local infusion during surgery, local application such as a cream or ointment, injection, catheter, or implant. Administration may also be by direct injection at the site of the diseased tissue or organ.

In some embodiments of the methods described herein, a pharmaceutical composition suitable for oral administration is provided in the form of: discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; powder or granule; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is provided in the form of a pill, a sugar drug (electuary), or a paste.

Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent or lubricant, surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be suitable for such administration in terms of dosage. Push-fit capsules may contain the active ingredient admixed with fillers (such as lactose), binders (such as starches) and/or lubricants (such as talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In some embodiments, a stabilizer is added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel (carbopol gel), polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee coating to identify or characterize different combinations of active compound doses.

In some embodiments of the methods described herein, the pharmaceutical composition is formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example in ampoules or in multi-dose containers with the addition of a preservative. The composition may take the form of a suspension, solution or emulsion, such as in an oily or aqueous vehicle, and may contain a formulation (formulatory agent), such as a suspension, stabilizer and/or dispersant. The compositions may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. The aqueous injection suspension may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

The pharmaceutical compositions may also be formulated as depot formulations. Such long acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular implantation) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., formulated as an emulsion in an acceptable oil) or ion exchange resins, or may be formulated as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

Examples

The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

As used herein, the following abbreviations should be understood to have the following meanings, unless otherwise indicated:

ACN or MeCN acetonitrile

AcOH acetic acid

Ac acetyl group

BINAP 2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl

Bn benzyl

BOC or Boc carbamic acid tert-butyl ester

i-Bu isobutyl

t-Bu tert-butyl

DCM dichloromethane (CH) ₂ Cl ₂ )

DIBAL-H diisobutylaluminum hydride

DIPEA or DIEA diisopropylethylamine

DMAP 4- (N, N-dimethylamino) pyridine

DME 1, 2-dimethoxyethane

DMF N, N-dimethylformamide

DMA N, N-dimethylacetamide

DMSO dimethyl sulfoxide

Dppf or Dppf 1,1' -bis (diphenylphosphine) ferrocene

EDC or EDCI N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride

Eq equivalent

Et ethyl group

Et ₂ O-diethyl ether

EtOH ethanol

EtOAc ethyl acetate

HPLC high performance liquid chromatography

Potassium KHMDS bis (trimethylsilyl) amide

Sodium NaHMDS bis (trimethylsilyl) amide

LiHMDS lithium bis (trimethylsilyl) amide

LAH lithium aluminate anhydride

LCMS liquid chromatography-mass spectrometry

Me methyl group

MeOH methanol

MS mass spectrum

Ms methylsulfonyl group

NMR nuclear magnetic resonance

Ph phenyl

iPr/i-Pr isopropyl

RP-HPLC reversed phase high pressure liquid chromatography

RT room temperature

TBS t-Butyldimethylsilyl group

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl group

TsOH/p-TsOH p-toluene sulfonic acid

Example 1: synthesis of 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7- (3-hydroxynaphthalen-1-yl) pyrido [4,3-d ] pyrimidin-5 (6H) -one (compound 103)

To a stirred solution of ethyl 4-chloro-6-methyl-2- (methylthio) pyrimidine-5-carboxylate (1-1) (988 mg,4 mmol) in dichloromethane (15 mL) was added triethylamine (835. Mu.L, 6 mmol) followed by (1R, 5S) -3, 8-diazabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (934 mg,4.4 mmol). The reaction mixture was stirred for 1 hour, diluted with water and extracted with dichloromethane. Combining the combined organic layers, passing through anhydrous Na ₂ SO ₄ Dried, filtered, and then concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 50% ethyl acetate/hexane to give compound 1-2 (1.65 g). ESI-MS m/z 423.2[ M+H ]] ⁺ 。

To a stirred solution of compounds 1-2 (730 mg,1.73 mmol) in anhydrous THF (10 mL) was added a 2M solution of lithium diisopropylamide in THF (3.03 mL,6.06 mmol) at-78deg.C under nitrogen. The reaction mixture was stirred for 30 minutes, then dimethyl carbonate (262 μl,3.1 mmol) was added. The reaction mixture was stirred at this temperature for 30 minutes, then slowly warmed up for 3 hours. The resulting mixture was treated with saturated NH ₄ The aqueous Cl solution was quenched and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ Dried, filtered, and then concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 70% ethyl acetate/hexane to give compounds 1 to 3 (606 mg). 481.2[ M+H ] ESI-MS m/z] ⁺ 。

A reaction mixture of compounds 1-3 (606 mg,1.26 mmol) and 2, 4-dimethoxybenzylamine (1.14 mL,7.58 mmol) in dioxane (5 mL) was heated at 140℃for 4 hours under microwave radiation. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with 0 to 70% ethyl acetate/hexane to give compounds 1 to 4 (428 mg). ESI-MS m/z 616.3[ M+H ]] ⁺ 。

To stirring of Compounds 1-4 (200 mg,0.33 mmol) in methanol (8 mL) at RTTo the solution was added a solution of 25% sodium methoxide in methanol (150. Mu.L, 0.65 mmol). The reaction mixture was stirred for 1 hour and concentrated. The residue was dissolved in water and acidified to pH 3-4 with 10% aqueous citric acid. The solid was collected, washed with water and dried in vacuo to give compounds 1-5 (180 mg). ESI-MS m/z 570.2[ M+H ]] ⁺ 。

To a stirred solution of compounds 1-5 (180 mg,0.31 mmol) in dichloromethane (4 mL) under nitrogen in an ice-water bath was added triethylamine (86. Mu.L, 0.62 mmol) followed by a 1M solution of trifluoromethanesulfonic anhydride in dichloromethane (450. Mu.L, 0.45 mmol). The reaction mixture was stirred for 30 min and concentrated. The residue was purified by silica gel column chromatography eluting with 0-40% ethyl acetate/hexane to give compounds 1-6 (197 mg). ESI-MS m/z 702.1[ M+H ] ] ⁺ 。

Compounds 1-6 (197mg, 0.28 mmol), 3-hydroxynaphthalene-1-boronic acid (80 mg,0.42 mmol), K ₃ PO ₄ (107 mg,0.5 mmol) and dichloro [1,1' -bis (di-tert-butylphosphino) ferrocene]The reaction mixture of palladium (II) (34 mg,0.056 mmol) in a mixed solvent of dioxane-water (6 ml, 3:1) was heated at 90 ℃ for 2 hours. The filtrate was concentrated by filtration through celite, and the residue was purified by silica gel column chromatography with 0-80% ethyl acetate/hexane to give compounds 1-7 (40 mg). ESI-MS m/z 696.2[ M+H ]] ⁺ 。

To a stirred solution of compounds 1-7 (40 mg,0.057 mmol) in dichloromethane (2 mL) was added 3-chloroperbenzoic acid (+.77%) (38 mg,0.17 mmol) under an ice water bath. The reaction mixture was stirred for 1 hour. Adding saturated NaHCO ₃ The aqueous solution was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and then concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane to give compounds 1-8 (20 mg). ESI-MS m/z 728.2[ M+H ]] ⁺ 。

To a stirred suspension of sodium hydride (60% dispersion in mineral oil) (4 mg,0.11 mmol) in DMF (0.5 mL) was added ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol (17 mg,0.11 mmol) in DMF (0.5 mL) at room temperature under nitrogen. The reaction mixture was stirred for 15 min, then compound 1-8 (20 mg,0.027 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 50 ℃ for 40 minutes. Cooling, adding saturated NH ₄ Aqueous Cl and ethyl acetate were used to extract the reaction mixture. The combined organic layers were washed with water, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and then concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane, then 0-10% ethyl acetate/MeOH to give compounds 1-9 (9 mg). ESI-MS m/z 807.3[ M+H ]] ⁺ 。

The reaction mixture of compounds 1-9 (9 mg) in 50% trifluoroacetic acid in dichloromethane (2 mL) was stirred at room temperature overnight and concentrated. The residue was purified by semi-preparative HPLC (5-60% CH ₃ CN/H ₂ O, 0.1% formic acid) to give compound 103 (2 mg) as formate. ESI-MS m/z 557.3; ¹ HNMR(400MHz,d ₆ δ11.50 (s, 1H), 8.29 (s, 1H x 2) (1 formic acid), 7.78 (dd, j=14.4 and 8.3hz, 2H), 7.46 (t, j=7.3 hz, 1H), 7.32 (t, j=7.3 hz, 1H) 7.27 (d, j=2.2 hz, 1H), 7.17 (d, j=2.3 hz, 1H), 6.20 (s, 1H), 5.33-5.20 (m, 1H), 4.10-3.95 (m, 3H), 4.06 (d, j=10.3 hz, 1H), 3.95 (d, j=10.3 hz, 1H), 3.60-3.50 (m, 2H), 3.35-3.25 (m, 2H), 3.14-3.06 (m, 2H), 3.05-2.98 (m, 1H), 2.35-2.98 (m, 1H), 4.10-3.95 (m, 3H), 4.06 (d, 1H), 3.35-1.95 (m, 1H).

EXAMPLE 2 Synthesis of 7- (2-amino-7-fluorobenzo [ d ] thiazol-4-yl) -4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6-cyclopropyl-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5 (6H) -one (compound 104)

A reaction mixture of Compounds 1-3 (480 mg,1 mmol) and cyclopropylamine (700. Mu.L, 10 mmol) in xylene (6 mL) was heated at 120deg.C overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with 0 to 100% ethyl acetate/hexane to give compound 2-1 (204 mg). ESI-MS m/z 506.2[ M+H ]] ⁺ 。

To a stirred solution of compound 2-1 (204 mg,0.40 mmol) in methanol (8 mL) was added a 25% sodium methoxide solution in methanol (183. Mu.L, 0.81 mmol). The reaction mixture was stirred at 50 ℃ for 30 minutes and concentrated. The residue was dissolved in water and acidified to pH 3-4 with 10% aqueous citric acid. The solid was collected, washed with water, and then dried in vacuo to give compound 2-2 (177 mg). ESI-MS m/z 460.2[ M+H ]] ⁺ 。

To a stirred solution of compound 2-2 (177 mg,0.38 mmol) in dichloromethane (5 mL) under nitrogen in an ice-water bath was added triethylamine (107. Mu.L, 0.77 mmol) followed by a 1M solution of trifluoromethanesulfonic anhydride in dichloromethane (570. Mu.L, 0.57 mmol). The reaction mixture was stirred for 30 min and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 50% ethyl acetate/hexane to give compound 2-3 (150 mg). ESI-MS m/z 592.2[ M+H ] ] ⁺ 。

Compound 2-3 (150 mg,0.25 mmol), (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d ]]Thiazol-4-yl) boronic acid (120 mg,0.38 mmol), K ₃ PO ₄ (80 mg,0.38 mmol) and dichloro [1,1' -bis (di-tert-butylphosphino) ferrocene]The reaction mixture of palladium (II) (30 mg,0.05 mmol) in a mixed solvent of dioxane-water (6 ml, 3:1) was heated at 90 ℃ for 2 hours, filtered through celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography with 0-50% ethyl acetate/hexane to give compound 2-4 (70 mg). ESI-MS m/z 710.2[ M+H ]] ⁺ 。

To a stirred solution of compounds 2-4 (70 mg,0.099 mmol) in dichloromethane (2 mL) was added 3-chloroperbenzoic acid (+.77%) (45 mg,0.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, saturated NaHCO was added ₃ The aqueous solution was extracted with dichloromethane. The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane to give compounds 2-5 (20 mg) and compounds 2-6 (45 mg). Compound 2-5ESI-MS m/z 742.2[ M+H ]] ⁺ . Compound 2-6ESI-MS m/z 726.2[ M+H ]] ⁺ 。

Sodium hydride (60% in mineral oil) (10 mg,0.26 mmol) in DMF (0To the stirred suspension in 5 mL) was added ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolidin-7 a-yl) methanol (43 mg,0.26 mmol) in DMF (1 mL). The reaction mixture was stirred for 15 min, then compound 2-5 (20 mg,0.027 mmol) and compound 2-6 (45 mg,0.062 mmol) in DMF (1.5 mL) were added. The reaction mixture was stirred at 50 ℃ for 40 minutes. Cooling, adding saturated NH ₄ Aqueous Cl and ethyl acetate were used to extract the reaction mixture. The combined organic layers were washed with water, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and then concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane, then 0-10% ethyl acetate/MeOH to give compounds 2-7 (13 mg). ESI-MS m/z 821.3[ M+H ]] ⁺ 。

The reaction mixture of compounds 2-7 (13 mg) in 20% trifluoroacetic acid in dichloromethane (2 mL) was stirred at room temperature for 4 hours and concentrated. The residue was purified by semi-preparative HPLC (5-60% CH ₃ CN/H ₂ O, 0.1% formic acid) to give compound 104 (3 mg) as formate. 621.2[ M+H ] ESI-MS m/z] ⁺ ； ¹ HNMR (400 mhz, d 6-DMSO): δ8.31 (s, 1H) (1 formic acid), 8.00 (s, 2H), 7.35 (dd, j=8.4 and 5.7hz, 1H), 7.03 (t, j=8.7 hz, 1H), 6.08 (s, 1H), 5.30-5.20 (m, 1H), 4.25-4.10 (m, 1H), 4.04 (d, j=10.3 hz, 1H), 3.93 (d, j=10.3 hz, 1H), 3.56-3.30 (m, 6H), 3.10-3.04 (m, 2H), 3.01-2.98 (m, 1H), 2.95-2.88 (m, 1H), 2.85-2.78 (m, 1H), 2.15-1.92 (m, 3H), 1.90-1.55 (m, 7H), 0.80-0.70 (m, 0.44H).

Example 2a: synthesis of 5- (7- (2-amino-7-fluorobenzo [ d ] thiazol-4-yl) -6-cyclopropyl-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-oxo-5, 6-dihydropyrido [4,3-d ] pyrimidin-4-yl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine-3-carbonitrile (compound 453)

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BnOH (26.2 g,243 mmol) was added to a solution of t-BuOK (27.2 g,243 mmol) in THF (250 mL) at 0deg.C, and the resulting mixture was stirred under argon atmosphere at 60deg.C for 1.5 hours. Will beThe mixture was cooled to 0 ℃ and the solution was added to a solution of compound 1-1 (50 g,202 mmol) in THF (100 mL) at-20 ℃ under an argon atmosphere. The mixture was stirred under argon at-20 ℃ for 1 hour. at-20deg.C, the mixture was treated with NH ₄ Aqueous Cl (200 mL) was diluted and extracted with EtOAc (3X 200 mL). The organic layer was washed with brine (200 mL), and dried over Na ₂ SO ₄ Dried, filtered, and the filtrate was concentrated by vacuum to give compound 3-2 (67 g, crude), which was used directly in the next step. ESI-MS m/z 319.1[ M+H ]] ⁺ 。

LiHMDS (643 mL,643mmol, 1M) was added to a solution of compound 3-2 (81.7 g,257 mmol) in THF (817 mL) under argon at-78deg.C, and the resulting mixture was stirred at this temperature for 1 hour. Dimethyl carbonate (23.1 g,257 mmol) was added at-78℃and the reaction mixture was then allowed to warm naturally to room temperature and stirred for 2 hours. The mixture was treated with NH at 0deg.C ₄ Aqueous Cl (1L) was diluted, extracted with EtOAc (3X 1L), and the organic layer was washed with brine (1L) and with Na ₂ SO ₄ Dried, and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column (15% etoac in PE) to give compound 3-3 (84 g). ESI-MS m/z 377.1[ M+H ]] ⁺ 。

At N ₂ LiHMDS (1M) (2.86 mL,2.86 mmol) was added to a suspension of compound 3-3 (1.1 g,2.86 mmol) in THF (15 mL) at-70deg.C. The mixture was warmed to 0 ℃ and stirred at 0 ℃ for 1 hour. The mixture was cooled to-70 ℃ and NFSI (924 mg,2.86 mmol) in THF (5 mL) was added. The mixture was warmed to 0 ℃ and stirred at 0 ℃ for 1 hour. Adding NH ₄ Aqueous Cl (5 mL) was used to quench the mixture and extracted with EA (15 ml×3). The organic layer was concentrated, and the residue was purified by flash column chromatography on silica gel (eluting with 0-15% EA in PE) to give compound 3-4 (850 mg). ESI-MS m/z 395.1[ M+H ]] ⁺ 。

To a suspension of compound 3-4 (700 mg,1.776 mmol) in EtOH (10 mL) was added DBU (1 mL). Cyclopropylamine (2 mL) was then added and stirred at room temperature until the mixture became clear. The mixture was stirred at room temperature for 1 hour. KOH powder (100 mg,1.776 mmol) was added and the mixture was stirred for 0.5 h. The mixture was poured into ice water and ph=4 to 5 was adjusted with HCl. The resulting precipitate was filtered to give compound 3-5 (470 mg). ESI-MS m/z 374.0[ M+H ] ] ⁺ 。

To a suspension of compounds 3-5 (9.0 g,24.13 mmol) in dry DCM (450 mL) was added a 4M HCl solution in dioxane (200 mL). The reaction mixture was stirred at 50℃for 3 hours. The mixture was concentrated and diluted with tert-butyl methyl ether. The solid was collected, washed with t-butyl methyl ether and dried to give compound 3-6 (5.6 g). 284.2[ M+H ] ESI-MS m/z] ⁺ 。

Compound 3-6 (5.6 g) was dissolved in POCl ₃ (230 mL) and heated to 105℃and the mixture was stirred at 105℃for 3 hours. The mixture was concentrated in vacuo, the residue was diluted with ice water and extracted with ethyl acetate. The combined organic layers were washed with water, brine and then concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 70% ethyl acetate/hexane to give compound 3 to 7 (2.2 g). ESI-MS m/z 320.1[ M+H ]] ⁺ 。

To a solution of compound 3-7 (170 mg,0.53 mmol) in DCM (10 mL) were added TEA (108 mg,1.07 mmol) and 4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyrazine-3-carbonitrile (110 mg,0.75 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 0-60% ea in PE) to give compound 3-8 (260 mg). ESI-MS m/z 402.0[ M+H ] ] ⁺ 。

To a solution of compounds 3-8 (240 mg,0.56 mmol) in DCM (10 ml) at room temperature was added m-CPBA (241 mg,1.39 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 0-60% ea in PE) to give compound 3-9 (240 mg). ESI-MS m/z 464.2[ M+H ]] ⁺ 。

At N ₂ Next, naH was added to a suspension of ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (106 mg,0.66 mmol) in THF (5 mL)27mg,0.66 mmol) and the mixture was stirred at 0℃for 1 hour. At N ₂ Compounds 3-9 (120 mg,0.22 mmol) were added and the reaction mixture was stirred at 0deg.C for 1 hr. Water (5 mL) was added and the residue extracted with EA (15 mL. Times.3). The organic layer was concentrated and the residue was purified by flash column chromatography on silica gel (eluting with 0-10% meoh in DCM) to give compound 3-10 (70 mg). ESI-MS m/z 543.3[ M+H ]] ⁺ 。

To a solution of compounds 3-10 (50 mg,0.09 mmol) in DMF (2 mL) was added (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d ] under argon]Thiazol-4-yl) boronic acid (72 mg,0.23 mmol) and the resulting mixture was bubbled with argon for 1 hour. Addition of Cs ₂ CO ₃ (90 mg,0.28 mmol) and DPEPhosPdCl ₂ (20 mg). The reaction mixture was then stirred under argon at 110℃for 3 hours. The mixture was filtered through celite and rinsed with ethyl acetate. The combined organic layers were concentrated and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/PE, then 0-20% meoh/DCM. The combined fractions were concentrated and the residue was further purified by preparative TLC plate (MeOH: dcm=15:1) to give compounds 3-11 (15 mg). ESI-MS m/z 775.2[ M+H ]] ⁺ 。

To a solution of compound 3-11 (15 mg,0.02 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) to give compound 453 (6.66 mg). ESI-MS m/z 675.2[ M+H ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD):δ7.92(s,1H),7.44–7.35(m,1H),7.03(t,J＝8.9Hz,1H),5.49(d,J＝52.2Hz,1H),5.02(s,2H),4.56(dd,J＝30.8,11.0Hz,4H),4.27(s,2H),3.67(t,J＝67.9Hz,4H),2.98(s,1H),2.67–2.43(m,2H),2.26(dd,J＝66.7,33.7Hz,4H),0.63(t,J＝65.1Hz,4H)。

Example 2b: synthesis of 4- (4- (3-oxa-7, 9-diazabicyclo [3.3.1] nonan-9-yl) -6-cyclopropyl-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5-oxo-5, 6-dihydropyrido [4,3-d ] pyrimidin-7-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile (compound 447)

To a stirred solution of compound 3-7 (50 mg,0.16 mmol) in DCM (3 mL) at room temperature was added Et ₃ N (43. Mu.L, 0.31 mmol) followed by the addition of 3-oxa-7, 9-diazabicyclo [3.3.1 ]]Nonane (53 mg,0.23 mmol). The reaction mixture was stirred for 30 minutes and then concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 100% ethyl acetate/hexane to give compound 4-1 (70 mg). ESI-MS m/z 512.3[ M+H ]] ⁺ 。

To a stirred solution of compound 4-1 (70 mg,0.14 mmol) in DCM (3 mL) was added m-CPBA (77%) (80 mg,0.34 mmol) at room temperature. The reaction mixture was stirred for 2.5 hours and then partially concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 100% ethyl acetate/hexane to give compound 4-2 (60 mg). ESI-MS m/z 544.3[ M+H ]] ⁺ 。

Compound 4-2 (60 mg,0.11 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (53 mg,0.33 mmol) andthe reaction mixture of molecular sieves (overdried and cooled) in anhydrous toluene (3 mL) was stirred in an ice-water bath for 40 min, then NaOtBu (32 mg,0.33 mmol) was added. The reaction mixture was stirred at this temperature for 30 minutes. The mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine and concentrated. The residue was purified by column chromatography on silica gel with 0-100% ethyl acetate/hexane, with 0.5% Et ₃ N was then purified with 0-20% MeOH/ethyl acetate to give compound 4-3 (58 mg). ESI-MS m/z 623.4[ M+H ]] ⁺ 。

To compound 4-3 (58 mg,0.093 mmol), (3-cyano-4- (5, 5-dimethyl-1, 3, 2-dioxaborane-2-yl) -7-fluorobenzo [ b)]Thiophene-2-yl) carbamic acid tert-butyl ester (75 mg,0.19 mmol), DPEphosPdCl ₂ (14 mg,0.019 mmol) cesium carbonate (76 mg, 0) was added to a reaction mixture in toluene (2.5 mL)23 mmol). The reaction mixture was degassed and purged with nitrogen, then heated at 105 ℃ overnight. Filtered through celite and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with 0-20% MeOH/ethyl acetate, with 0.5% Et ₃ N, then HPLC (10-95% CH ₃ CN/H ₂ O, 0.1% formic acid). The combined fractions were lyophilized to give compound 4-4.ESI-MS m/z 879.5[ M+H ]] ⁺ 。

The reaction solution of compound 4-4 in 20% TFA/DCM (2 mL) was stirred at room temperature for 2 hours and then concentrated. The residue was purified by preparative HPLC (5-65% ch ₃ CN/H ₂ O, 0.1% formic acid) to give compound 447 as a formate (1.5 mg). ESI-MS m/z 679.4[ M+H ]] ⁺ 。

Example 2c: synthesis of 7- (2-amino-7-fluorobenzo [ d ] thiazol-4-yl) -4- (azepan-1-yl) -6-cyclopropyl-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5 (6H) -one (compound 449)

To a stirred solution of compound 3-7 (34 mg,0.11 mmol) in DCM (2 mL) at RT was added Et ₃ N (29. Mu.L, 0.21 mmol) followed by hexamethyleneimine (16 mg,0.16 mmol). The reaction mixture was stirred for 30 minutes and then concentrated. The residue was purified by silica gel column chromatography eluting with 0-60% ethyl acetate/hexane to give compound 5-1 (35 mg). ESI-MS m/z 383.2[ M+H ]] ⁺ 。

To a stirred solution of compound 5-1 (35 mg,0.16 mmol) in DCM (2 mL) was added m-CPBA (77%) (51 mg,0.23 mmol) at room temperature. The reaction mixture was stirred for 2.5 hours, and then purified by silica gel column chromatography, eluting with 0-100% ethyl acetate/hexane, to give compound 5-2 (47 mg). ESI-MS m/z 415.2[ M+H ]] ⁺ 。

Compound 5-2 (47 mg,0.11 mmol), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (54 mg,0.34 mmol) andthe reaction mixture of molecular sieves (overdried and cooled) in anhydrous toluene (3 mL) was stirred in an ice-water bath for 40 min, then NaOtBu (33 mg,0.34 mmol) was added. The reaction mixture was stirred at this temperature for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and then concentrated. The residue was purified by column chromatography on silica gel with 0-100% ethyl acetate/hexane and 0.5% Et ₃ N was purified to give Compound 5-3 (43 mg). ESI-MS m/z 494.3[ M+H ]] ⁺ 。

Compound 5-3 (43 mg,0.09 mmol), (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d ]]Thiazol-4-yl) boronic acid (56 mg,0.18 mmol), pd (PPh) ₃ ) ₄ (23 mg,0.02 mmol) in 1, 4-dioxane (2 mL) was added to Na ₂ CO ₃ In a 2M solution in water (112. Mu.L, 0.23 mmol). The reaction mixture was degassed and purged with nitrogen and then heated at 95 ℃ overnight. The mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with 0-100% ethyl acetate/hexane and 0.5% et ₃ N was purified to give compound 5-4.ESI-MS m/z 726.5[ M+H ]] ⁺ 。

The reaction solution of compound 5-4 in 20% TFA/DCM (2 mL) was stirred at room temperature for 3 hours and then concentrated. The residue was purified by preparative HPLC (5-60% ch ₃ CN/H ₂ O, 0.1% formic acid) to give compound 449 (11 mg) as formate. ESI-MS m/z 626.4[ M+H ]] ⁺ ； ¹ HNMR(400MHz,DMSO-d6):δ8.05(s,2H),7.41(dd,J＝8.5and 5.6Hz,1H),7.07(t,J＝8.8Hz,1H),5.35-5.20(m,1H),4.10-3.95(m,2H),3.75-3.45(m,7H),3.10-2.98(m,3H),2.85-2.75(m,2H),2.10-2.08(m,1H),2.06-2.02(m,1H),2.00-1.92(m,1H),1.88-1.72(m,4H),1.54-1.38(m,4H),0.65-0.60(m,1H),0.52-0.48(m,1H),0.38-0.32(m,2H)。

Example 2d: synthesis of 7- (2-amino-7-fluorobenzo [ d ] thiazol-4-yl) -6-cyclopropyl-4- ((1R, 5S) -8- (2, 2-difluorocyclopropane-1-carbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5 (6H) -one (compound 452)

To a solution of compound 3-7 (315 mg,0.99 mmol) in DCM (4 mL) was added (1R, 5S) -3, 8-diazabicyclo [3.2.1 ] in DCM (3 mL)]Octane-8-carboxylic acid tert-butyl ester (230 mg,1.08 mmol) and Et ₃ N (300 mg,2.96 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (eluting with 0-40% EA in PE) to give compound 6-1 (350 mg). ESI-MS m/z 496.1[ M+H ]] ⁺ 。

To a solution of compound 6-1 (350 mg,0.71 mmol) in DCM (5 mL) was added m-CPBA (308 mg,1.77 mmol) at 0deg.C, and the reaction mixture was stirred at room temperature for 2 hours. By HNaO ₃ The mixture was diluted with aqueous S (10 mL) and extracted with DCM (3X 20 mL). The organic layer was treated with NaHCO ₃ Aqueous (3X 10 mL) and brine (10 mL) washed with Na ₂ SO ₄ Dried, filtered, and the filtrate was concentrated in vacuo to give compound 6-2 (300 mg), which was used directly in the next step. ESI-MS m/z 528.3[ M+H ]] ⁺ 。

To a solution of ((7 aS) -2-fluorotetrahydro-1H-pyrrolazin-7 a (5H) -yl) methanol (136 mg,0.85 mmol) in THF (3 mL) was added t-BuOK (1.13 mL,1.13mmol,1 m) under argon at-20 ℃ and the resulting mixture stirred at this temperature for 1 hour. Compound 6-2 (300 mg,0.57 mmol) in THF (5 mL) was added at-20deg.C and the mixture was stirred at this temperature for 2 hours. at-20deg.C with NH ₄ The mixture was diluted with aqueous Cl (10 mL) and extracted with DCM (3X 20 mL). The organic layer was washed with brine (10 mL), and dried over Na ₂ SO ₄ Dried, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 0-15% MeOH in DCM) to give compound 6-3 (230 mg). ESI-MS m/z 607.3[ [M+H] ⁺ 。

To a solution of 6-3 (50 mg,0.08 mmol) in DMF (2 mL) under argon was added (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d)]Thiazol-4-yl) boronic acid (66 mg,0.21 mmol) and the resulting mixture was bubbled with argon for 1 hour. Addition of Cs ₂ CO ₃ (81 mg,0.25 mmol) and DPEPhosPdCl ₂ (20 mg). The reaction mixture was then stirred under argon at 110℃for 4 hours. The mixture was filtered through celite and rinsed with ethyl acetate. The combined organic layers were concentrated and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/PE, then 0-20% meoh/DCM. The combined fractions were concentrated and the residue was further purified by preparative TLC plate (MeOH: dcm=15:1) to give compound 6-4 (50 mg). ESI-MS m/z 839.4[ M+H ]] ⁺ 。

To a solution of compound 6-4 (50 mg, crude) in DCM (3 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by preparative HPLC (FA) to give compound 6-5 (8 mg). ESI-MS m/z 639.3[ M+H ] ] ⁺ 。

To a solution of 6-5 (8 mg,0.013 mmol) in DMF (0.1 mL) was added 2, 2-difluorocyclopropane-1-carboxylic acid (1.5 mg,0.013 mmol), HATU (4.7 mg,0.013 mmol) and DIEA (5 mg,0.038 mmol), and the resulting mixture was stirred at room temperature under argon for 2 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (FA) to give compound 452 (3 mg). ESI-MS m/z 743.3[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD):δ8.45(s,2H),7.38(dd,J＝8.4,5.4Hz,1H),7.02(t,J＝8.8Hz,1H),5.47(d,J＝52.7Hz,2H),4.48(dd,J＝30.4,11.5Hz,3H),3.66(s,4H),3.01(dd,J＝33.1,22.2Hz,3H),2.46(d,J＝22.3Hz,2H),2.30(d,J＝8.8Hz,1H),2.21(t,J＝12.1Hz,3H),2.03(d,J＝25.4Hz,4H),1.90(d,J＝16.4Hz,4H),0.79(s,1H),0.50(d,J＝37.9Hz,4H)。

Example 2e: synthesis of 7- (2-amino-7-fluorobenzo [ d ] thiazol-4-yl) -4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -6-cyclopropyl-8-fluoro-2- ((S) -1- ((S) -1-methylpyrrolidin-2-yl) ethoxy) pyrido [4,3-d ] pyrimidin-5 (6H) -one (compound 448)

To a stirred solution of compounds 3-4 (220 mg,1.0 eq) in dichloromethane (2 mL) at 0 ℃ was added mCPBA (143 mg,1.5 eq) and the resulting mixture was stirred at 0 ℃ for 30 min. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with ethyl acetate/hexane to give compound 7-1 (222.8 mg). ESI-MS m/z 411.2[ M+H ]] ⁺ 。

To a solution of compound 7-1 (222.8 mg,1.0 eq.) in 1, 4-dioxane (1.0 mL) was added DIEA (141 ul,1.5 eq.) and (1S) -1- [ (2S) -1-methylpyrrolidin-2-yl ]Ethanol (77.2 mg,1.1 eq) and the resulting mixture was stirred at 100 ℃ for 2 hours. The mixture was concentrated and the residue was purified by reverse phase chromatography, water/CH ₃ CN elution to give Compound 7-2 (88.1 mg). ESI-MS m/z 476.3[ M+H ]] ⁺ 。

To a solution of compound 7-2 (88.1 mg,1.0 eq.) in MeOH (2.0 mL) was added cyclopropylamine (255 ul,20.0 eq.) and NaOMe (25%) (60 ul,1.5 eq.) and the resulting mixture was stirred at 50 ℃ for 1 hour. The mixture was concentrated and the residue was purified by reverse phase chromatography, water/CH ₃ CN elution to give Compound 7-3 (40.8 mg). ESI-MS m/z 379.3[ M+H ]] ⁺ 。

Compound 7-3 (40.8 mg,1.0 eq.) was dissolved in POCl ₃ (2.0 mL) and stirred at 105℃for 24 hours. The mixture was concentrated to remove volatiles to give compound 7-4, which was used directly in the next step. ESI-MS m/z 401.2[ M+H ]] ⁺ 。

To a solution of the crude compound 7-4 obtained above in DCM (5 mL) was added DIEA (177 ul,10.0 eq.) and (1R, 5S) -3, 8-diazabicyclo [3.2.1 ] at 0deg.C]Tert-butyl octane-3-carboxylate (65 mg,3.0 eq) and the resulting mixture was stirred at 0 ℃ for 10 min. The mixture was concentrated and the residue was purified by silica gel column chromatography with ethyl acetate +. Hexane was eluted to give compound 7-5 (20.5 mg). ESI-MS m/z 577.4[ M+H ]] ⁺ 。

Compound 7-5 (20.5 mg,1.0 eq), 2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d]Thiazol-4-yl) boronic acid (22 mg,2.0 eq), K ₂ CO ₃ (14.3 mg,3.0 eq.) and dichloro [1,1' -bis (di-tert-butylphosphino) ferrocene]The reaction mixture of palladium (II) (8.2 mg, catalyst) in a mixed solvent of dioxane-water (3 ml, 3:1) was stirred at 90 ℃ for 2 hours. The mixture was concentrated and the residue was purified by reverse phase chromatography, water/CH ₃ CN elution to give Compound 7-6 (9.2 mg). ESI-MS m/z 809.5[ M+H ]] ⁺ 。

The reaction mixture of compounds 7-6 (9.2 mg) in 20% trifluoroacetic acid in dichloromethane (2 mL) was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (5-60% ch ₃ CN/H ₂ O, 0.1% formic acid) to give compound 448 (1.96 mg) as formate. ESI-MS m/z 609.4[ M+H ]] ⁺ 。

Example 2f: synthesis of 7- (2-amino-7-fluorobenzo [ d ] thiazol-4-yl) -6-cyclopropyl-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -4- (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyrido [4,3-d ] pyrimidin-5 (6H) -one (compound 451)

To a solution of compound 3-7 (100 mg,0.157 mmol) in DCM (5 mL) was added hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (80 mg,0.376 mmol) and Et ₃ N (40 mg,0.314 mmol) and the resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (eluting with 0-60% ea in PE) to give compound 8-1 (170 mg). ESI-MS m/z 496.3[ M+H ]] ⁺ 。

To a solution of compound 8-1 (170 mg,0.34 mmol) in DCM (5 mL) at 0deg.C was added m-CPBA (120 mg,0.68 mmol) and the mixture was taken upThe resulting mixture was stirred at room temperature for 2.5 hours. With Na ₂ SO ₃ The mixture was diluted with aqueous solution (10 mL) and extracted with DCM (3×10 mL). The organic layer was treated with NaHCO ₃ Aqueous (3X 10 mL) and brine (10 mL) were washed with Na ₂ SO ₄ Dried, filtered, and the filtrate was concentrated in vacuo to give compound 8-2 (150 mg, crude), which was used in the next step. ESI-MS m/z 528.1[ M+H ]] ⁺ 。

To a solution of the compound ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (120 mg,0.75 mmol) in THF (5 mL) was added t-BuOK (0.75 mL,0.75mmol,1 m) under argon at-20 ℃ and the resulting mixture was stirred at this temperature for 30 minutes. Compound 8-2 (200 mg,0.37 mmol) in THF (5 mL) was added at-20deg.C and the mixture was stirred at this temperature for 1 hour. At this temperature with NH ₄ The mixture was diluted with aqueous Cl (20 mL) and extracted with EtOAc (3X 10 mL). The organic layer was washed with brine (10 mL), and dried over Na ₂ SO ₄ Dried, filtered, and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 0-15% MeOH in DCM) to give compound 8-3 (150 mg). ESI-MS m/z 607.3[ M+H ]] ⁺ 。

To a solution of 8-3 (100 mg,0.16 mmol) in DMF (3 mL) under argon was added (2- ((tert-butoxycarbonyl) amino) -7-fluorobenzo [ d ]]Thiazol-4-yl) boronic acid (132 mg,0.16 mmol) and the resulting mixture was bubbled with argon for 1 hour. Addition of Cs ₂ CO ₃ (162 mg,0.48 mmol) and DPEPhosPdCl ₂ (20 mg) and the mixture was stirred under argon at 110℃for 4 hours. The mixture was filtered through celite and rinsed with ethyl acetate. The combined organic layers were concentrated and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/PE, then 0-20% meoh/DCM. The combined fractions were concentrated and the residue was purified by preparative TLC plate (MeOH: dcm=15:1) to give compound 8-4 (35 mg). ESI-MS m/z 839.3[ M+H ]] ⁺ 。

To a solution of compound 8-4 (30 mg) in DCM (3 mL) was added TFA (1 mL), and the reaction mixture was stirred at room temperature for 1 hr . The mixture was concentrated, and the residue was purified by preparative HPLC (FA) to give compound 451 (6.10 mg). ESI-MS m/z 639.2[ M+H ]] ⁺ ；

¹ H NMR(400MHz,DMSO-d6):δ10.89(s,1H),9.00(s,2H),8.05(s,2H),7.50–7.29(m,1H),7.09(t,J＝8.8Hz,1H),5.51(d,J＝55.1Hz,1H),4.49(s,2H),3.95–3.67(m,7H),3.57(s,3H),3.08(s,5H),2.83(s,1H),2.12(s,3H),1.99(s,1H),1.24(s,2H),0.59(d,J＝30.4Hz,2H),0.40(s,2H)。

The compounds in table 6 were or could be prepared in a similar manner to that described in examples 1, 2 and 2a-2 f.

TABLE 6

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Example 3: ras sequence

Human K-Ras4b (SEQ ID NO. 1): 1MTEYKLVVVGAGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET 51CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI 101KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ

151GVDDAFYTLV REIRKHKEKM SKDGKKKKKK SKTKCVIM

Example 4: protein expression

DNA expression constructs encoding one or more protein sequences of interest (e.g., kras fragments thereof, mutant variants thereof, etc.) and their corresponding DNA sequences were optimized for expression in e.coli (e.coli) and synthesized by GeneArt Technology, e.g., life Technologies. In some cases, the protein sequence of interest is fused to a tag (e.g., glutathione S-transferase (GST), histidine (His), or any other affinity tag) to facilitate recombinant expression and purification of the protein of interest. Such tags may be cleaved after purification. Alternatively, such tags may remain intact attached to the target protein and may not interfere with the activity of the target protein (e.g., target binding and/or phosphorylation).

The resulting expression construct is additionally encoded with (i) att site sequences at the 5 'and 3' ends for subcloning into various vectors of interest using, for example, gateway Technology, and (ii) Tobacco Etch Virus (TEV) protease sites for proteolytic cleavage of one or more tag sequences. The vector of interest used may be a pET vector series from Novagen (e.g., with an ampicillin resistance gene) providing a GST tag fused to the N-terminus of the integrated gene of interest, and/or a pET vector series (e.g., with an ampicillin resistance gene) providing a HIS tag fused to the N-terminus of the integrated gene. To generate the final expression vector, the expression construct for the protein of interest is cloned into any of the vectors of interest that are used. The expression vector is transformed into an E.coli strain such as BL21 (DE 3). Cultivation of the transformed strain was performed in 10L and 1L fermenters for expression. Cultures were grown to a density of 0.6 (OD 600) at 37℃for example in a superfine broth (Terrific Broth media) with 200. Mu.g/mL ampicillin (MP Biomedicals, cat. No. 1 13045032), shifted to a temperature of about 27℃for K-Ras expression vector, induced for expression with 100mM IPTG, and further cultured for 24 hours. After culturing, the transformed E.coli cells were harvested by centrifugation, and the resulting pellet was suspended in a lysis buffer as provided below and lysed via a three pass high pressure device. The lysate was centrifuged (49000 g,45min,4 ℃), and the supernatant was used for further purification.

Example 5: ras protein purification

Ras (e.g., K-Ras wild-type or mutant such as K-Ras G12S, K-Ras G12D, K-Ras G12V or K-Ras G12C) constructs or variants thereof are tagged with GST. Coli cultures from a 10L fermenter were lysed in lysis buffer (50 mM Tris hcl7.5, 500mM NaCl, 1mM DTT, 0.5% CHAPS, complete protease inhibitor cocktail- (Roche)). As a first chromatography step, the centrifuged lysate was incubated with 50mL glutathione agarose 4B (Macherey-Nagel; 745500.100) in a spin flask (16 h,10' O). The protein-loaded glutathione sepharose 4B is transferred to a chromatography column connected to a chromatography system, e.g. Akta chromatography system. The column was washed with wash buffer (50 mM Tris HCl7.5, 500mM NaCl, 1mM DTT) and the bound protein was eluted with elution buffer (50 mM Tris HCl7.5, 500mM NaCl, 1mM DTT, 15mM glutathione). The main fractions of the elution peaks (monitored by OD 280) were pooled. For further purification by size exclusion chromatography, the above elution volumes were applied to a Superdex 200HR preparative column (GE Healthcare) and the resulting peak fractions of the eluted fusion proteins were collected. The final purified protein construct may be subjected to natural mass spectrometry analysis to assess its homogeneous GDP loading.

Example 6: HTRF (homogeneous time resolved fluorescence) resonance energy transfer assay

The ability of the compounds of the present disclosure to reduce Ras signaling output can be demonstrated by HTRF assays. This assay can also be used to assess the selective inhibition or reduction of the signaling output of a mutant Ras protein (e.g., G12D, G12S, G12C, G12V, G13D, G13S, G C or G13V) relative to wild-type or relative to a different mutant Ras protein. For example, the equilibrium interaction of wild-type Kras or K-Ras mutants (e.g., wild-type or mutants thereof) with SOS1 (e.g., hSOS 1) can be assessed as an indicator or indication of the ability of the subject compound to bind and inhibit Ras protein. The HTRF assay detects from (i) a Fluorescence Resonance Energy Transfer (FRET) donor (e.g., anti-GST-europium) bound to the GST-tagged K-Ras mutant to (ii) a FRET acceptor (e.g., anti-6 His-XL 665) bound to His-tagged hSOS 1.

The assay buffer may comprise about 5mM HEPES pH 7.4, about 150mM NaCl, about 1mM DTT, 0.05% BSA, and 0.0025% (v/v) Igepal. Ras working solutions are prepared in assay buffers that typically contain appropriate amounts of protein construct (e.g., GST-tagged K-Ras mutant) and FRET donor (e.g., anti-GST-Eu (K), from Cisbio France). SOS1 working solutions were prepared in assay buffers containing appropriate amounts of protein construct (e.g., his-hSOS 1) and FRET receptor (e.g., anti-6 His-XL665 from Cisbio France). The appropriate amount of protein construct will depend on the range of activity or range of IC50 values being detected or under study. To detect IC50 in the range of 500nM, protein constructs of the same molar concentration range can be used. Inhibitor control solutions were prepared in assay buffer containing a significant amount of FRET acceptor without SOS1 protein.

A fixed volume of DMSO with or without test compounds was transferred into 384 well plates. Ras working solution was added to all wells of the test plate. SOS1 working solution was added to all wells except the wells that were subsequently filled with inhibitor control solution. After incubation for about 10min or longer, fluorescence was measured using an M1000Pro plate reader (Tecan) using HTRF detection (excitation 337nm, emission 1:620nm, emission 2:665 nm). The compounds at different concentrations were tested in duplicate (e.g., 10 μΜ, 2.5 μΜ, 0.63 μΜ, 0.16 μΜ, 0.04 μΜ, 0.01 μΜ test compounds). Ratiometric data (i.e., emission 2 divided by emission 1) was used to calculate IC50 values for Ras using GraphPad Prism (GraphPad software). Following this general procedure, samples were tested with or without the subject compounds disclosed herein (including the compounds exemplified in table 6) to assess their ability to inhibit K-Ras mutants relative to another mutant or wild-type. Signal transduction outputs measured from the IC50 values can be obtained and the ratio of IC50 of one mutant relative to another can be calculated. For example, the selective decrease in K-Ras G12D signaling output can be demonstrated by a ratio greater than 1. Specifically, a selective decrease in K-Ras G12D signaling relative to K-Ras WT signaling was demonstrated as a ratio of IC50 (for K-Ras WT) to IC50 (for K-Ras G12D) greater than 1. In embodiments, it is contemplated that one or more of the subject compounds disclosed herein selectively inhibit Ras mutants (e.g., G12C, G D, G12S, G1V, G C or G13D) at least 1-fold, and in some cases greater than 2-fold, 3-fold, 4-fold, or 5-fold over wild-type. In embodiments, the compounds listed in table 7 below show the indicated IC50 values for KRas mutant G12D. In embodiments, the subject compounds are expected to exhibit an IC50 of less than 500nM, less than 100nM, 50nM, 10nM, or even less for KRas mutants (e.g., G12C, G12D, G12S, G1V, G C or G13D).

TABLE 7

'++ + +' means an IC50 of about or less than about 1.5. Mu.M, and '++' means an IC50 greater than about 1.5. Mu.M.

Example 7: GTPase Activity assay

The ability of any of the compounds of the present disclosure to inhibit Ras protein signaling can be demonstrated by reduced gtpase activity. This assay can also be used to assess the selective inhibition of mutant Ras proteins relative to wild-type or relative to different mutant Ras proteins. For example, assays can be used to determine the ability of a subject compound to selectively inhibit Kras G12D relative to wild type, G12S relative to wild type, kras G12V relative to wild type, krasG12S relative to KrasG12V, krasG S relative to KrasG12D, krasG12D relative to KrasG12S, or KrasG12D relative to KrasG 12V. Specifically, intrinsic and GTPase-stimulated GTPase activity of the K-Ras construct or mutant thereof can be measured using the Enzcheck phosphate assay system (Life Technologies). For example, by exposure to EDTA-containing exchange buffer, at room temperature in buffer (20 mmol/L Tris (pH 8.0), 50mM NaCl) K-Ras WT, K-Ras D154Q mutant protein, K-Ras G12D mutant protein, K-Ras G12S mutant protein and K-Ras G12D/D154Q mutant protein (2.5 mg/ml) with GTP loading 2 hours. Protein buffer was exchanged to assay buffer (30 mM Tris (pH 7.5), 1mM DTT) and the concentration was adjusted to 2mg/ml. GTP loading was verified by back-extraction of nucleotides using 6M urea and evaluation of nucleotide peaks by HPLC using ion exchange columns. The assay was performed in a clear 384 well plate (Costar) by combining the K-Ras protein loaded with GTP (final 50 mM) with 2-amino-6-mercapto-7-methylpurine ribonucleoside (MESG) (final 200 mM) and purine nucleotide phosphorylase (final 5U/ml). By adding MgCl at a working concentration of 40mM ₂ To initiate GTP hydrolysis. For GAP stimulation, ras P21 protein activator 1 (P120 GAP) can be included at 50 mM. Can be used at 20deg.CAbsorbance at 360nm was measured every 8 to 15 seconds for 1,000 seconds. Samples were tested with or without the subject compounds disclosed herein to assess the inhibitory capacity of each compound on signaling of a given target Ras protein (e.g., a given mutant Kras).

Example 8: nucleotide exchange assay

The ability of the compounds of the present disclosure to inhibit Ras protein signaling can be demonstrated by reduced nucleotide exchange activity. This assay can also be used to assess the selective inhibition of mutant Ras proteins relative to wild-type or relative to different mutant Ras proteins. For example, 250nM or 500nM GDP-loaded K-Ras proteins (e.g., wild-type or mutants thereof, including those mentioned in example 7) are each incubated with different concentrations of the compound (e.g., about 60 μΜ, about 20 μΜ, about 6.7 μΜ, about 2.2 μΜ, about 0.7 μΜ, about 0.2 μΜ subject compounds). Control reactions without the subject compound are also included. SOS1 (catalytic domain) protein was added to the K-Ras protein solution. By adding fluorescent-labeled GDP (5' -guanosine diphosphate, BODIPY) ^TM FL 2'- (or-3') -O- (N- (2-aminoethyl) carbamate) to a final concentration of 0.36. Mu.M to initiate the nucleotide exchange reaction. Fluorescence was measured every 30s for 70 minutes at 490nm/515nm (excitation/emission) in an M1000Pro plate reader (Tecan). The data were output and analyzed using GraphPad Prism (GraphPad software) to calculate IC50. Samples can be tested with or without the subject compounds disclosed herein (including the compounds exemplified in table 1) to assess the ability of a compound to inhibit K-Ras signaling or its IC50 against a given target Ras protein (e.g., a given mutant K-Ras).

Example 9: modification of test Ras proteins

Test compounds were prepared as 10mM stock solutions in DMSO (Fisher accession number BP 231-100). KRAS proteins (e.g., his-tagged GDP-loaded wild-type 1-169, his-tagged GDP-loaded G12C 1-169, his-tagged GDP-loaded G12D 1-169, or His-tagged GDP-loaded G12S 1-169) were diluted to about 2. Mu.M in an appropriate buffer (e.g., hepes buffer under physiological conditions). To test for KRAS modification, compounds were diluted in DMSO to 50X final test concentration in 96 well storage plates. Mu.l of diluted 50X compound was added to the appropriate wells in the PCR plate (Fisher catalog number AB-0800). Approximately 49 μl of stock protein solution was added to each well of a 96-well PCR plate. The reaction was carefully mixed. The plates were well sealed with an aluminum plate seal and stored in drawers for 24 hours at room temperature. Mu.l of 2% formic acid in MilliQ H2O (Fisher catalog No. A117-50) was then added to each well, followed by mixing with a pipette. The plates were then resealed with an aluminum seal and stored until mass spectrometry.

The extent of covalent modification of KRAS proteins can be determined by liquid chromatography electrospray mass spectrometry of intact proteins on a Thermo Q-actual Plus mass spectrometer. 20 μl of the sample was injected into a bioZen 3.6 μm complete C4 column (Phenomenex catalog No. 00B-4767-AN) placed in a column oven set at 40deg.C and the separation was performed using a suitable LC gradient from about 20% to about 60% solvent B. Solvent a was 0.1% formic acid and solvent B was 0.1% formic acid in acetonitrile. The HESI source settings were set to 40, 5 and 1 for sheath, auxiliary and purge gas flows, respectively. The spray voltage was 4kV and the capillary temperature was 320 ℃. The S-lens RF level was 50 and the assist gas heater temperature was set to 200 ℃. Mass spectra were obtained using a scan range of 650 to 1750m/z, using positive polarity with a mass resolution of 70,000, AGC target of 1e6 ions and maximum injection time of 250 ms. The recorded protein mass spectra were deconvolved from the original data file using version Protein Deconvolution 4.0.0 (Thermo). The protein mass and the adduct mass are output along with their peak intensities. The peak intensities of the unmodified and modified proteins were used to calculate the percent covalent modification of KRAS proteins based on the following equation: % KRAS protein modification= ((KRAS-compound)/(KRAS) + (KRAS-compound)). Times.100.

Example 10: ras cell assay

The ability of any compound of the present disclosure to inhibit Ras protein signaling can be demonstrated by inhibiting the growth of a given Kras mutant cell. For example, this assay can also be used to assess selective growth inhibition of mutant Ras proteins relative to wild-type or relative to different mutant Ras proteins.

a. Growth of cells with K-Ras G12C mutations

MIA PaCa-2 (ATCC CRL-1420) and NCI-H1792 (ATCC CRL-5895) cell lines contain the G12C mutation and can be used to assess Ras cell signaling in vitro, for example, in response to the subject inhibitor compounds of the present disclosure. This cellular assay can also be used to discern selective inhibition of the subject compounds against certain types of Kras mutants, for example by using MIA PaCa-2 (G12C-driven tumor cell line) as a comparison, inhibition of KrasG12D is more potent relative to KrasG12C mutants. MIA PaCa-2 medium was prepared with DMEM/Ham's F12 (e.g. with stabilized glutamine), 10% FCS and 2.5% horse serum. NCI-H1792 medium was prepared with RPMI 1640 (e.g. with stabilized glutamine) and 10% FCS.

On the first date (e.g., day 1), soft Agar (Select Agar, invitrogen, at ddH) ₂ 3% in O, autoclaved) and the temperature was adjusted at 48 ℃. The appropriate medium (i.e., medium) was warmed to 37 ℃. Agar (3%) was diluted 1:5 (=0.6%) in medium and 50 ml/well was plated into 96-well plates (Corning, # 3904) and then incubated at room temperature for agar solidification. 3% agar was diluted to 0.25% in medium (1:12 dilution) and the tempering was at 42 ℃. Cells were digested with trypsin, counted, and temperature regulated at 37 ℃. Cells (e.g., MIA PaCa-2 (at about 125-150 cells), NCI-H1792 (at about 1000 cells)) were resuspended in 100ml of 0.25% agar and plated, followed by incubation at room temperature for agar solidification. The wells were covered with 50mL of medium. Adjacent wells (master wells) in separate plates were plated for time zero determination. All plates were at 37℃and 5% CO ₂ Incubate overnight.

On the second date (e.g., day 2), the time zero value is measured. A40 mL volume of Cell Titer 96 aqueous solution (Promega) was added to each well and at 37℃and 5% CO ₂ Incubate in the dark. Absorption can be measured at 490nm and reference wavelength 660 nm. Testing of DMSO pre-dilution, e.g. with HP dispenser The compound is added to the target wells to achieve one or more desired concentrations (e.g., 0.3% final DMSO concentration).

On the tenth day (e.g., day 10), the absorbance of wells treated with test compound and control wells is measured with, for example, cell Titer 96AQUeous and analyzed as compared to the time zero measurement. Four parameter fitting was used to determine the IC50 values. The resulting IC50 value is a measure of the ability of a compound herein to reduce cell growth of Ras-driven cells (e.g., tumor cell lines) in vitro and/or in vivo.

b. Growth of cells with K-Ras G12D mutations

ASPC-1 (ATCC CRL-1682), panc-10.05 (ATCC CRL-2547), a427, GP2D cell line, or any other cell line comprising a G12D mutation may be used to assess Ras cell signaling in vitro, e.g., in response to the compounds herein. For example, ASPC-1 medium was prepared with RPMI-1640 and 10% heat inactivated FBS. Panc-10.05 medium was prepared with RPMI-1640, 10 units/ml human recombinant insulin and 10% FBS. A427 cell culture was prepared with RPMI-1640 and 10% heat inactivated FBS. Cell growth was assessed using CellTiter-Glo (CTG) luminescence-based assays (Promega) as a measure of the ability of the compounds herein to inhibit Ras signaling in cells. Cells (e.g., 800 per well) were seeded in their respective media in standard tissue culture treated 384 well format plates (Falcon # 08-772-116) or ultra low adsorption surface 384 well format plates (S-Bio # MS-9384 UZ). The next day after plating, cells are treated with a series of dilutions (e.g., a 9-point 3-fold dilution series) of the compounds herein (e.g., about 40 μl final volume per well). Cell viability may be monitored (e.g., after about 5 days) according to manufacturer's recommendations, with CellTiter-Glo reagent (e.g., about 10 μl) added, vigorously mixed, covered, and placed on a plate shaker (e.g., about 20 min) to ensure adequate cell lysis prior to assessment of luminescence signals. Four parameter fitting was used to determine the IC50 values. The resulting IC50 value is a measure of the ability of a compound herein to reduce cell growth of Ras-driven cells (e.g., tumor cell lines) in vitro and/or in vivo. Four parameter fitting was used to determine the IC50 values. The resulting IC50 value is a measure of the ability of a compound herein to reduce cell growth of Ras-driven cells (e.g., tumor cell lines) in vitro and/or in vivo. The ability of one or more compounds illustrated in table 6 to inhibit the growth of one or more cell lines comprising a given Kras mutation was demonstrated using the procedure described above. Corresponding assays for other mutants (e.g., G12S, G12C, G V, G13D, G13S, G C or G13V) were performed in a similar manner with appropriate cell lines.

Example 11: in vivo Ras inhibition

In a mouse tumor xenograft model (e.g., in a K-Ras mutant (G12D, G S, G12C, G12V, G13D, G13S, G C or G13V), an in vivo reduction in Ras signaling output by a compound of the present disclosure was determined in a model utilizing cells comprising a KRas G12D mutant (e.g., G12D, G12S, G12C, G12V, G13D, G13S, G C or G13V) to produce a xenograft model comparable to the xenograft model exemplified below.

Xenografts with K-Ras G12C mutations

In one example, a tumor xenograft is established by administering tumor cells (e.g., miappa a-2 cells) having a K-Ras G12C mutation into a mouse, e.g., injecting tumor cells to the right of female bontacnmri-Foxn 1nu mice between 6 and 8 weeks of age.

In the case of the subcutaneous (s.c.) MIAPaCa-2 xenograft mouse model, MIA PaCa-2 cells were grown in cell culture flasks in a suitable medium. Cultures at 37℃and 5% CO ₂ Incubate in humid environment, medium exchange or subculture 2-3 times per week. For injection, cultured tumor cells were mixed with PBS including 5% FCS and Matrigel at a ratio of 1:1. Approximately 1x10E7 cells in a volume of 100 μl were subcutaneously injected into each mouse to establish tumors. Once the tumor reaches the desired size (e.g., about 86 to about 170mm ³ Or about 115 to about 170mm ³ ) Mice were randomly divided into treatment groups of 7-10 mice. Treatment with the subject compounds or controls disclosed herein (e.g., vehicle controls) can be performed at randomizationDay starts and may continue until the study ends (e.g., 22 days). The test samples were administered twice daily using a tube feeding needle at a volume of 10mL/kg per mouse at an administration plus volume of 10mL/kg, 6 hours apart. In some cases, the test compound was dissolved in 0.5% dmso (or 0.5% and 0.5% natrosol) in sterile PBS.

Mice were housed under standardized conditions of 21.5±1.5 ℃ and 55±10% humidity. Standardized irradiated diets and autoclaved tap water were provided ad libitum. In some cases, a tag (e.g., an ear tag, a microchip implanted subcutaneously under isoflurane anesthesia) is used to identify each mouse. Tumor diameters were measured two to three times per week with calipers. The volume (in mm) of each tumor was calculated according to the formula "tumor volume= (pi. Times. Length. Times. Width 2)/6" ³ Meter). To monitor the side effects of the treatment, mice are checked daily for abnormalities and body weight is determined, e.g., daily. Animals were sacrificed at the end of the study. For ethical reasons, early stage of study is sacrificed with necrotic tumor or tumor size exceeding 1500mm ³ Is a natural animal.

Xenografts with K-Ras G12D mutations

In another example, a tumor xenograft is established by administering tumor cells (e.g., ASPC-1 cells) having a K-Ras mutation (e.g., G12D, G12S, G12C, G12V, G13D, G13S, G C or G13V) into a mouse. Female 6 to 8 week old athymic BALB/c (NCr) nu/nu nude mice were used for xenografts. Tumor cells are harvested on the day of use (e.g., about 5X 10 ⁶ And injection is performed in Matrigel/PBS (e.g., 50% final concentration in 100 μl) with reduced growth factors. One flank of each mouse was inoculated subcutaneously. Mice were monitored daily, weighed twice a week, and caliper measurements were started when tumors became visible. For efficacy studies, animals were randomly assigned to treatment groups by an algorithm that assigns animals to groups to achieve the best case distribution of average tumor size with the lowest possible standard deviation. Tumor volume can be calculated by measuring two perpendicular diameters using the formula: (L×w) ² ) And/2, wherein L and w refer to the length and width tumor diameters, respectively. Can be used forTo calculate the percent tumor volume change using the following formula: (V) _{Final result} –V _{Initial initiation} )/V _{Initial initiation} X 100. The percent tumor growth inhibition (TGI%) can be calculated using the following formula: TGI% = 100× (1- (mean V of treatment group) _{Final result} –V _{Initial initiation} ) (average V of control group) _{Final result} –V _{Initial initiation} ). When the tumor reaches a threshold average size (e.g., about 200-400mm ³ ) At this time, mice were randomly divided into 3-10 mice per group and vehicle (e.g., 100%) was administered by oral gavage using, for example, a calendar) Or the subject compounds disclosed herein. The results may be expressed as the mean and standard deviation of the mean.

Example 12: metabolic (microsomal) stability assay

The metabolic stability of the test compounds was determined using pooled liver microsomes (mouse or human liver microsomes) at 37 ℃. An aliquot of 10 μl of 50 μM test compound was mixed with 490 μl of 0.611mg/mL liver microsomes, and then 50 μl of the mixture was dispensed into 96 well tubes and warmed at 37 ℃ for 10 minutes. The reaction was started by adding 50. Mu.L of pre-warmed NADPH regeneration system solution (1.2. Mu.L of solution, 240. Mu.L of solution B, mixed with 10.56ml of KPBS) and then incubated at 37 ℃. The final incubation solution contained 100mM potassium phosphate (pH 7.4), 1.3mM NADP+, 3.3mM glucose 6-phosphate, 0.4 units/mL glucose 6-phosphate dehydrogenase, 3.3mM magnesium chloride, 0.3mg/mL liver microsomes, and 0.5. Mu.M test article. After 0, 15, 30 and 60 minutes in the shaking incubator, the reaction was terminated by adding 100. Mu.L of acetonitrile containing 200nM buspirone as an internal standard. All incubations were performed in duplicate. The plate was vigorously vortexed by using a Fisher Scientific microplate vortexer mixer (Henry troemerer, US). The samples were then centrifuged at 3500rpm for 10 minutes (4 ℃) using a Sorvall Legend XRT centrifuge (Thermo Scientific, GE). The supernatant (40 μl) was transferred to a clean 96-well deep plate. 160. Mu.L of ultrapure water (Milli-Q, millipore Corporation) containing 0.1% (v/v) formic acid (Fisher Chemical) was added to each well, thoroughly mixed, and LC/MS/MS analysis was performed in MRM positive ion mode.

All samples were measured using a mass spectrometer (QTrap 5500 quadrupole/ion trap) coupled Shimadzu HPLC system. The HPLC system consisted of a Shimadzu series degasser, a binary quaternary gradient pump (binary quaternary gradient pump), a column heater coupled to an autosampler and Phenomenex Gemini-NX, C18,3.0 μm or Phenomenex Lunar, C8,5.0 μm HPLC column (Phenomenex, torrance, CA) and eluted with a mobile phase gradient consisting of solution a (0.1% aqueous formic acid) and solution B (0.1% acetonitrile formic acid). The column temperature was maintained at 40 ℃. All analytes were detected using positive ion mode electrospray ionization (es+).

The metabolic degradation half-life of the test compound was calculated by plotting the disappearance of the test compound over time during incubation with liver microparticles. Each plot was fitted to the first order equation of elimination of the test compound (remaining compound%) versus time using nonlinear regression (equation 1).

Equation 1:

wherein C is _t Is the average relative substrate concentration at time t, and C ₀ Is the initial concentration at time 0 (0.5. Mu.M). It should be noted that the area ratio of the substrate peak to the internal standard peak is proportional to the analyte concentration and is used in the regression analysis to derive the value of k.

Half-life t of metabolic (microsomal) stability _1/2 The elimination constant k from the test compound is derived using equation 2 below.

Equation 2:

example 13: mouse and human protein binding assays to assess free drug concentration

The assay is used to determine plasma protein binding of test compounds in plasma of human and animal species using a Rapid Equilibrium Dialysis (RED) device for equilibrium dialysis and LC-MS/MS for sample analysis. The test compound is incorporated. Stock solutions of test compounds were prepared at a concentration of 5 mM. mu.L of 5mM working solution was added to 1000. Mu.L of plasma. The final concentration was 5. Mu.M. The incorporated plasma was placed on a shaker and gently stirred for approximately 20 minutes. A 300 μl volume of plasma sample (containing 5 μΜ test compound from each species) was added to the designated RED device donor chamber, followed by 500 μl of potassium phosphate buffer to the corresponding acceptor chamber in duplicate. The RED device was then sealed with a sealing tape and shaken at 150RPM for 4 hours at 37 ℃. Post-dialysis donor and acceptor compartment samples were prepared for LC-MS/MS analysis, including the addition of standard samples for internal standards for bioanalytical analysis. Warfarin and propranolol were purchased from Sigma-Aldrich (st.louis, MO) and used as positive controls for low plasma protein binding and high plasma protein binding, respectively.

All samples were analyzed using a Agilent Technologies 6430 triple quadrupole LC/MS system. The HPLC system consisted of: an Agilent 1290Infinity liquid chromatograph coupled to an autoinjector (Agilent 1290Infinity LC syringe HTC), and a Phenomenex Gemini-NX, C18,3.0 μm or Phenomenex Lunar, C8,5.0 μm HPLC column (Phenomenex, torrance, CA), and eluted using a mobile phase gradient consisting of solution a (0.1% aqueous formic acid) and solution B (0.1% acetonitrile formic acid). The column temperature was maintained at 40 ℃. All analytes were detected by positive ion mode electrospray ionization (es+). The percentage of test compound bound to plasma was calculated according to equations 3 and 4.

Equation 3

Equation 4

Plasma protein bound test compound% = 100-free test compound%

Claims

wherein the method comprises the steps of

W is C (O), S (O) or S (O) ₂ ；

R ¹⁰ is-L ⁷ -R ⁷ ；

R ⁷ is a 3-12 membered nitrogen containing heterocycloalkyl or a 5-12 membered nitrogen containing heteroaryl, wherein said 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution;

wherein the bond to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein said C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a Substitution of；

R ⁶ is-L ² -R ⁵ ；

R ¹⁷ is-L ¹ -R ¹⁹ ；

R ^1e 、R ^1f And R is ^1g Independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R is ^1f And R is ^1g To form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein said 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring is optionally substituted with one, two or three R ²⁰ⁱ Substitution;

R ¹⁹ selected from C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl, wherein said C _3-12 Cycloalkyl, C _2-11 Heterocycloalkyl, C _6-12 Aryl and C _2-12 Heteroaryl is optionally substituted with one, two, three, four, five, six or seven R ¹ⁱ Substitution;

x is C (R) ³ ) Or N;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

each R ²⁴ Independently selected from H and C _1-6 An alkyl group;

Represents a single bond or a double bond such that all valences are satisfied.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C (R ³ )。

3. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein J is C (R ¹⁶ ) And V is C (R ¹⁷ )。

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C (O).

6. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure:

7. the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure:

8. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure:

9. the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein L ⁷ Is a key.

10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein L ⁷ is-NH-.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ Is a 3-12 membered nitrogen containing heterocycloalkyl, wherein said 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R ¹ Substituted, optionally with one or more R ⁴ Substituted, and optionally with one or more R ⁶ Substitution; and is also provided with

Wherein the bond to the same or adjacent atoms is selected from R ¹ 、R ⁴ And R is ⁶ Optionally linked to form C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl, wherein said C _3-12 Cycloalkyl, C _1-11 Heterocycloalkyl, C _6-12 Aryl or C _1-11 Heteroaryl is optionally substituted with one, two or three R ^20a And (3) substitution.

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein

R ⁷ Is that

p is an integer from 0 to 12;

X ³ Selected from N, C, C (R) ⁶ ) And C (R) ⁴ )。

13. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein

R ⁷ Is that

And p is an integer of 0 to 12.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁶ Independently selected from hydrogen and halogen.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁶ Independently selected from hydrogen and fluorine.

16. The method according to any one of claims 1-15A compound or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl, wherein C _1-6 Alkyl, C _3-10 Cycloalkyl and C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20c Substitution, said R ^20c Independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl and C _2-9 A heterocycloalkyl group.

17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from the group consisting of methyl, cyclopropyl, cyclobutyl and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl and oxetanyl are optionally substituted with one, two or three R's independently selected from fluoro, methyl, cyclopropyl, cyclobutyl and oxetanyl ^20c And (3) substitution.

18. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ Selected from methyl, cyclopropyl, cyclobutyl and oxetanyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R ³ Is hydrogen or CN.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein L ¹ Is a key.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein L ¹ Selected from C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -C (O) -, -NHC (O) -, -C (O) NH-, CH ₂ O、CH ₂ NH and CH ₂ 。

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ Is a single ring.

23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ Is a bicyclic ring system.

24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ Is a polycyclic system.

25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ The method comprises the following steps:

Q ¹ 、Q ³ and Q ⁵ Is independently N or C (R) ^1d )；

Q ⁴ And Q ⁶ Is independently O, S, C (R) ^1a )(R ^1b ) Or N (R) ^1c )；

Each R ^1a 、R ^1b 、R ^1d 、R ^1f 、R ^1g And R is ^1h Each independently selected from hydrogen, halogen, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl, C _1-9 Heteroaryl, -OR ¹² 、-SR ¹² 、-N(R ¹² )(R ¹³ )、-C(O)OR ¹² 、-OC(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)OR ¹⁵ 、-N(R ¹⁴ )S(O) ₂ R ¹⁵ 、-C(O)R ¹⁵ 、-S(O)R ¹⁵ 、-OC(O)R ¹⁵ 、-C(O)N(R ¹² )(R ¹³ )、-C(O)C(O)N(R ¹² )(R ¹³ )、-N(R ¹⁴ )C(O)R ¹⁵ 、-S(O) ₂ R ¹⁵ 、-S(O) ₂ N(R ¹² )(R ¹³ )-、S(＝O)(＝NH)N(R ¹² )(R ¹³ )、-CH ₂ C(O)N(R ¹² )(R ¹³ )、-CH ₂ N(R ¹⁴ )C(O)R ¹⁵ 、-CH ₂ S(O) ₂ R ¹⁵ and-CH ₂ S(O) ₂ N(R ¹² )(R ¹³ ) Wherein C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-10 Cycloalkyl, C _2-9 Heterocycloalkyl, C _6-10 Aryl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ²⁰ⁱ Substitution; or R bonded to the same carbon ^1a And R is ^1b To form a 3-to 10-membered heterocycloalkyl ring or C _3-10 Cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or two R's bonded to adjacent atoms ^1a To form a 3-to 10-membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring wherein the 3-10 membered heterocycloalkyl ringBase ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or R is ^1h With R bound to adjacent atoms ^1a 、R ^1b 、R ^1c And R is ^1d Is linked to form a 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring or C _3-10 Cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C _6-10 Aryl ring, 5-12 membered heteroaryl ring and C _3-10 Cycloalkyl rings are optionally substituted with one, two or three R' s ²⁰ⁱ Substitution; or R is ^1f And R is ^1g To form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein said 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring is optionally substituted with one, two or three R ²⁰ⁱ Substitution; and is also provided with

26. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁹ The method comprises the following steps:

/>

27. the compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein R ² Selected from the group consisting of/>

/>

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each L ² Independently a key.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein each R ⁵ Independently selected from: -H, -NH ₂ 、-OH、-NH(C _1-6 Alkyl group),

-CN、

/>

And m is 0, 1, 2 or 3 when present.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ independently-C (O) R ¹⁵ 。

31. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the R ¹⁵ Independently selected from C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl, wherein C _2-6 Alkenyl, C _2-6 Alkynyl, C _2-9 Heterocycloalkyl and C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f And (3) substitution.

32. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the R ¹⁵ Independently C _2-6 Alkenyl group, wherein C _2-6 Alkenyl is optionally substituted with one, two or three R ^20f And (3) substitution.

33. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the R ¹⁵ Independently C _2-9 Heterocycloalkyl, wherein C _2-9 Heterocycloalkyl is optionally substituted with one, two or three R ^20f And (3) substitution.

34. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein the R ¹⁵ Independently C _1-9 Heteroaryl, wherein C _1-9 Heteroaryl is optionally substituted with one, two or three R ^20f And (3) substitution.

35. The compound of any one of claims 30-34, or a pharmaceutically acceptable salt or solvate thereof, wherein the R ⁴ Is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine or aspartic acid residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein.

36. Having the formula A-L ^AB -a compound of B wherein

A is a monovalent form of a compound of any one of claims 1 to 35;

L ^AB are covalent linkers that bind to a and B; and is also provided with

B is a monovalent form of a degradation enhancer.

37. The compound of claim 36, wherein the degradation enhancer is capable of binding a protein selected from the group consisting of: E3A, mdm2, APC, EDD1, SOCS/BC-box/eloBC/CUL 5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE B, UBOX5 UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WWP1, WWP2, parkinson's protein, MKRN1, CMA (chaperone-mediated autophagy), SCFB-TRCP (jump-hysteresis-F box (. Beta. -TRCP) ubiquitin complex), b-TRCP (b-transduced repeat-containing protein), cIAP1 (apoptosis inhibitor protein 1), APC/C (late promoting complex/cell cycle body), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL) 4 ^CRBN ) Ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, ahR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, atorvastatin, ibbean and CC-885.

38. The compound of claim 36, wherein the degradation enhancer is capable of binding a protein selected from the group consisting of: UBE2A, UBE2B, UBE2C, UBE D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE V2U, UBE V1, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.

39. The compound of any one of claims 36 to 38, wherein L ^AB is-L ^AB1 -L ^AB2 -L ^AB3 -L ^AB4 -L ^AB5 -；

L ^AB1 、L ^AB2 、L ^AB3 、L ^AB4 And L ^AB5 Independently is a bond, -O-, -N (R) ¹⁴ )-、-C(O)-、-N(R ¹⁴ )C(O)-、-C(O)N(R ¹⁴ )-、-S-、-S(O) ₂ -、-S(O)-、-S(O) ₂ N(R ¹⁴ )-、-S(O)N(R ¹⁴ )-、-N(R ¹⁴ )S(O)-、-N(R ¹⁴ )S(O) ₂ -、C _1-6 Alkylene, (-O-C) _1-6 Alkyl group _z -、(-C _1-6 alkyl-O) _z -、C _2-6 Alkenylene, C _2-6 Alkynylene, C _1-6 Halogenated alkylene, C _3-12 Cycloalkylene, C _1-11 Heterocycloalkylene, C _6-12 Arylene or C _1-11 Heteroarylene group, wherein C _1-6 Alkylene, C _2-6 Alkenylene, C _2-6 Alkynylene, C _1-6 Halogenated alkylene, C _3-12 Cycloalkylene, C _1-11 Heterocycloalkylene, C _6-12 Arylene or C _1-11 Heteroarylene optionallyIs one, two or three R ^20j Substitution; wherein (-O-C) _1-6 Alkyl group _z -and (-C) _1-6 alkyl-O) _z -each C _1-6 Alkyl is optionally substituted with one, two or three R ^20j Substitution;

z is independently an integer from 0 to 10;

each R ²³ Independently selected from H and C _1-6 An alkyl group;

40. The compound of any one of claims 36 to 38, wherein L ^AB Is- (O-C) ₂ Alkyl group _z -, and z is an integer from 1 to 10.

41. The compound of any one of claims 36 to 38, wherein L ^AB Is- (C) ₂ alkyl-O-) _z -, and z is an integer from 1 to 10.

42. The compound of any one of claims 36 to 38, wherein L ^AB Is- (CH) ₂ ) _z1 L ^AB2 (CH ₂ O) _z2 -, wherein L ^AB2 Is a bond, 5-or 6-membered heterocycloalkylene or heteroarylene, phenylene, - (C) ₂ -C ₄ ) Alkynylene, -SO ₂ -or-NH-; and is combined withAnd z1 and z2 are independently integers from 0 to 10.

43. The compound of any one of claims 36 to 38, wherein L ^AB Is- (CH) ₂ ) _z1 (CH ₂ O) _z2 -wherein z1 and z2 are each independently integers from 0 to 10.

44. The compound of any one of claims 36 to 38, wherein L ^AB Is a PEG linker.

45. The compound of any one of claims 36 to 44, wherein B is a monovalent form of a compound selected from the group consisting of:

46. a pharmaceutical composition comprising a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

47. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof.

48. A method of modulating the activity of a Ras protein, the method comprising contacting a Ras protein with an effective amount of a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.

49. The method of one of claims 47-48, comprising administering an additional agent or therapy.

50. A method of inhibiting cell growth, the method comprising administering to a cell expressing a Ras protein an effective amount of a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting growth of the cell.

51. The method of claim 50, comprising administering an additional agent to the cell.

52. A Ras protein bound by the compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, wherein the activity of the Ras protein is reduced compared to a Ras protein not bound to the compound.